@article {750, title = {Regional and racial differences in the prevalence of physician-diagnosed essential tremor in the United States.}, journal = {Mov Disord}, volume = {18}, year = {2003}, month = {2003 Sep}, pages = {1035-40}, abstract = {

For reasons that are unclear, prevalence estimates of essential tremor (ET) differ considerably across the United States. Separate communities have never been sampled within the framework of the same study to substantiate these differences. We estimated the prevalence of physician-diagnosed ET in the elderly in four communities in the United States in whom the same screening questions were used, and examined whether this prevalence differed between Caucasians and African Americans. The Cardiovascular Health Study recruited a sample of Medicare beneficiaries >/=65 years of age from four communities in different regions of the United States. In 1998 to 1999, 3,494 participants (mean age, 80.0 years; range, 70-103 years) answered a 12-question screen for ET, including the question, "has a doctor diagnosed you as having familial tremor or benign essential tremor?" Fifty-four participants reported that a doctor had diagnosed them as having ET (1.5\%; 95\% confidence interval, [CI], 1.1-2.0\%). Prevalence was similar across the four communities (1.1-2.0\%). A larger proportion of Caucasians than African Americans reported a diagnosis of ET (1.7\% vs. 0.4\%; odds ratio = 4.9; 95\% CI, 1.2-20.2; P = 0.028). In a logistic regression analysis, physician-diagnosed ET was associated with Caucasian ethnicity (P = 0.038) but not with age, gender, education, mental status or depression scores, income, smoking status, or alcohol consumption. When a standardized screening question was used, the proportion of participants with physician-diagnosed ET was similar across four communities, suggesting that the prevalence of this condition may be less variable than is often reported. Caucasians were five times more likely to have physician-diagnosed ET than were African Americans. This study does not provide an explanation for this difference, which deserves further study.

}, keywords = {African Continental Ancestry Group, Aged, Aged, 80 and over, Essential Tremor, European Continental Ancestry Group, Female, Humans, Male, Physicians, Prevalence, United States}, issn = {0885-3185}, doi = {10.1002/mds.10492}, author = {Louis, Elan D and Fried, Linda P and Fitzpatrick, Annette L and Longstreth, William T and Newman, Anne B} } @article {829, title = {Coronary artery calcium: associations with brain magnetic resonance imaging abnormalities and cognitive status.}, journal = {J Am Geriatr Soc}, volume = {53}, year = {2005}, month = {2005 Apr}, pages = {609-15}, abstract = {

OBJECTIVES: To evaluate the association between coronary atherosclerosis and subclinical brain magnetic resonance imaging (MRI) abnormalities and between coronary atherosclerosis and abnormal cognitive function (dementia/mild cognitive impairment).

DESIGN: Cross-sectional.

SETTING: The Cardiovascular Health Study (CHS), an epidemiological study of risk factors for cardiovascular disease in older adults.

PARTICIPANTS: Four hundred nine men and women, mean age 79, recruited from the Pittsburgh center of the CHS.

MEASUREMENTS: Coronary atherosclerosis was defined according to the level of coronary artery calcification (CAC), as measured using electronic beam tomography. Subclinical brain MRI abnormalities included ventricular enlargement, white matter hyperintensities, and number of subcortical brain infarcts. Brain MRI and CAC measurements were performed between 1998 and 2000 at the Pittsburgh center of the CHS. Prevalence of brain MRI abnormalities and abnormal cognitive status were examined across quartiles of the CAC score, before and after controlling for age. Multivariate logistic regression models were used to assess whether CAC level was associated with abnormalities of brain MRI or abnormal cognitive status.

RESULTS: Older adults with high CAC scores were more likely to have more-severe brain MRI abnormalities, including subcortical infarction and high white matter hyperintensities. The associations between CAC and ventricular enlargement showed a similar but not significant trend. The presence of any of the MRI abnormalities attenuated the association between CAC and abnormal cognitive status.

CONCLUSION: Older adults with higher levels of CAC were more likely to have more-severe brain MRI abnormalities and abnormal cognitive status.

