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1.
Ann Neurol ; 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144793

RESUMO

OBJECTIVE: To characterize trajectories of normative cognitive aging. METHODS: Older persons without dementia at study enrollment (n = 1,010) had annual cognitive testing for up to 24 years (mean = 9.9 years, standard deviation = 5.0), died, and underwent a neuropathologic examination to quantify 9 postmortem markers of common neurodegenerative and cerebrovascular conditions. To accommodate the heterogeneity in cognitive trajectories, we used functional mixed effects models, which allow individuals to have different patterns of cognitive decline under a unified model structure. RESULTS: In a functional mixed effects model, postmortem markers (Alzheimer disease pathology, Lewy bodies, transactive response DNA-binding protein 43 pathology, hippocampal sclerosis, atherosclerosis, gross infarcts) were associated with global cognitive decline. Residual global cognitive decline after adjustment for neuropathologic burden was weakly related to age at death; it occurred in only about one-third of participants, mostly proximate to death. Results were comparable after eliminating the initial cognitive assessments to minimize retest learning or controlling for frailty proximate to death. Analyses were also conducted with composite measures of episodic memory and perceptual speed. Residual decline not attributable to neuropathologic burden was confined to a subset for each outcome and was most evident proximate to death. Age at death was unrelated to residual decline in episodic memory but was related to residual decline in perceptual speed. INTERPRETATION: Late life cognitive loss mainly reflects non-normative pathologic and mortality-related processes rather than normative age-related processes. ANN NEUROL 2020.

2.
J Am Geriatr Soc ; 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32092157

RESUMO

BACKGROUND/OBJECTIVES: Decision making in financial and healthcare matters is of critical importance for well-being in old age. Preliminary work suggests racial differences in decision making; however, the factors that drive racial differences in decision making remain unclear. We hypothesized literacy, particularly financial and health literacy, mediates racial differences in decision making. DESIGN: Community-based epidemiologic cohort study. SETTING: Communities in northeastern Illinois. PARTICIPANTS: Nondemented Black participants (N = 138) of the Rush Alzheimer's Disease Center Minority Aging Research Study and the Rush Memory and Aging Project who completed decision-making and literacy measures were matched to White participants (N = 138) according to age, education, sex, and global cognition using Mahalanobis distance (total N = 276). MEASUREMENTS: All participants completed clinical assessments, a decision-making measure that resembles real-world materials relevant to finance and healthcare, and a financial and health literacy measure. Regression models were used to examine racial differences in decision making and test the hypothesis that literacy mediates this association. In secondary analyses, we examined the impact of literacy in specific domains of decision making (financial and healthcare). RESULTS: In models adjusted for age, education, sex, and global cognition, older Black adults performed lower than older White adults on literacy (ß = -8.20; SE = 1.34; 95% CI = -10.82 to -5.57; P < .01) and separately on decision making (ß = -.80; SE = .23; 95% CI = -1.25 to -.34; P < .01). However, when decision making was regressed on both race and literacy, the association of race was attenuated and became nonsignificant (ß = -.45; SE = .24; 95% CI = -.93 to .02; P = .06), but literacy remained significantly associated with decision making (ß = .04; SE = .01; 95% CI = .02-.06; P < .01). In secondary models, a similar pattern was observed for both financial and healthcare decision making. CONCLUSIONS: Racial differences in decision making are largely mediated by literacy. These findings suggest that efforts to improve literacy may help reduce racial differences in decision making and improve health and well-being for diverse populations.

