@article {723, title = {Evaluation of dementia in the cardiovascular health cognition study.}, journal = {Neuroepidemiology}, volume = {22}, year = {2003}, month = {2003 Jan-Feb}, pages = {1-12}, abstract = {

OBJECTIVE: To describe a methodology to evaluate dementia and frequency of different types of dementia and prevalence of the Cardiovascular Health Study (CHS).

METHODS: The CHS is a longitudinal study of cardiovascular disease among community-dwelling individuals over the age of 65. Of the 5,888 participants in the original study, 3,608 had a magnetic resonance imaging (MRI) of the brain in 1991, and formed the cohort for the dementia study. The CHS included yearly measures of cognitive function and, from 1998 to 2000, participants were evaluated for dementia by detailed neurological, and neuropsychological examinations. The possible cases of dementia and mild cognitive impairment (MCI) were adjudicated by a review committee of neurologists and psychiatrists.

RESULTS: There were 480 cases of (13.3\%) incident dementia in the total sample, 227 (6.3\%) prevalent dementia, 577 (16.0\%) MCI, and 2,318 (64.4\%) normal. The adjudication committee classified 69\% of the incident dementia as Alzheimer{\textquoteright}s disease (AD), 11\% as vascular dementia (VaD), 16\% as both, and 4\% as other types. There was a substantial agreement between pre- and postMRI diagnosis of types of dementia. The frequency of dementia within the CHS cohort which survived to the end of the study in 1998-1999, was 13.5\% for white men, 14.5\% for white women, 22.2\% for black men and 23.4\% for black women.

CONCLUSION: The CHS has developed a methodology for longitudinal studies of dementia in large cohorts and represents the largest study of dementia including cognitive testing, MRI and genetic markers.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Cardiovascular Diseases, Cognition Disorders, Cohort Studies, Cross-Sectional Studies, Dementia, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Prevalence, Risk Factors, Sex Distribution}, issn = {0251-5350}, doi = {10.1159/000067110}, author = {Lopez, Oscar L and Kuller, Lewis H and Fitzpatrick, Annette and Ives, Diane and Becker, James T and Beauchamp, Norman} } @article {755, title = {Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 1.}, journal = {Arch Neurol}, volume = {60}, year = {2003}, month = {2003 Oct}, pages = {1385-9}, abstract = {

OBJECTIVE: To examine the prevalence of mild cognitive impairment (MCI) and its diagnostic classification in the Cardiovascular Health Study (CHS) Cognition Study.

DESIGN: The CHS Cognition Study is an ancillary study of the CHS that was conducted to determine the presence of MCI and dementia in the CHS cohort.

SETTING: Multicenter population study.

PATIENTS: We examined 3608 participants in the CHS who had undergone detailed neurological, neuropsychological, neuroradiological, and psychiatric testing to identify dementia and MCI.

MAIN OUTCOME MEASURES: The prevalence of MCI was determined for the whole cohort, and specific subtypes of MCI were examined in detail only at the Pittsburgh, Pa, center (n = 927). Mild cognitive impairment was classified as either MCI amnestic-type or MCI multiple cognitive deficits-type.

RESULTS: The overall prevalence of MCI was 19\% (465 of 2470 participants); prevalence increased with age from 19\% in participants younger than 75 years to 29\% in those older than 85 years. The overall prevalence of MCI at the Pittsburgh center was 22\% (130 of 599 participants); prevalence of the MCI amnesic-type was 6\% and of the MCI multiple cognitive deficits-type was 16\%.

CONCLUSIONS: Twenty-two percent of the participants aged 75 years or older had MCI. Mild cognitive impairment is a heterogeneous syndrome, where the MCI amnestic-type is less frequent than the MCI multiple cognitive deficits-type. Most of the participants with MCI had comorbid conditions that may affect their cognitive functions.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cognition Disorders, Cohort Studies, Dementia, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Memory Disorders, Neuropsychological Tests, Pennsylvania, Population, Psychiatric Status Rating Scales}, issn = {0003-9942}, doi = {10.1001/archneur.60.10.1385}, author = {Lopez, Oscar L and Jagust, William J and DeKosky, Steven T and Becker, James T and Fitzpatrick, Annette and Dulberg, Corinne and Breitner, John and Lyketsos, Constantine and Jones, Beverly and Kawas, Claudia and Carlson, Michelle and Kuller, Lewis H} } @article {724, title = {Risk factors for dementia in the cardiovascular health cognition study.}, journal = {Neuroepidemiology}, volume = {22}, year = {2003}, month = {2003 Jan-Feb}, pages = {13-22}, abstract = {

BACKGROUND: The Cardiovascular Health Cognition Study has evaluated the determinants of dementia among 3,608 participants that had a magnetic resonance imaging (MRI) of the brain in 1991 and were followed to 1998-1999.

METHODS: There were 480 incident dementia cases, 330 (69\%) were classified as Alzheimer{\textquoteright}s disease (AD).

RESULTS: In univariate analysis, low scores on the Modified Mini-Mental State Examination (3MSE) and on the Digit Symbol Substitution Test as well as declines in scores over time prior to the development of dementia were significant predictors of dementia. A high ventricular grade on the MRI (atrophy) as well as high white matter grade, a number of brain infarcts on the MRI were all determinants of dementia. Apolipoprotein E epsilon4 (Apo(E-4)) was also a powerful predictor of dementia. In a multivariate Cox proportional hazards model controlling for race, gender and grade, the hazard ratios for age (1.1), 3MSE score (0.9), ventricular size (1.4), white matter grade (1.8), presence of large infarcts >3 mm (1.3) and Apo(E-4) (2.1) were significant predictors of dementia. The combination of an Apo(E-4) genotype, 3MSE score <90, > or =5 ventricular grade, > or =3 white matter grade at the time of the MRI were associated with a 17-fold increased risk (95\% CI: 8.6-34.9) of dementia as compared to individuals with none of the above attributes.

CONCLUSIONS: Measures of cognition, Apo(E-4) and MRI of the brain are strong predictors of both dementia and of AD.

}, keywords = {Aged, Aged, 80 and over, Apolipoproteins E, Cardiovascular Diseases, Cognition Disorders, Dementia, Female, Genotype, Humans, Magnetic Resonance Imaging, Male, Odds Ratio, Predictive Value of Tests, Proportional Hazards Models, Risk Factors}, issn = {0251-5350}, doi = {10.1159/000067109}, author = {Kuller, Lewis H and Lopez, Oscar L and Newman, Anne and Beauchamp, Norman J and Burke, Greg and Dulberg, Corinne and Fitzpatrick, Annette and Fried, Linda and Haan, Mary N} } @article {756, title = {Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2.}, journal = {Arch Neurol}, volume = {60}, year = {2003}, month = {2003 Oct}, pages = {1394-9}, abstract = {

OBJECTIVE: To examine the risk factors for mild cognitive impairment (MCI) in a longitudinal population study-the Cardiovascular Health Study Cognition Study.

DESIGN: We examined the factors that in the period 1991 through 1994 predicted the development of MCI in all participants of the Cardiovascular Health Study Cognition Study. Further examination was conducted in the Pittsburgh, Pa, cohort (n = 927), where participants with MCI were classified as having either the MCI amnestic-type or the MCI multiple cognitive deficits-type.

SETTING: Multicenter population study.

PATIENTS: This study includes all participants of the Cardiovascular Health Study Cognition Study (n = 3608) who had a magnetic resonance imaging (MRI) scan of the brain between 1991 and 1994, and detailed neuropsychological, neurological, and medical evaluations to identify the presence of MCI or dementia in the period 1998 to 1999. The mean time between the closest clinical examination to the MRI and the diagnostic evaluation for cognitive disorders was 5.8 years for the Cardiovascular Health Study Cognition Study cohort and 6.0 years for the Pittsburgh cohort.

MAIN OUTCOME MEASURES: Risk factors for MCI at the time of the MRI were identified using logistic regression, controlling for age, race, educational level, baseline Modified Mini-Mental State Examination and Digit Symbol Test scores, measurements of depression, MRI findings (atrophy, ventricular volume, white matter lesions, and infarcts), the presence of the apolipoprotein E (APOE) epsilon4 allele, hypertension, diabetes mellitus, and heart disease.

RESULTS: Mild cognitive impairment (n = 577) was associated with race (African American), low educational level, low Modified Mini-Mental State Examination and Digit Symbol Test scores, cortical atrophy, MRI-identified infarcts, and measurements of depression. The MCI amnestic-type was associated with MRI-identified infarcts, the presence of the APOE epsilon4 allele, and low Modified Mini-Mental State Examination scores. The MCI multiple cognitive deficits-type was associated with low Modified Mini-Mental State Examination and Digit Symbol Test scores.

CONCLUSIONS: The development of MCI is associated with measurements of cognition and depression, racial and constitutional factors, and cerebrovascular disease. Early cognitive deficits seem to be a common denominator for the 2 forms of MCI; the presence of cerebrovascular disease and the APOE epsilon4 allele is associated with the amnestic type of MCI.

}, keywords = {Aged, Apolipoprotein E4, Apolipoproteins E, Brain, Cardiovascular Diseases, Cognition Disorders, Cohort Studies, Depressive Disorder, Female, Humans, Logistic Models, Longitudinal Studies, Magnetic Resonance Imaging, Male, Mood Disorders, Pennsylvania, Population, Risk Factors}, issn = {0003-9942}, doi = {10.1001/archneur.60.10.1394}, author = {Lopez, Oscar L and Jagust, William J and Dulberg, Corinne and Becker, James T and DeKosky, Steven T and Fitzpatrick, Annette and Breitner, John and Lyketsos, Constantine and Jones, Beverly and Kawas, Claudia and Carlson, Michelle and Kuller, Lewis H} } @article {762, title = {Incidence and prevalence of dementia in the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {52}, year = {2004}, month = {2004 Feb}, pages = {195-204}, abstract = {

OBJECTIVES: To estimate the incidence and prevalence of dementia, Alzheimer{\textquoteright}s disease (AD), and vascular dementia (VaD) in the Cardiovascular Health Study (CHS) cohort.

DESIGN: Longitudinal cohort study using prospectively and retrospectively collected data to evaluate dementia.

SETTING: Four U.S. communities.

PARTICIPANTS: There were 3,602 CHS participants, including 2,865 white and 492 African-American participants free of dementia, who completed a cranial magnetic resonance image between 1992 and 1994 and were followed for an average of 5.4 years.

MEASUREMENTS: Dementia was classified by neurologist/psychiatrist committee review using neuropsychological tests, neurological examinations, medical records, physician questionnaires, and proxy/informant interviews. Demographics and apolipoprotein E (APOE) genotype were collected at baseline. Incidence by type of dementia was determined using National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer{\textquoteright}s Disease and Related Disorders Association criteria for AD and Alzheimer{\textquoteright}s Disease Diagnostic and Treatment Center{\textquoteright}s State of California criteria for VaD.

RESULTS: Classification resulted in 227 persons with prevalent dementia at entry into the study and 480 incident cases during follow-up. Incidence rates of dementia scaled to age 80 were 34.7 per 1,000 person-years for white women, 35.3 for white men, 58.8 for African-American women, and 53.0 for African-American men. Sex differences were not significant within race. Adjusted for age and education, racial differences were only of borderline significance and may have been influenced by ascertainment methodology. Rates differed substantially by educational attainment but were only significant for whites. Those with the APOE epsilon4 allele had an incidence rate at age 80 of 56.4, compared with 29.6 for those without this allele (P<.001). In whites, type-specific incidence at age 80 was 19.2 for AD versus 14.6 for VaD. These rates were 34.7 and 27.2 for African Americans. At termination of observation, women had only a slightly higher prevalence of dementia (16.0\%) than men (14.7\%).

CONCLUSION: Sex and racial differences were not found, and VaD was higher than reported in other studies. These data provide new estimates of dementia incidence in a community sample for projection of future burden.

}, keywords = {African Americans, Age Distribution, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Dementia, Dementia, Vascular, Education, European Continental Ancestry Group, Female, Humans, Incidence, Longitudinal Studies, Male, Prevalence, Proportional Hazards Models, Risk Factors, Sex Distribution, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2004.52058.x}, author = {Fitzpatrick, Annette L and Kuller, Lewis H and Ives, Diane G and Lopez, Oscar L and Jagust, William and Breitner, John C S and Jones, Beverly and Lyketsos, Constantine and Dulberg, Corinne} } @article {824, title = {Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study.}, journal = {Am J Epidemiol}, volume = {161}, year = {2005}, month = {2005 Apr 01}, pages = {639-51}, abstract = {

Physical activity may help preserve cognitive function and decrease dementia risk, but epidemiologic findings are inconsistent. The authors conducted a prospective study to determine the association between physical activity and risk of dementia, Alzheimer{\textquoteright}s disease, and vascular dementia. The US study population comprised 3,375 men and women aged 65 years or older, free of dementia at baseline, who participated in the Cardiovascular Health Cognition Study in 1992-2000. Leisure-time energy expenditure and an activity index reflecting number of different physical activities were calculated. Analyses were based on Cox proportional hazards models. There were 480 incident cases of dementia over an average of 5.4 years of follow-up. After multivariate adjustment, participants in the highest quartile of physical energy expenditure had a relative risk of dementia of 0.85 (95\% confidence interval: 0.61, 1.19) compared with those in the lowest quartile, and participants engaging in >or=4 activities had a relative risk of dementia of 0.51 (95\% confidence interval: 0.33, 0.79) compared with those engaging in 0-1 activity. These associations were more marked in apolipoprotein E genotype (APOE) epsilon4 allele noncarriers but were absent in carriers. A similar pattern was observed for Alzheimer{\textquoteright}s disease and vascular dementia. Mechanisms to explain the observed relations deserve further study.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Dementia, Dementia, Vascular, Female, Genotype, Humans, Male, Motor Activity, Proportional Hazards Models, Prospective Studies, Risk Factors, United States}, issn = {0002-9262}, doi = {10.1093/aje/kwi092}, author = {Podewils, Laura Jean and Guallar, Eliseo and Kuller, Lewis H and Fried, Linda P and Lopez, Oscar L and Carlson, Michelle and Lyketsos, Constantine G} } @article {846, title = {Statin use and the risk of incident dementia: the Cardiovascular Health Study.}, journal = {Arch Neurol}, volume = {62}, year = {2005}, month = {2005 Jul}, pages = {1047-51}, abstract = {

BACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce cardiovascular risk through mechanisms that might affect the development of dementia.

OBJECTIVE: To evaluate whether statin use is associated with a lower risk of dementia compared with never use of lipid-lowering agents (LLAs).

DESIGN: Cohort study of community-dwelling adults 65 years and older. The analysis included 2798 participants free of dementia at baseline.

MAIN OUTCOME MEASURES: Using Cox proportional hazards regression analysis, we estimated the risk of incident all-cause and type-specific dementia associated with time-dependent statin therapy compared with never use of LLAs. The primary analyses incorporated a 1-year lag between exposure and outcome. Secondary analyses included the final year of exposure and modeled statin use as current use vs nonuse to simulate a case-control approach.

RESULTS: Compared with never use of LLAs, ever use of statins was not associated with the risk of all-cause dementia (multivariable-adjusted hazard ratio [HR], 1.08; 95\% confidence interval [CI], 0.77-1.52), Alzheimer disease alone (HR, 1.21; 95\% CI, 0.76-1.91), mixed Alzheimer disease and vascular dementia (HR, 0.87; 95\% CI, 0.44-1.72), or vascular dementia alone (HR, 1.36; 95\% CI, 0.61-3.06). In contrast, in secondary analyses, current use of statins compared with nonuse of LLAs was associated with HRs of 0.69 (95\% CI, 0.46-1.02) for all-cause dementia and 0.56 (95\% CI, 0.35-0.92) for any Alzheimer disease.

CONCLUSIONS: In this cohort study, statin therapy was not associated with a decreased risk of dementia. Methodological differences may explain why results of this cohort investigation differ from those of prior case-control studies. Additional investigation is needed to determine whether and for whom statin use may affect dementia risk.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cohort Studies, Dementia, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipidemias, Male}, issn = {0003-9942}, doi = {10.1001/archneur.62.7.1047}, author = {Rea, Thomas D and Breitner, John C and Psaty, Bruce M and Fitzpatrick, Annette L and Lopez, Oscar L and Newman, Anne B and Hazzard, William R and Zandi, Peter P and Burke, Gregory L and Lyketsos, Constantine G and Bernick, Charles and Kuller, Lewis H} } @article {823, title = {Survival following dementia onset: Alzheimer{\textquoteright}s disease and vascular dementia.}, journal = {J Neurol Sci}, volume = {229-230}, year = {2005}, month = {2005 Mar 15}, pages = {43-9}, abstract = {

Survival following the onset of dementia has been reported to vary from 3 to over 9 years. We examined mortality in 3602 participants of the Cardiovascular Health (CHS) Cognition Study in four US communities evaluated for dementia incidence between 1992 and 1999 and followed for 6.5 years. By June 2000, 33 of 62 (53.2\%) participants who developed vascular dementia (VaD) had died compared to 79 of 245 (32.2\%) with Alzheimer{\textquoteright}s disease (AD), 66 of 151 (43.7\%) with both AD and VaD, and 429 of 2318 (18.5\%) with normal cognition. Using Cox proportional hazards regression with a time-dependent covariate for dementia status adjusted for age, gender and race, individuals with VaD were more than four times as likely to die during follow-up than those with normal cognition (HR: 4.4, 95\% CI: 3.1-6.3). The hazard ratios were 2.1 (95\% CI: 1.6-2.7) for AD and 2.5 (95\% CI: 1.9-3.3) for both types. Adjusted accelerated life models estimated median survival from dementia onset to death as 3.9 years for those with VaD, 7.1 years for AD, 5.4 years for mixed dementia, and 11.0 years for matched controls with normal cognition. While persons with VaD died primarily from cerebrovascular disease, those with AD/mixed dementia died more frequently from dementia/failure to thrive.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Brain, Capillaries, Cerebral Amyloid Angiopathy, Cerebrovascular Circulation, Cerebrovascular Disorders, Female, Frontal Lobe, Humans, Male, Middle Aged, Prospective Studies}, issn = {0022-510X}, doi = {10.1016/j.jns.2004.11.022}, author = {Fitzpatrick, Annette L and Kuller, Lewis H and Lopez, Oscar L and Kawas, Claudia H and Jagust, William} } @article {891, title = {Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study.}, journal = {Arch Gen Psychiatry}, volume = {63}, year = {2006}, month = {2006 Mar}, pages = {273-9}, abstract = {

CONTEXT: Depressive symptoms are common in patients with dementia and may be associated with increased risk of developing dementia. It has been hypothesized that depressive symptoms and dementia may be attributable to underlying vascular disease in some older persons.

OBJECTIVES: To test the hypotheses (1) that depressive symptoms are associated with increased risk of developing mild cognitive impairment (MCI), a preclinical state that often precedes dementia, and (2) that the association between depressive symptoms and MCI is attributable to underlying vascular disease.

DESIGN: Prospective, population-based, longitudinal study.

SETTING: Random sample of adults 65 years or older recruited from 4 US communities.

PARTICIPANTS: Subjects were 2220 participants in the Cardiovascular Health Study Cognition Study with high cognitive function at baseline. Depressive symptoms were measured at baseline using the 10-item Center for Epidemiological Studies Depression Scale and were classified as none (0-2 points), low (3-7 points), and moderate or high (>/=8 points). Vascular disease measures at baseline included confirmed history of stroke, transient ischemic attack, diabetes mellitus, or hypertension; carotid artery stenosis; ankle-arm blood pressure index; and small or large infarcts or white matter disease on cerebral magnetic resonance imaging. Mild cognitive impairment was diagnosed after 6 years of follow-up based on the consensus of a team of dementia experts using standard clinical criteria.

MAIN OUTCOME MEASURE: Diagnosis of MCI.

RESULTS: Depressive symptoms at baseline were associated with increased risk of MCI (10.0\%, 13.3\%, and 19.7\% for those with no, low, and moderate or high depressive symptoms, respectively). This association was diminished only slightly by adjustment for vascular disease measures and demographics. Vascular disease measures also were associated with increased risk of MCI, and these associations were not diminished by adjustment for depressive symptoms or demographics.

CONCLUSION: Depressive symptoms were associated with increased risk of MCI, and this association was independent of underlying vascular disease.

}, keywords = {Aged, Cerebrovascular Disorders, Cognition Disorders, Comorbidity, Dementia, Dementia, Vascular, Depressive Disorder, Female, Follow-Up Studies, Geriatric Assessment, Humans, Longitudinal Studies, Male, Prospective Studies, Psychiatric Status Rating Scales, Risk Factors, Sampling Studies, Vascular Diseases}, issn = {0003-990X}, doi = {10.1001/archpsyc.63.3.273}, author = {Barnes, Deborah E and Alexopoulos, George S and Lopez, Oscar L and Williamson, Jeff D and Yaffe, Kristine} } @article {945, title = {Cerebral ventricular changes associated with transitions between normal cognitive function, mild cognitive impairment, and dementia.}, journal = {Alzheimer Dis Assoc Disord}, volume = {21}, year = {2007}, month = {2007 Jan-Mar}, pages = {14-24}, abstract = {

Expansion of the cerebral ventricles may occur at an accelerated rate in subjects with dementia, but the time course of expansion during transitions between normal cognitive function, mild cognitive impairment (MCI), and dementia is not well understood. Furthermore, the effects of cardiovascular risk factors on rate of ventricular expansion are unclear. We used a fully automated segmentation technique to measure change rate in lateral ventricle-to-brain ratio (VBR) on 145 longitudinal pairs of magnetic resonance images of subjects in the Cardiovascular Health Study Cognition Study from the Pittsburgh Center. A multivariate model analyzed VBR change rate, accounting for dementia statuses at both imaging times (normal, MCI, or dementia), age, sex, education, race, magnetic resonance-defined infarcts, Center for Epidemiology Studies Depression Scale, baseline ventricular volume, and cardiovascular risk factors. VBR change was faster in subjects who were demented or transitioned from MCI to dementia, compared with subjects normal at both images and subjects who transitioned from normal to MCI or dementia. Patients with diabetes had faster VBR change. Ventricular expansion may accelerate late in the progression from normal cognitive function to dementia, and may be modulated by diabetes.

}, keywords = {Aged, Aged, 80 and over, Case-Control Studies, Cerebral Ventricles, Cognition Disorders, Dementia, Disease Progression, Female, Humans, Image Processing, Computer-Assisted, Longitudinal Studies, Magnetic Resonance Imaging, Male, Risk Factors, Severity of Illness Index, Time Factors}, issn = {0893-0341}, doi = {10.1097/WAD.0b013e318032d2b1}, author = {Carmichael, Owen T and Kuller, Lewis H and Lopez, Oscar L and Thompson, Paul M and Dutton, Rebecca A and Lu, Allen and Lee, Sharon E and Lee, Jessica Y and Aizenstein, Howard J and Meltzer, Carolyn C and Liu, Yanxi and Toga, Arthur W and Becker, James T} } @article {960, title = {Focal atrophy and cerebrovascular disease increase dementia risk among cognitively normal older adults.}, journal = {J Neuroimaging}, volume = {17}, year = {2007}, month = {2007 Apr}, pages = {148-55}, abstract = {

BACKGROUND AND PURPOSE: This study investigated the association of medial temporal lobe (MTL) atrophy and cerebrovascular disease (white matter hyperintensities [WMH], subclinical infarcts) with the risk of developing Alzheimer{\textquoteright}s disease (AD) among cognitively normal older adults.

METHODS: Risk of developing AD was examined for 155 cognitively normal older adults (77.4 years, 60\% women, 81\% white). The MTL volumes and the presence of WMH and of subclinical infarcts were determined from brain magnetic resonance imaging (MRI) at the beginning of the study. Follow-up cognitive evaluations (average 4.3 years) identified those who developed AD.

RESULTS: The presence of either MTL atrophy or subclinical infarcts was independently and significantly associated with a greater risk to develop AD (OR [95\% CI]: 4.4 [1.5, 12.3] and 2.7 [1.0, 7.1], respectively). In addition, those participants with both MTL atrophy and at least one brain infarct had a 7-fold increase in the risk of developing AD (OR [95\% CI]: 7.0 [1.5, 33.1]), compared to those who had neither of these conditions.

CONCLUSIONS: In cognitively normal older adults, markers of neurodegeneration (as reflected by MTL atrophy) and of cerebrovascular disease (as reflected by infarcts on MRI) independently contribute to the risk to develop AD.

}, keywords = {Aged, Alzheimer Disease, Analysis of Variance, Atrophy, Cerebrovascular Disorders, Cognition, Female, Humans, Logistic Models, Longitudinal Studies, Magnetic Resonance Imaging, Male, Risk Factors, Temporal Lobe, United States}, issn = {1051-2284}, doi = {10.1111/j.1552-6569.2007.00093.x}, author = {Rosano, Caterina and Aizenstein, Howard J and Wu, Minjie and Newman, Anne B and Becker, James T and Lopez, Oscar L and Kuller, Lewis H} } @article {947, title = {Incidence of dementia in mild cognitive impairment in the cardiovascular health study cognition study.}, journal = {Arch Neurol}, volume = {64}, year = {2007}, month = {2007 Mar}, pages = {416-20}, abstract = {

OBJECTIVES: To examine the incidence of dementia in subjects with mild cognitive impairment (MCI) in the Cardiovascular Health Study Cognition Study.

DESIGN: Prospective epidemiological study.

SETTING: The Cardiovascular Health Study Cognition Study of Pittsburgh, Pa, was conducted from 2002 through 2003 to determine the incidence of dementia in participants classified as having MCI in 1998 and 1999. Subjects There were 136 subjects with MCI. Mild cognitive impairment was subclassified as MCI amnestic type and MCI multiple cognitive deficits type (MCI-MCDT); subjects with MCI-MCDT were also grouped based on the presence of a memory impairment. Subjects with MCI were classified as possible when there were comorbidities that could explain the subjects{\textquoteright} cognitive deficits and as probable when there were none. Main Outcome Measure Dementia.

RESULTS: The incidence of all dementias in the subjects with MCI was 147 per 1000 person-years (mean follow-up overall, 4.3 years). Of the 136 subjects with MCI, 69 (51\%) in 1998 through 1999 progressed to dementia (57 [83\%] to Alzheimer disease [AD]), but 25 (18\%) returned to normal. Of the 10 subjects with probable MCI amnestic type, 7 (70\%) progressed to dementia (all of them to AD) and none returned to normal, whereas 7 (41\%) of the 17 subjects with possible MCI amnestic type became demented (6 [86\%] to AD) and 3 (18\%) returned to normal. Of the 40 subjects with probable MCI-MCDT, 21 (52\%) progressed to dementia (17 [81\%] to AD) and 2 (5\%) returned to normal. Of the 69 subjects with possible MCI-MCDT, 34 (49\%) progressed to dementia (28 [82\%] to AD) and 20 (29\%) returned to normal. Among the subjects with probable MCI-MCDT, 15 (54\%) of 28 with and 6 (50\%) of 12 without memory deficits progressed to dementia.

