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BACKGROUND: There is a dearth of studies examining the associations of objectively measured dual sensory impairment (DSI) with incident mobility and activities of daily life (ADL) difficulty longitudinally. METHODS: Cox proportional hazards models were used to examine the associations of DSI and single sensory impairment (hearing, vision) with incident mobility difficulty (many problems or inability to walk ¼ mile and/or climb 10 steps) and ADL difficulty up to six years of follow-up among 2,020 participants of the Health, Aging and Body Composition Study, a cohort of older adults aged 70–79 years from Pittsburgh, PA and Memphis, TN. Vision impairment (VI) was defined as impaired visual acuity (20/50 or worse on Bailey-Lovie distance test) and contrast sensitivity (25 decibels. Models were adjusted by age, race, sex, education, diabetes, depressive symptoms, hypertension, gait speed from 20-meter walk, global cognition score, prevalent cardiovascular disease, and body mass index. RESULTS: There were 23% with DSI (n=459). DSI was associated with increased risk of both incident report of mobility (Hazard Ratio [HR]=2.25, 95% Confidence Interval [CI]: 1.47, 3.43) and ADL difficulty (HR=2.26, 95% CI: 1.50, 3.40). Neither VI nor HI alone were associated with risk of either outcome. CONCLUSIONS: DSI is associated with increased risk of incident mobility and ADL difficulty. Rehabilitation and adaptive environmental changes for individuals living with DSI may be important to maximize mobility and daily function.

ObjectiveDue to the long prodromal period for dementia pathology, approaches are needed to detect cases before clinically recognizable symptoms are apparent, by which time it is likely too late to intervene. This study contrasted two theoretically-based algorithms for classifying early cognitive impairment (ECI) in adults aged ≥50 enrolled in the Baltimore Longitudinal Study of Aging.MethodTwo ECI algorithms were defined as poor performance (1 standard deviation [SD] below age-, sex-, race-, and education-specific means) in: (1) Card Rotations or California Verbal Learning Test (CVLT) immediate recall and (2) ≥1 (out of 2) memory or ≥3 (out of 6) non- memory tests. We evaluated concurrent criterion validity against consensus diagnoses of mild cognitive impairment (MCI) or dementia and global cognitive scores using receiver operating characteristic (ROC) curve analysis. Predictive criterion validity was evaluated using Cox proportional hazards models to examine the associations between algorithmic status and future adjudicated MCI/dementia.ResultsAmong 1,851 participants (mean age=65.2±11.8 years, 50% women, 74% white), the two ECI algorithms yielded comparably moderate concurrent criterion validity with adjudicated MCI/dementia. For predictive criterion validity, the algorithm based on impairment in Card Rotations or CVLT immediate recall was the better predictor of MCI/dementia (HR=3.53, 95%CI: 1.59-7.84) over 12.3 follow-up years.ConclusionsImpairment in visuospatial ability or memory may be capable of detecting early cognitive changes in the preclinical phase among cognitively normal individuals.

Background Much is known about individual sensory deficits among older adults, but there is a dearth of information about the prevalence of multiple concurrent sensory deficits in this population. Methods We evaluated the prevalence of individual and multiple sensory impairments at the most recent clinic visit among participants aged 24 years and older in the Baltimore Longitudinal Study of Aging (BLSA) (hearing, vision, olfaction, proprioception, and vestibular function) and Atherosclerosis Risk in Communities Study (ARIC) (hearing, vision, olfaction). We compared observed prevalence of multiple sensory impairments with expected prevalence based on compounded probabilities of multiple impairments using Fisher Exact Tests. Also, we evaluated the comparability of different measures used between these two studies. Results In both studies, the prevalence of each individual sensory impairment was common (>10%), and higher with older age, and the most common pattern of co-occurring sensory impairments was hearing and visual impairments (17.4% [BLSA]; 50.2% [ARIC]). In BLSA, the pattern that differed the most between observed and expected prevalence was combined hearing, vision, and olfactory impairments (observed 5.2% vs 1.4% expected, p = .01). In ARIC, this difference was much smaller (observed 8.1% vs 7.2% expected, p = .49). Conclusions Although concurrent hearing and vision impairments were the most common co-occurring deficits, combined hearing, vision, and olfactory impairments are most likely to co-occur above chance, especially at older ages.

Objectives:Vision and hearing impairments affect 55% of people aged 60+ years and are associated with lower cognitive test performance; however, tests rely on vision, hearing, or both. We hypothesized that scores on tests that depend on vision or hearing are different among those with vision or hearing impairments, respectively, controlling for underlying cognition.Methods:Leveraging cross-sectional data from the Baltimore Longitudinal Study of Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), we used item response theory to test for differential item functioning (DIF) by vision impairment (better eye presenting visual acuity worse than 20/40) and hearing impairment (better ear .5–4 kHz pure-tone average > 25 decibels).Results:We identified DIF by vision impairment for tests whose administrations do not rely on vision [e.g., Delayed Word Recall both in ARIC-NCS: .50 logit difference between impaired and unimpaired (p = .04) and in BLSA: .62 logits (p = .02)] and DIF by hearing impairment for tests whose administrations do not rely on hearing [Digit Symbol Substitution test in BLSA: 1.25 logits (p = .001) and Incidental Learning test in ARIC-NCS: .35 logits (p = .001)]. However, no individuals had differences between unadjusted and DIF-adjusted measures of greater than the standard error of measurement.Conclusions:DIF by sensory impairment in cognitive tests was independent of administration characteristics, which could indicate that elevated cognitive load among persons with sensory impairment plays a larger role in test performance than previously acknowledged. While these results were unexpected, neither of these samples are nationally representative and each has unique selection factors; thus, replication is critical.