3.
Alzheimers Dement ; 16(1): 209-218, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914231

RESUMO

INTRODUCTION: Reduced hippocampal volume is associated with late-life cognitive decline, but prior studies have not determined whether this association persists after accounting for Alzheimer's disease (AD) and other neuropathologies. METHODS: Participants were 531 deceased older adults from community-based cohort studies of aging who had undergone annual cognitive evaluations. At death, brain tissue underwent neuropathologic examination and magnetic resonance imaging (MRI). Linear mixed models examined whether hippocampal volume measured via MRI accounted for variation in decline rate of global cognition and five cognitive domains, above and beyond neuropathologic indices. RESULTS: Demographics and indices of AD, cerebrovascular disease, Lewy body disease, hippocampal sclerosis, TDP-43, and atherosclerosis accounted for 42.6% of the variation in global cognitive decline. Hippocampal volume accounted for an additional 5.4% of this variation and made similar contributions in four of the five cognitive domains. DISCUSSION: Hippocampal volume is associated with late-life cognitive decline, above and beyond contributions from common neuropathologic indices.

4.
Neurology ; 94(1): e42-e50, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31792096

RESUMO

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.

5.
J Sleep Res ; 29(1): e12889, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31257666

RESUMO

The high prevalence of obstructive sleep apnea has led to increasing interest in ambulatory diagnosis. The SleepMinder™ (SM) is a novel non-contact device that employs radiofrequency wave technology to assess the breathing pattern, and thereby estimate obstructive sleep apnea severity. We assessed the performance of SleepMinder™ in the home diagnosis of obstructive sleep apnea. One-hundred and twenty-two subjects were prospectively recruited in two protocols, one from an unselected sleep clinic cohort (n = 67, mean age 51 years) and a second from a hypertension clinic cohort (n = 55, mean age 58 years). All underwent 7 consecutive nights of home monitoring (SMHOME ) with the SleepMinder™ as well as inpatient-attended polysomnography in the sleep clinic cohort or cardiorespiratory polygraphy in the hypertension clinic cohort with simultaneous SleepMinder™ recordings (SMLAB ). In the sleep clinic cohort, median SMHOME apnea-hypopnea index correlated significantly with polysomnography apnea-hypopnea index (r = .68; p < .001), and in the hypertension clinic cohort with polygraphy apnea-hypopnea index (r = .7; p < .001). The median SMHOME performance against polysomnography in the sleep clinic cohort showed a sensitivity and specificity of 72% and 94% for apnea-hypopnea index ≥ 15. Device performance was inferior in females. In the hypertension clinic cohort, SMHOME showed a 50% sensitivity and 72% specificity for apnea-hypopnea index ≥ 15. SleepMinder™ classified 92% of cases correctly or within one severity class of the polygraphy classification. Night-to-night variability in home testing was relatively high, especially at lower apnea-hypopnea index levels. We conclude that the SleepMinder™ device provides a useful ambulatory screening tool, especially in a population suspected of obstructive sleep apnea, and is most accurate in moderate-severe obstructive sleep apnea.

6.
Neurology ; 94(2): e142-e152, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31757868

RESUMO

OBJECTIVE: To investigate the contribution of Alzheimer disease (AD) vs non-AD neuropathologies to hippocampal atrophy. METHODS: The Religious Orders Study and Rush Memory and Aging Project are clinicopathologic cohort studies of aging. The current study included 547 participants who had undergone brain autopsy and postmortem hippocampal volume measurement by November 1, 2018. Hippocampal volume was measured with postmortem MRI via a 3D region of interest applied to the hippocampal formation. Neuropathologies were measured via uniform structured evaluations. Linear regression analyses estimated the proportion of variance of hippocampal volume attributable to AD and non-AD neuropathologies. RESULTS: The average age at death was 90 years, and the average hippocampal volume was 2.1 mL. AD, transactive response DNA-binding protein 43 (TDP), hippocampal sclerosis (HS), and atherosclerosis were associated with hippocampal volume. After demographics and total hemisphere volume were controlled for, 7.0% of the variance (95% bootstrapped confidence interval [CI] 4.3%-10.5%) of hippocampal volume was attributable to AD pathology. TDP/HS explained an additional 4.5% (95% CI 2.2%-7.6%). Among individuals with Alzheimer dementia (n = 232), 3.1% (95% CI 0.6%-7.7%) of the variance was attributable to AD pathology, and TDP/HS explained an additional 6.1% (95% CI 2.2%-11.6%). Among those without Alzheimer dementia (n = 307), 3.2% (95% CI 0.9%-7.3%) of the variance was attributable to AD pathology, and TDP/HS explained an additional 1.1%, which did not reach statistical significance. Lewy bodies and vascular diseases had modest contribution to the variance of hippocampal volume. CONCLUSIONS: Both AD and TDP/HS contribute to hippocampal volume loss in older-old persons, with TDP/HS more strongly associated with hippocampal volume than AD in Alzheimer dementia.

