Showing papers by "Lisa L. Barnes published in 2018"

Analysis of shared heritability in common disorders of the brain

Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Religious Orders Study and Rush Memory and Aging Project.

Abstract: Background The Religious Orders Study and Rush Memory and Aging Project are both ongoing longitudinal clinical-pathologic cohort studies of aging and Alzheimer's disease (AD). Objectives To summarize progress over the past five years and its implications for understanding neurodegenerative diseases. Methods Participants in both studies are older adults who enroll without dementia and agree to detailed longitudinal clinical evaluations and organ donation. The last review summarized findings through the end of 2011. Here we summarize progress and study findings over the past five years and discuss new directions for how these studies can inform on aging and AD in the future. Results We summarize 1) findings on the relation of neurobiology to clinical AD; 2) neurobiologic pathways linking risk factors to clinical AD; 3) non-cognitive AD phenotypes including motor function and decision making; 4) the development of a novel drug discovery platform. Conclusion Complexity at multiple levels needs to be understood and overcome to develop effective treatments and preventions for cognitive decline and AD dementia.

Understanding the impact of sex and gender in Alzheimer's disease: A call to action

Abstract: Introduction Precision medicine methodologies and approaches have advanced our understanding of the clinical presentation, development, progression, and management of Alzheimer's disease (AD) dementia. However, sex and gender have not yet been adequately integrated into many of these approaches. Methods The Society for Women's Health Research Interdisciplinary Network on AD, comprised of an expert panel of scientists and clinicians, reviewed ongoing and published research related to sex and gender differences in AD. Results The current review is a result of this Network's efforts and aims to: (1) highlight the current state-of-the-science in the AD field on sex and gender differences; (2) address knowledge gaps in assessing sex and gender differences; and (3) discuss 12 priority areas that merit further research. Discussion The exclusion of sex and gender has impeded faster advancement in the detection, treatment, and care of AD across the clinical spectrum. Greater attention to these differences will improve outcomes for both sexes.

Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau.

Abstract: Importance The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association betweenAPOEalleles and markers of AD neuropathology in a sex-specific manner. Objective To evaluate sex differences in the association betweenAPOEand markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy. Design, Setting, and Participants This multicohort study selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals and included population-based and clinic-based samples. Inclusion in our analysis requiredAPOEgenotype data and either CSF data available for analysis. Analyses began on November 6, 2017, and were completed on December 20, 2017. Main Outcomes and Measures Biomarker analyses included levels of β-amyloid 42, total tau, and phosphorylated tau measured in CSF. Autopsy analyses included Consortium to Establish a Registry for Alzheimer’s Disease staging for neuritic plaques and Braak staging for neurofibrillary tangles. Results Of the 1798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1690 were white, and the mean (SD) age was 70 [9] years. Of the 5109 patients in the autopsy cohort, 2813 were women, 4953 were white, and the mean (SD) age was 84 (9) years. After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction betweenAPOE-e4 and sex on CSF total tau (β = 0.41; 95% CI, 0.27-0.55;P Conclusions and Relevance We provide robust evidence of a stronger association betweenAPOE-e4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly,APOE-e4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association betweenAPOEand CSF measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggest thatAPOEmay modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.

Cognitive Aging in Black and White Americans: Cognition, Cognitive Decline, and Incidence of Alzheimer Disease Dementia

Abstract: Background:US-based studies have reported that older blacks perform worse than older whites on cognitive tests and have higher risk of Alzheimer disease dementia (AD). It is unclear whether these findings reflect differences in cognitive decline.Methods:The Chicago Health and Aging Project followed

Nutrients and bioactives in green leafy vegetables and cognitive decline: Prospective study.

