Publications by authors named "Adam M Brickman"

275 Publications

Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease.

Alzheimers Dement (Amst) 2021 5;13(1):e12197. Epub 2021 Jul 5.

The Florey Institute University of Melbourne Parkville Victoria Australia.

Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment.

Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally.

Results: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset.

Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.
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http://dx.doi.org/10.1002/dad2.12197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256623PMC
July 2021

Epigenetic aging biomarkers associated with cognitive impairment in older African American adults with HIV.

Clin Infect Dis 2021 Jun 18. Epub 2021 Jun 18.

Department of Medicine, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.

Background: Accelerated epigenetic aging using DNA methylation (DNAm)-based biomarkers has been reported in people with HIV (PWH), but limited data are available among African Americans (AA), women, and older PWH.

Methods: DNAm was measured using Illumina EPIC Arrays for 107 (69 PWH and 38 HIV-seronegative controls) AA adults ≥60 years in New York City. Six DNAm-based biomarkers of aging were estimated: (1) epigenetic age acceleration (EAA), (2) extrinsic epigenetic age acceleration (EEAA), (3) intrinsic epigenetic age acceleration (IEAA), (4) GrimAge, (5) PhenoAge, and (6) DNAm-estimated telomere length (DNAm-TL). The NIH Toolbox Cognition Battery (domains: executive function, attention, working memory, processing speed, and language) and Montreal Cognitive Assessment (MoCA) were administered. Participants were assessed for frailty by the Fried criteria.

Results: The PWH and control groups did not differ by sex, chronological age, or ethnicity. 83% of PWH had a viral load <50 copies/mL and 94% had a recent CD4 ≥200 cells/µL. The PWH group had a higher EAA, EEAA, GrimAge, and PhenoAge, and a lower DNAm-TL compared to the controls. IEAA was not different between groups. For PWH, there were significant negative correlations between IEAA and executive function, attention, and working memory and PhenoAge and attention. No associations between biomarkers and frailty were detected.

Conclusion: Evidence of epigenetic age acceleration was observed in AA older PWH using DNAm-based biomarkers of aging. There was no evidence of age acceleration independent of cell type composition (IEAA) associated with HIV, but this measure was associated with decreased cognitive function among PWH.
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http://dx.doi.org/10.1093/cid/ciab563DOI Listing
June 2021

Patterns of tau pathology identified with F-MK-6240 PET imaging.

Alzheimers Dement 2021 May 31. Epub 2021 May 31.

Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.

Introduction: Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of F-MK-6240 in a clinical sample and determined the relationships among F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers.

Methods: Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aβ) , tau, and phosphorylated tau (p-tau).

Results: F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aβ . F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants.

Discussion: F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.
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http://dx.doi.org/10.1002/alz.12384DOI Listing
May 2021

Altered connectivity of the default mode network in cognitively stable adults with Down syndrome: "Accelerated aging" or a prelude to Alzheimer's disease?

Alzheimers Dement (Amst) 2021 20;13(1):e12105. Epub 2021 May 20.

Department of Neurology Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA.

Introduction: Most individuals with Down syndrome (DS) have the neuropathological changes of Alzheimer's disease (AD) by age 40 and will have developed dementia by age 60. Alterations of the intrinsic connectivity of the default mode network (DMN) are associated with AD in the neurotypical population. In this study, we sought to determine whether, and how, connectivity between the hubs of the DMN were altered in cognitively stable adults with DS who did not have evidence of either mild cognitive impairment or AD.

Methods: Resting state functional MRI scans were collected from 26 healthy adults with DS and 26 healthy age-matched non-DS controls. Nodes comprising the DMN were generated as ROI's (regions of interest) and inter-nodal correlations estimated.

Results: Analysis of intra-network connectivity of the DMN revealed anterior-posterior DMN dissociation and hyper- and hypo-connectivity, suggesting "accelerated aging" in DS.

Discussion: Disruption of the DMN may serve as a prelude for AD in DS.
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http://dx.doi.org/10.1002/dad2.12105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136300PMC
May 2021

In Vivo Amyloid, Neurodegeneration, and Verbal Learning in Late Middle-Aged Hispanics.

J Alzheimers Dis 2021 ;82(1):317-325

Department of Medicine, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.

Background: The National Institute on Aging (NIA)/Alzheimer's Association (AA) 2018 framework conceptualizes Alzheimer's disease (AD) biologically. Evidence of brain amyloid by biomarkers defines AD pathologic change and the Alzheimer's continuum. The presence of tau or neurodegeneration in the absence of amyloid defines non-AD pathologic change.

Objective: To examine the relation of in vivo amyloid and neurodegeneration with verbal learning, one of the cognitive abilities affected early in AD, in late middle age.

Methods: This was a cross-sectional study of amyloid and neurodegeneration biomarkers in a community-based cohort of 350 late-middle aged Hispanics without dementia (mean age: 64.15±3.34; 72.0%women). Amyloid (A) was measured as global standardized uptake value ratio (SUVR) with 18F-Florbetaben positron emission tomography (PET). Neurodegeneration (N) was ascertained as cortical thickness (CT) in AD signature areas using brain magnetic resonance imaging. We examined A/N continuously, categorically, by A/N profiles, and profile categories. The amyloid threshold for positivity was defined using the K means method. The CT threshold was defined as 2 standard deviations below the mean CT. Verbal learning was ascertained using total recall and delayed recall in the Buschke Selective Reminding test (SRT).

Results: Higher cortical thickness was associated with higher performance in SRT delayed recall. Amyloid SUVR was not related to SRT performance. The low CT category was associated with lower performance in SRT delayed recall, while Amyloid categories were not related to any SRT score. The non-AD pathologic change group (A-N+) performed worse in SRT delayed recall compared to the Normal A/N profile group (A-N-).