7.
J Hypertens ; 38(1): 59-64, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31503136

RESUMO

OBJECTIVES: Decision making, key to successful aging, has implications for financial success, physical health, and well being. While poor decision making has been linked with increased risk of mortality, age-related cognitive decline, and dementia, less is known regarding its associations with chronic disease indicators. We investigated the associations of decision making with blood pressure (BP) values [i.e., SBP, mean arterial pressure (MAP), and pulse pressure (PP), separately] in a community-based cohort study of aging. METHODS: Participants were 908 nondemented older adults (age ∼81 years; 75% women) from the Rush Memory and Aging Project. Decision making was measured using questions designed to simulate materials used in financial and healthcare settings in the real world and yielded a total score and domain-specific health and financial decision making scores. Two seated and one standing BP measurement were taken with all three contributing to average SBP, MAP that is, [SBP + (2 × DBP)]/3, and PP, that is, SBP - DBP. Participants were queried about hypertension status and antihypertension medications were visually inspected and coded. Participants also underwent medical history and cognitive assessments. RESULTS: In separate multivariable linear regression models, total decision making scores were inversely associated with SBP, MAP, and PP after adjusting for age, sex, education, antihypertension medication use, diabetes, and cumulative cardiovascular disease burden (P values = 0.03). Decision making remained associated with these BP values after additional adjustment for global cognition. CONCLUSION: Poorer decision making is associated with higher BP values in nondemented older adults.

8.
Neurobiol Aging ; 83: 145-149, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31732018

RESUMO

An accurate assessment of the impact of reserve on cognitive functioning in older individuals with brain pathology requires careful measurement of each and an assessment of the extent to which each influences the other. Studies to integrate information about molecular biology, neuropathology, behavioral aspects of cognitive decline, and cognitive resilience will be of particular importance. In addition, more work is needed to improve our understanding of the effect of systemic factors on brain health and function. It seems likely that, even in later life, the brain's plasticity may allow for a positive response to stimulation. The ultimate goal of this research is to create a validated set of variables and interventions-and to understand the biology underlying them-that are useful not only in describing an individual's cognitive state but also in identifying promising paths for treatment and prevention of cognitive decline.

9.
Ann Clin Transl Neurol ; 6(11): 2140-2149, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31568713

RESUMO

OBJECTIVE: Cognitive variability is a potentially important source of heterogeneity in longitudinal cognitive profiles. We examined the extent to which common age-related neuropathologies including Lewy bodies and Alzheimer's disease (AD) contribute to yearly variability in late life cognition. METHODS: Data came from 1321 community-dwelling older adults who were followed annually for up to 23 years, died and underwent brain autopsy. Cognition was assessed via a comprehensive testing battery. Uniform neuropathologic evaluations assessed burdens of Lewy bodies, AD, infarcts, TDP, hippocampal sclerosis, amyloid angiopathy, atherosclerosis, and arteriolosclerosis. Using mixed effects models, yearly variability in cognition, characterized as within-person variability of annual cognitive scores, was regressed on the nine neuropathologic indices. RESULTS: The average age of decedents was 90 years and 69% were female. At autopsy, about two thirds met the pathologic criteria for AD. Neocortical Lewy bodies were present in 13% of the individuals. Other neuropathologic conditions also were common. All neuropathologic indices except for microinfarcts were associated with cognitive decline. Individuals with neocortical Lewy bodies had almost twice the yearly variability in cognition compared to those without. Individuals with AD had about 70% more variability compared to those without. Yearly variability was present among persons with vascular diseases but to a lesser degree than neocortical Lewy bodies and AD. INTERPRETATION: Lewy body pathology is associated with pronounced variability in annual cognitive assessments but this finding is not unique to this pathology. Comparable variability is present among persons with AD pathology and to a lesser extent among persons with cerebrovascular pathologies.

