Publications by authors named "Sudha Seshadri"

390 Publications

Cognitive Impairment After Intracerebral Hemorrhage: A Systematic Review of Current Evidence and Knowledge Gaps.

Front Neurol 2021 27;12:716632. Epub 2021 Aug 27.

Center for Outcomes Research, Houston Methodist Research Institute, Houston Methodist, Houston, TX, United States.

Cognitive impairment (CI) is commonly observed after intracerebral hemorrhage (ICH). While a growing number of studies have explored this association, several evidence gaps persist. This review seeks to investigate the relationship between CI and ICH. A two-stage systematic review of research articles, clinical trials, and case series was performed. Initial search used the keywords ["Intracerebral hemorrhage" OR "ICH"] AND ["Cognitive Impairment" OR "Dementia OR "Cognitive Decline"] within the PubMed (last accessed November 3rd, 2020) and ScienceDirect (last accessed October 27th, 2020) databases, without publication date limits. Articles that addressed CI and spontaneous ICH were accepted if CI was assessed after ICH. Articles were rejected if they did not independently address an adult human population or spontaneous ICH, didn't link CI to ICH, were an unrelated document type, or were not written in English. A secondary snowball literature search was performed using reviews identified by the initial search. The Agency for Healthcare research and Quality's assessment tool was used to evaluate bias within studies. Rates of CI and contributory factors were investigated. Search yielded 32 articles that collectively included 22,631 patients. Present evidence indicates a high rate of post-ICH CI (65-84%) in the acute phase (<4 weeks) which is relatively lower at 3 (17.3-40.2%) and 6 months (19-63.3%). Longer term follow-up (≥1 year) demonstrates a gradual increase in CI. Advanced age, female sex, and prior stroke were associated with higher rates of CI. Associations between post-ICH CI and cerebral microbleeds, superficial siderosis, and ICH volume also exist. Pre-ICH cognitive assessment was missing in 28% of included studies. The Mini Mental State Evaluation (44%) and Montreal Cognitive Assessment (16%) were the most common cognitive assessments, albeit with variable thresholds and definitions. Studies rarely (<10%) addressed racial and ethnic disparities. Current findings suggest a dynamic course of post-ICH cognitive impairment that may depend on genetic, sociodemographic and clinical factors. Methodological heterogeneity prevented meta-analysis, limiting results. There is a need for the methodologies and time points of post-ICH cognitive assessments to be harmonized across diverse clinical and demographic populations.
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http://dx.doi.org/10.3389/fneur.2021.716632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429504PMC
August 2021

Hearing Function: Identification of New Candidate Genes Further Explaining the Complexity of This Sensory Ability.

Genes (Basel) 2021 Aug 10;12(8). Epub 2021 Aug 10.

Institute for Maternal and Child Health-IRCCS, Burlo Garofolo, 34127 Trieste, Italy.

To date, the knowledge of the genetic determinants behind the modulation of hearing ability is relatively limited. To investigate this trait, we performed Genome-Wide Association Study (GWAS) meta-analysis using genotype and audiometric data (hearing thresholds at 0.25, 0.5, 1, 2, 4, and 8 kHz, and pure-tone averages of thresholds at low, medium, and high frequencies) collected in nine cohorts from Europe, South-Eastern USA, Caucasus, and Central Asia, for an overall number of ~9000 subjects. Three hundred seventy-five genes across all nine analyses were tagged by single nucleotide polymorphisms (SNPs) reaching a suggestive -value ( < 10). Amongst these, 15 were successfully replicated using a gene-based approach in the independent Italian Salus in the Apulia cohort ( = 1774) at the nominal significance threshold ( < 0.05). In addition, the expression level of the replicated genes was assessed in published human and mouse inner ear datasets. Considering expression patterns in humans and mice, eleven genes were considered particularly promising candidates for the hearing function: , , , , , , , and . These findings represent a further contribution to our understanding of the genetic basis of hearing function and its related diseases.
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http://dx.doi.org/10.3390/genes12081228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394865PMC
August 2021

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

SARS-CoV-2 Susceptibility and COVID-19 Mortality Among Older Adults With Cognitive Impairment: Cross-Sectional Analysis From Hospital Records in a Diverse US Metropolitan Area.