CONCLUSIONS: Subjects with MCI are at high risk for dementia. The probable MCI diagnosis identified individuals in the earliest stages of dementia, usually AD, whereas the possible MCI diagnosis identified a more heterogeneous group. However, this latter group had only a slightly lower rate of conversion to dementia than the group with probable MCI, suggesting that even with comorbid conditions, there is a high likelihood of the presence of a progressive dementing disorder.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular System, Cognition Disorders, Dementia, Disease Progression, Female, Humans, Incidence, Male, Retrospective Studies}, issn = {0003-9942}, doi = {10.1001/archneur.64.3.416}, author = {Lopez, Oscar L and Kuller, Lewis H and Becker, James T and Dulberg, Corinne and Sweet, Robert A and Gach, H Michael and DeKosky, Steven T} } @article {889, title = {Ventricular volume and dementia progression in the Cardiovascular Health Study.}, journal = {Neurobiol Aging}, volume = {28}, year = {2007}, month = {2007 Mar}, pages = {389-97}, abstract = {

Elevated cerebral ventricular volume may be associated with dementia risk and progression. A fully-automated technique that agreed highly with radiological readings was used to estimate lateral ventricle volume on MR scans done at baseline in 1997-99 of 377 subjects in the Cardiovascular Health Study (CHS) from the Pittsburgh Center. 327 subjects were normal or diagnosed with mild cognitive impairment (MCI) at baseline and were evaluated 4 years later. Baseline ventricular volume was analyzed in multivariate models with age, gender, education level, presence and incidence of cerebral infarcts, and dementia category (normal, MCI, or dementia) at baseline and follow-up as fixed effects. Ventricular volume at baseline was significantly higher among subjects normal at baseline and demented 4 years later. Age, gender, education level, and dementia progression were significant factors affecting ventricular volume. Ventricular volume was higher in dementia compared to MCI, higher in MCI compared to controls, and higher in Possible-Alzheimer{\textquoteright}s-disease (AD) dementia compared to Probable-AD. Larger ventricles in healthy subjects may indicate susceptibility to, or progression of, dementia-related pathology.

}, keywords = {Aged, Aged, 80 and over, Aging, Cognition Disorders, Cross-Sectional Studies, Dementia, Disease Progression, Female, Follow-Up Studies, Humans, Lateral Ventricles, Linear Models, Magnetic Resonance Imaging, Male, Predictive Value of Tests, Prospective Studies, Retrospective Studies, Time Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2006.01.006}, author = {Carmichael, Owen T and Kuller, Lewis H and Lopez, Oscar L and Thompson, Paul M and Dutton, Rebecca A and Lu, Allen and Lee, Sharon E and Lee, Jessica Y and Aizenstein, Howard J and Meltzer, Carolyn Cidis and Liu, Yanxi and Toga, Arthur W and Becker, James T} } @article {1005, title = {Abnormal regional cerebral blood flow in cognitively normal elderly subjects with hypertension.}, journal = {Stroke}, volume = {39}, year = {2008}, month = {2008 Feb}, pages = {349-54}, abstract = {

BACKGROUND AND PURPOSE: The purpose of this study was to examine regional cerebral blood flow (rCBF) in normal cognitive-performing subjects with hypertension (HTN) using continuous arterial spin-labeled MRI. The most common explanation for the effect of blood pressure on cognition is that HTN increases the risk of cerebrovascular disease, and it may increase the risk for Alzheimer disease possibly through small vessel disease, ischemia, oxidative stress, and inflammation. However, few studies to date have examined the rCBF of cognitively normal subjects with HTN in population-based cohorts, and none have used continuous arterial spin-labeled MRI. This is a noninvasive technique that does not require either injections or ionizing radiation and can measure absolute rCBF rates over the entire brain.

METHODS: rCBF was measured at 1.5 T using continuous arterial spin-labeled MRI in 41 cognitively normal subjects who were participating in the Cardiovascular Health Study Cognition Study. A deformable atrophy-corrected registration method was used to warp the rCBF maps to the standard colin27 brain space. Image and cluster-based statistical analyses were performed between subject groups.

RESULTS: Cognitively normal subjects with HTN (n=19) had decreased rCBF in the putamen, globus pallidus, bilaterally, and in the left hippocampus compared with normotensives (n=22). In addition, decreased rCBF was observed in the right and left anterior cingulate gyrus with extension to the subcallosal region, left posterior cingulate gyrus and medial precuneus, left lateral inferior and superior frontal, and inferior parietal, left orbitofrontal, and left superior temporal cortices.

CONCLUSIONS: rCBF is affected in normal subjects with HTN, not only in the subcortical regions, but also in limbic and paralimbic structures. We hypothesize that the HTN creates a vulnerability state for the development of neurodegenerative disorders, especially Alzheimer disease.

}, keywords = {Aged, Aged, 80 and over, Cerebral Cortex, Cerebrovascular Circulation, Cognition, Cognition Disorders, Female, Globus Pallidus, Gyrus Cinguli, Humans, Hypertension, Magnetic Resonance Imaging, Male, Putamen, Spin Labels}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.107.495457}, author = {Dai, Weiying and Lopez, Oscar L and Carmichael, Owen T and Becker, James T and Kuller, Lewis H and Gach, H Michael} } @article {1009, title = {Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study.}, journal = {Arch Neurol}, volume = {65}, year = {2008}, month = {2008 Jan}, pages = {89-93}, abstract = {

BACKGROUND: Diabetes and the apolipoprotein E epsilon4 allele (APOE epsilon4) increase the risk for Alzheimer disease (AD). We hypothesize that APOE epsilon4 may modify the risk for AD in individuals with diabetes.

OBJECTIVE: To examine the joint effect of type 2 diabetes and APOE epsilon4 on the risk of AD, AD with vascular dementia (mixed AD), and vascular dementia without AD.

DESIGN: The Cardiovascular Health Study (CHS) Cognition Study (1992-2000) is a prospective study designed to identify all existing and new cases of dementia among study participants. Diagnoses were made according to international criteria for dementia and subtypes. There were 2547 dementia-free participants in the CHS Cognition Study cohort with complete information on APOE epsilon4 and type 2 diabetes status; among these, 411 new cases of dementia developed. Risk of dementia was estimated with a Cox proportional hazard model adjusted for age and other demographic and cardiovascular risk factors.

RESULTS: Compared with those who had neither type 2 diabetes nor APOE epsilon4, those with both factors had a significantly higher risk of AD (hazard ratio, 4.58; 95\% confidence interval, 2.18-9.65) and mixed AD (hazard ratio, 3.89; 95\% confidence interval, 1.46-10.40).

CONCLUSION: These data suggest that having both diabetes and APOE epsilon4 increases the risk of dementia, especially for AD and mixed AD.

}, keywords = {African Americans, Age Factors, Aged, Alzheimer Disease, Apolipoprotein E4, Cognition, Cohort Studies, Confidence Intervals, Dementia, Vascular, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Genotype, Humans, Longitudinal Studies, Male, Neuropsychological Tests, Proportional Hazards Models, Prospective Studies, Risk Factors, Sex Factors}, issn = {0003-9942}, doi = {10.1001/archneurol.2007.29}, author = {Irie, Fumiko and Fitzpatrick, Annette L and Lopez, Oscar L and Kuller, Lewis H and Peila, Rita and Newman, Anne B and Launer, Lenore J} } @article {1118, title = {Depressed mood is not a risk factor for incident dementia in a community-based cohort.}, journal = {Am J Geriatr Psychiatry}, volume = {17}, year = {2009}, month = {2009 Aug}, pages = {653-63}, abstract = {

OBJECTIVES: To determine the relationship between depressed mood and the development of Alzheimer disease in cognitively normal individuals.

DESIGN: Longitudinal and observational.

SETTING: Community-based cohort study.

PARTICIPANTS: A total of 288 participants in the Cardiovascular Health Study-Cognition Study (mean age: 77.52, SD =3.65, range: 70-89). All of the participants were adjudicated as cognitively normal in 1998/1999, and all had at least three visits before 1998/1999 with measures of cognition and mood state. The mean length of follow-up from 1998-1999 to 2007 was 7.1 years (range: 1-9 years, median =9 years).

MEASUREMENTS: The Center for Epidemiological Studies-Depression Scale (CESD) was used to index mood state, and the Modified Mini-Mental State Examination (3MSE) was the index of cognitive function among participants before 1998/1999. These measures were considered in two ways: participants were classified according to: 1) whether they showed a high-negative correlation between their CESD and 3MSE scores (i.e., indicating that greater depression was linked to poorer cognition) and 2) whether they showed persistently elevated CESD scores. The study outcome, development of dementia (N = 48), was based on consensus classifications, which was based on detailed neuropsychological and neurological exams.

RESULTS: The authors could find no consistent relationship between mood state, either alone or in relation to cognitive status, and the subsequent development of dementia. Those individuals whose cognitive functions were highly correlated with their mood state were no more likely to develop dementia than other participants. Those who had persistently depressed mood were also no more likely to develop dementia than those without persistently depressed mood.

CONCLUSION: Within the confines of this prospective, community-based study of elderly adults, the authors could not find strong evidence to support the hypothesis that mood disturbance was linked with the development of dementia.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Cognition Disorders, Dementia, Depression, Female, Follow-Up Studies, Humans, Incidence, Longitudinal Studies, Magnetic Resonance Imaging, Male, Mental Status Schedule, Prospective Studies, Psychiatric Status Rating Scales, Residence Characteristics, Risk Factors}, issn = {1545-7214}, author = {Becker, James T and Chang, Yue-Fang and Lopez, Oscar L and Dew, Mary Amanda and Sweet, Robert A and Barnes, Deborah and Yaffe, Kristine and Young, Jeffrey and Kuller, Lewis and Reynolds, Charles F} } @article {1092, title = {Genomewide association studies of stroke.}, journal = {N Engl J Med}, volume = {360}, year = {2009}, month = {2009 Apr 23}, pages = {1718-28}, abstract = {

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.

METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.

RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95\% confidence interval [CI], 1.19 to 1.42) and 1.33 (95\% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11\% and 12\% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95\% CI, 1.01 to 1.79; P=0.04) and 1.42 (95\% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95\% CI, 1.01 to 1.37; P=0.03) and 1.19 (95\% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.

CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

}, keywords = {African Continental Ancestry Group, Aged, Chromosomes, Human, Pair 12, Cohort Studies, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk Factors, Stroke}, issn = {1533-4406}, doi = {10.1056/NEJMoa0900094}, author = {Ikram, M Arfan and Seshadri, Sudha and Bis, Joshua C and Fornage, Myriam and DeStefano, Anita L and Aulchenko, Yurii S and Debette, Stephanie and Lumley, Thomas and Folsom, Aaron R and van den Herik, Evita G and Bos, Michiel J and Beiser, Alexa and Cushman, Mary and Launer, Lenore J and Shahar, Eyal and Struchalin, Maksim and Du, Yangchun and Glazer, Nicole L and Rosamond, Wayne D and Rivadeneira, Fernando and Kelly-Hayes, Margaret and Lopez, Oscar L and Coresh, Josef and Hofman, Albert and DeCarli, Charles and Heckbert, Susan R and Koudstaal, Peter J and Yang, Qiong and Smith, Nicholas L and Kase, Carlos S and Rice, Kenneth and Haritunians, Talin and Roks, Gerwin and de Kort, Paul L M and Taylor, Kent D and de Lau, Lonneke M and Oostra, Ben A and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Boerwinkle, Eric and Psaty, Bruce M and Mosley, Thomas H and van Duijn, Cornelia M and Breteler, Monique M B and Longstreth, W T and Wolf, Philip A} } @article {1086, title = {Imaging cerebral blood flow in the cognitively normal aging brain with arterial spin labeling: implications for imaging of neurodegenerative disease.}, journal = {J Neuroimaging}, volume = {19}, year = {2009}, month = {2009 Oct}, pages = {344-52}, abstract = {

INTRODUCTION: Arterial spin labeling (ASL) is a safe, noninvasive imaging method for evaluating cerebral blood flow (rCBF). The purpose of this article is to present ASL imaging features of 38 elderly cognitively normals (CN) with their rCBF values and an averaged profile of targeted anatomic regions rCBF values.

METHODS: Thirty-eight CN underwent MR imaging especially ASL with voxel morphometric techniques fusing the MR anatomical and ASL images to a standard reference brain (colin27). The ASL images were fused to echo planar images, which were then coregistered to high-resolution anatomical SPGR images. rCBF was calculated per region of interest using a modified continuous arterial spin labeling (CASL) convolutional method. Anatomical regions were selected and identified by the Talairach atlas in SPM2.

RESULTS: We identified areas of decreased and increased perfusion (compared to the averaged rCBF of all 38 CN) corresponding to decreased and increased quantified rCBF. The most common sites for decreased perfusion were precuneus (53\%), superior temporal (48\%), and orbitofrontal (37\%), and for increased perfusion the caudate (39\%), posterior cingulate (34\%), anterior cingulate (32\%), and amygdala (32\%).

CONCLUSION: There are regional variations in rCBF both increased and decreased with the posterior cingulate and precuneus cortex showing the highest averaged values and signal intensity (bright spots). These variations represent the normal profile of a CN elderly brain, with higher perfusion in areas associated with cognition, memory, and behavior. It is necessary to understand these normal variations in order to determine if there are perfusion changes in ASL detected in neurodegenerative disorders such as Alzheimer{\textquoteright}s disease.

}, keywords = {Aged, 80 and over, Aging, Brain, Brain Mapping, Cerebrovascular Circulation, Female, Humans, Magnetic Resonance Imaging, Male, Neurodegenerative Diseases, Signal Processing, Computer-Assisted, Spin Labels}, issn = {1552-6569}, doi = {10.1111/j.1552-6569.2008.00277.x}, author = {Lee, Charles and Lopez, Oscar L and Becker, James T and Raji, Cyrus and Dai, Weiying and Kuller, Lewis H and Gach, H Michael} } @article {1085, title = {Midlife and late-life obesity and the risk of dementia: cardiovascular health study.}, journal = {Arch Neurol}, volume = {66}, year = {2009}, month = {2009 Mar}, pages = {336-42}, abstract = {

BACKGROUND: While high adiposity in middle age appears to be related to greater dementia risk, studies exploring this association in the elderly are conflicting.

OBJECTIVE: To evaluate associations between midlife and late-life obesity and risk of dementia.

DESIGN: Prospective study with mean follow-up of 5.4 years (1992-1994 through 1999).

SETTING: Community-dwelling sample in 4 US sites recruited from Medicare eligibility files.

PARTICIPANTS: A total of 2798 adults without dementia (mean age, 74.7 years; 59.1\% women) participating in the Cardiovascular Health Study who underwent magnetic resonance imaging were measured for height and weight at baseline at age 65 years or older (late life), and self-reported weight at age 50 years (midlife). Body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) was calculated at both times.

MAIN OUTCOME MEASURES: Dementia, Alzheimer disease, and vascular dementia classified by a multidisciplinary committee using standardized criteria.

RESULTS: Classification resulted in 480 persons with incident dementia, 245 with Alzheimer disease (no vascular dementia), and 213 with vascular dementia (with or without Alzheimer disease). In evaluations of midlife obesity, an increased risk of dementia was found for obese (BMI >30) vs normal-weight (BMI 20-25) persons, adjusted for demographics (hazard ratio [HR], 1.39; 95\% confidence interval [CI], 1.03-1.87) and for cardiovascular risk factors (1.36; 0.94-1.95). The risk estimates were reversed in assessments of late-life BMI. Underweight persons (BMI <20) had an increased risk of dementia (1.62; 1.02-2.64), whereas being overweight (BMI >25-30) was not associated (0.92; 0.72-1.18) and being obese reduced the risk of dementia (0.63; 0.44-0.91) compared with those with normal BMI.

CONCLUSION: These results help explain the "obesity paradox" as differences in dementia risk across time are consistent with physical changes in the trajectory toward disability.

}, keywords = {Aged, Aged, 80 and over, Aging, Alzheimer Disease, Anthropometry, Body Mass Index, Dementia, Vascular, Evaluation Studies as Topic, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Obesity, Prospective Studies, Risk, Survival Analysis}, issn = {1538-3687}, doi = {10.1001/archneurol.2008.582}, author = {Fitzpatrick, Annette L and Kuller, Lewis H and Lopez, Oscar L and Diehr, Paula and O{\textquoteright}Meara, Ellen S and Longstreth, W T and Luchsinger, Jos{\'e} A} } @article {1071, title = {Mild cognitive impairment and alzheimer disease: patterns of altered cerebral blood flow at MR imaging.}, journal = {Radiology}, volume = {250}, year = {2009}, month = {2009 Mar}, pages = {856-66}, abstract = {

PURPOSE: To examine regional cerebral blood flow (rCBF) in incident mild cognitive impairment (MCI) and Alzheimer disease (AD) by using continuous arterial spin-labeling (CASL) magnetic resonance (MR) imaging.

MATERIALS AND METHODS: This study was approved by the local institutional review board and was compliant with HIPAA regulations. Informed consent was obtained. rCBF was measured in 38 control subjects, 29 MCI patients, and 37 AD patients who were participating in a longitudinal epidemiologic study. Multisection CASL MR imaging with alternating single and double adiabatic inversion pulses and ramp-sampled echo-planar imaging were performed to acquire 19 contiguous axial sections. Voxel-level rCBF was compared among groups by using an analysis of variance design; clusters of voxels with significant group differences were identified. Multiple regression models controlled for age, sex, and presence of hypertension and related the mean rCBF in those clusters to the presence of MCI and AD.

RESULTS: MCI and AD patients had decreased rCBF in the posterior cingulate gyrus (P = .01) with extension to the medial precuneus compared with that in control subjects. MCI patients had increased rCBF in the left hippocampus (P < .001), right amygdala (P = .007), and rostral head of the right caudate nucleus and ventral putamen and globus pallidus (P = .003) compared with that in control subjects. AD patients had decreased rCBF relative to that in control subjects and MCI patients in the left inferior parietal (P = .005), left lateral frontal (P < .001), left superior temporal (P = .001), and left orbitofrontal (P = .003) cortices. AD patients had increased rCBF in the right anterior cingulate gyrus (P = .02) compared with that in control subjects.

CONCLUSION: The transition from normal cognition to AD is associated with dynamic pathologic processes in the brain, and this is reflected by both decreases and increases in rCBF. Increases in rCBF suggest a cellular and vascular compensatory process associated with incipient AD.

SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/2503080751/DC1.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cerebrovascular Circulation, Cognition Disorders, Female, Humans, Magnetic Resonance Imaging, Male}, issn = {1527-1315}, doi = {10.1148/radiol.2503080751}, author = {Dai, Weiying and Lopez, Oscar L and Carmichael, Owen T and Becker, James T and Kuller, Lewis H and Gach, H Michael} } @article {1120, title = {Brain structure and obesity.}, journal = {Hum Brain Mapp}, volume = {31}, year = {2010}, month = {2010 Mar}, pages = {353-64}, abstract = {

Obesity is associated with increased risk for cardiovascular health problems including diabetes, hypertension, and stroke. These cardiovascular afflictions increase risk for cognitive decline and dementia, but it is unknown whether these factors, specifically obesity and Type II diabetes, are associated with specific patterns of brain atrophy. We used tensor-based morphometry (TBM) to examine gray matter (GM) and white matter (WM) volume differences in 94 elderly subjects who remained cognitively normal for at least 5 years after their scan. Bivariate analyses with corrections for multiple comparisons strongly linked body mass index (BMI), fasting plasma insulin (FPI) levels, and Type II Diabetes Mellitus (DM2) with atrophy in frontal, temporal, and subcortical brain regions. A multiple regression model, also correcting for multiple comparisons, revealed that BMI was still negatively correlated with brain atrophy (FDR <5\%), while DM2 and FPI were no longer associated with any volume differences. In an Analysis of Covariance (ANCOVA) model controlling for age, gender, and race, obese subjects with a high BMI (BMI > 30) showed atrophy in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus compared with individuals with a normal BMI (18.5-25). Overweight subjects (BMI: 25-30) had atrophy in the basal ganglia and corona radiata of the WM. Overall brain volume did not differ between overweight and obese persons. Higher BMI was associated with lower brain volumes in overweight and obese elderly subjects. Obesity is therefore associated with detectable brain volume deficits in cognitively normal elderly subjects.

}, keywords = {Age Factors, Aged, Analysis of Variance, Body Mass Index, Brain, Continental Population Groups, Diabetes Mellitus, Type 2, Fasting, Female, Humans, Insulin, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Nerve Fibers, Unmyelinated, Obesity, Organ Size, Regression Analysis, Sex Factors}, issn = {1097-0193}, doi = {10.1002/hbm.20870}, author = {Raji, Cyrus A and Ho, April J and Parikshak, Neelroop N and Becker, James T and Lopez, Oscar L and Kuller, Lewis H and Hua, Xue and Leow, Alex D and Toga, Arthur W and Thompson, Paul M} } @article {1178, title = {Commentary on "Developing a national strategy to prevent dementia: Leon Thal Symposium 2009." Dementia risk indices: A framework for identifying individuals with a high dementia risk.}, journal = {Alzheimers Dement}, volume = {6}, year = {2010}, month = {2010 Mar}, pages = {138-41}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Dementia, Diagnosis, Differential, Disability Evaluation, Early Diagnosis, Humans, National Health Programs, Predictive Value of Tests, Prognosis, Risk Assessment, Risk Factors, United States}, issn = {1552-5279}, doi = {10.1016/j.jalz.2010.01.005}, author = {Barnes, Deborah E and Covinsky, Kenneth E and Whitmer, Rachel A and Kuller, Lewis H and Lopez, Oscar L and Yaffe, Kristine} } @article {1199, title = {Genome-wide analysis of genetic loci associated with Alzheimer disease.}, journal = {JAMA}, volume = {303}, year = {2010}, month = {2010 May 12}, pages = {1832-40}, abstract = {

CONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).

OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).

DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.

MAIN OUTCOME MEASURE: Presence of Alzheimer disease.

RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95\% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95\% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).

CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

}, keywords = {Age of Onset, Aged, Alzheimer Disease, Case-Control Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Odds Ratio, Polymorphism, Single Nucleotide}, issn = {1538-3598}, doi = {10.1001/jama.2010.574}, author = {Seshadri, Sudha and Fitzpatrick, Annette L and Ikram, M Arfan and DeStefano, Anita L and Gudnason, Vilmundur and Boada, Merce and Bis, Joshua C and Smith, Albert V and Carassquillo, Minerva M and Lambert, Jean Charles and Harold, Denise and Schrijvers, Elisabeth M C and Ramirez-Lorca, Reposo and Debette, Stephanie and Longstreth, W T and Janssens, A Cecile J W and Pankratz, V Shane and Dartigues, Jean Fran{\c c}ois and Hollingworth, Paul and Aspelund, Thor and Hernandez, Isabel and Beiser, Alexa and Kuller, Lewis H and Koudstaal, Peter J and Dickson, Dennis W and Tzourio, Christophe and Abraham, Richard and Antunez, Carmen and Du, Yangchun and Rotter, Jerome I and Aulchenko, Yurii S and Harris, Tamara B and Petersen, Ronald C and Berr, Claudine and Owen, Michael J and Lopez-Arrieta, Jesus and Varadarajan, Badri N and Becker, James T and Rivadeneira, Fernando and Nalls, Michael A and Graff-Radford, Neill R and Campion, Dominique and Auerbach, Sanford and Rice, Kenneth and Hofman, Albert and Jonsson, Palmi V and Schmidt, Helena and Lathrop, Mark and Mosley, Thomas H and Au, Rhoda and Psaty, Bruce M and Uitterlinden, Andr{\'e} G and Farrer, Lindsay A and Lumley, Thomas and Ruiz, Agustin and Williams, Julie and Amouyel, Philippe and Younkin, Steve G and Wolf, Philip A and Launer, Lenore J and Lopez, Oscar L and van Duijn, Cornelia M and Breteler, Monique M B} } @article {1208, title = {Obesity is linked with lower brain volume in 700 AD and MCI patients.}, journal = {Neurobiol Aging}, volume = {31}, year = {2010}, month = {2010 Aug}, pages = {1326-39}, abstract = {

Obesity is associated with lower brain volumes in cognitively normal elderly subjects, but no study has yet investigated the effects of obesity on brain structure in patients with mild cognitive impairment (MCI) or Alzheimer{\textquoteright}s disease (AD). To determine if higher body mass index (BMI) is associated with brain volume deficits in cognitively impaired elderly subjects, we analyzed brain magnetic resonance imaging (MRI) scans of 700 MCI or AD patients from 2 different cohorts: the Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI) and the Cardiovascular Health Study-Cognition Study (CHS-CS). Tensor-based morphometry (TBM) was used to create 3-dimensional maps of regional tissue excess or deficits in subjects with MCI (ADNI, n = 399; CHS-CS, n = 77) and AD (ADNI, n = 188; CHS, n = 36). In both AD and MCI groups, higher body mass index was associated with brain volume deficits in frontal, temporal, parietal, and occipital lobes; the atrophic pattern was consistent in both ADNI and CHS populations. Cardiovascular risk factors, especially obesity, should be considered as influencing brain structure in those already afflicted by cognitive impairment and dementia.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Atrophy, Body Mass Index, Brain, Cognition Disorders, Cohort Studies, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Obesity, Organ Size, Prospective Studies, Risk Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2010.04.006}, author = {Ho, April J and Raji, Cyrus A and Becker, James T and Lopez, Oscar L and Kuller, Lewis H and Hua, Xue and Lee, Suh and Hibar, Derrek and Dinov, Ivo D and Stein, Jason L and Jack, Clifford R and Weiner, Michael W and Toga, Arthur W and Thompson, Paul M} } @article {1225, title = {The effects of physical activity, education, and body mass index on the aging brain.}, journal = {Hum Brain Mapp}, volume = {32}, year = {2011}, month = {2011 Sep}, pages = {1371-82}, abstract = {

Normal human aging is accompanied by progressive brain tissue loss and cognitive decline; however, several factors are thought to influence brain aging. We applied tensor-based morphometry to high-resolution brain MRI scans to determine whether educational level or physical activity was associated with brain tissue volumes in the elderly, particularly in regions susceptible to age-related atrophy. We mapped the 3D profile of brain volume differences in 226 healthy elderly subjects (130F/96M; 77.9 {\textpm} 3.6 SD years) from the Cardiovascular Health Study-Cognition Study. Statistical maps revealed the 3D profile of brain regions whose volumes were associated with educational level and physical activity (based on leisure-time energy expenditure). After controlling for age, sex, and physical activity, higher educational levels were associated with ~2-3\% greater tissue volumes, on average, in the temporal lobe gray matter. After controlling for age, sex, and education, greater physical activity was associated with ~2-2.5\% greater average tissue volumes in the white matter of the corona radiata extending into the parietal-occipital junction. Body mass index (BMI) was highly correlated with both education and physical activity, so we examined BMI as a contributing factor by including physical activity, education, and BMI in the same model; only BMI effects remained significant. This is one of the largest MRI studies of factors influencing structural brain aging, and BMI may be a key factor explaining the observed relationship between education, physical activity, and brain structure. Independent contributions to brain structure could not be teased apart as all these factors were highly correlated with one another.

