Publications by authors named "Aron S Buchman"

207 Publications

Racial Differences in the Effect of HIV Status on Motor and Pulmonary Function and Mobility Disability in Older Adults.

J Racial Ethn Health Disparities 2021 Aug 17. Epub 2021 Aug 17.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Background: Older Black adults face a disproportionate burden of HIV prevalence, but less is known about racial disparities in age-related outcomes in HIV. We assessed the effect of HIV status and race on motor and pulmonary function, as well as how they contribute to mobility disability.

Setting: Community-based study; Chicago, IL METHODS: Participants were 363 community-dwelling adults age ≥ 50 years, 48% living with HIV, and 68% Black. Participants with HIV were recruited from a specialty HIV clinic, and participants without HIV (comparable on key demographic, lifestyle, and behavioral characteristics) were recruited from the community. Measures included motor function summarized by 10 motor performance measures, pulmonary function summarized by 3 measures assessed using handheld spirometry, and self-reported mobility disability.

Results: In fully adjusted linear models, HIV was associated with better motor (β = 9.35, p < 0.001) and pulmonary function (β = 16.34, p < 0.001). For pulmonary function, the effect of HIV status was moderated by race (interaction between Black race and HIV status: β =  - 11.66, p = 0.02), indicating that better pulmonary function among participants with HIV was less evident among Black participants. In fully adjusted models, odds of mobility disability did not differ by race, HIV status, or pulmonary function; better motor function was associated with lower odds of mobility disability (OR = 0.91 per 1-point higher, 95% CI 0.88-0.93).

Conclusion: Better motor and pulmonary function exhibited by participants with HIV could reflect access to medical care. Racial differences in lung function among participants with HIV indicate potential disparities in prevention or treatment of pulmonary disease or underlying risk factors.
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http://dx.doi.org/10.1007/s40615-021-01126-0DOI Listing
August 2021

Latent Cognitive Class at Enrollment Predicts Future Cognitive Trajectories of Decline in a Community Sample of Older Adults.

J Alzheimers Dis 2021 Jul 30. Epub 2021 Jul 30.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Background: Methods that can identify subgroups with different trajectories of cognitive decline are crucial for isolating the biologic mechanisms which underlie these groupings.

Objective: This study grouped older adults based on their baseline cognitive profiles using a latent variable approach and tested the hypothesis that these groups would differ in their subsequent trajectories of cognitive change.

Methods: In this study we applied time-varying effects models (TVEMs) to examine the longitudinal trajectories of cognitive decline across different subgroups of older adults in the Rush Memory and Aging Project.

Results: A total of 1,662 individuals (mean age = 79.6 years, SD = 7.4, 75.4%female) participated in the study; these were categorized into five previously identified classes of older adults differing in their baseline cognitive profiles: Superior Cognition (n = 328, 19.7%), Average Cognition (n = 767, 46.1%), Mixed-Domains Impairment (n = 71, 4.3%), Memory-Specific Impairment (n = 274, 16.5%), and Frontal Impairment (n = 222, 13.4%). Differences in the trajectories of cognition for these five classes persisted during 8 years of follow-up. Compared with the Average Cognition class, The Mixed-Domains and Memory-Specific Impairment classes showed steeper rates of decline, while other classes showed moderate declines.

Conclusion: Baseline cognitive classes of older adults derived through the use of latent variable methods were associated with distinct longitudinal trajectories of cognitive decline that did not converge during an average of 8 years of follow-up.
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http://dx.doi.org/10.3233/JAD-210484DOI Listing
July 2021

Association of cardiovascular risk burden with risk of dementia and brain pathologies: A population-based cohort study.

Alzheimers Dement 2021 Jul 26. Epub 2021 Jul 26.

Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China.

Introduction: The impact of cardiovascular risk burden on brain pathologies remains unclear. We aimed to examine the association of the Framingham General Cardiovascular Risk Score (FGCRS) with dementia risk, and brain pathologies.

Methods: Within the Rush Memory and Aging Project, 1588 dementia-free participants were assessed on FGCRS at baseline and followed up to 21 years. During the follow-up, 621 participants died and underwent autopsies.

Results: The multi-adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) of FGCRS were 1.03 (1.00-1.07) for dementia and 1.04 (1.01-1.07) for Alzheimer's disease (AD) dementia. Further, a higher FGCRS was associated with higher gross chronic cerebral infarctions (odds ratio [OR] 1.08, 95% CI 1.02-1.14), cerebral atherosclerosis (OR 1.10, 95% CI 1.03-1.17), and global AD pathology (OR 1.06, 95% CI 1.01-1.12).

Conclusions: A higher FGCRS is associated with an increased risk of dementia and AD dementia. Both vascular and AD pathologies in the brain may underlie this association.
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http://dx.doi.org/10.1002/alz.12343DOI Listing
July 2021

Physical activity, brain tissue microstructure, and cognition in older adults.

PLoS One 2021 7;16(7):e0253484. Epub 2021 Jul 7.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, United States of America.

Objective: To test whether postmortem MRI captures brain tissue characteristics that mediate the association between physical activity and cognition in older adults.

Methods: Participants (N = 318) were older adults from the Rush Memory and Aging Project who wore a device to quantify physical activity and also underwent detailed cognitive and motor testing. Following death, cerebral hemispheres underwent MRI to quantify the transverse relaxation rate R2, a metric related to tissue microstructure. For analyses, we reduced the dimensionality of the R2 maps from approximately 500,000 voxels to 30 components using spatial independent component analysis (ICA). Via path analysis, we examined whether these R2 components attenuated the association between physical activity and cognition, controlling for motor abilities and indices of common brain pathologies.

Results: Two of the 30 R2 components were associated with both total daily physical activity and global cognition assessed proximate to death. We visualized these components by highlighting the clusters of voxels whose R2 values contributed most strongly to each. One of these spatial signatures spanned periventricular white matter and hippocampus, while the other encompassed white matter of the occipital lobe. These two R2 components partially mediated the association between physical activity and cognition, accounting for 12.7% of the relationship (p = .01). This mediation remained evident after controlling for motor abilities and neurodegenerative and vascular brain pathologies.

Conclusion: The association between physically activity and cognition in older adults is partially accounted for by MRI-based signatures of brain tissue microstructure. Further studies are needed to elucidate the molecular mechanisms underlying this pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253484PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262790PMC
July 2021

Circadian disturbances in Alzheimer's disease progression: a prospective observational cohort study of community-based older adults.

