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Objectives: Sensory impairment is a hypothesized risk factor for cognitive decline; however, the psychosocial pathways are not well understood. We evaluated whether the association between visual impairment (VI) and cognitive decline was partially mediated via depressive symptoms, loneliness, or social activity., Methods: We used data from 2601 older adults enrolled in the Memory and Aging Project in 1997 and the Minority Aging Research Study in 2004 with neuropsychological tests across five domains measured annually for up to 16 years. VI was assessed with the Rosenbaum Pocket Vision Screener. Depressive symptoms, loneliness, and social activity were self-reported using validated scales. We used structural equation models to estimate the associations of VI with baseline and change in cognitive function, directly and indirectly through each mediator (depressive symptoms, loneliness, and social activity). We evaluated mediation via "psychological distress" using a latent variable combining depressive symptoms and loneliness., Results: The association between VI and global cognitive decline was mediated via lower social activity (indirect effect) [95% confidence interval (CI)] of linear slope: -0.025 (-0.048, -0.011), via loneliness (-0.011 [95% CI: -0.028, -0.002]), and via psychological distress (-0.017 [95% CI: -0.042, -0.003]). We did not find sufficient evidence for mediation via depressive symptoms alone., Conclusions: The harmful effect of VI on cognitive decline may be partially mediated through loneliness and lower social activity., (© 2024 John Wiley & Sons Ltd.)

Liver biotransformation enzymes have long been thought to enable animals to feed on diets rich in xenobiotic compounds. However, despite decades of pharmacological research in humans and rodents, little is known about hepatic gene expression in specialized mammalian herbivores feeding on toxic diets. Leveraging a recently identified population of the desert woodrat (Neotoma lepida) found to be highly tolerant to toxic creosote bush (Larrea tridentata), we explored the expression changes of suites of biotransformation genes in response to diets enriched with varying amounts of creosote resin. Analysis of hepatic RNA-seq data indicated a dose-dependent response to these compounds, including the upregulation of several genes encoding transcription factors and numerous phase I, II, and III biotransformation families. Notably, elevated expression of five biotransformation families - carboxylesterases, cytochromes P450, aldo-keto reductases, epoxide hydrolases, and UDP-glucuronosyltransferases - corresponded to species-specific duplication events in the genome, suggesting that these genes play a prominent role in N. lepida's adaptation to creosote bush. Building on pharmaceutical studies in model rodents, we propose a hypothesis for how the differentially expressed genes are involved in the biotransformation of creosote xenobiotics. Our results provide some of the first details about how these processes likely operate in the liver of a specialized mammalian herbivore., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Gain/amplification of 1q21 (≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma, can negatively affect prognosis, due to its involvement in resistance to anti-myeloma therapy and disease progression. In this updated subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285) in relapsed/refractory multiple myeloma (RRMM), we evaluated progression-free survival (PFS) and depth of response with the anti-CD38 antibody isatuximab plus carfilzomib-dexamethasone (Isa-Kd) versus Kd, in 1q21+ patients and related subgroups, at long-term follow-up (44.2 months). Our analysis included patients with 1q21+ (≥3 copies, with/without high-risk chromosomal abnormality [HRCA]), isolated 1q21+ (≥3 copies, without HRCA), gain(1q21) (3 copies, with/without HRCA), and amp(1q21) (≥4 copies, with/without HRCA). PFS benefit was achieved with Isa-Kd versus Kd in patients with 1q21+ (HR 0.58, 95% CI: 0.37-0.92), with isolated 1q21+ (HR 0.49, 95% CI: 0.27-0.92), with gain(1q21), or amp(1q21), consistent with the overall population and prior interim 1q21+ subgroup analyses. Median PFS with Isa-Kd versus Kd was 25.8 versus 16.2 months in 1q21+ patients and 38.2 versus 16.2 months in patients with isolated 1q21+. Clinically meaningful, higher rates of very good partial response or better, complete response or better (≥CR), minimal residual disease (MRD) negativity, and MRD negativity and ≥CR were reached with Isa-Kd versus Kd in patients with 1q21+, isolated 1q21+, gain(1q21), or amp(1q21). In Isa-Kd and Kd, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in 1q21+ patients, 36.2% versus 12.9% in patients with isolated 1q21+, 27.9% versus 13.5% in patients with gain(1q21), and 31.3% versus 20.0% in patients with amp(1q21), respectively. In conclusion, addition of Isa to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd, in 1q21+ patients at higher risk of progression, including patients with isolated 1q21+, gain(1q21), and amp(1q21), thus supporting Isa-Kd an effective treatment option for patients with RRMM., (© 2024 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Patients with multiple myeloma (MM) who experience early relapse within 12 months of therapy initiation are considered functional high-risk and represent an unmet need, needing better therapies to improve outcomes. The final IKEMA (clinicaltrials gov. identifier: NCT03275285) progression-free survival (PFS) analysis confirmed the significant PFS improvement reported at interim analysis with isatuximab (Isa) plus carfilzomib and dexamethasone (Kd; Isa-Kd) versus Kd in patients with relapsed MM (updated median PFS: 35.7 vs. 19.2 months; hazard ratio [HR] =0.58, 95% confidence interval [CI]: 0.42- 0.79). This IKEMA subgroup analysis examined efficacy and safety of Isa-Kd versus Kd in patients who experienced early (n=61 [Isa-Kd], n=46 [Kd]) vs. late relapse (n=104 [Isa-Kd], n=72 [Kd]). As expected, more aggressive features in baseline characteristics were observed in early relapse patients. Consistent with IKEMA overall population results, median PFS (early relapse: 24.7 vs. 17.2 months, HR=0.662, 95% CI: 0.407-1.077; late relapse: 42.7 vs. 21.9 months, HR=0.542, 95% CI: 0.355- 0.826), minimal residual disease negativity (MRD-) (early relapse: 24.6% vs. 15.2%; late relapse: 37.5% vs. 16.7%), and MRD- complete response (≥CR) rates (early relapse: 18.0% vs. 10.9%; late relapse: 30.8% vs. 13.9%) were higher with Isa-Kd versus Kd, respectively, in both early and late relapse patients. Grade ≥3, serious treatment-emergent adverse events, and death rates were higher in the late relapse Isa-Kd arm. However, the numbers of deaths were low and treatment exposure was significantly longer in Isa-Kd versus Kd late relapse patients. These results support the addition of Isa to Kd as standardof- care therapy for relapsed and/or refractory MM regardless of relapse timing.