10.
Ann Neurol ; 86(6): 844-852, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31614018

RESUMO

OBJECTIVE: To test the hypothesis that Alzheimer's disease and related neuropathologies contribute to the association between hospitalization and cognitive decline in old age. METHODS: As part of a longitudinal clinical-pathologic cohort study, 526 older persons (mean age at death = 90.9 years, 71% female) without dementia at baseline completed annual cognitive testing and were autopsied at death. Hospitalization information was obtained from linked Medicare claims records. Neuropathologic examination assessed ß-amyloid burden, tau tangle density, neocortical Lewy bodies, hippocampal sclerosis, chronic gross and microscopic cerebral infarcts, and transactive response DNA binding protein 43 kDa. RESULTS: Over a mean of 5.1 years, a total of 1,383 hospitalizations occurred, and the mean annual rate of hospitalization was 0.5 (standard deviation = 0.6, median = 0.4). Higher rate of hospitalization was not directly related to higher burden for any of the neuropathologic markers. Higher rate of hospitalization was associated with more rapid cognitive decline (estimate = -0.042, standard error [SE] = 0.012, p < 0.001), and after controlling for all 7 neuropathologic markers, the association was essentially the same (estimate = -0.040, SE = 0.013, p = 0.002). In a multivariable model with 3-way interactions of neuropathologic markers with hospitalization rate and time, the association between hospitalization rate and faster cognitive decline was greater in persons with more tangle pathology (estimate for interaction = -0.007, SE = 0.002, p = 0.002) and in persons with neocortical Lewy bodies (estimate for interaction = -0.117, SE = 0.042, p = 0.005). INTERPRETATION: Older persons with more hospitalizations experienced faster rates of cognitive decline, and this association was more pronounced in persons with more tau tangle density and with neocortical Lewy body pathologies. ANN NEUROL 2019;86:844-852.

11.
Aging Clin Exp Res ; 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273677

RESUMO

BACKGROUND: Health and financial literacy are central to older adults' well-being and financial standing, but the relation of literacy with mortality in advanced age remains unclear. AIMS: To determine whether lower literacy, as reflected in measures of total literacy and subscales of health and financial literacy, was associated with an increased risk of mortality. METHODS: Participants were 931 community-based older adults from the Rush Memory and Aging Project [age: mean (SD) = 80.9 (7.6), range 58.8-100.8], an ongoing, prospective observational cohort study of aging. Participants were without dementia at the time literacy was assessed. Proportional hazards models were used to determine whether literacy measures were associated with mortality. RESULTS: During up to 8 years of follow-up, 224 (24.1% of 931) participants died. In models that adjusted for age, sex, and education, lower total, health, and financial literacy were each associated with an increased risk of mortality (total literacy: HR = 1.020, 95% CI 1.010-1.031, p < 0.001; health literacy: HR = 1.015, 95% CI 1.008-1.023, p < 0.001; financial literacy: HR = 1.013, 95% CI 1.003-1.023, p = 0.014). These associations persisted after additionally adjusting for income and indices of health status; however, only the association of lower health literacy with mortality persisted after further adjusting for a robust measure of global cognition. DISCUSSION: We suspect that the current associations of lower literacy with mortality reflect the detrimental effect of early pathologic brain aging on literacy. CONCLUSIONS: Lower literacy, particularly lower health literacy, is associated with mortality in advanced age.