}, keywords = {Aged, Brain, Calcinosis, Cognition Disorders, Coronary Artery Disease, Cross-Sectional Studies, Dementia, Female, Humans, Logistic Models, Magnetic Resonance Imaging, Male, Risk Factors, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.53208.x}, author = {Rosano, Caterina and Naydeck, Barbara and Kuller, Lewis H and Longstreth, William T and Newman, Anne B} } @article {830, title = {Subclinical brain magnetic resonance imaging abnormalities predict physical functional decline in high-functioning older adults.}, journal = {J Am Geriatr Soc}, volume = {53}, year = {2005}, month = {2005 Apr}, pages = {649-54}, abstract = {

OBJECTIVES: To determine whether severity of subclinical brain magnetic resonance imaging (MRI) abnormalities predicts incident self-reported physical impairment or rate of decline in motor performance.

DESIGN: Longitudinal analysis, average follow-up time: 4.0 years.

SETTING: Cardiovascular Health Study (CHS).

PARTICIPANTS: CHS participants with modified Mini-Mental State Examination (3MS) score of 80 or greater, no self-reported disability, no history of stroke, and at least one assessment of mobility (n=2,450, mean age=74.4).

MEASUREMENTS: Brain MRI abnormalities (ventricular enlargement, white matter hyperintensities, subcortical and basal ganglia small brain infarcts), self-reported physical impairment (difficulty walking half a mile or with one or more activities of daily living), and motor performance (gait speed, timed chair stand).

RESULTS: After adjusting for demographics, cardiovascular risk factors, and diseases, risk of incident self-reported physical impairment was 35\% greater for those with severe ventricular enlargement than for those with minimal ventricular enlargement, 22\% greater for those with moderate white matter hyperintensities than for those with minimal white matter hyperintensities, and 26\% greater for participants with at least one brain infarct than for those with no infarcts. Those with moderate to severe brain abnormalities experienced faster gait speed decline (0.02 m/s per year) than those with no MRI abnormalities (0.01 m/s per year). Further adjustment for incident stroke, incident dementia, and 3MS score did not substantially attenuate hazard ratios for incident self-reported physical impairment or coefficients for decline in gait speed.

CONCLUSION: Subclinical structural brain abnormalities in high-functioning older adults can increase the risk of developing physical disabilities and declining in motor performance.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Brain, Female, Follow-Up Studies, Gait, Humans, Incidence, Magnetic Resonance Imaging, Male, Proportional Hazards Models, Psychomotor Disorders, Risk Factors, United States}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.53214.x}, author = {Rosano, Caterina and Kuller, Lewis H and Chung, Hyoju and Arnold, Alice M and Longstreth, William T and Newman, Anne B} } @article {866, title = {Quantitative measures of gait characteristics indicate prevalence of underlying subclinical structural brain abnormalities in high-functioning older adults.}, journal = {Neuroepidemiology}, volume = {26}, year = {2006}, month = {2006}, pages = {52-60}, abstract = {

Abnormal gait in high-functioning older adults may indicate underlying subtle structural brain abnormalities. We tested the hypothesis that temporal and spatial parameters of gait, including speed, stride length and double support time, are cross-sectionally associated with white matter hyperintensity, subcortical infarcts or brain atrophy on brain MRI. We examined 321 men and women (mean age = 78.3) participating to the Cardiovascular Health Study who were free of dementia or stroke at the time of the gait assessment. Analyses were set with gait as independent variable and brain MRIs as dependent variables. Gait measures were determined from the footfalls recorded on a 4-meter-long instrumented walking surface, the GaitMat II. Brain MRIs were examined for the presence of white matter hyperintensity (WMG, graded from 0 to 9), brain infarcts (predominantly subcortical) and ventricular enlargement (graded from 0 to 9). Slower gait, shorter stride length and longer double support times were associated with greater prevalence of white matter grade > or =3 (p = 0.02), and at least 1 brain infarct (p = 0.04) independent of age. In multivariate logistic regression models adjusted for demographics and clinical cardiovascular diseases, those with gait speed <1.02 m/s were more likely to have WMG > or =3 and at least 1 brain infarct, compared with those with faster gait - odds ratio (OR): 2.85, 95\% confidence interval (95\% CI): 1.35, 6.02, and OR: 2.09, 95\% CI: 1.04, 4.19. Shorter stride length was also associated with greater probability of having at least 1 brain infarct (gait stride <0.88 vs. >1.10 m: OR: 3.20, 95\% CI: 1.49, 6.88), while longer double support times were associated with a greater probability of having WMG > or =3 (double support time >0.19 vs. <0.14 s: OR: 2.3, 95\% CI: 1.1, 4.7) independent of demographics and clinical cardiovascular diseases. Gait parameters were not significantly associated with ventricular grade. In summary, in this group of high-functioning older adults, poorer gait speed, shorter stride and longer double support time are associated with high white matter disease and subclinical strokes.