Background: Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DL CO ), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment., Results: Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DL CO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DL CO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event., Conclusion: Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691., (© 2023. The Author(s).)

Objective: Due 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., Method: Two 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., Results: Among 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., Conclusions: Impairment in visuospatial ability or memory may be capable of detecting early cognitive changes in the preclinical phase among cognitively normal individuals.

The cerebellum is involved in higher-order cognitive functions, e.g., learning and memory, and is susceptible to age-related atrophy. Yet, the cerebellum's role in age-related cognitive decline remains largely unknown. We investigated cross-sectional and longitudinal associations between cerebellar volume and verbal learning and memory. Linear mixed effects models and partial correlations were used to examine the relationship between changes in cerebellum volumes (total cerebellum, cerebellum white matter [WM], cerebellum hemisphere gray matter [GM], and cerebellum vermis subregions) and changes in verbal learning and memory performance among 549 Baltimore Longitudinal Study of Aging participants (2,292 visits). All models were adjusted by baseline demographic characteristics (age, sex, race, education), and APOE e4 carrier status. In examining associations between change with change, we tested an additional model that included either hippocampal (HC), cuneus, or postcentral gyrus (PoCG) volumes to assess whether cerebellar volumes were uniquely associated with verbal learning and memory. Cross-sectionally, the association of baseline cerebellum GM and WM with baseline verbal learning and memory was age-dependent, with the oldest individuals showing the strongest association between volume and performance. Baseline volume was not significantly associated with change in learning and memory. However, analysis of associations between change in volumes and changes in verbal learning and memory showed that greater declines in verbal memory were associated with greater volume loss in cerebellum white matter, and preserved GM volume in cerebellum vermis lobules VI-VII. The association between decline in verbal memory and decline in cerebellar WM volume remained after adjustment for HC, cuneus, and PoCG volume. Our findings highlight that associations between cerebellum volume and verbal learning and memory are age-dependent and regionally specific., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: Enzyme replacement therapy with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is indicated for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children and adults. An ongoing, open-label, long-term study (NCT02004704) assessed the safety and efficacy of olipudase alfa in 5 adults with ASMD., Results: After 6.5 years of treatment, there were no discontinuations, no olipudase-alfa-related serious adverse events, and no new safety signals compared to earlier assessments. Most treatment-emergent adverse events were mild in intensity (1742/1766, 98.6%). Among treatment-related adverse events (n = 657), more than half were considered infusion-associated reactions (n = 403, 61.3%) such as headache, nausea, abdominal pain, arthralgia, pyrexia, and fatigue. No patient developed neutralizing anti-drug antibodies to cellular uptake, and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Improvements (decreases) in spleen and liver volumes progressed through 6.5 years (mean changes from baseline of -59.5% and  -43.7%, respectively). There was a mean increase in diffusing capacity of the lung for carbon monoxide from baseline of 55.3%, accompanied by improvements in interstitial lung disease parameters. Lipid profiles at baseline indicated dyslipidemia. All patients had sustained decreases in pro-atherogenic lipid levels and increases in anti-atherogenic lipid levels following olipudase alfa treatment., Conclusions: Olipudase alfa is the first disease-specific treatment for ASMD. This study demonstrates that long-term treatment with olipudase alfa is well-tolerated and is associated with sustained improvements in relevant disease clinical measures. NCT02004704 registered 26 November 2013, https://clinicaltrials.gov/ct2/show/NCT02004704?term=NCT02004704&draw=2&rank=1 ., (© 2023. The Author(s).)

