Publications by authors named "Alexa Beiser"

247 Publications

Association of Social Support With Brain Volume and Cognition.

JAMA Netw Open 2021 Aug 2;4(8):e2121122. Epub 2021 Aug 2.

The Framingham Study, Boston, Massachusetts.

Importance: Cognitive resilience refers to the general capacity of cognitive processes to be less susceptible to differences in brain structure from age- and disease-related changes. Studies suggest that supportive social networks reduce Alzheimer disease and related disorder (ADRD) risk by enhancing cognitive resilience, but data on specific social support mechanisms are sparse.

Objective: To examine the association of individual forms of social support with a global neuroanatomical measure of early ADRD vulnerability and cognition.

Design, Setting, And Participants: This retrospective cross-sectional analysis used prospectively collected data from Framingham Study participants without dementia, stroke, or other neurological conditions who underwent brain magnetic resonance imaging and neuropsychological testing at the same visit. Data from this large, population-based, longitudinal cohort were collected from June 6, 1997, to December 13, 1999 (original cohort), and from September 11, 1998, to October 26, 2001 (offspring cohort). Data were analyzed from May 22, 2017, to June 1, 2021.

Exposures: Total cerebral volume and, as a modifying exposure variable, self-reported availability of 5 types of social support measured by the Berkman-Syme Social Network Index.

Main Outcomes And Measures: The primary outcome was a global measure of cognitive function. Cognitive resilience was defined as the modification of total cerebral volume's association with cognition, such that smaller β estimates (presented in SD units) indicate greater cognitive resilience (ie, better cognitive performance than estimated by lower total cerebral volume).

Results: The study included 2171 adults (164 in the original cohort and 2007 in the offspring cohort; mean [SD] age, 63 [10] years; 1183 [54%] female). High listener availability was associated with greater cognitive resilience (β = 0.08, P < .001) compared with low listener availability (β = 0.20, P = .002). Overall findings persisted after adjustment for potential confounders. Other forms of social support were not significant modifiers (advice: β = -0.04; P = .40 for interaction; love-affection: β = -0.07, P = .28 for interaction; emotional support: β = -0.02, P = .73 for interaction; and sufficient contact: β = -0.08; P = .11 for interaction).

Conclusions And Relevance: The results of this cross-sectional cohort study suggest that social support in the form of supportive listening is associated with greater cognitive resilience, independently modifying the association between lower total cerebral volume and poorer cognitive function that would otherwise indicate increased ADRD vulnerability at the preclinical stage. A refined understanding of social support mechanisms has the potential to inform strategies to reduce ADRD risk and enhance cognitive resilience.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.21122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369356PMC
August 2021

Insomnia symptom severity and cognitive performance: Moderating role of APOE genotype.

Alzheimers Dement 2021 Jul 26. Epub 2021 Jul 26.

The Framingham Heart Study, Framingham, Massachusetts, USA.

Introduction: We evaluated whether insomnia symptom severity was associated with cognitive function, and whether this relationship was modified by biomarkers associated with Alzheimer's disease risk.

Methods: We examined insomnia symptoms and neuropsychological performance 3.4 years later in 511 dementia-free Framingham Heart Study participants (62.65 ± 8.7 years, 50.9% male). Additionally, we explored insomnia symptoms combined with self-reported short habitual sleep duration and effect modification by apolipoprotein E (APOE) ε4 allele status.

Results: More severe insomnia symptoms were associated with lower performance on global cognition, and immediate and delayed Logical Memory recall, especially when insomnia symptoms were combined with short sleep duration. The association between insomnia symptoms and poorer memory recall was more pronounced in APOE ε4 allele carriers.

Discussion: Insomnia symptom severity was associated with worse subsequent global cognitive and memory performance, which was especially apparent in APOE ε4 allele carriers, suggesting that poor sleep might be particularly detrimental when the brain is already vulnerable to neurodegeneration.
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http://dx.doi.org/10.1002/alz.12405DOI Listing
July 2021

Coronary Artery Calcium Assessed Years Before Was Positively Associated With Subtle White Matter Injury of the Brain in Asymptomatic Middle-Aged Men: The Framingham Heart Study.

Circ Cardiovasc Imaging 2021 Jul 14;14(7):e011753. Epub 2021 Jul 14.

Department of Hygiene, Wakayama Medical University, Japan (H.S., A.F.).

Background: Using magnetic resonance diffusion tensor imaging, we previously showed a cross-sectional association between carotid-femoral pulse wave velocity, a measure of aortic stiffness, and subtle white matter injury in clinically asymptomatic middle-age adults. While coronary artery calcium (CAC) is a robust measure of atherosclerosis, and a predictor of stroke and dementia, whether it predicts diffusion tensor imaging-based subtle white matter injury in the brain remains unknown.

Methods: In FHS (Framingham Heart Study), an observational study, third-generation participants were assessed for CAC (2002-2005) and brain magnetic resonance imaging (2009-2014). Outcomes were diffusion tensor imaging-based measures; free water, fractional anisotropy, and peak width of mean diffusivity. After excluding the participants with neurological conditions and missing covariates, we categorized participants into 3 groups according to CAC score (0, 0 < to 100, and >100) and calculated a linear trend across the CAC groups. In secondary analyses treating CAC score as continuous, we computed slope of the outcomes per 20 to 80th percentiles higher log-transformed CAC score using linear regression.

Results: In a total of 1052 individuals analyzed (mean age 45.4 years, 45.4% women), 71.6%, 22.4%, and 6.0% had CAC score of 0, 0 < to 100, and >100, respectively. We observed a significant linear trend of fractional anisotropy, but not other measures, across the CAC groups after multivariable adjustment. In the secondary analyses, CAC was associated with lower fractional anisotropy in men but not in women.

Conclusions: CAC may be a promising tool to predict prevalent subtle white matter injury of the brain in asymptomatic middle-aged men.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.011753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323993PMC
July 2021

Mind Diet Adherence and Cognitive Performance in the Framingham Heart Study.

J Alzheimers Dis 2021 ;82(2):827-839

The Framingham Heart Study, Framingham, MA, USA.

Background: Adherence to the Mediterranean-DASH for Neurodegenerative Delay (MIND) diet has previously been associated with cognitive decline and dementia. To our knowledge, no prior study has investigated the association between the MIND diet and measures of brain volume, silent brain infarcts (SBIs), or brain atrophy.

Objective: We evaluated whether adherence to the MIND diet associated with superior cognitive function, larger brain volumes, fewer SBIs, and less cognitive decline in the community-based Framingham Heart Study.