}, keywords = {Aged, Aged, 80 and over, Aging, Analysis of Variance, Body Mass Index, Brain, Brain Mapping, Educational Status, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Motor Activity, Neuropsychological Tests, Statistics as Topic}, issn = {1097-0193}, doi = {10.1002/hbm.21113}, author = {Ho, April J and Raji, Cyrus A and Becker, James T and Lopez, Oscar L and Kuller, Lewis H and Hua, Xue and Dinov, Ivo D and Stein, Jason L and Rosano, Caterina and Toga, Arthur W and Thompson, Paul M} } @article {1298, title = {Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium.}, journal = {Ann Neurol}, volume = {69}, year = {2011}, month = {2011 Jun}, pages = {928-39}, abstract = {

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 {\texttimes} 10(-9) ; p(replication) = 1.3 {\texttimes} 10(-7) ; p(combined) = 4.0 {\texttimes} 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 {\texttimes} 10(-9) ), rs11869977 (p = 5.7 {\texttimes} 10(-9) ), rs936393 (p = 6.8 {\texttimes} 10(-9) ), rs3744017 (p = 7.3 {\texttimes} 10(-9) ), and rs1055129 (p = 4.1 {\texttimes} 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8\% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

}, keywords = {Aged, Aged, 80 and over, Cerebral Cortex, Chromosomes, Human, Pair 17, Cognition Disorders, Cohort Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Middle Aged, Movement Disorders, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Residence Characteristics, RNA, Messenger}, issn = {1531-8249}, doi = {10.1002/ana.22403}, author = {Fornage, Myriam and Debette, Stephanie and Bis, Joshua C and Schmidt, Helena and Ikram, M Arfan and Dufouil, Carole and Sigurdsson, Sigurdur and Lumley, Thomas and DeStefano, Anita L and Fazekas, Franz and Vrooman, Henri A and Shibata, Dean K and Maillard, Pauline and Zijdenbos, Alex and Smith, Albert V and Gudnason, Haukur and de Boer, Renske and Cushman, Mary and Mazoyer, Bernard and Heiss, Gerardo and Vernooij, Meike W and Enzinger, Christian and Glazer, Nicole L and Beiser, Alexa and Knopman, David S and Cavalieri, Margherita and Niessen, Wiro J and Harris, Tamara B and Petrovic, Katja and Lopez, Oscar L and Au, Rhoda and Lambert, Jean-Charles and Hofman, Albert and Gottesman, Rebecca F and Garcia, Melissa and Heckbert, Susan R and Atwood, Larry D and Catellier, Diane J and Uitterlinden, Andr{\'e} G and Yang, Qiong and Smith, Nicholas L and Aspelund, Thor and Romero, Jose R and Rice, Kenneth and Taylor, Kent D and Nalls, Michael A and Rotter, Jerome I and Sharrett, Richey and van Duijn, Cornelia M and Amouyel, Philippe and Wolf, Philip A and Gudnason, Vilmundur and van der Lugt, Aad and Boerwinkle, Eric and Psaty, Bruce M and Seshadri, Sudha and Tzourio, Christophe and Breteler, Monique M B and Mosley, Thomas H and Schmidt, Reinhold and Longstreth, W T and DeCarli, Charles and Launer, Lenore J} } @article {1227, title = {Trajectory of cognitive decline as a predictor of psychosis in early Alzheimer disease in the cardiovascular health study.}, journal = {Am J Geriatr Psychiatry}, volume = {19}, year = {2011}, month = {2011 Feb}, pages = {160-8}, abstract = {

OBJECTIVE: To compare the trajectories of cognitive decline between groups with, and without, the later development of psychotic symptoms during Alzheimer disease (AD) or mild cognitive impairment (MCI).

DESIGN: : The authors examined cognitive function in a new analysis of an existing data set, the Cardiovascular Health Study, an epidemiologic, longitudinal follow-up study. Our analyses examined 9 years of follow-up data.

SETTING: Community.

PARTICIPANTS: The authors examined subjects who were without dementia at study entry, received a diagnosis of AD or MCI during follow-up, and had been rated on the Neuropsychiatric Inventory for the presence of psychosis; 362 participants for the modified Mini-Mental State Examination (3MS) analysis and 350 participants for the digit symbol substitution test (DSST) analysis had sufficient follow-up data and apolipoprotein-∊ (APOE) genotyping.

MEASUREMENTS: The 3MS and DSST were administered annually and analyzed using mixed-effects models including APOE4 status.

RESULTS: : Mean 3MS and DSST scores did not differ between AD with psychosis (AD + P) and without psychosis groups at baseline. The 3MS and DSST scores decreased more rapidly in subjects who ultimately developed psychosis.

CONCLUSIONS: Individuals who ultimately develop psychosis have more rapid cognitive deterioration during the earliest phases of AD than individuals with AD not developing psychosis. The genetic and other neurobiologic factors leading to the expression of AD + P may exert their effects by acceleration of the neurodegenerative process.

}, keywords = {Aged, Alzheimer Disease, Chi-Square Distribution, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Neuropsychological Tests, Psychiatric Status Rating Scales, Psychotic Disorders, Time Factors}, issn = {1545-7214}, doi = {10.1097/JGP.0b013e3181e446c8}, author = {Emanuel, James E and Lopez, Oscar L and Houck, Patricia R and Becker, James T and Weamer, Elise A and Demichele-Sweet, Mary Ann A and Kuller, Lewis and Sweet, Robert A} } @article {6135, title = {Common folate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment.}, journal = {Neuroimage Clin}, volume = {1}, year = {2012}, month = {2012}, pages = {179-87}, abstract = {

A commonly carried C677T polymorphism in a folate-related gene, MTHFR, is associated with higher plasma homocysteine, a well-known mediator of neuronal damage and brain atrophy. As homocysteine promotes brain atrophy, we set out to discover whether people carrying the C677T MTHFR polymorphism which increases homocysteine, might also show systematic differences in brain structure. Using tensor-based morphometry, we tested this association in 359 elderly Caucasian subjects with mild cognitive impairment (MCI) (mean age: 75~{\textpm}~7.1~years) scanned with brain MRI and genotyped as part of Alzheimer{\textquoteright}s Disease Neuroimaging Initiative. We carried out a replication study in an independent, non-overlapping sample of 51 elderly Caucasian subjects with MCI (mean age: 76~{\textpm}~5.5~years), scanned with brain MRI and genotyped for MTHFR, as part of the Cardiovascular Health Study. At each voxel in the brain, we tested to see where regional volume differences were associated with carrying one or more MTHFR {\textquoteright}T{\textquoteright} alleles. In ADNI subjects, carriers of the MTHFR risk allele had detectable brain volume deficits, in the white matter, of up to 2-8\% per risk T allele locally at baseline and showed accelerated brain atrophy of 0.5-1.5\% per T allele at 1~year follow-up, after adjusting for age and sex. We replicated these brain volume deficits of up to 5-12\% per MTHFR T allele in the independent cohort of CHS subjects. As expected, the associations weakened after controlling for homocysteine levels, which the risk gene affects. The MTHFR risk variant may thus promote brain atrophy by elevating homocysteine levels. This study aims to investigate the spatially detailed effects of this MTHFR polymorphism on brain structure in 3D, pointing to a causal pathway that may promote homocysteine-mediated brain atrophy in elderly people with MCI.

}, issn = {2213-1582}, doi = {10.1016/j.nicl.2012.09.012}, author = {Rajagopalan, Priya and Jahanshad, Neda and Stein, Jason L and Hua, Xue and Madsen, Sarah K and Kohannim, Omid and Hibar, Derrek P and Toga, Arthur W and Jack, Clifford R and Saykin, Andrew J and Green, Robert C and Weiner, Michael W and Bis, Joshua C and Kuller, Lewis H and Riverol, Mario and Becker, James T and Lopez, Oscar L and Thompson, Paul M} } @article {1405, title = {Effect of Alzheimer{\textquoteright}s disease risk genes on trajectories of cognitive function in the Cardiovascular Health Study.}, journal = {Am J Psychiatry}, volume = {169}, year = {2012}, month = {2012 Sep}, pages = {954-62}, abstract = {

OBJECTIVE: The trajectory of cognitive decline in patients with late-onset Alzheimer{\textquoteright}s disease varies widely. Genetic variations in CLU, PICALM, and CR1 are associated with Alzheimer{\textquoteright}s disease, but it is unknown whether they exert their effects by altering cognitive trajectory in elderly individuals at risk for the disease.

METHOD: The authors developed a Bayesian model to fit cognitive trajectories in a cohort of elderly subjects and test for genetic effects. They first validated the model{\textquoteright}s ability to detect the previously established effects of APOE ε4 alleles on age at cognitive decline and of psychosis on the rate of cognitive decline in 802 subjects from the Cardiovascular Health Cognition Study who did not have dementia at study entry and developed incident dementia during follow-up. The authors then evaluated the effects of CLU, PICALM, and CR1 on age and rate of decline in 1,831 subjects who did not have dementia at study entry and then did or did not develop incident dementia by study{\textquoteright}s end.

RESULTS: The model generated robust fits to the observed cognitive trajectory data, and validation analysis supported the model{\textquoteright}s utility. CLU and CR1 were associated with more rapid cognitive decline. PICALM was associated with an earlier age at midpoint of cognitive decline. Associations remained after accounting for the effects of APOE and demographic factors.

CONCLUSIONS: Evaluation of cognitive trajectories provides a powerful approach to dissecting genetic effects on the processes leading to cognitive deterioration and Alzheimer{\textquoteright}s disease.

}, keywords = {Age of Onset, Aged, Alleles, Alzheimer Disease, Apolipoprotein E4, Bayes Theorem, Clusterin, Cohort Studies, Dementia, Disease Progression, Female, Genetic Predisposition to Disease, Humans, Male, Models, Psychological, Monomeric Clathrin Assembly Proteins, Polymorphism, Single Nucleotide, Receptors, Complement 3b, Risk Factors}, issn = {1535-7228}, doi = {10.1176/appi.ajp.2012.11121815}, author = {Sweet, Robert A and Seltman, Howard and Emanuel, James E and Lopez, Oscar L and Becker, James T and Bis, Joshua C and Weamer, Elise A and Demichele-Sweet, Mary Ann A and Kuller, Lewis H} } @article {1557, title = {Incidence of mild cognitive impairment in the Pittsburgh Cardiovascular Health Study-Cognition Study.}, journal = {Neurology}, volume = {79}, year = {2012}, month = {2012 Oct 09}, pages = {1599-606}, abstract = {

OBJECTIVES AND METHODS: The purpose of this study was to examine the incidence of mild cognitive impairment (MCI) and patterns of progression from incident MCI to dementia in 285 cognitively normal subjects (mean age, 78.9 years) in the Cardiovascular Health Study-Cognition Study from 1998-1999 to 2010-2011.

RESULTS: Two hundred (70\%) of the participants progressed to MCI; the age-adjusted incidence of MCI was 111.09 (95\% confidence interval, 88.13-142.95) per 1,000 person-years. A total of 107 (53.5\%) of the incident MCI subjects progressed to dementia. The mean time from MCI to dementia was 2.8 {\textpm} 1.8 years. Forty (20\%) of the incident MCI cases had an "unstable" course: 19 (9.5\%) converted to MCI and later returned to normal; 10 (5\%) converted to MCI, to normal, and later back to MCI; 7 (3.5\%) converted to MCI, to normal, to MCI, and later to dementia; and 4 (2\%) converted to MCI, to normal, and later to dementia. There was an increased mortality rate among the cognitively normal group (110.10 per 1,000 person-years) compared to those with incident MCI who converted to dementia (41.32 per 1,000 person-years).

CONCLUSIONS: The majority of the subjects aged >80 years developed an MCI syndrome, and half of them progressed to dementia. Once the MCI syndrome was present, the symptoms of dementia appeared within 2 to 3 years. Progression from normal to MCI or from normal to MCI to dementia is not always linear; subjects who developed MCI and later returned to normal can subsequently progress to dementia. Competing mortality and morbidity influence the study of incident MCI and dementia in population cohorts.

}, keywords = {Aged, Aged, 80 and over, Cognitive Dysfunction, Dementia, Disease Progression, Female, Health Surveys, Humans, Incidence, Male, Risk Factors, Severity of Illness Index}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e31826e25f0}, author = {Lopez, Oscar L and Becker, James T and Chang, Yue-Fang and Sweet, Robert A and DeKosky, Steven T and Gach, Michael H and Carmichael, Owen T and McDade, Eric and Kuller, Lewis H} } @article {1367, title = {Markers of cholesterol metabolism in the brain show stronger associations with cerebrovascular disease than Alzheimer{\textquoteright}s disease.}, journal = {J Alzheimers Dis}, volume = {30}, year = {2012}, month = {2012}, pages = {53-61}, abstract = {

Cholesterol metabolism is believed to play a role in the development of Alzheimer{\textquoteright}s disease (AD). Oxysterol metabolites of cholesterol, 24S-hydroxycholesterol (24-OHC, a brain-derived oxysterol) and 27-hydroxycholesterol (27-OHC, a peripherally derived oxysterol) cross the blood brain barrier and have been associated with AD. We investigated whether oxysterols were associated with markers of cerebrovascular disease prior to the onset of cognitive impairment. Oxysterols were quantified in 105 participants (average age: 80 {\textpm} 4 years) from the Pittsburgh Cardiovascular Health Study Cognition Study who remained cognitively normal at blood draw in 2002, had MRI in 1992 and 1998, and annual cognitive assessment for incident AD and mild cognitive impairment made by consensus conference between 1998 and 2010. Higher plasma levels of 24-OHC were associated with age, gender, the presence of high grade white matter hyperintensities, and brain infarcts on prior MRI. Participants with higher plasma 24-OHC and a greater ratio of 24-OHC/27-OHC were also more likely to develop incident cognitive impairment over 8 years of follow-up. Higher levels of 24-OHC suggest increased cholesterol metabolism occurring in the brains of participants with cerebrovascular disease prior to the onset of cognitive impairment. Measurement of oxysterols may provide information about cholesterol metabolism and brain disease over the cognitive impairment process.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoprotein E4, Brain, Cerebrovascular Disorders, Cognition Disorders, Cohort Studies, Female, Humans, Hydroxycholesterols, Magnetic Resonance Imaging, Male, Retrospective Studies}, issn = {1875-8908}, doi = {10.3233/JAD-2012-111460}, author = {Hughes, Timothy M and Kuller, Lewis H and Lopez, Oscar L and Becker, James T and Evans, Rhobert W and Sutton-Tyrrell, Kim and Rosano, Caterina} } @article {1333, title = {White matter lesions and brain gray matter volume in cognitively normal elders.}, journal = {Neurobiol Aging}, volume = {33}, year = {2012}, month = {2012 Apr}, pages = {834.e7-16}, abstract = {

Cerebral white matter lesions (WMLs) reflect small vessel disease, are common in elderly individuals, and are associated with cognitive impairment. We sought to determine the relationships between WMLs, age, gray matter (GM) volume, and cognition in the Cardiovascular Health Study (CHS). From the Cardiovascular Health Study we selected 740 cognitively normal controls with a 1.5 T magnetic resonance imaging (MRI) scan of the brain and a detailed diagnostic evaluation. WML severity was determined using a standardized visual rating system. GM volumes were analyzed using voxel-based morphometry implemented in the Statistical Parametric Mapping software. WMLs were inversely correlated with GM volume, with the greatest volume loss in the frontal cortex. Age-related atrophy was observed in the hippocampus and posterior cingulate cortex. Regression analyses revealed links among age, APOE*4 allele, hypertension, WMLs, GM volume, and digit symbol substitution test scores. Both advancing age and hypertension predict higher WML load, which is itself associated with GM atrophy. Longitudinal data are needed to confirm the temporal sequence of events leading to a decline in cognitive function.

}, keywords = {Aged, Aged, 80 and over, Aging, Apolipoprotein E4, Brain, Cognition Disorders, Female, Humans, Imaging, Three-Dimensional, Leukoaraiosis, Longitudinal Studies, Magnetic Resonance Imaging, Male, Memory Disorders, Mental Status Schedule, Neuropsychological Tests, Regression Analysis, Retrospective Studies}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2011.08.010}, author = {Raji, Cyrus A and Lopez, Oscar L and Kuller, Lewis H and Carmichael, Owen T and Longstreth, William T and Gach, H Michael and Boardman, John and Bernick, Charles B and Thompson, Paul M and Becker, James T} } @article {6107, title = {Long-term survival in adults 65 years and older with white matter hyperintensity: association with performance on the digit symbol substitution test.}, journal = {Psychosom Med}, volume = {75}, year = {2013}, month = {2013 Sep}, pages = {624-31}, abstract = {

OBJECTIVE: White matter hyperintensity (WMH) confers increased mortality risk in patients with cardiovascular diseases. However, little is known about differences in survival times among adults 65 years and older who have WMH and live in the community. To characterize the factors that may reduce mortality risk in the presence of WMH, measures of race, sex, apolipoprotein E4, neuroimaging, and cardiometabolic, physiological, and psychosocial characteristics were examined, with a particular focus on information processing as measured by the Digit Symbol Substitution Test (DSST).

METHODS: Cox proportional models were used to estimate mortality risks in a cohort of 3513 adults (74.8 years, 58\% women, 84\% white) with WMH (0-9 points), DSST (0-90 points), risk factor assessment in 1992 to 1994, and data on mortality and incident stroke in 2009 (median follow-up [range] = 14.2 [0.5-18.1] years).

RESULTS: WMH predicted a 48\% greater mortality risk (age-adjusted hazard ratio [HR; 95\% confidence interval {CI}] for WMH >3 points = 1.48 [1.35-1.62]). This association was attenuated after adjustment for DSST (HR [CI] = 1.38 [1.27-1.51]) or lacunar infarcts (HR [CI] = 1.37 [1.25,1.50]) but not after adjustment for other factors. The interaction between DSST and WMH was significant (p = .011). In fully adjusted models stratified by WMH of 3 or higher, participants with DSST greater than or equal to median had a 34\% lower mortality risk among those with WMH of 3 or higher (n = 532/1217) and a 28\% lower mortality risk among those with WMH lower than 3 (n = 1364/2296), compared with participants with DSST less than median (HR [95\% CI] = 0.66 [0.55-0.81] and 0.72 [0.62-0.83], respectively).

CONCLUSIONS: WMH is associated with increased long-term mortality risk in community-dwelling adults 65 years and older. The increased risk is attenuated for those with higher DSST. Assessment of cognitive function with DSST may improve risk stratification of individuals with WMH.

}, keywords = {Aged, Apolipoprotein E4, Biomarkers, Brain, Cardiovascular Diseases, Epidemiologic Methods, Female, Humans, Life Style, Magnetic Resonance Imaging, Male, Neuroimaging, Neuropsychological Tests, Reaction Time, Sex Factors, Stroke, Survivors}, issn = {1534-7796}, doi = {10.1097/PSY.0b013e31829c1df2}, author = {Rosano, Caterina and Chang, Yue-Fang and Kuller, Lewis H and Guralnik, Jack M and Studenski, Stephanie A and Aizenstein, Howard J and Gianaros, Peter J and Lopez, Oscar L and Longstreth, William T and Newman, Anne B} } @article {6339, title = {Effect of dementia on the use of drugs for secondary prevention of ischemic heart disease.}, journal = {J Aging Res}, volume = {2014}, year = {2014}, month = {2014}, pages = {897671}, abstract = {

Background. Dementia and cardiovascular disease (CVD) are frequently comorbid. The presence of dementia may have an effect on how CVD is treated. Objective. To examine the effect of dementia on the use of four medications recommended for secondary prevention of ischemic heart disease (IHD): angiotensin-converting enzyme inhibitors, beta-blockers, lipid-lowering medications, and antiplatelet medications. Design. Retrospective analysis of data from the Cardiovascular Health Study: Cognition Study. Setting and Subjects. 1,087 older adults in four US states who had or developed IHD between 1989 and 1998. Methods. Generalized estimating equations to explore the association between dementia and the use of guideline-recommended medications for the secondary prevention of IHD. Results. The length of follow-up for the cohort was 8.7 years and 265 (24\%) had or developed dementia during the study. Use of medications for the secondary prevention of IHD for patients with and without dementia increased during the study period. In models, subjects with dementia were not less likely to use any one particular class of medication but were less likely to use two or more classes of medications as a group (OR, 0.60; 95\% CI, 0.36-0.99). Conclusions. Subjects with dementia used fewer guideline-recommended medications for the secondary prevention of IHD than those without dementia.

}, issn = {2090-2204}, doi = {10.1155/2014/897671}, author = {Fowler, Nicole R and Barnato, Amber E and Degenholtz, Howard B and Curcio, Angela M and Becker, James T and Kuller, Lewis H and Lopez, Oscar L} } @article {6617, title = {Gene-wide analysis detects two new susceptibility genes for Alzheimer{\textquoteright}s disease.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e94661}, abstract = {

BACKGROUND: Alzheimer{\textquoteright}s disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer{\textquoteright}s Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer{\textquoteright}s cases and 48,466 controls.

PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4{\texttimes}10-6) and 14 (IGHV1-67 p = 7.9{\texttimes}10-8) which indexed novel susceptibility loci.

SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer{\textquoteright}s disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer{\textquoteright}s disease.

}, keywords = {Alzheimer Disease, Carrier Proteins, Case-Control Studies, Genome-Wide Association Study, Heat-Shock Proteins, Humans, Polymorphism, Single Nucleotide, Receptors, Antigen, B-Cell}, issn = {1932-6203}, doi = {10.1371/journal.pone.0094661}, author = {Escott-Price, Valentina and Bellenguez, C{\'e}line and Wang, Li-San and Choi, Seung-Hoan and Harold, Denise and Jones, Lesley and Holmans, Peter and Gerrish, Amy and Vedernikov, Alexey and Richards, Alexander and DeStefano, Anita L and Lambert, Jean-Charles and Ibrahim-Verbaas, Carla A and Naj, Adam C and Sims, Rebecca and Jun, Gyungah and Bis, Joshua C and Beecham, Gary W and Grenier-Boley, Benjamin and Russo, Giancarlo and Thornton-Wells, Tricia A and Denning, Nicola and Smith, Albert V and Chouraki, Vincent and Thomas, Charlene and Ikram, M Arfan and Zelenika, Diana and Vardarajan, Badri N and Kamatani, Yoichiro and Lin, Chiao-Feng and Schmidt, Helena and Kunkle, Brian and Dunstan, Melanie L and Vronskaya, Maria and Johnson, Andrew D and Ruiz, Agustin and Bihoreau, Marie-Th{\'e}r{\`e}se and Reitz, Christiane and Pasquier, Florence and Hollingworth, Paul and Hanon, Olivier and Fitzpatrick, Annette L and Buxbaum, Joseph D and Campion, Dominique and Crane, Paul K and Baldwin, Clinton and Becker, Tim and Gudnason, Vilmundur and Cruchaga, Carlos and Craig, David and Amin, Najaf and Berr, Claudine and Lopez, Oscar L and De Jager, Philip L and Deramecourt, Vincent and Johnston, Janet A and Evans, Denis and Lovestone, Simon and Letenneur, Luc and Hernandez, Isabel and Rubinsztein, David C and Eiriksdottir, Gudny and Sleegers, Kristel and Goate, Alison M and Fi{\'e}vet, Nathalie and Huentelman, Matthew J and Gill, Michael and Brown, Kristelle and Kamboh, M Ilyas and Keller, Lina and Barberger-Gateau, Pascale and McGuinness, Bernadette and Larson, Eric B and Myers, Amanda J and Dufouil, Carole and Todd, Stephen and Wallon, David and Love, Seth and Rogaeva, Ekaterina and Gallacher, John and George-Hyslop, Peter St and Clarimon, Jordi and Lleo, Alberto and Bayer, Anthony and Tsuang, Debby W and Yu, Lei and Tsolaki, Magda and Boss{\`u}, Paola and Spalletta, Gianfranco and Proitsi, Petra and Collinge, John and Sorbi, Sandro and Garcia, Florentino Sanchez and Fox, Nick C and Hardy, John and Naranjo, Maria Candida Deniz and Bosco, Paolo and Clarke, Robert and Brayne, Carol and Galimberti, Daniela and Scarpini, Elio and Bonuccelli, Ubaldo and Mancuso, Michelangelo and Siciliano, Gabriele and Moebus, Susanne and Mecocci, Patrizia and Zompo, Maria Del and Maier, Wolfgang and Hampel, Harald and Pilotto, Alberto and Frank-Garc{\'\i}a, Ana and Panza, Francesco and Solfrizzi, Vincenzo and Caffarra, Paolo and Nacmias, Benedetta and Perry, William and Mayhaus, Manuel and Lannfelt, Lars and Hakonarson, Hakon and Pichler, Sabrina and Carrasquillo, Minerva M and Ingelsson, Martin and Beekly, Duane and Alvarez, Victoria and Zou, Fanggeng and Valladares, Otto and Younkin, Steven G and Coto, Eliecer and Hamilton-Nelson, Kara L and Gu, Wei and Razquin, Cristina and Pastor, Pau and Mateo, Ignacio and Owen, Michael J and Faber, Kelley M and Jonsson, Palmi V and Combarros, Onofre and O{\textquoteright}Donovan, Michael C and Cantwell, Laura B and Soininen, Hilkka and Blacker, Deborah and Mead, Simon and Mosley, Thomas H and Bennett, David A and Harris, Tamara B and Fratiglioni, Laura and Holmes, Clive and de Bruijn, Renee F A G and Passmore, Peter and Montine, Thomas J and Bettens, Karolien and Rotter, Jerome I and Brice, Alexis and Morgan, Kevin and Foroud, Tatiana M and Kukull, Walter A and Hannequin, Didier and Powell, John F and Nalls, Michael A and Ritchie, Karen and Lunetta, Kathryn L and Kauwe, John S K and Boerwinkle, Eric and Riemenschneider, Matthias and Boada, Merce and Hiltunen, Mikko and Martin, Eden R and Schmidt, Reinhold and Rujescu, Dan and Dartigues, Jean-Fran{\c c}ois and Mayeux, Richard and Tzourio, Christophe and Hofman, Albert and N{\"o}then, Markus M and Graff, Caroline and Psaty, Bruce M and Haines, Jonathan L and Lathrop, Mark and Pericak-Vance, Margaret A and Launer, Lenore J and Van Broeckhoven, Christine and Farrer, Lindsay A and van Duijn, Cornelia M and Ramirez, Alfredo and Seshadri, Sudha and Schellenberg, Gerard D and Amouyel, Philippe and Williams, Julie} } @article {6592, title = {Regular fish consumption and age-related brain gray matter loss.}, journal = {Am J Prev Med}, volume = {47}, year = {2014}, month = {2014 Oct}, pages = {444-51}, abstract = {

BACKGROUND: Brain health may be affected by modifiable lifestyle factors; consuming fish and antioxidative omega-3 fatty acids may reduce brain structural abnormality risk.

PURPOSE: To determine whether dietary fish consumption is related to brain structural integrity among cognitively normal elders.

METHODS: Data were analyzed from 260 cognitively normal individuals from the Cardiovascular Health Study with information on fish consumption from the National Cancer Institute Food Frequency Questionnaire and brain magnetic resonance imaging (MRI). The relationship between fish consumption data collected in 1989-1990 and brain structural MRI obtained in 1998-1999 was assessed using voxel-based morphometry in multiple regression analyses in 2012. Covariates were age, gender, race, education, white matter lesions, MRI-identified infarcts, waist-hip ratio, and physical activity as assessed by the number of city blocks walked in 1 week. Volumetric changes were further modeled with omega-3 fatty acid estimates to better understand the mechanistic link between fish consumption, brain health, and Alzheimer disease.

RESULTS: Weekly consumption of baked or broiled fish was positively associated with gray matter volumes in the hippocampus, precuneus, posterior cingulate, and orbital frontal cortex even after adjusting for covariates. These results did not change when including omega-3 fatty acid estimates in the analysis.

CONCLUSIONS: Dietary consumption of baked or broiled fish is related to larger gray matter volumes independent of omega-3 fatty acid content. These findings suggest that a confluence of lifestyle factors influence brain health, adding to the growing body of evidence that prevention strategies for late-life brain health need to begin decades earlier.