Conclusion: In late middle-aged Hispanics without dementia, non-AD pathologic change, but not the Alzheimer's continuum, was related to verbal learning.
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http://dx.doi.org/10.3233/JAD-201304DOI Listing
January 2021

Social network characteristics moderate associations between cortical thickness and cognitive functioning in older adults.

Alzheimers Dement 2021 May 18. Epub 2021 May 18.

Department of Psychology, University of Michigan, Ann Arbor, Michigan, USA.

Introduction: Prior research suggests that the strength of association between Alzheimer's disease (AD) pathology and lower cognitive performance is influenced by modifiable psychosocial factors, such as social network size. However, little is known about distinct social relationship types.

Methods: The current cross-sectional study used data from the Washington Heights-Inwood Columbia Aging Project to examine whether social network characteristics (i.e., total size, spouse/partner, number of children, other relatives, friends) moderate associations between cortical thickness in regions implicated in AD and cognitive performance.

Results: Lower cortical thickness was associated with worse global cognition among individuals with smaller friend networks, but not among individuals with larger friend networks. This pattern of results was most prominent for language and speed/executive functioning.

Discussion: Longitudinal and intervention studies are needed to determine whether these cross-sectional findings reflect a protective effect of later-life friendships for maintaining cognitive performance in the context of poorer brain health.
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http://dx.doi.org/10.1002/alz.12383DOI Listing
May 2021

Socioeconomic and psychosocial mechanisms underlying racial/ethnic disparities in cognition among older adults.

Neuropsychology 2021 Mar;35(3):265-275

Department of Neurology, Gertrude H. Sergievsky Center, Columbia University.

Racial/ethnic disparities in cognitive aging are only partly attributable to socioeconomic indicators. Psychosocial factors, such as discrimination and perceived control, also differ across racial/ethnic groups, and emerging literature highlights their potential role in contributing to cognitive disparities in addition to socioeconomic status. 1,463 older adults (51% Hispanic, 27% non-Hispanic Black, and 22% non-Hispanic White) in the Washington Heights-Inwood Columbia Aging Project completed cognitive and psychosocial measures, including a comprehensive neuropsychological battery, Everyday and Major Experiences of Lifetime Discrimination scales, and the Perceived Control scale. Mediation models quantified separate indirect effects of Black race and Hispanic ethnicity on global cognitive composite scores through education, income, discrimination, and external perceived control. Educational attainment, income, and perceived control each mediated racial/ethnic disparities in global cognition. Socioeconomic indicators (i.e., lower education and lower income) explained approximately 50% of the Black-White and Hispanic-White disparities in global cognition, and more external perceived control explained an additional 5%-8%. Hispanics reported the lowest levels of discrimination, while non-Hispanic Blacks reported the highest levels. However, neither everyday nor major lifetime discrimination was associated with global cognition. Significant racial/ethnic disparities in global cognition remained after accounting for the included socioeconomic and psychosocial factors. This study suggests that psychosocial factors may explain racial/ethnic disparities in cognitive aging above and beyond socioeconomic indicators. More external perceived control, which could reflect chronic exposure to interpersonal and institutional marginalization, may be a particularly salient psychosocial risk factor for poorer cognitive aging among non-Hispanic Black and Hispanic older adults. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/neu0000720DOI Listing
March 2021

Association of Life's Simple 7 with incident dementia and its modification by the apolipoprotein E genotype.

Alzheimers Dement 2021 May 2. Epub 2021 May 2.

The Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University, New York, USA.

Introduction: There is limited and inconsistent reporting on the association between Life's Simple 7 (LS7) and dementia in the elderly population.

Methods: Based on the Washington Heights-Inwood Columbia Aging Project (WHICAP), LS7 scores were estimated to assess cardiovascular health status. Associations between LS7 scores and incident dementia were investigated by Cox proportional hazards models.

Results: Among 1987 subjects, 291 incident cases of dementia were identified over a median follow-up of 5.84 years. Compared with subjects in the poor cardiovascular health group (scores 0 to 5), those in intermediate (6 to 9) and optimal (10 to 14) groups had lower dementia risk, with the hazard ratio (HR; 95% confidence interval) being 0.74 (0.54 to 1.00) and 0.59 (0.38 to 0.91), respectively. These results were significant in apolipoprotein E genotype ε4 (APOE ε4) allele non-carriers but not in carriers.

Discussion: Higher LS7 scores are protective for dementia, especially among the APOE ε4 noncarriers.
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http://dx.doi.org/10.1002/alz.12359DOI Listing
May 2021

Development of novel measures for Alzheimer's disease prevention trials (NoMAD).

Contemp Clin Trials 2021 Jul 30;106:106425. Epub 2021 Apr 30.

Division of Geriatric Psychiatry, New York State Psychiatric Institute, New York, NY, USA; Department of Psychiatry, Columbia University Medical Center, New York, NY, USA. Electronic address:

Introduction: Assessment of cognition and everyday function is essential in clinical trials for Alzheimer's disease (AD). Two novel measures of cognition (No Practice Effects (NPE) cognitive battery and Miami Computerized Functional Assessment Scale (CFAS)) were designed to have robust psychometric properties and reduced practice and ceiling effects. This study aims to evaluate if the NPE and CFAS demonstrate stronger psychometric properties and reduced practice effects compared with established measures, including the Preclinical Alzheimer Cognitive Composite (PACC), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Functional Activities Questionnaire (FAQ).

Methods: This parallel group, four-site study will randomize 320 cognitively intact adults aged 60 to 85 years to novel or well-established measures of cognition and function. All participants will receive assessments at baseline (week 0), 3-months, and 12-months, as well as a brain MRI scan and Apolipoprotein E genetic test at study entry. Analyses will determine psychometric properties of the NPE and CFAS, compare the sensitivity of measures to AD risk markers, and identify cognitive domains within the NPE.