Methods: 2,092 participants (mean±SD, age 61±9) completed Food Frequency Questionnaires, averaged across a maximum of 3-time points (examination cycles 5, 6, and 7), cognitive testing at examination cycle 7 (present study baseline: 1998-2001) and after a mean±SD of 6.6±1.1 years from baseline (n = 1,584). A subset of participants also completed brain magnetic resonance imaging (MRI) at examination cycle 7 (n = 1,904). In addition, participants with dementia, stroke, and other relevant neurological diseases such as significant head trauma, subdural hematoma, or multiple sclerosis were excluded from the analyses.

Results: Higher MIND diet scores were associated with better global cognitive function (β±SE,+0.03SD±0.01; p = 0.004), verbal memory, visual memory, processing speed, verbal comprehension/reasoning, and with larger total brain volume (TBV) following adjustments for clinical, lifestyle and demographic covariates, but not with other brain MRI measures (i.e., hippocampal volume, lateral ventricular volume, white matter hyperintensity volume, and SBIs) or cognitive decline.

Conclusion: Higher MIND diet scores associated with better cognitive performance and larger TBV at baseline, but not with cognitive decline. Clinical trials are needed to ascertain whether adopting the MIND diet affects trajectories of cognitive decline.
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http://dx.doi.org/10.3233/JAD-201238DOI Listing
September 2021

Herpes Labialis, Chlamydophila pneumoniae, Helicobacter pylori, and Cytomegalovirus Infections and Risk of Dementia: The Framingham Heart Study.

J Alzheimers Dis 2021 ;82(2):593-605

Glenn Biggs Institute of Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA.

Background: An association between chronic infectious diseases and development of dementia has been suspected for decades, based on the finding of pathogens in postmortem brain tissue and on serological evidence. However, questions remain regarding confounders, reverse causality, and how accurate, reproducible and generalizable those findings are.

Objective: Investigate whether exposure to Herpes simplex (manifested as herpes labialis), Chlamydophila pneumoniae (C. pneumoniae), Helicobacter pylori (H. pylori), and cytomegalovirus (CMV) modifies the risk of dementia in a populational cohort.

Methods: Questionnaires regarding incidence of herpes infections were administered to Original Framingham Study participants (n = 2,632). Serologies for C. pneumoniae, H. pylori, and CMV were obtained in Original (n = 2,351) and Offspring cohort (n = 3,687) participants. Participants are under continuous dementia surveillance. Brain MRI and neuropsychological batteries were administered to Offspring participants from 1999-2005. The association between each infection and incident dementia was tested with Cox models. Linear models were used to investigate associations between MRI or neuropsychological parameters and serologies.

Results: There was no association between infection serologies and dementia incidence, total brain volume, and white matter hyperintensities. Herpes labialis was associated with reduced 10-year dementia risk (HR 0.66, CI 0.46-0.97), but not for the duration of follow-up. H. pylori antibodies were associated with worse global cognition (β -0.14, CI -0.22, -0.05).

Conclusion: We found no association between measures of chronic infection and incident dementia, except for a reduction in 10-year dementia risk for patients with herpes labialis. This unexpected result requires confirmation and further characterization, concerning antiviral treatment effects and capture of episodes.
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http://dx.doi.org/10.3233/JAD-200957DOI Listing
September 2021

Association of Midlife Depressive Symptoms with Regional Amyloid-β and Tau in the Framingham Heart Study.

J Alzheimers Dis 2021 ;82(1):249-260

Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA.

Background: Depressive symptoms predict increased risk for dementia decades before the emergence of cognitive symptoms. Studies in older adults provide preliminary evidence for an association between depressive symptoms and amyloid-β (Aβ) and tau accumulation. It is unknown if similar alterations are observed in midlife when preventive strategies may be most effective.

Objective: The study aim was to evaluate the association between depressive symptoms and cerebral Aβ and tau in a predominately middle-aged cohort with examination of the apolipoprotein (APOE) ɛ4 allele as a moderator.

Methods: Participants included 201 adults (mean age 53±8 years) who underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Depressive symptoms were evaluated with the Center for Epidemiological Studies Depression Scale (CES-D) at the time of PET imaging, as well as eight years prior. Associations between depressive symptoms at both timepoints, as well as depression (CES-D≥16), with regional Aβ and tau PET retention were evaluated with linear regression adjusting for age and sex. Interactions with the APOE ɛ4 allele were explored.

Results: Depressive symptoms and depression were not associated with PET outcomes in the overall sample. However, among APOE ɛ4 allele carriers, there was a significant cross-sectional association between depressive symptoms and increased tau PET uptake in the entorhinal cortex (β= 0.446, SE = 0.155, p = 0.006) and amygdala (β= 0.350, SE = 0.133, p = 0.012).

Conclusion: Although longitudinal studies are necessary, the results suggest that APOE ɛ4 carriers with depressive symptoms may present with higher susceptibility to early tau accumulation in regions integral to affective regulation and memory consolidation.
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http://dx.doi.org/10.3233/JAD-210232DOI Listing
September 2021

Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants.

Alzheimers Dement 2021 May 18. Epub 2021 May 18.

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures.

Methods: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk.

Results: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition.

Discussion: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.
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http://dx.doi.org/10.1002/alz.12333DOI Listing
May 2021

Bone Mineral Density Measurements and Association With Brain Structure and Cognitive Function: The Framingham Offspring Cohort.

Alzheimer Dis Assoc Disord 2021 May 11. Epub 2021 May 11.

The Framingham Heart Study, Framingham Department of Neurology, Boston University School of Medicine Department of Biostatistics, Boston University School of Public Health, Boston, MA Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases Department of Population Health Sciences, University of Texas Health Science Center, San Antonio, TX Department of Neurology, University of California, Davis Division of Geriatrics, David Geffen School of Medicine at the University of California, Los Angeles, CA.

Background: Bone mineral density (BMD) is a potential surrogate marker of lifetime estrogen exposure previously linked to increased risk of Alzheimer dementia among elderly women. We examine the association between BMD in the "young old" with imaging biomarkers of brain aging and cognitive performance.

Methods: Offspring participants (N=1905, mean age 66) of a population-based cohort who had BMD, brain imaging and detailed cognitive assessment were included in the study. Sex-stratified, linear, and logistic regression models were used for analysis.

Results: Higher femoral neck BMD was associated with lower white matter hyperintensity burden and better performance on Trails B-A in both sexes, even after adjustment for cerebrovascular risk factors. Among women, the positive association with Trails B-A performance was seen only in APOE4 allele carriers. Higher BMD measurements were linked to better visual reproductions test performance in men. Finally, among women, higher femoral trochanter BMD was associated with better logical memory and Hooper visual organization test performance.