}, keywords = {Aged, Aged, 80 and over, Animals, Brain, Cross-Sectional Studies, Diet, Fatty Acids, Omega-3, Female, Fishes, Gray Matter, Humans, Life Style, Magnetic Resonance Imaging, Male, Regression Analysis, Surveys and Questionnaires}, issn = {1873-2607}, doi = {10.1016/j.amepre.2014.05.037}, author = {Raji, Cyrus A and Erickson, Kirk I and Lopez, Oscar L and Kuller, Lewis H and Gach, H Michael and Thompson, Paul M and Riverol, Mario and Becker, James T} } @article {9409, title = {A self-report risk index to predict occurrence of dementia in three independent cohorts of older adults: the ANU-ADRI.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e86141}, abstract = {

BACKGROUND AND AIMS: The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer{\textquoteright}s disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts.

METHODS: This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age >=53 years), the Kungsholmen Project (KP) (n = 905, age >=75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age >=65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index.

RESULTS: For the ANU-ADRI using available data, the MAP study c-statistic was 0{\textperiodcentered}637 (95\% CI 0{\textperiodcentered}596-0{\textperiodcentered}678), for the KP study it was 0{\textperiodcentered}740 (0{\textperiodcentered}712-0{\textperiodcentered}768) and for the CVHS it was 0{\textperiodcentered}733 (0{\textperiodcentered}691-0{\textperiodcentered}776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95\% CI 0.650-0.727), 0.666 (0.628-0.704) and 0.734 (0.707-0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427-0.554) to 0.595 (0.565-0.625).

CONCLUSION: A composite risk score derived from the ANU-ADRI weights including 8-10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up.

}, keywords = {Adult, Aged, Aged, 80 and over, Alzheimer Disease, Dementia, Female, Humans, Incidence, Male, Middle Aged, Risk, ROC Curve, Self Report}, issn = {1932-6203}, doi = {10.1371/journal.pone.0086141}, author = {Anstey, Kaarin J and Cherbuin, Nicolas and Herath, Pushpani M and Qiu, Chengxuan and Kuller, Lewis H and Lopez, Oscar L and Wilson, Robert S and Fratiglioni, Laura} } @article {7017, title = {Vitamin D and the risk of dementia and Alzheimer disease.}, journal = {Neurology}, volume = {83}, year = {2014}, month = {2014 Sep 2}, pages = {920-8}, abstract = {

OBJECTIVE: To determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease.

METHODS: One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population-based Cardiovascular Health Study between 1992-1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992-1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer{\textquoteright}s Disease and Related Disorders Association criteria.

RESULTS: During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95\% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (>=25 to <50 nmol/L) were 2.25 (95\% CI: 1.23-4.13) and 1.53 (95\% CI: 1.06-2.21) compared to participants with sufficient concentrations (>=50 nmol/L). The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 (95\% CI: 1.02-4.83) and 1.69 (95\% CI: 1.06-2.69). In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L.

CONCLUSION: Our results confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease. This adds to the ongoing debate about the role of vitamin D in nonskeletal conditions.

}, keywords = {Aged, Alzheimer Disease, Dementia, Female, Follow-Up Studies, Humans, Incidence, Male, Proportional Hazards Models, Risk Factors, United States, Vitamin D, Vitamin D Deficiency}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000000755}, author = {Littlejohns, Thomas J and Henley, William E and Lang, Iain A and Annweiler, Cedric and Beauchet, Olivier and Chaves, Paulo H M and Fried, Linda and Kestenbaum, Bryan R and Kuller, Lewis H and Langa, Kenneth M and Lopez, Oscar L and Kos, Katarina and Soni, Maya and Llewellyn, David J} } @article {6815, title = {Association of Alzheimer{\textquoteright}s disease GWAS loci with MRI markers of brain aging.}, journal = {Neurobiol Aging}, volume = {36}, year = {2015}, month = {2015 Apr}, pages = {1765.e7-16}, abstract = {

Whether novel risk variants of Alzheimer{\textquoteright}s disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta {\textpm} SE = -0.047 {\textpm} 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

}, keywords = {Aging, Alleles, Alzheimer Disease, Apolipoproteins E, Brain, Female, Genome-Wide Association Study, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Organ Size, Polymorphism, Single Nucleotide, Risk, Sialic Acid Binding Ig-like Lectin 3}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2014.12.028}, author = {Chauhan, Ganesh and Adams, Hieab H H and Bis, Joshua C and Weinstein, Galit and Yu, Lei and T{\"o}glhofer, Anna Maria and Smith, Albert Vernon and van der Lee, Sven J and Gottesman, Rebecca F and Thomson, Russell and Wang, Jing and Yang, Qiong and Niessen, Wiro J and Lopez, Oscar L and Becker, James T and Phan, Thanh G and Beare, Richard J and Arfanakis, Konstantinos and Fleischman, Debra and Vernooij, Meike W and Mazoyer, Bernard and Schmidt, Helena and Srikanth, Velandai and Knopman, David S and Jack, Clifford R and Amouyel, Philippe and Hofman, Albert and DeCarli, Charles and Tzourio, Christophe and van Duijn, Cornelia M and Bennett, David A and Schmidt, Reinhold and Longstreth, William T and Mosley, Thomas H and Fornage, Myriam and Launer, Lenore J and Seshadri, Sudha and Ikram, M Arfan and Debette, Stephanie} } @article {6822, title = {Empirically Derived Trajectories to Dementia Over 15 Years of Follow-up Identified by Using Mixed Membership Models.}, journal = {Am J Epidemiol}, volume = {182}, year = {2015}, month = {2015 Aug 15}, pages = {366-74}, abstract = {

Alzheimer disease is the most common form of dementia in the elderly, and the complex relationships among risk factors produce highly variable natural histories from normal cognition through the prodromal stage of mild cognitive impairment (MCI) to clinical dementia. We used a novel statistical approach, mixed membership trajectory models, to capture the variety of such pathways in 652 participants in the Cardiovascular Health Study Cognition Study over 22 years of follow-up (1992-2014). We identified 3 trajectories: a "healthy" profile with a peak probability of MCI between 95 and 100 years of age and only a 50\% probability of dementia by age 100; an "intermediate" profile with a peak probability of MCI between 85 and 90 years of age and progression to dementia between 90 and 95 years; and an "unhealthy" profile with a peak probability of progressing to MCI between ages 75 and 80 years and to dementia between the ages of 80 and 85 years. Hypertension, education, race, and the ϵ4 allele of the apolipoprotein E gene all affected the closeness of an individual to 1 or more of the canonical trajectories. These results provide new insights into the natural history of Alzheimer disease and evidence for a potential difference in the pathophysiology of the development of dementia.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoprotein E4, Cardiovascular Diseases, Comorbidity, Dementia, Diabetes Mellitus, Disease Progression, Female, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Male, Mild Cognitive Impairment, Neuroimaging, Prevalence, Proportional Hazards Models, Risk Factors, Sex Distribution}, issn = {1476-6256}, doi = {10.1093/aje/kwv051}, author = {Lecci, Fabrizio and Junker, Brian and Kuller, Lewis H and Lopez, Oscar L and Becker, James T} } @article {6853, title = {Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies.}, journal = {Atherosclerosis}, volume = {243}, year = {2015}, month = {2015 Nov}, pages = {44-52}, abstract = {

BACKGROUND AND AIMS: Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification).

METHODS: Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992-1993.

RESULTS: Among Caucasians, both rs2248690 and rs4917 were associated with 12\% lower fetuin-A concentrations per minor allele (P~<~0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95\% CI: 1.00-1.26) for rs2248690 and 1.02 (0.91-1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95\% CI: 0.70-1.00) for rs2248690 and 0.97 (95\% CI: 0.82-1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93-1.34) and 1.06 (0.93-1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048).

CONCLUSION: Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.

}, keywords = {Aged, Aged, 80 and over, alpha-2-HS-Glycoprotein, Carotid Intima-Media Thickness, Coronary Vessels, Female, Genetic Variation, Genotype, Heart Diseases, Humans, Insulin Resistance, Longitudinal Studies, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Vascular Calcification}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2015.08.031}, author = {Laugsand, Lars E and Ix, Joachim H and Bartz, Traci M and Djouss{\'e}, Luc and Kizer, Jorge R and Tracy, Russell P and Dehghan, Abbas and Rexrode, Kathryn and Lopez, Oscar L and Rimm, Eric B and Siscovick, David S and O{\textquoteright}Donnell, Christopher J and Newman, Anne and Mukamal, Kenneth J and Jensen, Majken K} } @article {6684, title = {Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.}, journal = {Biol Psychiatry}, volume = {77}, year = {2015}, month = {2015 Apr 15}, pages = {749-63}, abstract = {

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged >=45 years. Replication of suggestive associations (p < 5 {\texttimes} 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 {\texttimes} 10(-10)) and replication cohorts (p = 5.65 {\texttimes} 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 {\texttimes} 10(-8), and rs6813517 [SPOCK3], p = 2.58 {\texttimes} 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

}, keywords = {Aged, Aged, 80 and over, Aging, Apolipoproteins E, Claudin-5, Cohort Studies, Female, Genome-Wide Association Study, Genotype, Humans, Male, Memory Disorders, Middle Aged, Polymorphism, Single Nucleotide, Proteins, Proteoglycans, Regression Analysis, Sulfotransferases, Verbal Learning}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2014.08.027}, author = {Debette, Stephanie and Ibrahim Verbaas, Carla A and Bressler, Jan and Schuur, Maaike and Smith, Albert and Bis, Joshua C and Davies, Gail and Wolf, Christiane and Gudnason, Vilmundur and Chibnik, Lori B and Yang, Qiong and DeStefano, Anita L and de Quervain, Dominique J F and Srikanth, Velandai and Lahti, Jari and Grabe, Hans J and Smith, Jennifer A and Priebe, Lutz and Yu, Lei and Karbalai, Nazanin and Hayward, Caroline and Wilson, James F and Campbell, Harry and Petrovic, Katja and Fornage, Myriam and Chauhan, Ganesh and Yeo, Robin and Boxall, Ruth and Becker, James and Stegle, Oliver and Mather, Karen A and Chouraki, Vincent and Sun, Qi and Rose, Lynda M and Resnick, Susan and Oldmeadow, Christopher and Kirin, Mirna and Wright, Alan F and Jonsdottir, Maria K and Au, Rhoda and Becker, Albert and Amin, Najaf and Nalls, Mike A and Turner, Stephen T and Kardia, Sharon L R and Oostra, Ben and Windham, Gwen and Coker, Laura H and Zhao, Wei and Knopman, David S and Heiss, Gerardo and Griswold, Michael E and Gottesman, Rebecca F and Vitart, Veronique and Hastie, Nicholas D and Zgaga, Lina and Rudan, Igor and Polasek, Ozren and Holliday, Elizabeth G and Schofield, Peter and Choi, Seung Hoan and Tanaka, Toshiko and An, Yang and Perry, Rodney T and Kennedy, Richard E and Sale, Mich{\`e}le M and Wang, Jing and Wadley, Virginia G and Liewald, David C and Ridker, Paul M and Gow, Alan J and Pattie, Alison and Starr, John M and Porteous, David and Liu, Xuan and Thomson, Russell and Armstrong, Nicola J and Eiriksdottir, Gudny and Assareh, Arezoo A and Kochan, Nicole A and Widen, Elisabeth and Palotie, Aarno and Hsieh, Yi-Chen and Eriksson, Johan G and Vogler, Christian and van Swieten, John C and Shulman, Joshua M and Beiser, Alexa and Rotter, Jerome and Schmidt, Carsten O and Hoffmann, Wolfgang and N{\"o}then, Markus M and Ferrucci, Luigi and Attia, John and Uitterlinden, Andr{\'e} G and Amouyel, Philippe and Dartigues, Jean-Fran{\c c}ois and Amieva, H{\'e}l{\`e}ne and R{\"a}ikk{\"o}nen, Katri and Garcia, Melissa and Wolf, Philip A and Hofman, Albert and Longstreth, W T and Psaty, Bruce M and Boerwinkle, Eric and DeJager, Philip L and Sachdev, Perminder S and Schmidt, Reinhold and Breteler, Monique M B and Teumer, Alexander and Lopez, Oscar L and Cichon, Sven and Chasman, Daniel I and Grodstein, Francine and M{\"u}ller-Myhsok, Bertram and Tzourio, Christophe and Papassotiropoulos, Andreas and Bennett, David A and Ikram, M Arfan and Deary, Ian J and van Duijn, Cornelia M and Launer, Lenore and Fitzpatrick, Annette L and Seshadri, Sudha and Mosley, Thomas H} } @article {6540, title = {Physical activity, body mass index, and brain atrophy in Alzheimer{\textquoteright}s disease.}, journal = {Neurobiol Aging}, volume = {36 Suppl 1}, year = {2015}, month = {2015 Jan}, pages = {S194-S202}, abstract = {

The purpose of this study was to use a novel imaging biomarker to assess associations between physical activity (PA), body mass index (BMI), and brain structure in normal aging, mild cognitive impairment, and Alzheimer{\textquoteright}s dementia. We studied 963 participants (mean age: 74.1 {\textpm} 4.4 years) from the multisite Cardiovascular Health Study including healthy controls (n~= 724), Alzheimer{\textquoteright}s dementia patients (n~=~104), and people with mild cognitive impairment (n~= 135). Volumetric brain images were processed using tensor-based morphometry to analyze regional brain volumes. We regressed the local brain tissue volume on reported PA and computed BMI, and performed conjunction analyses using both variables. Covariates included age, sex, and study site. PA was independently associated with greater whole brain and regional brain volumes and reduced ventricular dilation. People with higher BMI had lower whole brain and regional brain volumes. A PA-BMI conjunction analysis showed brain preservation with PA and volume loss with increased BMI in overlapping brain regions. In one of the largest voxel-based cross-sectional studies to date, PA and lower BMI may be beneficial to the brain across the spectrum of aging and neurodegeneration.

}, keywords = {Aged, Aged, 80 and over, Aging, Alzheimer Disease, Atrophy, Biomarkers, Body Mass Index, Brain, Cognitive Dysfunction, Cross-Sectional Studies, Diffusion Magnetic Resonance Imaging, Female, Humans, Magnetic Resonance Imaging, Male, Motor Activity, Neuroimaging}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2014.05.036}, author = {Boyle, Christina P and Raji, Cyrus A and Erickson, Kirk I and Lopez, Oscar L and Becker, James T and Gach, H Michael and Longstreth, W T and Teverovskiy, Leonid and Kuller, Lewis H and Carmichael, Owen T and Thompson, Paul M} } @article {6593, title = {Relationship between Systemic and Cerebral Vascular Disease and Brain Structure Integrity in Normal Elderly Individuals.}, journal = {J Alzheimers Dis}, volume = {44}, year = {2015}, month = {2015}, pages = {319-28}, abstract = {

Cerebral white matter lesions (WMLs) are considered a reflection of cerebral and systemic small vessel disease (SVD), and are associated with reductions in brain volume. Like the brain, the kidney is also sensitive to factors that affect vasculature. Glomerular dysfunction due to renal vascular damage can be measured with different biochemical parameters, such as creatinine or cystatin C, although cystatin C is considered to be more accurate than creatinine in the elderly. The purpose of the study was to determine whether manifestations of SVD in the kidney can predict SVD-based damage to the brain. We examined the relationship between glomerular dysfunction as a measure of SVD on WMLs, gray matter (GM) volume, and cognition in 735 cognitively normal participants from the Cardiovascular Health Study Cognition Study. The multivariate analyses controlled for demographic characteristics, hypertension, heart disease, diabetes, Apolipoprotein 4 allele, C reactive protein, lipids, physical activity, smoking, and body mass index (BMI). Elevated cystatin C levels were associated with lower neuropsychological test scores, the presence of MRI-identified brain infarcts, the severity of WMLs, and GM atrophy five years later. In adjusted models, GM volume was significantly associated with cystatin-C only until BMI and severity of WMLs were added to the model, meaning that the effect of SVD on GM volume is mediated by these two variables. These findings suggest that age-related SVD is a process that leads to altered brain structure, and creates a vulnerability state for cognitive decline.

}, keywords = {Aged, Aged, 80 and over, Analysis of Variance, Brain, Cerebrovascular Disorders, Female, Humans, Image Processing, Computer-Assisted, Logistic Models, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Peripheral Vascular Diseases, Predictive Value of Tests, Retrospective Studies, White Matter}, issn = {1875-8908}, doi = {10.3233/JAD-141077}, author = {Riverol, Mario and Becker, James T and Lopez, Oscar L and Raji, Cyrus A and Thompson, Paul M and Carmichael, Owen T and Gach, H Michael and Longstreth, William T and Fried, Linda and Tracy, Russell P and Kuller, Lewis H} } @article {6773, title = {Voxel Level Survival Analysis of Grey Matter Volume and Incident Mild Cognitive Impairment or Alzheimer{\textquoteright}s Disease.}, journal = {J Alzheimers Dis}, volume = {46}, year = {2015}, month = {2015}, pages = {167-78}, abstract = {

The purpose of this study was to identify, at the voxel level, brain regions associated with the time to develop mild cognitive impairment (MCI) or Alzheimer{\textquoteright}s disease (AD) from normal cognition. We analyzed incident MCI (n = 58) or AD (n = 151) in 292 cognitively normal participants in the Cardiovascular Health Study-Cognition Study (mean age = 79.2 {\textpm} 3.6 years). We used segmented, modulated grey matter maps from 3D (spoiled gradient echo) MRI scans obtained in 1998/99 (with clinical follow-up through 2012) that were smoothed with a 3-D 4 mm Gaussian filter. We fit approximately 1.92 million voxel-level Cox proportional hazard models to examine the grey matter volume effect on time to event, adjusting for age, sex, and diabetes. We used the significance threshold of p <  0.005 with contiguity threshold of at least 68 voxels (false detection probability <2.5{\texttimes}10 -8). Areas within the mesial temporal lobe (MTL), anterior temporal lobe, hippocampus, and posterior cingulate gyrus were associated with time to MCI or AD. The presence of white matter lesions (a marker of small vessel disease in the brain) was associated with the volumes of the MTL and precuneus; MRI-identified infarcts also predicted MTL volume. These findings are important because we identified critical brain regions that predict a person{\textquoteright}s increased likelihood of developing MCI or AD over a decade prior to the onset of clinical symptoms; these critical brain regions were themselves affected by the presence of vascular disease.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Chi-Square Distribution, Disease Progression, Female, Gray Matter, Humans, Incidence, Magnetic Resonance Imaging, Male, Mild Cognitive Impairment, Neuropsychological Tests, Psychiatric Status Rating Scales, Survival Analysis}, issn = {1875-8908}, doi = {10.3233/JAD-150047}, author = {Zeifman, Lubov E and Eddy, William F and Lopez, Oscar L and Kuller, Lewis H and Raji, Cyrus and Thompson, Paul M and Becker, James T} } @article {7000, title = {Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health Study.}, journal = {J Alzheimers Dis}, volume = {52}, year = {2016}, month = {2016}, pages = {719-29}, abstract = {

BACKGROUND: Physical activity (PA) can be neuroprotective and reduce the risk for Alzheimer{\textquoteright}s disease (AD). In assessing physical activity, caloric expenditure is a proxy marker reflecting the sum total of multiple physical activity types conducted by an individual.

OBJECTIVE: To assess caloric expenditure, as a proxy marker of PA, as a predictive measure of gray matter (GM) volumes in the normal and cognitively impaired elderly persons.

METHODS: All subjects in this study were recruited from the Institutional Review Board approved Cardiovascular Health Study (CHS), a multisite population-based longitudinal study in persons aged 65 and older. We analyzed a sub-sample of CHS participants 876 subjects (mean age 78.3, 57.5\% F, 42.5\% M) who had i) energy output assessed as kilocalories (kcal) per week using the standardized Minnesota Leisure-Time Activities questionnaire, ii) cognitive assessments for clinical classification of normal cognition, mild cognitive impairment (MCI), and AD, and iii) volumetric MR imaging of the brain. Voxel-based morphometry modeled the relationship between kcal/week and GM volumes while accounting for standard covariates including head size, age, sex, white matter hyperintensity lesions, MCI or AD status, and site. Multiple comparisons were controlled using a False Discovery Rate of 5 percent.

RESULTS: Higher energy output, from a variety of physical activity types, was associated with larger GM volumes in frontal, temporal, and parietal lobes, as well as hippocampus, thalamus, and basal ganglia. High levels of caloric expenditure moderated neurodegeneration-associated volume loss in the precuneus, posterior cingulate, and cerebellar vermis.

CONCLUSION: Increasing energy output from a variety of physical activities is related to larger gray matter volumes in the elderly, regardless of cognitive status.

}, issn = {1875-8908}, doi = {10.3233/JAD-160057}, author = {Raji, Cyrus A and Merrill, David A and Eyre, Harris and Mallam, Sravya and Torosyan, Nare and Erickson, Kirk I and Lopez, Oscar L and Becker, James T and Carmichael, Owen T and Gach, H Michael and Thompson, Paul M and Longstreth, W T and Kuller, Lewis H} } @article {7260, title = {Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer{\textquoteright}s Disease.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 Oct}, pages = {e1006327}, abstract = {

We performed an exome-wide association analysis in 1393 late-onset Alzheimer{\textquoteright}s disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5\% versus <0.05\% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95\% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006327}, author = {Jakobsdottir, Johanna and van der Lee, Sven J and Bis, Joshua C and Chouraki, Vincent and Li-Kroeger, David and Yamamoto, Shinya and Grove, Megan L and Naj, Adam and Vronskaya, Maria and Salazar, Jose L and DeStefano, Anita L and Brody, Jennifer A and Smith, Albert V and Amin, Najaf and Sims, Rebecca and Ibrahim-Verbaas, Carla A and Choi, Seung-Hoan and Satizabal, Claudia L and Lopez, Oscar L and Beiser, Alexa and Ikram, M Arfan and Garcia, Melissa E and Hayward, Caroline and Varga, Tibor V and Ripatti, Samuli and Franks, Paul W and Hallmans, G{\"o}ran and Rolandsson, Olov and Jansson, Jan-H{\r a}kon and Porteous, David J and Salomaa, Veikko and Eiriksdottir, Gudny and Rice, Kenneth M and Bellen, Hugo J and Levy, Daniel and Uitterlinden, Andr{\'e} G and Emilsson, Valur and Rotter, Jerome I and Aspelund, Thor and O{\textquoteright}Donnell, Christopher J and Fitzpatrick, Annette L and Launer, Lenore J and Hofman, Albert and Wang, Li-San and Williams, Julie and Schellenberg, Gerard D and Boerwinkle, Eric and Psaty, Bruce M and Seshadri, Sudha and Shulman, Joshua M and Gudnason, Vilmundur and van Duijn, Cornelia M} } @article {6877, title = {Risk of dementia and death in the long-term follow-up of the Pittsburgh Cardiovascular Health Study-Cognition Study.}, journal = {Alzheimers Dement}, volume = {12}, year = {2016}, month = {2016 Feb}, pages = {170-83}, abstract = {

INTRODUCTION: Increasing life expectancy has resulted in a larger population of older individuals at risk of dementia.

METHODS: The Cardiovascular Health Study-Cognition Study followed 532 participants from 1998-99 (mean age 79) to 2013 (mean age 93) for death and dementia.

RESULTS: Risk of death was determined by extent of coronary artery calcium, high-sensitivity cardiac troponin, brain natriuretic peptide, and white matter grade. Significant predictors of dementia were age, apolipoprotein-E4, vocabulary raw score, hippocampal volume, ventricular size, cognitive performance, and number of blocks walked. By 2013, 160 of 532 were alive, including 19 cognitively normal. Those with normal cognition had higher grade education, better cognition test scores, greater hippocampal volume, faster gait speed, and number of blocks walked as compared with survivors who were demented.

DISCUSSION: Few survived free of dementia and disability. Prevention and delay of cognitive decline for this older population is an imperative.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Apolipoprotein E4, Brain, Cardiovascular Diseases, Cognition, Dementia, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Pennsylvania, Risk Factors, Walking}, issn = {1552-5279}, doi = {10.1016/j.jalz.2015.08.165}, author = {Kuller, Lewis H and Lopez, Oscar L and Becker, James T and Chang, Yuefang and Newman, Anne B} } @article {6998, title = {Subclinical Cardiovascular Disease and Death, Dementia, and Coronary Heart Disease in Patients 80+ Years.}, journal = {J Am Coll Cardiol}, volume = {67}, year = {2016}, month = {2016 Mar 8}, pages = {1013-22}, abstract = {

BACKGROUND: The successful prevention and treatment of coronary heart disease (CHD) and stroke has resulted in a substantial increase in longevity, with subsequent growth in the population of older people at risk for dementia.

OBJECTIVES: The authors evaluated the relationship of coronary and other peripheral atherosclerosis to risk of death, dementia, and CHD in the very elderly. Because the extent of vascular disease differs substantially between men and women, sex- and race-specific analyses were included, with a specific focus on women with low coronary artery calcium (CAC) Agatston scores.

METHODS: We evaluated the relationship between measures of subclinical cardiovascular disease (CAC, carotid intimal medial thickness, stenosis, and ankle brachial index) and risk of dementia, CHD, and total mortality in 532 participants of the Cardiovascular Health Study-Cognition Study from 1998/1999 (mean age, 80 years) to 2012/2013 (mean age, 93 years).

RESULTS: Thirty-six percent of participants had CAC scores >400. Women and African-Americans had lower CAC scores. Few men had low CAC scores. CAC score and number of coronary calcifications were directly related to age-adjusted total mortality and CHD. The age-specific incidence of dementia was higher than for CHD. Only about 25\% of deaths were caused by CHD and 16\% by dementia. Approximately 64\% of those who died had a prior diagnosis of dementia. White women with low CAC scores had a significantly decreased incidence of dementia.

CONCLUSIONS: In subjects 80+ years of age, there is a greater incidence of dementia than of CHD. CAC, as a marker of atherosclerosis, is a determinant of mortality, and risk of CHD and myocardial infarction. White women with low CAC scores had a significantly decreased risk of dementia. A very important unanswered question, especially in the very elderly, is whether prevention of atherosclerosis and its complications is associated with less Alzheimer disease pathology and dementia. (Cardiovascular Health Study [CHS]; NCT00005133).

}, keywords = {Age Factors, Aged, 80 and over, Cause of Death, Coronary Artery Disease, Dementia, Female, Humans, Incidence, Male, Pennsylvania, Retrospective Studies, Risk Factors, Survival Rate}, issn = {1558-3597}, doi = {10.1016/j.jacc.2015.12.034}, author = {Kuller, Lewis H and Lopez, Oscar L and Mackey, Rachel H and Rosano, Caterina and Edmundowicz, Daniel and Becker, James T and Newman, Anne B} } @article {6999, title = {Vitamin D and Memory Decline: Two Population-Based Prospective Studies.}, journal = {J Alzheimers Dis}, volume = {50}, year = {2016}, month = {2016}, pages = {1099-108}, abstract = {

BACKGROUND: Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown.

OBJECTIVE: To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline.

METHODS: We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey{\textquoteright}s Auditory Verbal Learning Test (in the LASA) were used to assess visual and verbal memory, respectively.

RESULTS: In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95\% CI: -0.06 to 0.01) and -0.10 SD (95\% CI: -0.19 to -0.02) per year respectively in visual memory compared to those sufficient (p = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95\% CI: -0.01 to 0.02) and -0.01 SD (95\% CI: -0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p = 0.34).

CONCLUSIONS: Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes.

