Publications by authors named "Philip A Wolf"

193 Publications

Distribution of cerebral microbleeds in the East and West: Individual participant meta-analysis.

Neurology 2019 03 1;92(10):e1086-e1097. Epub 2019 Feb 1.

From the Stroke Research Center, Department of Brain Repair & Rehabilitation, Institute of Neurology (Y.Y., D.W., A.C., D.J.W.), and Department of Statistical Science (G.A.), UCL, London, UK; Division of Neurology (Y.Y., H.H.), Department of Internal Medicine, Saga University Faculty of Medicine, Japan; Department of Neurology (A.B., S.R.P., J.R.R., S.S., P.A.W.), Boston University and the NHLBI's Framingham Heart Study; Department of Biostatistics (A.B., S.R.P.), Boston University, MA; Department of Radiology (M.A.v.B.), Leiden University Medical Center, the Netherlands; Department of Neurology (C.D.), University of California Davis; Department of Neurology (D.D.), Huashan Hospital, Fudan University, Shanghai, China; Icelandic Heart Association (V.G.), Kopavogur; University of Iceland (V.G.), Reykjavik; Department of Neurosurgery (T.I.), Kushiro City General Hospital; Faculty of Collaborative Regional Innovation (K.K.), Ehime University, Matsuyama, Japan; Department of Neurology (H.-M.K.), SMG-SNU Boramae Medical Center, Seoul, Republic of Korea; Intramural Research Program (L.J.L.), National Institute on Aging, Bethesda, MD; Therese Pei Fong Chow Research Center for Prevention of Dementia (V.M., Z.W., Y.X.), Department of Medicine and Therapeutics, The Chinese University of Hong Kong, China; Stroke and Aging Research Group, Department of Medicine, School of Clinical Science at Monash Health (T.P., V.S.), and Department of Medicine, Peninsula Health and Clinical School, Central Clinical School (V.S.), Monash University, Melbourne, Australia; Center for Emotional and Behavioral Disorders (Y. Takashima), Hizen Psychiatric Center, Saga, Japan; Department of Diagnostic Radiology and Nuclear Medicine (Y. Tsushima), Gunma University Graduate School of Medicine; Research Program for Diagnostic and Molecular Imaging (Y. Tsushima), Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research, Maebashi; and Department of Neurology (S.Y.), Faculty of Medicine, Shimane University, Izumo, Japan.

Objective: We investigated differences in the anatomical distribution of cerebral microbleeds (CMBs) on MRI, hypothesized to indicate the type of underlying cerebral small vessel disease (SVD), between Eastern and Western general populations.

Methods: We analyzed data from 11 studies identified by a PubMed search between 1996 and April 2014 according to the Preferred Reporting Items for a Systematic Review and Meta-analysis of Individual Participant Data. Study quality measures indicated low or medium risk of bias. We included stroke-free participants from populations aged between 55 and 75 years, categorized by geographic location (Eastern or Western). We categorized CMB distribution (strictly lobar, deep and/or infratentorial [D/I], or mixed [i.e., CMBs located in both lobar and D/I regions]). We tested the hypothesis that Eastern and Western populations have different anatomical distributions of CMBs using multivariable mixed effects logistic regression analyses adjusted for age, sex, and hypertension and clustering by institution.

Results: Among 8,595 stroke-free individuals (mean age [SD] 66.7 [5.6] years; 48% male; 42% from a Western population), 624 (7.3%) had CMBs (strictly lobar in 3.1%; D/I or mixed in 4.2%). In multivariable mixed effects models, Eastern populations had higher odds of D/I or mixed CMBs (adjusted odds ratio 2.78, 95% confidence interval [CI] 1.77-4.35) compared to Western populations. Eastern populations had a higher number of D/I or mixed CMBs (adjusted prevalence ratio 2.83, 95% CI 1.27-6.31).

Conclusions: Eastern and Western general populations have different anatomical distributions of CMBs, suggesting differences in the spectrum of predominant underlying SVDs, with potential implications for SVD diagnosis and treatment.
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http://dx.doi.org/10.1212/WNL.0000000000007039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442016PMC
March 2019

Baseline White Matter Hyperintensities and Hippocampal Volume are Associated With Conversion From Normal Cognition to Mild Cognitive Impairment in the Framingham Offspring Study.

Alzheimer Dis Assoc Disord 2018 Jan-Mar;32(1):50-56

Taub Institute for Research on Alzheimer's Disease and the Aging Brain.

Introduction: We examined associations between magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration with mild cognitive impairment (MCI) diagnosis at baseline and conversion from normal cognition to MCI at follow-up.

Methods: Framingham Offspring participants underwent brain MRI and neuropsychological assessment at baseline (n=1049) and follow-up (n=561). Participants were classified at baseline and at follow-up as cognitively normal or MCI using sensitive neuropsychological criteria. White matter hyperintensity (WMH) volume, covert brain infarcts, hippocampal volume, and total cerebral brain volume were quantified.

Results: Baseline measures of WMH and hippocampal volume were associated with MCI status cross-sectionally and also with conversion from normal cognition to MCI at 6.5-year follow-up. Annualized change rates in total cerebral brain volume and hippocampal volume were associated with conversion from normal cognition to MCI to follow-up.

Discussion: Baseline WMH and hippocampal volume are markers that are both associated with conversion from normal cognition to MCI, highlighting the role of both vascular lesions and neurodegeneration in MCI.
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http://dx.doi.org/10.1097/WAD.0000000000000215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821543PMC
September 2019

Association of descending thoracic aortic plaque with brain atrophy and white matter hyperintensities: The Framingham Heart Study.

Atherosclerosis 2017 10 23;265:305-311. Epub 2017 Jun 23.

Department of Neurology, Boston University School of Medicine, 72 East Concord Street, C-3, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute's Framingham Study, 73 Mt. Wayte Avenue, Suite 2, Framingham, MA 01702, USA.

Background And Aims: Aortic atherosclerosis is an aggregate marker of vascular risk factor exposure and has been associated with intracranial atherosclerosis and stroke. We hypothesized that atherosclerosis of the descending aorta (DAo) could be a risk marker for brain aging and injury.

Methods: We evaluated 1527 participants (mean age 59.9 years, 53.5% women) in the Framingham Offspring cohort who underwent both aortic and brain MRI. Participants were free of clinical stroke, dementia, or other neurological illness at the time of axial MRI of the thoracic and abdominal DAo and subsequent brain MRI. We related the prevalence and burden of aortic plaque to total cerebral brain volume (TCBV) and white matter hyperintensity volume (WMHV). An additional analysis compared incidence of stroke or TIA in participants with and without DAo plaques.

Results: Presence of thoracic DAo plaque (8%) was associated with decreased TCBV in sex-pooled analysis (-0.77, SE 0.25, p = 0.002, equivalent to 4.5 years of aging) and with increased WMHV only in men (0.26, SE 0.12, p = 0.032, equivalent to 6.5 years aging). We observed similar associations of DAo plaque burden with TCBV and WMHV. There were 43 strokes and 11 TIAs in prospective follow-up (median 7 years). Presence of DAo plaque was not associated with subsequent stroke or TIA.