Conclusion: Among the "young old," higher BMD is associated with less white matter hyperintensity burden and better, domain-specific, cognitive performance. This suggests that lifetime estrogen exposure may modulate the degree of cumulative vascular brain injury independent of cerebrovascular risk factors.
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http://dx.doi.org/10.1097/WAD.0000000000000453DOI Listing
May 2021

Autonomic Imbalance and Risk of Dementia and Stroke: The Framingham Study.

Stroke 2021 Jun 20;52(6):2068-2076. Epub 2021 Apr 20.

The Framingham Study, MA (K.D.-P., A.S.B., S.S.).

[Figure: see text].
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http://dx.doi.org/10.1161/STROKEAHA.120.030601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154675PMC
June 2021

Associations of the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay diet with cardiac remodelling in the community: the Framingham Heart Study.

Br J Nutr 2021 Feb 23:1-9. Epub 2021 Feb 23.

Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.

Normal cardiac function is directly associated with the maintenance of cerebrovascular health. Whether the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet, designed for the maintenance of neurocognitive health, is associated with cardiac remodelling is unknown. We evaluated 2512 Framingham Offspring Cohort participants who attended the eighth examination cycle and had available dietary and echocardiographic data (mean age 66 years; 55 % women). Using multivariable regression, we related the cumulative MIND diet score (independent variable) to left ventricular (LV) ejection fraction, left atrial emptying fraction, LV mass (LVM), E/e' ratio (dependent variables; primary), global longitudinal strain, global circumferential strain (GCS), mitral annular plane systolic excursion, longitudinal segmental synchrony, LV hypertrophy and aortic root diameter (secondary). Adjusting for age, sex and energy intake, higher cumulative MIND diet scores were associated with lower values of indices of LV diastolic (E/e' ratio: logβ = -0·03) and systolic function (GCS: β = -0·04) and with higher values of LVM (logβ = 0·02), all P ≤ 0·01. We observed effect modification by age in the association between the cumulative MIND diet score and GCS. When we further adjusted for clinical risk factors, the associations of the cumulative MIND diet score with GCS in participants ≥66 years (β = -0·06, P = 0·005) and LVM remained significant. In our community-based sample, relations between the cumulative MIND diet score and cardiac remodelling differ among indices of LV structure and function. Our results suggest that favourable associations between a higher cumulative MIND diet score and indices of LV function may be influenced by cardiometabolic and lifestyle risk factors.
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http://dx.doi.org/10.1017/S0007114521000660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380746PMC
February 2021

Incidence of Transient Ischemic Attack and Association With Long-term Risk of Stroke.

JAMA 2021 01;325(4):373-381

Framingham Heart Study, Framingham, Massachusetts.

Importance: Accurate estimation of the association between transient ischemic attack (TIA) and risk of subsequent stroke can help to improve preventive efforts and limit the burden of stroke in the population.

Objective: To determine population-based incidence of TIA and the timing and long-term trends of stroke risk after TIA.

Design, Setting, And Participants: Retrospective cohort study (Framingham Heart Study) of prospectively collected data of 14 059 participants with no history of TIA or stroke at baseline, followed up from 1948-December 31, 2017. A sample of TIA-free participants was matched to participants with first incident TIA on age and sex (ratio, 5:1).

Exposures: Calendar time (TIA incidence calculation, time-trends analyses), TIA (matched longitudinal cohort).

Main Outcomes And Measures: The main outcomes were TIA incidence rates; proportion of stroke occurring after TIA in the short term (7, 30, and 90 days) vs the long term (>1-10 years); stroke after TIA vs stroke among matched control participants without TIA; and time trends of stroke risk at 90 days after TIA assessed in 3 epochs: 1954-1985, 1986-1999, and 2000-2017.

Results: Among 14 059 participants during 66 years of follow-up (366 209 person-years), 435 experienced TIA (229 women; mean age, 73.47 [SD, 11.48] years and 206 men; mean age, 70.10 [SD, 10.64] years) and were matched to 2175 control participants without TIA. The estimated incidence rate of TIA was 1.19/1000 person-years. Over a median of 8.86 years of follow-up after TIA, 130 participants (29.5%) had a stroke; 28 strokes (21.5%) occurred within 7 days, 40 (30.8%) occurred within 30 days, 51 (39.2%) occurred within 90 days, and 63 (48.5%) occurred more than 1 year after the index TIA; median time to stroke was 1.64 (interquartile range, 0.07-6.6) years. The age- and sex-adjusted cumulative 10-year hazard of incident stroke for patients with TIA (130 strokes among 435 cases) was 0.46 (95% CI, 0.39-0.55) and for matched control participants without TIA (165 strokes among 2175) was 0.09 (95% CI, 0.08-0.11); fully adjusted hazard ratio [HR], 4.37 (95% CI, 3.30-5.71; P < .001). Compared with the 90-day stroke risk after TIA in 1948-1985 (16.7%; 26 strokes among 155 patients with TIA), the risk between 1986-1999 was 11.1% (18 strokes among 162 patients) and between 2000-2017 was 5.9% (7 strokes among 118 patients). Compared with the first epoch, the HR for 90-day risk of stroke in the second epoch was 0.60 (95% CI, 0.33-1.12) and in the third epoch was 0.32 (95% CI, 0.14-0.75) (P = .005 for trend).

Conclusions And Relevance: In this population-based cohort study from 1948-2017, the estimated crude TIA incidence was 1.19/1000 person-years, the risk of stroke was significantly greater after TIA compared with matched control participants who did not have TIA, and the risk of stroke after TIA was significantly lower in the most recent epoch from 2000-2017 compared with an earlier period from 1948-1985.
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http://dx.doi.org/10.1001/jama.2020.25071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838926PMC
January 2021

Cortical superficial siderosis in the general population: The Framingham Heart and Rotterdam studies.

Int J Stroke 2021 Oct 21;16(7):798-808. Epub 2021 Jan 21.

Erasmus MC, Rotterdam, The Netherlands.

Objective: We aimed to characterize cortical superficial siderosis, its determinants and sequel, in community-dwelling older adults.

Methods: The sample consisted of Framingham ( = 1724; 2000-2009) and Rotterdam ( = 4325; 2005-2013) study participants who underwent brain MRI. In pooled individual-level analysis, we compared baseline characteristics in patients with cortical superficial siderosis to two reference groups: (i) persons without hemorrhagic MRI markers of cerebral amyloid angiopathy (no cortical superficial siderosis and no microbleeds) and (ii) those with presumed cerebral amyloid angiopathy based on the presence of strictly lobar microbleeds but without cortical superficial siderosis.

