Publications by authors named "Sue E Leurgans"

124 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 ;83(2):641-652

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
January 2021

MIND Diet, Common Brain Pathologies, and Cognition in Community-Dwelling Older Adults.

J Alzheimers Dis 2021 ;83(2):683-692

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

Background: MIND diet, a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet, is associated with a slower cognitive decline and lower risk of Alzheimer's disease (AD) dementia in older adults.

Objective: We aim to examine whether the association of the MIND diet with cognition is independent of common brain pathologies.

Methods: Utilizing data from the Rush Memory and Aging Project (MAP), a longitudinal clinical-pathologic study, we studied 569 decedents with valid dietary data, cognitive testing proximate to death, and complete autopsy data at the time of these analyses. A series of regression analyses were used to examine associations of the MIND diet, dementia-related brain pathologies, and global cognition proximate to death adjusting for age, sex, education, APOEɛ4, late-life cognitive activities, and total energy intake.

Results: A higher MIND diet score was associated with better global cognitive functioning proximate to death (β= 0.119, SE = 0.040, p = 0.003), and neither the strength nor the significance of association changed substantially when AD pathology and other brain pathologies were included in the model. The β-estimate after controlling for global AD pathology was 0.111 (SE = 0.037, p = 0.003). The MIND diet-cognition relationship remained significant when we restricted our analysis to individuals without mild cognitive impairment at the baseline (β= 0.121, SE = 0.042, p = 0.005) or in people diagnosed with postmortem diagnosis of AD based on NIA-Reagan consensus recommendations (β= 0.114, SE = 0.050, p = 0.023).

Conclusion: MIND diet is associated with better cognitive functioning independently of common brain pathology, suggesting that the MIND diet may contribute to cognitive resilience in the elderly.
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http://dx.doi.org/10.3233/JAD-210107DOI Listing
January 2021

ARTS: A novel In-vivo classifier of arteriolosclerosis for the older adult brain.

Neuroimage Clin 2021 24;31:102768. Epub 2021 Jul 24.

Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Dept. of Diagnostic Radiology & Nuc Med, Rush University Medical Center, Chicago, IL, USA. Electronic address:

Brain arteriolosclerosis, one of the main pathologies of cerebral small vessel disease, is common in older adults and has been linked to lower cognitive and motor function and higher odds of dementia. In spite of its frequency and associated morbidity, arteriolosclerosis can only be diagnosed at autopsy. Therefore, the purpose of this work was to develop an in-vivo classifier of arteriolosclerosis based on brain MRI. First, an ex-vivo classifier of arteriolosclerosis was developed based on features related to white matter hyperintensities, diffusion anisotropy and demographics by applying machine learning to ex-vivo MRI and pathology data from 119 participants of the Rush Memory and Aging Project (MAP) and Religious Orders Study (ROS), two longitudinal cohort studies of aging that recruit non-demented older adults. The ex-vivo classifier showed good performance in predicting the presence of arteriolosclerosis, with an average area under the receiver operating characteristic curve AUC = 0.78. The ex-vivo classifier was then translated to in-vivo based on available in-vivo and ex-vivo MRI data on the same participants. The in-vivo classifier was named ARTS (short for ARTerioloSclerosis), is fully automated, and provides a score linked to the likelihood a person suffers from arteriolosclerosis. The performance of ARTS in predicting the presence of arteriolosclerosis in-vivo was tested in a separate, 91% dementia-free group of 79 MAP/ROS participants and exhibited an AUC = 0.79 in persons with antemortem intervals shorter than 2.4 years. This level of performance in mostly non-demented older adults is notable considering that arteriolosclerosis can only be diagnosed at autopsy. The scan-rescan reproducibility of the ARTS score was excellent, with an intraclass correlation of 0.99, suggesting that application of ARTS in longitudinal studies may show high sensitivity in detecting small changes. Finally, higher ARTS scores in non-demented older adults were associated with greater decline in cognition two years after baseline MRI, especially in perceptual speed which has been linked to arteriolosclerosis and small vessel disease. This finding was shown in a separate group of 369 non-demented MAP/ROS participants and was validated in 72 non-demented Black participants of the Minority Aging Research Study (MARS) and also in 244 non-demented participants of the Alzheimer's Disease Neuroimaging Initiative 2 and 3. The results of this work suggest that ARTS may have broad implications in the advancement of diagnosis, prevention and treatment of arteriolosclerosis. ARTS is publicly available at https://www.nitrc.org/projects/arts/.
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http://dx.doi.org/10.1016/j.nicl.2021.102768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329541PMC
September 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

The link between social and emotional isolation and dementia in older black and white Brazilians.

Int Psychogeriatr 2021 Jun 15:1-7. Epub 2021 Jun 15.

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

Objective: To examine the link between social and emotional isolation and likelihood of dementia among older black and white Brazilians.

Design: Cross-sectional clinical-pathological cohort study.

Setting: Medical center in Sao Paulo, Brazil.

Participants: As part of the Pathology, Alzheimer's and Related Dementias Study, we conducted uniform structured interviews with knowledgeable informants (72% children) of 1,493 older (age > 65) Brazilian decedents.

Measurements: The interview included measures of social isolation (number of family and friends in at least monthly contact with decedent), emotional isolation (short form of UCLA Loneliness Scale), and major depression plus the informant portion of the Clinical Dementia Rating Scale to diagnose dementia and its precursor, mild cognitive impairment (MCI).