Lancet Healthy Longev 2020 Dec 12;1(3):e96-e105. Epub 2020 Nov 12.

Medical Biodynamics Program, Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.

Background: Circadian disturbances are commonly seen in people with Alzheimer's disease and have been reported in individuals without symptoms of dementia but with Alzheimer's pathology. We aimed to assess the temporal relationship between circadian disturbances and Alzheimer's progression.

Methods: We did a prospective cohort study of 1401 healthy older adults (aged >59 years) enrolled in the Rush Memory and Aging Project (Rush University Medical Center, Chicago, IL, USA) who had been followed up for up to 15 years. Participants underwent annual assessments of cognition (with a battery of 21 cognitive performance tests) and motor activities (with actigraphy). Four measures were extracted from actigraphy to quantify daily and circadian rhythmicity, which were amplitude of 24-h activity rhythm, acrophase (representing peak activity time), interdaily stability of 24-h activity rhythm, and intradaily variability for hourly fragmentation of activity rhythm. We used Cox proportional hazards models and logistic regressions to assess whether circadian disturbances predict an increased risk of incident Alzheimer's dementia and conversion of mild cognitive impairment to Alzheimer's dementia. We used linear mixed-effects models to investigate how circadian rhythms changed longitudinally and how the change integrated to Alzheimer's progression.

Findings: Participants had a median age of 81·8 (IQR 76·3-85·7) years. Risk of developing Alzheimer's dementia was increased with lower amplitude (1 SD decrease, hazard ratio [HR] 1·39, 95% CI 1·19-1·62) and higher intradaily variability (1 SD increase, 1·22, 1·04-1·43). In participants with mild cognitive impairment, increased risk of Alzheimer's dementia was predicted by lower amplitude (1 SD decrease, HR 1·46, 95% CI 1·24-1·72), higher intradaily variability (1 SD increase, 1·36, 1·15-1·60), and lower interdaily stability (1 SD decrease, 1·21, 1·02-1·44). A faster transition to Alzheimer's dementia in participants with mild cognitive impairment was predicted by lower amplitude (1 SD decrease, odds ratio [OR] 2·08, 95% CI 1·53-2·93), increased intradaily variability (1 SD increase, 1·97, 1·43-2·79), and decreased interdaily stability (1 SD decrease, 1·35, 1·01-1·84). Circadian amplitude, acrophase, and interdaily stability progressively decreased over time, and intradaily variability progressively increased over time. Alzheimer's progression accelerated these aging effects by doubling or more than doubling the annual changes in these measures after the diagnosis of mild cognitive impairment, and further doubled them after the diagnosis of Alzheimer's dementia. The longitudinal change of global cognition positively correlated with the longitudinal changes in amplitude and interdaily stability and negatively correlated with the longitudinal change in intradaily variability.

Interpretation: Our results indicate a link between circadian dysregulation and Alzheimer's progression, implying either a bidirectional relation or shared common underlying pathophysiological mechanisms.

Funding: National Institutes of Health, and the BrightFocus Foundation.
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http://dx.doi.org/10.1016/s2666-7568(20)30015-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232345PMC
December 2020

The association of epigenetic clocks in brain tissue with brain pathologies and common aging phenotypes.

Neurobiol Dis 2021 Sep 19;157:105428. Epub 2021 Jun 19.

Rush Alzheimer's Disease Center, Chicago, IL, United States of America; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States of America.

Epigenetic clocks are calculated by combining DNA methylation states across select CpG sites to estimate biologic age, and have been noted as the most successful markers of biologic aging to date. Yet, limited research has considered epigenetic clocks calculated in brain tissue. We used DNA methylation states in dorsolateral prefrontal cortex specimens from 721 older participants of the Religious Orders Study and Rush Memory and Aging Project, to calculate DNA methylation age using four established epigenetic clocks: Hannum, Horvath, PhenoAge, GrimAge, and a new Cortical clock. The four established clocks were trained in blood samples (Hannum, PhenoAge, GrimAge) or using 51 human tissue and cell types (Horvath); the recent Cortical clock is the first trained in postmortem cortical tissue. Participants were recruited beginning in 1994 (Religious Orders Study) and 1997 (Memory and Aging Project), and followed annually with questionnaires and clinical evaluations; brain specimens were obtained for 80-90% of participants. Mean age at death was 88.0 (SD 6.7) years. We used linear regression, logistic regression, and linear mixed models, to examine relations of epigenetic clock ages to neuropathologic and clinical aging phenotypes, controlling for chronologic age, sex, education, and depressive symptomatology. Hannum, Horvath, PhenoAge and Cortical clock ages were related to pathologic diagnosis of Alzheimer's disease (AD), as well as to Aβ load (a hallmark pathology of Alzheimer's disease). However, associations were substantially stronger for the Cortical than other clocks; for example, each standard deviation (SD) increase in Hannum, Horvath, and PhenoAge clock age was related to approximately 30% greater likelihood of pathologic AD (all p < 0.05), while each SD increase in Cortical age was related to 90% greater likelihood of pathologic AD (odds ratio = 1.91, 95% confidence interval 1.38, 2.62). Moreover, Cortical age was significantly related to other AD pathology (eg, mean tau tangle density, p = 0.003), and to odds of neocortical Lewy body pathology (for each SD increase in Cortical age, odds ratio = 2.00, 95% confidence 1.27, 3.17), although no clocks were related to cerebrovascular neuropathology. Cortical age was the only epigenetic clock significantly associated with the clinical phenotypes examined, from dementia to cognitive decline (5 specific cognitive systems, and a global cognitive measure averaging 17 tasks) to Parkinsonian signs. Overall, our findings provide evidence of the critical necessity for bespoke clocks of brain aging for advancing research to understand, and eventually prevent, neurodegenerative diseases of aging.
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http://dx.doi.org/10.1016/j.nbd.2021.105428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373772PMC
September 2021

Association of Lewy Bodies With Age-Related Clinical Characteristics in Black and White Decedents.

Neurology 2021 08 4;97(8):e825-e835. Epub 2021 Jun 4.

From the Departments of Pathology (Neuropathology) (S.N., J.A.S.), Neurological Sciences (L.L.B., L.Y., A.S.B., D.A.B., J.A.S., R.S.W.), and Psychiatry and Behavioral Sciences (L.L.B., R.S.W.), Rush Alzheimer Disease Center and Rush University Medical Center, Chicago, IL.