Front Neurol 2021 22;12:692662. Epub 2021 Jul 22.

Center for Outcomes Research, Houston Methodist, Houston, TX, United States.

Persistent knowledge gaps exist as to the extent that preexisting cognitive impairment is a risk factor for susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mortality from the coronavirus disease 2019 (COVID-19). We conducted a cross-sectional analysis of adults tested for SARS-CoV-2 at a tertiary healthcare system. Cognitive impairment was identified utilizing diagnosis codes (mild cognitive impairment, Alzheimer's disease, vascular, and other dementias) or cognitive impairment-specific medication use. Propensity score (PS) matched analyses were utilized to report odds ratios (OR) and 95% confidence intervals (CI) for association of cognitive impairment with SARS-CoV-2 susceptibility and COVID-19 mortality. Between March-3rd and December-11th, 2020, 179,979 adults were tested, of whom 21,607 (12.0%) tested positive. We identified 6,364 individuals with preexisting cognitive impairment (mean age: 78.5 years, 56.8% females), among whom 843 (13.2%) tested positive and 139 (19.5%) of those hospitalized died. In the pre-PS matched cohort, cognitive impairment was significantly associated with increased SARS-CoV-2 susceptibility (OR, CI: 1.12, 1.04-1.21) and COVID-19 mortality (OR, CI: 2.54, 2.07-3.12). One-to-one matches were identified for 6,192 of 6,364 (97.3%) individuals with prior cognitive impairment and 687 of 712 (96.5%) hospitalized patients with prior cognitive impairment. In the fully balanced post-matched cohort, preexisting cognitive impairment was significantly associated with higher likelihood of SARS-CoV-2 infection (OR, CI: 1.51, 1.35-1.70); however, cognitive impairment did not confer higher risk of COVID-19 mortality (OR, CI: 0.96, 0.73-1.25). To mitigate the effects of healthcare catastrophes such as the COVID-19 pandemic, strategies for targeted prevention and risk-stratified comorbidity management are warranted among the vulnerable sub-population living with cognitive impairment.
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http://dx.doi.org/10.3389/fneur.2021.692662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344862PMC
July 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

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 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

Asymmetry of Hippocampal Tau Pathology in Primary Age-Related Tauopathy and Alzheimer Disease.

J Neuropathol Exp Neurol 2021 Apr;80(5):436-445

From the Department of Pathology and Laboratory Medicine, Upstate Medical University, Syracuse, New York, USA.

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as neurofibrillary degeneration generally restricted to the medial temporal region (Braak stage I-IV) with complete or near absence of diffuse and neuritic plaques. Symptoms range in severity but are generally milder and later in onset than in Alzheimer disease (AD). Recently, an early predilection for neurofibrillary degeneration in the hippocampal CA2 subregion has been demonstrated in PART, whereas AD neuropathologic change (ADNC) typically displays relative sparing of CA2 until later stages. In this study, we utilized a semiquantitative scoring system to evaluate asymmetry of neurofibrillary degeneration between left and right hippocampi in 67 PART cases and 17 ADNC cases. 49% of PART cases demonstrated asymmetric findings in at least one hippocampal subregion, and 79% of the asymmetric cases displayed some degree of CA2 asymmetry. Additionally, 19% of cases revealed a difference in Braak score between the right and left hippocampi. There was a significant difference in CA2 neurofibrillary degeneration (p = 0.0006) and CA2/CA1 ratio (p < 0.0001) when comparing the contralateral sides, but neither right nor left was more consistently affected. These data show the importance of analyzing bilateral hippocampi in the diagnostic evaluation of PART and potentially of other neurodegenerative diseases.
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http://dx.doi.org/10.1093/jnen/nlab032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054137PMC
April 2021

Blood biomarkers for dementia in Hispanic and non-Hispanic White adults.

Alzheimers Dement (N Y) 2021 9;7(1):e12164. Epub 2021 Apr 9.

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

Introduction: The study evaluated if blood markers reflecting diverse biological pathways differentiate clinical diagnostic groups among Hispanic and non-Hispanic White adults.