Conclusions: In this cross-sectional community-based study, we found DAo plaque is associated with accelerated brain aging. These data underscore the potential implications of incidentally identified subclinical aortic atherosclerosis and question whether targeted intervention in these high risk individuals can modulate cognitive decline.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.06.919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617776PMC
October 2017

Overweight, Obesity, and Survival After Stroke in the Framingham Heart Study.

J Am Heart Assoc 2017 Jun 24;6(6). Epub 2017 Jun 24.

Department of Neurology, School of Medicine, Boston University, Boston, MA.

Background: We investigated how body weight affects survival after stroke, leveraging the availability of multiple prestroke body mass index (BMI) measurements and using a nested case-control design in a community-based sample.

Methods And Results: We compared all-cause mortality in participants stratified by prestroke weight. Separate analyses were performed for ischemic stroke and all stroke and for age-, sex-, and BMI category-matched stroke-free controls. Participants were grouped into BMI categories and followed for up to 10 years. Differences in survival were tested for interaction by case status. In sensitivity analysis, to exclude those with prestroke weight loss, we restricted the reference group to participants with 2 consistently normal BMI measurements within 10 years before stroke/matching. There were 782 stroke cases (age 71±9, 51% female participants, 87% ischemic stroke) and 2346 controls (age 72±9, 51% female participants). Overweight participants with ischemic stroke had a lower mortality compared with those with normal weight (hazard ratio [HR]=0.70, 95%CI 0.55-0.90, =0.005). The association of reduced mortality with BMI ≥25, compared with normal-weight BMI 18.5 to <25, was pronounced among ischemic stroke cases but diminished with inclusion of hemorrhagic strokes (case-control interaction =0.051 and =0.130, respectively). Compared with participants with stable normal weight, moderately increased weight was protective after ischemic stroke (overweight HR=0.72, 95%CI 0.53-0.99, =0.041).

Conclusions: Overweight and mildly obese participants had better 10-year survival after ischemic stroke compared with normal-weight participants, even after excluding persons with recent prestroke weight loss. There may be unknown protective factors associated with a moderately increased body weight before stroke.
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http://dx.doi.org/10.1161/JAHA.116.004721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669145PMC
June 2017

Practical risk score for 5-, 10-, and 20-year prediction of dementia in elderly persons: Framingham Heart Study.

Alzheimers Dement 2018 01 13;14(1):35-42. Epub 2017 Jun 13.

Department of Graduate Medical Sciences, Boston University School of Medicine, Boston, MA, USA; Framingham Heart Study, Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA. Electronic address:

Introduction: With a rapidly aging population, general practitioners are confronting the challenge of how to determine those who are at greatest risk for dementia and potentially need more specialized follow-up to mitigate symptoms early in its course. We created a practical dementia risk score and provided individualized estimates of future dementia risk.

Methods: Using the Framingham Heart Study data, we built our prediction model using Cox proportional hazard models and developed a point system for the risk score and risk estimates.

Results: The score system used total points ranging from -1 to 31 and stratifies individuals into different levels of risk. We estimated 5-, 10-, and 20-year dementia risk prediction and incorporated these into the points system.

Discussion: This risk score system provides a practical tool because all included predictors are easy to assess by practitioners. It can be used to estimate future probabilities of dementia for individuals.
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http://dx.doi.org/10.1016/j.jalz.2017.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729055PMC
January 2018

Revised Framingham Stroke Risk Profile to Reflect Temporal Trends.

Circulation 2017 Mar 3;135(12):1145-1159. Epub 2017 Feb 3.

From Inserm, Bordeaux Population Health Research Center, UMR 1219, Univ. Bordeaux, France (C.D., C.T., C.S., G.C.); ISPED, Univ. Bordeaux, France (C.D., C.S., G.C.); CHU de Bordeaux, Pole de sante publique, France (C.D., C.T., G.C.); Department of Neurology, School of Medicine (A.B., P.A.W., J.J.H., H.J.A., M.K.-H., C.S.K., A.P., J.R.R., S.S.), Department of Biostatistics, School of Public Health (A.B., L.S.), and Department of Mathematics (R.B.D.), Boston University, MA; National Heart, Lung, and Blood Institute's Framingham Heart Study, MA (A.B., P.A.W., A.J.W., J.J.H., H.J.A., M.K.-H., C.S.K., A.P., J.R.R., R.B.D., R.S.V., S.S.); Department of Biostatistics, Drexel University School of Public Health, Philadelphia, PA (L.A.M.); Departments of Epidemiology (V.J.H.) and Biostatistics (G.H.), School of Public Health, University of Alabama at Birmingham; and INSERM Unit 1061, Montpellier University, France (K.R.).

Background: Age-adjusted stroke incidence has decreased over the past 50 years, likely as a result of changes in the prevalence and impact of various stroke risk factors. An updated version of the Framingham Stroke Risk Profile (FSRP) might better predict current risks in the FHS (Framingham Heart Study) and other cohorts. We compared the accuracy of the standard (old) and of a revised (new) version of the FSRP in predicting the risk of all-stroke and ischemic stroke and validated this new FSRP in 2 external cohorts, the 3C (3 Cities) and REGARDS (Reasons for Geographic and Racial Differences in Stroke) studies.

Methods: We computed the old FSRP as originally described and a new model that used the most recent epoch-specific risk factor prevalence and hazard ratios for individuals ≥55 years of age and for the subsample ≥65 years of age (to match the age range in REGARDS and 3C studies, respectively) and compared the efficacy of these models in predicting 5- and 10-year stroke risks.

Results: The new FSRP was a better predictor of current stroke risks in all 3 samples than the old FSRP (calibration χ of new/old FSRP: in men: 64.0/12.1, 59.4/30.6, and 20.7/12.5; in women: 42.5/4.1, 115.4/90.3, and 9.8/6.5 in FHS, REGARDS, and 3C, respectively). In the REGARDS, the new FSRP was a better predictor among whites compared with blacks.

Conclusions: A more contemporaneous, new FSRP better predicts current risks in 3 large community samples and could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.021275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504355PMC
March 2017

Cerebral Microbleeds as Predictors of Mortality: The Framingham Heart Study.

Stroke 2017 03 31;48(3):781-783. Epub 2017 Jan 31.

From the Department of Neurology (J.R.R., A.B., P.A.W., C.S.K., S.S.), Section of Preventive Medicine (V.S.R.), and Department of Cardiology (V.S.R.), School of Medicine and Department of Biostatistics (S.R.P., A.B., J.J.H.), School of Public Health at Boston University, MA; Department of Medicine-Neurology, McMaster University and Population Health Research Institute, Hamilton, Ontario, Canada (A.S.); Department of Neurology, University of California-Davis (C.D.); and the NHLBI's Framingham Heart Study, Framingham, MA (J.R.R., S.R.P., A.B., J.J.H., P.A.W., C.S.K., V.S.R., S.S.).

Background And Purpose: Cerebral microbleeds (CMB) represent a common magnetic resonance imaging marker of cerebral small vessel disease, increasingly recognized as a subclinical marker of stroke and dementia risk. CMB detection may reflect the cumulative effect of vascular risk burden and be a marker of higher mortality. We investigated the relation of CMB to risk of death in community dwelling participants free of stroke and dementia.

Methods: We evaluated 1963 Framingham Original and Offspring Cohort participants (mean age 67 years; 54% women) with available brain magnetic resonance imaging and mortality data. Using Cox proportional hazards models, we related CMB to all-cause, cardiovascular, and stroke-related mortality.