Discussion: Practice effects have been a major limitation of Alzheimer's disease clinical trials that typically assess cognitive changes over serial assessments. Detection of functional impairment in cognitively normal individuals with biomarkers for Alzheimer's disease requires instruments sensitive to very subtle functional changes. This study is intended to support the validation of two new composite measures, the NPE battery and the CFAS, which may advance clinical testing of interventions for individuals across the spectrum of early stage Alzheimer's disease.

Trial Registration: NCT03900273.
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http://dx.doi.org/10.1016/j.cct.2021.106425DOI Listing
July 2021

Sex differences in in vivo tau neuropathology in a multiethnic sample of late middle-aged adults.

Neurobiol Aging 2021 Jul 23;103:109-116. Epub 2021 Mar 23.

Department of Medicine, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Epidemiology, Joseph P. Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA.

It is unclear whether women have higher brain tau pathology. The objective of this study was to examine whether women have higher tau burden than men, and whether tau differences are independent of amyloid β (Aβ) burden. We conducted a cross-sectional analysis of a multiethnic sample of 252 nondemented late middle-aged (mean age: 64.1 years) adults with tau and amyloid Positron Emission Tomography (PET) data. Tau burden was measured as global standardized uptake value ratio (SUVR) in the middle/inferior temporal gyri and medial temporal cortex with F-MK-6240 PET. Aβ was measured as global SUVR with F-Florbetaben PET. Women had higher middle/inferior temporal gyri tau SUVR compared to men. However, no sex differences in the medial temporal cortex were observed. Women had higher brain Aβ SUVR compared to men. Continuous Aβ SUVR was positively correlated with medial temporal cortex and middle/inferior temporal gyri tau SUVR. However, there was no evidence of effect modification by Aβ SUVR on sex and tau. Compared with men, women in late middle age show higher tau burden, independent of Aβ.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178209PMC
July 2021

Right parahippocampal volume deficit in an older population with posttraumatic stress disorder.

J Psychiatr Res 2021 05 17;137:368-375. Epub 2021 Mar 17.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University Medical Center, USA. Electronic address:

Background: Posttraumatic Stress Disorder (PTSD) is an increasingly prevalent condition among older adults and may escalate further as the general population including veterans from recent conflicts grow older. Despite growing evidence of higher medical comorbidity, cognitive impairment and dementia, and disability in older individuals with PTSD, there are very few studies examining brain cortical structure in this population. Hence, we examined cortical volumes in a cross-sectional study of veterans and civilians aged ≥50 years, of both sexes and exposed to trauma (interpersonal, combat, non-interpersonal).

Methods: Cortical volumes were obtained from T1-weighted structural MRI and compared between individuals with PTSD and Trauma Exposed Healthy Controls (TEHC) adjusting for age, sex, estimated intracranial volume, depression severity, and time elapsed since trauma exposure.

Results: The PTSD group (N = 55) had smaller right parahippocampal gyrus compared to TEHC (N = 36), corrected p(p) = 0.034, with an effect size of 0.75 (Cohen's d), with no significant group differences in other cortical areas.

Conclusions: These findings are different from the structural brain findings reported in studies in younger age groups (larger parahippocampal volume in PTSD patients), suggesting a possible significant change in brain structure as PTSD patients age. These results need replication in longitudinal studies across the age-span to test whether they are neuroanatomical markers representing disease vulnerability, trauma resilience or pathological neurodegeneration associated with cognitive impairment and dementia.
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http://dx.doi.org/10.1016/j.jpsychires.2021.03.015DOI Listing
May 2021

Olfactory Impairment Is Related to Tau Pathology and Neuroinflammation in Alzheimer's Disease.

J Alzheimers Dis 2021 ;80(3):1051-1065

Taub Institute, Columbia University Irving Medical Center, New York, NY, USA.

Background: Olfactory impairment is evident in Alzheimer's disease (AD); however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood.

Objective: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation.

Methods: Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18F-MK-6240 PET (measuring tau pathology) and fifty-three underwent 11C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ42).

Results: Low UPSIT performance was associated with greater18F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex, and posterior cingulate cortex (p < 0.05). Similar relationships were seen for 11C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p < 0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p < 0.01).

Conclusion: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration.NCT Registration Numbers: NCT03373604; NCT02831283.
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http://dx.doi.org/10.3233/JAD-201149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044007PMC
January 2021

Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis.

BMJ 2021 02 25;372:n156. Epub 2021 Feb 25.

Department of Epidemiology and Biostatistics, University of California, San Francisco, 550 16th Street, San Francisco, CA, USA

Objective: To evaluate trials of drugs that target amyloid to determine whether reductions in amyloid levels are likely to improve cognition.

Design: Instrumental variable meta-analysis.

Setting: 14 randomized controlled trials of drugs for the prevention or treatment of Alzheimer's disease that targeted an amyloid mechanism, identified from ClinicalTrials.gov.

Population: Adults enrolled in randomized controlled trials of amyloid targeting drugs. Inclusion criteria for trials vary, but typically include adults aged 50 years or older with a diagnosis of mild cognitive impairment or Alzheimer's disease, and amyloid positivity at baseline.

Main Outcome Measures: Analyses included trials for which information could be obtained on both change in brain amyloid levels measured with amyloid positron emission tomography and change in at least one cognitive test score reported for each randomization arm.

Results: Pooled results from the 14 randomized controlled trials were more precise than estimates from any single trial. The pooled estimate for the effect of reducing amyloid levels by 0.1 standardized uptake value ratio units was an improvement in the mini-mental state examination score of 0.03 (95% confidence interval -0.06 to 0.1) points. This study provides a web application that allows for the re-estimation of the results when new data become available and illustrates the magnitude of the new evidence that would be necessary to achieve a pooled estimate supporting the benefit of reducing amyloid levels.