Results: Among a total of 6049 participants, 4846 did not have any microbleeds or cortical superficial siderosis (80%), 401 had deep/mixed microbleeds (6.6%), 776 had strictly lobar microbleeds without cortical superficial siderosis (12.8%) and 26 had cortical superficial siderosis with/without microbleeds (0.43%). In comparison to participants without microbleeds or cortical superficial siderosis and to those with strictly lobar microbleeds but without cortical superficial siderosis, participants with cortical superficial siderosis were older (OR 1.09 per year, 95% CI 1.05, 1.14;  < 0.001 and 1.04, 95% CI 1.00, 1.09;  = 0.058, respectively), had overrepresentation of the APOE ɛ4 allele (5.19, 2.04, 13.25;  = 0.001 and 3.47, 1.35, 8.92;  = 0.01), and greater prevalence of intracerebral hemorrhage (72.57, 9.12, 577.49;  < 0.001 and 81.49, 3.40, >999.99;  = 0.006). During a mean follow-up of 5.6 years, 42.4% participants with cortical superficial siderosis had a stroke (five intracerebral hemorrhage, two ischemic strokes and four undetermined strokes), 19.2% had transient neurological deficits and 3.8% developed incident dementia.

Conclusion: Our study adds supporting evidence to the association between cortical superficial siderosis and cerebral amyloid angiopathy within the general population. Community-dwelling persons with cortical superficial siderosis may be at high risk for intracerebral hemorrhage and future neurological events.
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http://dx.doi.org/10.1177/1747493020984559DOI Listing
October 2021

The cortical origin and initial spread of medial temporal tauopathy in Alzheimer's disease assessed with positron emission tomography.

Sci Transl Med 2021 01;13(577)

Massachusetts General Hospital, Boston, MA 02114, USA.

Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-β (Aβ) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before Aβ in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, Aβ burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data ( = 104), tracked Aβ-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global Aβ burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer's tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.
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http://dx.doi.org/10.1126/scitranslmed.abc0655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978042PMC
January 2021

Interleukin-6 Interacts with Sleep Apnea Severity when Predicting Incident Alzheimer's Disease Dementia.

J Alzheimers Dis 2021 ;79(4):1451-1457

The Framingham Heart Study, Framingham, MA, USA.

Because of their roles as potential risk factors, we evaluated whether obstructive sleep apnea (OSA) severity interacts with interleukin-6 (IL-6) in predicting incident dementia of the Alzheimer's type (DAT). In 269 dementia-free participants, IL-6 and the apnea-hypopnea index (AHI) were measured at baseline and incident DAT was surveilled for up to 22.8 years. Cox models revealed a significant interaction: In the lowest IL-6 quartile only, a higher AHI was associated with an elevated risk of DAT. The association between OSA severity and incident DAT might be especially apparent in the absence of inflammation or absence of potential benefits from IL-6.
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http://dx.doi.org/10.3233/JAD-200545DOI Listing
September 2021

Slow-Wave Sleep and MRI Markers of Brain Aging in a Community-Based Sample.

Neurology 2021 03 22;96(10):e1462-e1469. Epub 2020 Dec 22.

From the Framingham Heart Study (A.-A.B., A.S.B., J.R.R., C.L.S., J.M.Z., S.S., M.P.P. J.J.H.); Department of Neurology (A.-A.B., A.S.B., C.L.S., S.S., J.J.H.), Boston University School of Medicine; Department of Biostatistics (A.S.B., J.J.H. ), Boston University School of Public Health, MA; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (V.M., C.L.S., S.S., J.J.H.), and Department of Population Health Sciences (J.J.H.), University of Texas Health Sciences Center, San Antonio; Centre for Advanced Research in Sleep Medicine (E.S.), Hôpital du Sacré-Coeur de Montréal, CIUSSS-NIM; Department of Neuroscience (E.S.), Université de Montréal, Quebec, Canada; Department of Neurology (C.D., P.M.), and School of Medicine and Imaging of Dementia and Aging Laboratory, Center for Neuroscience (P.M.), University of California, Davis, Sacramento; Division of Sleep and Circadian Disorders (S.R., D.J.G.), Brigham & Women's Hospital; Beth Israel Deaconess Medical Center (S.R., D.J.G.); Division of Sleep Medicine Harvard Medical School, Boston, MA; VA Boston Healthcare System (D.J.G.), Boston, MA; Turner Institute for Brain and Mental Health (M.P.P.), School of Psychological Sciences, Monash University, Melbourne, VIC, Australia; and Harvard T.H. Chan School of Public Health (M.P.P.), Boston, MA.

Objective: To test the hypothesis that reduced slow-wave sleep, or N3 sleep, which is thought to underlie the restorative functions of sleep, is associated with MRI markers of brain aging, we evaluated this relationship in the community-based Framingham Heart Study Offspring cohort using polysomnography and brain MRI.

Methods: We studied 492 participants (age 58.8 ± 8.8 years, 49.4% male) free of neurological diseases who completed a brain MRI scan and in-home overnight polysomnography to assess slow-wave sleep (absolute duration and percentage of total sleep). Volumes of total brain, total cortical, frontal cortical, subcortical gray matter, hippocampus, and white matter hyperintensities were investigated as a percentage of intracranial volume, and the presence of covert brain infarcts was evaluated. Linear and logistic regression models were adjusted for age, age squared, sex, time interval between polysomnography and MRI (3.3 ± 1.0 years), ε4 carrier status, stroke risk factors, sleeping pill use, body mass index, and depression.

Results: Less slow-wave sleep was associated with lower cortical brain volume (absolute duration, β [standard error] = 0.20 [0.08], = 0.015; percentage, 0.16 [0.08], = 0.044), lower subcortical brain volume (percentage, 0.03 [0.02], = 0.034), and higher white matter hyperintensities volume (absolute duration, -0.12 [0.05], = 0.010; percentage, -0.10 [0.04], = 0.033). Slow-wave sleep duration was not associated with hippocampal volume or the presence of covert brain infarcts.

Conclusion: Loss of slow-wave sleep might facilitate accelerated brain aging, as evidence by its association with MRI markers suggestive of brain atrophy and injury. Alternatively, subtle injuries and accelerated aging might reduce the ability of the brain to produce slow-wave sleep.
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http://dx.doi.org/10.1212/WNL.0000000000011377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055313PMC
March 2021

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Bi-directional association between epilepsy and dementia: The Framingham Heart Study.

Neurology 2020 12 23;95(24):e3241-e3247. Epub 2020 Oct 23.