Results: Participants with CMB (8.9%) had higher prevalence of cardiovascular risk factors and use of preventive medications. During a mean follow-up of 7.2±2.6 years, we observed 296 deaths. In age- and sex-adjusted analysis, CMB were associated with increased all-cause mortality (hazards ratio, 1.39; 95% confidence interval 1.03-1.88), a relation that was no longer significant after adjustment for cardiovascular risk and preventive medication use (hazards ratio, 1.15; 95% confidence interval, 0.82-1.63).

Conclusions: CMBs may represent the deleterious effect of cardiovascular risk factors in the cerebral vasculature. Although their presence was associated with increased all-cause mortality, the effect was no longer present after accounting for vascular risk factors and preventive treatment use. Further studies are required to clarify the role of cardiovascular preventive therapies for prevention of mortality in persons with incidental detection of CMB.
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http://dx.doi.org/10.1161/STROKEAHA.116.015354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330856PMC
March 2017

Stroke as the Initial Manifestation of Atrial Fibrillation: The Framingham Heart Study.

Stroke 2017 02 12;48(2):490-492. Epub 2017 Jan 12.

From the Cardiovascular Research Center (S.A.L., L.-C.W., P.T.E.) and Cardiac Arrhythmia Service (S.A.L., P.T.E.), Massachusetts General Hospital, Boston; Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA (X.Y., J.R.R., P.A.W., S.S., E.J.B.); Cardiology Division, Department of Medicine, University of Massachusetts Medical School, Worcester (D.D.M.); Boston University School of Medicine, MA (H.J.A., J.R.R., P.A.W., S.S., E.J.B.); Department of Neurology, Boston Medical Centre, MA (H.J.A., J.R.R., C.S.K., S.S.); Pulmonary Center and the Section of Pulmonary and Critical Care Medicine, Department of Medicine (A.J.W.) and Preventive Medicine Section, Department of Medicine (E.J.B.), Boston University School of Medicine, MA; and Section of Cardiovascular Medicine and Department of Epidemiology, School of Public Health, Boston University, MA (E.J.B.).

Background And Purpose: To prevent strokes that may occur as the first manifestation of atrial fibrillation (AF), screening programs have been proposed to identify patients with undiagnosed AF who may be eligible for treatment with anticoagulation. However, the frequency with which patients with AF present with stroke as the initial manifestation of the arrhythmia is unknown.

Methods: We estimated the frequency with which AF may present as a stroke in 1809 community-based Framingham Heart Study participants with first-detected AF and without previous strokes, by tabulating the frequencies of strokes occurring on the same day, within 30 days before, 90 days before, and 365 days before first-detected AF. Using previously reported AF incidence rates, we estimated the incidence of strokes that may represent the initial manifestation of AF.

Results: We observed 87 strokes that occurred ≤1 year before AF detection, corresponding to 1.7% on the same day, 3.4% within 30 days before, 3.7% within 90 days before, and 4.8% ≤1 year before AF detection. We estimated that strokes may present as the initial manifestation of AF at a rate of 2 to 5 per 10 000 person-years, in both men and women.

Conclusions: We observed that stroke is an uncommon but measureable presenting feature of AF. Our data imply that emphasizing cost-effectiveness of population-wide AF-screening efforts will be important given the relative infrequency with which stroke represents the initial manifestation of AF.
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http://dx.doi.org/10.1161/STROKEAHA.116.015071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5262530PMC
February 2017

Neuropsychological Criteria for Mild Cognitive Impairment and Dementia Risk in the Framingham Heart Study.

J Int Neuropsychol Soc 2016 10 31;22(9):937-943. Epub 2016 Mar 31.

3Framingham Heart Study,Framingham,Massachusetts.

Objectives: To refine mild cognitive impairment (MCI) diagnostic criteria, we examined progression to dementia using two approaches to identifying MCI.

Methods: A total of 1203 Framingham Heart Study participants were classified at baseline as cognitively normal or MCI (overall and four MCI subtypes) via conventional Petersen/Winblad criteria (single cognitive test impaired per domain, >1.5 SD below expectations) or Jak/Bondi criteria (two tests impaired per domain, >1 SD below norms). Cox proportional hazards models were constructed to examine the association between each MCI definition and incident dementia.

Results: The Petersen/Winblad criteria classified 34% of participants as having MCI while the Jak/Bondi criteria classified 24% as MCI. Over a mean follow-up of 9.7 years, 58 participants (5%) developed incident dementia. Both MCI criteria were associated with incident dementia [Petersen/Winblad: hazards ratio (HR) = 2.64; p-value=.0002; Jak/Bondi: HR=3.30; p-value <.0001]. When both MCI definitions were included in the same model, only the Jak/Bondi definition remained statistically significantly associated with incident dementia (HR=2.47; p-value=.008). Multi-domain amnestic and single domain non-amnestic MCI subtypes were significantly associated with incident dementia for both diagnostic approaches (all p-values <.01).

Conclusions: The Jak/Bondi MCI criteria had a similar association with dementia as the conventional Petersen/Winblad MCI criteria, despite classifying ~30% fewer participants as having MCI. Further exploration of alternative methods to conventional MCI diagnostic criteria is warranted. (JINS, 2016, 22, 937-943).
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045758PMC
http://dx.doi.org/10.1017/S1355617716000199DOI Listing
October 2016

Circulating biomarkers and incident ischemic stroke in the Framingham Offspring Study.

Neurology 2016 Sep 24;87(12):1206-11. Epub 2016 Aug 24.

From the McMaster University and Population Health Research Institute (A.S.), Hamilton, Canada; Boston University School of Public Health (S.R.P., A.S.B., E.J.B.), Boston; and Boston University School of Medicine (A.S., A.S.B., C.S.K., P.A.W., R.S.V., E.J.B., S.S., J.R.R.), Boston, MA.

Objective: We related a panel of inflammatory biomarkers to risk of incident ischemic stroke (IIS) in a community-dwelling sample.

Methods: Stroke-free Framingham offspring attending examination cycle 7 (1998-2001) had 15 circulating inflammatory biomarkers measured. Cox proportional hazard models were used to calculate the hazard ratios (HRs) of IIS per SD increment of each biomarker. Model 1 included age and sex. Model 2 additionally adjusted for systolic blood pressure, hypertension treatment, current smoking, diabetes, cardiovascular disease, and atrial fibrillation. The continuous net reclassification improvement was used to assess the improvement in IIS risk prediction of statistically significant biomarkers from our main analysis over traditional stroke risk factors.

Results: In 3,224 participants (mean age 61 ± 9 years, 54% women), 98 experienced IIS (mean follow-up of 9.8 [±2.2] years). In model 1, ln-C-reactive protein (ln-CRP) (HR 1.28, 95% confidence interval [CI] 1.04-1.56), ln-tumor necrosis factor receptor 2 (ln-TNFR2) (HR 1.33, 95% CI 1.09-1.63), ln-total homocysteine (ln-tHcy) (HR 1.32, 95% CI 1.11-1.58), and vascular endothelial growth factor (VEGF) (HR 1.25, 95% CI 1.07-1.46) were associated with risk of IIS. All associations, except for ln-CRP, remained significant in model 2 (ln-TNFR2: HR 1.24, 95% CI 1.02-1.51; ln-tHcy: HR 1.20, 95% CI 1.01-1.43; and VEGF: HR 1.21, 95% CI 1.04-1.42). The addition of these 4 biomarkers to the clinical Framingham Stroke Risk Profile score improved stroke risk prediction (net reclassification improvement: 0.34, 0.12-0.57; p < 0.05).