}, issn = {1875-8908}, doi = {10.3233/JAD-150811}, author = {Ku{\'z}ma, El{\.z}bieta and Soni, Maya and Littlejohns, Thomas J and Ranson, Janice M and van Schoor, Natasja M and Deeg, Dorly J H and Comijs, Hannie and Chaves, Paulo H M and Kestenbaum, Bryan R and Kuller, Lewis H and Lopez, Oscar L and Becker, James T and Langa, Kenneth M and Henley, William E and Lang, Iain A and Ukoumunne, Obioha C and Llewellyn, David J} } @article {7126, title = {Vitamin D and Risk of Neuroimaging Abnormalities.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0154896}, abstract = {

Vitamin D deficiency has been linked with an increased risk of incident all-cause dementia and Alzheimer{\textquoteright}s disease. The aim of the current study was to explore the potential mechanisms underlying these associations by determining whether low vitamin D concentrations are associated with the development of incident cerebrovascular and neurodegenerative neuroimaging abnormalities. The population consisted of 1,658 participants aged >=65 years from the US-based Cardiovascular Health Study who were free from prevalent cardiovascular disease, stroke and dementia at baseline in 1992-93. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected at baseline. The first MRI scan was conducted between 1991-1994 and the second MRI scan was conducted between 1997-1999. Change in white matter grade, ventricular grade and presence of infarcts between MRI scan one and two were used to define neuroimaging abnormalities. During a mean follow-up of 5.0 years, serum 25(OH)D status was not significantly associated with the development of any neuroimaging abnormalities. Using logistic regression models, the multivariate adjusted odds ratios (95\% confidence interval) for worsening white matter grade in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (>=25-50 nmol/L) were 0.76 (0.35-1.66) and 1.09 (0.76-1.55) compared to participants with sufficient concentrations (>=50 nmol/L). The multivariate adjusted odds ratios for ventricular grade in participants who were severely 25(OH)D deficient and deficient were 0.49 (0.20-1.19) and 1.12 (0.79-1.59) compared to those sufficient. The multivariate adjusted odds ratios for incident infarcts in participants who were severely 25(OH)D deficient and deficient were 1.95 (0.84-4.54) and 0.73 (0.47-1.95) compared to those sufficient. Overall, serum vitamin D concentrations could not be shown to be associated with the development of cerebrovascular or neurodegenerative neuroimaging abnormalities in Cardiovascular Health Study participants.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0154896}, author = {Littlejohns, Thomas J and Kos, Katarina and Henley, William E and Lang, Iain A and Annweiler, Cedric and Beauchet, Olivier and Chaves, Paulo H M and Kestenbaum, Bryan R and Kuller, Lewis H and Langa, Kenneth M and Lopez, Oscar L and Llewellyn, David J} } @article {7348, title = {Coronary Artery Bypass Graft Surgery and Dementia Risk in the Cardiovascular Health Study.}, journal = {Alzheimer Dis Assoc Disord}, year = {2017}, month = {2017 Mar 03}, abstract = {

INTRODUCTION: The association between history of coronary artery bypass graft surgery (CABG) and dementia risk remains unclear.

METHODS: We conducted a prospective cohort analysis using data on 3155 elderly adults free from prevalent dementia from the US population-based Cardiovascular Health Study (CHS) with adjudicated incident all-cause dementia, Alzheimer disease (AD), vascular dementia (VaD), and mixed dementia.

RESULTS: In the CHS, the hazard ratio (HR) for all-cause dementia was 1.93 [95\% confidence interval (CI), 1.36-2.74] for those with CABG history compared with those with no CABG history after adjustment for potential confounders. Similar HRs were observed for AD (HR=1.71; 95\% CI, 0.98-2.98), VaD (HR=1.42; 95\% CI, 0.56-3.65), and mixed dementia (HR=2.73; 95\% CI, 1.55-4.80). The same pattern of results was observed when these CHS findings were pooled with a prior prospective study, the pooled HRs were 1.96 (95\% CI, 1.42-2.69) for all-cause dementia, 1.71 (95\% CI, 1.04-2.79) for AD and 2.20 (95\% CI, 0.78-6.19) for VaD.

DISCUSSION: Our results suggest CABG history is associated with long-term dementia risk. Further investigation is warranted to examine the causal mechanisms which may explain this relationship or whether the association reflects differences in coronary artery disease severity.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

}, issn = {1546-4156}, doi = {10.1097/WAD.0000000000000191}, author = {Ku{\'z}ma, El{\.z}bieta and Airdrie, Jac and Littlejohns, Thomas J and Lourida, Ilianna and Thompson-Coon, Jo and Lang, Iain A and Scrobotovici, Monica and Thacker, Evan L and Fitzpatrick, Annette and Kuller, Lewis H and Lopez, Oscar L and Longstreth, William T and Ukoumunne, Obioha C and Llewellyn, David J} } @article {7453, title = {Physical activity predicts reduced plasma β amyloid in the Cardiovascular Health Study.}, journal = {Ann Clin Transl Neurol}, volume = {4}, year = {2017}, month = {2017 May}, pages = {284-291}, abstract = {

OBJECTIVE: Higher levels of physical activity (PA) reduce the risk of cognitive impairment, but the underlying mechanisms are unclear. Using longitudinal data from the Cardiovascular Health Study, we examined whether PA predicted plasma Aβ levels and risk for cognitive decline 9-13 years later.

METHODS: Linear and logistic regressions (controlling for APOE status, age, gender, body mass index, cardiovascular disease, brain white matter lesions, and cystatin C levels) tested associations between PA, Aβ, and cognitive impairment in a sample of 149 cognitively normal older adults (mean age 83 years).

RESULTS: More PA at baseline predicted lower levels of Aβ 9-13 years later. Higher Aβ levels at year 9 predicted greater risk for cognitive impairment at year 13. Levels of Aβ at year 9 mediated the relationship between PA and cognitive impairment.

INTERPRETATION: Greater PA may reduce plasma levels of a neurotoxic peptide at an age when the risk for cognitive impairment is especially high.

}, issn = {2328-9503}, doi = {10.1002/acn3.397}, author = {Stillman, Chelsea M and Lopez, Oscar L and Becker, James T and Kuller, Lewis H and Mehta, Pankaj D and Tracy, Russell P and Erickson, Kirk I} } @article {7587, title = {Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer{\textquoteright}s disease.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Sep}, pages = {1373-1384}, abstract = {

We identified rare coding variants associated with Alzheimer{\textquoteright}s disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 {\texttimes} 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 {\texttimes} 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer{\textquoteright}s disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 {\texttimes} 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 {\texttimes} 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 {\texttimes} 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer{\textquoteright}s disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer{\textquoteright}s disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer{\textquoteright}s disease.

}, keywords = {Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Exome, Gene Expression Profiling, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Linkage Disequilibrium, Membrane Glycoproteins, Microglia, Odds Ratio, Phospholipase C gamma, Polymorphism, Single Nucleotide, Protein Interaction Maps, Receptors, Immunologic, Sequence Homology, Amino Acid}, issn = {1546-1718}, doi = {10.1038/ng.3916}, author = {Sims, Rebecca and van der Lee, Sven J and Naj, Adam C and Bellenguez, C{\'e}line and Badarinarayan, Nandini and Jakobsdottir, Johanna and Kunkle, Brian W and Boland, Anne and Raybould, Rachel and Bis, Joshua C and Martin, Eden R and Grenier-Boley, Benjamin and Heilmann-Heimbach, Stefanie and Chouraki, Vincent and Kuzma, Amanda B and Sleegers, Kristel and Vronskaya, Maria and Ruiz, Agustin and Graham, Robert R and Olaso, Robert and Hoffmann, Per and Grove, Megan L and Vardarajan, Badri N and Hiltunen, Mikko and N{\"o}then, Markus M and White, Charles C and Hamilton-Nelson, Kara L and Epelbaum, Jacques and Maier, Wolfgang and Choi, Seung-Hoan and Beecham, Gary W and Dulary, C{\'e}cile and Herms, Stefan and Smith, Albert V and Funk, Cory C and Derbois, C{\'e}line and Forstner, Andreas J and Ahmad, Shahzad and Li, Hongdong and Bacq, Delphine and Harold, Denise and Satizabal, Claudia L and Valladares, Otto and Squassina, Alessio and Thomas, Rhodri and Brody, Jennifer A and Qu, Liming and S{\'a}nchez-Juan, Pascual and Morgan, Taniesha and Wolters, Frank J and Zhao, Yi and Garcia, Florentino Sanchez and Denning, Nicola and Fornage, Myriam and Malamon, John and Naranjo, Maria Candida Deniz and Majounie, Elisa and Mosley, Thomas H and Dombroski, Beth and Wallon, David and Lupton, Michelle K and Dupuis, Jos{\'e}e and Whitehead, Patrice and Fratiglioni, Laura and Medway, Christopher and Jian, Xueqiu and Mukherjee, Shubhabrata and Keller, Lina and Brown, Kristelle and Lin, Honghuang and Cantwell, Laura B and Panza, Francesco and McGuinness, Bernadette and Moreno-Grau, Sonia and Burgess, Jeremy D and Solfrizzi, Vincenzo and Proitsi, Petra and Adams, Hieab H and Allen, Mariet and Seripa, Davide and Pastor, Pau and Cupples, L Adrienne and Price, Nathan D and Hannequin, Didier and Frank-Garc{\'\i}a, Ana and Levy, Daniel and Chakrabarty, Paramita and Caffarra, Paolo and Giegling, Ina and Beiser, Alexa S and Giedraitis, Vilmantas and Hampel, Harald and Garcia, Melissa E and Wang, Xue and Lannfelt, Lars and Mecocci, Patrizia and Eiriksdottir, Gudny and Crane, Paul K and Pasquier, Florence and Boccardi, Virginia and Hen{\'a}ndez, Isabel and Barber, Robert C and Scherer, Martin and Tarraga, Lluis and Adams, Perrie M and Leber, Markus and Chen, Yuning and Albert, Marilyn S and Riedel-Heller, Steffi and Emilsson, Valur and Beekly, Duane and Braae, Anne and Schmidt, Reinhold and Blacker, Deborah and Masullo, Carlo and Schmidt, Helena and Doody, Rachelle S and Spalletta, Gianfranco and Jr, W T Longstreth and Fairchild, Thomas J and Boss{\`u}, Paola and Lopez, Oscar L and Frosch, Matthew P and Sacchinelli, Eleonora and Ghetti, Bernardino and Yang, Qiong and Huebinger, Ryan M and Jessen, Frank and Li, Shuo and Kamboh, M Ilyas and Morris, John and Sotolongo-Grau, Oscar and Katz, Mindy J and Corcoran, Chris and Dunstan, Melanie and Braddel, Amy and Thomas, Charlene and Meggy, Alun and Marshall, Rachel and Gerrish, Amy and Chapman, Jade and Aguilar, Miquel and Taylor, Sarah and Hill, Matt and Fair{\'e}n, M{\`o}nica D{\'\i}ez and Hodges, Angela and Vellas, Bruno and Soininen, Hilkka and Kloszewska, Iwona and Daniilidou, Makrina and Uphill, James and Patel, Yogen and Hughes, Joseph T and Lord, Jenny and Turton, James and Hartmann, Annette M and Cecchetti, Roberta and Fenoglio, Chiara and Serpente, Maria and Arcaro, Marina and Caltagirone, Carlo and Orfei, Maria Donata and Ciaramella, Antonio and Pichler, Sabrina and Mayhaus, Manuel and Gu, Wei and Lleo, Alberto and Fortea, Juan and Blesa, Rafael and Barber, Imelda S and Brookes, Keeley and Cupidi, Chiara and Maletta, Raffaele Giovanni and Carrell, David and Sorbi, Sandro and Moebus, Susanne and Urbano, Maria and Pilotto, Alberto and Kornhuber, Johannes and Bosco, Paolo and Todd, Stephen and Craig, David and Johnston, Janet and Gill, Michael and Lawlor, Brian and Lynch, Aoibhinn and Fox, Nick C and Hardy, John and Albin, Roger L and Apostolova, Liana G and Arnold, Steven E and Asthana, Sanjay and Atwood, Craig S and Baldwin, Clinton T and Barnes, Lisa L and Barral, Sandra and Beach, Thomas G and Becker, James T and Bigio, Eileen H and Bird, Thomas D and Boeve, Bradley F and Bowen, James D and Boxer, Adam and Burke, James R and Burns, Jeffrey M and Buxbaum, Joseph D and Cairns, Nigel J and Cao, Chuanhai and Carlson, Chris S and Carlsson, Cynthia M and Carney, Regina M and Carrasquillo, Minerva M and Carroll, Steven L and Diaz, Carolina Ceballos and Chui, Helena C and Clark, David G and Cribbs, David H and Crocco, Elizabeth A and DeCarli, Charles and Dick, Malcolm and Duara, Ranjan and Evans, Denis A and Faber, Kelley M and Fallon, Kenneth B and Fardo, David W and Farlow, Martin R and Ferris, Steven and Foroud, Tatiana M and Galasko, Douglas R and Gearing, Marla and Geschwind, Daniel H and Gilbert, John R and Graff-Radford, Neill R and Green, Robert C and Growdon, John H and Hamilton, Ronald L and Harrell, Lindy E and Honig, Lawrence S and Huentelman, Matthew J and Hulette, Christine M and Hyman, Bradley T and Jarvik, Gail P and Abner, Erin and Jin, Lee-Way and Jun, Gyungah and Karydas, Anna and Kaye, Jeffrey A and Kim, Ronald and Kowall, Neil W and Kramer, Joel H and LaFerla, Frank M and Lah, James J and Leverenz, James B and Levey, Allan I and Li, Ge and Lieberman, Andrew P and Lunetta, Kathryn L and Lyketsos, Constantine G and Marson, Daniel C and Martiniuk, Frank and Mash, Deborah C and Masliah, Eliezer and McCormick, Wayne C and McCurry, Susan M and McDavid, Andrew N and McKee, Ann C and Mesulam, Marsel and Miller, Bruce L and Miller, Carol A and Miller, Joshua W and Morris, John C and Murrell, Jill R and Myers, Amanda J and O{\textquoteright}Bryant, Sid and Olichney, John M and Pankratz, Vernon S and Parisi, Joseph E and Paulson, Henry L and Perry, William and Peskind, Elaine and Pierce, Aimee and Poon, Wayne W and Potter, Huntington and Quinn, Joseph F and Raj, Ashok and Raskind, Murray and Reisberg, Barry and Reitz, Christiane and Ringman, John M and Roberson, Erik D and Rogaeva, Ekaterina and Rosen, Howard J and Rosenberg, Roger N and Sager, Mark A and Saykin, Andrew J and Schneider, Julie A and Schneider, Lon S and Seeley, William W and Smith, Amanda G and Sonnen, Joshua A and Spina, Salvatore and Stern, Robert A and Swerdlow, Russell H and Tanzi, Rudolph E and Thornton-Wells, Tricia A and Trojanowski, John Q and Troncoso, Juan C and Van Deerlin, Vivianna M and Van Eldik, Linda J and Vinters, Harry V and Vonsattel, Jean Paul and Weintraub, Sandra and Welsh-Bohmer, Kathleen A and Wilhelmsen, Kirk C and Williamson, Jennifer and Wingo, Thomas S and Woltjer, Randall L and Wright, Clinton B and Yu, Chang-En and Yu, Lei and Garzia, Fabienne and Golamaully, Feroze and Septier, Gislain and Engelborghs, Sebastien and Vandenberghe, Rik and De Deyn, Peter P and Fernadez, Carmen Mu{\~n}oz and Benito, Yoland Aladro and Thonberg, H{\r a}kan and Forsell, Charlotte and Lilius, Lena and Kinhult-St{\r a}hlbom, Anne and Kilander, Lena and Brundin, RoseMarie and Concari, Letizia and Helisalmi, Seppo and Koivisto, Anne Maria and Haapasalo, Annakaisa and Dermecourt, Vincent and Fi{\'e}vet, Nathalie and Hanon, Olivier and Dufouil, Carole and Brice, Alexis and Ritchie, Karen and Dubois, Bruno and Himali, Jayanadra J and Keene, C Dirk and Tschanz, JoAnn and Fitzpatrick, Annette L and Kukull, Walter A and Norton, Maria and Aspelund, Thor and Larson, Eric B and Munger, Ron and Rotter, Jerome I and Lipton, Richard B and Bullido, Mar{\'\i}a J and Hofman, Albert and Montine, Thomas J and Coto, Eliecer and Boerwinkle, Eric and Petersen, Ronald C and Alvarez, Victoria and Rivadeneira, Fernando and Reiman, Eric M and Gallo, Maura and O{\textquoteright}Donnell, Christopher J and Reisch, Joan S and Bruni, Amalia Cecilia and Royall, Donald R and Dichgans, Martin and Sano, Mary and Galimberti, Daniela and St George-Hyslop, Peter and Scarpini, Elio and Tsuang, Debby W and Mancuso, Michelangelo and Bonuccelli, Ubaldo and Winslow, Ashley R and Daniele, Antonio and Wu, Chuang-Kuo and Peters, Oliver and Nacmias, Benedetta and Riemenschneider, Matthias and Heun, Reinhard and Brayne, Carol and Rubinsztein, David C and Bras, Jose and Guerreiro, Rita and Al-Chalabi, Ammar and Shaw, Christopher E and Collinge, John and Mann, David and Tsolaki, Magda and Clarimon, Jordi and Sussams, Rebecca and Lovestone, Simon and O{\textquoteright}Donovan, Michael C and Owen, Michael J and Behrens, Timothy W and Mead, Simon and Goate, Alison M and Uitterlinden, Andr{\'e} G and Holmes, Clive and Cruchaga, Carlos and Ingelsson, Martin and Bennett, David A and Powell, John and Golde, Todd E and Graff, Caroline and De Jager, Philip L and Morgan, Kevin and Ertekin-Taner, Nilufer and Combarros, Onofre and Psaty, Bruce M and Passmore, Peter and Younkin, Steven G and Berr, Claudine and Gudnason, Vilmundur and Rujescu, Dan and Dickson, Dennis W and Dartigues, Jean-Fran{\c c}ois and DeStefano, Anita L and Ortega-Cubero, Sara and Hakonarson, Hakon and Campion, Dominique and Boada, Merce and Kauwe, John Keoni and Farrer, Lindsay A and Van Broeckhoven, Christine and Ikram, M Arfan and Jones, Lesley and Haines, Jonathan L and Tzourio, Christophe and Launer, Lenore J and Escott-Price, Valentina and Mayeux, Richard and Deleuze, Jean-Francois and Amin, Najaf and Holmans, Peter A and Pericak-Vance, Margaret A and Amouyel, Philippe and van Duijn, Cornelia M and Ramirez, Alfredo and Wang, Li-San and Lambert, Jean-Charles and Seshadri, Sudha and Williams, Julie and Schellenberg, Gerard D} } @article {7570, title = {Subclinical Atherosclerosis, Cardiac and Kidney Function, Heart Failure, and Dementia in the Very Elderly.}, journal = {J Am Heart Assoc}, volume = {6}, year = {2017}, month = {2017 Jul 22}, abstract = {

BACKGROUND: Heart failure (HF) and dementia are major causes of disability and death among older individuals. Risk factors and biomarkers of HF may be determinants of dementia in the elderly. We evaluated the relationship between biomarkers of cardiovascular disease and HF and risk of dementia and death. Three hypotheses were tested: (1) higher levels of high-sensitivity cardiac troponin T, N-terminal of prohormone brain natriuretic peptide, and cystatin C predict risk of death, cardiovascular disease, HF, and dementia; (2) higher levels of cardiovascular disease biomarkers are associated with increased risk of HF and then secondary increased risk of dementia; and (3) risk of dementia is lower among participants with a combination of lower coronary artery calcium, atherosclerosis, and lower high-sensitivity cardiac troponin T (myocardial injury).

METHODS AND RESULTS: The Cardiovascular Health Study Cognition Study was a continuation of the Cardiovascular Health Study limited to the Pittsburgh, PA, center from 1998-1999 to 2014. In 1992-1994, 924 participants underwent magnetic resonance imaging of the brain. There were 199 deaths and 116 developed dementia before 1998-1999. Of the 609 participants eligible for the Pittsburgh Cardiovascular Health Study Cognition Study, 87.5\% (n=532) were included in the study. There were 120 incident HF cases and 72\% had dementia. In 80 of 87, dementia preceded HF. A combination of low coronary artery calcium score and low high-sensitivity cardiac troponin T was significantly associated with reduced risk of dementia and HF.

CONCLUSIONS: Most participants with HF had dementia but with onset before HF. Lower high-sensitivity cardiac troponin T and coronary artery calcium was associated with low risk of dementia based on a small number of events.

CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005133.

}, issn = {2047-9980}, doi = {10.1161/JAHA.116.005353}, author = {Kuller, Lewis H and Lopez, Oscar L and Gottdiener, John S and Kitzman, Dalane W and Becker, James T and Chang, Yuefang and Newman, Anne B} } @article {7554, title = {Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium.}, journal = {Eur J Epidemiol}, volume = {32}, year = {2017}, month = {2017 Oct}, pages = {931-938}, abstract = {

Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.

}, issn = {1573-7284}, doi = {10.1007/s10654-017-0320-5}, author = {Chibnik, Lori B and Wolters, Frank J and B{\"a}ckman, Kristoffer and Beiser, Alexa and Berr, Claudine and Bis, Joshua C and Boerwinkle, Eric and Bos, Daniel and Brayne, Carol and Dartigues, Jean-Fran{\c c}ois and Darweesh, Sirwan K L and Debette, Stephanie and Davis-Plourde, Kendra L and Dufouil, Carole and Fornage, Myriam and Grasset, Leslie and Gudnason, Vilmundur and Hadjichrysanthou, Christoforos and Helmer, Catherine and Ikram, M Arfan and Ikram, M Kamran and Kern, Silke and Kuller, Lewis H and Launer, Lenore and Lopez, Oscar L and Matthews, Fiona and Meirelles, Osorio and Mosley, Thomas and Ower, Alison and Psaty, Bruce M and Satizabal, Claudia L and Seshadri, Sudha and Skoog, Ingmar and Stephan, Blossom C M and Tzourio, Christophe and Waziry, Reem and Wong, Mei Mei and Zettergren, Anna and Hofman, Albert} } @article {7912, title = {Aortic Stiffness is Associated with Increased Risk of Incident Dementia in Older Adults.}, journal = {J Alzheimers Dis}, volume = {66}, year = {2018}, month = {2018}, pages = {297-306}, abstract = {

Cardiovascular disease risk factors, including age, hypertension, and diabetes, contribute to aortic stiffness and subclinical cardiovascular and brain disease, increasing dementia risk. Aortic stiffness, measured by carotid-femoral pulse wave velocity (cfPWV), reduces the buffering of pulsatile blood flow, exposing cerebral small arteries to microvascular damage. High cfPWV is related to white matter hyperintensities and brain amyloid deposition, and to cognitive decline, but it is unclear whether cfPWV independently predicts incident dementia. Therefore, we tested the hypothesis that cfPWV predicts incident dementia in older adults, independent of potential confounders. The Cardiovascular Health Study Cognition Study followed 532 non-demented older adults with annual cognitive exams from 1998-99 through 2013. CfPWV was measured on 356 (mean age = 78, 59\% women) between 1996-2000. Over 15 years, 212 (59.6\%) developed dementia (median time from cfPWV measurement = 4 years). In age and sex-adjusted Cox models, cfPWV was significantly associated with increased risk of dementia, but systolic blood pressure, mean arterial pressure and pulse pressure were not. CfPWV (transformed as - 1/cfPWV) remained significantly associated with dementia risk when further adjusted for education, race, APOEɛ4, diabetes, body mass index, mean arterial pressure, and anti-hypertensive medication (hazard ratio = 1.60, 95\% CI = 1.02, 2.51). Results were similar when further adjusted for baseline global cognition, subclinical brain measures, and coronary artery calcification. Finally, higher cfPWV was related to lower physical activity intensity and higher systolic blood pressure, heart rate, and waist circumference measured 5 years prior. An important unanswered question is whether interventions to slow arterial stiffening can reduce the risk of dementia.