Introduction: Sensory impairment (SI) is linked to cognitive decline, but its association with early cognitive impairment (ECI) is unclear., Methods: Sensory functions (vision, hearing, vestibular function, proprioception, and olfaction) were measured between 2012 and 2018 in 414 Baltimore Longitudinal Study of Aging (BLSA) participants (age 74 ± 9 years; 55% women). ECI was defined as 1 standard deviation below age-, sex-, race-, and education-specific mean performance in Card Rotations or California Verbal Learning Test immediate recall. Log binomial models (cross-sectional analysis) and Cox regression models (time-to-event analysis) were used to examine the association between SI and ECI., Results: Cross-sectionally, participants with ≥3 SI had twice the prevalence of ECI (prevalence ratio = 2.10, p  = 0.02). Longitudinally, there was no significant association between SI and incident ECI over up to 6 years of follow-up., Discussion: SI is associated with higher prevalence, but not incident ECI. Future studies with large sample sizes need to further elucidate the relationship between SI and ECI., Highlights: Sensory impairment is associated with high prevalence of early cognitive impairmentMultisensory impairment may pose a strong risk of early changes in cognitive functionIdentifying multisensory impairment may help early detection of dementia., Competing Interests: Frank R. Lin reports being a consultant to Frequency Therapeutics, receiving speaker honoraria from Caption Call, and being the director of a public health research center based at the Johns Hopkins Bloomberg School of Public Health funded in part by Cochlear Ltd. There are no potential conflicts of interest among other authors on the paper. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Olipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12-17 year], nine children [6-11 year], and seven infants/early child [1-5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704). Efficacy endpoints include spleen and liver volumes, diffusing capacity of the lung for carbon monoxide (DL CO ), high-resolution computed tomography (HRCT) lung imaging, lipid profiles, liver function tests, and height Z-scores., Results: All 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively (p < 0.0001) and mean percent-predicted-DL CO increased by 46.6% (p < 0.0001) in nine patients who performed the test at baseline. Lipid profiles and elevated liver transaminase levels that improved or normalized by 1 year remained stable. Mean height Z-scores improved in all age groups (mean change from baseline 1.17, P < 0.0001)., Conclusion: Olipudase alfa was generally well-tolerated during 2 years of treatment. Improvements in clinically relevant disease endpoints observed during the first year of treatment were maintained or augmented in the second year. Trial registration NCT02004704 registered 26 Nov 2013, https://clinicaltrials.gov/ct2/show/record/NCT02004704 ., (© 2022. The Author(s).)