Background and Objectives Leisure activity engagement (LAE) may reduce the risk of incident dementia. However, cognitive performance may predict LAE change. We evaluated the temporal ordering of overall and subtypes of LAE (intellectual, physical, and social) and cognitive performance (global, language, memory, and visuospatial function) among non-demented older adults. Research Design and Methods The Washington Heights–Inwood Columbia Aging Project concurrently administered a survey measure of 13 leisure activities and a neuropsychological battery every 18–24 months for up to 14 years to 5,384 racially and ethnically diverse participants. We used parallel process conditional latent growth curve models to examine temporal ordering in the overall sample and within baseline diagnostic groups (mild cognitive impairment [MCI] vs. cognitively normal). Results Levels and changes of overall and subtypes of LAE were positively correlated with cognitive performance in the overall sample and within each diagnostic group. In the overall sample, higher initial memory was associated with slower declines in social LAE (estimate = 0.019, 95% confidence interval [95% CI]: 0.001–0.037). Among MCI, higher initial physical LAE was associated with slower declines in memory (estimate = 0.034, 95% CI: 0.001–0.067), but higher initial intellectual LAE was related to steeper declines in visuospatial function (estimate = −0.028, 95% CI: −0.052 to −0.004). Among cognitively normal, higher initial memory was associated with slower declines in intellectual LAE (estimate = 0.012, 95% CI: 0.002−0.022). Discussion and Implications Dynamic interplay of LAE with cognitive performance was observed across diagnostic groups. Levels of LAE subtypes could be more predictive of change in certain cognitive domains within older adults with MCI.

A high hippocampal volume polygenic predictor score (HV-PPS), computed based on GWAS summary statistics (n = 33,536), could be protective against declines in brain volume and cognition in older adults. Linear mixed-effects models with random intercepts and slopes were used to estimate associations of HV-PPS with baseline and annual rate of change in both brain volumes (n = 508) and cognitive performance (n = 1041) in Caucasian Baltimore Longitudinal Study of Aging participants. Higher HV-PPS was associated with greater baseline volumes of the hippocampus and parahippocampal gyrus, and slower rates of ventricular enlargement and volume loss in frontal and parietal white matter, all adjusted for intracranial volume. In addition, higher HV-PPS was associated with better executive function performance and slower rates of decline in verbal fluency scores over time. Individuals with a genetic predisposition toward larger hippocampal volumes show better baseline executive function, slower decline in verbal fluency performance, and slower rates of longitudinal brain atrophy.

To discriminate among degrees of auditory performance of the Digits-in-Noise (DIN) test.We performed Pearson's correlations and age- and sex-adjusted linear regression models to examine the correlation between pure-tone average (PTA) from pure-tone audiometric tests and speech recognition thresholds (SRT) from the DIN test. Then, optimal SRT cut-points by PTA-defined hearing status (0-25 dB HL [normal], 26-40 dB HL [mild hearing loss], 41-50 dB HL [moderate hearing loss]) were compared across three methods: Youden, Nearest, and Liu. SRT-defined categories of auditory performance were compared to PTA-defined hearing categories to examine the convergence of similar categories.The correlation between SRT and PTA was 0.65 (95% Confidence Interval: 0.63, 0.67) in the overall sample. The variability of SRT explained by PTA after age and sex adjustment was 54%. Optimal cut-points for the overall sample across the three methods were: ≤ -5.55 dB SNR (normal); -5.55 to ≤ -3.80 dB SNR (insufficient performance); -3.80 dB SNR (poor performance). When comparing the SRT- or PTA-defined categories, 59.8% had concordant hearing categories and 40.2% had discordant hearing categories.Discrimination of degrees of auditory performance may add greater utility of the DIN test.

Background In older persons, neuropsychological function, especially sensorimotor function, is strongly associated with mobility. Hearing impairment is related to poor mobility, and we hypothesize that such relationships would be stronger in persons with compromised sensorimotor function than those with preserved sensorimotor function. Methods We analyzed 601 cognitively normal (Mini-Mental State Examination ≥24 or free of cognitive impairment/dementia) Baltimore Longitudinal Study of Aging participants aged 50 or older with concurrent data on hearing (better ear pure-tone average [PTA]), mobility (6 m usual gait, 400 m endurance walk), and neuropsychological function including attention via Trail Making Test (TMT)-A, executive function via the difference between TMT-A and B, and Digit Symbol Substitution Test, and manual dexterity via Pegboard performance. We examined the association of PTA, each cognitive measure, and their interaction with mobility using multivariable linear regression, adjusted for covariates. Results After covariate adjustment, there were significant interactions between PTA and all cognitive measures in the association with 400 m endurance walking speed as the outcome. There was also a significant interaction between PTA and pegboard nondominant hand performance in the association with 6 m gait as the outcome. In all these cases, the PTA–mobility relationship was stronger among participants with lower cognition. Conclusion Impaired hearing more strongly relates to poor mobility among those with compromised neuropsychological performance, especially manual dexterity reflecting the motor–cognitive interface and sensorimotor function, than those with preserved neuropsychological performance. Future longitudinal studies are needed to test whether hearing impairment more strongly predicts mobility decline over time in older persons with compromised neuropsychological function.

Objectives Late-life depression is a comorbidity that may co-occur in older adults with hearing loss—each has prevalent and independent modifiable risk factors for dementia. Methods Using data from 1,820 Health, Aging and Body Composition study participants (74 ± 2.8 years, 38% Black race), we compared the hearing loss–dementia/cognitive decline relationship between those with normal hearing/mild hearing loss and those with moderate or greater hearing loss. Using linear mixed-effects and Cox proportional hazard models, we investigated if the associations between hearing loss and cognitive decline or dementia (Modified Mini-Mental State [3MS] Examination and Digit Symbol Substitution Test [DSST]) differed by the presence or absence of depressive symptoms. Depressive symptoms were defined as Center for Epidemiologic Study—Depression scale 10 ≥10 at one or more visits from Years 1–5. Algorithmic incident dementia was defined using medication use, hospitalizations, and cognitive test scores. Audiometric hearing loss was measured at Year 5 and categorized as normal/mild versus moderate or greater hearing loss. Results Having both hearing loss and depressive symptoms (vs. having neither) was associated with faster rates of decline in 3MS Examination (β = −0.30; 95% confidence interval [CI]: −0.78, −0.19) and DSST (β = −0.35; 95% CI: −0.67, −0.03) over 10 years of follow-up. Having both hearing loss and depressive symptoms (vs. neither) was associated with increased risk (hazard ratio [HR]: 2.91; 95% CI: 1.59, 5.33 vs. HR: 1.54; 95% CI: 1.10, 2.15 hearing loss only and HR: 2.35; 95% CI: 1.56, 3.53 depressive symptoms only) of incident dementia in multivariable-adjusted Cox proportional hazards models. Discussion Comorbid conditions among hearing-impaired older adults should be considered and may aid in dementia prevention and management strategies.