Results: Decedents had a median social network size of 8.0 (interquartile range = 9.0) and a median loneliness score of 0.0 (interquartile range = 1.0). On the Clinical Dementia Rating Scale, 947 persons had no cognitive impairment, 122 had MCI, and 424 had dementia. In a logistic regression model adjusted for age, education, sex, and race, both smaller network size (odds ratio [OR] = 0.975; 95% confidence interval [CI]: 0.962, 0.989) and higher loneliness (OR = 1.145; 95% CI: 1.060, 1.237) were associated with higher likelihood of dementia. These associations persisted after controlling for depression (present in 10.4%) and did not vary by race. After controlling for depression, neither network size nor loneliness was related to MCI.

Conclusion: Social and emotional isolation are associated with higher likelihood of dementia in older black and white Brazilians.
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http://dx.doi.org/10.1017/S1041610221000673DOI Listing
June 2021

Bootstrap approach for meta-synthesis of MRI findings from multiple scanners.

J Neurosci Methods 2021 08 27;360:109229. Epub 2021 May 27.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, 60612, United States; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, United States; Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL 60612, United States.

Background: Neuroimaging data from large epidemiologic cohort studies often come from multiple scanners. The variations of MRI measurements due to differences in magnetic field strength, image acquisition protocols, and scanner vendors can influence the interpretation of aggregated data. The purpose of the present study was to compare methods that meta-analyze findings from a small number of different MRI scanners.

Methods: We proposed a bootstrap resampling method using individual participant data and compared it with two common random effects meta-analysis methods, DerSimonian-Laird and Hartung-Knapp, and a conventional pooling method that combines MRI data from different scanners. We first performed simulations to compare the power and coverage probabilities of the four methods in the absence and presence of scanner effects on measurements. We then examined the association of age with white matter hyperintensity (WMH) volumes from 787 participants.

Results: In simulations, the bootstrap approach performed better than the other three methods in terms of coverage probability and power when scanner differences were present. However, the bootstrap approach was consistent with pooling, the optimal approach, when scanner differences were absent. In the association of age with WMH volume, we observed that age was significantly associated with WMH volumes using the bootstrap approach, pooling, and the DerSimonian-Laird method, but not using the Hartung-Knapp method (p < 0.0001 for the bootstrap approach, DerSimonian-Laird, and pooling but p = 0.1439 for the Hartung-Knapp approach).

Conclusion: The bootstrap approach using individual participant data is suitable for integrating outcomes from multiple MRI scanners regardless of absence or presence of scanner effects on measurements.
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http://dx.doi.org/10.1016/j.jneumeth.2021.109229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324567PMC
August 2021

Proteomic identification of select protein variants of the SNARE interactome associated with cognitive reserve in a large community sample.

Acta Neuropathol 2021 05 1;141(5):755-770. Epub 2021 Mar 1.

Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.

Age-related neuropathologies progressively impair cognitive abilities by damaging synaptic function. We aimed to identify key components within the presynaptic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) machinery associated with cognitive performance and estimate their potential contribution to brain reserve in old age. We used targeted SRM proteomics to quantify amounts of 60 peptides, encoded in 30 different genes, in postmortem specimens of the prefrontal cortex from 1209 participants of two aging studies, with available antemortem cognitive evaluations and postmortem neuropathologic assessments. We found that select (but not all) proteoforms are strongly associated with cognitive function and the burden of Alzheimer's disease (AD) pathology. Specifically, greater abundance of STX1A (but not other syntaxins), SYT12, full-length SNAP25, and the GABAergic STXBP1 variant were robustly associated with better cognitive performance. By contrast, greater abundance of other presynaptic proteins (e.g., STXBP5 or tomosyn, STX7, or SYN2) showed a negative influence on cognition. Regression models adjusting for demographic and pathologic variables showed that altered levels of these protein species explained 7.7% additional between-subject variance in cognition (more than any individual age-related neuropathology in the model), suggesting that these molecules constitute key elements of brain reserve. Network analyses indicated that those peptides associated with brain reserve, and closest to the SNARE fusogenic activity, showed greater centrality measures and were better connected in the network. Validation assays confirmed the selective loss of the STX1A (but not STX1B) isoform in cognitively impaired cases. In rodent and human brains, STX1A was selectively located at glutamatergic terminals. However, in AD brains, STX1A was redistributed adjacent to neuritic pathology, and markedly expressed in astrocytes. Our study provides strong evidence, indicating that select presynaptic proteins are key in maintaining brain reserve. Compromised ability to sustain expression levels of these proteins may trigger synaptic dysfunction and concomitant cognitive impairment.
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http://dx.doi.org/10.1007/s00401-021-02282-7DOI Listing
May 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

Neuroticism, negative life events, and dementia in older White and Black Brazilians.

Int J Geriatr Psychiatry 2021 06 23;36(6):901-908. Epub 2021 Jan 23.

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

Objective: Exposure to negative life events (NLEs) and neuroticism are associated with dementia. It is unknown whether neuroticism explains or modifies the association of NLEs with dementia in older Black and White Brazilians.