}, issn = {1875-8908}, doi = {10.3233/JAD-180449}, author = {Cui, Chendi and Sekikawa, Akira and Kuller, Lewis H and Lopez, Oscar L and Newman, Anne B and Kuipers, Allison L and Mackey, Rachel H} } @article {7849, title = {Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Sep 26}, pages = {3945}, abstract = {

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 {\texttimes} 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-06234-w}, author = {Vojinovic, Dina and Adams, Hieab H and Jian, Xueqiu and Yang, Qiong and Smith, Albert Vernon and Bis, Joshua C and Teumer, Alexander and Scholz, Markus and Armstrong, Nicola J and Hofer, Edith and Saba, Yasaman and Luciano, Michelle and Bernard, Manon and Trompet, Stella and Yang, Jingyun and Gillespie, Nathan A and van der Lee, Sven J and Neumann, Alexander and Ahmad, Shahzad and Andreassen, Ole A and Ames, David and Amin, Najaf and Arfanakis, Konstantinos and Bastin, Mark E and Becker, Diane M and Beiser, Alexa S and Beyer, Frauke and Brodaty, Henry and Bryan, R Nick and B{\"u}low, Robin and Dale, Anders M and De Jager, Philip L and Deary, Ian J and DeCarli, Charles and Fleischman, Debra A and Gottesman, Rebecca F and van der Grond, Jeroen and Gudnason, Vilmundur and Harris, Tamara B and Homuth, Georg and Knopman, David S and Kwok, John B and Lewis, Cora E and Li, Shuo and Loeffler, Markus and Lopez, Oscar L and Maillard, Pauline and El Marroun, Hanan and Mather, Karen A and Mosley, Thomas H and Muetzel, Ryan L and Nauck, Matthias and Nyquist, Paul A and Panizzon, Matthew S and Pausova, Zdenka and Psaty, Bruce M and Rice, Ken and Rotter, Jerome I and Royle, Natalie and Satizabal, Claudia L and Schmidt, Reinhold and Schofield, Peter R and Schreiner, Pamela J and Sidney, Stephen and Stott, David J and Thalamuthu, Anbupalam and Uitterlinden, Andr{\'e} G and Vald{\'e}s Hern{\'a}ndez, Maria C and Vernooij, Meike W and Wen, Wei and White, Tonya and Witte, A Veronica and Wittfeld, Katharina and Wright, Margaret J and Yanek, Lisa R and Tiemeier, Henning and Kremen, William S and Bennett, David A and Jukema, J Wouter and Paus, Tom{\'a}{\v s} and Wardlaw, Joanna M and Schmidt, Helena and Sachdev, Perminder S and Villringer, Arno and Grabe, Hans J{\"o}rgen and Longstreth, W T and van Duijn, Cornelia M and Launer, Lenore J and Seshadri, Sudha and Ikram, M Arfan and Fornage, Myriam} } @article {7683, title = {Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Apr}, pages = {524-537}, abstract = {

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and~using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0058-3}, author = {Malik, Rainer and Chauhan, Ganesh and Traylor, Matthew and Sargurupremraj, Muralidharan and Okada, Yukinori and Mishra, Aniket and Rutten-Jacobs, Loes and Giese, Anne-Katrin and van der Laan, Sander W and Gretarsdottir, Solveig and Anderson, Christopher D and Chong, Michael and Adams, Hieab H H and Ago, Tetsuro and Almgren, Peter and Amouyel, Philippe and Ay, Hakan and Bartz, Traci M and Benavente, Oscar R and Bevan, Steve and Boncoraglio, Giorgio B and Brown, Robert D and Butterworth, Adam S and Carrera, Caty and Carty, Cara L and Chasman, Daniel I and Chen, Wei-Min and Cole, John W and Correa, Adolfo and Cotlarciuc, Ioana and Cruchaga, Carlos and Danesh, John and de Bakker, Paul I W and DeStefano, Anita L and den Hoed, Marcel and Duan, Qing and Engelter, Stefan T and Falcone, Guido J and Gottesman, Rebecca F and Grewal, Raji P and Gudnason, Vilmundur and Gustafsson, Stefan and Haessler, Jeffrey and Harris, Tamara B and Hassan, Ahamad and Havulinna, Aki S and Heckbert, Susan R and Holliday, Elizabeth G and Howard, George and Hsu, Fang-Chi and Hyacinth, Hyacinth I and Ikram, M Arfan and Ingelsson, Erik and Irvin, Marguerite R and Jian, Xueqiu and Jimenez-Conde, Jordi and Johnson, Julie A and Jukema, J Wouter and Kanai, Masahiro and Keene, Keith L and Kissela, Brett M and Kleindorfer, Dawn O and Kooperberg, Charles and Kubo, Michiaki and Lange, Leslie A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lee, Jin-Moo and Lemmens, Robin and Leys, Didier and Lewis, Cathryn M and Lin, Wei-Yu and Lindgren, Arne G and Lorentzen, Erik and Magnusson, Patrik K and Maguire, Jane and Manichaikul, Ani and McArdle, Patrick F and Meschia, James F and Mitchell, Braxton D and Mosley, Thomas H and Nalls, Michael A and Ninomiya, Toshiharu and O{\textquoteright}Donnell, Martin J and Psaty, Bruce M and Pulit, Sara L and Rannikmae, Kristiina and Reiner, Alexander P and Rexrode, Kathryn M and Rice, Kenneth and Rich, Stephen S and Ridker, Paul M and Rost, Natalia S and Rothwell, Peter M and Rotter, Jerome I and Rundek, Tatjana and Sacco, Ralph L and Sakaue, Saori and Sale, Mich{\`e}le M and Salomaa, Veikko and Sapkota, Bishwa R and Schmidt, Reinhold and Schmidt, Carsten O and Schminke, Ulf and Sharma, Pankaj and Slowik, Agnieszka and Sudlow, Cathie L M and Tanislav, Christian and Tatlisumak, Turgut and Taylor, Kent D and Thijs, Vincent N S and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tiedt, Steffen and Trompet, Stella and Tzourio, Christophe and van Duijn, Cornelia M and Walters, Matthew and Wareham, Nicholas J and Wassertheil-Smoller, Sylvia and Wilson, James G and Wiggins, Kerri L and Yang, Qiong and Yusuf, Salim and Bis, Joshua C and Pastinen, Tomi and Ruusalepp, Arno and Schadt, Eric E and Koplev, Simon and Bj{\"o}rkegren, Johan L M and Codoni, Veronica and Civelek, Mete and Smith, Nicholas L and Tr{\'e}gou{\"e}t, David A and Christophersen, Ingrid E and Roselli, Carolina and Lubitz, Steven A and Ellinor, Patrick T and Tai, E Shyong and Kooner, Jaspal S and Kato, Norihiro and He, Jiang and van der Harst, Pim and Elliott, Paul and Chambers, John C and Takeuchi, Fumihiko and Johnson, Andrew D and Sanghera, Dharambir K and Melander, Olle and Jern, Christina and Strbian, Daniel and Fernandez-Cadenas, Israel and Longstreth, W T and Rolfs, Arndt and Hata, Jun and Woo, Daniel and Rosand, Jonathan and Par{\'e}, Guillaume and Hopewell, Jemma C and Saleheen, Danish and Stefansson, Kari and Worrall, Bradford B and Kittner, Steven J and Seshadri, Sudha and Fornage, Myriam and Markus, Hugh S and Howson, Joanna M M and Kamatani, Yoichiro and Debette, Stephanie and Dichgans, Martin and Malik, Rainer and Chauhan, Ganesh and Traylor, Matthew and Sargurupremraj, Muralidharan and Okada, Yukinori and Mishra, Aniket and Rutten-Jacobs, Loes and Giese, Anne-Katrin and van der Laan, Sander W and Gretarsdottir, Solveig and Anderson, Christopher D and Chong, Michael and Adams, Hieab H H and Ago, Tetsuro and Almgren, Peter and Amouyel, Philippe and Ay, Hakan and Bartz, Traci M and Benavente, Oscar R and Bevan, Steve and Boncoraglio, Giorgio B and Brown, Robert D and Butterworth, Adam S and Carrera, Caty and Carty, Cara L and Chasman, Daniel I and Chen, Wei-Min and Cole, John W and Correa, Adolfo and Cotlarciuc, Ioana and Cruchaga, Carlos and Danesh, John and de Bakker, Paul I W and DeStefano, Anita L and Hoed, Marcel den and Duan, Qing and Engelter, Stefan T and Falcone, Guido J and Gottesman, Rebecca F and Grewal, Raji P and Gudnason, Vilmundur and Gustafsson, Stefan and Haessler, Jeffrey and Harris, Tamara B and Hassan, Ahamad and Havulinna, Aki S and Heckbert, Susan R and Holliday, Elizabeth G and Howard, George and Hsu, Fang-Chi and Hyacinth, Hyacinth I and Ikram, M Arfan and Ingelsson, Erik and Irvin, Marguerite R and Jian, Xueqiu and Jimenez-Conde, Jordi and Johnson, Julie A and Jukema, J Wouter and Kanai, Masahiro and Keene, Keith L and Kissela, Brett M and Kleindorfer, Dawn O and Kooperberg, Charles and Kubo, Michiaki and Lange, Leslie A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lee, Jin-Moo and Lemmens, Robin and Leys, Didier and Lewis, Cathryn M and Lin, Wei-Yu and Lindgren, Arne G and Lorentzen, Erik and Magnusson, Patrik K and Maguire, Jane and Manichaikul, Ani and McArdle, Patrick F and Meschia, James F and Mitchell, Braxton D and Mosley, Thomas H and Nalls, Michael A and Ninomiya, Toshiharu and O{\textquoteright}Donnell, Martin J and Psaty, Bruce M and Pulit, Sara L and Rannikmae, Kristiina and Reiner, Alexander P and Rexrode, Kathryn M and Rice, Kenneth and Rich, Stephen S and Ridker, Paul M and Rost, Natalia S and Rothwell, Peter M and Rotter, Jerome I and Rundek, Tatjana and Sacco, Ralph L and Sakaue, Saori and Sale, Mich{\`e}le M and Salomaa, Veikko and Sapkota, Bishwa R and Schmidt, Reinhold and Schmidt, Carsten O and Schminke, Ulf and Sharma, Pankaj and Slowik, Agnieszka and Sudlow, Cathie L M and Tanislav, Christian and Tatlisumak, Turgut and Taylor, Kent D and Thijs, Vincent N S and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tiedt, Steffen and Trompet, Stella and Tzourio, Christophe and van Duijn, Cornelia M and Walters, Matthew and Wareham, Nicholas J and Wassertheil-Smoller, Sylvia and Wilson, James G and Wiggins, Kerri L and Yang, Qiong and Yusuf, Salim and Amin, Najaf and Aparicio, Hugo S and Arnett, Donna K and Attia, John and Beiser, Alexa S and Berr, Claudine and Buring, Julie E and Bustamante, Mariana and Caso, Valeria and Cheng, Yu-Ching and Choi, Seung Hoan and Chowhan, Ayesha and Cullell, Natalia and Dartigues, Jean-Fran{\c c}ois and Delavaran, Hossein and Delgado, Pilar and D{\"o}rr, Marcus and Engstr{\"o}m, Gunnar and Ford, Ian and Gurpreet, Wander S and Hamsten, Anders and Heitsch, Laura and Hozawa, Atsushi and Ibanez, Laura and Ilinca, Andreea and Ingelsson, Martin and Iwasaki, Motoki and Jackson, Rebecca D and Jood, Katarina and Jousilahti, Pekka and Kaffashian, Sara and Kalra, Lalit and Kamouchi, Masahiro and Kitazono, Takanari and Kjartansson, Olafur and Kloss, Manja and Koudstaal, Peter J and Krupinski, Jerzy and Labovitz, Daniel L and Laurie, Cathy C and Levi, Christopher R and Li, Linxin and Lind, Lars and Lindgren, Cecilia M and Lioutas, Vasileios and Liu, Yong Mei and Lopez, Oscar L and Makoto, Hirata and Martinez-Majander, Nicolas and Matsuda, Koichi and Minegishi, Naoko and Montaner, Joan and Morris, Andrew P and Mui{\~n}o, Elena and M{\"u}ller-Nurasyid, Martina and Norrving, Bo and Ogishima, Soichi and Parati, Eugenio A and Peddareddygari, Leema Reddy and Pedersen, Nancy L and Pera, Joanna and Perola, Markus and Pezzini, Alessandro and Pileggi, Silvana and Rabionet, Raquel and Riba-Llena, Iolanda and Ribas{\'e}s, Marta and Romero, Jose R and Roquer, Jaume and Rudd, Anthony G and Sarin, Antti-Pekka and Sarju, Ralhan and Sarnowski, Chloe and Sasaki, Makoto and Satizabal, Claudia L and Satoh, Mamoru and Sattar, Naveed and Sawada, Norie and Sibolt, Gerli and Sigurdsson, {\'A}sgeir and Smith, Albert and Sobue, Kenji and Soriano-T{\'a}rraga, Carolina and Stanne, Tara and Stine, O Colin and Stott, David J and Strauch, Konstantin and Takai, Takako and Tanaka, Hideo and Tanno, Kozo and Teumer, Alexander and Tomppo, Liisa and Torres-Aguila, Nuria P and Touze, Emmanuel and Tsugane, Shoichiro and Uitterlinden, Andr{\'e} G and Valdimarsson, Einar M and van der Lee, Sven J and V{\"o}lzke, Henry and Wakai, Kenji and Weir, David and Williams, Stephen R and Wolfe, Charles D A and Wong, Quenna and Xu, Huichun and Yamaji, Taiki and Sanghera, Dharambir K and Melander, Olle and Jern, Christina and Strbian, Daniel and Fernandez-Cadenas, Israel and Longstreth, W T and Rolfs, Arndt and Hata, Jun and Woo, Daniel and Rosand, Jonathan and Par{\'e}, Guillaume and Hopewell, Jemma C and Saleheen, Danish and Stefansson, Kari and Worrall, Bradford B and Kittner, Steven J and Seshadri, Sudha and Fornage, Myriam and Markus, Hugh S and Howson, Joanna M M and Kamatani, Yoichiro and Debette, Stephanie and Dichgans, Martin} } @article {7788, title = {Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 May 29}, pages = {2098}, abstract = {

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 {\texttimes} 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3\% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-04362-x}, author = {Davies, Gail and Lam, Max and Harris, Sarah E and Trampush, Joey W and Luciano, Michelle and Hill, W David and Hagenaars, Saskia P and Ritchie, Stuart J and Marioni, Riccardo E and Fawns-Ritchie, Chloe and Liewald, David C M and Okely, Judith A and Ahola-Olli, Ari V and Barnes, Catriona L K and Bertram, Lars and Bis, Joshua C and Burdick, Katherine E and Christoforou, Andrea and DeRosse, Pamela and Djurovic, Srdjan and Espeseth, Thomas and Giakoumaki, Stella and Giddaluru, Sudheer and Gustavson, Daniel E and Hayward, Caroline and Hofer, Edith and Ikram, M Arfan and Karlsson, Robert and Knowles, Emma and Lahti, Jari and Leber, Markus and Li, Shuo and Mather, Karen A and Melle, Ingrid and Morris, Derek and Oldmeadow, Christopher and Palviainen, Teemu and Payton, Antony and Pazoki, Raha and Petrovic, Katja and Reynolds, Chandra A and Sargurupremraj, Muralidharan and Scholz, Markus and Smith, Jennifer A and Smith, Albert V and Terzikhan, Natalie and Thalamuthu, Anbupalam and Trompet, Stella and van der Lee, Sven J and Ware, Erin B and Windham, B Gwen and Wright, Margaret J and Yang, Jingyun and Yu, Jin and Ames, David and Amin, Najaf and Amouyel, Philippe and Andreassen, Ole A and Armstrong, Nicola J and Assareh, Amelia A and Attia, John R and Attix, Deborah and Avramopoulos, Dimitrios and Bennett, David A and B{\"o}hmer, Anne C and Boyle, Patricia A and Brodaty, Henry and Campbell, Harry and Cannon, Tyrone D and Cirulli, Elizabeth T and Congdon, Eliza and Conley, Emily Drabant and Corley, Janie and Cox, Simon R and Dale, Anders M and Dehghan, Abbas and Dick, Danielle and Dickinson, Dwight and Eriksson, Johan G and Evangelou, Evangelos and Faul, Jessica D and Ford, Ian and Freimer, Nelson A and Gao, He and Giegling, Ina and Gillespie, Nathan A and Gordon, Scott D and Gottesman, Rebecca F and Griswold, Michael E and Gudnason, Vilmundur and Harris, Tamara B and Hartmann, Annette M and Hatzimanolis, Alex and Heiss, Gerardo and Holliday, Elizabeth G and Joshi, Peter K and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and Karlsson, Ida and Kleineidam, Luca and Knopman, David S and Kochan, Nicole A and Konte, Bettina and Kwok, John B and Le Hellard, Stephanie and Lee, Teresa and Lehtim{\"a}ki, Terho and Li, Shu-Chen and Liu, Tian and Koini, Marisa and London, Edythe and Longstreth, Will T and Lopez, Oscar L and Loukola, Anu and Luck, Tobias and Lundervold, Astri J and Lundquist, Anders and Lyytik{\"a}inen, Leo-Pekka and Martin, Nicholas G and Montgomery, Grant W and Murray, Alison D and Need, Anna C and Noordam, Raymond and Nyberg, Lars and Ollier, William and Papenberg, Goran and Pattie, Alison and Polasek, Ozren and Poldrack, Russell A and Psaty, Bruce M and Reppermund, Simone and Riedel-Heller, Steffi G and Rose, Richard J and Rotter, Jerome I and Roussos, Panos and Rovio, Suvi P and Saba, Yasaman and Sabb, Fred W and Sachdev, Perminder S and Satizabal, Claudia L and Schmid, Matthias and Scott, Rodney J and Scult, Matthew A and Simino, Jeannette and Slagboom, P Eline and Smyrnis, Nikolaos and Soumar{\'e}, A{\"\i}cha and Stefanis, Nikos C and Stott, David J and Straub, Richard E and Sundet, Kjetil and Taylor, Adele M and Taylor, Kent D and Tzoulaki, Ioanna and Tzourio, Christophe and Uitterlinden, Andre and Vitart, Veronique and Voineskos, Aristotle N and Kaprio, Jaakko and Wagner, Michael and Wagner, Holger and Weinhold, Leonie and Wen, K Hoyan and Widen, Elisabeth and Yang, Qiong and Zhao, Wei and Adams, Hieab H H and Arking, Dan E and Bilder, Robert M and Bitsios, Panos and Boerwinkle, Eric and Chiba-Falek, Ornit and Corvin, Aiden and De Jager, Philip L and Debette, Stephanie and Donohoe, Gary and Elliott, Paul and Fitzpatrick, Annette L and Gill, Michael and Glahn, David C and H{\"a}gg, Sara and Hansell, Narelle K and Hariri, Ahmad R and Ikram, M Kamran and Jukema, J Wouter and Vuoksimaa, Eero and Keller, Matthew C and Kremen, William S and Launer, Lenore and Lindenberger, Ulman and Palotie, Aarno and Pedersen, Nancy L and Pendleton, Neil and Porteous, David J and R{\"a}ikk{\"o}nen, Katri and Raitakari, Olli T and Ramirez, Alfredo and Reinvang, Ivar and Rudan, Igor and Schmidt, Reinhold and Schmidt, Helena and Schofield, Peter W and Schofield, Peter R and Starr, John M and Steen, Vidar M and Trollor, Julian N and Turner, Steven T and van Duijn, Cornelia M and Villringer, Arno and Weinberger, Daniel R and Weir, David R and Wilson, James F and Malhotra, Anil and McIntosh, Andrew M and Gale, Catharine R and Seshadri, Sudha and Mosley, Thomas H and Bressler, Jan and Lencz, Todd and Deary, Ian J} } @article {7676, title = {Systemic inflammation as a predictor of brain aging: Contributions of physical activity, metabolic risk, and genetic risk.}, journal = {Neuroimage}, volume = {172}, year = {2018}, month = {2018 May 15}, pages = {118-129}, abstract = {

Inflammatory processes may contribute to risk for Alzheimer{\textquoteright}s disease (AD) and age-related brain degeneration. Metabolic and genetic risk factors, and physical activity may, in turn, influence these inflammatory processes. Some of these risk factors are modifiable, and interact with each other. Understanding how these processes together relate to brain aging will help to inform future interventions to treat or prevent cognitive decline. We used brain magnetic resonance imaging (MRI) to scan 335 older adult humans (mean age 77.3 {\textpm} 3.4 years) who remained non-demented for the duration of the 9-year longitudinal study. We used structural equation modeling (SEM) in a subset of 226 adults to evaluate whether measures of baseline peripheral inflammation (serum C-reactive protein levels; CRP), mediated the baseline contributions of genetic and metabolic risk, and physical activity, to regional cortical thickness in AD-relevant brain regions at study year 9. We found that both baseline metabolic risk and AD risk variant apolipoprotein E ε4 (APOE4), modulated baseline serum CRP. Higher baseline CRP levels, in turn, predicted thinner regional cortex at year 9, and mediated an effect between higher metabolic risk and thinner cortex in those regions. A higher polygenic risk score composed of variants in immune-associated AD risk genes (other than APOE) was associated with thinner regional cortex. However, CRP levels did not mediate this effect, suggesting that other mechanisms may be responsible for the elevated AD risk. We found interactions between genetic and environmental factors and structural brain health. Our findings support the role of metabolic risk and peripheral inflammation in age-related brain decline.

}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2017.12.027}, author = {Corlier, Fabian and Hafzalla, George and Faskowitz, Joshua and Kuller, Lewis H and Becker, James T and Lopez, Oscar L and Thompson, Paul M and Braskie, Meredith N} } @article {8206, title = {Genetic architecture of subcortical brain structures in 38,851 individuals.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Nov}, pages = {1624-1636}, abstract = {

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0511-y}, author = {Satizabal, Claudia L and Adams, Hieab H H and Hibar, Derrek P and White, Charles C and Knol, Maria J and Stein, Jason L and Scholz, Markus and Sargurupremraj, Muralidharan and Jahanshad, Neda and Roshchupkin, Gennady V and Smith, Albert V and Bis, Joshua C and Jian, Xueqiu and Luciano, Michelle and Hofer, Edith and Teumer, Alexander and van der Lee, Sven J and Yang, Jingyun and Yanek, Lisa R and Lee, Tom V and Li, Shuo and Hu, Yanhui and Koh, Jia Yu and Eicher, John D and Desrivi{\`e}res, Sylvane and Arias-Vasquez, Alejandro and Chauhan, Ganesh and Athanasiu, Lavinia and Renter{\'\i}a, Miguel E and Kim, Sungeun and Hoehn, David and Armstrong, Nicola J and Chen, Qiang and Holmes, Avram J and den Braber, Anouk and Kloszewska, Iwona and Andersson, Micael and Espeseth, Thomas and Grimm, Oliver and Abramovic, Lucija and Alhusaini, Saud and Milaneschi, Yuri and Papmeyer, Martina and Axelsson, Tomas and Ehrlich, Stefan and Roiz-Santia{\~n}ez, Roberto and Kraemer, Bernd and H{\r a}berg, Asta K and Jones, Hannah J and Pike, G Bruce and Stein, Dan J and Stevens, Allison and Bralten, Janita and Vernooij, Meike W and Harris, Tamara B and Filippi, Irina and Witte, A Veronica and Guadalupe, Tulio and Wittfeld, Katharina and Mosley, Thomas H and Becker, James T and Doan, Nhat Trung and Hagenaars, Saskia P and Saba, Yasaman and Cuellar-Partida, Gabriel and Amin, Najaf and Hilal, Saima and Nho, Kwangsik and Mirza-Schreiber, Nazanin and Arfanakis, Konstantinos and Becker, Diane M and Ames, David and Goldman, Aaron L and Lee, Phil H and Boomsma, Dorret I and Lovestone, Simon and Giddaluru, Sudheer and Le Hellard, Stephanie and Mattheisen, Manuel and Bohlken, Marc M and Kasperaviciute, Dalia and Schmaal, Lianne and Lawrie, Stephen M and Agartz, Ingrid and Walton, Esther and Tordesillas-Gutierrez, Diana and Davies, Gareth E and Shin, Jean and Ipser, Jonathan C and Vinke, Louis N and Hoogman, Martine and Jia, Tianye and Burkhardt, Ralph and Klein, Marieke and Crivello, Fabrice and Janowitz, Deborah and Carmichael, Owen and Haukvik, Unn K and Aribisala, Benjamin S and Schmidt, Helena and Strike, Lachlan T and Cheng, Ching-Yu and Risacher, Shannon L and P{\"u}tz, Benno and Fleischman, Debra A and Assareh, Amelia A and Mattay, Venkata S and Buckner, Randy L and Mecocci, Patrizia and Dale, Anders M and Cichon, Sven and Boks, Marco P and Matarin, Mar and Penninx, Brenda W J H and Calhoun, Vince D and Chakravarty, M Mallar and Marquand, Andre F and Macare, Christine and Kharabian Masouleh, Shahrzad and Oosterlaan, Jaap and Amouyel, Philippe and Hegenscheid, Katrin and Rotter, Jerome I and Schork, Andrew J and Liewald, David C M and de Zubicaray, Greig I and Wong, Tien Yin and Shen, Li and S{\"a}mann, Philipp G and Brodaty, Henry and Roffman, Joshua L and de Geus, Eco J C and Tsolaki, Magda and Erk, Susanne and van Eijk, Kristel R and Cavalleri, Gianpiero L and van der Wee, Nic J A and McIntosh, Andrew M and Gollub, Randy L and Bulayeva, Kazima B and Bernard, Manon and Richards, Jennifer S and Himali, Jayandra J and Loeffler, Markus and Rommelse, Nanda and Hoffmann, Wolfgang and Westlye, Lars T and Vald{\'e}s Hern{\'a}ndez, Maria C and Hansell, Narelle K and van Erp, Theo G M and Wolf, Christiane and Kwok, John B J and Vellas, Bruno and Heinz, Andreas and Olde Loohuis, Loes M and Delanty, Norman and Ho, Beng-Choon and Ching, Christopher R K and Shumskaya, Elena and Singh, Baljeet and Hofman, Albert and van der Meer, Dennis and Homuth, Georg and Psaty, Bruce M and Bastin, Mark E and Montgomery, Grant W and Foroud, Tatiana M and Reppermund, Simone and Hottenga, Jouke-Jan and Simmons, Andrew and Meyer-Lindenberg, Andreas and Cahn, Wiepke and Whelan, Christopher D and van Donkelaar, Marjolein M J and Yang, Qiong and Hosten, Norbert and Green, Robert C and Thalamuthu, Anbupalam and Mohnke, Sebastian and Hulshoff Pol, Hilleke E and Lin, Honghuang and Jack, Clifford R and Schofield, Peter R and M{\"u}hleisen, Thomas W and Maillard, Pauline and Potkin, Steven G and Wen, Wei and Fletcher, Evan and Toga, Arthur W and Gruber, Oliver and Huentelman, Matthew and Davey Smith, George and Launer, Lenore J and Nyberg, Lars and J{\"o}nsson, Erik G and Crespo-Facorro, Benedicto and Koen, Nastassja and Greve, Douglas N and Uitterlinden, Andr{\'e} G and Weinberger, Daniel R and Steen, Vidar M and Fedko, Iryna O and Groenewold, Nynke A and Niessen, Wiro J and Toro, Roberto and Tzourio, Christophe and Longstreth, William T and Ikram, M Kamran and Smoller, Jordan W and van Tol, Marie-Jose and Sussmann, Jessika E and Paus, Tom{\'a}{\v s} and Lema{\^\i}tre, Herv{\'e} and Schroeter, Matthias L and Mazoyer, Bernard and Andreassen, Ole A and Holsboer, Florian and Depondt, Chantal and Veltman, Dick J and Turner, Jessica A and Pausova, Zdenka and Schumann, Gunter and van Rooij, Daan and Djurovic, Srdjan and Deary, Ian J and McMahon, Katie L and M{\"u}ller-Myhsok, Bertram and Brouwer, Rachel M and Soininen, Hilkka and Pandolfo, Massimo and Wassink, Thomas H and Cheung, Joshua W and Wolfers, Thomas and Martinot, Jean-Luc and Zwiers, Marcel P and Nauck, Matthias and Melle, Ingrid and Martin, Nicholas G and Kanai, Ryota and Westman, Eric and Kahn, Ren{\'e} S and Sisodiya, Sanjay M and White, Tonya and Saremi, Arvin and van Bokhoven, Hans and Brunner, Han G and V{\"o}lzke, Henry and Wright, Margaret J and van {\textquoteright}t Ent, Dennis and N{\"o}then, Markus M and Ophoff, Roel A and Buitelaar, Jan K and Fern{\'a}ndez, Guill{\'e}n and Sachdev, Perminder S and Rietschel, Marcella and van Haren, Neeltje E M and Fisher, Simon E and Beiser, Alexa S and Francks, Clyde and Saykin, Andrew J and Mather, Karen A and Romanczuk-Seiferth, Nina and Hartman, Catharina A and DeStefano, Anita L and Heslenfeld, Dirk J and Weiner, Michael W and Walter, Henrik and Hoekstra, Pieter J and Nyquist, Paul A and Franke, Barbara and Bennett, David A and Grabe, Hans J and Johnson, Andrew D and Chen, Christopher and van Duijn, Cornelia M and Lopez, Oscar L and Fornage, Myriam and Wardlaw, Joanna M and Schmidt, Reinhold and DeCarli, Charles and De Jager, Philip L and Villringer, Arno and Debette, Stephanie and Gudnason, Vilmundur and Medland, Sarah E and Shulman, Joshua M and Thompson, Paul M and Seshadri, Sudha and Ikram, M Arfan} } @article {7977, title = {Genetic meta-analysis of diagnosed Alzheimer{\textquoteright}s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Mar}, pages = {414-430}, abstract = {