12.
Acta Neuropathol Commun ; 7(1): 104, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269985

RESUMO

Age is the most robust risk factor for Alzheimer's dementia, however there is little data on the relation of age to Alzheimer's disease (AD) and other common neuropathologies that contribute to Alzheimer's dementia. We use data from two community-based, clinical-pathologic cohorts to examine the association of age with AD and other common pathologies. Participants were 1420 autopsied individuals from the Religious Orders Study or Rush Memory and Aging Project who underwent annual clinical evaluations for diagnosis of Alzheimer's dementia, mild cognitive impairment (MCI), and level of cognition. The neuropathologic traits of interest were pathologic AD according to modified NIA-Reagan criteria, three quantitative measures of AD pathology (global AD pathology score, ß-amyloid load and PHFtau tangle density), macro- and micro-scopic infarcts, neocortical Lewy bodies, TDP-43 and hippocampal sclerosis. Semiparametric generalized additive models examined the nonlinear relationship between age and the clinical and pathological outcomes. The probability of Alzheimer's dementia at death increased with age such that for every additional year of age, the log odds of Alzheimer's dementia was 0.067 higher, corresponding to an odds ratio of 1.070 (p < 0.001). Results were similar for cognitive impairment and level of cognition. By contrast, a nonlinear relationship of age with multiple indices of AD pathology was observed (all ps < 0.05), such that pathologic AD reached a peak around 95 years of age and leveled off afterwards; the quantitative measures of AD pathology were significantly lower at ages above 95. The association of age with other neuropathologies was quite distinct from that of AD in that most increased with advancing age. AD pathology appears to peak around 95 years of age while other common pathologies continue to increase with age.

14.
Alzheimer Dis Assoc Disord ; 33(4): 315-320, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31305319

RESUMO

BACKGROUND: Low health and financial literacy may be an early behavioral manifestation of cognitive impairment, dementia, and accumulating Alzheimer pathology. However, there are limited studies investigating the behavioral features associated with hyperphosphorylated transactive response DNA-binding protein-43 (TDP-43), a common age-related pathology, and even fewer studies investigating the neurobiological basis underlying low literacy in aging. OBJECTIVE: To test the hypothesis that TDP-43 pathology is associated with lower literacy. MATERIALS AND METHODS: Data came from 293 community-based older persons who were enrolled in 2 ongoing studies of aging. Participants completed literacy and cognitive assessments, consented to brain donation, and underwent detailed neuropathologic evaluation for Alzheimer disease (AD) and TDP-43. Linear regression models assessed the association of TDP-43 with literacy after adjusting for demographics, and AD pathology. Posthoc pairwise comparisons examined whether the level of literacy differed by TDP-43 stage. RESULTS: TDP-43 pathology was associated with lower literacy (estimate=-3.16; SE=0.86; P<0.001), above and beyond demographics and AD pathology, and this association persisted even after additionally adjusting for global cognition (estimate=-1.53; SE=0.74; P=0.038). Further, literacy was lower among persons with neocortical TDP-43 pathology compared with those without TDP-43 pathology. CONCLUSIONS: TDP-43 pathology is associated with lower health and financial literacy in old age, above and beyond AD pathology.

15.
Neuropsychology ; 33(7): 975-985, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31204814

RESUMO

OBJECTIVE: Greater financial and health literacy are associated with better cognition; however, research suggests that some individuals exhibit differences, or discrepancies, in these abilities in old age. We investigated discrepancies between literacy and cognition and factors associated with such discrepancies in older adults without dementia. METHOD: Participants (N = 714; Mage = 81.4; education: M = 15.4; 75.4% female; 5.2% non-White) from the Rush Memory and Aging Project completed cognitive assessments and a financial and health literacy measure that yielded a total literacy score. Participants were characterized into three groups: (a) total literacy scores that are more than one standard deviation (1 SD) above cognition (L > C), (b) total literacy scores falling more than 1 SD below cognition (L < C), and (c) total literacy within 1 SD of cognition (L = C). Logistic regressions were employed to investigate associations between demographic and psychosocial variables and discrepancy group status. RESULTS: Of the 714 participants, 24% showed significant discrepancies. In fully adjusted models, in reference to the L = C group, male sex was associated with greater odds of being in the L > C group (odds ratio [OR] = 2.32, 95% CI [1.33, 4.03], p = .003) and lower odds of being in the L < C group (OR = 0.31, 95% CI [0.14, 0.66], p = .002), higher income was associated with lower odds of being in either discrepancy group (L < C OR = 0.87, 95% CI [0.79, 0.96], p = .004; L > C OR = 0.86, 95% CI [0.76, 0.96], p = .007), and higher trust was associated with lower odds of being in the L > C group (OR = 0.92, 95% CI [0.85, 0.99], p = .030). CONCLUSIONS: Findings support literacy and cognition as partially dissociable constructs and highlight important factors associated with discrepancies between literacy and cognition. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Cognição , Economia , Alfabetização em Saúde , Competência em Informação , Idoso , Idoso de 80 Anos ou mais , Envelhecimento Cognitivo , Feminino , Humanos , Renda , Masculino , Fatores Sexuais , Fatores Socioeconômicos , Confiança
16.
Brain ; 142(6): 1503-1527, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31039256