Methods: A total of 1747 decedents 65 years and older White and Black (11% Black and 23% Mixed) Brazilians, 53% women, were included in the analyses. Data were obtained in a face-to-face interview with an informant (71% their children) who knew the decedents for 47 years on average. Dementia was classified using the Clinical Dementia Rating. NLEs were assessed with a 10-item scale involving common problems (e.g., death, illness, alcoholism, and financial). Neuroticism was assessed with a 6-item neuroticism scale adapted from the NEO Five-Factor Inventory. Models adjusted for age, sex, and education. Black and mixed-race were combined in the analyses.

Results: NLEs (median of 2) were more common in Blacks than Whites (2.04 vs. 1.82, p = 0.007). More NLEs increased the odds of dementia (OR = 1.112, β = 0.106, p = 0.002), similarly in Blacks and Whites (β  = 0.046, p = 0.526). More NLEs were also associated with higher neuroticism (β = 0.071, p < 0.0001), in Whites but not in Blacks (β  = -0.048, p = 0.006). Neuroticism was associated with higher odds of dementia (OR = 1.658, β = 0.506, p=<0.001), in Whites but not in Blacks (β  = -0.420, p = 0.040). Overall, 34% of the effect of NLEs on dementia was associated with the underlying neuroticism trait in Whites (65%, Indirect OR = 1.060, p < 0.001) but no association was evident in Blacks (6%, Indirect OR = 1.008, p = 0.326). Neuroticism did not moderate the association of NLEs with dementia (OR = 0.979, β = -0.021, p = 0.717).

Conclusion: The association of NLEs and dementia is partially explained by neuroticism in older White but not in Blacks Brazilians.
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http://dx.doi.org/10.1002/gps.5491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384138PMC
June 2021

Association of serial position scores on memory tests and hippocampal-related neuropathologic outcomes.

Neurology 2020 12 3;95(24):e3303-e3312. Epub 2020 Nov 3.

From the Department of Psychology (K.M.G.), York University, Toronto; Department of Psychiatry (W.G.H.), University of British Columbia, Vancouver Canada; and Departments of Neurological Sciences (R.S.W., S.E.L., D.A.B.), Psychiatry and Behavioral Sciences (R.S.W., P.A.B.), and Pathology (J.A.S.), Rush University Medical Center, Chicago, IL.

Objective: To determine whether serial position scores in verbal memory differentiate hippocampal-related neuropathologic outcomes, we examined these associations in a sample of older adults without dementia who underwent autopsy.

Methods: We used data from the Rush Memory and Aging Project, a longitudinal clinical-pathologic cohort study of community-dwelling adults. A total of 701 participants (mean age 82.7, 71.2% female) completed baseline cognitive evaluations and underwent brain autopsy to identify pathologic Alzheimer disease (AD), TDP-43 inclusions (defining limbic-predominant age-related TDP-43 encephalopathy [LATE]), and hippocampal sclerosis. The Consortium to Establish a Registry for Alzheimer's Disease word list memory test immediate recall trials provided serial position scores, which index the proportion of words recalled from the beginning (primacy scores) and end (recency scores) of a word list. Binary and ordinal logistic regressions examined associations between serial position scores and neuropathologic outcomes. Secondary outcomes included Alzheimer dementia and mild cognitive impairment proximate to death.

Results: Primacy and recency scores were uncorrelated ( = 0.07). Each SD of better primacy score was associated with lower likelihood of neuropathologic changes (24% lower LATE, 31% lower pathologic AD, 37% lower hippocampal sclerosis). For pathologic AD, better baseline primacy scores were associated with a 36% lower likelihood of comorbidity with LATE or hippocampal sclerosis. Primacy scores better discriminated between clinical diagnoses proximate to death, including those with mild cognitive impairment compared to no impairment. Recency scores showed weaker or no associations.

Conclusions: Primacy scores may be particularly sensitive markers of AD and related hippocampal neuropathologies. The differential predictive value of serial position scores suggests they offer complementary information about disease outcomes in addition to the routinely used total recall scores.
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http://dx.doi.org/10.1212/WNL.0000000000010952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836661PMC
December 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

Acculturation in Context: The Relationship Between Acculturation and Socioenvironmental Factors With Level of and Change in Cognition in Older Latinos.

J Gerontol B Psychol Sci Soc Sci 2021 03;76(4):e129-e139

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

Objectives: Latinos are 1.5 times as likely to develop Alzheimer's dementia as non-Latino Whites. This health disparity may arise from multiple influences with culturally relevant factors receiving increasing attention. Models of acculturation stress the importance of considering acculturation-related factors within the context of socioenvironmental factors to better capture the Latino experience in the United States.

Methods: We measured 10 acculturation and contextually-related variables in 199 Latinos (age 69.7 years) without dementia participating in Rush Alzheimer's Disease Center studies. We tested the relationship between these variables via Principal Component Analysis (PCA), then investigated how resulting components associated with level of and longitudinal change in global and domain-specific cognition using separate linear mixed-effects models adjusted for relevant confounders and their interactions with time.

Results: The PCA revealed a 3-factor unrotated solution (variance explained ~70%). Factor 1, representing acculturation-related aspects of nativity, language- and social-based acculturation, was positively associated with level, but not change, in global cognition, semantic memory, and perceptual speed. Factor 2, representing contextually-related socioenvironmental experiences of discrimination, social isolation, and social networks, was negatively associated with level of global cognition, episodic and working memory, and faster longitudinal decline in visuospatial ability. Factor 3 (familism only) did not associate with level or change in any cognitive outcome.