Risk for late-onset Alzheimer{\textquoteright}s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer{\textquoteright}s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer{\textquoteright}s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 {\texttimes} 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0358-2}, author = {Kunkle, Brian W and Grenier-Boley, Benjamin and Sims, Rebecca and Bis, Joshua C and Damotte, Vincent and Naj, Adam C and Boland, Anne and Vronskaya, Maria and van der Lee, Sven J and Amlie-Wolf, Alexandre and Bellenguez, C{\'e}line and Frizatti, Aura and Chouraki, Vincent and Martin, Eden R and Sleegers, Kristel and Badarinarayan, Nandini and Jakobsdottir, Johanna and Hamilton-Nelson, Kara L and Moreno-Grau, Sonia and Olaso, Robert and Raybould, Rachel and Chen, Yuning and Kuzma, Amanda B and Hiltunen, Mikko and Morgan, Taniesha and Ahmad, Shahzad and Vardarajan, Badri N and Epelbaum, Jacques and Hoffmann, Per and Boada, Merce and Beecham, Gary W and Garnier, Jean-Guillaume and Harold, Denise and Fitzpatrick, Annette L and Valladares, Otto and Moutet, Marie-Laure and Gerrish, Amy and Smith, Albert V and Qu, Liming and Bacq, Delphine and Denning, Nicola and Jian, Xueqiu and Zhao, Yi and Del Zompo, Maria and Fox, Nick C and Choi, Seung-Hoan and Mateo, Ignacio and Hughes, Joseph T and Adams, Hieab H and Malamon, John and Sanchez-Garcia, Florentino and Patel, Yogen and Brody, Jennifer A and Dombroski, Beth A and Naranjo, Maria Candida Deniz and Daniilidou, Makrina and Eiriksdottir, Gudny and Mukherjee, Shubhabrata and Wallon, David and Uphill, James and Aspelund, Thor and Cantwell, Laura B and Garzia, Fabienne and Galimberti, Daniela and Hofer, Edith and Butkiewicz, Mariusz and Fin, Bertrand and Scarpini, Elio and Sarnowski, Chloe and Bush, Will S and Meslage, St{\'e}phane and Kornhuber, Johannes and White, Charles C and Song, Yuenjoo and Barber, Robert C and Engelborghs, Sebastiaan and Sordon, Sabrina and Voijnovic, Dina and Adams, Perrie M and Vandenberghe, Rik and Mayhaus, Manuel and Cupples, L Adrienne and Albert, Marilyn S and De Deyn, Peter P and Gu, Wei and Himali, Jayanadra J and Beekly, Duane and Squassina, Alessio and Hartmann, Annette M and Orellana, Adelina and Blacker, Deborah and Rodriguez-Rodriguez, Eloy and Lovestone, Simon and Garcia, Melissa E and Doody, Rachelle S and Munoz-Fernadez, Carmen and Sussams, Rebecca and Lin, Honghuang and Fairchild, Thomas J and Benito, Yolanda A and Holmes, Clive and Karamuji{\'c}-{\v C}omi{\'c}, Hata and Frosch, Matthew P and Thonberg, H{\r a}kan and Maier, Wolfgang and Roschupkin, Gena and Ghetti, Bernardino and Giedraitis, Vilmantas and Kawalia, Amit and Li, Shuo and Huebinger, Ryan M and Kilander, Lena and Moebus, Susanne and Hernandez, Isabel and Kamboh, M Ilyas and Brundin, RoseMarie and Turton, James and Yang, Qiong and Katz, Mindy J and Concari, Letizia and Lord, Jenny and Beiser, Alexa S and Keene, C Dirk and Helisalmi, Seppo and Kloszewska, Iwona and Kukull, Walter A and Koivisto, Anne Maria and Lynch, Aoibhinn and Tarraga, Lluis and Larson, Eric B and Haapasalo, Annakaisa and Lawlor, Brian and Mosley, Thomas H and Lipton, Richard B and Solfrizzi, Vincenzo and Gill, Michael and Longstreth, W T and Montine, Thomas J and Frisardi, Vincenza and Diez-Fairen, Monica and Rivadeneira, Fernando and Petersen, Ronald C and Deramecourt, Vincent and Alvarez, Ignacio and Salani, Francesca and Ciaramella, Antonio and Boerwinkle, Eric and Reiman, Eric M and Fi{\'e}vet, Nathalie and Rotter, Jerome I and Reisch, Joan S and Hanon, Olivier and Cupidi, Chiara and Andre Uitterlinden, A G and Royall, Donald R and Dufouil, Carole and Maletta, Raffaele Giovanni and de Rojas, Itziar and Sano, Mary and Brice, Alexis and Cecchetti, Roberta and George-Hyslop, Peter St and Ritchie, Karen and Tsolaki, Magda and Tsuang, Debby W and Dubois, Bruno and Craig, David and Wu, Chuang-Kuo and Soininen, Hilkka and Avramidou, Despoina and Albin, Roger L and Fratiglioni, Laura and Germanou, Antonia and Apostolova, Liana G and Keller, Lina and Koutroumani, Maria and Arnold, Steven E and Panza, Francesco and Gkatzima, Olymbia and Asthana, Sanjay and Hannequin, Didier and Whitehead, Patrice and Atwood, Craig S and Caffarra, Paolo and Hampel, Harald and Quintela, In{\'e}s and Carracedo, Angel and Lannfelt, Lars and Rubinsztein, David C and Barnes, Lisa L and Pasquier, Florence and Fr{\"o}lich, Lutz and Barral, Sandra and McGuinness, Bernadette and Beach, Thomas G and Johnston, Janet A and Becker, James T and Passmore, Peter and Bigio, Eileen H and Schott, Jonathan M and Bird, Thomas D and Warren, Jason D and Boeve, Bradley F and Lupton, Michelle K and Bowen, James D and Proitsi, Petra and Boxer, Adam and Powell, John F and Burke, James R and Kauwe, John S K and Burns, Jeffrey M and Mancuso, Michelangelo and Buxbaum, Joseph D and Bonuccelli, Ubaldo and Cairns, Nigel J and McQuillin, Andrew and Cao, Chuanhai and Livingston, Gill and Carlson, Chris S and Bass, Nicholas J and Carlsson, Cynthia M and Hardy, John and Carney, Regina M and Bras, Jose and Carrasquillo, Minerva M and Guerreiro, Rita and Allen, Mariet and Chui, Helena C and Fisher, Elizabeth and Masullo, Carlo and Crocco, Elizabeth A and DeCarli, Charles and Bisceglio, Gina and Dick, Malcolm and Ma, Li and Duara, Ranjan and Graff-Radford, Neill R and Evans, Denis A and Hodges, Angela and Faber, Kelley M and Scherer, Martin and Fallon, Kenneth B and Riemenschneider, Matthias and Fardo, David W and Heun, Reinhard and Farlow, Martin R and K{\"o}lsch, Heike and Ferris, Steven and Leber, Markus and Foroud, Tatiana M and Heuser, Isabella and Galasko, Douglas R and Giegling, Ina and Gearing, Marla and H{\"u}ll, Michael and Geschwind, Daniel H and Gilbert, John R and Morris, John and Green, Robert C and Mayo, Kevin and Growdon, John H and Feulner, Thomas and Hamilton, Ronald L and Harrell, Lindy E and Drichel, Dmitriy and Honig, Lawrence S and Cushion, Thomas D and Huentelman, Matthew J and Hollingworth, Paul and Hulette, Christine M and Hyman, Bradley T and Marshall, Rachel and Jarvik, Gail P and Meggy, Alun and Abner, Erin and Menzies, Georgina E and Jin, Lee-Way and Leonenko, Ganna and Real, Luis M and Jun, Gyungah R and Baldwin, Clinton T and Grozeva, Detelina and Karydas, Anna and Russo, Giancarlo and Kaye, Jeffrey A and Kim, Ronald and Jessen, Frank and Kowall, Neil W and Vellas, Bruno and Kramer, Joel H and Vardy, Emma and LaFerla, Frank M and J{\"o}ckel, Karl-Heinz and Lah, James J and Dichgans, Martin and Leverenz, James B and Mann, David and Levey, Allan I and Pickering-Brown, Stuart and Lieberman, Andrew P and Klopp, Norman and Lunetta, Kathryn L and Wichmann, H-Erich and Lyketsos, Constantine G and Morgan, Kevin and Marson, Daniel C and Brown, Kristelle and Martiniuk, Frank and Medway, Christopher and Mash, Deborah C and N{\"o}then, Markus M and Masliah, Eliezer and Hooper, Nigel M and McCormick, Wayne C and Daniele, Antonio and McCurry, Susan M and Bayer, Anthony and McDavid, Andrew N and Gallacher, John and McKee, Ann C and van den Bussche, Hendrik and Mesulam, Marsel and Brayne, Carol and Miller, Bruce L and Riedel-Heller, Steffi and Miller, Carol A and Miller, Joshua W and Al-Chalabi, Ammar and Morris, John C and Shaw, Christopher E and Myers, Amanda J and Wiltfang, Jens and O{\textquoteright}Bryant, Sid and Olichney, John M and Alvarez, Victoria and Parisi, Joseph E and Singleton, Andrew B and Paulson, Henry L and Collinge, John and Perry, William R and Mead, Simon and Peskind, Elaine and Cribbs, David H and Rossor, Martin and Pierce, Aimee and Ryan, Natalie S and Poon, Wayne W and Nacmias, Benedetta and Potter, Huntington and Sorbi, Sandro and Quinn, Joseph F and Sacchinelli, Eleonora and Raj, Ashok and Spalletta, Gianfranco and Raskind, Murray and Caltagirone, Carlo and Boss{\`u}, Paola and Orfei, Maria Donata and Reisberg, Barry and Clarke, Robert and Reitz, Christiane and Smith, A David and Ringman, John M and Warden, Donald and Roberson, Erik D and Wilcock, Gordon and Rogaeva, Ekaterina and Bruni, Amalia Cecilia and Rosen, Howard J and Gallo, Maura and Rosenberg, Roger N and Ben-Shlomo, Yoav and Sager, Mark A and Mecocci, Patrizia and Saykin, Andrew J and Pastor, Pau and Cuccaro, Michael L and Vance, Jeffery M and Schneider, Julie A and Schneider, Lori S and Slifer, Susan and Seeley, William W and Smith, Amanda G and Sonnen, Joshua A and Spina, Salvatore and Stern, Robert A and Swerdlow, Russell H and Tang, Mitchell and Tanzi, Rudolph E and Trojanowski, John Q and Troncoso, Juan C and Van Deerlin, Vivianna M and Van Eldik, Linda J and Vinters, Harry V and Vonsattel, Jean Paul and Weintraub, Sandra and Welsh-Bohmer, Kathleen A and Wilhelmsen, Kirk C and Williamson, Jennifer and Wingo, Thomas S and Woltjer, Randall L and Wright, Clinton B and Yu, Chang-En and Yu, Lei and Saba, Yasaman and Pilotto, Alberto and Bullido, Mar{\'\i}a J and Peters, Oliver and Crane, Paul K and Bennett, David and Bosco, Paola and Coto, Eliecer and Boccardi, Virginia and De Jager, Phil L and Lleo, Alberto and Warner, Nick and Lopez, Oscar L and Ingelsson, Martin and Deloukas, Panagiotis and Cruchaga, Carlos and Graff, Caroline and Gwilliam, Rhian and Fornage, Myriam and Goate, Alison M and S{\'a}nchez-Juan, Pascual and Kehoe, Patrick G and Amin, Najaf and Ertekin-Taner, Nilifur and Berr, Claudine and Debette, Stephanie and Love, Seth and Launer, Lenore J and Younkin, Steven G and Dartigues, Jean-Fran{\c c}ois and Corcoran, Chris and Ikram, M Arfan and Dickson, Dennis W and Nicolas, Ga{\"e}l and Campion, Dominique and Tschanz, JoAnn and Schmidt, Helena and Hakonarson, Hakon and Clarimon, Jordi and Munger, Ron and Schmidt, Reinhold and Farrer, Lindsay A and Van Broeckhoven, Christine and C O{\textquoteright}Donovan, Michael and DeStefano, Anita L and Jones, Lesley and Haines, Jonathan L and Deleuze, Jean-Francois and Owen, Michael J and Gudnason, Vilmundur and Mayeux, Richard and Escott-Price, Valentina and Psaty, Bruce M and Ramirez, Alfredo and Wang, Li-San and Ruiz, Agustin and van Duijn, Cornelia M and Holmans, Peter A and Seshadri, Sudha and Williams, Julie and Amouyel, Phillippe and Schellenberg, Gerard D and Lambert, Jean-Charles and Pericak-Vance, Margaret A} } @article {7966, title = {High-dimensional longitudinal classification with the multinomial fused lasso.}, journal = {Stat Med}, year = {2019}, month = {2019 Jan 30}, abstract = {

We study regularized estimation in high-dimensional longitudinal classification problems, using the lasso and fused lasso regularizers. The constructed coefficient estimates are piecewise constant across the time dimension in the longitudinal problem, with adaptively selected change points (break points). We present an efficient algorithm for computing such estimates, based on proximal gradient descent. We apply our proposed technique to a longitudinal data set on Alzheimer{\textquoteright}s disease from the Cardiovascular Health Study Cognition Study. Using data analysis and a simulation study, we motivate and demonstrate several practical considerations such as the selection of tuning parameters and the assessment of model stability. While race, gender, vascular and heart disease, lack of caregivers, and deterioration of learning and memory are all important predictors of dementia, we also find that these risk factors become more relevant in the later stages of life.

}, issn = {1097-0258}, doi = {10.1002/sim.8100}, author = {Adhikari, Samrachana and Lecci, Fabrizio and Becker, James T and Junker, Brian W and Kuller, Lewis H and Lopez, Oscar L and Tibshirani, Ryan J} } @article {8437, title = {Associations of body composition with incident dementia in older adults: Cardiovascular Health Study-Cognition Study.}, journal = {Alzheimers Dement}, year = {2020}, month = {2020 Aug 17}, abstract = {

INTRODUCTION: A body of literature reported associations between late-life general adiposity measures (eg, body mass index) and dementia. Little is known about the association of late-life body composition with dementia risk.

METHODS: We determined this association among cognitively normal participants from the Cardiovascular Health Study- Cognition Study. Body composition was assessed by dual-energy x-ray absorptiometry in 1994-1995. Dementia was ascertained at annual follow-up from 1998-1999 to 2013. Associations of body composition with incident dementia were assessed by the Fine-Gray model.

RESULT: Among 344 participants (mean age 78, 62.2\% women), body composition was significantly different between men and women, despite similar body mass indexes (BMIs). Increased dementia risk was significantly associated with lower lean mass in men and marginally with low appendicular lean mass in women.

DISCUSSION: Decreased lean mass was an indicator of increased dementia risk in older adults. Studies should test whether preventing lean mass loss in older adults reduces dementia risk.

}, issn = {1552-5279}, doi = {10.1002/alz.12125}, author = {Cui, Chendi and Mackey, Rachel H and Shaaban, C Elizabeth and Kuller, Lewis H and Lopez, Oscar L and Sekikawa, Akira} } @article {8392, title = {Brachial Flow-mediated Dilation and Risk of Dementia: The Cardiovascular Health Study.}, journal = {Alzheimer Dis Assoc Disord}, volume = {34}, year = {2020}, month = {2020 Jul-Sep}, pages = {272-274}, abstract = {

INTRODUCTION: Brachial flow-mediated dilation (FMD) is a physiologic measure of endothelial function. We determined the prospective association of brachial FMD with incident dementia among older adults.

METHODS: We included 2777 Cardiovascular Health Study participants who underwent brachial FMD measurement. Incident dementia was ascertained by medication use, International Classification of Diseases-9 codes, requirement for a proxy, and death certificates and calibrated to gold-standard assessments performed in a subset of the cohort.

RESULTS: Mean participant age at time of brachial FMD measurement was 77.9 years. We identified 1650 incident dementia cases (median follow-up=10.5 y). After adjusting for age, race, sex, education, clinic site, and baseline arterial diameter, risk of dementia for participants in the highest quartile of percent brachial FMD did not differ from those in lowest quartile (hazard ratio=0.89, 95\% confidence interval: 0.77, 1.03).

CONCLUSIONS: Brachial FMD, measured late in life, is not associated with an increased risk of incident dementia.

}, issn = {1546-4156}, doi = {10.1097/WAD.0000000000000394}, author = {Garg, Parveen K and Tan, Annabel X and Odden, Michelle C and Gardin, Julius M and Lopez, Oscar L and Newman, Anne B and Rawlings, Andreea M and Mukamal, Kenneth J} } @article {8382, title = {Cerebral Blood Flow Is Associated with Diagnostic Class and Cognitive Decline in Alzheimer{\textquoteright}s Disease.}, journal = {J Alzheimers Dis}, volume = {76}, year = {2020}, month = {2020}, pages = {1103-1120}, abstract = {

BACKGROUND: Reliable cerebral blood flow (CBF) biomarkers using a noninvasive imaging technique are sought to facilitate early diagnosis and intervention in early Alzheimer{\textquoteright}s disease (AD).

OBJECTIVE: We aim to identify brain regions in which CBF values are affected and related to cognitive decline in early AD using a large cohort.

METHODS: Perfusion MRIs using continuous arterial spin labeling were acquired at 1.5 T in 58 normal controls (NC), 50 mild cognitive impairments (MCI), and 40 AD subjects from the Cardiovascular Health Study Cognition Study. Regional absolute CBF and normalized CBF (nCBF) values, without and with correction of partial volume effects, were compared across three groups. Association between regional CBF values and Modified Mini-Mental State Examination (3MSE) were investigated by multiple linear regression analyses adjusted for cardiovascular risk factors.

RESULTS: After correcting for partial volume effects and cardiovascular risk factors, ADs exhibited decreased nCBF with the strongest reduction in the bilateral posterior cingulate \& precuneus region (p < 0.001) compared to NCs, and the strongest reduction in the bilateral superior medial frontal region (p < 0.001) compared to MCIs. MCIs exhibited the strongest nCBF decrease in the left hippocampus and nCBF increase in the right inferior frontal and insular region. The 3MSE scores within the symptomatic subjects were significantly associated with nCBF in the bilateral posterior and middle cingulate and parietal (p < 0.001), bilateral superior medial frontal (p < 0.001), bilateral temporoparietal (p < 0.02), and right hippocampus (p = 0.02) regions.

CONCLUSION: Noninvasive perfusion MRI can detect functional changes across diagnostic class and serve as a staging biomarker of cognitive status.

}, issn = {1875-8908}, doi = {10.3233/JAD-200034}, author = {Duan, Wenna and Sehrawat, Parshant and Balachandrasekaran, Arvind and Bhumkar, Ashish B and Boraste, Paresh B and Becker, James T and Kuller, Lewis H and Lopez, Oscar L and Gach, H Michael and Dai, Weiying} } @article {8479, title = {Estrogen, brain structure, and cognition in postmenopausal women.}, journal = {Hum Brain Mapp}, year = {2020}, month = {2020 Sep 10}, abstract = {

Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer{\textquoteright}s disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia-yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self-reported HT use on brain volume in 562 elderly women (71-94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate-adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design.

}, issn = {1097-0193}, doi = {10.1002/hbm.25200}, author = {Boyle, Christina P and Raji, Cyrus A and Erickson, Kirk I and Lopez, Oscar L and Becker, James T and Gach, H Michael and Kuller, Lewis H and Longstreth, William and Carmichael, Owen T and Riedel, Brandalyn C and Thompson, Paul M} } @article {8406, title = {Long-term cognitive decline and mortality after carotid endarterectomy.}, journal = {Clin Neurol Neurosurg}, volume = {194}, year = {2020}, month = {2020 Jul}, pages = {105823}, abstract = {

OBJECTIVES: To date no studies have evaluated long term cognitive decline after carotid endarterectomy (CEA). We evaluated whether participants who had CEA were at increased risk of cognitive decline over participants who didn{\textquoteright}t undergo CEA.

PATIENTS AND METHODS: The patients in the study were participants in the Cardiovascular Health Study (CHS), a study of 5201 men and women over the age of 65 who were recruited from four communities (Pittsburgh, Pennsylvania; Sacramento, California; Winston-Salem, North Carolina; Hagerstown, Maryland) in 1988-89. The outcomes measured were 1) Decline in 3MSE and digit symbol substitution test (DSST) scores after CEA compared to before CEA. 2) All-cause mortality in CHS cohort among participants who did and did not have CEA.

RESULTS: CEA patients had significantly greater annual decrease in the DSST scores -2.43 (SD 4.21) compared to those who did not have a CEA -1.1 (SD 2.57) (p < 0.001) but this was not seen in the 3MSE scores. CEA patients had increased the risk of decline in DSST (OR 2.41, 95 \% CI 1.49, 3.88) and 3MSE (OR 2.17, 95 \% CI 1.35, 3.48) scores after adjusting for age, gender, race and educational status. CEA was associated with all-cause mortality in the long term with a HR of 2.72 (95 \% CI 2.22, 3.34) after adjusting for covariates. Participants with lower baseline 3MSE scores HR 1.39 (1.27, 1.51), lower DSST scores <34 HR 1.69(1.54, 1.85) were more likely deceased.

CONCLUSIONS: CEA patients are at increased risk of lower scores on 3MSE and DSST testing in the long term. Mortality in the CHS cohort was higher in participants who underwent CEA. Further, lower 3MSE and DSST scores increased the risk of mortality.

}, issn = {1872-6968}, doi = {10.1016/j.clineuro.2020.105823}, author = {Thirumala, Parthasarathy D and Reddy, Rajiv P and Lopez, Oscar L and Chang, Yue-Fang and Becker, James T and Kuller, Lewis H} } @article {8441, title = {Orthostatic Hypotension, Dizziness, Neurology Outcomes, and Death in Older Adults.}, journal = {Neurology}, year = {2020}, month = {2020 Jul 30}, abstract = {

OBJECTIVE: To test the hypothesis that orthostatic hypotension (OH) might cause cerebral hypoperfusion and injury, we examined the longitudinal relationship between orthostatic hypotension (OH) or orthostatic symptoms and incident neurologic outcomes in a community population of older adults.

METHODS: Cardiovascular Health Study (CHS) participants (>=65yrs) without dementia or stroke had blood pressure (BP) measured after lying 20-minutes and after standing 3-minutes. Participants reported dizziness immediately upon standing and any dizziness in the past 2wks. OH was defined as a drop in standing systolic/diastolic BP >=20/>=10mmHg. We determined the association between OH or dizziness with (1) MRI brain findings (ventricular size, white matter hyperintensities, brain infarcts) using linear or logistic regression, (2) cognitive function (baseline and over time) using generalized estimating equations, and (3) prospective adjudicated events (dementia, stroke, death) using Cox models. Models were adjusted for demographic characteristics and OH risk factors. We used multiple imputation to account for missing OH or dizziness (N=534).

RESULTS: Prior to imputation, there were 5,007 participants (mean age 72.7{\textpm}5.5yrs, 57.6\% women, 10.9\% black, 16\% with OH). OH was modestly associated with death (HR=1.11; 95\%CI:1.02,1.20), but not MRI findings, cognition, dementia, or stroke. In contrast, dizziness upon standing was associated with lower baseline cognition (β=-1.20;-1.94,-0.47), incident dementia (HR=1.32;1.04,1.62), incident stroke (HR=1.22;1.06,1.41), and death (HR=1.13; 1.06,1.21). Similarly, dizziness over the past two weeks was associated with higher white matter grade (β=0.16;0.03,0.30), brain infarcts (OR=1.31;1.06,1.63), lower baseline cognition (β=-1.18;-2.01,-0.34), and death (HR=1.13;1.04,1.22).

CONCLUSIONS: Dizziness was more consistently associated with neurologic outcomes than OH 3-minutes after standing. Delayed OH assessments may miss pathologic information related to cerebral injury.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000010456}, author = {Juraschek, Stephen P and Longstreth, W T and Lopez, Oscar L and Gottdiener, John S and Lipsitz, Lewis A and Kuller, Lewis H and Mukamal, Kenneth J} } @article {8399, title = {Sex Differences in the Association Between Pentraxin 3 and Cognitive Decline: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {75}, year = {2020}, month = {2020 Jul 13}, pages = {1523-1529}, abstract = {

BACKGROUND: The importance of systemic inflammation, measured by C-reactive protein, in cognitive decline has been demonstrated; however, the role of vascular inflammation is less understood. Pentraxin 3 (PTX3) is a novel marker of vascular inflammation.

METHODS: We followed adults 65 and older, free of cardiovascular disease (CVD) for up to 9 years (n = 1,547) in the Cardiovascular Health Study. We evaluated the relationship between PTX3 and change in cognitive function, measured using the Modified Mini-Mental State Examination (3MSE), and incident cognitive impairment (3MSE < 80). Mediation by CVD events, and effect modification by sex and apolipoprotein E ɛ4 allele (APOE4) were also examined.

RESULTS: The average decline in 3MSE was 0.77 points per year. The association between PTX3 and change in 3MSE differed between women and men (p = .02). In the adjusted model, each standard deviation higher in PTX3 was associated with a 0.20 greater decline in 3MSE score per year in women over follow-up (95\% CI: -0. 37, -0.03; p = .02), compared to no change in men (β = 0.07; 95\% CI: -0.08, 0.22). CVD events had a minor effect on the associations. No effect modification by APOE4 was found, although we observed the association of PTX3 and cognitive impairment in women was attenuated and nonsignificant after adjustment for APOE4. There was a paradoxical protective association between PTX3 and reduced cognitive impairment in men, even after adjustment for APOE4.

CONCLUSIONS: We found that vascular inflammation was significantly associated with cognitive decline in older women, but not men.

}, issn = {1758-535X}, doi = {10.1093/gerona/glz217}, author = {Miller, Lindsay M and Jenny, Nancy S and Rawlings, Andreea M and Arnold, Alice M and Fitzpatrick, Annette L and Lopez, Oscar L and Odden, Michelle C} } @article {8988, title = {Association of low-frequency and rare coding variants with information processing speed.}, journal = {Transl Psychiatry}, volume = {11}, year = {2021}, month = {2021 12 04}, pages = {613}, abstract = {

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67\%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 {\texttimes} 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

}, keywords = {Adult, Aging, Cognition, Genome-Wide Association Study, Geroscience, Humans, Polymorphism, Single Nucleotide, Ubiquitin-Protein Ligases}, issn = {2158-3188}, doi = {10.1038/s41398-021-01736-6}, author = {Bressler, Jan and Davies, Gail and Smith, Albert V and Saba, Yasaman and Bis, Joshua C and Jian, Xueqiu and Hayward, Caroline and Yanek, Lisa and Smith, Jennifer A and Mirza, Saira S and Wang, Ruiqi and Adams, Hieab H H and Becker, Diane and Boerwinkle, Eric and Campbell, Archie and Cox, Simon R and Eiriksdottir, Gudny and Fawns-Ritchie, Chloe and Gottesman, Rebecca F and Grove, Megan L and Guo, Xiuqing and Hofer, Edith and Kardia, Sharon L R and Knol, Maria J and Koini, Marisa and Lopez, Oscar L and Marioni, Riccardo E and Nyquist, Paul and Pattie, Alison and Polasek, Ozren and Porteous, David J and Rudan, Igor and Satizabal, Claudia L and Schmidt, Helena and Schmidt, Reinhold and Sidney, Stephen and Simino, Jeannette and Smith, Blair H and Turner, Stephen T and van der Lee, Sven J and Ware, Erin B and Whitmer, Rachel A and Yaffe, Kristine and Yang, Qiong and Zhao, Wei and Gudnason, Vilmundur and Launer, Lenore J and Fitzpatrick, Annette L and Psaty, Bruce M and Fornage, Myriam and Arfan Ikram, M and van Duijn, Cornelia M and Seshadri, Sudha and Mosley, Thomas H and Deary, Ian J} } @article {8834, title = {Cardiovascular damage phenotypes and all-cause and CVD mortality in older adults.}, journal = {Ann Epidemiol}, volume = {63}, year = {2021}, month = {2021 Jul 30}, pages = {35-40}, abstract = {

PURPOSE: The association between CVD risk factors and mortality is well established, however, current tools for addressing subgroups have focused on the overall burden of disease. The identification of risky combinations of characteristics may lead to a better understanding of physiologic pathways that underlie morbidity and mortality in older adults.

METHODS: Participants included 5067 older adults from the Cardiovascular Health Study, followed for up to 6 years. Using latent class analysis (LCA), we created CV damage phenotypes based on probabilities of abnormal brain infarctions, major echocardiogram abnormalities, N-terminal probrain natriuretic peptide, troponin T, interleukin-6, c reactive-protein, galectin-3, cystatin C. We assigned class descriptions based on the probability of having an abnormality among risk factors, such that a healthy phenotype would have low probabilities in all risk factors. Participants were assigned to phenotypes based on the maximum probability of membership. We used Cox-proportional hazards regression to evaluate the association between the categorical CV damage phenotype and all-cause and CVD-mortality.