}, keywords = {Aged, Brain, Cerebral Infarction, Cerebral Ventricles, Cerebrovascular Disorders, Cohort Studies, Dementia, Female, Gait, Gait Disorders, Neurologic, Humans, Hypertension, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Stroke, United States}, issn = {0251-5350}, doi = {10.1159/000089240}, author = {Rosano, Caterina and Brach, Jennifer and Longstreth, William T and Newman, Anne B} } @article {1054, title = {Anemia is associated with the progression of white matter disease in older adults with high blood pressure: the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {56}, year = {2008}, month = {2008 Oct}, pages = {1867-72}, abstract = {

OBJECTIVES: To investigate whether anemia predicts worsening white matter hyperintensities (WMHs) in older community-dwellers.

DESIGN: Prospective cohort study.

SETTING: Older community-dwellers.

PARTICIPANTS: One thousand eight hundred forty-six Cardiovascular Health Study (CHS) participants (mean age 73.7 +/- 4.4, 41\% male, 15.6\% African American).

MEASUREMENTS: Participants had hemoglobin measured and brain magnetic resonance imaging (MRI) in 1992/93 and a second brain MRI in 1997/98. Anemia was defined according to World Health Organization criteria (hemoglobin <12 g/dL in women and <13 g/dL in men). Worsening WMHs were determined according to standardized side-by-side readings.

RESULTS: After 5 years, WMHs worsened in 517 participants (28\%). Progression was not associated with anemia in the whole sample, in sex or race strata, or in other prespecified subgroups (participants with renal dysfunction or diabetes mellitus), except in participants with high blood pressure (>or=140/90 mmHg). Of the 678 participants with high blood pressure, those with anemia (10.5\%) had a 1.79 times greater risk of WMHs worsening (95\% confidence interval=1.06-2.98; P for interaction between anemia and high blood pressure=.01) independent of demographics, baseline WMHs, cardiovascular risk factors and comorbidities, medications, renal function, inflammation, and incident stroke (logistic regression models). There was no greater risk in participants with anemia with normal blood pressure.

CONCLUSION: Anemia may contribute to worsening of WMHs in older adults with high blood pressure.

}, keywords = {Aged, Anemia, Brain, Cardiovascular Diseases, Disease Progression, Female, Humans, Hypertension, Leukoaraiosis, Magnetic Resonance Imaging, Male}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2008.01950.x}, author = {Inzitari, Marco and Studenski, Stephanie and Rosano, Caterina and Zakai, Neil A and Longstreth, William T and Cushman, Mary and Newman, Anne B} } @article {1279, title = {Association of HSP70 and its co-chaperones with Alzheimer{\textquoteright}s disease.}, journal = {J Alzheimers Dis}, volume = {25}, year = {2011}, month = {2011}, pages = {93-102}, abstract = {

The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer{\textquoteright}s disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; n = 806) and Cardiovascular Health Study (CHS; n = 2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32 kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis = 0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD. These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Cohort Studies, Genetic Association Studies, Genetic Variation, HSP70 Heat-Shock Proteins, Humans, Middle Aged, Molecular Chaperones, Polymorphism, Single Nucleotide}, issn = {1875-8908}, doi = {10.3233/JAD-2011-101560}, author = {Broer, Linda and Ikram, Mohammad Arfan and Schuur, Maaike and DeStefano, Anita L and Bis, Joshua C and Liu, Fan and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Beiser, Alexa S and Longstreth, William T and Hofman, Albert and Aulchenko, Yurii and Seshadri, Sudha and Fitzpatrick, Annette L and Oostra, Ben A and Breteler, Monique M B and van Duijn, Cornelia M} } @article {1276, title = {High blood pressure accelerates gait slowing in well-functioning older adults over 18-years of follow-up.}, journal = {J Am Geriatr Soc}, volume = {59}, year = {2011}, month = {2011 Mar}, pages = {390-7}, abstract = {

OBJECTIVES: To examine whether the association between hypertension and decline in gait speed is significant in well-functioning older adults and whether other health-related factors, such as brain, kidney, and heart function, can explain it.