Methods: Within Hispanic (n = 1193) and non-Hispanic White (n = 650) participants, serum total tau (t-tau), neurofilament light (NfL), ubiquitin carboxyl-terminal hydrolase LI, glial fibrillary acidic protein (GFAP), soluble cluster of differentiation-14, and chitinase-3-like protein 1 (YKL-40) were quantified. Mixed-effects partial proportional odds ordinal logistic regression and linear mixed-effects models were used to evaluate the association of biomarkers with diagnostic group and cognition, adjusting for age, sex, ethnicity, apolipoprotein E ε4, education, and site.

Results: T-tau, NfL, GFAP, and YKL-40 discriminated between diagnostic groups (receiver operating curve: 0.647-0.873). Higher t-tau (odds ratio [OR] = 1.671, 95% confidence interval [CI] = 1.457-1.917,  < .001), NfL (OR = 2.150, 95% CI = 1.819-2.542,  < .001), GFAP (OR = 2.283, 95% CI = 1.915-2.722,  < .001), and YKL-40 (OR = 1.288, 95% CI = 1.125-1.475,  < .001) were associated with increased likelihood of dementia relative to cognitively unimpaired and mild cognitive impairment groups. Higher NfL was associated with poorer global cognition (β = -0.455, standard error [SE] = 0.083,  < .001), semantic fluency (β = -0.410, SE = 0.133,  = .002), attention/processing speed (β = 2.880, SE = 0.801,  < .001), and executive function (β = 5.965, SE = 2.037,  = .003). Higher GFAP was associated with poorer global cognition (β = -0.345, SE = 0.092,  = .001), learning (β = -1.426, SE = 0.359,  < .001), and memory (β = -0.890, SE = 0.266,  < .001). Higher YKL-40 (β = -0.537, SE = 0.186,  = .004) was associated with lower memory scores. Interactions with ethnicity were observed for learning (NfL, GFAP, YKL-40), memory (NfL, GFAP), and semantic fluency (NfL; interaction terms < .008), which were generally no longer significant in a demographically matched subset of Hispanic and non-Hispanic White participants.

Discussion: Blood biomarkers of neuronal/axonal and glial injury differentiated between clinical diagnostic groups in a bi-ethnic cohort of Hispanic and non-Hispanic Whites. Our results add to the growing literature indicating that blood biomarkers may be viable tools for detecting neurodegenerative conditions and highlight the importance of validation in diverse cohorts.
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http://dx.doi.org/10.1002/trc2.12164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033409PMC
April 2021

Multiomics integrative analysis identifies allele-specific blood biomarkers associated to Alzheimer's disease etiopathogenesis.

Aging (Albany NY) 2021 Apr 12;13(7):9277-9329. Epub 2021 Apr 12.

Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Alzheimer's disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analysed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by haplotype ( and ). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterised a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in and AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.
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http://dx.doi.org/10.18632/aging.202950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064208PMC
April 2021

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

medRxiv 2021 Mar 20. Epub 2021 Mar 20.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.
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http://dx.doi.org/10.1101/2021.03.19.21253986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987050PMC
March 2021

Midlife vascular risk factors and risk of incident dementia: Longitudinal cohort and Mendelian randomization analyses in the UK Biobank.

Alzheimers Dement 2021 Mar 22. Epub 2021 Mar 22.

Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University LMU, Munich, Germany.

Introduction: Midlife clustering of vascular risk factors has been associated with late-life dementia, but causal effects of individual biological and lifestyle factors remain largely unknown.

Methods: Among 229,976 individuals (mean follow-up 9 years), we explored whether midlife cardiovascular health measured by Life's Simple 7 (LS7) is associated with incident all-cause dementia and whether the individual components of the score are causally associated with dementia.

Results: Adherence to the biological metrics of LS7 (blood pressure, cholesterol, glycemic status) was associated with lower incident dementia risk (hazard ratio = 0.93 per 1-point increase, 95% confidence interval [CI; 0.89-0.96]). In contrast, there was no association between the composite LS7 score and the lifestyle subscore (smoking, body mass index, diet, physical activity) and incident dementia. In Mendelian randomization analyses, genetically elevated blood pressure was associated with higher risk of dementia (odds ratio = 1.31 per one-standard deviation increase, 95% CI [1.05-1.60]).

Discussion: These findings underscore the importance of blood pressure control in midlife to mitigate dementia risk.
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http://dx.doi.org/10.1002/alz.12320DOI Listing
March 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

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
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

MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols.