RESULTS: The analysis yielded 5 CV damage phenotypes consistent with the following descriptions: healthy (59\%), cardio-renal (11\%), cardiac (15\%), multisystem morbidity (6\%), and inflammatory (9\%). All four phenotypes were statistically associated with a greater risk of all-cause mortality when compared with the healthy phenotype. The multisystem morbidity phenotype had the greatest risk of all-cause death (HR: 4.02; 95\% CI: 3.44, 4.70), and CVD-mortality (HR: 4.90, 95\% CI: 3.95, 6.06).

CONCLUSIONS: Five CV damage phenotypes emerged from CVD risk factor measures. CV damage across multiple systems confers a greater mortality risk compared to damage in any single domain.

}, issn = {1873-2585}, doi = {10.1016/j.annepidem.2021.07.012}, author = {Miller, Lindsay M and Wu, Chenkai and Hirsch, Calvin H and Lopez, Oscar L and Cushman, Mary and Odden, Michelle C} } @article {8773, title = {Cerebral Blood Flow Predicts Conversion of Mild Cognitive Impairment into Alzheimer{\textquoteright}s Disease and Cognitive Decline: An Arterial Spin Labeling Follow-up Study.}, journal = {J Alzheimers Dis}, volume = {82}, year = {2021}, month = {2021}, pages = {293-305}, abstract = {

BACKGROUND: This is the first longitudinal study to assess regional cerebral blood flow (rCBF) changes during the progression from normal control (NC) through mild cognitive impairment (MCI) and Alzheimer{\textquoteright}s disease (AD).

OBJECTIVE: We aim to determine if perfusion MRI biomarkers, derived from our prior cross-sectional study, can predict the onset and cognitive decline of AD.

METHODS: Perfusion MRIs using arterial spin labeling (ASL) were acquired in 15 stable-NC, 14 NC-to-MCI, 16 stable-MCI, and 18 MCI/AD-to-AD participants from the Cardiovascular Health Study (CHS) cognition study. Group comparisons, predictions of AD conversion and time to conversion, and Modified Mini-Mental State Examination (3MSE) from rCBF were performed.

RESULTS: Compared to the stable-NC group: 1) the stable-MCI group exhibited rCBF decreases in the right temporoparietal (p = 0.00010) and right inferior frontal and insula (p = 0.0094) regions; and 2) the MCI/AD-to-AD group exhibited rCBF decreases in the bilateral temporoparietal regions (p = 0.00062 and 0.0035). Compared to the NC-to-MCI group, the stable-MCI group exhibited a rCBF decrease in the right hippocampus region (p = 0.0053). The baseline rCBF values in the posterior cingulate cortex (PCC) (p = 0.0043), bilateral superior medial frontal regions (BSMF) (p = 0.012), and left inferior frontal (p = 0.010) regions predicted the 3MSE scores for all the participants at follow-up. The baseline rCBF in the PCC and BSMF regions predicted the conversion and time to conversion from MCI to AD (p < 0.05; not significant after multiple corrections).

CONCLUSION: We demonstrated the feasibility of ASL in detecting rCBF changes in the typical AD-affected regions and the predictive value of baseline rCBF on AD conversion and cognitive decline.

}, issn = {1875-8908}, doi = {10.3233/JAD-210199}, author = {Duan, Wenna and Zhou, Grace D and Balachandrasekaran, Arvind and Bhumkar, Ashish B and Boraste, Paresh B and Becker, James T and Kuller, Lewis H and Lopez, Oscar L and Gach, H Michael and Dai, Weiying} } @article {8990, title = {Association of Serum Neurofilament Light Chain Concentration and MRI Findings in Older Adults: The Cardiovascular Health Study.}, journal = {Neurology}, volume = {98}, year = {2022}, month = {2022 Mar 01}, pages = {e903-e911}, abstract = {

BACKGROUND AND OBJECTIVES: Neurofilament light chain (NfL) in blood is a sensitive but nonspecific marker of brain injury. This study sought to evaluate associations between NfL concentration and MRI findings of vascular brain injury in older adults.

METHODS: A longitudinal cohort study included 2 cranial MRI scans performed about 5 years apart and assessed for white matter hyperintensities (WMH) and infarcts. About 1 year before their second MRI, 1,362 participants (median age 77 years, 61.4\% women) without a history of TIA or stroke had measurement of 4 biomarkers: NfL, total tau, glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L1. Most (n = 1,279) also had the first MRI scan, and some (n = 633) had quantitative measurements of hippocampal and WMH. In primary analyses, we assessed associations of NfL with a 10-point white matter grade (WMG) and prevalent infarcts on second MRI and with worsening WMG and incident infarct comparing the 2 scans. A value <0.0125 (0.05/4) was considered significant for these analyses. We also assessed associations with hippocampal and WMH volume.

RESULTS: In fully adjusted models, log(NfL) concentration was associated with WMG (β = 0.27; = 2.3 {\texttimes} 10) and worsening WMG (relative risk [RR] 1.24; = 0.0022), but less strongly with prevalent brain infarcts (RR 1.18; = 0.013) and not with incident brain infarcts (RR 1.18; = 0.18). Associations were also present with WMH volume (β = 2,242.9, = 0.0036). For the other 3 biomarkers, the associations for log (GFAP) concentration with WMG and worsening WMG were significant.

DISCUSSION: Among older adults without a history of stroke, higher serum NfL concentration was associated with covert MRI findings of vascular brain injury, especially the burden of WMH and its worsening. Whether these results offer opportunities for the use of NfL as a noninvasive biomarker of WMH or to control vascular risk factors remains to be determined.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000013229}, author = {Fohner, Alison E and Bartz, Traci M and Tracy, Russell P and Adams, Hieab H H and Bis, Joshua C and Djouss{\'e}, Luc and Satizabal, Claudia L and Lopez, Oscar L and Seshadri, Sudha and Mukamal, Kenneth J and Kuller, Lewis H and Psaty, Bruce M and Longstreth, W T} } @article {9163, title = {Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis.}, journal = {J Alzheimers Dis}, year = {2022}, month = {2022 Oct 03}, abstract = {

BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent.

OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables.

METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses.

RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95\% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume.

CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

}, issn = {1875-8908}, doi = {10.3233/JAD-220667}, author = {Frenzel, Stefan and Bis, Josh C and Gudmundsson, Elias F and O{\textquoteright}Donnell, Adrienne and Simino, Jeannette and Yaqub, Amber and Bartz, Traci M and Brusselle, Guy G O and B{\"u}low, Robin and DeCarli, Charles S and Ewert, Ralf and Gharib, Sina A and Ghosh, Saptaparni and Gireud-Goss, Monica and Gottesman, Rebecca F and Ikram, M Arfan and Knopman, David S and Launer, Lenore J and London, Stephanie J and Longstreth, W T and Lopez, Oscar L and Melo van Lent, Debora and O{\textquoteright}Connor, George and Satizabal, Claudia L and Shrestha, Srishti and Sigurdsson, Sigurdur and Stubbe, Beate and Talluri, Rajesh and Vasan, Ramachandran S and Vernooij, Meike W and V{\"o}lzke, Henry and Wiggins, Kerri L and Yu, Bing and Beiser, Alexa S and Gudnason, Vilmundur and Mosley, Thomas and Psaty, Bruce M and Wolters, Frank J and Grabe, Hans J and Seshadri, Sudha} } @article {9088, title = {Pattern of Altered Magnetization Transfer Rate in Alzheimer{\textquoteright}s Disease.}, journal = {J Alzheimers Dis}, year = {2022}, month = {2022 Jun 09}, abstract = {

BACKGROUND: Biomarkers for Alzheimer{\textquoteright}s disease (AD) are crucial for early diagnosis and treatment monitoring once disease modifying therapies become available.

OBJECTIVE: This study aims to quantify the forward magnetization transfer rate (kfor) map from brain tissue water to macromolecular protons and use it to identify the brain regions with abnormal kfor in AD and AD progression.

METHODS: From the Cardiovascular Health Study (CHS) cognition study, magnetization transfer imaging (MTI) was acquired at baseline from 63 participants, including 20 normal controls (NC), 18 with mild cognitive impairment (MCI), and 25 AD subjects. Of those, 53 participants completed a follow-up MRI scan and were divided into four groups: 15 stable NC, 12 NC-to-MCI, 12 stable MCI, and 14 MCI/AD-to-AD subjects. kfor maps were compared across NC, MCI, and AD groups at baseline for the cross-sectional study and across four longitudinal groups for the longitudinal study.

RESULTS: We found a lower kfor in the frontal gray matter (GM), parietal GM, frontal corona radiata (CR) white matter (WM) tracts, frontal and parietal superior longitudinal fasciculus (SLF) WM tracts in AD relative to both NC and MCI. Further, we observed progressive decreases of kfor in the frontal GM, parietal GM, frontal and parietal CR WM tracts, and parietal SLF WM tracts in stable MCI. In the parietal GM, parietal CR WM tracts, and parietal SLF WM tracts, we found trend differences between MCI/AD-to-AD and stable NC.

CONCLUSION: Forward magnetization transfer rate is a promising biomarker for AD diagnosis and progression.

}, issn = {1875-8908}, doi = {10.3233/JAD-220335}, author = {Duan, Wenna and Sehrawat, Parshant and Zhou, Tony D and Becker, James T and Lopez, Oscar L and Gach, H Michael and Dai, Weiying} } @article {9438, title = {Association of a blood-based aging biomarker index with death and chronic disease: Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2023}, month = {2023 Jul 19}, abstract = {

BACKGROUND: A goal of gerontology is to discover phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers that are strongly associated with mortality could be used to define such a phenotype. However, the relation of such an index with multiple chronic conditions warrants further exploration.

METHODS: A Biomarker Index (BI) was constructed in the Cardiovascular Health Study (N=3197), with a mean age of 74 years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor-1, interleukin-6, amino-terminal pro-B-type natriuretic peptide, cystatin-C, C-reactive protein, tumor necrosis factor-alpha soluble receptor 1, fasting insulin, and fasting glucose, and was built based on their relationships with mortality. Cox proportional hazards models predicting a composite of death and chronic disease involving cardiovascular disease, dementia, and cancer were calculated with 6 years of follow-up.

RESULTS: The hazard ratio (HR, 95\% CI) for the composite outcome of death or chronic disease per category of BI was 1.65 (1.52, 1.80) and 1.75 (1.58, 1.94) in women and men, respectively. The HR (95\% CI) per 5 years of age was 1.57 (1.48, 1.67) and 1.55 (1.44, 1.67) in women and men, respectively. Moreover, BI could attenuate the effect of age on the composite outcome by 16.7\% and 22.0\% in women and men, respectively.

CONCLUSIONS: BI was significantly and independently associated with a composite outcome of death and chronic disease, and attenuated the effect of age. The BI that is composed of plasma biomarkers may be a practical intermediate phenotype for interventions aiming to modify the course of aging.

}, issn = {1758-535X}, doi = {10.1093/gerona/glad172}, author = {Zhang, Xiao and Sanders, Jason L and Boudreau, Robert M and Arnold, Alice M and Justice, Jamie N and Espeland, Mark A and Kuchel, George A and Barzilai, Nir and Kuller, Lewis H and Lopez, Oscar L and Kritchevsky, Stephen B and Newman, Anne B} } @article {9411, title = {Clonal hematopoiesis is associated with protection from Alzheimer{\textquoteright}s disease.}, journal = {Nat Med}, volume = {29}, year = {2023}, month = {2023 Jul}, pages = {1662-1670}, abstract = {

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer{\textquoteright}s disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 {\texttimes} 10), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.

}, issn = {1546-170X}, doi = {10.1038/s41591-023-02397-2}, author = {Bouzid, Hind and Belk, Julia A and Jan, Max and Qi, Yanyan and Sarnowski, Chloe and Wirth, Sara and Ma, Lisa and Chrostek, Matthew R and Ahmad, Herra and Nachun, Daniel and Yao, Winnie and Beiser, Alexa and Bick, Alexander G and Bis, Joshua C and Fornage, Myriam and Longstreth, William T and Lopez, Oscar L and Natarajan, Pradeep and Psaty, Bruce M and Satizabal, Claudia L and Weinstock, Joshua and Larson, Eric B and Crane, Paul K and Keene, C Dirk and Seshadri, Sudha and Satpathy, Ansuman T and Montine, Thomas J and Jaiswal, Siddhartha} } @article {9480, title = {CogDrisk, ANU-ADRI, CAIDE, and LIBRA Risk Scores for Estimating Dementia Risk.}, journal = {JAMA Netw Open}, volume = {6}, year = {2023}, month = {2023 Aug 01}, pages = {e2331460}, abstract = {

IMPORTANCE: While the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI), Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), and Lifestyle for Brain Health (LIBRA) dementia risk tools have been widely used, a large body of new evidence has emerged since their publication. Recently, Cognitive Health and Dementia Risk Index (CogDrisk) and CogDrisk for Alzheimer disease (CogDrisk-AD) risk tools have been developed for the assessment of dementia and AD risk, respectively, using contemporary evidence; comparison of the relative performance of these risk tools is limited.

OBJECTIVE: To evaluate the performance of CogDrisk, ANU-ADRI, CAIDE, LIBRA, and modified LIBRA (LIBRA with age and sex estimates from ANU-ADRI) in estimating dementia and AD risks (with CogDrisk-AD and ANU-ADRI).

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study obtained data from the Rush Memory and Aging Project (MAP), the Cardiovascular Health Study Cognition Study (CHS-CS), and the Health and Retirement Study-Aging, Demographics and Memory Study (HRS-ADAMS). Participants who were free of dementia at baseline were included. The factors were component variables in the risk tools that included self-reported baseline demographics, medical risk factors, and lifestyle habits. The study was conducted between November 2021 and March 2023, and statistical analysis was performed from January to June 2023.

MAIN OUTCOMES AND MEASURES: Risk scores were calculated based on available factors in each of these cohorts. Area under the receiver operating characteristic curve (AUC) was calculated to measure the performance of each risk score. Multiple imputation was used to assess whether missing data may have affected estimates for dementia risk.

RESULTS: Among the 6107 participants in 3 validation cohorts included for this study, 2184 participants without dementia at baseline were available from MAP (mean [SD] age, 80.0 [7.6] years; 1606 [73.5\%] female), 548 participants without dementia at baseline were available from HRS-ADAMS (mean [SD] age, 79.5 [6.3] years; 288 [52.5\%] female), and 3375 participants without dementia at baseline were available from CHS-CS (mean [SD] age, 74.8 [4.9] years; 1994 [59.1\%] female). In all 3 cohorts, a similar AUC for dementia was obtained using CogDrisk, ANU-ADRI, and modified LIBRA (MAP cohort: CogDrisk AUC, 0.65 [95\% CI, 0.61-0.69]; ANU-ADRI AUC, 0.65 [95\% CI, 0.61-0.69]; modified LIBRA AUC, 0.65 [95\% CI, 0.61-0.69]; HRS-ADAMS cohort: CogDrisk AUC, 0.75 [95\% CI, 0.71-0.79]; ANU-ADRI AUC, 0.74 [95\% CI, 0.70-0.78]; modified LIBRA AUC, 0.75 [95\% CI, 0.71-0.79]; CHS-CS cohort: CogDrisk AUC, 0.70 [95\% CI, 0.67-0.72]; ANU-ADRI AUC, 0.69 [95\% CI, 0.66-0.72]; modified LIBRA AUC, 0.70 [95\% CI, 0.68-0.73]). The CAIDE and LIBRA also provided similar but lower AUCs than the 3 aforementioned tools (eg, MAP cohort: CAIDE AUC, 0.50 [95\% CI, 0.46-0.54]; LIBRA AUC, 0.53 [95\% CI, 0.48-0.57]). The performance of CogDrisk-AD and ANU-ADRI in estimating AD risks was also similar.

CONCLUSIONS AND RELEVANCE: CogDrisk and CogDrisk-AD performed similarly to ANU-ADRI in estimating dementia and AD risks. These results suggest that CogDrisk and CogDrisk-AD, with a greater range of modifiable risk factors compared with other risk tools in this study, may be more informative for risk reduction.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Australia, Cohort Studies, Female, Heart Disease Risk Factors, Humans, Male, Risk Factors}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2023.31460}, author = {Huque, Md Hamidul and Kootar, Scherazad and Eramudugolla, Ranmalee and Han, S Duke and Carlson, Michelle C and Lopez, Oscar L and Bennett, David A and Peters, Ruth and Anstey, Kaarin J} } @article {9287, title = {Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease.}, journal = {Neurobiol Aging}, volume = {122}, year = {2023}, month = {2023 Feb}, pages = {107-111}, abstract = {

A rare missense APOE variant (L28P; APOE*4Pittsburgh), which is present only in populations with European ancestry, has been reported to be a risk factor for late-onset Alzheimer{\textquoteright}s disease (LOAD). However, due to the complete linkage disequilibrium of L28P with APOE*4 (C112R), its independent genetic association is uncertain. The original association study implicating L28P with LOAD risk was carried out in a relatively small sample size. In the current study, we have re-evaluated this association in a large case-control sample of 15,762 White U.S. subjects and investigated its independent effect in APOE 3/4 subjects, as L28P has been observed only in the heterozygous state of APOE*4 carriers and 3/4 is the most common genotype containing the APOE*4 allele. The heterozygous carrier frequency of L28P, all with APOE*4, was about 3-fold higher in AD cases than in cognitively intact controls (0.845\% vs. 0.277\%). The age- and sex-adjusted meta-analysis odds ratio (OR) was 2.87 (95\% CI: 1.34 - 6.13;~=~0.0066). Among APOE 3/4 subjects, age- and sex-adjusted meta-analysis OR was 1.53 (95\% CI: 0.70 - 3.36; p~=~0.28), indicating its effect was independent of APOE*4. The lack of statistical significance appears mainly due to the low power of 4138 subjects with the 3/4 genotype (12\% power at α= 0.05) compared to the required sample of 139,088 subjects with the 3/4 genotype to detect an OR of 1.5 at α= 0.05 and 80\% power. Our data suggesting that L28P has an independent genetic effect on AD risk is reinforced by earlier experimental findings showing that this mutation leads to significant structural and conformational changes in the ApoE4 molecule and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. Additional functional studies in cell-based systems and animal models will help to delineate its functional significance in the etiology of AD.

}, keywords = {Alleles, Alzheimer Disease, Animals, Apolipoprotein E3, Apolipoprotein E4, Apolipoproteins E, Genotype, Heterozygote}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2022.11.007}, author = {Fan, KangHsien and Francis, Lily and Aslam, M Muaaz and Bedison, Margret A and Lawrence, Elizabeth and Acharya, Vibha and Snitz, Beth E and Ganguli, Mary and DeKosky, Steven T and Lopez, Oscar L and Feingold, Eleanor and Kamboh, M Ilyas} } @article {9413, title = {Longitudinal Patterns of Brain Changes in a Community Sample in Relation to Aging and Cognitive Status.}, journal = {J Alzheimers Dis}, year = {2023}, month = {2023 Jun 20}, abstract = {

BACKGROUND: Aging and Alzheimer{\textquoteright}s disease (AD) are characterized by widespread cortical and subcortical atrophy. Though atrophy patterns between aging and AD overlap considerably, regional differences between these two conditions may exist. Few studies, however, have investigated these patterns in large community samples.

OBJECTIVE: Elaborate longitudinal changes in brain morphometry in relation to aging and cognitive status in a well-characterized community cohort.

METHODS: Clinical and neuroimaging data were compiled from 72 participants from the Cardiovascular Health Study-Cognition Study, a community cohort of healthy aging and probable AD participants. Two time points were identified for each participant with a mean follow-up time of 5.36 years. MRI post-processing, morphometric measurements, and statistical analyses were performed using FreeSurfer, Version 7.1.1.

RESULTS: Cortical volume was significantly decreased in the bilateral superior frontal, bilateral inferior parietal, and left superior parietal regions, among others. Cortical thickness was significantly reduced in the bilateral superior frontal and left inferior parietal regions, among others. Overall gray and white matter volumes and hippocampal subfields also demonstrated significant reductions. Cortical volume atrophy trajectories between cognitively stable and cognitively declined participants were significantly different in the right postcentral region.

CONCLUSION: Observed volume reductions were consistent with previous studies investigating morphometric brain changes. Patterns of brain atrophy between AD and aging may be different in magnitude but exhibit widespread spatial overlap. These findings help characterize patterns of brain atrophy that may reflect the general population. Larger studies may more definitively establish population norms of aging and AD-related neuroimaging changes.

}, issn = {1875-8908}, doi = {10.3233/JAD-230080}, author = {Chwa, Won Jong and Lopez, Oscar L and Longstreth, W T and Dai, Weiying and Raji, Cyrus A} } @article {9238, title = {Neighborhood greenspace and cognition: The cardiovascular health study.}, journal = {Health Place}, volume = {79}, year = {2023}, month = {2023 Jan 03}, pages = {102960}, abstract = {

OBJECTIVES: We examined whether greenspace measures (overall percent greenspace and forest, and number of greenspace types) were associated with clinically adjudicated dementia status.

METHODS: In a sample of non-demented older adults (n~=~2141, average age~=~75.3 years) from the Cardiovascular Health and Cognition Study, Cox proportional hazard and logistic regression analyses were used to estimate associations of baseline greenspace with risks of incident dementia and MCI, respectively, while adjusting for demographics, co-morbidities, and other neighborhood factors. We derived quartiles of percent greenness (greenspace), forest (percent tree canopy cover), and tertiles of greenspace diversity (number of greenspace types) for 5-km radial buffers around participant{\textquoteright}s residences at study entry (1989-1990) from the 1992 National Land Cover Dataset. Dementia status and mild cognitive impairment (MCI) over 10 years was clinically adjudicated.

RESULTS: We observed no significant association between overall percent greenspace and risk of mild cognitive impairment or dementia and mostly null results for forest and greenspace diversity. Forest greenspace was associated with lower odds of MCI (OR quartile 4 versus 1: 0.54, 95\% CI: 0.29-0.98) and greenspace diversity was associated with lower hazard of incident dementia (HR tertile 2 versus 1: 0.70, 95\% CI~=~0.50-0.99).

DISCUSSION: We found divergent results for different types of greenspace and mild cognitive impairment or dementia. Improved greenspace type and diversity measurement could better characterize the association between greenspace and cognition.

}, issn = {1873-2054}, doi = {10.1016/j.healthplace.2022.102960}, author = {Godina, Sara L and Rosso, Andrea L and Hirsch, Jana A and Besser, Lilah M and Lovasi, Gina S and Donovan, Geoffrey H and Garg, Parveen K and Platt, Jonathan M and Fitzpatrick, Annette L and Lopez, Oscar L and Carlson, Michelle C and Michael, Yvonne L} } @article {9389, title = {Prospective Longitudinal Perfusion in Probable Alzheimer{\textquoteright}s Disease Correlated with Atrophy in Temporal Lobe.}, journal = {Aging Dis}, year = {2023}, month = {2023 May 09}, abstract = {

Reduced cerebral blood flow (CBF) in the temporoparietal region and gray matter volumes (GMVs) in the temporal lobe were previously reported in patients with mild cognitive impairment (MCI) and Alzheimer{\textquoteright}s disease (AD). However, the temporal relationship between reductions in CBF and GMVs requires further investigation. This study sought to determine if reduced CBF is associated with reduced GMVs, or vice versa. Data came from 148 volunteers of the Cardiovascular Health Study Cognition Study (CHS-CS), including 58 normal controls (NC), 50 MCI, and 40 AD who had perfusion and structural MRIs during 2002-2003 (Time 2). Sixty-three of the 148 volunteers had follow-up perfusion and structural MRIs (Time 3). Forty out of the 63 volunteers received prior structural MRIs during 1997-1999 (Time 1). The relationships between GMVs and subsequent CBF changes, and between CBF and subsequent GMV changes were investigated. At Time 2, we observed smaller GMVs (p<0.05) in the temporal pole region in AD compared to NC and MCI. We also found associations between: (1) temporal pole GMVs at Time 2 and subsequent declines in CBF in this region (p=0.0014) and in the temporoparietal region (p=0.0032); (2) hippocampal GMVs at Time 2 and subsequent declines in CBF in the temporoparietal region (p=0.012); and (3) temporal pole CBF at Time 2 and subsequent changes in GMV in this region (p = 0.011). Therefore, hypoperfusion in the temporal pole may be an early event driving its atrophy. Perfusion declines in the temporoparietal and temporal pole follow atrophy in this temporal pole region.

}, issn = {2152-5250}, doi = {10.14336/AD.2023.0430}, author = {Zhou, Tony D and Zhang, Zongpai and Balachandrasekaran, Arvind and Raji, Cyrus A and Becker, James T and Kuller, Lewis H and Ge, Yulin and Lopez, Oscar L and Dai, Weiying and Gach, H Michael} } @article {9616, title = {Trajectory of Cognitive Function After Incident Heart Failure.}, journal = {medRxiv}, year = {2024}, month = {2024 Feb 11}, abstract = {

BACKGROUND: The size/magnitude of cognitive changes after incident heart failure (HF) are unclear. We assessed whether incident HF is associated with changes in cognitive function after accounting for pre-HF cognitive trajectories and known determinants of cognition.

METHODS: This pooled cohort study included adults without HF, stroke, or dementia from six US population-based cohort studies from 1971-2019: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study. Linear mixed-effects models estimated changes in cognition at the time of HF (change in the intercept) and the rate of cognitive change over the years after HF (change in the slope), controlling for pre-HF cognitive trajectories and participant factors. Change in global cognition was the primary outcome. Change in executive function and memory were secondary outcomes. Cognitive outcomes were standardized to a -score metric (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition.

RESULTS: The study included 29,614 adults (mean [SD] age was 61.1 [10.5] years, 55\% female, 70.3\% White, 22.2\% Black 7.5\% Hispanic). During a median follow-up of 6.6 (Q1-Q3: 5-19.8) years, 1,407 (4.7\%) adults developed incident HF. Incident HF was associated with an acute decrease in global cognition (-1.08 points; 95\% CI -1.36, -0.80) and executive function (-0.65 points; 95\% CI -0.96, -0.34) but not memory (-0.51 points; 95\% CI -1.37, 0.35) at the time of the event. Greater acute decreases in global cognition after HF were seen in those with older age, female sex and White race. Individuals with incident HF, compared to HF-free individuals, demonstrated faster declines in global cognition (-0.15 points per year; 95\% CI, -0.21, -0.09) and executive function (-0.16 points per year; 95\% CI -0.23, -0.09) but not memory ( -0.11 points per year; 95\% CI -0.26, 0.04) compared with pre-HF slopes.

CONCLUSIONS: In this pooled cohort study, incident HF was associated with an acute decrease in global cognition and executive function at the time of the event and faster declines in global cognition and executive function over the following years.

}, doi = {10.1101/2024.02.09.24302608}, author = {Shore, Supriya and Li, Hanyu and Zhang, Min and Whitney, Rachael and Gross, Alden L and Bhatt, Ankeet S and Nallamothu, Brahmajee K and Giordani, Bruno and Brice{\~n}o, Emily M and Sussman, Jeremy B and Gutierrez, Jose and Yaffe, Kristine and Griswold, Michael and Johansen, Michelle C and Lopez, Oscar L and Gottesman, Rebecca F and Sidney, Stephen and Heckbert, Susan R and Rundek, Tatjana and Hughes, Timothy M and Longstreth, William T and Levine, Deborah A} }