Abstract: Objective To increase understanding of the biological mechanisms underlying the association, we investigated the individual relations to cognitive decline of the primary nutrients and bioactives in green leafy vegetables, including vitamin K (phylloquinone), lutein, β-carotene, nitrate, folate, kaempferol, and α-tocopherol. Methods This was a prospective study of 960 participants of the Memory and Aging Project, ages 58–99 years, who completed a food frequency questionnaire and had ≥2 cognitive assessments over a mean 4.7 years. Results In a linear mixed model adjusted for age, sex, education, participation in cognitive activities, physical activities, smoking, and seafood and alcohol consumption, consumption of green leafy vegetables was associated with slower cognitive decline; the decline rate for those in the highest quintile of intake (median 1.3 servings/d) was slower by β = 0.05 standardized units ( p = 0.0001) or the equivalent of being 11 years younger in age. Higher intakes of each of the nutrients and bioactives except β-carotene were individually associated with slower cognitive decline. In the adjusted models, the rates for the highest vs the lowest quintiles of intake were β = 0.02, p = 0.002 for phylloquinone; β = 0.04, p = 0.002 for lutein; β = 0.05, p p = 0.02 for α-tocopherol; β = 0.04, p = 0.002 for nitrate; β = 0.04, p = 0.003 for kaempferol; and β = 0.02, p = 0.08 for β-carotene. Conclusions Consumption of approximately 1 serving per day of green leafy vegetables and foods rich in phylloquinone, lutein, nitrate, folate, α-tocopherol, and kaempferol may help to slow cognitive decline with aging.

Late-life blood pressure association with cerebrovascular and Alzheimer disease pathology

Abstract: Objective To examine associations of average and change in late-life blood pressure (BP) with cerebrovascular and Alzheimer disease (AD) neuropathology in a large group of decedents followed longitudinally in vivo. Methods This clinical-pathologic study was derived from prospective, community-based cohort studies of aging with similar design and data collection. Measurements of systolic BP (SBP) and diastolic BP (DBP) were obtained annually (mean follow-up 8 years, SD = 4.8). Postmortem neuropathologic evaluations documented diseases of aging. Using regression analyses, we examined associations of average and decline in late-life SBP, and separately in DBP, with neuropathology. Results In 1,288 persons (mean age at death = 88.6 years; 65% women), the mean standardized person-specific SBP across the study was 134 (SD = 13) and DBP was 71 (SD = 8) mm Hg. The odds of brain infarcts were increased for participants with a higher mean SBP. Specifically, a person with a 1 SD SBP above the mean (147 vs 134 mm Hg) would have a 46% increased odds of having one or more infarcts, and an increased odds of gross infarct (46%) and microinfarct (36%). Furthermore, a more rapidly declining SBP slope over time increased the odds of one or more infarcts. Mean DBP, not slope, was related to brain infarcts. AD pathology analyses showed an association of a higher mean SBP with higher number of tangles ( p = 0.038) but not plaques or other pathology (all p > 0.06). Changes in BP were not significantly related to AD pathology. Conclusions Higher average late-life SBP and DBP, and independently a faster decline in SBP, are associated with increasing number of brain infarcts, including gross and microinfarcts. We found some evidence for a relation of SBP with AD, specifically tangles. Both average and decline in BP are related to brain disease.

Body Mass Index and Decline in Cognitive Function in Older Black and White Persons

Abstract: Background While body mass index (BMI) is higher in black compared to white persons, little is known about BMI and change in cognition in cohorts with a large proportion of blacks. We examine relations of BMI with decline in global cognition and five cognitive domains, in older blacks and whites, and determine whether relations differ by race. Methods Participants were 2,134 persons without baseline dementia (33% black; 75% women; mean age =77.9 [range 53-100] and education = 14.7 years, Mini-Mental State Examination = 28.0), enrolled in one of two longitudinal, community-based cohort studies of aging (Minority Aging Research Study; Rush Memory and Aging Project). Summary scores of global cognition and five domains were based on 19 neuropsychological tests administered annually. Mixed-effects models, controlling for age, sex, education, and race, were used to examine the relation of baseline BMI to change in cognition. Results Baseline BMI = 28.4 units (30.3 in blacks [95% confidence interval (CI): 27.2-27.7]; 27.4 in whites [95% CI: 29.8-30.7]). During a mean annual follow-up of 6 years (SD = 4), lower baseline BMI was related to faster decline in global cognition (p = .002), and semantic memory (p .08). The relationship of BMI with change in cognition was not modified by race (all p > .09). Conclusions Late-life lower BMI relates to faster rates of decline in cognition, specifically semantic memory and episodic memory, in both blacks and whites. The effect of BMI on cognition appears to be similar in both racial groups.