Conclusions: Pooled evidence from available trials reporting both reduction in amyloid levels and change in cognition suggests that amyloid reduction strategies do not substantially improve cognition.
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http://dx.doi.org/10.1136/bmj.n156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905687PMC
February 2021

Automated detection of cerebral microbleeds on T2*-weighted MRI.

Sci Rep 2021 Feb 17;11(1):4004. Epub 2021 Feb 17.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Cerebral microbleeds, observed as small, spherical hypointense regions on gradient echo (GRE) or susceptibility weighted (SWI) magnetic resonance imaging (MRI) sequences, reflect small hemorrhagic infarcts, and are associated with conditions such as vascular dementia, small vessel disease, cerebral amyloid angiopathy, and Alzheimer's disease. The current gold standard for detecting and rating cerebral microbleeds in a research context is visual inspection by trained raters, a process that is both time consuming and subject to poor reliability. We present here a novel method to automate microbleed detection on GRE and SWI images. We demonstrate in a community-based cohort of older adults that the method is highly sensitive (greater than 92% of all microbleeds accurately detected) across both modalities, with reasonable precision (fewer than 20 and 10 false positives per scan on GRE and SWI, respectively). We also demonstrate that the algorithm can be used to identify microbleeds over longitudinal scans with a higher level of sensitivity than visual ratings (50% of longitudinal microbleeds correctly labeled by the algorithm, while manual ratings was 30% or lower). Further, the algorithm identifies the anatomical localization of microbleeds based on brain atlases, and greatly reduces time spent completing visual ratings (43% reduction in visual rating time). Our automatic microbleed detection instrument is ideal for implementation in large-scale studies that include cross-sectional and longitudinal scanning, as well as being capable of performing well across multiple commonly used MRI modalities.
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http://dx.doi.org/10.1038/s41598-021-83607-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889861PMC
February 2021

Insights into the role of diet and dietary flavanols in cognitive aging: results of a randomized controlled trial.

Sci Rep 2021 Feb 15;11(1):3837. Epub 2021 Feb 15.

Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, 622 West 168th St., New York, NY, 10032, USA.

With the world's population aging, age-related memory decline is an impending cognitive epidemic. Assessing the impact of diet on cognitive aging, we conducted a controlled, randomized, parallel-arm dietary intervention with 211 healthy adults (50-75 years) investigating effects of either a placebo or 260, 510 and 770 mg/day of cocoa flavanols for 12-weeks followed by 8-weeks washout. The primary outcome was a newly-developed object-recognition task localized to the hippocampus' dentate gyrus. Secondary outcomes included a hippocampal-dependent list-learning task and a prefrontal cortex-dependent list-sorting task. The alternative Healthy Eating Index and a biomarker of flavanol intake (gVLM) were measured. In an MRI substudy, hippocampal cerebral blood volume was mapped. Object-recognition and list-sorting performance did not correlate with baseline diet quality and did not improve after flavanol intake. However, the hippocampal-dependent list-learning performance was directly associated with baseline diet quality and improved after flavanol intake, particularly in participants in the bottom tertile of baseline diet quality. In the imaging substudy, a region-of-interest analysis was negative but a voxel-based-analysis suggested that dietary flavanols target the dentate gyrus. While replication is needed, these findings suggest that diet in general, and dietary flavanols in particular, may be associated with memory function of the aging hippocampus and normal cognitive decline.
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http://dx.doi.org/10.1038/s41598-021-83370-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884710PMC
February 2021

Plasma p-tau181, p-tau217, and other blood-based Alzheimer's disease biomarkers in a multi-ethnic, community study.

Alzheimers Dement 2021 Feb 13. Epub 2021 Feb 13.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.

Introduction: Blood-based Alzheimer's disease (AD) biomarkers provide opportunities for community studies and across ethnic groups. We investigated blood biomarker concentrations in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multi-ethnic community study of aging and dementia.

Methods: We measured plasma amyloid beta (Aβ)40, Aβ42, total tau (t-tau), phosphorylated tau (p-tau)181, and p-tau217, and neurofilament light chain (NfL) in 113 autopsied participants (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as predictors of incident clinical AD.

Results: P-tau181, p-tau217, and NfL concentrations were elevated in pathologically and clinically diagnosed AD. Decreased Aβ42/Aβ40 ratio and increased p-tau217 and p-tau181 were associated with subsequent AD diagnosis.

Discussion: Blood-based AD biomarker concentrations are associated with pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be incorporated into multi-ethnic, community-based studies.
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http://dx.doi.org/10.1002/alz.12301DOI Listing
February 2021

Associations Between Loneliness, Reading Ability and Episodic Memory in Non-Hispanic Black and White Older Adults.

Arch Clin Neuropsychol 2021 Feb 8. Epub 2021 Feb 8.

Department of Psychology, University of Michigan, Ann Arbor, MI 48109, USA.

Objective: Reading ability reflects a variety of beneficial life course exposures and may better index these exposures above and beyond education in racially diverse samples. Growing evidence suggests a negative impact of perceived loneliness on late-life cognitive health when parsing out the effect of other aspects of social relations. Few studies have examined how loneliness interacts with the reading ability or whether it operates differently in Black older adults who have higher dementia risk than Whites.

Methods: Participants in this cross-sectional study were drawn from the Washington Heights-Inwood Columbia Aging Project (n = 425 older adults, Mage = 74.23; 58% Black). Linear regressions estimated the main effects and interactions involving reading ability, loneliness, and race (non-Hispanic Black vs. non-Hispanic White) on episodic memory, controlling for age, sex/gender, and years of education. Subsequent models additionally controlled for income, employment status, depressive symptoms, disease burden, marital status, social network size, and number of social groups.