From the Framingham Heart Study (M.S., A.S.B., J.J.H., S.S.); Department of Neurology (M.S., A.S.B., J.J.H., S.S.), Boston University School of Medicine; Department of Biostatistics (A.S.B., J.J.H.), Boston University School of Public Health, MA; Department of Neurology (T.J.P.), Yale University School of Medicine, New Haven, CT; Department of Neurology (O.D., D.F.), NYU Grossman School of Medicine, New York, NY; and University of Texas Health Sciences Center (S.S.), San Antonio. Dr. Himali is currently affiliated with the Department of Population Health Sciences, University of Texas Health Science Center, San Antonio.

Objective: To assess the risk of incident epilepsy among participants with prevalent dementia and the risk of incident dementia among participants with prevalent epilepsy in the Framingham Heart Study (FHS).

Methods: We analyzed prospectively collected data in the Original and Offspring FHS cohorts. To determine the risk of developing epilepsy among participants with dementia and the risk of developing dementia among participants with epilepsy, we used separate, nested, case-control designs and matched each case to 3 age-, sex- and FHS cohort-matched controls. We used Cox proportional hazards regression analysis, adjusting for sex and age. In secondary analysis, we investigated the role of education level and ε4 allele status in modifying the association between epilepsy and dementia.

Results: A total of 4,906 participants had information on epilepsy and dementia and dementia follow-up after age 65. Among 660 participants with dementia and 1,980 dementia-free controls, there were 58 incident epilepsy cases during follow-up. Analysis comparing epilepsy risk among dementia cases vs controls yielded a hazard ratio (HR) of 1.82 (95% confidence interval 1.05-3.16, = 0.034). Among 43 participants with epilepsy and 129 epilepsy-free controls, there were 51 incident dementia cases. Analysis comparing dementia risk among epilepsy cases vs controls yielded a HR of 1.99 (1.11-3.57, = 0.021). In this group, among participants with any post-high school education, prevalent epilepsy was associated with a nearly 5-fold risk for developing dementia (HR 4.67 [1.82-12.01], = 0.001) compared to controls of the same educational attainment.

Conclusions: There is a bi-directional association between epilepsy and dementia. with either condition carrying a nearly 2-fold risk of developing the other when compared to controls.
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http://dx.doi.org/10.1212/WNL.0000000000011077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836659PMC
December 2020

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

Growth Differentiation Factor 15 and NT-proBNP as Blood-Based Markers of Vascular Brain Injury and Dementia.

J Am Heart Assoc 2020 10 14;9(19):e014659. Epub 2020 Sep 14.

Framingham Heart Study Framingham MA.

Background GDF15 (growth differentiation factor 15) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may offer promise as biomarkers for cognitive outcomes, including dementia. We determined the association of these biomarkers with cognitive outcomes in a community-based cohort. Methods and Results Plasma GDF15 (n=1603) and NT-proBNP levels (n=1590) (53% women; mean age, 68.7 years) were measured in dementia-free Framingham Offspring cohort participants at examination 7 (1998-2001). Participants were followed up for incident dementia. Secondary outcomes included Alzheimer disease dementia, magnetic resonance imaging structural brain measures, and neurocognitive performance. During a median 11.8-year follow-up, 131 participants developed dementia. On multivariable Cox proportional-hazards analysis, higher circulating GDF15 was associated with an increased risk of incident all-cause and Alzheimer disease dementia (hazard ratio [HR] per SD increment in natural log-transformed biomarker value, 1.54 [95% CI, 1.22-1.95] and 1.37 [95% CI, 1.03-1.81], respectively), whereas higher plasma NT-proBNP was also associated with an increased risk of all-cause dementia (HR, 1.32; 95% CI, 1.05-1.65). Elevated GDF15 was associated with lower total brain and hippocampal volumes, greater white matter hyperintensity volume, and poorer cognitive performance. Elevated NT-proBNP was associated with greater white matter hyperintensity volume and poorer cognitive performance. Addition of both biomarkers to a conventional risk factor model improved dementia risk classification (net reclassification improvement index, 0.25; 95% CI, 0.05-0.45). Conclusions Elevated plasma GDF15 and NT-proBNP were associated with vascular brain injury on magnetic resonance imaging, poorer neurocognitive performance, and increased risk of incident dementia in individuals aged >60 years. Both biomarkers improved dementia risk classification beyond that of traditional clinical risk factors, indicating their potential value in predicting incident dementia.
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http://dx.doi.org/10.1161/JAHA.119.014659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792414PMC
October 2020

Association of common genetic variants with brain microbleeds: A genome-wide association study.

Neurology 2020 12 10;95(24):e3331-e3343. Epub 2020 Sep 10.