Seasonal plasticity of cognition and related biological measures in adults with and without Alzheimer disease: Analysis of multiple cohorts.

Abstract: Background There are few data concerning the association between season and cognition and its neurobiological correlates in older persons-effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects. Methods and findings We analyzed data from 3,353 participants from 3 observational community-based cohort studies of older persons (the Rush Memory and Aging Project [MAP], the Religious Orders Study [ROS], and the Minority Aging Research Study [MARS]) and 2 observational memory-clinic-based cohort studies (Centre de Neurologie Cognitive [CNC] study at Lariboisiere Hospital and the Sunnybrook Dementia Study [SDS]). We performed neuropsychological testing and, in subsets of participants, evaluated cerebrospinal fluid AD biomarkers, standardized structured autopsy measures, and/or prefrontal cortex gene expression by RNA sequencing. We examined the association between season and these variables using nested multiple linear and logistic regression models. There was a robust association between season and cognition that was replicated in multiple cohorts (amplitude = 0.14 SD [a measure of the magnitude of seasonal variation relative to overall variability; 95% CI 0.07-0.23], p = 0.007, in the combined MAP, ROS, and MARS cohorts; amplitude = 0.50 SD [95% CI 0.07-0.66], p = 0.017, in the SDS cohort). Average composite global cognitive function was higher in the summer and fall compared to winter and spring, with the difference equivalent in cognitive effect to 4.8 years' difference in age (95% CI 2.1-8.4, p = 0.002). Further, the odds of meeting criteria for mild cognitive impairment or dementia were higher in the winter and spring (odds ratio 1.31 [95% CI 1.10-1.57], p = 0.003). These results were robust against multiple potential confounders including depressive symptoms, sleep, physical activity, and thyroid status and persisted in cases with AD pathology. Moreover, season had a marked effect on cerebrospinal fluid Aβ 42 level (amplitude 0.30 SD [95% CI 0.10-0.64], p = 0.003), which peaked in the summer, and on the brain expression of 4 cognition-associated modules of co-expressed genes (m6: amplitude = 0.44 SD [95% CI 0.21-0.65], p = 0.0021; m13: amplitude = 0.46 SD [95% CI 0.27-0.76], p = 0.0009; m109: amplitude = 0.43 SD [95% CI 0.24-0.67], p = 0.0021; and m122: amplitude 0.46 SD [95% CI 0.20-0.71], p = 0.0012), which were in phase or anti-phase to the rhythms of cognition and which were in turn associated with binding sites for several seasonally rhythmic transcription factors including BCL11A, CTCF, EGR1, MEF2C, and THAP1. Limitations include the evaluation of each participant or sample once per annual cycle, reliance on self-report for measurement of environmental and behavioral factors, and potentially limited generalizability to individuals in equatorial regions or in the southern hemisphere. Conclusions Season has a clinically significant association with cognition and its neurobiological correlates in older adults with and without AD pathology. There may be value in increasing dementia-related clinical resources in the winter and early spring, when symptoms are likely to be most pronounced. Moreover, the persistence of robust seasonal plasticity in cognition and its neurobiological correlates, even in the context of concomitant AD pathology, suggests that targeting environmental or behavioral drivers of seasonal cognitive plasticity, or the key transcription factors and genes identified in this study as potentially mediating these effects, may allow us to substantially improve cognition in adults with and without AD.