Results: Higher reading ability was associated with better memory, but loneliness was not associated with memory. The positive association between reading ability and memory was weaker among individuals with greater loneliness, and this interaction did not differ by race.

Conclusions: Loneliness may suppress the protective effect of higher reading ability on cognitive health among both Black and White older adults. Future longitudinal work is needed to clarify causal relationships among loneliness, reading ability, and memory decline.
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http://dx.doi.org/10.1093/arclin/acab001DOI Listing
February 2021

Association of White Matter Integrity With Executive Function and Antidepressant Treatment Outcome in Patients With Late-Life Depression.

Am J Geriatr Psychiatry 2021 Jan 23. Epub 2021 Jan 23.

Department of Psychiatry (XH, JRS, PJB, SPR, BRR), Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; The New York State Psychiatric Institute (XH, EP, YK, CMG, JC, JRS, PJB, SPR, BRR), New York, NY.

Objective: While patients with late-life depression (LLD) often exhibit microstructural white matter alterations that can be identified with diffusion tensor imaging (DTI), there is a dearth of information concerning the links between DTI findings and specific cognitive performance, as well as between DTI measures and antidepressant treatment outcomes.

Design: Neuroimaging and cognitive tests were conducted at baseline in 71 older adults participating in a larger, 8-week duration antidepressant randomized controlled trial. Correlations between DTI measures of white matter integrity evaluated with tract-based spatial statistics, baseline neurocognitive performance, and prospective antidepressant treatment outcome were evaluated.

Results: Fractional anisotropy (FA), an index of white matter integrity, was significantly positively associated with better cognitive function as measured by the Initiation/Perseveration subscale of the Dementia Rating Scale in the bilateral superior longitudinal fasciculus (SLF), bilateral SLF-temporal, and right corticospinal tract (CST). An exploratory analysis limited to these tracts revealed that increased FA in the right CST, right SLF, and right SLF-temporal tracts was correlated with a greater decrease in depressive symptoms. Increased FA in the right CST predicted a greater chance of remission, while increased FA in the right CST and the right SLF predicted a greater chance of treatment response.

Conclusion: In late-life depression LLD subjects, white matter integrity was positively associated with executive function in white matter tracts which act as key connecting structures underlying the cognitive control network. These tracts may play a role as a positive prognostic factor in antidepressant treatment outcome.
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http://dx.doi.org/10.1016/j.jagp.2021.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298620PMC
January 2021

Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease.

Neurology 2021 03 25;96(12):e1632-e1645. Epub 2021 Jan 25.

From the Departments of Radiology (N.J.-M., T.M.B., B.A.G., G.C., P.M., R.C.H., T.L.S.B.), Neurology (E.M., J.H., B.M.A., R.J.P., J.C.M., R.J.B.), Psychological and Brain Sciences (J.H.), Psychiatry (C.C., C.M.K.), and Pathology and Immunology (R.J.P.) and Division of Biostatistics (G.W., C.X.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimers Institute (Y.S.), Phoenix, AZ; Department of Cognitive Neurology and Neuropsychology (R.F.A.), Instituto de Investigaciones Neurológicas Fleni, Buenos Aires, Argentina; Departments of Neurology and Clinical and Translational Science (S.B.B.), University of Pittsburgh School of Medicine, PA; Department of Neurology (A.M.B.), Taub Institute for Research on Alzheimers Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY; Neuroscience Research Australia (W.S.B., P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales (W.S.B.), Sydney, Australia; Dementia Research Centre and UK Dementia Research Institute (D.M.C., N.C.F., A.O.), UCL Queen Square Institute of Neurology, London, UK; Departments of Neurology (J.P.C., K.A.J.) and Radiology (K.A.J.), Massachusetts General Hospital, Boston; Department of Neurology (H.C.C., J.M.R.), Keck School of Medicine of USC, Los Angeles, CA; Department of Psychiatry and Human Behavior (S.C., A.K.W.L., S.S.), Memory and Aging Program, Butler Hospital, Brown University Alpert Medical School, Providence, RI; Center for Neuroimaging, Department of Radiology and Imaging Science (M.R.F., A.J.S.), Department of Pathology and Laboratory Medicine (B.G.), and Indiana Alzheimers Disease Research Center (A.J.S.), Indiana University School of Medicine, Indianapolis; Departments of Molecular Imaging and Neurology (M.F.), Royal Prince Alfred Hospital, University of Sydney, Australia; Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; German Center for Neurodegenerative Diseases (DZNE) (C.L., J.L., I.Y.); Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy (C.L.), University of Tübingen; Department of Neurology (J.L., I.Y.), Ludwig-Maximilians-Universität München; Munich Cluster for Systems Neurology (SyNergy) (J.L., I.Y.), Germany; Florey Institute and The University of Melbourne (C.L.M.), Australia; Department of Neurology (J.M.N.), Columbia University Irving Medical Center, New York, NY; Department of Radiology (K.K., C.R.J., G.M.P.), Mayo Clinic, Rochester, MN; Department of Molecular Imaging and Therapy (C.C.R., V.L.V.), Austin Health, University of Melbourne, Heidelberg, Australia; Clinical Research Center for Dementia (H.S.), Osaka City University; Department of Neurology (M.S.), Hirosaki University Graduate School of Medicine; and Department of Neurology (K.S.), The University of Tokyo, Japan.

Objective: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD).

Methods: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease.

Results: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year).

Conclusion: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.
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http://dx.doi.org/10.1212/WNL.0000000000011542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032370PMC
March 2021

Modeling autosomal dominant Alzheimer's disease with machine learning.