DESIGN: Longitudinal cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Of 2,733 potential participants with a brain magnetic resonance imaging (MRI) scan, measures of mobility and systolic blood pressure (BP), no self-reported disability in 1992 to 1994 (baseline), and with at least 1 follow-up gait speed measurement through 1997 to 1999, 643 (aged 73.6, 57\% female, 15\% black) who had received a second MRI in 1997 to 1999 and an additional gait speed measure in 2005 to 2006 were included.

MEASUREMENTS: Mixed models with random slopes and intercepts were adjusted for age, race, and sex. Main explanatory factors included white matter hyperintensity progression, baseline cystatin-C, and left cardiac ventricular mass. Incidence of stroke and dementia, BP trajectories, and intake of antihypertensive medications during follow-up were tested as other potential explanatory factors.

RESULTS: Higher systolic BP was associated with faster rate of gait speed decline in this selected group of 643 participants, and results were similar in the parent cohort (N = 2,733). Participants with high BP (n = 293) had a significantly faster rate of gait speed decline than those with baseline BP less than 140/90 mmHg and no history of hypertension (n = 350). Rates were similar for those with history of hypertension who were uncontrolled (n = 110) or controlled (n = 87) at baseline and for those who were newly diagnosed (n = 96) at baseline. Adjustment for explanatory factors or for other covariates (education, prevalent cardiovascular disease, physical activity, vision, mood, cognition, muscle strength, body mass index, osteoporosis) did not change the results.

CONCLUSION: High BP accelerates gait slowing in well-functioning older adults over a long period of time, even for those who control their BP or develop hypertension later in life. Health-related measurements did not explain these associations. Future studies to investigate the mechanisms linking hypertension to slowing gait in older adults are warranted.

}, keywords = {Aged, Antihypertensive Agents, Comorbidity, Female, Follow-Up Studies, Gait, Geriatric Assessment, Humans, Hypertension, Longitudinal Studies, Magnetic Resonance Imaging, Male, Risk Factors, Statistics, Nonparametric}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2010.03282.x}, author = {Rosano, Caterina and Longstreth, William T and Boudreau, Robert and Taylor, Christopher A and Du, Yan and Kuller, Lewis H and Newman, Anne B} } @article {1334, title = {Slower gait, slower information processing and smaller prefrontal area in older adults.}, journal = {Age Ageing}, volume = {41}, year = {2012}, month = {2012 Jan}, pages = {58-64}, abstract = {

BACKGROUND: Slower gait in older adults is related to smaller volume of the prefrontal area (PFAv). The pathways underlying this association have not yet been explored. Understanding slowing gait could help improve function in older age. We examine whether the association between smaller PFAv and slower gait is explained by lower performance on numerous neuropsychological tests.

HYPOTHESIS: We hypothesise that slower information processing explains this association, while tests of language or memory will not.

METHODS: Data on brain imaging, neuropsychological tests (information processing speed, visuospatial attention, memory, language, mood) and time to walk 15 feet were obtained in 214 adults (73.3 years, 62\% women) free from stroke and dementia. Covariates included central (white matter hyperintensities, vision) and peripheral contributors of gait (vibration sense, muscle strength, arthritis, body mass index), demographics (age, race, gender, education), as well as markers of prevalent vascular diseases (cardiovascular disease, diabetes and ankle arm index).

RESULTS: In linear regression models, smaller PFAv was associated with slower time to walk independent of covariates. This association was no longer significant after adding information processing speed to the model. None of the other neuropsychological tests significantly attenuated this association.

CONCLUSIONS: We conclude that smaller PFAv may contribute to slower gait through slower information processing. Future longitudinal studies are warranted to examine the casual relationship between focal brain atrophy with slowing in information processing and gait.

}, keywords = {Affect, Aged, Aged, 80 and over, Aging, Attention, Body Mass Index, Cross-Sectional Studies, Female, Gait Disorders, Neurologic, Geriatric Assessment, Humans, Male, Memory, Mental Disorders, Mental Processes, Muscle Strength, Neuroimaging, Neuropsychological Tests, Prefrontal Cortex, Prevalence, Walking}, issn = {1468-2834}, doi = {10.1093/ageing/afr113}, author = {Rosano, Caterina and Studenski, Stephanie A and Aizenstein, Howard J and Boudreau, Robert M and Longstreth, William T and Newman, Anne B} } @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 {5849, title = {Adiposity and cognitive decline in the cardiovascular health study.}, journal = {Neuroepidemiology}, volume = {40}, year = {2013}, month = {2013}, pages = {274-81}, abstract = {

BACKGROUND: Studies relating adiposity to cognition in the elderly show conflicting results, which may be explained by the choice of adiposity measures. Thus, we studied the longitudinal associations of different adiposity measures, fat mass by bioelectrical impedance analysis, body mass index (BMI) and waist circumference (WC), with cognitive performance in the Cardiovascular Health Study.