Objective: The associations of Lewy bodies (LBs) with olfactory dysfunction, parkinsonism, and higher odds of dementia were assessed in Black and White community-dwelling elders and racial differences in these associations were tested.

Methods: Black decedents (n = 81) were matched 2-to-1 by age, sex, years of education, and follow-up time in the study with White decedents (n = 154) from 4 longitudinal studies of dementia and aging. Participants underwent uniform clinical examination and cognitive, motor, and olfactory testing. LBs were detected in 7 brain regions by α-synuclein immunohistochemistry and racial differences in their association with olfaction, parkinsonism, and odds of dementia were determined using regression analyses.

Results: The mean scores of the odor test, global parkinsonism signs, and global cognition were lower in Black than White decedents; the frequency of dementia was similar in both groups. The frequency of LBs was similar in Black and White decedents (∼25%), as was the frequency of LBs in individual brain regions, while the mean LB counts/mm were similar in all regions except the cingulate cortex, which showed higher mean LB counts in Black decedents. In regression analyses, LBs were associated with impaired olfaction (-2.23, 95% confidence interval [CI] -3.45 to -1.01) and higher odds of dementia (odds ratio 3.0, 95% CI 1.10-8.17) in both racial groups; an association with parkinsonism was stronger in Black than White decedents.

Conclusions: The frequency, distribution, and clinical manifestations of LBs are similar in Black and White elders.
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http://dx.doi.org/10.1212/WNL.0000000000012324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397586PMC
August 2021

Objective Assessment of Daytime Napping and Incident Heart Failure in 1140 Community-Dwelling Older Adults: A Prospective, Observational Cohort Study.

J Am Heart Assoc 2021 Jun 2;10(12):e019037. Epub 2021 Jun 2.

Medical Biodynamics ProgramDivision of Sleep and Circadian DisordersBrigham and Women's Hospital Boston MA.

Background Disrupted nighttime sleep has been associated with heart failure (HF). However, the relationship between daytime napping, an important aspect of sleep behavior commonly seen in older adults, and HF remains unclear. We sought to investigate the association of objectively assessed daytime napping and risk of incident HF during follow-up. Methods and Results We studied 1140 older adults (age, 80.7±7.4 [SD] years; female sex, 867 [76.1%]) in the Rush Memory and Aging Project who had no HF at baseline and were followed annually for up to 14 years. Motor activity (ie, actigraphy) was recorded for ≈10 days at baseline. We assessed daytime napping episodes between 9 am and 7 pm objectively from actigraphy using a previously published algorithm for sleep detection. Cox proportional hazards models examined associations of daily napping duration and frequency with incident HF. Eighty-six participants developed incident HF, and the mean onset time was 5.7 years (SD, 3.4; range, 1-14). Participants who napped longer than 44.4 minutes (ie, the median daily napping duration) showed a 1.73-fold higher risk of developing incident HF than participants who napped <44.4 minutes. Consistently, participants who napped >1.7 times/day (ie, the median daily napping frequency) showed a 2.20-fold increase compared with participants who napped <1.7 times/day. These associations persisted after adjustment for covariates, including nighttime sleep, comorbidities, and cardiovascular disease/risk factors. Conclusions Longer and more frequent objective napping predicted elevated future risk of developing incident HF. Future studies are needed to establish underlying mechanisms.
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http://dx.doi.org/10.1161/JAHA.120.019037DOI Listing
June 2021

Cortical proteins may provide motor resilience in older adults.

Sci Rep 2021 May 28;11(1):11311. Epub 2021 May 28.

Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 West Harrison Street, Jelke Building, Suite 100, Chicago, IL, 60612, USA.

Motor resilience proteins may be a high value therapeutic target that offset the negative effects of pathologies on motor function. This study sought to identify cortical proteins associated with motor decline unexplained by brain pathologies that provide motor resilience. We studied 1226 older decedents with annual motor testing, postmortem brain pathologies and quantified 226 proteotypic peptides in prefrontal cortex. Twenty peptides remained associated with motor decline in models controlling for ten brain pathologies (FDR < 0.05). Higher levels of nine peptides and lower levels of eleven peptides were related to slower decline. A higher motor resilience protein score based on averaging the levels of all 20 peptides was related to slower motor decline, less severe parkinsonism and lower odds of mobility disability before death. Cortical proteins may provide motor resilience. Targeting these proteins in further drug discovery may yield novel interventions to maintain motor function in old age.
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http://dx.doi.org/10.1038/s41598-021-90859-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163829PMC
May 2021

Sarcopenia is associated with incident Alzheimer's dementia, mild cognitive impairment, and cognitive decline.

J Am Geriatr Soc 2021 Jul 5;69(7):1826-1835. Epub 2021 May 5.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.

Objective: We examined whether sarcopenia is associated with the occurrence of late-life cognitive impairment.

Methods: Nondemented older adults (N = 1175) underwent annual testing with 17 cognitive tests summarized as a global cognitive score. A composite sarcopenia score was constructed based on muscle mass measured with bioelectrical impedance and muscle function based on grip strength. Cox proportional hazard models were employed to examine associations of sarcopenia with incident Alzheimer's dementia (AD) and incident mild cognitive impairment (MCI). Linear mixed-effect models determined the association of sarcopenia with cognitive decline. All models controlled for age, sex, education, race, and height squared.

Results: Average follow-up was 5.6 years. More severe sarcopenia at baseline was associated with a higher risk of incident AD (hazard ratio [HR], 1.50 [95% confidence interval 1.20-1.86]; p < 0.001) and of MCI (1.21 [1.01-1.45]; 0.04) and a faster rate of cognitive decline (estimate = -0.013; p = 0.01). Analyses of the individual components of sarcopenia showed that muscle function was associated with incident AD, incident MCI, and cognitive decline with and without a term for lean muscle mass in the model. In contrast, lean muscle mass was not associated with incident cognitive impairment or cognitive decline when a term for muscle function was included in the model.

Conclusions: Poor muscle function, but not reduced lean muscle mass, drives the association of sarcopenia with late-life cognitive impairment. Further work is needed to identify features of muscle structure, which may increase the specificity of sarcopenia for identifying older adults at risk for late-life cognitive impairment.
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http://dx.doi.org/10.1111/jgs.17206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286176PMC
July 2021

Disrupted Rest-Activity Rhythms and Cerebral Small Vessel Disease Pathology in Older Adults.

Stroke 2021 Jul 27;52(7):2427-2431. Epub 2021 Apr 27.

Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada (R.S., A.S.P.L.).