Background: Established associations between hearing loss and cognitive decline were primarily defined by pure-tone audiometry, which reflects peripheral hearing ability. Speech-in-noise performance, which reflects central hearing ability, is more limited in prior literature. We examined the longitudinal associations of audiometric hearing and speech-in-noise performance with cognitive decline., Methods: We studied 702 participants aged ≥60 years in the Baltimore Longitudinal Study of Aging 2012-2019. Global and domain-specific (language, memory, attention, executive function, visuospatial ability) cognitive performance were assessed by the cognitive assessment battery. Hearing thresholds at 0.5, 1, 2, and 4 kilohertz obtained from pure-tone audiometry were averaged to calculate better-ear pure-tone average (PTA) and participants were categorized as having hearing loss (>25 decibels hearing level [dB HL]) or normal hearing (≤25 dB HL). Speech-in-noise performance was assessed by the Quick Speech-in-Noise (QuickSIN) test, and participants were categorized as having below-median (worse) or above-median performance. Linear mixed effects models with random intercepts and slopes were used to assess baseline cognitive performance and cognitive decline by hearing status. Models adjusted for demographic, lifestyle and disease factors., Results: Participants with audiometric hearing loss showed similar baseline cognitive performance but faster decline in global cognitive function, language, executive function, and attention. Participants with below-median QuickSIN score showed worse baseline cognitive performance in all domains and faster decline in global cognitive function, language, memory, executive function and attention., Conclusions: Audiometric hearing might be targeted to delay cognitive decline. Speech-in-noise performance might be a novel marker and might be more sensitive to memory decline., Competing Interests: Author FL reported being a consultant to Frequency Therapeutics, receiving speaker honoraria from Caption Call, and being the director of a public health research center funded in part by a philanthropic donation from Cochlear Ltd. to the Johns Hopkins Bloomberg School of Public Health. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Armstrong, Agrawal, Gross, Schrack, Lin, Ferrucci, Resnick, Deal and Powell.)

Objective: We explored the associations of dual sensory impairment (DSI) with long-term depressive and anxiety symptoms as well as low perceived social support (LPSS) as a modifier of these associations., Methods: Multinomial logistic regression models were used to examine the associations of DSI and single sensory impairment (hearing [pure-tone average > 25 dB] and vision [impaired visual acuity and/or contrast sensitivity]) with long-term depressive symptom (≥8 on the 10-item Center for Epidemiologic Studies-Depression Scale) and anxiety symptom (present on the Hopkins Symptom Checklist) latent classes from group-based trajectory models (rare/never; mild/moderate increasing; chronically high) among 2102 Health, Aging and Body Composition Study participants (mean age:74.0 ± 2.8 years; 51.9 % female) over 10 years. Models were adjusted by demographic characteristics and cardiovascular risk factors, and LPSS. An additional model evaluated the two-way interaction between DSI and LPSS., Results: DSI was associated with increased risk of being chronically depressed (Risk Ratio, RR = 1.99, 95 % Confidence Interval, CI: 1.25, 3.17), not mild/moderate increasingly depressed (RR = 1.25, 95 % CI: 0.91, 1.71). DSI had increased risk of being mild/moderate increasingly anxious (RR = 1.60, 95 % CI: 1.16, 2.19) and chronically anxious (RR = 1.86, 95 % CI: 1.05, 3.27) groups, as compared to no impairments. Hearing impairment was associated with being mild/moderate increasingly anxious (RR = 1.34, 95 % CI: 1.01, 1.79). No other associations were found for single sensory impairments. LPSS did not modify associations., Limitations: Sensory measures were time-fixed, and LPSS, depression and anxiety measures were self-reported., Conclusions: Future research is warranted to determine if DSI therapies may lessen long-term chronically high depressive and anxiety symptoms., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: 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., Method: 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., Results: 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., Conclusions: 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., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (Published by Oxford University Press on behalf of The Gerontological Society of America 2022.)

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., (Published by Oxford University Press on behalf of The Gerontological Society of America 2021.)

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 2020 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 (<1.3 log units on Pelli-Robson test), and hearing impairment (HI) was defined as pure-tone average in better-hearing ear >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 was 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., (© 2022 The American Geriatrics Society.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (Published by Oxford University Press on behalf of The Gerontological Society of America 2021.)

Background: Item response theory (IRT) methods for addressing differential item functioning (DIF) can detect group differences in responses to individual items (e.g., bias). IRT and DIF-detection methods have been used increasingly often to identify bias in cognitive test performance by characteristics (DIF grouping variables) such as hearing impairment, race, and educational attainment. Previous analyses have not considered the effect of missing data on inferences, although levels of missing cognitive data can be substantial in epidemiologic studies., Methods: We used data from Visit 6 (2016-2017) of the Atherosclerosis Risk in Communities Neurocognitive Study (N = 3,580) to explicate the effect of artificially imposed missing data patterns and imputation on DIF detection., Results: When missing data was imposed among individuals in a specific DIF group but was unrelated to cognitive test performance, there was no systematic error. However, when missing data was related to cognitive test performance and DIF group membership, there was systematic error in DIF detection. Given this missing data pattern, the median DIF detection error associated with 10%, 30%, and 50% missingness was -0.03, -0.08, and -0.14 standard deviation (SD) units without imputation, but this decreased to -0.02, -0.04, and -0.08 SD units with multiple imputation., Conclusions: Incorrect inferences in DIF testing have downstream consequences for the use of cognitive tests in research. It is therefore crucial to consider the effect and reasons behind missing data when evaluating bias in cognitive testing., (© 2022. The Author(s).)