Conclusions: Higher levels of 4 biomarkers-CRP, tHcy, TNFR2, and VEGF-increased risk of IIS and improved the predictive ability of the Framingham Stroke Risk Profile score. Further research is warranted to explore their role as potential therapeutic targets.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035987PMC
http://dx.doi.org/10.1212/WNL.0000000000003115DOI Listing
September 2016

Pulse Pressure Is Associated With Early Brain Atrophy and Cognitive Decline: Modifying Effects of APOE-ε4.

Alzheimer Dis Assoc Disord 2016 Jul-Sep;30(3):210-5

*Department of Psychology, University of Southern California, Los Angeles∥Veterans Affairs San Diego Healthcare System¶Department of Psychiatry, University of California, San Diego, La Jolla, CA†The Framingham Heart Study, FraminghamDepartments of ‡Biostatistics§Department of Neurology, Boston University School of Medicine, Boston, MA#Department of Psychiatry, University of Illinois at Chicago, Chicago, IL**Drexel Neuroscience Institute, College of Medicine, Drexel University, Philadelphia, PA.

We investigated whether midlife pulse pressure is associated with brain atrophy and cognitive decline, and whether the association was modified by apolipoprotein-E ε4 (APOE-ε4) and hypertension. Participants (549 stroke-free and dementia-free Framingham Offspring Cohort Study participants, age range=55.0 to 64.9 y) underwent baseline neuropsychological and magnetic resonance imaging (subset, n=454) evaluations with 5- to 7-year follow-up. Regression analyses investigated associations between baseline pulse pressure (systolic-diastolic pressure) and cognition, total cerebral volume and temporal horn ventricular volume (as an index of smaller hippocampal volume) at follow-up, and longitudinal change in these measures. Interactions with APOE-ε4 and hypertension were assessed. Covariates included age, sex, education, assessment interval, and interim stroke. In the total sample, baseline pulse pressure was associated with worse executive ability, lower total cerebral volume, and greater temporal horn ventricular volume 5 to 7 years later, and longitudinal decline in executive ability and increase in temporal horn ventricular volume. Among APOE-ε4 carriers only, baseline pulse pressure was associated with longitudinal decline in visuospatial organization. Findings indicate arterial stiffening, indexed by pulse pressure, may play a role in early cognitive decline and brain atrophy in mid to late life, particularly among APOE-ε4 carriers.
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http://dx.doi.org/10.1097/WAD.0000000000000127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999260PMC
November 2017

Association between atrial fibrillation and volumetric magnetic resonance imaging brain measures: Framingham Offspring Study.

Heart Rhythm 2016 10 11;13(10):2020-4. Epub 2016 Jul 11.

Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; The Framingham Heart Study, Framingham, Massachusetts. Electronic address:

Background: The increased risk of stroke and cognitive impairment associated with atrial fibrillation (AF) is well documented. However, there is a paucity of research investigating the relations between AF and brain morphology.

Objective: The purpose of this study was to investigate the association between AF and brain volume measures on magnetic resonance imaging (MRI).

Methods: The study sample included stroke- and dementia-free participants who attended the Framingham Heart Study offspring cohort 7th examination cycle (1999-2005) and underwent contemporaneous MRI. We examined the association between prevalent AF and brain volume measures (total cerebral volume, frontal lobe volume, temporal lobe volume, temporal horn volume, hippocampal volume, and white matter hyperintensity volume) with linear regression. We first adjusted models for age and sex, and then for vascular risk factors and APOE4.

Results: We studied 2144 individuals (mean age 61.8 ± 9.3 years; 54% women); 73 participants (3.4%) had prevalent AF at the time of MRI. In age- and sex-adjusted models, AF was inversely associated with total cerebral brain volume, frontal brain volume, and temporal brain volume. After further adjustment for vascular risk factors and APOE4, AF remained associated with frontal brain volume.

Conclusion: After accounting for vascular risk factor burden, prevalent AF was associated with lobar indexes of vascular brain aging but not with expected white matter changes.
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http://dx.doi.org/10.1016/j.hrthm.2016.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035234PMC
October 2016

Population Normative Data for the CERAD Word List and Victoria Stroop Test in Younger- and Middle-Aged Adults: Cross-Sectional Analyses from the Framingham Heart Study.

Exp Aging Res 2016 Jul-Sep;42(4):315-28

a Boston University School of Medicine , Boston , Massachusetts , USA.

Background/study Context: To provide baseline normative data on tests of verbal memory and executive function for nondemented younger- and middle-aged adults.

Methods: The Consortium to Establish a Registry for Alzheimer's Disease word list memory task (CERAD-WL) and Victoria Stroop Test (VST) were administered to 3362 Framingham Heart Study (FHS) volunteer participants aged 24-78 years. Analyses of the effects of age, gender, and education were conducted. Normative data on traditional measures and error responses are reported for each test.

Results: Traditional measures were significantly associated with both age and education in this cohort. Error responses also evidenced significant age and education effects.

Conclusion: These data provide a normative comparison for assessment of verbal memory and executive functioning capabilities in younger- and middle-aged adults and may be utilized as a tool for preclinical studies of disease in this population.
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http://dx.doi.org/10.1080/0361073X.2016.1191838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946576PMC
April 2017

Interaction Between Midlife Blood Glucose and APOE Genotype Predicts Later Alzheimer's Disease Pathology.

J Alzheimers Dis 2016 07;53(4):1553-62

Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.

Elevated blood glucose and the apolipoprotein (APOE) ɛ4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer's disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE ɛ4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE ɛ4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment.
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http://dx.doi.org/10.3233/JAD-160163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494258PMC
July 2016

Effects of white matter integrity and brain volumes on late life depression in the Framingham Heart Study.

Int J Geriatr Psychiatry 2017 02 5;32(2):214-221. Epub 2016 Apr 5.

Department of Neurology, Boston University School of Medicine, Boston, MA, USA.

Background: It is unclear whether brain white matter hyperintensities (WMHI) causes or is a result of late life depression. We used the Framingham Heart Study offspring to examine whether indices of brain aging are related to incident depression in the elderly.

Methods: The Center for Epidemiologic Studies Depression Scale (CES-D) was administered along with a brain MRI scan at baseline and was re-administered (n = 1212) at an average 6.6 + 0.6 year follow-up. The outcomes (i) change in CES-D scores from baseline; (ii) depression defined as CES-D ≥16; (iii) severe depression defined as CES-D ≥21; and (iv) CES-D cutoff scores and/or on antidepressant were used.

Results: Among those who did not have depression at baseline, 9.1% (n = 110) developed depression, 4.0% (n = 48) developed severe depressive symptoms, and 11.1% (n = 135) were put on antidepressants. When depressive symptoms only was the outcome, we found that baseline WMHI was positively associated with change in CES-D scores and that those with an extensive WMHI at baseline had a high risk of developing severe depressive symptoms; the relationship was strengthened in the absence of cardiovascular diseases. In contrast, when depressive symptoms or taking antidepressant was the outcome, larger total cerebral brain volume and temporal lobe brain volume, but not WMHI, were negatively associated with the development of depression.