Alzheimers Dement 2021 06 21;17(6):1005-1016. Epub 2021 Jan 21.

German Center for Neurodegenerative Diseases, Munich, Germany.

Introduction: Machine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease.

Methods: Longitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non-carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein ε4 (APOE ε4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status.

Results: The Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R  = 0.95), fluorodeoxyglucose (R  = 0.93), and atrophy (R  = 0.95) in mutation carriers compared to non-carriers.

Discussion: Results suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions.
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http://dx.doi.org/10.1002/alz.12259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195816PMC
June 2021

Resting-State Functional Connectivity Disruption as a Pathological Biomarker in Autosomal Dominant Alzheimer Disease.

Brain Connect 2021 Apr 31;11(3):239-249. Epub 2021 Mar 31.

Department of Neurology, Washington University in Saint Louis, St. Louis, Missouri, USA.

Identify a global resting-state functional connectivity (gFC) signature in mutation carriers (MC) from the Dominantly Inherited Alzheimer Network (DIAN). Assess the gFC with regard to amyloid (A), tau (T), and neurodegeneration (N) biomarkers, and estimated years to symptom onset (EYO). Cross-sectional measures were assessed in MC ( = 171) and mutation noncarrier (NC) ( = 70) participants. A functional connectivity (FC) matrix that encompassed multiple resting-state networks was computed for each participant. A global FC was compiled as a single index indicating FC strength. The gFC signature was modeled as a nonlinear function of EYO. The gFC was linearly associated with other biomarkers used for assessing the AT(N) framework, including cerebrospinal fluid (CSF), positron emission tomography (PET) molecular biomarkers, and structural magnetic resonance imaging. The gFC was reduced in MC compared with NC participants. When MC participants were differentiated by clinical dementia rating (CDR), the gFC was significantly decreased in MC CDR >0 (demented) compared with either MC CDR 0 (cognitively normal) or NC participants. The gFC varied nonlinearly with EYO and initially decreased at EYO = -24 years, followed by a stable period followed by a further decline near EYO = 0 years. Irrespective of EYO, a lower gFC associated with values of amyloid PET, CSF Aβ, CSF p-tau, CSF t-tau, 18F-fluorodeoxyglucose, and hippocampal volume. The gFC correlated with biomarkers used for defining the AT(N) framework. A biphasic change in the gFC suggested early changes associated with CSF amyloid and later changes associated with hippocampal volume.
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http://dx.doi.org/10.1089/brain.2020.0808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182476PMC
April 2021

Comparing cortical signatures of atrophy between late-onset and autosomal dominant Alzheimer disease.

Neuroimage Clin 2020 5;28:102491. Epub 2020 Nov 5.

Department of Radiology, Department of Neurology, Department of Psychiatry, Department of Pathology and Immunology, Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO, USA.

Defining a signature of cortical regions of interest preferentially affected by Alzheimer disease (AD) pathology may offer improved sensitivity to early AD compared to hippocampal volume or mesial temporal lobe alone. Since late-onset Alzheimer disease (LOAD) participants tend to have age-related comorbidities, the younger-onset age in autosomal dominant AD (ADAD) may provide a more idealized model of cortical thinning in AD. To test this, the goals of this study were to compare the degree of overlap between the ADAD and LOAD cortical thinning maps and to evaluate the ability of the ADAD cortical signature regions to predict early pathological changes in cognitively normal individuals. We defined and analyzed the LOAD cortical maps of cortical thickness in 588 participants from the Knight Alzheimer Disease Research Center (Knight ADRC) and the ADAD cortical maps in 269 participants from the Dominantly Inherited Alzheimer Network (DIAN) observational study. Both cohorts were divided into three groups: cognitively normal controls (n = 381; n = 145), preclinical (n = 153; n = 76), and cognitively impaired (n = 54; n = 48). Both cohorts underwent clinical assessments, 3T MRI, and amyloid PET imaging with either C-Pittsburgh compound B or F-florbetapir. To generate cortical signature maps of cortical thickness, we performed a vertex-wise analysis between the cognitively normal controls and impaired groups within each cohort using six increasingly conservative statistical thresholds to determine significance. The optimal cortical map among the six statistical thresholds was determined from a receiver operating characteristic analysis testing the performance of each map in discriminating between the cognitively normal controls and preclinical groups. We then performed within-cohort and cross-cohort (e.g. ADAD maps evaluated in the Knight ADRC cohort) analyses to examine the sensitivity of the optimal cortical signature maps to the amyloid levels using only the cognitively normal individuals (cognitively normal controls and preclinical groups) in comparison to hippocampal volume. We found the optimal cortical signature maps were sensitive to early increases in amyloid for the asymptomatic individuals within their respective cohorts and were significant beyond the inclusion of hippocampus volume, but the cortical signature maps performed poorly when analyzing across cohorts. These results suggest the cortical signature maps are a useful MRI biomarker of early AD-related neurodegeneration in preclinical individuals and the pattern of decline differs between LOAD and ADAD.
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http://dx.doi.org/10.1016/j.nicl.2020.102491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689410PMC
June 2021

Mediators and Moderators of the Association Between Perceived Stress and Episodic Memory in Diverse Older Adults.

J Int Neuropsychol Soc 2020 Dec 9:1-13. Epub 2020 Dec 9.

Department of Psychology, University of Michigan, 530 Church St., Ann Arbor, MI48109, USA.

Objective: Stress is a risk factor for numerous negative health outcomes, including cognitive impairment in late-life. The negative association between stress and cognition may be mediated by depressive symptoms, which separate studies have identified as both a consequence of perceived stress and a risk factor for cognitive decline. Pathways linking perceived stress, depressive symptoms, and cognition may be moderated by sociodemographics and psychosocial resources. The goal of this cross-sectional study was to identify modifying factors and enhance understanding of the mechanisms underlying the stress-cognition association in a racially and ethnically diverse sample of older adults.