Metabolic syndrome (MetS) has been linked to increased risk of developing cognitive impairment and dementia including Alzheimer's disease. It remains unclear whether and at what stage in the adult lifespan MetS and its components begin to alter the trajectory of cognitive performance. In the present study, 2,892 Framingham Offspring participants completed health assessments every four years since 1971 and underwent repeat neuropsychological testing from 1999 to 2014. We estimated the associations of levels and changes in cognitive trajectories with hazard of MetS using a joint growth/survival model. All models were adjusted for baseline age, sex, education, and smoking status. Findings showed that both mid-life and late-life MetS were associated with lower level of cognitive functioning but not cognitive trajectories. Associations were strongest among those who were nondemented and apolipoprotein (APOE) ɛ4 noncarriers. In addition, individuals with the most rapid cognitive decline were more likely to have MetS. The pattern of results showed that associations between MetS and cognition varied, depending upon whether the sample was stratified by genetic and cognitive status and whether we considered cognitive performance as a continuous variable or examined categorical groupings. Given that mid-life MetS was associated with poorer cognition at age 55, cognitive changes may occur early during the MetS process. Our findings suggest that those with MetS are at greater risk of dementia given their lower level of cognitive functioning and also suggest that MetS may be a risk factor for decline in the absence of known risk factors including the APOEɛ4 allele.

Background Hearing loss (HL) and menopausal hormone therapy (conjugated equine estrogens [CEE] and/or medroxyprogesterone acetate [MPA]) are separately associated with cognitive decline and increased risk of incident cognitive impairment. Joint effects of HL and HT could be associated with additive or synergistic decline in global cognition and risk of incident cognitive impairment among postmenopausal women. Methods Using the Women’s Health Initiative (WHI) Memory Study, 7,220 postmenopausal women with measures of HL, global cognition (Modified Mini-Mental State Examination score), and cognitive impairment (centrally adjudicated diagnoses of mild cognitive impairment and dementia) from 1996 to 2009. Multivariable linear mixed-effects models were used to analyze rate of change in global cognition. Accelerated failure time models were used to evaluate time to incident cognitive impairment, stratified by HT. Results Within the CEE-Alone trial, observed adverse effects of CEE-Alone on change in global cognition did not differ by HL, and estimated joint effects of HL and CEE-Alone were not associated with incident cognitive impairment. Within the CEE+MPA trial, while HL did not independently accelerate time to cognitive impairment, the adverse effect of CEE+MPA on global cognition was heightened in older women with HL. Older women on CEE+MPA either with HL (time ratio [TR] = 0.82, 95% confidence interval [CI]: 0.71, 0.94) or with normal hearing (TR = 0.86, 95% CI: 0.76, 0.97) had faster time to cognitive impairment than those with normal hearing and placebo. Conclusions HL may accentuate the adverse effect of CEE+MPA, not CEE-Alone, on global cognitive decline, not incident cognitive impairment, among postmenopausal women on HT.

Driving after cannabis use (DACU) and riding with a cannabis-impaired driver (RWCD) are national public health concerns. Though driving impairments and increased crash risk make DACU and RWCD two of the riskiest cannabis-related behaviors, many continue to drive after use and ride with others who are under the influence and do not view DACU or RWCD as dangerous. The current study examined the efficacy of an accessible, low-cost, mobile phone-based brief intervention aimed at reducing DACU and RWCD among college cannabis users in the context of a randomized three-group pilot trial.Participants were 97 college cannabis users (67.4 % women; average age = 21.34; 80.4 % Caucasian) who endorsed DACU at least three times in the past three months. After completing baseline measures, the study randomly assigned participants to one of three conditions: a) a substance impaired-driving personalized feedback plus MI-style interactive text messaging intervention (PF + MIT); b) a substance impaired-driving personalized feedback only intervention (PF); and c) a substance information control condition (IC). All conditions completed outcome measures three months postintervention.Generalized linear mixed models (GLMM) analyses indicated that after controlling for sex, cannabis users in the PF + MIT condition significantly reduced DACU and RWCD over time compared to those in the IC condition.These findings provide preliminary support for the short-term efficacy of a mobile phone-based intervention in decreasing DACU and RWCD among college cannabis users. Future research should determine whether these reductions in driving behaviors persist past three months.

BackgroundSeveral studies have demonstrated that age-related hearing loss is associated with cognitive decline. We investigated whether subclinical hearing loss (SCHL) or imperfect hearing traditionally categorized as normal (pure-tone average ≤25 dB) may be similarly linked to cognitive decline and risk of incident mild cognitive impairment (MCI)/dementia.MethodsParticipants from the Baltimore Longitudinal Study of Aging were cognitively normal adults at least 50 years old with cognitive assessments from 1991 to 2019 and pure-tone average ≤25 dB measured between 1991 and 1994 (n = 263). The exposure was hearing based on the better ear pure-tone average. Outcomes were test scores in various cognitive domains. Multivariable linear-mixed effects models were developed to analyze the association between hearing and change in cognition over time, adjusting for age, sex, education, vascular burden, and race. Kaplan–Meier survival curves and Cox proportional hazards models portrayed associations between hearing and incident MCI/dementia diagnosis based on predefined criteria.ResultsOf 263 participants, 145 (55.1%) were female; mean age was 68.3 years (SD = 8.9). Follow-up ranged up to 27.7 years (mean = 11.7 years). Adjusting for multiple comparisons, a 10-dB increase in hearing loss was associated with an annual decline of −0.02 SD (95% confidence interval: −0.03, −0.01) in Letter Fluency. No significant relationships were observed between hearing and incident MCI/dementia.ConclusionsA relationship between SCHL and cognitive decline was observed for the Letter Fluency test. Further studies are necessary to determine where in the spectrum of hearing loss there begins to be an observable relationship between hearing and cognitive decline.