METHODS: Cognitive performance was assessed with the modified Mini-Mental State Examination, the Digit Symbol Substitution Test, and a composite of both. We used linear mixed models to estimate rates of change in cognitive function scores associated with adiposity measured at baseline.

RESULTS: The final sample was comprised of 2,681 women (57.9\%) and 1,949 men (42.1\%) aged 73 {\textpm} 5.2 and 73.9 {\textpm} 5.6 years, respectively. Adiposity was associated with slower cognitive decline in most analyses. Results were similar for fat mass, BMI and WC. Higher fat-free mass was also related to slower cognitive decline. Results were similar in analyses excluding persons with cancer, smokers, and persons with short follow-up, poor self-reported health, or persons with cardiovascular disease.

CONCLUSIONS: Higher adiposity and higher fat-free mass in the elderly was related to better cognitive performance. This finding was not explained by confounding by preexisting conditions.

}, keywords = {Adiposity, Aged, Aged, 80 and over, Body Mass Index, Cardiovascular Diseases, Cognition Disorders, Electric Impedance, Female, Humans, Male, Risk Factors, Waist Circumference, Waist-Hip Ratio}, issn = {1423-0208}, doi = {10.1159/000345136}, author = {Luchsinger, Jos{\'e} A and Biggs, Mary L and Kizer, Jorge R and Barzilay, Joshua and Fitzpatrick, Annette and Newman, Anne and Longstreth, William T and Lopez, Oscar and Siscovick, David and Kuller, Lewis} } @article {6177, title = {Circulating omega-3 polyunsaturated fatty acids and subclinical brain abnormalities on MRI in older adults: the Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {2}, year = {2013}, month = {2013 Oct 10}, pages = {e000305}, abstract = {

BACKGROUND: Consumption of tuna or other broiled or baked fish, but not fried fish, is associated with fewer subclinical brain abnormalities on magnetic resonance imaging (MRI). We investigated the association between plasma phospholipid omega-3 polyunsaturated fatty acids (PUFAs), objective biomarkers of exposure, and subclinical brain abnormalities on MRI.

METHODS AND RESULTS: In the community-based Cardiovascular Health Study, 3660 participants aged >= 65 underwent brain MRI in 1992-1994, and 2313 were rescanned 5 years later. MRIs were centrally read by neuroradiologists in a standardized, blinded manner. Participants with recognized transient ischemic attacks or stroke were excluded. Phospholipid PUFAs were measured in stored plasma collected in 1992-1993 and related to cross-sectional and longitudinal MRI findings. After multivariable adjustment, the odds ratio for having a prevalent subclinical infarct was 0.60 (95\% CI, 0.44 to 0.82; P for trend = 0.001) in the highest versus lowest long-chain omega-3 PUFA quartile. Higher long-chain omega-3 PUFA content was also associated with better white matter grade, but not with sulcal or ventricular grades, markers of brain atrophy, or with incident subclinical infarcts. The phospholipid intermediate-chain omega-3 PUFA alpha-linolenic acid was associated only with modestly better sulcal and ventricular grades. However, this finding was not supported in the analyses with alpha-linolenic acid intake.

CONCLUSIONS: Among older adults, higher phospholipid long-chain omega-3 PUFA content was associated with lower prevalence of subclinical infarcts and better white matter grade on MRI. Our results support the beneficial effects of fish consumption, the major source of long-chain omega-3 PUFAs, on brain health in later life. The role of plant-derived alpha-linolenic acid in brain health requires further investigation.