From the Departments of Epidemiology (M.J.K., H.H.H.A., D.V., S.J.v.d.L., P.Y., M.W.V., N.A., C.M.v.D., M.A.I.), Radiology and Nuclear Medicine (H.H.H.A., P.Y., A.v.d.L., M.W.V.), and Clinical Genetics (H.H.H.A.), Erasmus MC University Medical Center, Rotterdam, the Netherlands; Stroke Research Group, Department of Clinical Neurosciences (D.L., M.T., J.L., D.J.T., H.S.M.), University of Cambridge, UK; Department of Neurology (J.R.J.R., C.L.S., J.J.H., A.S.B., C.D., S. Seshadri), Boston University School of Medicine; The Framingham Heart Study (J.R.J.R., C.L.S., J.J.H., A.S.B., S. Seshadri), MA; Department of Biostatistics (A.V.S.), University of Michigan, Ann Arbor; Icelandic Heart Association (A.V.S., S. Sigurdsson, V.G.), Kopavogur, Iceland; Brown Foundation Institute of Molecular Medicine, McGovern Medical School (M.F.), and Human Genetics Center, School of Public Health (M.F.), University of Texas Health Science Center at Houston; Clinical Division of Neurogeriatrics, Department of Neurology (E.H., L.P., R.S.), Institute for Medical Informatics, Statistics and Documentation (E.H.), and Gottfried Schatz Research Center, Department of Molecular Biology and Biochemistry (Y.S., H.S.), Medical University of Graz, Austria; Center of Cerebrovascular Diseases, Department of Neurology (J.L.), West China Hospital, Sichuan University, Chengdu; Stroke Research Centre, Queen Square Institute of Neurology (I.C.H., D.W., H.H., D.J.W.), University College London, UK; Department of Neurosurgery (I.C.H.), Klinikum rechts der Isar, University of Munich, Germany; Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology (M.L., D.C.M.L., M.E.B., I.J.D., J.M.W.), and Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute (M.E.B., J.M.W.), University of Edinburgh, UK; Department of Internal Medicine, Section of Gerontology and Geriatrics (S.T.), Department of Cardiology (S.T., J.v.d.G., J.W.J.), Section of Molecular Epidemiology, Biomedical Data Sciences (E.B.v.d.A., M.B., P.E.S.), Leiden Computational Biology Center, Biomedical Data Sciences (E.B.v.d.A.), Department of Radiology (J.v.d.G.), and Einthoven Laboratory for Experimental Vascular Medicine (J.W.J.), Leiden University Medical Center, the Netherlands; Department of Neurology (A.-K.G., N.S.R.), Massachusetts General Hospital, Harvard Medical School, Boston; Memory Aging and Cognition Center (S.H., C.C.), National University Health System, Singapore; Department of Pharmacology (S.H., C.C.) and Saw Swee Hock School of Public Health (S.H.), National University of Singapore and National University Health System, Singapore; Pattern Recognition & Bioinformatics (E.B.v.d.A.), Delft University of Technology, the Netherlands; Department of Biostatistics (S.L., J.J.H., Q.Y., A.S.B.), Boston University School of Public Health, MA; Department of Radiology (C.R.J., K.K.), Mayo Clinic, Rochester, MN; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., S. Seshadri), UT Health San Antonio, TX; Department of Medicine, Division of Geriatrics (B.G.W., T.H.M), and Memory Impairment and Neurodegenerative Dementia (MIND) Center (T.H.M.), University of Mississippi Medical Center, Jackson; Singapore Eye Research Institute (C.Y.C., J.Y.K., T.Y.W.); Department of Neuroradiology (Z.M., J.M.W.), NHS Lothian, Edinburgh; Institute of Cardiovascular and Medical Sciences (D.J.S.), College of Medical, Veterinary and Life Sciences, University of Glasgow, UK; Division of Cerebrovascular Neurology (R.F.G.), Johns Hopkins University, Baltimore, MD; Department of Neuroradiology (A.D.M.), Atkinson Morley Neurosciences Centre, St George's NHS Foundation Trust, London, UK; Department of Neurology (C.D.), University of California at Davis; Nuffield Department of Population Health (C.M.v.D.), University of Oxford, UK; Laboratory of Epidemiology and Population Sciences (L.J.L.), National Institute on Aging, Baltimore, MD; and Faculty of Medicine (V.G.), University of Iceland, Reykjavik, Iceland.

Objective: To identify common genetic variants associated with the presence of brain microbleeds (BMBs).

Methods: We performed genome-wide association studies in 11 population-based cohort studies and 3 case-control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI sequences, and further classified as lobar or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs.

Results: BMBs were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the region reached genome-wide significance for its association with BMB (lead rs769449; odds ratio [OR] [95% confidence interval (CI)] 1.33 [1.21-1.45]; = 2.5 × 10). ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19-1.50]; = 1.0 × 10) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86-1.25]; = 0.68). ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB.

Conclusions: Genetic variants in the region are associated with the presence of BMB, most likely due to the ε4 allele count related to a higher number of strictly lobar BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.
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http://dx.doi.org/10.1212/WNL.0000000000010852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836652PMC
December 2020

Systemic inflammation as a moderator between sleep and incident dementia.

Sleep 2021 02;44(2)

The Framingham Heart Study, Framingham, MA.

Study Objectives: To determine whether C-reactive protein (CRP), a marker of systemic inflammation, moderates the association between sleep and incident dementia.

Methods: We studied Framingham Heart Study participants who completed at baseline a serum CRP assessment and in-home polysomnography to measure sleep duration, sleep efficiency, sleep latency, wake after sleep onset (WASO), number of awakenings, arousal index, and apnea-hypopnea index. Participants were divided into groups according to their CRP level: low (<1 mg/L), average (1-3 mg/L), and high inflammation (>3 mg/L). Surveillance for outcomes (incident all-cause and Alzheimer's disease [AD] dementia) commenced at baseline and continued up to 22.5 years.

Results: In 291 participants (mean age 67.5 ± 4.9 years, 51.6% men) followed for 13.4 ± 5.4 years, we observed 43 cases of all-cause dementia, 33 of which were clinically consistent with AD. Whereas no direct association between CRP or sleep exposures was observed with incident dementia, CRP levels interacted with nighttime wakefulness when predicting both incident all-cause and AD dementia. In the high CRP group, longer WASO (hazard ratio [HR], 2.89; 95% CI, 1.31-6.34) and more nighttime awakenings (HR, 4.55; 95% CI, 1.19-17.38) were associated with higher risk of incident dementia. In the low CRP group, fewer nighttime awakenings were associated with a higher risk of incident dementia (HR, 0.07; 95% CI, 0.01-0.68).

Conclusions: Our findings suggest that inflammation moderates the association between sleep, particularly nighttime wakefulness, and dementia risk. The presence of inflammation may be an important determinant in evaluating how sleep disturbances relate to neurodegeneration.
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http://dx.doi.org/10.1093/sleep/zsaa164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879417PMC
February 2021

Mid to Late Life Hypertension Trends and Cerebral Small Vessel Disease in the Framingham Heart Study.

Hypertension 2020 09 31;76(3):707-714. Epub 2020 Jul 31.

From the Department of Neurology, Boston University School of Medicine, MA (R.E.P., A.S.B., H.A., S.S., J.R.R.).

The duration and lifetime pattern of hypertension is related to risk of stroke and dementia. In turn, cerebral small vessel disease (CSVD) is the most frequent form of cerebrovascular disease underlying dementia and stroke. Thus, study of the relation of mid to late life hypertension trends with CSVD late in life will help understand hypertension's role and inform preventive efforts of CSVD consequences. We studied 1686 Framingham Heart Study Offspring cohort participants free of stroke and dementia, who were examined in mid and late life, and had available brain magnetic resonance imaging during late life. We related hypertension trends between mid and late life (normotension-normotension N-N, normotension-hypertension N-H, hypertension-hypertension H-H) to cerebral microbleeds and covert brain infarcts (CBI), overall and stratified by brain topography. We used multivariable logistic regression analyses to calculate odds ratio and 95% CIs for CSVD measures. The prevalence of CSVD in late life was 8% for cerebral microbleeds and 13% for covert brain infarcts and increased with longer hypertension exposure across all brain regions. Compared with the trend pattern of N-N, both N-H and H-H trends had higher odds of mixed cerebral microbleeds (2.71 [1.08-6.80], and 3.44 [1.39-8.60], respectively); H-H also had higher odds of any cerebral microbleeds or covert brain infarcts (1.54 [1.12-2.20]), and any covert brain infarcts (1.55 [1.08-2.20]). The burden of CSVD also increased with longer hypertension exposure. Our results highlight hypertension having a major role in subclinical CSVD, across subtypes and brain regions, and call attention to improve recognition and treatment of hypertension early in life.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577565PMC
September 2020

Cardiovascular health, genetic risk, and risk of dementia in the Framingham Heart Study.