Memory complaints, dementia, and neuropathology in older blacks and whites.

Abstract: OBJECTIVE To determine relationships of memory complaints to cognitive function and decline, incident dementia, and neurodegenerative and other neuropathologies, as well as the population-attributable risk for dementia in older black and white persons. METHODS A total of 4,015 community-based persons (28% black; 74% women; mean baseline age = 78 years) were enrolled in 1 of 4 longitudinal cohort studies, and another 2,937 in a population-based cohort. Memory scores, assessed using 2 questions (5-point Likert scales) were categorized as complaints present or absent. Global cognition and 5 cognitive domains were derived from annual neuropsychological tests. Dementia was assessed from these tests and additional data. Neuropathologic data were available for 1,350 deceased subjects with brain autopsies. Regression and mixed effects models were used to examine relationships of memory complaints to cognition and neuropathology. RESULTS Baseline memory complaints (n = 1,310; 33% of 4,015) were associated with lower cognition and faster decline in all domains (global score estimate = -0.032, standard error = 0.004, p < 0.0001), during a mean follow-up of 6 (standard deviation = 2) years. Persons with memory complaints had higher dementia risk (hazard ratio = 1.64, 95% confidence interval [CI] = 1.42-1.89) and odds of pathologic Alzheimer disease (odds ratio [OR] = 1.96, 95% CI = 1.51-2.54), neocortical Lewy bodies (OR = 2.47, 95% CI = 1.54-3.96), and other neurodegenerative pathologies. Results for dementia risk were similar among blacks and whites. Among 2,937 older persons in a population-based cohort with similar data, the population-attributable risk for incident dementia due to memory complaints was 14.0% (95% CI = 2.6-23.0), and did not vary between the black and white groups. INTERPRETATION Memory complaints are common in older black and white persons, and relate to cognitive decline, dementia risk, and neurodegenerative pathologies. Ann Neurol 2018;83:718-729.

Secular Trends in Cognitive Performance in Older Black and White U.S. Adults, 1993-2012: Findings From the Chicago Health and Aging Project.

Abstract: Objective To characterize secular trends from 1993 to 2012 in cognitive performance using a cohort of older black and white U.S. adults, and compare trends by race. Method Our data come from 8,906 participants of the Chicago Health and Aging Project (CHAP), a longitudinal, population-based cohort (age ≥ 67, 60% black). Participants underwent cognitive assessments in six 3-year study cycles from 1993 to 1996 through 2010 to 2012. We computed 3 measures of cognitive performance: global cognition, episodic memory, and perceptual speed. Results Mean performance in terms of global cognitive score followed a secular pattern of modest decline over the 6 study cycles. The trend was most pronounced for perceptual speed. Mean scores among black participants were consistently lower than those for whites; these disparities in mean performance narrowed over time, especially on perceptual speed, but appeared to widen at the last cycle. Global scores among the upper quartile of performers rose slightly, but scores among the lowest quartile of performers dropped precipitously. Discussion Between 1993 and 2012, secular trends in cognitive performance in this established cohort did not follow a clear pattern of improvement, contrasting with previous research. But patterns differed by cognitive domain, performance level, and race.

Blood pressure and risk of incident Alzheimer's disease dementia by antihypertensive medications and APOE ε4 allele