Discussion: Acculturation- and contextually-related factors differentiated from each other and differentially contributed to cognition and cognitive decline in older Latinos. Providers should query acculturation and lived experiences when evaluating cognition in older Latinos.
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http://dx.doi.org/10.1093/geronb/gbaa156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955974PMC
March 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

Brain tocopherol levels are associated with lower activated microglia density in elderly human cortex.

Alzheimers Dement (N Y) 2020 24;6(1):e12021. Epub 2020 Aug 24.

Rush Institute for Healthy Aging Rush University Medical Center Chicago Illinois.

Introduction: Higher brain tocopherol levels have been associated with lower levels of Alzheimer's disease (AD) neuropathology; however, the underlying mechanisms are unclear.

Methods: We studied the relations of α- and γ-tocopherol brain levels to microglia density in 113 deceased participants from the Memory and Aging Project. We used linear regression analyses to examine associations between tocopherol levels and microglia densities in a basic model adjusted for age, sex, education, apolipoprotein E ()ε4 genotype (any ε4 allele vs. none) , and post-mortem time interval, and a second model additionally adjusted for total amyloid load and neurofibrillary tangle severity.

Results: Higher α- and γ-tocopherol levels were associated with lower total and activated microglia density in cortical but not in subcortical brain regions. The association between cortical α-tocopherol and total microglia density remained statistically significant after adjusting for AD neuropathology.

Discussion: These results suggest that the relation between tocopherols and AD might be partly explained by the alleviating effects of tocopherols on microglia activation.
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http://dx.doi.org/10.1002/trc2.12021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444784PMC
August 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

Neuropathologic and Cognitive Correlates of Enlarged Perivascular Spaces in a Community-Based Cohort of Older Adults.

Stroke 2020 09 6;51(9):2825-2833. Epub 2020 Aug 6.

Department of Biomedical Engineering, Illinois Institute of Technology, Chicago (C.J.P., N.M., K.A.).

Background And Purpose: Enlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function, and vascular dementia. However, the relationship of EPVS with age-related neuropathologies is not well understood. Therefore, the purpose of this study was to assess the neuropathologic correlates of EPVS in a large community-based cohort of older adults. The cognitive correlates of EPVS over and beyond those of other pathologies were also assessed.

Methods: This study included 654 older deceased and autopsied participants of 3 longitudinal community-based studies of aging that had available data on cognition, ex vivo brain magnetic resonance imaging, and detailed neuropathologic examination. EPVS seen on ex vivo magnetic resonance imaging were histologically validated. Experienced observers rated EPVS burden in ex vivo magnetic resonance imaging using a semiquantitative 4-level scale. Elastic-net regularized ordinal logistic regression was used to investigate associations of EPVS burden with age-related neuropathologies. Mixed-effects models of cognition controlling for neuropathologies, demographics, and clinical factors, were used to determine whether EPVS burden has additional contributions to cognitive decline.

Results: EPVS burden in the whole group was associated with gross infarcts (odds ratio=1.67, =0.0017) and diabetes mellitus (odds ratio=1.73, =0.004). When considering only nondemented participants (with mild or no cognitive impairment), EPVS burden was associated with gross infarcts (odds ratio=1.74, =0.016) and microscopic infarcts (odds ratio=1.79, =0.013). EPVS burden was associated with faster decline in visuospatial abilities (estimate=-0.009, =0.028), in the whole group, as well as lower levels of semantic memory (estimate=-0.13, =0.048) and visuospatial abilities (estimate=-0.11, =0.016) at the time of death.

Conclusions: EPVS and infarcts may share similar neurobiological pathways regardless of dementia status. EPVS burden is linked to diabetes mellitus independently of neuropathologies, extending recent findings in animal studies implicating diabetes mellitus in impairment of the glymphatic system. Finally, EPVS burden may reflect additional brain tissue injury that may contribute to cognitive decline, not captured with traditional neuropathologic measures.
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http://dx.doi.org/10.1161/STROKEAHA.120.029388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484322PMC
September 2020

Total daily physical activity, brain pathologies, and parkinsonism in older adults.

PLoS One 2020 29;15(4):e0232404. Epub 2020 Apr 29.

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

Objective: We examined the association of physical activity, postmortem brain pathologies, and parkinsonism proximate to death in older adults.

Methods: We studied the brains of 447 older decedents participating in a clinical-autopsy cohort study. We deployed a wrist worn activity monitor to record total daily physical activity during everyday living in the community-setting. Parkinsonism was assessed with 26 items of a modified motor portion of Unified Parkinson's Disease Rating Scale (UPDRS). We used linear regression models, controlling for age and sex, to examine the association of physical activity with parkinsonism with and without indices of Alzheimer's disease and related disorders (ADRD) pathologies. In separate models, we added interaction terms to examine if physical activity modified the associations of brain pathologies with parkinsonism.

Results: Mean age at death was 90.9 (SD, 6.2), mean severity of parkinsonism was 14.1 (SD, 9.2, Range 0-59.4), and 350 (77%) had evidence of more than one ADRD pathologies. Higher total daily physical activity was associated with less severe parkinsonism (Estimate, -0.315, S.E., 0.052, p<0.001). The association of more physical activity with less severe parkinsonism persisted after adding terms for ten brain pathologies (Estimate, -0.283, S.E., 0.052, p<0.001). The associations of brain pathologies with more severe parkinsonism did not vary with the level of physical activity.