Cognitive aging varies tremendously across individuals and is often accompanied by regionally specific reductions in gray matter (GM) volume, even in the absence of disease. Rhesus monkeys provide a primate model unconfounded by advanced neurodegenerative disease, and the current study used a recognition memory test (delayed non-matching to sample; DNMS) in conjunction with structural imaging and voxel-based morphometry (VBM) to characterize age-related differences in GM volume and brain-behavior relationships. Consistent with expectations from a long history of neuropsychological research, DNMS performance in young animals prominently correlated with the volume of multiple structures in the medial temporal lobe memory system. Less anticipated correlations were also observed in the cingulate and cerebellum. In aged monkeys, significant volumetric correlations with DNMS performance were largely restricted to the prefrontal cortex and striatum. Importantly, interaction effects in an omnibus analysis directly confirmed that the associations between volume and task performance in the MTL and prefrontal cortex are age-dependent. These results demonstrate that the regional distribution of GM volumes coupled with DNMS performance changes across the lifespan, consistent with the perspective that the aged primate brain retains a substantial capacity for structural reorganization.

Effects of Alzheimer's disease (AD) risk factors on brain volume changes may partly explain what happens during the preclinical AD stage in people who develop subsequent cognitive impairment (SI). We investigated predictors of neurodegeneration, measured by MRI-based volume loss, in older adults before diagnosis of cognitive impairment. There were 623 cognitively normal and 65 SI Baltimore Longitudinal Study of Aging participants (age 55–92 years) enrolled in the neuroimaging substudy from 1994 to 2015. Mixed-effects regression was used to assess the associations of AD risk factors (age, APOE e4 carrier status, diabetes, hypertension, obesity, current smoking, and elevated cholesterol) with brain regional volume change among the overall sample and by diagnostic status. Older age, APOE e4 carrier status, hypertension, and HDL cholesterol were predictors of volumetric change. Among SI participants only, hypertension, obesity, and APOE e4 carrier status were associated with greater declines in selected brain regions. SI individuals in the preclinical AD stage are vulnerable to risk factors that have either a protective or null effect in cognitively normal individuals.

BACKGROUND: There are currently no disease-targeted treatments for cognitive or behavioral symptoms in patients with behavioral variant frontotemporal dementia (bvFTD). OBJECTIVE: To determine the effect of tolcapone, a specific inhibitor of Catechol-O-Methyltransferase (COMT), in patients with bvFTD. METHODS: In this randomized, double-blind, placebo-controlled, cross-over study at two study sites, we examined the effect of tolcapone on 28 adult outpatients with bvFTD. The primary outcome was reaction time on the N-back cognitive test. As an imaging outcome, we examined differences in the resting blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal intensity between subjects on placebo versus tolcapone performing the N-back test. Secondary outcomes included measures of cognitive performance and behavioral disturbance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Neuropsychiatric Inventory-Questionnaire (NPI-Q), and Clinical Global Impressions scale (CGI). RESULTS: Tolcapone was well tolerated and no patients dropped out. The most frequent treatment-related adverse event during tolcapone treatment was elevated liver enzymes (21%). There were no significant differences between tolcapone treatment and placebo in the primary or imaging outcomes. However, there were significant differences between RBANS total scores (p < 0.01), NPI-Q total scores (p = 0.04), and CGI total scores (p = 0.035) between treatment conditions which were driven by differences between baseline and tolcapone conditions. Further, there was a trend toward significance between tolcapone and placebo on the CGI (p = 0.078). CONCLUSIONS: Further study of COMT inhibition and related approaches with longer duration of treatment and larger sample sizes in frontotemporal lobar degeneration-spectrum disorders may be warranted.

Background: Alzheimer’s disease (AD) is now understood to have a long preclinical phase in which pathology starts to accumulate in the absence of clinical symptoms. Identifying the temporal stages of accelerated cognitive decline in this phase may help in developing more sensitive neuropsychological tools for early screening of preclinical cognitive decline. Change-point analyses are increasingly used to characterize the temporal stages of accelerated cognitive decline in the preclinical stages of AD. However, statistical comparisons of change-points between specific cognitive measures have not been reported. Objective: To characterize and compare the temporal stages of accelerated decline in performance on multiple cognitive tests in a sample of participants from the Baltimore Longitudinal Study on Aging (BLSA) who later developed AD. Methods: 165 older adults (baseline age range: 61.1–91.2) from the Baltimore Longitudinal Study of Aging developed AD during follow-up. Linear and non-linear mixed models were fit for 11 cognitive measures to determine change-points in rates of decline before AD diagnosis. Bootstrapping was used to compare the timing of change-points across cognitive measures. Results: Change-points followed by accelerated decline ranged from 15.5 years (Standard Error (S.E.) = 1.72) for Card Rotations to 1.9 years (S.E. = 0.68) for the Trail-Making A test before AD diagnosis. Accelerated decline in Card Rotations occurred significantly earlier than all other measures, including learning and memory measures. Conclusion: Results suggest that visuospatial ability, as assessed by Card Rotations, may have the greatest utility as an early predictive tool in identifying preclinical AD.

Background Previous studies identifying hearing loss as a promising modifiable risk factor for cognitive decline mostly adjusted for baseline age solely. As such a faster cognitive decline at a higher age, which is expected considering the non-linear relationship between cognition and age, may have been overlooked. Therefore it remains uncertain whether effects of hearing loss on cognitive decline extend beyond age-related declines of cognitive function. Methods 3,590 non-demented participants were eligible for analysis at baseline, and a maximum of 837 participants were eligible for the longitudinal analysis. Hearing loss was defined at baseline. Cognitive function was measured at baseline and at follow-up (4.4 years [SD: 0.2]). Multivariable linear regression analysis was used for the cross-sectional analysis. Linear mixed models were used to assess the longitudinal association between hearing loss and cognitive decline over time while adjusting for confounders and the interaction of age and follow-up time. Results Hearing loss was associated with lower cognitive function at baseline. Moreover, hearing loss was associated with accelerated cognitive decline over time on a memory test. After additionally adjusting for the interaction between age and follow-up time, we found that hearing loss did not accelerate cognitive decline anymore. Conclusions Hearing loss was associated with lower cognitive function at baseline and accelerated cognitive decline on a memory test. The association between hearing loss and accelerated cognitive decline was non-significant after additional adjustment for non-linear age effects. More evidence is needed to ensure the role of hearing loss as a modifiable risk factor for cognitive decline.