Abstract: Objective To examine the association of blood pressure (BP) with incident Alzheimer's disease (AD) dementia. Methods This work is based on a longitudinal, cohort study of 18 years, the Chicago Health and Aging Project (CHAP) performed in 2,137 participants (55% black) with systolic BP measured around 8.1 years before incident AD dementia. Results The association of BP with risk of AD dementia was U-shaped, with the lowest risks of AD dementia near the center of the systolic BP (SBP) and diastolic BP (DBP) distributions, and modestly elevated risk at lower BPs, and greater risk at higher BPs. The degree of U-shape and the range of lowest risk (threshold ranges) varied with antihypertensive medication use and presence of the APOE e4 allele. The U-shape was most prominent for the subgroup not taking antihypertensive medications and having an APOE e4 allele. At higher BPs, those having the APOE e4 allele and not receiving antihypertensive medication were at greater risk of AD dementia than other groups: The risk of incident AD dementia increased by 100% (relative risk [RR] = 2.00; 95% confidence interval [CI] = 1.70, 2.31) for every 10 mm Hg increase in SBP above 140 mm Hg. For DBP, the risk of incident of AD dementia increased by 57% (RR = 1.57; 95% CI = 1.33, 1.86) for every 5 mm Hg increase in DBP above 76 mm Hg. Interpretation The BP risk of AD dementia association is U-shaped, with elevated risk at lower and higher BPs. People having the APOE e4 allele and not receiving antihypertensive medication with higher BPs have notably elevated risk of AD dementia. Ann Neurol 2018;83:935-944.

APOE genotypes as a risk factor for age-dependent accumulation of cerebrovascular disease in older adults.

Abstract: Introduction Apolipoprotein E (APOE) is a susceptibility gene for late-onset Alzheimer's disease neuropathology; less is known about the relationship between APOE and cerebrovascular disease (CVD) neuropathology. Methods We investigated associations of APOE status with arteriolosclerosis, macroinfarcts and microinfarcts, and atherosclerosis in 1383 adults (65.9–108.2 years at death) with and without dementia. Excluding e2/e4 carriers, multivariable regressions for each CVD-related neuropathology compared e4 and e2 carriers to e3/e3 carriers adjusting for confounders including age and Alzheimer's neuropathology. Results Three hundred forty-two individuals (24.7%; ∼87.7 years at death; 39.9% nondemented) were e3/e4 or e4/e4, and 180 (13.0%; ∼89.9 years at death; 66.6% nondemented) were e2/e3 or e2/e2. e4 carriers had higher odds of macroinfarcts (odds ratio = 1.41, 95% confidence interval: 1.02–1.94, P = .03), whereas e2 carriers had higher odds of moderate-to-severe arteriolosclerosis (odds ratio = 1.68, 95% confidence interval: 1.15–2.45, P = .006) compared to e3/e3 carriers. Age-stratified analyses suggested that these relationships were driven by e4 carriers Discussion APOE differentially affects type and timing of CVD-related neuropathology.

Effects of Fish Oil on HIV-Related Inflammation and Markers of Immunosenescence: A Randomized Clinical Trial.

Abstract: Objective: To explore the safety and efficacy of fish oil to modulate parameters of inflammation and immunosenescence in HIV-infected older adults. Design: This study uses a randomized, controlled, double-blind clinical trial. Setting: The study was conducted in an outpatient HIV/AIDS clinic in a large urban Midwestern city in the United States. Subjects: A total of 37 clinically stable HIV-infected adults between the ages of 40 and 70 years of age participated. Interventions: Fish oil 1.6 g/day was administered for 12 weeks or placebo. Outcome measures: Inflammatory cytokine production, surface markers of immunosenescence, and adverse events were measured. Results: After 12 weeks of supplementation, there were no significant differences between the treatment and control groups on any measures of inflammation or immunosenescence in both CD4+ and CD8+ T lymphocytes. More participants in the treatment group reported adverse gastrointestinal events compared with the control group. Conclusions: A 12-...