Background And Purpose: The pathogenesis of cerebral small vessel disease remains incompletely understood. The relationship between circadian rhythm disturbances and histopathologic measures of cerebral small vessel disease has not been studied. We hypothesized that disrupted circadian rest-activity rhythms would be associated with a higher burden of cerebral small vessel disease pathology.

Methods: We studied 561 community-dwelling older adults (mean age at death, 91.2, 27.4% male) from the Rush Memory and Aging Project. We used actigraphy to quantify several measures of 24-hour rest-activity rhythmicity, including interdaily stability, intradaily variability, and amplitude, and used ordinal logistic regression models to relate these measures to the severity of cerebral arteriolosclerosis, atherosclerosis, macroinfarcts, and microinfarcts, assessed at autopsy.

Results: Lower interdaily stability was associated with a higher burden of arteriolosclerosis, higher intradaily variability was associated with a higher burden of atherosclerosis and subcortical infarcts, and lower amplitude was associated with a higher burden of arteriosclerosis, atherosclerosis and subcortical macroinfarcts. Moreover, the associations between interdaily stability and arteriolosclerosis and intradaily variability and subcortical infarcts were independent of cardiovascular risk factors, sleep fragmentation, and medical comorbidities.

Conclusions: Disrupted rest-activity rhythms are associated with a greater burden of cerebral small vessel disease in older adults.
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http://dx.doi.org/10.1161/STROKEAHA.120.030870DOI Listing
July 2021

Late-Life Vascular Risk Score in Association With Postmortem Cerebrovascular Disease Brain Pathologies.

Stroke 2021 Jun 12;52(6):2060-2067. Epub 2021 Apr 12.

Rush Alzheimer's Disease Center (S.O., L.Y., A.C., Z.A., L.L.B., J.A.S., D.A.B., A.S.B.), Rush University Medical Center, Chicago, IL.

Background And Purpose: The general cardiovascular Framingham risk score (FRS) identifies adults at increased risk for stroke. We tested the hypothesis that baseline FRS is associated with the presence of postmortem cerebrovascular disease (CVD) pathologies.

Methods: We studied the brains of 1672 older decedents with baseline FRS and measured CVD pathologies including macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. We employed a series of logistic regressions to examine the association of baseline FRS with each of the 5 CVD pathologies.

Results: Average age at baseline was 80.5±7.0 years and average age at death was 89.2±6.7 years. A higher baseline FRS was associated with higher odds of macroinfarcts (odds ratio, 1.10 [95% CI, 1.07-1.13], <0.001), microinfarcts (odds ratio, 1.04 [95% CI, 1.01-1.07], =0.009), atherosclerosis (odds ratio, 1.07 [95% CI, 1.04-1.11], <0.001), and arteriolosclerosis (odds ratio, 1.04 [95% CI, 1.01-1.07], =0.005). C statistics for these models ranged from 0.537 to 0.595 indicating low accuracy for predicting CVD pathologies. FRS was not associated with the presence of cerebral amyloid angiopathy.

Conclusions: A higher FRS score in older adults is associated with higher odds of some, but not all, CVD pathologies, with low discrimination at the individual level. Further work is needed to develop a more robust risk score to identify adults at risk for accumulating CVD pathologies.
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http://dx.doi.org/10.1161/STROKEAHA.120.030226DOI Listing
June 2021

Novel Variance-Component TWAS method for studying complex human diseases with applications to Alzheimer's dementia.

PLoS Genet 2021 04 2;17(4):e1009482. Epub 2021 Apr 2.

Center for Computational and Quantitative Genetics, Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.

Transcriptome-wide association studies (TWAS) have been widely used to integrate transcriptomic and genetic data to study complex human diseases. Within a test dataset lacking transcriptomic data, traditional two-stage TWAS methods first impute gene expression by creating a weighted sum that aggregates SNPs with their corresponding cis-eQTL effects on reference transcriptome. Traditional TWAS methods then employ a linear regression model to assess the association between imputed gene expression and test phenotype, thereby assuming the effect of a cis-eQTL SNP on test phenotype is a linear function of the eQTL's estimated effect on reference transcriptome. To increase TWAS robustness to this assumption, we propose a novel Variance-Component TWAS procedure (VC-TWAS) that assumes the effects of cis-eQTL SNPs on phenotype are random (with variance proportional to corresponding reference cis-eQTL effects) rather than fixed. VC-TWAS is applicable to both continuous and dichotomous phenotypes, as well as individual-level and summary-level GWAS data. Using simulated data, we show VC-TWAS is more powerful than traditional TWAS methods based on a two-stage Burden test, especially when eQTL genetic effects on test phenotype are no longer a linear function of their eQTL genetic effects on reference transcriptome. We further applied VC-TWAS to both individual-level (N = ~3.4K) and summary-level (N = ~54K) GWAS data to study Alzheimer's dementia (AD). With the individual-level data, we detected 13 significant risk genes including 6 known GWAS risk genes such as TOMM40 that were missed by traditional TWAS methods. With the summary-level data, we detected 57 significant risk genes considering only cis-SNPs and 71 significant genes considering both cis- and trans- SNPs, which also validated our findings with the individual-level GWAS data. Our VC-TWAS method is implemented in the TIGAR tool for public use.
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http://dx.doi.org/10.1371/journal.pgen.1009482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046351PMC
April 2021

Systemic brain derived neurotrophic factor but not intestinal barrier integrity is associated with cognitive decline and incident Alzheimer's disease.

PLoS One 2021 4;16(3):e0240342. Epub 2021 Mar 4.

Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America.

The inflammatory hypothesis posits that sustained neuroinflammation is sufficient to induce neurodegeneration and the development of Alzheimer's disease (AD) and Alzheimer's dementia. One potential source of inflammation is the intestine which harbors pro-inflammatory microorganisms capable of promoting neuroinflammation. Systemic inflammation is robustly associated with neuroinflammation as well as low levels of brain derived neurotrophic factor (BDNF) in the systemic circulation and brain. Thus, in this pilot study, we tested the hypothesis that intestinal barrier dysfunction precedes risk of death, incident AD dementia and MCI, cognitive impairment and neuropathology. Serum BDNF was associated with changes in global cognition, working memory, and perceptual speed but not risk of death, incident AD dementia, incident MCI, or neuropathology. Neither of the markers of intestinal barrier integrity examined, including lipopolysaccharide binding protein (LBP) nor intestinal fatty acid binding protein (IFABP), were associated with risk of death, incident AD dementia, incident mild cognitive impairment (MCI), change in cognition (global or domains), or neuropathology. Taken together, the data in this pilot study suggest that intestinal barrier dysfunction does not precede diagnosis of AD or MCI, changes in cognition, or brain pathology. However, since MCI and AD are related to global cognition, the findings with BDNF and the contiguous cognitive measures suggest low power with the trichotomous cognitive status measures. Future studies with larger sample sizes are necessary to further investigate the results from this pilot study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240342PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932071PMC
August 2021

Frequency of Parkinsonism and Parkinson Disease in African Americans in the Chicago Community.