Conclusion: The association of higher physical activity with less severe parkinsonism may be independent of the presence of ADRD brain pathologies. Further work is needed to identify mechanisms through which physical activity may maintain motor function in older adults.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232404PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190120PMC
July 2020

Dietary flavonols and risk of Alzheimer dementia.

Neurology 2020 04 29;94(16):e1749-e1756. Epub 2020 Jan 29.

From Rush Institute for Healthy Aging (T.M.H., P.A., Y.W., M.C.M.), Rush Alzheimer's Disease Center (S.E.L., D.A.B.), and Neurological Sciences (S.E.L., D.A.B.), Rush University Medical Center, Chicago, IL; and Jean Mayer USDA Human Nutrition Research Center on Aging (S.L.B.), Tufts University, Boston, MA.

Objective: To determine whether dietary intake of flavonols is associated with Alzheimer dementia.

Methods: The study was conducted among 921 participants of the Rush Memory and Aging Project (MAP), an ongoing community-based, prospective cohort. Participants completed annual neurologic evaluations and dietary assessments using a validated food frequency questionnaire.

Results: Among 921 MAP participants who initially had no dementia in the analyzed sample, 220 developed Alzheimer dementia. The mean age of the sample was 81.2 years (SD 7.2), with the majority (n = 691, 75%) being female. Participants with the highest intake of total flavonols had higher levels of education and more participation in physical and cognitive activities. In Cox proportional hazards models, dietary intakes of flavonols were inversely associated with incident Alzheimer dementia in models adjusted for age, sex, education, ɛ4, and participation in cognitive and physical activities. Hazard ratios (HRs) for the fifth vs first quintiles of intake were as follows: for total flavonol, 0.52 (95% confidence interval [CI], 0.33-0.84); for kaempferol, 0.49 (95% CI, 0.31-0.77); for myricetin, 0.62 (95% CI, 0.4-0.97); and for isorhamnetin, 0.62 (95% CI, 0.39-0.98). Quercetin was not associated with Alzheimer dementia (HR, 0.69; 95% CI, 0.43-1.09).

Conclusion: Higher dietary intakes of flavonols may be associated with reduced risk of developing Alzheimer dementia.
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http://dx.doi.org/10.1212/WNL.0000000000008981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282875PMC
April 2020

Proportion of cognitive loss attributable to terminal decline.

Neurology 2020 01 2;94(1):e42-e50. Epub 2019 Dec 2.

From the Departments of Neurological Sciences (R.S.W., L.Y., S.E.L., D.A.B.) and Behavioral Sciences (R.S.W., P.A.B.), Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL.

Objective: To estimate the proportion of late-life cognitive loss attributable to impending death.

Methods: Older persons (n = 1,071) in a longitudinal cohort study without dementia at enrollment underwent annual cognitive assessments (mean 10.6 years, SD 4.6, range 4-24) prior to death. We estimated the onset of terminal acceleration in cognitive decline and rates of decline before and after this point in change point models that allowed calculation of the percent of cognitive loss attributable to terminal decline. Outcomes were composite measures of global and specific cognitive functions. We also estimated dementia and mild cognitive impairment (MCI) incidence before and during the terminal period.

Results: A mean of 3.7 years before death (95% credible interval [CI] -3.8 to -3.5), the rate of global cognitive decline accelerated to -0.313 unit per year (95% CI -0.337 to -0.290), a more than 7-fold increase indicative of terminal decline. The mean global cognitive score dropped 0.377 unit (SD 0.516) assuming no terminal decline and 1.192 units (SD 1.080) with terminal decline. As a result, 71% (95% bootstrapped CI 0.70, 0.73) of overall global cognitive loss was terminal. In subsequent analyses, terminal decline accounted for 70% of episodic memory loss, 65% of semantic memory loss, 57% of working memory loss, 52% of perceptual speed loss, and 53% of visuospatial loss. MCI incidence in the preterminal and terminal periods was similar, but dementia incidence was more than 6-fold higher in the terminal period than preterminal.

Conclusion: Most late-life cognitive loss is driven by terminal decline.
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http://dx.doi.org/10.1212/WNL.0000000000008671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011688PMC
January 2020

Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults.

J Alzheimers Dis 2020 ;73(1):333-345

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

Background: The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood.

Objective: The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults.

Methods: Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo. All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies.

Results: WMH burden in the whole group was associated with both vascular and Alzheimer's disease (AD) pathologies: arteriolosclerosis (p < 10-4), gross (p < 10-4), and microscopic infarcts (p = 0.04), and amyloid-β plaques (p = 0.028). In non-demented participants (mild or no cognitive impairment) (N = 332), WMH burden was related to gross infarcts (p = 10-4) and arteriolosclerosis (p < 10-4), but not to AD pathology. Similarly, in those with no cognitive impairment (N = 178), WMH burden was related to gross infarcts (p = 8×10-4) and arteriolosclerosis (p = 0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (p = 0.038) and non-demented (p = 0.006) groups.

Conclusion: WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices.
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http://dx.doi.org/10.3233/JAD-190687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996196PMC
April 2021

Hip joint moments in symptomatic vs. asymptomatic people with mild radiographic hip osteoarthritis.