Conclusions: Brain WMHI is a probable risk factor for vascular depression in the elderly. The depression outcomes with and without antidepressant were related to different brain pathologies. Copyright © 2016 John Wiley & Sons, Ltd.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052093PMC
http://dx.doi.org/10.1002/gps.4469DOI Listing
February 2017

Carotid Atherosclerosis and Cerebral Microbleeds: The Framingham Heart Study.

J Am Heart Assoc 2016 Mar 18;5(3):e002377. Epub 2016 Mar 18.

Department of Neurology, School of Public Health at Boston University, Boston, MA NHLBI's Framingham Heart Study, Framingham, MA.

Background: Carotid atherosclerosis is associated with subclinical ischemic cerebrovascular disease, but its role in hemorrhage-prone small vessel disease-represented by cerebral microbleed (CMB)-is unclear, although vascular risk factors underlie both conditions. We hypothesized that persons with carotid atherosclerosis would have higher risk of CMB, particularly in deep regions.

Methods And Results: We studied 1243 participants in the Framingham Offspring Study (aged 56.9±8.8 years; 53% women) with carotid ultrasound available on 2 occasions (1995-1998 and 2005-2008) prior to brain magnetic resonance imaging. Using multivariable logistic regression, we related baseline carotid stenosis, baseline intima-media thickness, and site-specific carotid intima-media thickness progression (at internal and common carotid locations) to the prevalence and location (lobar or deep plus mixed) of CMB. In addition, we assessed effect modification by lipid levels and use of statin and antithrombotic medications. Carotid stenosis ≥25% (a marker of cerebrovascular atherosclerosis) was associated with presence of CMB overall (Odds Ratio 2.20, 95% CI 1.10-4.40) and at deep and mixed locations (odds ratio 3.60, 95% CI 1.23-10.5). Baseline carotid intima-media thickness was not associated with CMB. Progression of common carotid artery intima-media thickness among persons on hypertension treatment was associated with lower risk of deep and mixed CMB (odds ratio per SD 0.41, 95% CI 0.18-0.96).

Conclusions: Cumulative vascular risk factor exposure may increase the risk of CMB, especially in deep regions. The apparent paradoxical association of carotid intima-media thickness progression with lower risk of CMB may reflect benefits of intensive vascular risk factor treatment among persons with higher cardiovascular risk and deserves further investigation. If replicated, the results may have potential implications for assessment of preventive and therapeutic interventions for subclinical cerebral hemorrhage.
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http://dx.doi.org/10.1161/JAHA.115.002377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943235PMC
March 2016

Lifelong Reading Disorder and Mild Cognitive Impairment: Implications for Diagnosis.

J Alzheimers Dis 2016 ;50(1):41-5

Department of Neurology, Boston, University School of Medicine, Framingham Heart Study, Boston, MA, USA.

Although neuropsychological tests are commonly used in the evaluation of possible mild cognitive impairment (MCI), poor test scores may be indicative of factors other than neurological compromise. The current study assessed the role of lifelong reading disorder on MCI classification. Community dwelling older adults with a suspected developmental reading disorder were identified by inference based on reading test performance. Individuals with a suspected reading disorder were significantly more likely to perform at a level consistent with MCI on several commonly used neuropsychological tests. The findings suggest a relationship between a history of reading disorder and MCI classification.
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http://dx.doi.org/10.3233/JAD-150543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827707PMC
October 2016

Evaluation of power of the Illumina HumanOmni5M-4v1 BeadChip to detect risk variants for human complex diseases.

Eur J Hum Genet 2016 07 18;24(7):1029-34. Epub 2015 Nov 18.

Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.

Although emerging sequencing technologies can characterize all genetic variants, the cost is still high. Illumina released the HumanOmni5M-4v1 (Omni5) genotype array with ~4.3M assayed SNPs, a much denser array compared with other available arrays. The Omni5 balances both cost and array density. In this article, we illustrate the power of Omni5 to detect genetic associations. The Omni5 includes variants with a wide range of minor allele frequencies down to <1%. The theoretical power calculation examples indicate the increased power of the Omni5 array compared with other arrays with lower density when evaluating associations with some known loci, although there are exceptions. We further evaluate the genetic associations between known loci and several quantitative traits in the Framingham Heart Study: femoral neck bone mineral density, lumbar spine bone mineral density and hippocampal volume. Finally, we search genome wide for novel associations using the Omni5 genotypes. We compare our association results from Affymetrix 500K+MIPS 50K arrays and two imputed data sets: (1) HapMap Phase II and (2) 1000 Genomes reference panel. We observed increased evidence for genotype-phenotype associations with smaller P-values for selected known loci using the Omni5 genotypes. With limited sample sizes, we identify novel variants with genome-wide significant P-values. Our observations support the notion that dense genotyping using the Omni5 can be powerful in detecting novel associated variants. Comparison with imputed data with higher density also suggests that imputation helps but cannot replace genotyping, especially when imputation quality is low.
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http://dx.doi.org/10.1038/ejhg.2015.244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070895PMC
July 2016

Spectrum of cognition short of dementia: Framingham Heart Study and Mayo Clinic Study of Aging.

Neurology 2015 Nov 9;85(19):1712-21. Epub 2015 Oct 9.

From the Department of Neurology, Mayo Alzheimer's Disease Research Center (D.S.K., B.F.B., R.C.P., R.O.R., W.A.R.), Division of Epidemiology, Department of Health Sciences Research (R.O.R., M.M. Mielke, W.A.R., R.C.P.), Division of Biostatistics and Bioinformatics, Department of Health Sciences Research (V.S.P., J.A., R.H.C.), and Department of Psychiatry and Psychology, Division of Neurocognitive Disorders (R.J.I., M.M. Machulda, J.F.), College of Medicine, Mayo Clinic, Rochester, MN; and Departments of Neurology (A.B., S.D., R.A., S.A., P.A.W., S.S.) and Biostatistics (A.B.), Boston University Schools of Medicine and Public Health, MA.

Objective: To understand the neuropsychological basis of dementia risk among persons in the spectrum including cognitive normality and mild cognitive impairment.

Methods: We quantitated risk of progression to dementia in elderly persons without dementia from 2 population-based studies, the Framingham Heart Study (FHS) and Mayo Clinic Study of Aging (MCSA), aged 70 to 89 years at enrollment. Baseline cognitive status was defined by performance in 4 domains derived from batteries of neuropsychological tests (that were similar but not identical for FHS and MCSA) at cut scores corresponding to SDs of ≤-0.5, -1, -1.5, and -2 from normative means. Participants were characterized as having no cognitive impairment (reference group), or single or multiple amnestic or nonamnestic profiles at each cut score. Incident dementia over the following 6 years was determined by consensus committee at each study separately.

Results: The pattern of hazard ratios for incident dementia, rates of incident dementia and positive predictive values across cognitive test cut scores, and number of affected domains was similar although not identical across the FHS and MCSA. Dementia risks were higher for amnestic profiles than for nonamnestic profiles, and for multidomain compared with single-domain profiles.