J Gerontol A Biol Sci Med Sci 2021 Jun;76(7):1340-1345

Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.

Background: There is paucity of data about African American (AA) patients with Parkinson's disease (PD) and parkinsonism which may precede PD in older adults. Prior studies suggest that there are lower rates of PD in the AA population, with more cognitive impairment in AA with PD. This study aimed to investigate differences in PD, parkinsonism, and cognition between White and AA populations in 3 longitudinal epidemiologic cohort studies of aging.

Methods: This study examined parkinsonism, PD frequency, and cognition of community-dwelling older individuals in 3 longitudinal epidemiologic cohort studies. Parkinsonism was based on an exam utilizing the modified Unified Parkinson's Disease Rating Scale performed by a nurse. PD was based on self-report, medications used for treatment of PD, and examination findings. Cognition was assessed using 19 performance-based tests that assess 5 cognitive domains.

Results: AA participants were less likely to have parkinsonism compared to Whites, even with age and gender differences. Frequency of PD was not significant between groups. AA were more likely to have lower cognitive scores as compared to Whites. AA were less likely to have parkinsonism even with controlling for cognitive differences between groups.

Conclusions: Parkinsonian signs are present among AA in the community at lower rates than in White individuals. Cognitive profiles of AA and Whites with parkinsonism may be different, suggesting differing contributions of pathology to cognitive decline and parkinsonism between groups. Additional research is needed to understand the progression of parkinsonism to PD, as well as to understanding the cognitive differences in AA with parkinsonism.
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http://dx.doi.org/10.1093/gerona/glab042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202152PMC
June 2021

Quantitative mobility measures complement the MDS-UPDRS for characterization of Parkinson's disease heterogeneity.

Parkinsonism Relat Disord 2021 03 10;84:105-111. Epub 2021 Feb 10.

Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, 77030, USA; Center for Alzheimer's and Neurodegenerative Diseases, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address:

Introduction: Emerging technologies show promise for enhanced characterization of Parkinson's Disease (PD) motor manifestations. We evaluated quantitative mobility measures from a wearable device compared to the conventional motor assessment, the Movement Disorders Society-Unified PD Rating Scale part III (motor MDS-UPDRS).

Methods: We evaluated 176 PD subjects (mean age 65, 65% male, 66% H&Y stage 2) during routine clinic visits using the motor MDS-UPDRS and a 10-min motor protocol with a body-fixed sensor (DynaPort MT, McRoberts BV), including the 32-ft walk, Timed Up and Go (TUG), and standing posture with eyes closed. Regression models examined 12 quantitative mobility measures for associations with (i) motor MDS-UPDRS, (ii) motor subtype (tremor dominant vs. postural instability/gait difficulty), (iii) Montreal Cognitive Assessment (MoCA), and (iv) physical functioning disability (PROMIS-29). All analyses included age, gender, and disease duration as covariates. Models iii-iv were secondarily adjusted for motor MDS-UPDRS.

Results: Quantitative mobility measures from gait, TUG transitions, turning, and posture were significantly associated with motor MDS-UPDRS (7 of 12 measures, p < 0.05) and motor subtype (6 of 12 measures, p < 0.05). Compared with motor MDS-UPDRS, several quantitative mobility measures accounted for a 1.5- or 1.9-fold increased variance in either cognition or physical functioning disability, respectively. Among minimally-impaired subjects in the bottom quartile of motor MDS-UPDRS, including subjects with normal gait exam, the measures captured substantial residual motor heterogeneity.

Conclusion: Clinic-based quantitative mobility assessments using a wearable sensor captured features of motor performance beyond those obtained with the motor MDS-UPDRS and may offer enhanced characterization of disease heterogeneity.
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http://dx.doi.org/10.1016/j.parkreldis.2021.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987213PMC
March 2021

Incident mobility disability, parkinsonism, and mortality in community-dwelling older adults.

PLoS One 2021 3;16(2):e0246206. Epub 2021 Feb 3.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, United States of America.

Background: Mobility disability and parkinsonism are associated with decreased survival in older adults. This study examined the transition from no motor impairment to mobility disability and parkinsonism and their associations with death.

Methods: 867 community-dwelling older adults without mobility disability or parkinsonism at baseline were examined annually. Mobility disability was based on annual measured gait speed. Parkinsonism was based on the annual assessment of 26 items from the motor portion of the Unified Parkinson's Disease Rating Scale. A multistate Cox model simultaneously examined the incidences of mobility disability and parkinsonism and their associations with death.

Results: Average age at baseline was 75 years old and 318 (37%) died during 10 years of follow-up. Mobility disability was almost 2-fold more common than parkinsonism. Some participants developed mobility disability alone (42%), or parkinsonism alone (5%), while many developed both (41%). Individuals with mobility disability or parkinsonism alone had an increased risk of death, but their risk was less than the risk in individuals with both impairments. The risk of death did not depend on the order in which impairments occurred.

Conclusion: The varied patterns of transitions from no motor impairment to motor impairment highlights the heterogeneity of late-life motor impairment and its contribution to survival. Further studies are needed to elucidate the underlying biology of these different transitions and how they might impact survival.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246206PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857621PMC
July 2021

Motor function is the primary driver of the associations of sarcopenia and physical frailty with adverse health outcomes in community-dwelling older adults.

PLoS One 2021 2;16(2):e0245680. Epub 2021 Feb 2.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, United States of America.

Background: This study tested the hypothesis that sarcopenia and its constituent components, reduced lean muscle mass and impaired motor function, are associated with reduced survival and increased risk of incident disabilities.

Methods: 1466 community-dwelling older adults underwent assessment of muscle mass with bioelectrical impedance analysis (BIA), grip strength, gait speed and other components of physical frailty and annual self-report assessments of disability. We used Cox proportional hazards models that controlled for age, sex, race, education and height to examine the associations of a continuous sarcopenia metric with the hazard of death and incident disabilities.