Method: A linear regression estimated the association between perceived stress and episodic memory in 578 older adults (Mage = 74.58) in the Washington Heights-Inwood Columbia Aging Project. Subsequent models tested whether depressive symptoms mediated the stress-memory relationship and whether sociodemographics (gender, race, and ethnicity) or perceived control moderated these pathways.

Results: Independent of sociodemographics and chronic diseases, greater perceived stress was associated with worse episodic memory. This relationship was mediated by more depressive symptoms. Higher perceived control buffered the association between stress and depressive symptoms. There was no significant moderation by gender, race, or ethnicity.

Conclusion: Depressive symptoms may play a role in the negative association between perceived stress and cognition among older adults; however, longitudinal analyses and studies using experimental designs are needed. Perceived control is a modifiable psychological resource that may offset the negative impact of stress.
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http://dx.doi.org/10.1017/S1355617720001253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187476PMC
December 2020

Anterolateral entorhinal cortex volume is associated with memory retention in clinically unimpaired older adults.

Neurobiol Aging 2021 02 2;98:134-145. Epub 2020 Nov 2.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Gertrude H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY. Electronic address:

The entorhinal cortex is subdivided into anterolateral entorhinal cortex (alERC) and posteromedial entorhinal cortex (pmERC) subregions, which are theorized to support distinct cognitive roles. This distinction is particularly important as the alERC is one of the earliest cortical regions affected by Alzheimer's pathology and related neurodegeneration. The relative associations of alERC/pmERC with neuropsychological test performance have not been examined. We examined how alERC/pmERC volumes differentially relate to performance on 1) the Modified Rey Auditory Learning Test (ModRey), a verbal memory test designed to assess normal/preclinical populations, 2) the Montreal Cognitive Assessment (MoCA), and 3) the National Alzheimer's Coordinating Center neuropsychological battery. We also examined whether alERC/pmERC volumes correlate with Alzheimer's disease cerebrospinal fluid (CSF) biomarkers. In 65 cognitively healthy (CDR = 0) older adults, alERC, but not pmERC, volume was associated with ModRey memory retention. Only alERC volume differentiated between participants who scored above and below the MoCA cutoff score for impairment. Evaluating the MoCA subdomains revealed that alERC was particularly associated with verbal recall. On the National Alzheimer's Coordinating Center battery, both alERC and pmERC volumes were associated with Craft story recall and Benson figure copy, but only alERC volume was associated with Craft story retention and semantic fluency. Neither alERC nor pmERC volume correlated with CSF levels of amyloid or tau, and regression analyses showed that alERC volume and CSF amyloid levels were independently associated with ModRey retention performance. Taken together, these results suggest that the alERC is important for memory performance and that alERC volume differences are related to a pattern of neuropsychological test performance (i.e., impairments in episodic memory and semantic fluency) typically seen in clinical Alzheimer's disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870549PMC
February 2021

Cerebrovascular disease promotes tau pathology in Alzheimer's disease.

Brain Commun 2020 19;2(2):fcaa132. Epub 2020 Aug 19.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, G.H. Sergievsky Center, and Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Small vessel cerebrovascular disease, visualized as white matter hyperintensities on T2-weighted magnetic resonance imaging, contributes to the clinical presentation of Alzheimer's disease. However, the extent to which cerebrovascular disease represents an independent pathognomonic feature of Alzheimer's disease or directly promotes Alzheimer's pathology is unclear. The purpose of this study was to examine the association between white matter hyperintensities and plasma levels of tau and to determine if white matter hyperintensities and tau levels interact to predict Alzheimer's disease diagnosis. To confirm that cerebrovascular disease promotes tau pathology, we examined tau fluid biomarker concentrations and pathology in a mouse model of ischaemic injury. Three hundred ninety-one participants from the Alzheimer's Disease Neuroimaging Initiative (74.5 ± 7.1 years of age) were included in this cross-sectional analysis. Participants had measurements of plasma total-tau, cerebrospinal fluid beta-amyloid, and white matter hyperintensities, and were diagnosed clinically as Alzheimer's disease ( = 97), mild cognitive impairment ( = 186) or cognitively normal control ( = 108). We tested the relationship between plasma tau concentration and white matter hyperintensity volume across diagnostic groups. We also examined the extent to which white matter hyperintensity volume, plasma tau, amyloid positivity status and the interaction between white matter hyperintensities and plasma tau correctly classifies diagnostic category. Increased white matter hyperintensity volume was associated with higher plasma tau concentration, particularly among those diagnosed clinically with Alzheimer's disease. Presence of brain amyloid and the interaction between plasma tau and white matter hyperintensity volume distinguished Alzheimer's disease and mild cognitive impairment participants from controls with 77.6% and 63.3% accuracy, respectively. In 63 Alzheimer's Disease Neuroimaging Initiative participants who came to autopsy (82.33 ± 7.18 age at death), we found that higher degrees of arteriosclerosis were associated with higher Braak staging, indicating a positive relationship between cerebrovascular disease and neurofibrillary pathology. In a transient middle cerebral artery occlusion mouse model, aged mice that received transient middle cerebral artery occlusion, but not sham surgery, had increased plasma and cerebrospinal fluid tau concentrations, induced myelin loss, and hyperphosphorylated tau pathology in the ipsilateral hippocampus and cerebral hemisphere. These findings demonstrate a relationship between cerebrovascular disease, operationalized as white matter hyperintensities, and tau levels, indexed in the plasma, suggesting that hypoperfusive injury promotes tau pathology. This potential causal association is supported by the demonstration that transient cerebral artery occlusion induces white matter damage, increases biofluidic markers of tau, and promotes cerebral tau hyperphosphorylation in older-adult mice.
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http://dx.doi.org/10.1093/braincomms/fcaa132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660042PMC
August 2020

Assessment of Leisure Time Physical Activity and Brain Health in a Multiethnic Cohort of Older Adults.