OBJECTIVES: Cognitive frailty is a state at the lower end of the continuum of cognitive resilience in which one is at elevated risk for cognitive impairment and dementia. Metrics of a newly developed Cognitive Frailty Index (CFI) were examined for their association with objective functional limitations. METHODS: We used baseline data from 607 participants from the Baltimore Experience Corps Trial with measures on the CFI, a computerized Stroop test, and Short Physical Performance Battery (SPPB) score≤9. Multivariable log-binomial regression models were used to evaluate the associations of CFI metrics (mean reaction time (RT) for total, first-half and second-half trials per condition) with the SPPB. Latent growth models were used to create additional CFI metrics of initial level (intercept) and change (slope) in RT across accurate trials by easy (Color-X) and difficult (Color-Word) conditions. Models were adjusted for race, sex, age, income, major morbidities, depressive symptoms, self-reported health, and Stroop interference (for Color-Word condition only). RESULTS: All CFI RT metrics were associated with SPPB

Author(s): Power, Melinda C; Mormino, Elizabeth; Soldan, Anja; James, Bryan D; Yu, Lei; Armstrong, Nicole M; Bangen, Katherine J; Delano-Wood, Lisa; Lamar, Melissa; Lim, Yen Ying; Nudelman, Kelly; Zahodne, Laura; Gross, Alden L; Mungas, Dan; Widaman, Keith F; Schneider, Julie | Abstract: ObjectiveOur objectives were to characterize the inter-relation of known dementia-related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia.MethodsWe used data from 1,362 autopsied participants of three community-based clinicopathological cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively.ResultsAt time of death (mean age, 89 years), 44% of our sample had a clinical dementia diagnosis. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathology pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of amyloid beta plaques in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, wheraes the remaining three inter-related degenerative pathways together accounted for 68% (amyloid/tau, 24%; the Lewy body, 1%; and TDP-43/hippocampal sclerosis, 43%).InterpretationAge-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies. Ann Neurol 2018;84:10-22.

Objective To study whether depression contributes to the association between subclinical cardiovascular disease (CVD) and dementia, and identify the contribution's magnitude. Methods Among participants from the Cardiovascular Health Study Cognition Study who did not have baseline CVD-related events (N = 2,450), causal mediation methodology was implemented to examine whether late-life depressive symptoms, defined as 10-item Center for Epidemiologic Studies-Depression (mCES-D) Scale scores ≥8 from 2 to 3 years after baseline, partially mediated the association of baseline subclinical CVD (CAC, carotid intimal medial thickness, stenosis, and ankle brachial index) with mild cognitive impairment (MCI)/dementia onset occurring between 5 and 10 years from baseline. The total effect was decomposed into direct and indirect effects (via late-life depressive symptoms), obtained from an accelerated failure time model with weights derived from multivariable logistic regression of late-life depressive symptoms on subclinical CVD. Analyses were adjusted by baseline covariates: age, race, sex, poverty status, marital status, body mass index, smoking status, ApoE4 status, and mCES-D. Results Participants contributed 20,994 person-years of follow-up with a median follow-up time of 9.4 years. Subclinical CVD was associated with 12% faster time to MCI/dementia (time ratio [TR]: 0.88; 95% CI: 0.83, 0.93). The total effect of subclinical CVD on MCI/dementia onset was decomposed into a direct effect (TR: 0.95, 95% CI: 0.92, 0.98) and indirect effect (TR: 0.92, 95% CI: 0.88, 0.97); 64.5% of the total effect was mediated by late-life depressive symptoms. Conclusions These data suggest late-life depressive symptoms partially mediate the association of subclinical CVD with MCI/dementia onset.

OBJECTIVES: To determine whether caregiver relationship and race modify associations between physical functioning of persons with dementia and their caregiver’s burden and general depressive symptoms. METHOD: We pooled data from four behavioral intervention trials (N=1,211). Using latent growth modeling, we evaluated associations of physical functioning of persons with dementia with the level and rate of change in caregiver burden and general depressive symptoms of caregivers. We then tested for differences by caregiver relationship (spouse vs. non-spouse) and race (white vs. non-white). RESULTS: Persons with dementia were, on average, 81 years old (68% female) and followed up, on average, 0.5 years. More baseline physical impairment of persons with dementia was associated with less worsening in caregiver burden over time (β=−0.23, 95% CI: −0.29, −0.14). Neither caregiver relationship nor race of the caregiver modified this relationship. More impaired baseline physical functioning of persons with dementia was not associated with changes in depressive symptoms (β=−0.08, 95% CI: −0.17, 0.00), but was associated with less worsening in depressive symptoms among spousal (β=−0.08, 95% CI: −0.17, 0.00) and non-white (β=−0.08, 95% CI: −0.17, 0.00) caregivers. CONCLUSIONS: Dementia caregivers may experience reduced caregiver-related burden over time as a consequence of adjusting to the functional status of persons with dementia, while spousal and non-white caregivers may experience less depressive symptoms resultant of adjustment to functional status.

Objectives: To evaluate whether late-life depression mediates the association of subclinical cardiovascular disease (CVD) with all-cause mortality. Method: Using data from 3,473 Cardiovascular Health Study participants, the Cox proportional hazards model was used to examine the direct and indirect (via late-life depression) effects of the association between baseline subclinical CVD and all-cause mortality with weights derived from multivariable logistic regression of late-life depression on subclinical CVD. Results: Subclinical CVD led to a higher risk of all-cause mortality (hazard ratio [HR] = 1.51, 95% confidence interval, [CI] = [1.42, 1.94]). Total effect of subclinical CVD on all-cause mortality was decomposed into direct (HR = 1.41, 95% CI = [1.37, 1.58]) and indirect (HR = 1.07, 95% CI = [1.01, 1.23]) effects; 16.3% of the total effect of subclinical CVD on all-cause mortality was mediated by late-life depression. Discussion: Late-life depression accounts for little, if any, of the association between subclinical CVD, a risk factor of all-cause mortality, and all-cause mortality.