Neurology 2020 09 20;95(10):e1341-e1350. Epub 2020 Jul 20.

From the Departments of Biostatistics (G.M.P., A.S.B., V.X., A.L.D.) and Epidemiology (R.S.V.), Boston University School of Public Health; Boston University and NHLBI's Framingham Heart Study (A.S.B., C.L.S., V.X., R.S.V., A.L.D., S.S.), Framingham; Department of Neurology (A.S.B., C.L.S., A.L.D., S.S.), Boston University School of Medicine, MA; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases (C.L.S., S.S.), University of Texas Health Sciences Center, San Antonio; Sections of Preventive Medicine & Epidemiology and Cardiology (V.X., R.S.V.), Department of Medicine, Boston University, MA; Melbourne Dementia Research Centre (M.P.P.), The Florey Institute for Neuroscience and Mental Health; Faculty of Medicine, Dentistry, and Health Sciences (M.P.P.), University of Melbourne, Parkville; Centre for Human Psychopharmacology (M.P.P.), Swinburne University of Technology, Hawthorn, Australia; and Harvard T.H. Chan School of Public Health (M.P.P.), Boston, MA.

Objective: To determine the joint role of ideal cardiovascular health (CVH) and genetic risk on risk of dementia.

Methods: We categorized CVH on the basis of the American Heart Association Ideal CVH Index and genetic risk through a genetic risk score (GRS) of common genetic variants and the ε4 genotype in 1,211 Framingham Heart Study (FHS) offspring cohort participants. We used multivariable Cox proportional hazards regression models to examine the association between CVH, genetic risk, and incident all-cause dementia with up to 10 years of follow-up (mean 8.4 years, 96 incident dementia cases), adjusting for age, sex, and education.

Results: We observed that a high GRS (>80th percentile) was associated with a 2.6-fold risk of dementia (95% confidence interval [CI] of hazard ratio [HR] 1.23-5.29; = 0.012) compared with having a low GRS (<20th percentile); carrying at least 1 ε4 allele was associated with a 2.3-fold risk of dementia compared with not carrying an ε4 allele (95% CI of HR 1.49-3.53; = 0.0002), and having a favorable CVH showed a 0.45-fold lower risk of dementia (95% CI of HR 0.20-1.01; = 0.0527) compared to having an unfavorable CVH when all 3 components were included in the model. We did not observe an interaction between CVH and GRS ( = 0.99) or ε4 ( = 0.16).

Conclusions: We observed that both genetic risk and CVH contribute additively to dementia risk.
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http://dx.doi.org/10.1212/WNL.0000000000010306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538213PMC
September 2020

Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium.

Neurology 2020 08 1;95(5):e519-e531. Epub 2020 Jul 1.

From the Department of Epidemiology (F.J.W., L.B.C., R.W., D. Blacker, D. Bos, J.G., A.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Departments of Epidemiology (F.J.W., D. Bos, S.K.L.D., M.A.I., M.K.I., A.H.), Radiology and Nuclear Medicine (D. Bos), and Neurology (M.K.I.), Erasmus MC, Rotterdam, the Netherlands; Department of Neurology (L.B.C.), Massachusetts General Hospital, Boston; Department of Infectious Disease Epidemiology (R.A., F.d.W., C. Hadjichrysanthou, K.M.-M., M.M.W.), School of Public Health, Imperial College London, UK; Neuropsychiatry and Epidemiology and Clinical Research (C. Berr), INSERM, UMR 1061 Montpellier, Universite de Montpellier, France; Boston University School of Medicine (A.B., M.P.P., C.L.S., S.S.); Framingham Heart Study (A.B., M.P.P., C.L.S., S.S.), MA; Department of Biostatistics (A.B., K.L.D.-P.), Boston University School of Public Health, MA; Cardiovascular Health Research Unit, Departments of Medicine (J.C.B., B.M.P.) and Epidemiology and Health Services (B.M.P.), University of Washington, Seattle; Department of Psychiatry (D. Blacker), Massachusetts General Hospital, Charlestown; University of Cambridge (C. Brayne), UK; Bordeaux Population Health Research Center (J.-F.D., S.D., C.D., L.G., C. Helmer), INSERM, UMR 1219, University of Bordeaux; Department of Neurology (S.D.), Memory Clinic, Bordeaux University Hospital, France; McGovern Medical School (M.F.), University of Texas Health Science Center at Houston; Icelandic Heart Association (V.G.), Kopavogur; Faculty of Medicine (V.G.), University of Iceland, Reykjavik; Institute of Neuroscience and Physiology (E.J., S.K., I.S., H.W., A.Z.), Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Epidemiology, Graduate School of Public Health (L.H.K.), and Departments of Neurology and Psychiatry (O.L.L.), University of Pittsburgh, PA; Laboratory of Epidemiology and Population Sciences (L.L., O.M.), National Institute on Aging, Bethesda, MD; Institute of Health and Society (F.E.M., B.C.M.S.), Newcastle University, Newcastle upon Tyne, UK; MIND Center (T.H.M.), University of Mississippi Medical Center, Jackson; Melbourne Dementia Research Centre (M.P.P.), The Florey Institute for Neuroscience and Mental Health, Melbourne, Australia; Kaiser Permanente Washington Health Research Institute (B.M.P.), Seattle; and The Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., S.S.), UT Health San Antonio, TX.

Objective: To determine changes in the incidence of dementia between 1988 and 2015.

Methods: This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex.

Results: Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] vs 8% [0%-15%]).

Conclusion: The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.
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http://dx.doi.org/10.1212/WNL.0000000000010022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455342PMC
August 2020

Relation of plasma β-amyloid, clusterin, and tau with cerebral microbleeds: Framingham Heart Study.

Ann Clin Transl Neurol 2020 07 26;7(7):1083-1091. Epub 2020 Jun 26.

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

Objective: Cerebral microbleeds (CMBs) are associated with higher risk of stroke and dementia, predating clinical diagnosis by several years. CMB are considered markers of cerebral small vessel disease (CSVD): hypertensive (deep CMB) and cerebral amyloid angiopathy (lobar CMB). We related plasma β-Amyloid (40, 42 and their ratio), clusterin, and tau levels to CMB to elucidate their role as biomarkers for the angiopathies represented by CMB.

