@article {909, title = {Acceleration of cerebral ventricular expansion in the Cardiovascular Health Study.}, journal = {Neurobiol Aging}, volume = {28}, year = {2007}, month = {2007 Sep}, pages = {1316-21}, abstract = {

Interactions between prevalent late-life medical conditions and expansion of the cerebral ventricles are not well understood. Thirty elderly subjects received three magnetic resonance (MR) scans each, in 1997-1999, 2002-2004, and 2003-2005. A linear expansion model of MR-measured lateral ventricle volume was estimated for each subject by fitting a line to a plot of their 1997-1999 and 2002-2004 volumes as a function of time. Acceleration in ventricular expansion was defined as the deviation between the 2003-2005 volumes measured from MR and the 2003-2005 volumes predicted by the linear expansion model. Ventricular acceleration was analyzed in a multivariate model with age, race, history of heart disease, diabetes, and hypertension as fixed effects. Ventricular acceleration was significantly higher in non-whites, diabetics, and those without heart disease (p<0.05). Ventricular acceleration was higher in subjects with a history of hypertension, but the difference was not statistically significant (p=0.08). Acceleration of ventricular expansion in the elderly may be related to demographic and cardiovascular factors.

}, keywords = {Aged, Analysis of Variance, Cardiovascular Diseases, Cerebral Ventricles, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Reference Values, Retrospective Studies, Sex Factors, Time Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2006.06.016}, author = {Carmichael, Owen T and Kuller, L H and Lopez, O L and Thompson, P M and Dutton, R A and Lu, A and Lee, S E and Lee, J Y and Aizenstein, H J and Meltzer, C C and Liu, Y and Toga, A W and Becker, J T} } @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 {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 {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 {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 {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 {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 {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 {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} }