Alzheimers Dement 2021 04 21;17(4):704-715. Epub 2021 Jan 21.

Alzheimer's Clinical and Translational Research Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

The concept of vascular contributions to cognitive impairment and dementia (VCID) derives from more than two decades of research indicating that (1) most older individuals with cognitive impairment have post mortem evidence of multiple contributing pathologies and (2) along with the preeminent role of Alzheimer's disease (AD) pathology, cerebrovascular disease accounts for a substantial proportion of this contribution. Contributing cerebrovascular processes include both overt strokes caused by etiologies such as large vessel occlusion, cardioembolism, and embolic infarcts of unknown source, and frequently asymptomatic brain injuries caused by diseases of the small cerebral vessels. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy, when present at moderate or greater pathologic severity, are independently associated with worse cognitive performance and greater likelihood of dementia, particularly in combination with AD and other neurodegenerative pathologies. Based on this evidence, the US National Alzheimer's Project Act explicitly authorized accelerated research in vascular and mixed dementia along with frontotemporal and Lewy body dementia and AD itself. Biomarker development has been consistently identified as a key step toward translating scientific advances in VCID into effective prevention and treatment strategies. Validated biomarkers can serve a range of purposes in trials of candidate interventions, including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratifying study participants according to their prognosis for VCID progression or treatment response, (4) demonstrating an intervention's target engagement or pharmacodynamic mechanism of action, and (5) monitoring disease progression during treatment. Effective biomarkers allow academic and industry investigators to advance promising interventions at early stages of development and discard interventions with low success likelihood. The MarkVCID consortium was formed in 2016 with the goal of developing and validating fluid- and imaging-based biomarkers for the cerebral small vessel diseases associated with VCID. MarkVCID consists of seven project sites and a central coordinating center, working with the National Institute of Neurologic Diseases and Stroke and National Institute on Aging under cooperative agreements. Through an internal selection process, MarkVCID has identified a panel of 11 candidate biomarker "kits" (consisting of the biomarker measure and the clinical and cognitive data used to validate it) and established a range of harmonized procedures and protocols for participant enrollment, clinical and cognitive evaluation, collection and handling of fluid samples, acquisition of neuroimaging studies, and biomarker validation. The overarching goal of these protocols is to generate rigorous validating data that could be used by investigators throughout the research community in selecting and applying biomarkers to multi-site VCID trials. Key features of MarkVCID participant enrollment, clinical/cognitive testing, and fluid biomarker procedures are summarized here, with full details in the following text, tables, and supplemental material, and a description of the MarkVCID imaging biomarker procedures in a companion paper, "MarkVCID Cerebral small vessel consortium: II. Neuroimaging protocols." The procedures described here address a range of challenges in MarkVCID's design, notably: (1) acquiring all data under informed consent and enrollment procedures that allow unlimited sharing and open-ended analyses without compromising participant privacy rights; (2) acquiring the data in a sufficiently wide range of study participants to allow assessment of candidate biomarkers across the various patient groups who might ultimately be targeted in VCID clinical trials; (3) defining a common dataset of clinical and cognitive elements that contains all the key outcome markers and covariates for VCID studies and is realistically obtainable during a practical study visit; (4) instituting best fluid-handling practices for minimizing avoidable sources of variability; and (5) establishing rigorous procedures for testing the reliability of candidate fluid-based biomarkers across replicates, assay runs, sites, and time intervals (collectively defined as the biomarker's instrumental validity). Participant Enrollment Project sites enroll diverse study cohorts using site-specific inclusion and exclusion criteria so as to provide generalizable validation data across a range of cognitive statuses, risk factor profiles, small vessel disease severities, and racial/ethnic characteristics representative of the diverse patient groups that might be enrolled in a future VCID trial. MarkVCID project sites include both prospectively enrolling centers and centers providing extant data and samples from preexisting community- and population-based studies. With approval of local institutional review boards, all sites incorporate MarkVCID consensus language into their study documents and informed consent agreements. The consensus language asks prospectively enrolled participants to consent to unrestricted access to their data and samples for research analysis within and outside MarkVCID. The data are transferred and stored as a de-identified dataset as defined by the Health Insurance Portability and Accountability Act Privacy Rule. Similar human subject protection and informed consent language serve as the basis for MarkVCID Research Agreements that act as contracts and data/biospecimen sharing agreements across the consortium. Clinical and Cognitive Data Clinical and cognitive data are collected across prospectively enrolling project sites using common MarkVCID instruments. The clinical data elements are modified from study protocols already in use such as the Alzheimer's Disease Center program Uniform Data Set Version 3 (UDS3), with additional focus on VCID-related items such as prior stroke and cardiovascular disease, vascular risk factors, focal neurologic findings, and blood testing for vascular risk markers and kidney function including hemoglobin A1c, cholesterol subtypes, triglycerides, and creatinine. Cognitive assessments and rating instruments include the Clinical Dementia Rating Scale, Geriatric Depression Scale, and most of the UDS3 neuropsychological battery. The cognitive testing requires ≈60 to 90 minutes. Study staff at the prospectively recruiting sites undergo formalized training in all measures and review of their first three UDS3 administrations by the coordinating center. Collection and Handling of Fluid Samples Fluid sample types collected for MarkVCID biomarker kits are serum, ethylenediaminetetraacetic acid-plasma, platelet-poor plasma, and cerebrospinal fluid (CSF) with additional collection of packed cells to allow future DNA extraction and analyses. MarkVCID fluid guidelines to minimize variability include fasting morning fluid collections, rapid processing, standardized handling and storage, and avoidance of CSF contact with polystyrene. Instrumental Validation for Fluid-Based Biomarkers Instrumental validation of MarkVCID fluid-based biomarkers is operationally defined as determination of intra-plate and inter-plate repeatability, inter-site reproducibility, and test-retest repeatability. MarkVCID study participants both with and without advanced small vessel disease are selected for these determinations to assess instrumental validity across the full biomarker assay range. Intra- and inter-plate repeatability is determined by repeat assays of single split fluid samples performed at individual sites. Inter-site reproducibility is determined by assays of split samples distributed to multiple sites. Test-retest repeatability is determined by assay of three samples acquired from the same individual, collected at least 5 days apart over a 30-day period and assayed on a single plate. The MarkVCID protocols are designed to allow direct translation of the biomarker validation results to multicenter trials. They also provide a template for outside groups to perform analyses using identical methods and therefore allow direct comparison of results across studies and centers. All MarkVCID protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the MarkVCID kits will undergo biological validation to determine whether the candidate biomarker measures important aspects of VCID such as cognitive function. Analytic methods and results of these validation studies for the 11 MarkVCID biomarker kits will be published separately. The results of this rigorous validation process will ultimately determine each kit's potential usefulness for multicenter interventional trials aimed at preventing or treating small vessel disease related VCID.
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http://dx.doi.org/10.1002/alz.12215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122220PMC
April 2021