Results: Mean baseline age was about 80 years old and follow-up was 5.5 years. In a proportional hazards model controlling for age, sex, race, education and baseline sarcopenia, each 1-SD higher score on a continuous sarcopenia scale was associated with lower hazards of death (HR 0.70, 95%CI [0.62, 0.78]), incident IADL (HR 0.80,95%CI [0.70, 0.93]), incident ADL disability (HR 0.80 95%CI [71, 91]) and incident mobility disability (HR 0.81, 95%CI [0.70, 0.93]). Further analyses suggest that grip strength and gait speed rather than muscle mass drive the associations with all four adverse health outcomes. Similar findings were observed when controlling for additional measures used to assess physical frailty including BMI, fatigue and physical activity.

Conclusions: Motor function is the primary driver of the associations of sarcopenia and physical frailty with diverse adverse health outcomes. Further work is needed to identify other facets of muscle structure and motor function which together can identify adults at risk for specific adverse health outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245680PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853482PMC
July 2021

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Nat Commun 2021 01 28;12(1):654. Epub 2021 Jan 28.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10), arthritis (GDF5 p = 4 × 10), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
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http://dx.doi.org/10.1038/s41467-021-20918-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844411PMC
January 2021

Deterioration in Motor Function Over Time in Older Adults With Type 2 Diabetes is Associated with Accelerated Cognitive Decline.

Endocr Pract 2020 Oct;26(10):1143-1152

From the Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel; the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York. Electronic address:

Objective: Type 2 diabetes (T2D) is associated with motor impairments and a higher dementia risk. The relationships of motor decline with cognitive decline in T2D older adults has rarely been studied. Using data from the Israel Diabetes and Cognitive Decline study (N = 892), we examined associations of decline in motor function with cognitive decline over a 54-month period.

Methods: Motor function measures were strength (handgrip) and gait speed (time to walk 3 m). Participants completed a neuropsychologic battery of 13 tests transformed into z-scores, summarized into 4 cognitive domains: episodic memory, attention/working memory, executive functions, and language/semantic categorization. The average of the 4 domains' z-scores defined global cognition. Motor and cognitive functions were assessed in 18-months intervals. A random coefficients model delineated longitudinal relationships of cognitive decline with baseline and change from baseline in motor function, adjusting for sociodemographic, cardiovascular, and T2D-related covariates.

Results: Slower baseline gait speed levels were significantly associated with more rapid decline in global cognition (P = .004), language/semantic categorization (P = .006) and episodic memory (P = .029). Greater decline over time in gait speed was associated with an accelerated rate of decline in global cognition (P = .050), attention/working memory (P = .047) and language/semantic categorization (P<.001). Baseline strength levels were not associated with cognitive decline but the rate of declining strength was associated with an accelerated decline in executive functions (P = .025) and language/semantic categorization (P = .006).

Conclusion: In T2D older adults, the rate of decline in motor function, beyond baseline levels, was associated with accelerated cognitive decline, suggesting that cognitive and motor decline share common neuropathologic mechanisms in T2D.
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http://dx.doi.org/10.4158/EP-2020-0289DOI Listing
October 2020

Association of Low Systolic Blood Pressure with Postmortem Amyloid-β and Tau.

J Alzheimers Dis 2020 ;78(4):1755-1764

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Background: Vascular mechanisms may contribute to the accumulation of AD pathology.

Objective: We examined whether the burden of vascular risk factors proximate to death is associated with amyloid-β and tau levels or modified their known association.

Methods: We examined the brains of 1, 585 participants from two longitudinal community-based studies of older adults. Amyloid-β and tau were quantified by postmortem examination. The burden of vascular risk factors was summarized by calculating the Framingham general cardiovascular risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid-β and tau levels and examined if the FRS modified the association of the amyloid-β with tau.

Results: On average, participants were nearly 90 years old and two-thirds were women. The FRS was not associated with amyloid-β (Spearman r  = -0.00, p  = 0.918) or tau (r = 0.01, p = 0.701). However, the FRS as a whole (estimate = -0.022, SE = 0.008, p = 0.009), and specifically the systolic blood pressure (SBP) component (estimate = -0.033, SE = 0.012, p = 0.009), modified the association of the amyloid-β with tau. Further analysis showed that the association between amyloid-β and tau was stronger at lower levels of SBP.

Conclusion: Late-life vascular risk scores were not related to postmortem levels of amyloid-β or tau. However, lower levels of vascular risk scores and SBP were associated with a stronger association between amyloid-β and tau. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.
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http://dx.doi.org/10.3233/JAD-200412DOI Listing
January 2020

Association of Heel Bone Mineral Density With Incident Disability and Mortality in Community-Dwelling Older Adults.

JBMR Plus 2020 Sep 14;4(9):e10390. Epub 2020 Aug 14.

Rush Alzheimer's Disease Center Rush University Medical Center Chicago IL USA.

Age-related bone loss is common in older adults. However, the association of low bone mass with incident disability and mortality is not well established. A sample of 738 participants in the Rush Memory and Aging Project (MAP) was evaluated at baseline for bone mineral density (BMD) using quantitative ultrasound at the calcaneus. An annual interview assessed basic activities of daily living (BADL), instrumental activities of daily living (IADL), mobility disability, and history of hip fracture. The associations between baseline BMD and risk of death; incident BADL, IADL, and mobility disability; and hip fracture were investigated using Cox hazard models, adjusting for age, sex, education, race, and body mass index (BMI). The robustness of our findings was evaluated by adjusting for confounding factors and health conditions including joint pain, musculoskeletal medications, smoking status, motor function, global cognition, falls, cardiovascular events, and diabetes. Participants were on average (mean ± SD) 80.9 ± 7.0 years old, 72% female, and 3.8% black, with a baseline BMI of 27.3 ± 5.4 kg/m, and a baseline of BMD of 0.44 ± 0.14 g/cm. In models adjusted for age, sex, education, race, and BMI, lower BMD was associated with a higher rate of death (hazard ratio [HR] 1.20; 95% confidence interval [CI], 1.08-1.33), incident BADL disability (HR 1.20; 95% CI, 1.05-1.37), and hip fracture (HR 2.57; 95% CI, 1.72-3.82), but not of IADL disability (HR 1.00; 95% CI, 0.85-1.17) or mobility disability (HR 1.13; 95% CI, 0.97-1.32). The association between BMD and mortality was not significant in fully adjusted models, but the BMD and BADL associations remained significant in models adjusting for both demographic variables and BMD-modifying health conditions. BMD is associated with incident disability in older adults. © 2020 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507511PMC
September 2020

Neuropathologic burden and the degree of frailty in relation to global cognition and dementia.