Conclusions: Cognitive domain subtypes, defined by neuropsychologically derived cut scores and number of low-performing domains, differ substantially in prognosis in a conceptually logical manner that was consistent between FHS and MCSA. Neuropsychological characterization of elderly persons without dementia provides valuable information about prognosis. The heterogeneity of risk of dementia cannot be captured concisely with one test or a single definition or cutpoint.
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http://dx.doi.org/10.1212/WNL.0000000000002100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653114PMC
November 2015

Midlife Hypertension Risk and Cognition in the Non-Demented Oldest Old: Framingham Heart Study.

J Alzheimers Dis 2015 ;47(1):197-204

Framingham Heart Study, Department of Neurology, Boston University School of Medicine, Boston, MA, USA.

Midlife cardiovascular risk, hypertension (HTN) in particular, has been related cross-sectionally to poorer neuropsychological (NP) performance in middle age and older adults. This study investigated whether a similar relationship persists between midlife HTN or systolic blood pressure (SBP) and NP performance approximately 30 years later. 378 Framingham stroke and dementia-free Original cohort participants, with HTN and SBP ascertained between 50-60 years of age (mean age 55 ± 1, 65% women), were administered a NP assessment at age ≥80 years. Tests included Logical Memory, Visual Reproduction, Paired Associate, Hooper Visual Organization Test, Trail Making A & B, Digit Span Forward and Backward, Controlled Word Association Test (COWAT), and Similarities. Multivariable linear regression, adjusted for age, time interval between risk factor and NP testing, gender, and premorbid intelligence, assessed association between midlife HTN/SBP and NP outcomes. Midlife HTN was not significantly associated with NP outcome measures. Midlife SBP was associated with poorer Digit Span Forward and COWAT performance (p <  0.05). No significant interaction of age on HTN/SBP to NP associations was found. There was a significant interaction between ApoE4 status and SBP in their effects on COWAT (pinteraction = 0.074); SBP was negatively associated with COWAT only in those with the ApoE4 allele (p = 0.025). While midlife HTN is not associated with late life cognitive impairment, midlife SBP is related to late life attention and verbal fluency impairments, particularly among ApoE4+ individuals. These results offer insight into processes that are operative in the absence of overt cognitive impairment and dementia.
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http://dx.doi.org/10.3233/JAD-141881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827717PMC
June 2016

Normative Data for the Cognitively Intact Oldest-Old: The Framingham Heart Study.

Exp Aging Res 2015 ;41(4):386-409

a Department of Psychology , Minneapolis VA Healthcare System , Minneapolis , Minnesota , USA.

Unlabelled: BACKGROUND/STUDY CONTEXT: The number of individuals who reach extreme age is quickly increasing. Much of the current literature focuses on impaired cognition in extreme age, and debate continues regarding what constitutes "normal" cognition in extreme age. This study aimed to provide oldest-old normative data and to compare cognitive performances of cognitively intact elderly individuals from the Framingham Heart Study.

Methods: A total of 1302 individuals aged 65+ years from the Framingham Heart Study were separated into 5-year age bands and compared on cognitive tests. Multivariate linear regression analyses were conducted, adjusting for gender, the Wide Range Achievement Test-Third Edition (WRAT-III) Reading score, and cohort. Analyses also included comparisons between 418 individuals aged 80+ and 884 individuals aged 65-79, and comparisons within oldest-old age bands.

Results: Normative data for all participants are presented. Significant differences were found on most tests between age groups in the overall analysis between young-old and oldest-old, and analysis of oldest-old age bands also revealed select significant differences (all ps <.05).

Conclusion: As aging increases, significant cognitive differences and increased variability in performances are evident. These results support the use of age-appropriate normative data for oldest-old individuals.
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http://dx.doi.org/10.1080/0361073X.2015.1053755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621515PMC
April 2016

50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study.

Lancet 2015 Jul 7;386(9989):154-62. Epub 2015 May 7.

National Heart, Lung, and Blood Institute's Framingham Study, Framingham, MA, USA; Preventive Medicine Section, School of Medicine, Boston University, Boston, MA, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Comprehensive long-term data on atrial fibrillation trends in men and women are scant. We aimed to provide such data through analysis of the Framingham cohort over 50 years.

Methods: We investigated trends in incidence, prevalence, and risk factors for atrial fibrillation and its association with stroke and mortality after onset in 9511 participants enrolled in the Framingham Heart Study between 1958 and 2007. We analysed trends within 10 year groups (1958-67, 1968-77, 1978-87, 1988-97, and 1998-2007), stratified by sex.

Findings: During 50 years of observation (202,417 person-years), 1544 cases of new-onset atrial fibrillation occurred (of whom 723 [47%] were women). Between 1958-67 and 1998-2007, age-adjusted prevalence of atrial fibrillation quadrupled from 20·4 to 96·2 cases per 1000 person-years in men and from 13·7 to 49·4 cases per 1000 person-years in women; age-adjusted incidence increased from 3·7 to 13·4 new cases per 1000 person-years in men and from 2·5 to 8·6 new cases per 1000 person-years in women (ptrend<0·0001 for all comparisons). For atrial fibrillation diagnosed by electrocardiograph (ECG) during routine Framingham examinations, age-adjusted prevalence per 1000 person-years increased (12·6 in 1958-67 to 25·7 in 1998-2007 in men, ptrend=0·0007; 8·1 to 11·8 in women, ptrend=0·009). However, age-adjusted incidence of atrial fibrillation by Framingham Heart Study ECGs did not change significantly with time. Although the prevalence of most risk factors changed over time, their associated hazards for atrial fibrillation changed little. Multivariable-adjusted proportional hazards models revealed a 74% (95% CI 50-86%) decrease in stroke (hazards ratio [HR] 3·77, 95% CI 1·98-7·20 in 1958-1967 compared with 1998-2007; ptrend=0·0001) and a 25% (95% CI -3-46%) decrease in mortality (HR 1·34, 95% CI 0·97-1·86 in 1958-1967 compared with 1998-2007; ptrend=0·003) in 20 years following atrial fibrillation onset.

Interpretation: Trends of increased incidence and prevalence of atrial fibrillation in the community were probably partly due to enhanced surveillance. Measures are needed to enhance early detection of atrial fibrillation, through increased awareness coupled with targeted screening programmes and risk factor-specific prevention.

Funding: NIH, NHLBI, NINDS, Deutsche Forschungsgemeinschaft.
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http://dx.doi.org/10.1016/S0140-6736(14)61774-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553037PMC
July 2015

Glucose indices are associated with cognitive and structural brain measures in young adults.

Neurology 2015 Jun 6;84(23):2329-37. Epub 2015 May 6.

From the Department of Neurology (G.W., J.J.H., A.S.B., R.A., P.A.W., S.S.), Boston University School of Medicine, MA; The Framingham Heart Study (G.W., J.J.H., A.S.B., R.A., P.A.W., S.S.), MA; the Department of Neurology (P.M., C.D.), The University of California at Davis, Sacramento; and the Department of Biostatistics (A.S.B.), Boston University School of Public Health, MA.

Objective: To evaluate the possible early consequences of impaired glucose metabolism on the brain by assessing the relationship of diabetes, fasting blood glucose (FBG) levels, and insulin resistance with cognitive performance and brain integrity in healthy young and middle-aged adults.