Individual sensory deficits have been associated with adverse outcomes, including dementia, in older adults. Using data from the Baltimore Longitudinal Study of Aging (BLSA) (N=259) and Atherosclerosis Risk in Communities Study (ARIC) (N=962), we examined the prevalence of one, two, or three sensory deficits (hearing, vision, and olfaction) among older adults ≥70 years. Any hearing loss was the most prevalent sensory deficit (70-79 year-olds: 41.3% [BLSA] and 51.2% [ARIC]; ≥80 year-olds: 82.6% [BLSA] and 74.2% [ARIC]), followed by vision loss and olfactory loss. Hearing and vision impairments were more prevalent than hearing and olfactory losses as well as vision and olfactory losses in both age groups and studies There were few people with deficits in all three senses (70-79 year-olds: 3.3% [BLSA] and 2.0% [ARIC]; ≥80 year-olds: 5.8% [BLSA] and 7.4% [ARIC]). Further research should investigate the potential impact of multisensory impairments on older adults.

Background Active lifestyles are related to better cognitive aging outcomes, yet the unique role of different types of activity are unknown. Objective To examine the independent contributions of physical (PA) versus cognitive (CA) leisure activities to brain and cognitive aging. Methods Independent samples of non-demented older adults from University of California, San Francisco Hillblom Aging Network (UCSF; n = 344 typically aging) and University of California, Davis Diversity cohort (UCD; n = 485 normal to MCI) completed: 1) self-reported engagement in current PA and CA (UCSF: Physical Activity Scale for the Elderly and Cognitive Activity Scale; UCD: Life Experiences Assessment Form); 2) neuropsychological batteries; and 3) neuroimaging total gray matter volume, white matter hyperintensities, and/or global fractional anisotropy. PA and CA were simultaneously entered into multivariable linear regression models, adjusting for demographic characteristics and functional impairment severity. Results Brain outcomes: In UCSF, only PA was positively associated with gray matter volume and attenuated the relationship between age and fractional anisotropy. In UCD, only CA was associated with less white matter hyperintensities and attenuated the relationship between age and gray matter volume. Cognitive outcomes: In both cohorts, greater CA, but not PA, related to better cognition, independent of age and brain structure. In UCSF, CA attenuated the relationship between fractional anisotropy and cognition. In UCD, PA attenuated the association between white matter hyperintensities and cognition. Conclusions Although their specificity was not easily teased apart, both PA and CA are clearly related to better brain and cognitive resilience markers across cohorts with differing educational, racial, and disease statuses. PA and CA may independently contribute to converging neuroprotective pathways for brain and cognitive aging.

Background Hearing loss, a highly prevalent sensory impairment affecting older adults, is a risk factor for cognition decline. However, there were very limited studies on this association in low-resource countries. This study aimed to assess the association between self-reported hearing loss and cognitive decline, and whether engagement in leisure activities moderated this association among older adults in China. Methods Data were obtained from two waves of the nationally representative survey of China Longitudinal Healthy Longevity Survey (CLHLS) between 2011/12–2014. Eight thousand eight hundred forty-four individuals aged 65 years old or above with a dichotomized measure of self-reported hearing status were included. Modified Mini-Mental Examination (MMSE) was used to measure global cognition. Fixed-effects models were used to estimate whether leisure activity engagement moderated the association of self-perceived hearing loss with global cognitive change in the overall sample and sex subsamples. Results Self-reported hearing loss was associated with cognitive impairment, with an odds ratio of 2.48 [1.22, 5.06]. Sex difference in the association of hearing loss and cognitive impairment was not found. Self-reported hearing loss was associated with cognitive decline, with 8% increase in risk compared with those with normal hearing. Frequent engagement in leisure activities moderated the association between hearing loss and cognitive decline for the whole and male samples. Conclusion Hearing loss was associated with cognitive decline, and leisure activities engagement moderated the association among males rather than females.

Investigation of relationships between age-related changes in regional brain volumes and changes in domain-specific cognition could provide insights into the neural underpinnings of individual differences in cognitive aging. Domain-specific cognition (memory, verbal fluency, visuospatial ability) and tests of executive function and attention (Trail-Making Test Part A and B) and 47 brain volumes of interest (VOIs) were assessed in 836 Baltimore Longitudinal Study of Aging participants with mean follow-up of 4.1 years (maximum 23.1 years). To examine the correlation between changes in domain-specific cognition and changes in brain volumes, we used bivariate linear mixed effects models with unstructured variance-covariance structure to estimate longitudinal trajectories for each variable of interest and correlations among the random effects of these measures. Higher annual rates of memory decline were associated with greater volume loss in 14 VOIs primarily within the temporal and occipital lobes. Verbal fluency decline was associated with greater ventricular enlargement and volume loss in 24 VOIs within the frontal, temporal, and parietal lobes. Decline in visuospatial ability was associated with volume loss in 3 temporal and parietal VOIs. Declines on the attentional test were associated with volume loss in 4 VOIs located within temporal and parietal lobes. Greater declines on the executive function test were associated with greater ventricular enlargement and volume loss in 10 frontal, parietal, and temporal VOIs. Our findings highlight domain-specific patterns of regional brain atrophy that may contribute to individual differences in cognitive aging.