RESUMO

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-ß plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

17.
Am J Geriatr Psychiatry ; 27(8): 851-861, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30982702

RESUMO

OBJECTIVE: To test the hypothesis that late-life risk aversion is partly a prodromal sign of dementia. METHODS: The authors' design was a longitudinal clinical-pathologic cohort study. The setting included participants' residences in the Chicago area, and a total of 874 older persons without dementia were enrolled. At baseline, risk aversion was assessed with questions involving choices between certain smaller rewards and uncertain larger rewards. At annual intervals thereafter, participants underwent evaluations that included cognitive testing and diagnosis of mild cognitive impairment (MCI) and dementia. At death, a neuropathologic examination was done to quantify common pathologies linked to dementia. RESULTS: Risk aversion at study onset ranged from 0.05-0.91 (mean: 0.32, standard deviation: 0.31). During a mean of 4.6 years of follow-up, 123 (of 874) developed dementia. Higher risk aversion was associated with higher dementia incidence (hazard ratio [HR]: 2.08; 95% confidence interval: 1.18, 3.65) and more rapid decline in episodic (estimate: -0.062; standard error [SE]: 0.019; t [3677]: -3.33; p < 0.001) and semantic (estimate: -0.039; SE: 0.015; t [3655]: -2.61; p = 0.009) memory but not in other cognitive systems. Of 702 people without cognitive impairment at baseline, 223 developed incident MCI. Higher risk aversion was associated with higher incidence of MCI (HR: 2.10; 95% confidence interval: 1.34, 3.29) and more rapid episodic memory decline. In 181 neuropathologically examined individuals, higher risk aversion was associated with higher levels of plaques, tangles, and cerebral amyloid angiopathy. CONCLUSION: The results support the hypothesis that high risk aversion in old age is partly an early sign of the pathology of Alzheimer disease.

18.
Neuroepidemiology ; 53(1-2): 55-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30986783

RESUMO

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.

19.
Ann Intern Med ; 170(10): 702-709, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30986826

RESUMO

Background: Decreased scam awareness may be an early indicator of impending Alzheimer dementia and its precursor, mild cognitive impairment, but prior studies have not systematically examined the associations between scam awareness and adverse cognitive outcomes. Objective: To test the hypothesis that low scam awareness is associated with increased risk for incident Alzheimer dementia, mild cognitive impairment, and Alzheimer disease pathology in the brain. Design: Prospective cohort study of aging. Setting: Community-based study in the greater Chicago metropolitan area. Participants: 935 older persons initially free of dementia. Measurements: Scam awareness was measured via questionnaire, incident Alzheimer dementia and mild cognitive impairment were documented in detailed annual cognitive and clinical evaluations, and Alzheimer disease neuropathology was quantified after death among a subset of persons who died (n = 264). Proportional hazards models examined associations between scam awareness and incident Alzheimer dementia and mild cognitive impairment. Regression models examined associations between scam awareness and Alzheimer disease pathology, particularly ß-amyloid burden and tau tangle density. Results: During a mean of about 6 years (SD, 2.4) of observation, 151 persons (16.1%) developed Alzheimer dementia. Low scam awareness was associated with increased risk for Alzheimer dementia (hazard ratio [HR], 1.56 [95% CI, 1.21 to 2.01]; P < 0.001), such that each 1-unit increase in scam score (indicating lower awareness) was associated with about a 60% increase in dementia risk. Low scam awareness was also associated with increased risk for mild cognitive impairment (HR, 1.47 [CI, 1.20 to 1.81]; P < 0.001). These associations persisted even after adjustment for global cognitive function. Finally, low scam awareness was associated with a higher burden of Alzheimer pathology in the brain, particularly ß-amyloid (estimated increase [±SE] in ß-amyloid per 1-unit increase in scam score, 0.22 ± 0.10 unit; P = 0.029). Limitation: The measure of scam awareness used here is too weak for prediction at the individual level. Conclusion: Low scam awareness among older persons is a harbinger of adverse cognitive outcomes and is associated with Alzheimer disease pathology in the brain. Primary Funding Source: National Institute on Aging.