Methods: The sample included dementia-free participants (mean age 40 ± 9 years; 53% women) of the Framingham Heart Study third-generation cohort with cognitive testing of memory, abstract reasoning, visual perception, attention, and executive function (n = 2,126). In addition, brain MRI examination (n = 1,597) was used to determine white matter, gray matter, and white matter hyperintensity (WMH) volumes and fractional anisotropy measures. We used linear regression models to assess relationships between diabetes, FBG, and insulin resistance with cognition, lobar gray matter, and WMH volumes as well as voxel-based microstructural white matter integrity and gray matter density, adjusting for potential confounders. Mediating effect of brain lesions on the association of diabetes with cognitive performance was also tested.

Results: Diabetes was associated with worse memory, visual perception, and attention performance; increased WMH; and decreased total cerebral brain and occipital lobar gray matter volumes. The link of diabetes with attention and memory was mediated through occipital and frontal atrophy, and the latter also through hippocampal atrophy. Both diabetes and increased FBG were associated with large areas of reductions in gray matter density and fractional anisotropy on voxel-based analyses.

Conclusions: We found that hyperglycemia is associated with subtle brain injury and impaired attention and memory even in young adults, indicating that brain injury is an early manifestation of impaired glucose metabolism.
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http://dx.doi.org/10.1212/WNL.0000000000001655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464744PMC
June 2015

Long-term exposure to fine particulate matter, residential proximity to major roads and measures of brain structure.

Stroke 2015 May;46(5):1161-6

From the Cardiovascular Epidemiology Research Unit, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (E.H.W., M.A.M.); Exposure, Epidemiology and Risk Program, Department of Environmental Health (E.H.W., J.S., P.K.) and Department of Epidemiology (W.L., J.S., M.A.M.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Biostatistics, School of Public Health (S.R.P., A.S.B., R.A.) and Department of Neurology, School of Medicine (A.S.B., P.A.W., S.S.), Boston University, MA; Framingham Heart Study, MA (S.R.P., A.S.B., P.A.W., S.S.); Department of Geography and Environmental Development, Ben-Gurion University of the Negev, Beer Sheva, Israel (I.K.); and Department of Neurology and Center for Neuroscience, University of California, Davis (C.D.).

Background And Purpose: Long-term exposure to ambient air pollution is associated with cerebrovascular disease and cognitive impairment, but whether it is related to structural changes in the brain is not clear. We examined the associations between residential long-term exposure to ambient air pollution and markers of brain aging using magnetic resonance imaging.

Methods: Framingham Offspring Study participants who attended the seventh examination were at least 60 years old and free of dementia and stroke were included. We evaluated associations between exposures (fine particulate matter [PM2.5] and residential proximity to major roadways) and measures of total cerebral brain volume, hippocampal volume, white matter hyperintensity volume (log-transformed and extensive white matter hyperintensity volume for age), and covert brain infarcts. Models were adjusted for age, clinical covariates, indicators of socioeconomic position, and temporal trends.

Results: A 2-μg/m(3) increase in PM2.5 was associated with -0.32% (95% confidence interval, -0.59 to -0.05) smaller total cerebral brain volume and 1.46 (95% confidence interval, 1.10 to 1.94) higher odds of covert brain infarcts. Living further away from a major roadway was associated with 0.10 (95% confidence interval, 0.01 to 0.19) greater log-transformed white matter hyperintensity volume for an interquartile range difference in distance, but no clear pattern of association was observed for extensive white matter.

Conclusions: Exposure to elevated levels of PM2.5 was associated with smaller total cerebral brain volume, a marker of age-associated brain atrophy, and with higher odds of covert brain infarcts. These findings suggest that air pollution is associated with insidious effects on structural brain aging even in dementia- and stroke-free persons.
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http://dx.doi.org/10.1161/STROKEAHA.114.008348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414870PMC
May 2015

Verbal memory and brain aging: an exploratory analysis of the role of error responses in the Framingham Study.

Am J Alzheimers Dis Other Demen 2015 Sep 18;30(6):622-8. Epub 2015 Mar 18.

Department of Biostatistics, Boston University School of Public, Boston, MA, USA Boston University School of Medicine, Boston, MA, USA.

Objective: Analysis sought to determine whether Wechsler Memory Scale-Logical Memory (LM)-correct responses and errors were related to magnetic resonance imaging (MRI) brain volume measurements.

Methods: The LM immediate (LM-I) and LM delay (LM-D) free recall correct responses and related and unrelated errors were scored. Principal components analysis yielded a 3-factor solution: LM-I and LM-D correct responses, LM-I and LM-D-unrelated errors, and LM-I/-D-related errors. The MRI total cerebral brain volume, frontal brain volume, temporal horn volume (THV), and white matter hyperintensities volume (WMHIV) were obtained.

Results: Increasing THV (suggesting greater regional atrophy) was associated with lower scores on the LM-correct responses factor. Extensive WMHIV was associated with higher scores on the LM-related errors factor.

Conclusion: These results suggest that LM-correct responses could relate to emerging brain alterations. Longitudinal research might enhance the sensitivity of this test to identify preclinical impairment and persons at risk of mild cognitive impairment and dementia.
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http://dx.doi.org/10.1177/1533317515577184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536169PMC
September 2015

Low cardiac index is associated with incident dementia and Alzheimer disease: the Framingham Heart Study.

Circulation 2015 Apr 19;131(15):1333-9. Epub 2015 Feb 19.

From Vanderbilt Memory & Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN (A.L.J.); Departments of Neurology (A.S.B., J.J.H., S.S., P.A.W., R.A.) and Medicine (E.J.B.), Boston University School of Medicine, Boston, MA; National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA (A.S.B., J.J.H., S.S., C.J.O., P.A.W., R.A., E.J.B.); Departments of Epidemiology (E.J.B.) and Biostatistics (A.S.B.), Boston University School of Public Health, Boston, MA; and Departments of Medicine (Cardiovascular Division) (W.J.M.) and Radiology (W.J.M.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

Background: Cross-sectional epidemiological and clinical research suggests that lower cardiac index is associated with abnormal brain aging, including smaller brain volumes, increased white matter hyperintensities, and worse cognitive performances. Lower systemic blood flow may have implications for dementia among older adults.

Methods And Results: A total of 1039 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, and dementia formed our sample (age, 69±6 years; 53% women). Multivariable-adjusted proportional hazard models adjusting for Framingham Stroke Risk Profile score (age, sex, systolic blood pressure, antihypertensive medication, diabetes mellitus, cigarette smoking, cardiovascular disease history, atrial fibrillation), education, and apolipoprotein E4 status related cardiac magnetic resonance imaging-assessed cardiac index (cardiac output divided by body surface area) to incident all-cause dementia and Alzheimer disease (AD). Over the median 7.7-year follow-up period, 32 participants developed dementia, including 26 cases of AD. Each 1-SD unit decrease in cardiac index increased the relative risk of both dementia (hazard ratio [HR]=1.66; 95% confidence interval [CI], 1.11-2.47; P=0.013) and AD (HR=1.65; 95% CI, 1.07-2.54; P=0.022). Compared with individuals with normal cardiac index, individuals with clinically low cardiac index had a higher relative risk of dementia (HR=2.07; 95% CI, 1.02-4.19; P=0.044). If participants with clinically prevalent cardiovascular disease and atrial fibrillation were excluded (n=184), individuals with clinically low cardiac index had a higher relative risk of both dementia (HR=2.92; 95% CI, 1.34-6.36; P=0.007) and AD (HR=2.87; 95% CI, 1.21-6.80; P=0.016) compared with individuals with normal cardiac index.