OBJECTIVES Brain volumetric declines may underlie the association between hearing loss and dementia. While much is known about the peripheral auditory function and brain volumetric declines, poorer central auditory speech processing may also be associated with decreases in brain volumes. METHODS Central auditory speech processing, measured by the speech recognition threshold (SRT) from the Digits-in-Noise task, and neuroimaging assessments (structural magnetic resonance imaging [MRI] and fractional anisotropy and mean diffusivity from diffusion tensor imaging), were assessed cross-sectionally in 2,368 Rotterdam Study participants aged 51.8 to 97.8 years. SRTs were defined continuously and categorically by degrees of auditory performance (normal, insufficient, and poor). Brain volumes from structural MRI were assessed on a global and lobar level, as well as for specific dementia-related structures (hippocampus, entorhinal cortex, parahippocampal gyrus). Multivariable linear regression models adjusted by age, age-squared, sex, educational level, alcohol consumption, intracranial volume (MRI only), cardiovascular risk factors (hypertension, diabetes, obesity, current smoking), and pure-tone average were used to determine associations between SRT and brain structure. RESULTS Poorer central auditory speech processing was associated with larger parietal lobe volume (difference in mL per dB increase= 0.24, 95% CI: 0.05, 0.42), but not with diffusion tensor imaging measures. Degrees of auditory performance were not associated with brain volumes and white matter microstructure. CONCLUSIONS Central auditory speech processing in the presence of both vascular burden and pure-tone average may not be related to brain volumes and white matter microstructure. Longitudinal follow-up is needed to explore these relationships thoroughly.

IntroductionChange-point analyses are increasingly used to identify the temporal stages of accelerated cognitive decline in the preclinical stages of Alzheimer’s Disease (AD). However, statistical comparisons of change-points between specific cognitive measures have not been reported.Methods165 older adults (baseline age range: 61.1-91.2) from the Baltimore Longitudinal Study of Aging developed AD during follow-up. Linear and non-linear mixed models were fit for 11 cognitive measures to determine change-points in rates of decline before AD diagnosis. Bootstrapping was used to compare the timing of change-points across cognitive measures.ResultsChange-points followed by accelerated decline ranged from 15.5 years (Card Rotations) to 1.9 years (Trail-Making A) before AD diagnosis. Accelerated decline in Card Rotations occurred significantly earlier than all other measures, including learning and memory measures.DiscussionResults suggest that visuospatial ability, as assessed by Card Rotations, may have the greatest utility as an early predictive tool in identifying preclinical AD.

BACKGROUND: Hearing loss (HL) and menopausal hormone therapy (conjugated equine estrogens [CEE] and/or medroxyprogesterone acetate [MPA]) are separately associated with cognitive decline and increased risk of incident cognitive impairment. Joint effects of HL and HT could be associated with additive or synergistic decline in global cognition and risk of incident cognitive impairment among postmenopausal women. METHODS: Using the Women’s Health Initiative (WHI) Memory Study, 7,220 postmenopausal women with measures of HL, global cognition (Modified Mini-Mental State Examination score), and cognitive impairment (centrally adjudicated diagnoses of mild cognitive impairment and dementia) from 1996 to 2009. Multivariable linear mixed-effects models were used to analyze rate of change in global cognition. Accelerated failure time models were used to evaluate time to incident cognitive impairment, stratified by HT. RESULTS: Within the CEE-Alone trial, observed adverse effects of CEE-Alone on change in global cognition did not differ by HL, and estimated joint effects of HL and CEE-Alone were not associated with incident cognitive impairment. Within the CEE+MPA trial, while HL did not independently accelerate time to cognitive impairment, the adverse effect of CEE+MPA on global cognition was heightened in older women with HL. Older women on CEE+MPA either with HL (time ratio [TR] = 0.82, 95% confidence interval [CI]: 0.71, 0.94) or with normal hearing (TR = 0.86, 95% CI: 0.76, 0.97) had faster time to cognitive impairment than those with normal hearing and placebo. CONCLUSIONS: HL may accentuate the adverse effect of CEE+MPA, not CEE-Alone, on global cognitive decline, not incident cognitive impairment, among postmenopausal women on HT.

Objectives Investigate the cross-sectional association between hearing loss (HL), hearing aid use, and depressive symptoms in community-dwelling older adults. Method The analytic sample consisted of 3,188 participants (age range 71–94 years) in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Multivariable logistic regression was used to evaluate the association of audiometric hearing status and self-reported hearing aid use with depressive symptoms (11-item Center for Epidemiologic Studies Depression scale). Results 4.6% of participants had depressive symptoms. Forty percent had mild HL and 27% had moderate or greater HL. In multivariable-adjusted models, mild HL was associated with 1.90 times higher odds (95% confidence interval [CI] 1.20–3.01) and moderate or greater HL with 2.42 times higher odds (95% CI 1.44–4.07) of depressive symptoms compared to normal hearing. Each 10dB increase in HL was associated with 1.30 higher odds of depressive symptoms (95% CI 1.14–1.49). Hearing aid use was not associated with depressive symptoms among those with mild (odds ratio [OR] 0.94, 95% CI 0.35–2.54) or moderate or greater (OR 1.12, 95% CI 0.60–2.11) HL. Discussion Older adults with HL have higher odds of depressive symptoms compared to adults with normal hearing. Future studies are needed to assess whether hearing care is protective against depressive symptoms in older adults.

Importance There is a dearth of studies that examine the association between poorer hearing and change in cerebral white matter (WM) microstructure. Objective To examine the association of poorer hearing with baseline and change in WM microstructure among older adults. Design, Setting, and Participants This was a prospective cohort study that evaluated speech-in-noise, pure-tone audiometry, and WM microstructure, as measured by mean diffusivity (MD) and fractional anisotropy (FA), both of which were evaluated by diffusion tensor imaging (DTI) in 17 WM regions. Data were collected between October 2012 and December 2018 and analyzed between March 2019 and August 2019 with a mean follow-up time of 1.7 years. The study evaluated responses to the Baltimore Longitudinal Study of Aging among 356 cognitively normal adults who had at least 1 hearing assessment and DTI session. Excluded were those with baseline cognitive impairment, stroke, head injuries, Parkinson disease, and/or bipolar disorder. Exposures Peripheral auditory function was measured by pure-tone average in the better-hearing ear. Central auditory function was measured by signal-to-noise ratio score from a speech-in-noise task and adjusted by pure-tone average. Main Outcomes and Measures Linear mixed-effects models with random intercepts and slopes were used to examine the association of poorer peripheral and central auditory function with baseline and longitudinal DTI metrics in 17 WM regions, adjusting for baseline characteristics (age, sex, race, hypertension, elevated total cholesterol, and obesity). Results Of 356 cognitively normal adults included in the study, the mean (SD) age was 73.5 (8.8) years, and 204 (57.3%) were women. There were no baseline associations between hearing and DTI measures. Longitudinally, poorer peripheral hearing was associated with increases in MD in the inferior fronto-occipital fasciculus (β = 0.025; 95% CI, 0.008-0.042) and the body (β = 0.050; 95% CI, 0.015-0.085) of the corpus callosum, but there were no associations of peripheral hearing with FA changes in these tracts. Poorer central auditory function was associated with longitudinal MD increases (β = 0.031; 95% CI, 0.010-0.052) and FA declines (β = −1.624; 95% CI, −2.511 to −0.738) in the uncinate fasciculus. Conclusions and Relevance Findings of this cohort study suggest that poorer hearing is related to change in integrity of specific WM regions involved with auditory processing.