}, keywords = {Aged, Animals, Biomarkers, Brain, Cross-Sectional Studies, Fatty Acids, Omega-3, Female, Fishes, Humans, Magnetic Resonance Imaging, Male, Prospective Studies}, issn = {2047-9980}, doi = {10.1161/JAHA.113.000305}, author = {Virtanen, Jyrki K and Siscovick, David S and Lemaitre, Rozenn N and Longstreth, William T and Spiegelman, Donna and Rimm, Eric B and King, Irena B and Mozaffarian, Dariush} } @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 {6188, title = {Enhancing case ascertainment of Parkinson{\textquoteright}s disease using Medicare claims data in a population-based cohort: the Cardiovascular Health Study.}, journal = {Pharmacoepidemiol Drug Saf}, volume = {23}, year = {2014}, month = {2014 Feb}, pages = {119-27}, abstract = {

PURPOSE: We sought to improve a previous algorithm to ascertain Parkinson{\textquoteright}s disease (PD) in the Cardiovascular Health Study by incorporating additional data from Medicare outpatient claims. We compared our results to the previous algorithm in terms of baseline prevalence and incidence of PD, as well as associations with baseline smoking characteristics.

METHODS: Our original case ascertainment used self-reported diagnosis, antiparkinsonian medication, and hospitalization discharge International Classification of Diseases-Ninth version code. In this study, we incorporated additional data from fee-for-service Medicare claims, extended follow-up time, review of hospitalization records, and adjudicated cause of death. Two movement disorders specialists adjudicated final PD status. We used logistic regression models and controlled for age, sex, African American race, and education.

RESULTS: We identified 75 additional cases but reclassified 80 previously identified cases as not having PD. We observed significant inverse association with smoking status (odds ratio = 0.42; 95\% confidence interval (CI) = 0.22, 0.79), and inverse linear trends with pack-years (p = 0.005), and cigarettes per day (p = 0.019) with incident PD. All estimates were stronger than those from the previous algorithm.

CONCLUSIONS: Our enhanced method did not alter prevalence and incidence estimates compared with our previous algorithm. However, our enhanced method provided stronger estimates of association, potentially due to reduced level of disease misclassification.

}, keywords = {Aged, Aged, 80 and over, Algorithms, Antiparkinson Agents, Cohort Studies, Databases, Factual, Female, Hospitalization, Humans, Incidence, Logistic Models, Male, Medicare, Parkinson Disease, Prevalence, Prospective Studies, Smoking, Time Factors, United States}, issn = {1099-1557}, doi = {10.1002/pds.3552}, author = {Ton, Thanh G N and Biggs, Mary Lou and Comer, Diane and Curtis, Lesley and Hu, Shu-Ching and Thacker, Evan L and Searles Nielsen, Susan and Delaney, Joseph A and Landsittel, Douglas and Longstreth, William T and Checkoway, Harvey and Jain, Samay} } @article {6819, title = {Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Dec}, pages = {864-72}, abstract = {

BACKGROUND: Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers.

METHODS AND RESULTS: This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

CONCLUSIONS: These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.

}, keywords = {Adult, Aged, Amidohydrolases, Arginine, Binding Sites, Cohort Studies, Female, Genetic Loci, Genome-Wide Association Study, Genotype, HEK293 Cells, Humans, Male, Mediator Complex, Middle Aged, Polymorphism, Single Nucleotide, Protein Structure, Tertiary, Risk Factors, Stroke, Substrate Specificity, Transaminases}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000264}, author = {L{\"u}neburg, Nicole and Lieb, Wolfgang and Zeller, Tanja and Chen, Ming-Huei and Maas, Renke and Carter, Angela M and Xanthakis, Vanessa and Glazer, Nicole L and Schwedhelm, Edzard and Seshadri, Sudha and Ikram, Mohammad Arfan and Longstreth, William T and Fornage, Myriam and K{\"o}nig, Inke R and Loley, Christina and Ojeda, Francisco M and Schillert, Arne and Wang, Thomas J and Sticht, Heinrich and Kittel, Anja and K{\"o}nig, J{\"o}rg and Benjamin, Emelia J and Sullivan, Lisa M and Bernges, Isabel and Anderssohn, Maike and Ziegler, Andreas and Gieger, Christian and Illig, Thomas and Meisinger, Christa and Wichmann, H-Erich and Wild, Philipp S and Schunkert, Heribert and Psaty, Bruce M and Wiggins, Kerri L and Heckbert, Susan R and Smith, Nicholas and Lackner, Karl and Lunetta, Kathryn L and Blankenberg, Stefan and Erdmann, Jeanette and M{\"u}nzel, Thomas and Grant, Peter J and Vasan, Ramachandran S and B{\"o}ger, Rainer H} } @article {6212, title = {Plasma free fatty acids and risk of stroke in the Cardiovascular Health Study.}, journal = {Int J Stroke}, volume = {9}, year = {2014}, month = {2014 Oct}, pages = {917-20}, abstract = {

BACKGROUND: Although free fatty acids have been positively associated with risk factors for stroke, the role of plasma free fatty acids in the development of stroke has not been elucidated in older adults.