Background: Several 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., Methods: Participants 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., Results: Of 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., Conclusions: A 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., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (Published by Oxford University Press 2021.)

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.

Aberrant DNA methylation profiles have been implicated in numerous cardiovascular diseases; however, few studies have investigated how these epigenetic modifications contribute to stroke recurrence. The aim of this study was to identify methylation loci associated with the time to recurrent cerebro- and cardiovascular events in individuals of European and African descent. DNA methylation profiles were generated for 180 individuals from the Vitamin Intervention for Stroke Prevention clinical trial using Illumina HumanMethylation 450K BeadChip microarrays, resulting in beta values for 470,871 autosomal CpG sites. Ethnicity-stratified survival analyses were performed using Cox Proportional Hazards regression models for associations between each methylation locus and the time to recurrent stroke or composite vascular event. Results were validated in the Vall d'Hebron University Hospital cohort from Barcelona, Spain. Network analyses of the methylation loci were generated using weighted gene coexpression network analysis. Primary analysis identified four significant loci, cg04059318, ch.2.81927627R, cg03584380, and cg24875416, associated with time to recurrent stroke. Secondary analysis identified three loci, cg00076998, cg16758041, and cg02365967, associated with time to composite vascular endpoint. Locus cg03584380, which is located in an intron of ZDHHC6, was replicated in the Vall d'Hebron University Hospital cohort. The results from this study implicate the degree of methylation at cg03584380 is associated with the time of recurrence for stroke or composite vascular events across two ethnically diverse groups. Furthermore, modules of loci were associated with clinical traits and blood biomarkers including previous number of strokes, prothrombin fragments 1 + 2, thrombomodulin, thrombin-antithrombin complex, triglyceride levels, and tissue plasminogen activator. Ultimately, these loci could serve as potential epigenetic biomarkers that could identify at-risk individuals in recurrence-prone populations., Competing Interests: The authors have declared that no competing interests exist.

African Americans endure a nearly two-fold greater risk of suffering a stroke and are 2-3 times more likely to die from stroke compared to those of European ancestry. African Americans also have a greater risk of recurrent stroke and vascular events, which are deadlier and more disabling than incident stroke. Stroke is a multifactorial disease with both heritable and environmental risk factors. We conducted an integrative, multi-omic study on 922 plasma metabolites, 473,864 DNA methylation loci, and 556 variants from 50 African American participants of the Vitamin Intervention for Stroke Prevention clinical trial to help elucidate biomarkers contributing to recurrent stroke rates in this high risk population. Sixteen metabolites, including cotinine, N-delta-acetylornithine, and sphingomyelin (d17:1/24:1) were identified in t-tests of recurrent stroke outcome or baseline smoking status. Serum tricosanoyl sphingomyelin (d18:1/23:0) levels were significantly associated with recurrent stroke after adjusting for covariates in Cox Proportional Hazards models. Weighted Gene Co-expression Network Analysis identified moderate correlations between sphingolipid markers and clinical traits including days to recurrent stroke. Integrative analyses between genetic variants in sphingolipid pathway genes identified 29 nominal associations with metabolite levels in a one-way analysis of variance, while epigenomic analyses identified xenobiotics, predominately smoking-associated metabolites and pharmaceutical drugs, associated with methylation profiles. Taken together, our results suggest that metabolites, specifically those associated with sphingolipid metabolism, are potential plasma biomarkers for stroke recurrence in African Americans. Furthermore, genetic variation and DNA methylation may play a role in the regulation of these metabolites., Competing Interests: The authors have declared that no competing interests exist.

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: 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., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To discriminate among degrees of auditory performance of the Digits-in-Noise (DIN) test., Design: 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. Study Sample: 3422 Rotterdam Study participants aged 51-98 years between 2011 and 2014., Results: 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., Conclusions: Discrimination of degrees of auditory performance may add greater utility of the DIN test.

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.

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.

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., (Published by Elsevier Inc.)

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.

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.