Assuntos
Doença de Alzheimer/psicologia , Conscientização , Disfunção Cognitiva/psicologia , Fraude , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Chicago/epidemiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Estudos Prospectivos
20.
JAMA Neurol ; 76(7): 818-826, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31009033

RESUMO

Importance: ß-Amyloid deposits are a pathologic hallmark of Alzheimer disease (AD). However, the extent to which cortical ß-amyloid protein in the absence of insoluble deposits is associated with classic features of AD appear to be unknown. Objective: To examine the associations of cortical ß-amyloid protein in the absence of insoluble deposits with cognitive decline, neurofibrillary tangles, other age-associated neuropathologic conditions, and APOE. Design, Setting, and Participants: This analysis combines data from 2 community-based clinicopathologic cohort studies of aging. The Religious Orders Study started in 1994, and the Rush Memory and Aging Project started in 1997. Both studies are ongoing. Participants without known dementia were enrolled and agreed to annual clinical evaluations and brain donation after death. Primary analyses focused on individuals without ß-amyloid deposits. Data analyses occurred in mid-September 2018. Main Outcomes and Measures: ß-Amyloid protein abundance was measured by targeted proteomics using selected reaction monitoring. ß-Amyloid deposits were detected using immunohistochemistry. Other neuropathologic indices were quantified via uniform structured evaluation. Linear mixed models were used to examine the association of ß-amyloid protein with cognitive decline. Regression models examined the protein associations with neuropathologic outcomes and the APOE genotype. Results: By mid-September 2018, 3575 older persons were enrolled, and 1559 had died and undergone brain autopsy. Proteomic data were collected in 1208 individuals, and 5 with missing cognitive scores were excluded. Of the remaining 1203, primary analyses focused on 148 individuals (12.3%) without ß-amyloid deposits. In this group, the mean (SD) age at death was 87.0 (7.0) years, and 84 individuals (56.8%) were women. In the absence of ß-amyloid deposits, we did not observe an association of ß-amyloid protein with decline in episodic memory, but the protein was associated with faster rates of decline in processing speed (mean [SE] change, -0.014 [0.005]; P = .008) and visuospatial abilities (mean [SE] change, -0.013 [0.005]; P = .006). We did not observe protein association with paired helical filament tau tangle density. The protein was associated with amyloid angiopathy (odds ratio, 1.38 [95% CI, 1.15-1.67]; P < .001) but no other brain pathology. The associations with cognitive decline were unchanged after controlling for amyloid angiopathy. Neither APOE ε4 nor a polygenic Alzheimer risk score was associated with ß-amyloid protein. Conclusions and Relevance: Cortical ß-amyloid protein was associated with faster cognitive decline in the absence of ß-amyloid deposits, which supports the role of cortical soluble ß-amyloid as a neurotoxic agent in aging. The lack of protein association with paired helical filament tau tangles, episodic memory decline, or strong genetic drivers of deposited ß-amyloid suggests an underlying neuropathologic change that may differ from that of AD.

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