J Biomech 2019 Nov 8;96:109347. Epub 2019 Oct 8.

Department of Kinesiology and Nutrition, University of Illinois at Chicago, USA. Electronic address:

Our primary objective was to examine external hip joint moments during walking in people with mild radiographic hip osteoarthritis (OA) with and without symptoms and disease-free controls. Three groups were compared (symptomatic with mild radiographic hip OA, n = 12; asymptomatic with mild radiographic hip OA, n = 13; OA-free controls, n = 20). Measures of the external moment (peak and impulse) in the sagittal, frontal and transverse plane during walking were determined. Variables were compared according to group allocation using mixed linear regression models that included individual gait trials, with group allocation as fixed effect and walking speed as a random effect. Participants with evidence of radiographic disease irrespective of symptoms walked 14-16% slower compared to disease-free controls (p = 0.002). Radiographic disease without symptoms was not associated with any altered measures of hip joint moment compared to asymptomatic OA-free controls once speed was taken into account (p ≥ 0.099). People with both mild radiographic disease and symptoms had lower external peak hip adduction moment (p = 0.005) and lower external peak internal rotation moment (p < 0.001) accounting for walking speed. Among angular impulses, only the presence of symptoms was associated with a reduced hip internal rotation impulse (p = 0.002) in the symptomatic group. Collectively, our observations suggest that symptoms have additional mechanical associations from radiographic disease alone, and provide insight into potential early markers of hip OA. Future research is required to understand the implications of modifying walking speed and/or the external hip adduction and internal rotation moment in people with mild hip OA.
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http://dx.doi.org/10.1016/j.jbiomech.2019.109347DOI Listing
November 2019

Quantitative mobility metrics from a wearable sensor predict incident parkinsonism in older adults.

Parkinsonism Relat Disord 2019 08 22;65:190-196. Epub 2019 Jun 22.

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

Introduction: Mobility metrics derived from wearable sensor recordings are associated with parkinsonism in older adults. We examined if these metrics predict incident parkinsonism.

Methods: Parkinsonism was assessed annually in 683 ambulatory, community-dwelling older adults without parkinsonism at baseline. Four parkinsonian signs were derived from a modified Unified Parkinson's Disease Rating Scale (UPDRS). Parkinsonism was based on the presence of 2 or more signs. Participants wore a sensor on their back while performing a 32 foot walk, standing posture, and Timed Up and Go (TUG) tasks. 12 mobility scores were extracted. Cox proportional hazards models with backward elimination were used to identify combinations of mobility scores independently associated with incident parkinsonism.

Results: During follow-up of 2.5 years (SD = 1.28), 139 individuals developed parkinsonism (20.4%). In separate models, 6 of 12 mobility scores were individually associated with incident parkinsonism, including: Speed and Regularity (from 32 ft walk), Sway (from standing posture), and 3 scores from TUG subtasks (Posterior sit to stand transition, Range stand to sit transition, and Yaw, a measure of turning efficiency). When all mobility scores were analyzed together in a single model, 2 TUG subtask scores, Range from stand to sit transition (HR, 1.42, 95%CI, 1.09, 1.82) and Yaw from turning (HR, 0.56, 95%CI, 0.42, 0.73) were independently associated with incident parkinsonism. These results were unchanged when controlling for chronic health covariates.

Conclusion: Mobility metrics derived from a wearable sensor complement conventional gait testing and have potential to enhance risk stratification of older adults who may develop parkinsonism.
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http://dx.doi.org/10.1016/j.parkreldis.2019.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774889PMC
August 2019

Different Combinations of Mobility Metrics Derived From a Wearable Sensor Are Associated With Distinct Health Outcomes in Older Adults.

J Gerontol A Biol Sci Med Sci 2020 05;75(6):1176-1183

Rush Alzheimer's Disease Center, Chicago, Illinois.

Background: Gait speed is a robust nonspecific predictor of health outcomes. We examined if combinations of gait speed and other mobility metrics are associated with specific health outcomes.

Methods: A sensor (triaxial accelerometer and gyroscope) placed on the lower back, measured mobility in the homes of 1,249 older adults (77% female; 80.0, SD = 7.72 years). Twelve gait scores were extracted from five performances, including (a) walking, (b) transition from sit to stand, (c) transition from stand to sit, (d) turning, and (e) standing posture. Using separate Cox proportional hazards models, we examined which metrics were associated with time to mortality, incident activities of daily living disability, mobility disability, mild cognitive impairment, and Alzheimer's disease dementia. We used a single integrated analytic framework to determine which gait scores survived to predict each outcome.

Results: During 3.6 years of follow-up, 10 of the 12 gait scores predicted one or more of the five health outcomes. In further analyses, different combinations of 2-3 gait scores survived backward elimination and were associated with the five outcomes. Sway was one of the three scores that predicted activities of daily living disability but was not included in the final models for other outcomes. Gait speed was included along with other metrics in the final models predicting mortality and activities of daily living disability but not for other outcomes.

Conclusions: When analyzing multiple mobility metrics together, different combinations of mobility metrics are related to specific adverse health outcomes. Digital technology enhances our understanding of impaired mobility and may provide mobility biomarkers that predict distinct health outcomes.
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http://dx.doi.org/10.1093/gerona/glz160DOI Listing
May 2020

Expanding instrumented gait testing in the community setting: A portable, depth-sensing camera captures joint motion in older adults.