Neurology 2020 12 28;95(24):e3269-e3279. Epub 2020 Sep 28.

From the Departments of Medicine (L.M.K.W., O.T., S.D., M.K.A., J.D.F., K.R.), Physiotherapy (O.T.), Community Health and Epidemiology (S.K.), and Psychiatry (J.D.F.), Dalhousie University, Halifax, Canada; and Rush Alzheimer's Disease Center (D.A.B., A.S.B.), Rush University Medical Center, Chicago, IL.

Objective: To test the hypothesis that degree of frailty and neuropathologic burden independently contribute to global cognition and odds of dementia.

Methods: This was a secondary analysis of a prospective cohort study of older adults living in Illinois. Participants underwent an annual neuropsychological and clinical evaluation. We included 625 participants (mean age 89.7 ± 6.1 years; 67.5% female) who died and underwent autopsy. We quantified neuropathology using an index measure of 10 neuropathologic features: β-amyloid deposition, hippocampal sclerosis, Lewy bodies, tangle density, TDP-43, cerebral amyloid angiopathy, arteriolosclerosis, atherosclerosis, and gross and chronic cerebral infarcts. Clinical consensus determined dementia status, which we coded as no cognitive impairment, mild cognitive impairment, or dementia. A battery of 19 tests spanning multiple domains quantified global cognition. We operationalized frailty using a 41-item frailty index. We employed regression analyses to model relationships between neuropathology, frailty, and dementia.

Results: Both frailty and a neuropathology index were independently associated with global cognition and dementia status. These results held after controlling for traditional pathologic measures in a sample of participants with Alzheimer clinical syndrome. Frailty improved the fit of the model for dementia status (χ[2] 72.64; < 0.0001) and explained an additional 11%-12% of the variance in the outcomes.

Conclusion: Dementia is a multiply determined condition, to which both general health, as captured by frailty, and neuropathology significantly contribute. This integrative view of dementia and health has implications for prevention and therapy; specifically, future research should evaluate frailty as a means of dementia risk reduction.
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http://dx.doi.org/10.1212/WNL.0000000000010944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836651PMC
December 2020

Bayesian Genome-wide TWAS Method to Leverage both cis- and trans-eQTL Information through Summary Statistics.

Am J Hum Genet 2020 10 21;107(4):714-726. Epub 2020 Sep 21.

Center for Computational and Quantitative Genetics, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address:

Transcriptome-wide association studies (TWASs) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans-expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian genome-wide TWAS (BGW-TWAS) method that leverages both cis- and trans-eQTL information for a TWAS. Our BGW-TWAS method is based on Bayesian variable selection regression, which not only accounts for cis- and trans-eQTL of the target gene but also enables efficient computation by using summary statistics from standard eQTL analyses. Our simulation studies illustrated that BGW-TWASs achieved higher power compared to existing TWAS methods that do not assess trans-eQTL information. We further applied BWG-TWAS to individual-level GWAS data (N = ∼3.3K), which identified significant associations between the genetically regulated gene expression (GReX) of ZC3H12B and Alzheimer dementia (AD) (p value = 5.42 × 10), neurofibrillary tangle density (p value = 1.89 × 10), and global measure of AD pathology (p value = 9.59 × 10). These associations for ZC3H12B were completely driven by trans-eQTL. Additionally, the GReX of KCTD12 was found to be significantly associated with β-amyloid (p value = 3.44 × 10) which was driven by both cis- and trans-eQTL. Four of the top driven trans-eQTL of ZC3H12B are located within APOC1, a known major risk gene of AD and blood lipids. Additionally, by applying BGW-TWAS with summary-level GWAS data of AD (N = ∼54K), we identified 13 significant genes including known GWAS risk genes HLA-DRB1 and APOC1, as well as ZC3H12B.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536614PMC
October 2020

Semiautomatic morphometric analysis of skeletal muscle obtained by needle biopsy in older adults.

Geroscience 2020 12 18;42(6):1431-1443. Epub 2020 Sep 18.

Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Analysis of skeletal muscle mass and composition is essential for studying the biology of age-related sarcopenia, loss of muscle mass, and function. Muscle immunohistochemistry (IHC) allows for simultaneous visualization of morphological characteristics and determination of fiber type composition. The information gleaned from myosin heavy chain (MHC) isoform, and morphological measurements offer a more complete assessment of muscle health and properties than classical techniques such as SDS-PAGE and ATPase immunostaining; however, IHC quantification is a time-consuming and tedious method. We developed a semiautomatic method to account for issues frequently encountered in aging tissue. We analyzed needle-biopsied vastus lateralis (VL) of the quadriceps from a cohort of 14 volunteers aged 74.9 ± 2.2 years. We found a high correlation between manual quantification and semiautomatic analyses for the total number of fibers detected (r = 0.989) and total fiber cross-sectional area (r = 0.836). The analysis of the VL fiber subtype composition and the cross-sectional area also did not show statistically significant differences. The semiautomatic approach was completed in 10-15% of the time required for manual quantification. The results from these analyses highlight some of the specific issues which commonly occur in aged muscle. Our methods which address these issues underscore the importance of developing efficient, accurate, and reliable methods for quantitatively analyzing the skeletal muscle and the standardization of collection protocols to maximize the likelihood of preserving tissue quality in older adults. Utilizing IHC as a means of exploring the progression of disease, aging, and injury in the skeletal muscle allows for the practical study of muscle tissue down to the fiber level. By adding editing modules to our semiautomatic approach, we accurately quantified the aging muscle and addressed common technical issues.
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http://dx.doi.org/10.1007/s11357-020-00266-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732929PMC
December 2020

Automatic Quantification of Tandem Walking Using a Wearable Device: New Insights Into Dynamic Balance and Mobility in Older Adults.

J Gerontol A Biol Sci Med Sci 2021 01;76(1):101-107

Department of Physical Therapy, Tel Aviv University, Israel.

Background: Wearable sensors are increasingly employed to quantify diverse aspects of mobility. We developed novel tandem walking (TW) metrics, validated these measures using data from community-dwelling older adults, and evaluated their association with mobility disability and measures of gait and postural control.