INTRODUCTION: Questions remain about whether APOE-ε4 effects on cognitive decline are similar in men and women and how APOE-ε4 and age interact to influence decline in different cognitive domains. METHODS: In sex stratified analyses, age-dependent associations between APOE-ε4 status and longitudinal cognitive trajectories were examined in cognitively normal older adults (631 men, 561 women, baseline age range: 50–93, 6733 assessments). Where age-dependent relationships were found, age of divergence in trajectories for APOE genotypes was estimated. RESULTS: In men, APOE-ε4 had significant age-dependent effects on longitudinal decline in memory and executive function detectible from baseline age of 64 and 68, respectively. In women, APOE-ε4 had a significant age-dependent effect on longitudinal decline in attention detectible at baseline age of 66. No significant APOE-ε4 effects were found for language, visual-spatial ability or processing speed. DISCUSSION: Results highlight the importance of considering sex and age when assessing APOE-ε4 associated vulnerability to cognitive decline.

Objective Amyloid positivity is a biomarker of AD pathology, yet the associations between amyloid positivity and brain volumetric changes, especially in the hippocampus, are inconsistent. We hypothesize that sex differences in associations may contribute to inconsistent findings among cognitively normal older adults. Methods Using linear mixed effects models, we examined the association of amyloid positivity with prospective volumetric changes (mean = 3.3 visits) of parahippocampal gyrus (phg), hippocampus, entorhinal cortex (erc), precuneus, and fusiform gyrus among 171 Baltimore Longitudinal Study of Aging participants aged ≥55 years. Amyloid positivity was defined by a mean 11C-Pittsburgh Compound B (PiB) distribution volume ratio (DVR) cut-off of 1.062. All analyses included age, race, sex, education, APOE e4 carrier status, and two-way interactions of these covariates with time. Two-way interaction between sex and PiB+/− status and three-way interaction of sex and PiB+/− status with time were added to assess whether sex modified associations. Results PiB+ status was associated with greater volumetric declines in the phg (β = −0.036, SE = 0.011, p = 0.001) and erc (β = −0.019, SE = 0.009, p = 0.045). Sex modified the association of PiB+ status and rates of volumetric declines in fusiform (β = −0.117, SE = 0.049, p = 0.019). PiB+ males had steeper rates of volumetric declines in phg (β = −0.051, SE = 0.013, p, Highlights • Amyloid positivity is related to volume loss in regions of early AD pathology. • Sex modified the association of amyloid positivity and brain volumetric changes. • Amyloid-positive males were vulnerable to volume loss in regions of early AD. • Females with and without amyloid positivity had similar volume changes.

Importance: Dementia affects a large and growing population of older adults. Although past studies suggest an association between vision and cognitive impairment, there are limited data regarding longitudinal associations of vision with dementia. Objective: To evaluate associations between visual impairment and risk of cognitive impairment. Design, Setting, and Participants: A secondary analysis of a prospective longitudinal cohort study compared the likelihood of incident dementia or mild cognitive impairment (MCI) among women with and without baseline visual impairment using multivariable Cox proportional hazards regression models adjusting for characteristics of participants enrolled in Women's Health Initiative (WHI) ancillary studies. The participants comprised community-dwelling older women (age, 66-84 years) concurrently enrolled in WHI Sight Examination (enrollment 2000-2002) and WHI Memory Study (enrollment 1996-1998, ongoing). The study was conducted from 2000 to the present. Exposures: Objectively measured visual impairment at 3 thresholds (visual acuity worse than 20/40, 20/80, or 20/100) and self-reported visual impairment (determined using composite survey responses). Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs for incident cognitive impairment after baseline eye examination were determined. Cognitive impairment (probable dementia or MCI) was based on cognitive testing, clinical assessment, and centralized review and adjudication. Models for (1) probable dementia, (2) MCI, and (3) probable dementia or MCI were evaluated. Results: A total of 1061 women (mean [SD] age, 73.8 [3.7] years) were identified; 206 of these women (19.4%) had self-reported visual impairment and 183 women (17.2%) had objective visual impairment. Forty-two women (4.0%) were ultimately classified with probable dementia and 28 women (2.6%) with MCI that did not progress to dementia. Mean post-eye examination follow-up was 3.8 (1.8) years (range, 0-7 years). Women with vs without baseline objective visual impairment were more likely to develop dementia. Greatest risk for dementia was among women with visual acuity of 20/100 or worse at baseline (HR, 5.66; 95% CI, 1.75-18.37), followed by 20/80 or worse (HR, 5.20; 95% CI, 1.94-13.95), and 20/40 or worse (HR, 2.14; 95% CI, 1.08-4.21). Findings were similar for risk of MCI, with the greatest risk among women with baseline visual acuity of 20/100 or worse (HR, 6.43; 95% CI, 1.66-24.85). Conclusions and Relevance: In secondary analysis of a prospective longitudinal cohort study of older women with formal vision and cognitive function testing, objective visual impairment appears to be associated with an increased risk of incident dementia. However, incident cases of dementia and the proportion of those with visual impairment were low. Research is needed to evaluate the effect of specific ophthalmic interventions on dementia..