Conclusion: Lower cardiac index is associated with an increased risk for the development of dementia and AD.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.114.012438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398627PMC
April 2015

Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.

Biol Psychiatry 2015 Apr 25;77(8):749-63. Epub 2014 Nov 25.

Max Planck Institute for Intelligent Systems, Tübingen, Germany; Max Planck Institute for Developmental Biology, Tübingen, Germany.

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 × 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 × 10(-10)) and replication cohorts (p = 5.65 × 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 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 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.
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http://dx.doi.org/10.1016/j.biopsych.2014.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513651PMC
April 2015

Inflammatory biomarkers, cerebral microbleeds, and small vessel disease: Framingham Heart Study.

Neurology 2015 Feb 28;84(8):825-32. Epub 2015 Jan 28.

From McMaster University (A.S.), Hamilton, Canada; Harvard Medical School (A.S.), Boston; Boston University School of Public Health (S.R.P., A.S.B.); Boston University School of Medicine (A.S.B., R.S.V., E.J.B., C.S.K., P.A.W., J.R.R., S.S.), MA; and University of California (C.D.), Davis School of Medicine, Sacramento.

Objective: We investigated the association between circulating biomarkers of inflammation and MRI markers of small vessel disease.

Methods: We performed a cross-sectional study relating a panel of 15 biomarkers, representing systemic inflammation (high-sensitivity C-reactive protein, interleukin-6, monocyte chemotactic protein-1, tumor necrosis factor α, tumor necrosis factor receptor 2, osteoprotegerin, and fibrinogen), vascular inflammation (intercellular adhesion molecule 1, CD40 ligand, P-selectin, lipoprotein-associated phospholipase A2 mass and activity, total homocysteine, and vascular endothelial growth factor), and oxidative stress (myeloperoxidase) to ischemic (white matter hyperintensities/silent cerebral infarcts) and hemorrhagic (cerebral microbleeds) markers of cerebral small vessel disease (CSVD) on MRI in 1,763 stroke-free Framingham offspring (mean age 60.2 ± 9.1 years, 53.7% women).

Results: We observed higher levels of circulating tumor necrosis factor receptor 2 and myeloperoxidase in the presence of cerebral microbleed (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.1-4.1 and OR 1.5, 95% CI 1.1-2.0, respectively), higher levels of osteoprotegerin (OR 1.1, 95% CI 1.0-1.2), intercellular adhesion molecule 1 (OR 1.7, 95% CI 1.1-2.5), and lipoprotein-associated phospholipase A2 mass (OR 1.5, 95% CI 1.1-2.1), and lower myeloperoxidase (OR 0.8, 95% CI 0.7-1.0) in participants with greater white matter hyperintensity volumes and silent cerebral infarcts.

Conclusions: Our study supports a possible role for inflammation in the pathogenesis of CSVD, but suggests that differing inflammatory pathways may underlie ischemic and hemorrhagic subtypes. If validated in other samples, these biomarkers may improve stroke risk prognostication and point to novel therapeutic targets to combat CSVD.
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http://dx.doi.org/10.1212/WNL.0000000000001279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345647PMC
February 2015

Lipid and lipoprotein measurements and the risk of ischemic vascular events: Framingham Study.

Neurology 2015 Feb 7;84(5):472-9. Epub 2015 Jan 7.

From the Boston University Schools of Medicine and Public Health (A.P., A.S.B., J.W., J.J.H., M.K.-H., C.S.K., Q.Y., S.S., P.A.W.), Boston; and Framingham Heart Study (A.P., A.S.B., M.K.-H., C.S.K., Q.Y., S.S., P.A.W.), Framingham, MA.

Objectives: To examine the relationship between plasma lipid measurements and incident ischemic vascular events (ischemic stroke [IS], and as a positive control, myocardial infarction [MI]) in a community cohort.

Methods: In 6,276 stroke-free Framingham participants (aged 64 ± 10 years, 56% female), we related plasma lipid levels (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], and TC/HDL-C ratio) measured at the original cohort 15th (1977-1979) and 20th examination cycles (1986-1990) and (TC, HDL-C, TC/HDL-C ratio, triglycerides [TG], and low-density lipoprotein cholesterol [LDL-C]) measured at the offspring fourth examination (1995-1998), to 10-year risk of incident IS and MI. Utilizing genome-wide genotyping in the same subjects, we used mendelian randomization methods to assess whether observed associations were incidental or causal.

Results: During a mean follow-up of 9 years, 301 participants experienced incident IS. In multivariable-adjusted analyses, HDL-C ≤40 mg/dL and TC/HDL ratio ≥5 were associated with increased risk of IS (hazard ratio [95% confidence interval]: 1.59 [1.23-2.05], p < 0.001 and 1.47 [1.15-1.87], p < 0.001), but not TC or LDL-C. In adjusted analysis, a strong association between TG and IS was diminished. In the MI-free sample (n = 5,875, aged 64 ± 10 years, 58% female; 403 MI events), all lipid markers were associated with MI risk. A genetic risk score comprising 47 known determinants of circulating HDL-C was not associated with IS.

Conclusions: In a middle-aged to elderly community sample, we observed that low HDL-C and high TC/HDL-C ratio, but not LDL-C or TG were associated with risk of incident IS. We observed the usual associations between lipids and risk of MI. Our findings suggest an important, but less likely causal, role of HDL-C over other lipid biomarkers for optimal stroke risk stratification.
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http://dx.doi.org/10.1212/WNL.0000000000001202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336066PMC
February 2015

APOE and mild cognitive impairment: the Framingham Heart Study.

Age Ageing 2015 Mar 11;44(2):307-11. Epub 2014 Dec 11.

National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA Department of Neurology, Boston University School of Medicine, Boston, MA, USA.

Background: The risk apolipoprotein E-4 (APOE4) poses for mild cognitive impairment (MCI) may vary based on the neuropsychological definition of MCI.

Setting: A community-based cohort study.

Methods: Using two psychometric neuropsychological impairment definitions, we examined APOE4 and prevalent MCI among older adults or pre-MCI among middle-aged adults. Neuropsychological, clinical and genetic data were collected on 2,239 Framingham Offspring Cohort participants free from clinical stroke or dementia (62±9 years; 54% women). Prevalent amnestic MCI was defined from neuropsychological performances≥1.5 SD below the mean based on (i) age and education or (ii) age and Wide Range Achievement Test-3 Reading (WRAT-3 Reading) performance adjustment.

Results: In the entire sample, multivariable-adjusted logistic regressions found that APOE4 was associated with amnestic MCI when using the age and WRAT Reading definition (odds ratio [OR]=1.7, P=0.002) but not the age and education definition (OR=1.0, P=0.90). Results were modified by age, such that APOE4 was associated with amnestic MCI in participants≥65 years using both the age and WRAT Reading definition (OR=2.4, P<0.001) and the age and education definition (OR=1.7, P=0.04).

Conclusion: APOE4 risk for prevalent amnestic MCI varies depending on the definition of objective neuropsychological impairment for MCI. Our findings support existing literature emphasising the need to refine MCI neuropsychological profiling methods.
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http://dx.doi.org/10.1093/ageing/afu183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400527PMC
March 2015