Methods: Dementia, stroke, and other neurological disease-free Framingham Heart Study participants with available CMB and biomarker measurements were included. We related biomarker levels (standardized for analyses) to CMB presence overall and stratified by brain topography (any, lobar, deep), using multivariable logistic regression analyses.

Results: CMB were observed in 208 (5.7%) participants (mean age 57 years, 54% women). After multivariable adjustment, Aβ1-40 was associated with any CMB (OR (95%CI) 1.20 (0.99, 1.45) P = 0.062)) and lobar CMB (OR (95%CI) 1.33 (1.05, 1.68) P = 0.019), but not with deep CMB. Log-Aβ1-42 levels were not associated with CMB overall. Clusterin was related to mixed CMB (1.70 [1.05, 2.74], P = 0.031). Tau levels were associated with any CMB (OR (95%CI) 1.26 (1.07, 1.49) P = 0.006), lobar CMB (OR (95%CI) 1.26 (1.05, 1.52) P = 0.013), and with deep CMB (OR (95% CI) 1.46 (1.13, 1.89) P = 0.004).

Interpretation: We found that plasma Aβ1-40 and Tau are associated with CMB but further studies are needed to confirm their role in hemorrhage prone CSVD represented by CMB and as indicators of ongoing subclinical neuronal injury.
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http://dx.doi.org/10.1002/acn3.51066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359126PMC
July 2020

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.

Stroke 2020 07 10;51(7):2111-2121. Epub 2020 Jun 10.

Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA.

Background And Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings.

Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC.

Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (), 10q23.1 (), and 10q24.33 ( In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 () and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: (2q32.1), (3q27.1), (5q27.1), and (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype.

Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.
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http://dx.doi.org/10.1161/STROKEAHA.119.027544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365038PMC
July 2020

Assessment of Incidence and Risk Factors of Intracerebral Hemorrhage Among Participants in the Framingham Heart Study Between 1948 and 2016.

JAMA Neurol 2020 10;77(10):1252-1260

Framingham Heart Study, Framingham, Massachusetts.

Importance: Intracerebral hemorrhage (ICH) has the highest mortality of all stroke types and is the most serious complication of anticoagulation. Data regarding trends in ICH incidence and location-specific risk factors on the population level are conflicting.

Objective: To assess long-term population-based trends in the incidence of ICH, examine incidence rates stratified by deep and lobar locations, and characterize location-specific risk factors.

Design, Setting, And Participants: This longitudinal prospective community-based cohort study comprised 10 333 original participants (n = 5209; age range, 28-62 years) and offspring participants (n = 5124; age range, 5-70 years) from the Framingham Heart Study who were followed up from January 1, 1948, to December 31, 2016. Original and offspring patient cohorts were confirmed to have experienced a spontaneous ICH event through imaging or pathologic testing. A total of 129 participants were identified with a primary incident of ICH. After exclusions, the remaining 99 patients were divided into 2 nested case-control samples, which were created by stratifying the first incident of ICH by brain region (lobar ICH or deep ICH), with 55 patients included in the lobar ICH sample and 44 patients included in the deep ICH sample. Patients were matched by age and sex (1:4 ratio) with 396 individuals without any stroke event (the control group). No participant in the patient samples was excluded or approached for consent, as their initial consent to participate in the Framingham Heart Study included consent to follow-up of cardiovascular outcomes. Data were analyzed in October 2019.

Main Outcomes And Measures: The unadjusted and age-adjusted ICH incidence rates, assessed in 3 periods (period 1, from 1948-1986; period 2, from 1987-1999; and period 3, from 2000-2016) to study incidence trends. Nested case-control samples were used to examine baseline risk factors and medication exposures with the incidence of ICH events located in the lobar and deep brain regions within the 10 years before participants experienced a stroke event.

Results: Of 10 333 original and offspring participants in the Framingham Heart Study, 129 patients (72 women [55.8%]; mean [SD] age, 77 [11] years) experienced a primary ICH incident during a follow-up period of 68 years (301 282 person-years), with an incidence rate of 43 cases per 100 000 person-years. The unadjusted incidence rate increased over time, but the age-adjusted incidence rate decreased slightly between periods 2 and 3. An age-stratified analysis indicated a continued increase in ICH incidence among patients 75 years and older, reaching 176 cases per 100 000 person-years in period 3. A concurrent 3-fold increase in the use of anticoagulant medications was observed, from 4.4% in period 2 to 13.9% in period 3. The incidence rate increased substantially with age for both lobar and deep ICH. Higher systolic and diastolic blood pressure and statin medication use (odds ratio [OR], 4.07; 95% CI, 1.16-14.21; P = .03) were associated with the incidence of deep ICH. Higher systolic blood pressure and apolipoprotein E ε4 allele homozygosity (OR, 3.66; 95% CI, 1.28-10.43; P = .02) were associated with the incidence of lobar ICH.

Conclusions And Relevance: This study found that the incidence of ICH increased in the oldest patients. Hypertension is a treatable risk factor for both deep and lobar ICH, while the use of statin medications is associated with the risk of a deep ICH event.
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http://dx.doi.org/10.1001/jamaneurol.2020.1512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281354PMC
October 2020

The progression of carotid atherosclerosis and imaging markers of dementia.

Alzheimers Dement (N Y) 2020 14;6(1):e12015. Epub 2020 Apr 14.

Department of Neurology Boston University School of Medicine Boston Massachusetts USA.

Introduction: We studied the association of carotid intima-media thickness (CIMT) with hippocampal volume (HV) in community dwelling individuals, testing the hypothesis that persons with carotid atherosclerosis progression would have lower HV.

Methods: We studied 1376 Framingham Offspring participants with two carotid ultrasounds and brain magnetic resonance imaging (MRIs). We used multivariable linear regression analyses to relate CIMT progression and HV and total brain volume. Regression models were adjusted for demographics and vascular risk factors, time interval between imaging examinations, and baseline CIMT. We assessed effect modification by hypertension treatment (HRx).

Results: Participants with higher ICA IMT progression had significantly lower HV after adjustment for vascular risk factors and baseline IMT (standardized beta ± standard error: -0.067 ± 0.027,  = .01). We observed weaker association between ICA IMT change and HV among subjects treated for hypertension (β = -0.047,  = .19 vs β = -0.096,  = .026).

Discussion: Cumulative vascular risk factor exposure, reflected by CIMT progression, may increase the risk of neurodegeneration.
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http://dx.doi.org/10.1002/trc2.12015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154591PMC
April 2020
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