AIMS: We sought to examine the association between plasma free fatty acids and incident stroke.

METHODS: Prospective cohort of 4369 men and women>=65 years of age in the Cardiovascular Health Study. Plasma levels of free fatty acids were measured at the 1992-1993 examination and stroke events were adjudicated by a committee of experts including neurologists and neuroradiologists. Cox regression was used to estimate the relative risk of stroke associated with free fatty acids concentrations.

RESULTS: The average age among participants was 75{\textpm}5{\textperiodcentered}2 years. During a median follow-up of 11{\textperiodcentered}4 years, 732 incident strokes occurred. The crude incidence rates of stroke were 14{\textperiodcentered}5, 14{\textperiodcentered}9, and 17{\textperiodcentered}6 per 1000 person-years across increasing tertiles of plasma free fatty acids. The adjusted hazard ratio (95\% confidence interval) for incident stroke was 1{\textperiodcentered}05 (0{\textperiodcentered}97-1{\textperiodcentered}14) per standard deviation increase in plasma free fatty acids. Restriction to ischemic stroke did not alter the results [hazard ratio (95\% confidence interval): 1{\textperiodcentered}04 (0{\textperiodcentered}96-1{\textperiodcentered}14) per standard deviation higher free fatty acids], and there was no effect modification by adiposity (P interaction=0{\textperiodcentered}18) or by diabetes (P interaction=0{\textperiodcentered}15).

CONCLUSION: Our data did not show an association of plasma free fatty acids with incident stroke among community dwelling older adults.

}, keywords = {Aged, Biomarkers, Brain Ischemia, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Male, Prospective Studies, Risk, Stroke}, issn = {1747-4949}, doi = {10.1111/ijs.12216}, author = {Khawaja, Owais and Maziarz, Marlena and Biggs, Mary L and Longstreth, William T and Ix, Joachim H and Kizer, Jorge R and Zieman, Susan and Tracy, Russell P and Mozaffarian, Dariush and Mukamal, Kenneth J and Siscovick, David S and Djouss{\'e}, Luc} } @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 {7493, title = {Factors Associated With Ischemic Stroke Survival and Recovery in Older Adults.}, journal = {Stroke}, volume = {48}, year = {2017}, month = {2017 Jul}, pages = {1818-1826}, abstract = {

BACKGROUND AND PURPOSE: Little is known about factors that predispose older adults to poor recovery after a stroke. In this study, we sought to evaluate prestroke measures of frailty and related factors as markers of vulnerability to poor outcomes after ischemic stroke.

METHODS: In participants aged 65 to 99 years with incident ischemic strokes from the Cardiovascular Health Study, we evaluated the association of several risk factors (frailty, frailty components, C-reactive protein, interleukin-6, and cystatin C) assessed before stroke with stroke outcomes of survival, cognitive decline (>=5 points on Modified Mini-Mental State Examination), and activities of daily living decline (increase in limitations).

RESULTS: Among 717 participants with incident ischemic stroke with survival data, slow walking speed, low grip strength, and cystatin C were independently associated with shorter survival. Among participants <80 years of age, frailty and interleukin-6 were also associated with shorter survival. Among 509 participants with recovery data, slow walking speed, and low grip strength were associated with both cognitive and activities of daily living decline poststroke. C-reactive protein and interleukin-6 were associated with poststroke cognitive decline among men only. Frailty status was associated with activities of daily living decline among women only.

CONCLUSIONS: Markers of physical function-walking speed and grip strength-were consistently associated with survival and recovery after ischemic stroke. Inflammation, kidney function, and frailty also seemed to be determinants of survival and recovery after an ischemic stroke. These markers of vulnerability may identify targets for differing pre and poststroke medical management and rehabilitation among older adults at risk of poor stroke outcomes.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Brain Ischemia, Cohort Studies, Female, Follow-Up Studies, Frail Elderly, Humans, Male, Recovery of Function, Risk Factors, Stroke, Survival Rate}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.117.016726}, author = {Winovich, Divya Thekkethala and Longstreth, William T and Arnold, Alice M and Varadhan, Ravi and Zeki Al Hazzouri, Adina and Cushman, Mary and Newman, Anne B and Odden, Michelle C} }