Neopterin is associated with hippocampal subfield volumes and cognition in HIV

Abstract: Objective HIV infection sets off an immediate immune response and inflammatory cascade that can lead to neuronal injury and cognitive impairment, but the relationship between immune markers, regional brain volumes, and cognition remains understudied in HIV-infected adults. Methods Cross-sectional associations were examined between serum immune markers of activation (neopterin) and inflammation (interleukin [IL]-1β, IL-6, tumor necrosis factor alpha, and C-reactive protein) with regional brain volumes (cortical, subcortical, total gray matter, hippocampus, and subfields) and cognition in 66 HIV-infected, virally suppressed, adults who underwent 3.0-T MRI as part of the Research Core of the Rush Center of Excellence on Disparities in HIV and Aging. Immune markers were assayed from frozen plasma, values were entered into linear regression models as predictors of regional brain volumes, and interactive effects of immune response and regional brain volumes on cognition were examined. Results No inflammatory marker was associated with any regional brain volume. Higher neopterin level was associated with lower total hippocampal, presubiculum, and cornu ammonis (CA) subfield volumes. Higher neopterin level and lower total hippocampal volume were independently associated with lower episodic memory, and neopterin level fully mediated the effect of hippocampal atrophy on episodic memory. Higher neopterin levels were associated with lower presubiculum, CA1, and CA4/dentate volumes and lower semantic memory, working memory, and global cognition. Conclusion Immune activation in response to HIV infection, measured by neopterin, has a deleterious and targeted effect on regional brain structure, which can be visualized with clinically available MRI measures of hippocampus and its subfields, and this effect is associated with lower cognitive function.

Terminal decline of episodic memory and perceptual speed in a biracial population.

Abstract: We compared trajectories of terminal cognitive decline in older Black (n = 3372) and White (n = 1756) persons from a defined population who completed tests of episodic memory and perceptual speed at 3-year intervals for up to 18 years. During a mean of 9.9 years of observation, 1608 Black persons and 902 White persons died. Preterminal decline of episodic memory did not differ by race. Terminal episodic memory decline began earlier in Black persons (mean of 4.3 years before death) than in White persons (mean = 3.9 years) and progressed more slowly. By contrast, terminal decline of perceptual speed began earlier in White persons (mean = 5.0 years) than in Black persons (mean = 4.5 years). Rate of perceptual speed decline was more rapid in White persons than in Black persons in both the preterminal and terminal periods. The results indicate that terminal cognitive decline occurs in Black persons but suggest that the rate of cognitive decline during the terminal period is less rapid in Black persons than in White persons.

Antecedents and consequences of unawareness of memory impairment in dementia.

Abstract: OBJECTIVE To assess the prevalence, antecedents, and consequences of unawareness of memory impairment in dementia. METHOD Persons (n = 1,862) from a geographically defined community without dementia at enrollment subsequently underwent clinical classification (248 with dementia, 611 with mild cognitive impairment, 1,003 with no cognitive impairment), memory testing, and self-appraisal of memory. Memory performance was regressed on self-appraised memory, and the residuals served as an index of memory awareness. After clinical classification, participants completed brief cognitive testing at 3-year intervals for up to 15 years. RESULTS When unawareness was defined as a score at or below thresholds ranging from the 15th to 25th percentiles, it was more common in dementia (67%-83%) and mild cognitive impairment (15%-33%) than in no cognitive impairment (2%-6%; all p < .001). A continuous measure of awareness (M = 0.00, SD = 0.61) was reduced by 0.37-unit in mild cognitive impairment (SE = 0.04, p < .001) and 1.04-unit in dementia (SE = 0.06), p < .001) compared with those without cognitive impairment, and these associations were weaker in Black persons than White persons (estimate for dementia by race = 0.37, SE = 0.12, p = .003; estimate for mild cognitive impairment by race = 0.30, SE = 0.08, p < .001). Higher premorbid neuroticism was associated with better memory awareness in dementia. Higher memory awareness was not related to mortality in mild cognitive impairment or dementia but had a marginal association with slower cognitive decline in mild cognitive impairment. CONCLUSIONS Unawareness of memory impairment is a common manifestation of dementia, particularly in White persons, but is not strongly related to adverse disease outcomes. (PsycINFO Database Record (c) 2018 APA, all rights reserved).