PLoS One 2019 15;14(5):e0215995. Epub 2019 May 15.

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

Background: Currently, it is not feasible to obtain laboratory-based measures of joint motion in large numbers of older adults. We assessed the utility of a portable depth-sensing camera for quantifying hip and knee joint motion of older adults during mobility testing in the community.

Methods: Participants were 52 older adults enrolled in the Rush Memory and Aging Project, a community-based cohort study of aging. In a subset, we compared dynamic hip and knee flexion/extension obtained via the depth-sensing camera with that obtained concurrently using a laboratory-based optoelectronic motion capture system. Then we recorded participants' annual instrumented gait assessment in the community setting with the depth-sensing camera and examined the inter-relationships of hip and knee range of motion (ROM) with mobility metrics derived from a wearable sensor and other mobility-related health measures.

Results: In the community, we successfully acquired joint motion from 49/52 participants using the depth-sensing camera. Hip and knee ROMs were related to diverse sensor-derived metrics of mobility performance (hip: Pearson's r = 0.31 to 0.58; knee: Pearson's r = 0.29 to 0.51), as well as daily physical activity, conventional motor measures, self-report hip and knee pain and dysfunction, mobility disability, and falls.

Conclusions: The depth-sensing camera's high rate of successful data acquisition and correlations of its hip and knee ROMs with other mobility measures suggest that this device can provide a cost-efficient means of quantifying joint motion in large numbers of community-dwelling older adults who span the health spectrum.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215995PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519784PMC
January 2020

Incident Mobility Disability, Mild Cognitive Impairment, and Mortality in Community-Dwelling Older Adults.

Neuroepidemiology 2019 15;53(1-2):55-62. Epub 2019 Apr 15.

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

Background/aims: Mobility disability and mild cognitive impairment (MCI) are common in aging and both are associated with risk of death. This study tested the hypothesis that risk of death differs by the order in which mobility disability and MCI occurred.

Methods: One thousand two hundred and sixty-two community-dwelling older adults were unimpaired at baseline and followed annually. Mobility disability was based on measured gait speed, and MCI was based on cognitive performance tests. A multistate Cox model simultaneously examined incidences of mobility disability and MCI to determine whether the order of their occurrence is differentially associated with risk of death.

Results: The average age was 75.3 years and 70% were female. While mobility disability occurred more frequently than incident MCI, the subsequent risk of death was higher in participants who developed MCI alone compared to those who developed mobility disability alone (hazard ratio [HR] 1.70, p = 0.018). Of the participants who initially developed mobility disability, about half subsequently developed MCI that doubled their risk of death (HR 2.17, p < 0.001). By contrast, over two-third who developed MCI subsequently developed mobility disability, which did not further increase their risk of death.

Conclusion: Mobility disability occurs more frequently in community-dwelling older adults, but MCI is more strongly associated with mortality.
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http://dx.doi.org/10.1159/000499334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698403PMC
June 2020

Progressive parkinsonism in older adults is related to the burden of mixed brain pathologies.

Neurology 2019 04 20;92(16):e1821-e1830. Epub 2019 Mar 20.

From the Rush Alzheimer's Disease Center (A.S.B., L.Y., R.S.W., S.E.L., S.N., L.L.B., J.A.S., D.A.B.), and Departments of Neurological Sciences (A.S.B., L.Y., R.S.W., S.E.L., J.A.S., D.A.B.), Behavioral Sciences (R.S.W., L.L.B.), and Pathology (Neuropathology) (S.N., J.A.S.), Rush University Medical Center, Chicago, IL; Departments of Neurology, Molecular and Human Genetics, Neuroscience, and Program in Developmental Biology (J.M.S.), Baylor College of Medicine, Houston, TX; and Jan and Dan Duncan Neurological Research Institute (J.M.S.), Texas Children's Hospital, Houston.

Objective: To examine whether indices of Parkinson disease (PD) pathology and other brain pathologies are associated with the progression of parkinsonism in older adults.

Methods: We used data from decedents who had undergone annual clinical testing prior to death and structured brain autopsy. Parkinsonism was based on assessment with a modified Unified Parkinson's Disease Rating Scale and a clinical diagnosis of PD was based on medical history. We used a series of mixed-effects models controlling for age and sex to investigate the association of PD pathology (nigral neuronal loss and Lewy bodies) and indices of 8 other brain pathologies with the progression of parkinsonism prior to death.

Results: During an average of 8.5 years' follow-up, more than half (771/1,430, 53.9%) developed parkinsonism proximate to death. On average, parkinsonism was progressive (estimate 0.130, SE 0.005, < 0.001) in all older adults, but more rapid in adults with a clinical diagnosis of PD (n = 52; 3.6%) (estimate 0.066, SE 0.021, < 0.001). Progression of parkinsonism was more rapid in adults with PD pathology (estimate 0.087, SE 0.013, < 0.001). Alzheimer disease and several cerebrovascular pathologies were all independently associated with more rapid progression (all values <0.05). The association between a higher person-specific weighted pathology score and more rapidly progressive parkinsonism did not differ between individuals with and without a clinical diagnosis of PD (estimate 0.003, SE 0.047, = 0.957).