JAMA Netw Open 2020 11 2;3(11):e2026506. Epub 2020 Nov 2.

Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York.

Importance: Results from longitudinal studies suggest that regular leisure time physical activity (LTPA) is associated with reduced risk of dementia or Alzheimer disease. Data on the association between LTPA and brain magnetic resonance imaging (MRI) measures remain scarce and inconsistent.

Objective: To examine the association of LTPA and MRI-assessed brain aging measures in a multiethnic elderly population.

Design, Setting, And Participants: This cross-sectional study included 1443 older (≥65 years) adults without dementia who were participants of the Washington/Hamilton Heights-Inwood Columbia Aging Project study. LTPA, from self-reported questionnaire, was calculated as metabolic equivalent of energy expenditure. Both moderate to vigorous LTPA, assessed as meeting Physical Activity Guidelines for Americans (≥150 minutes/week) or not, and light-intensity LTPA were also examined.

Exposures: LTPA.

Main Outcomes And Measures: Primary outcomes included total brain volume (TBV), cortical thickness, and white matter hyperintensity volume, all derived from MRI scans with established methods and adjusted for intracranial volume when necessary. We examined the association of LTPA with these imaging markers using regression models adjusted for demographic, clinical, and vascular risk factors.

Results: The 1443 participants of the study had a mean (SD) age of 77.2 (6.4) years; 921 (63.8%) were women; 27.0%, 34.4%, and 36.3% were non-Hispanic White, non-Hispanic African American, and Hispanic individuals, respectively; and 27.3% carried the apolipoprotein E (APOE) ɛ4 allele. Compared with the LTPA of nonactive older adults, those with the most LTPA had larger (in cm3) TBV (β [SE], 13.17 [4.42] cm3; P = .003; P for trend = .006) and greater cortical thickness (β [SE], 0.016 [0.008] mm; P = .05; P for trend = .03). The effect size comparing the highest LTPA level with the nonactive group was equivalent to approximately 3 to 4 years of aging (β for 1 year older, -3.06 and -0.005 for TBV and cortical thickness, respectively). A dose-response association was found and even the lowest LTPA level had benefits (eg, TBV: β [SE], 9.03 [4.26] cm3; P = .03) compared with the nonactive group. Meeting Physical Activity Guidelines for Americans (TBV: β [SE], 18.82 [5.14] cm3; P < .001) and light-intensity LTPA (TBV: β [SE], 9.26 [4.29] cm3; P = .03) were also associated with larger brain measures. The association between LTPA and TBV was moderated by race/ethnicity, sex, and APOE status, but generally existed in all subgroups. The results remained similar after excluding participants with mild cognitive impairment.

Conclusions And Relevance: In this study, more physical activity was associated with larger brain volume in older adults. Longitudinal studies are warranted to explore the potential role of physical activity in brain health among older individuals.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.26506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677758PMC
November 2020

Brain amyloid and the transition to dementia in Down syndrome.

Alzheimers Dement (Amst) 2020 11;12(1):e12126. Epub 2020 Nov 11.

Department of Pediatrics Irvine Medical Center University of California Orange California USA.

Introduction: Down syndrome (DS) is associated with elevated risk for Alzheimer's disease (AD) due to amyloid beta (Aβ) lifelong accumulation. We hypothesized that the spatial distribution of brain Aβ predicts future dementia conversion in individuals with DS.

Methods: We acquired F-florbetapir positron emission tomography scans from 19 nondemented individuals with DS at baseline and monitored them for 4 years, with five individuals transitioning to dementia. Machine learning classification using an independent test set determined features on F-florbetapir standardized uptake value ratio maps that predicted transition.

Results: In addition to "AD signature" regions including the inferior parietal cortex, temporal lobes, and the cingulum, we found that Aβ cortical binding in the prefrontal and superior frontal cortices distinguished subjects who transitioned to dementia. Classification did well in predicting transitioners.

Discussion: Our study suggests that specific regional profiles of brain amyloid in older adults with DS may predict cognitive decline and are informative in evaluating the risk for dementia.
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http://dx.doi.org/10.1002/dad2.12126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656170PMC
November 2020

Alzheimer-related altered white matter microstructural integrity in Down syndrome: A model for sporadic AD?

Alzheimers Dement (Amst) 2020 7;12(1):e12040. Epub 2020 Nov 7.

G. H. Sergievsky Center and Taub Institute for Research on Alzheimer's Disease and the Aging Brain College of Physicians and Surgeons Columbia University New York New York USA.

Introduction: Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD)-associated neuropathology by the age of 40, with risk for dementia increasing from the early 50s. White matter (WM) pathology has been reported in sporadic AD, including early demyelination, microglial activation, loss of oligodendrocytes and reactive astrocytes but has not been extensively studied in the at-risk DS population.

Methods: Fifty-six adults with DS (35 cognitively stable adults, 11 with mild cognitive impairment, 10 with dementia) underwent diffusion-weighted magnetic resonance imaging (MRI), amyloid imaging, and had assessments of cognition and functional abilities using tasks appropriate for persons with intellectual disability.

Results: Early changes in late-myelinating and relative sparing of early-myelinating pathways, consistent with the retrogenesis model proposed for sporadic AD, were associated with AD-related cognitive deficits and with regional amyloid deposition.

Discussion: Our findings suggest that quantification of WM changes in DS could provide a promising and clinically relevant biomarker for AD clinical onset and progression.
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http://dx.doi.org/10.1002/dad2.12040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648416PMC
November 2020
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