Methods: Six hundred ninety-three community-dwelling older adults (age: 78.69 ± 7.12 years) wore a 3D accelerometer on their lower back while performing 3 tasks: TW, usual-walking, and quiet standing. Six new measures of TW were extracted from the sensor data along with the clinician's conventional assessment of TW missteps (ie, trip other loss of balance in which recovery occurred to prevent a fall) and duration. Principal component analysis transformed the 6 new TW measures into 2 summary TW composite factors. Logistic regression models evaluated whether these TW factors were independently associated with mobility disability.

Results: Both TW factors were moderately related to the TW conventional measures (r < 0.454, p < .001) and were mildly correlated with usual-walking (r < 0.195, p < .001) and standing, postural control (r < 0.119, p < .001). The TW frequency composite factor (p = .008), but not TW complexity composite factor (p = .246), was independently associated with mobility disability in a model controlling for age, sex, body mass index, race, conventional measures of TW, and other measures of gait and postural control.

Conclusions: Sensor-derived TW metrics expand the characterization of gait and postural control and suggest that they reflect a relatively independent domain of mobility. Further work is needed to determine if these metrics improve risk stratification for other adverse outcomes (eg, falls and incident disability) in older adults.
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http://dx.doi.org/10.1093/gerona/glaa235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756682PMC
January 2021

Representation of Older Latinxs in Cohort Studies at the Rush Alzheimer's Disease Center.

Neuroepidemiology 2020 9;54(5):404-418. Epub 2020 Sep 9.

Rush Alzheimer's Disease Center, Chicago, Illinois, USA.

The Rush Alzheimer's Disease Center (RADC) conducts 5 harmonized prospective clinical-pathologic cohort studies of aging - with 1 study, the Latino Core, focused exclusively on Latinxs, 2 studies consisting of mostly non-Latinx whites, and 2 studies of mostly non-Latinx blacks. This paper contextualizes the Latino Core within the other 4 harmonized RADC cohort studies. The overall aim of the paper is to provide information from the RADC, so that researchers can learn from our participants and procedures to better advance the science of Alzheimer's disease and related dementias in Latinxs. We describe an annual clinical evaluation that assesses risk factors for Alzheimer's dementia among older adults without known dementia at enrollment. As all RADC cohort studies offer brain donation as a part of research participation, we discuss our approach to brain donation and subsequent participant decision-making among older Latinxs. We also summarize baseline characteristics of older Latinxs across the 5 RADC cohort studies in relation to the baseline characteristics of non-Latinx blacks and non-Latinx whites. Finally, we outline challenges and considerations as well as potential next steps in cognitive aging research with older Latinxs.
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http://dx.doi.org/10.1159/000509626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572552PMC
September 2021

Association of Cardiovascular Risk Burden With Risk and Progression of Disability: Mediating Role of Cardiovascular Disease and Cognitive Decline.

J Am Heart Assoc 2020 09 1;9(18):e017346. Epub 2020 Sep 1.

Department of Epidemiology and Biostatistics School of Public Health Tianjin Medical University Tianjin China.

Background Cardiovascular risk burden has been linked to cardiovascular disease (CVD) and cognitive decline, but its association with disability is unclear. We aimed to examined the association of cardiovascular risk burden assessed by the Framingham general cardiovascular risk score (FGCRS) with the risk and progression of disability and estimated the extent to which CVD and cognitive decline mediate this association. Methods and Results A total of 1480 older adults with no disabilities (mean age=79.32±7.38 years) from the Rush Memory and Aging Project were followed for up to 21 years. FGCRS at baseline was calculated and categorized into tertiles. Disability was assessed annually with activities of daily living. The number of CVDs was calculated by summing up the CVD events. Global cognitive function was assessed annually with a battery of 19 tests. Data were analyzed using the Cox model, linear mixed effects model, and mediation analysis. At the end of the follow-up, 713 (48.2%) participants developed disability. Compared with the lowest tertile of the FGCRS, the multiadjusted hazards ratios of disability were 1.34 (95% CI, 1.11-1.62) for the highest tertile. In addition, the highest FGCRS was associated with a change in activities of daily living score over time (β=0.057; 95% CI, 0.021-0.093). The association between FGCRS and change in activities of daily living was 13.8% mediated by the accumulation of CVDs and 25.1% by cognitive decline, respectively. Conclusions Higher cardiovascular risk burden increased the risk of disability and accelerated its progression over time. CVD accumulation and cognitive decline may partially mediate the association.
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http://dx.doi.org/10.1161/JAHA.120.017346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726997PMC
September 2020

Brain pathologies are associated with both the rate and variability of declining motor function in older adults.

Acta Neuropathol 2020 10 14;140(4):587-589. Epub 2020 Aug 14.

Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 West Harrison Street, Jelke Building, Suite 100, Chicago, IL, 60612, USA.

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http://dx.doi.org/10.1007/s00401-020-02212-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501086PMC
October 2020

Person-Specific Contributions of Brain Pathologies to Progressive Parkinsonism in Older Adults.

J Gerontol A Biol Sci Med Sci 2021 03;76(4):615-621

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.

Background: Mixed-brain pathologies are the most common cause of progressive parkinsonism in older adults. We tested the hypothesis that the impact of individual pathologies associated with progressive parkinsonism differs among older adults.

Methods: Data were from 1089 decedents who had undergone annual clinical testing and autopsy. Parkinsonism was based on a modified United Parkinson's Disease Rating Scale. Linear mixed-effects models were employed, to investigate the combinations of 9 pathologies related to progressive parkinsonism. Then we estimated the person-specific contributions of each pathology for progressive parkinsonism.

Results: The average participant showed 3 pathologies. Parkinson's disease (PD) and 4 cerebrovascular pathologies (macroinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy [CAA]), but not Alzheimer's disease, TDP-43, hippocampal sclerosis, and microinfarcts, were independently associated with progressive parkinsonism. These pathologies accounted for 13% of additional variance of progressive parkinsonism. Thirty-one different combinations of these 5 pathologies were observed to be associated with progressive parkinsonism observed. On average, PD and CAA accounted, respectively, for 66% and 65% of person-specific progression of parkinsonism, while macroinfarcts, atherosclerosis, and arteriolosclerosis accounted for 41%-48%.

Conclusion: There is much greater heterogeneity in the comorbidity and relative impact of individual brain pathologies affecting progressive parkinsonism than previously recognized and this may account in part for its phenotypic heterogeneity in older adults.
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http://dx.doi.org/10.1093/gerona/glaa176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240996PMC
March 2021
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