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

Int J Stroke 2021 01 21:1747493020984559. 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
January 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

The chronic neuropsychiatric sequelae of COVID-19: The need for a prospective study of viral impact on brain functioning.

Alzheimers Dement 2021 Jun 5;17(6):1056-1065. Epub 2021 Jan 5.

The Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UTHSA, San Antonio, Texas, USA.

Introduction: The increasing evidence of SARS-CoV-2 impact on the central nervous system (CNS) raises key questions on its impact for risk of later life cognitive decline, Alzheimer's disease (AD), and other dementia.

Methods: The Alzheimer's Association and representatives from more than 30 countries-with technical guidance from the World Health Organization-have formed an international consortium to study the short-and long-term consequences of SARS-CoV-2 on the CNS-including the underlying biology that may contribute to AD and other dementias. This consortium will link teams from around the world covering more than 22 million COVID-19 cases to enroll two groups of individuals including people with disease, to be evaluated for follow-up evaluations at 6, 9, and 18 months, and people who are already enrolled in existing international research studies to add additional measures and markers of their underlying biology.

Conclusions: The increasing evidence and understanding of SARS-CoV-2's impact on the CNS raises key questions on the impact for risk of later life cognitive decline, AD, and other dementia. This program of studies aims to better understand the long-term consequences that may impact the brain, cognition, and functioning-including the underlying biology that may contribute to AD and other dementias.
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http://dx.doi.org/10.1002/alz.12255DOI Listing
June 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
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