Conclusion: The rate of progressive parkinsonism in older adults with and without a clinical diagnosis of PD is related to the burden of mixed brain pathologies.
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http://dx.doi.org/10.1212/WNL.0000000000007315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550497PMC
April 2019

Brain IGFBP-5 modifies the relation of depressive symptoms to decline in cognition in older persons.

J Affect Disord 2019 05 8;250:313-318. Epub 2019 Mar 8.

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

Background: Brain proteins, including Insulin-like Growth Factor Binding Protein 5 (IGFBP-5), have been associated with cognitive dysfunction in aging. Mechanisms linking depression with cognition are poorly understood. We hypothesize that the association of depressive symptoms with cognition is mediated or modified by brain proteins.

Methods: IGFBP-5, HSPB2, AK4, ITPK1 and PLXNB1 were measured in dorsolateral prefrontal cortex in 1057 deceased participants, who underwent annual assessments of depressive symptoms and cognition for a mean of 8.9 years. The average number of depressive symptoms per year before a dementia diagnosis was calculated for each person.

Results: A one standard deviation above the mean IGFBP-5 was associated with a 14% higher odds of having more depressive symptoms (p < 0.031). Higher IGFBP-5 was associated with faster decline in global cognition (p < 0.001) and five cognitive domains (p < 0.008), controlling for depressive symptoms. IGFBP-5 moderated the association of depressive symptoms with decline in global cognition (p = 0.045). IGFBP-5 mediated ten percent or less of the total effect of depressive symptoms on decline in global cognition and the cognitive domains (p > 0.070).

Limitations: Participants were volunteers and self-selection bias limits the generalizability of our findings. In addition, we used self-reported data on depressive symptoms. However, we also used data on depression medications as sensitivity analyses to confirm findings.

Conclusions: In old age, brain IGFBP-5 is associated with depressive symptoms and cognition. The association of depressive symptoms with cognitive decline is conditional on IGFBP-5.
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http://dx.doi.org/10.1016/j.jad.2019.03.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530787PMC
May 2019

Associations of amygdala volume and shape with transactive response DNA-binding protein 43 (TDP-43) pathology in a community cohort of older adults.

Neurobiol Aging 2019 05 31;77:104-111. Epub 2019 Jan 31.

Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Diagnostic Radiology, Rush University Medical Center, Chicago, IL, USA. Electronic address:

Transactive response DNA-binding protein 43 (TDP-43) pathology is common in old age and is strongly associated with cognitive decline and dementia above and beyond contributions from other neuropathologies. TDP-43 pathology in aging typically originates in the amygdala, a brain region also affected by other age-related neuropathologies such as Alzheimer's pathology. The purpose of this study was two-fold: to determine the independent effects of TDP-43 pathology on the volume, as well as shape, of the amygdala in a community cohort of older adults, and to determine the contribution of amygdala volume to the variance of the rate of cognitive decline after accounting for the contributions of neuropathologies and demographics. Cerebral hemispheres from 198 participants of the Rush Memory and Aging Project and the Religious Orders Study were imaged with MRI ex vivo and underwent neuropathologic examination. Measures of amygdala volume and shape were extracted for all participants. Regression models controlling for neuropathologies and demographics showed an independent negative association of TDP-43 with the volume of the amygdala. Shape analysis revealed a unique pattern of amygdala deformation associated with TDP-43 pathology. Finally, mixed-effects models showed that amygdala volume explained an additional portion of the variance of the rate of decline in global cognition, episodic memory, semantic memory, and perceptual speed, above and beyond what was explained by demographics and neuropathologies.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486844PMC
May 2019

Postmortem neurodegenerative markers and trajectories of decline in cognitive systems.

Neurology 2019 02 23;92(8):e831-e840. Epub 2019 Jan 23.

From the Departments of Neurological Sciences (R.S.W., J.Y., L.Y., S.E.L., A.W.C., J.A.S., D.A.B.), Behavioral Sciences (R.S.W., P.A.B.), and Pathology (J.A.S.), Rush University Medical Center, Rush Alzheimer's Disease Center, Chicago, IL.

Objective: To assess whether neurodegenerative pathologies are differentially related to trajectories of change in different cognitive abilities.

Methods: At annual intervals for up to 21 years, 915 older participants in a longitudinal clinical-pathologic cohort study completed a battery of 15 tests from which previously established composite measures of episodic memory, semantic memory, working memory, and perceptual speed were derived. At death, they underwent a neuropathologic examination to quantify Alzheimer disease pathology, Lewy bodies, transactive response DNA-binding protein 43 (TDP-43) pathology, and hippocampal sclerosis plus multiple markers of cerebrovascular disease. Time-varying effect models were used to assess change over time in the relation of neuropathologic markers to cognitive trajectories.

Results: Controlling for pathology, decline in perceptual speed was evident about 15 years before death; modest decline in semantic and working memory occurred later; and there was little change in episodic memory. Each neurodegenerative marker was associated with lower episodic memory function beginning about 10 to 16 years before death. As time before death decreased, Alzheimer disease pathology, Lewy bodies, and hippocampal sclerosis were associated with impairment in other cognitive domains but the association of TDP-43 pathology with cognition continued to be mainly confined to episodic memory.

Conclusions: The results suggest that episodic memory impairment is an early sign of multiple neurodegenerative conditions, which primarily differ in their associations with other cognitive systems.
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http://dx.doi.org/10.1212/WNL.0000000000006949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396970PMC
February 2019
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