Background: Depressive symptoms and hearing loss (HL) are independently associated with increased risk of incident disability; whether the increased risk is additive is unclear., Methods: Cox Proportional Hazards models were used to assess joint associations of HL (normal, mild, moderate/severe) and late-life depressive symptoms (defined by a score of ≥8 on the 10-item Center for Epidemiologic Studies-Depression scale) with onset of mobility disability (a lot of difficulty or inability to walk ¼ mile and/or climb 10 steps) and any disability in activities of daily living (ADL), among 2,196 participants of the Health, Aging and Body Composition Study, a cohort of well-functioning older adults aged 70-79 years. Models were adjusted for age, race, sex, education, diabetes, hypertension, and body mass index., Results: Relative to participants with normal hearing and without depressive symptoms, participants without depressive symptoms who had mild or moderate/severe HL had increased risk of incident mobility and ADL disability (hazard ratio [HR] for mobility disability, mild HL:1.34, 95% confidence interval [CI]: 1.09, 1.64 and HR for mobility disability, moderate/severe HL: 1.37, 95% CI: 1.08, 1.75 and HR for ADL disability, mild HL: 1.32, 95% CI: 1.08, 1.63, and HR for ADL disability, moderate/severe HL: 1.42, 95% CI: 1.11, 1.82). Among participants with depressive symptoms, mild HL (HR: 1.71, 95% CI: 1.09, 2.70) was associated with increased risk of incident mobility disability., Conclusions: Independent of depressive symptoms, risk of incident disability was greater in older adults with HL, regardless of severity. Further research into HL interventions may delay disability onset., (Published by Oxford University Press on behalf of The Gerontological Society of America 2018.)

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., (Published by Oxford University Press on behalf of The Gerontological Society of America 2019.)

Background: Hearing impairment (HI) could be a risk factor for cognitive decline, but cognition could plausibly also affect psychoacoustic assessment of hearing with audiometry. We examined the temporal sequence of hearing and cognitive function among nondemented, community-dwelling older adults., Methods: Hearing and cognition were assessed between 2012 and 2015 and 2 years thereafter in 313 nondemented participants aged ≥60 years in the Baltimore Longitudinal Study of Aging. Poorer hearing was defined by pure-tone average of 0.5-4 kHz tones in the better-hearing ear. Cognitive measures with either visual or auditory inputs were Trail-making Test Part B; Digit Symbol Substitution Test; California Verbal Learning Test immediate recall, short delay, and long delay; Digit Span Forward/Backward; Benton Visual Retention Test; and Mini-Mental State Examination. We used linear regression models for cross-sectional associations at each timepoint and autoregressive, cross-lagged models to evaluate whether baseline hearing impairment (Time 1) predicted cognitive performance 2 years after baseline (Time 2) and vice versa., Results: Cross-sectionally, there were no associations between poorer hearing and cognitive performance. Longitudinally, poorer hearing was associated with declines in California Verbal Learning Test immediate (β = -0.073, SE = 0.032, p = .024), short-delayed (β = -0.134, SE = 0.043, p = .002), long-delayed (β = -0.080, SE = 0.032, p = .012) recall, and Digit Span Forward (β = -0.074, SE = 0.029, p = .011).) from Time 1 to Time 2. Cognitive performance at Time 1 did not predict change in hearing status at Time 2., Conclusions: Audiometric hearing impairment predicted short-term cognitive declines in both California Verbal Learning Test and auditory stimuli for attention., (Published by Oxford University Press on behalf of The Gerontological Society of America 2018.)

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: 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 BLSA 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 Test Part A 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.

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 <9, yet latent growth model approaches were most informative. Initial levels of performance on easy (Risk Ratio, [RR] = 1.24; 95% Confidence Interval, [CI]: 1.03, 1.49) and difficult conditions (RR = 1.22; 95% CI: 1.05, 1.41), not rates of learning (slope) (RR = 1.08, 95% CI: 0.81, 1.45 and RR = 1.11, 95% CI: 0.96, 1.27 respectively), were associated with worse physical functioning. Conclusions : The association between the CFI and physical functioning demonstrates the interplay of cognitive frailty and worse objective mobility within a sociodemographic at-risk sample.

It is unclear how coronary heart disease (CHD) risk across the adult life span affects late-life cognition. We estimated associations of midlife and late-life elevated CHD risk with cognitive trajectories (general cognitive performance, processing speed/executive function, memory) in later life (after age 55 years or age 70 years) among 2,892 Framingham Offspring Study participants who had completed CHD risk assessments approximately every 4 years since 1971 and had undergone neuropsychological testing between 1999 and 2014. We stratified analyses by apolipoprotein E gene (APOE) Ɛ4 allele carrier status. Using linear mixed-effects models, elevated CHD risk in midlife (age 55 years) was associated with lower levels of general cognitive performance (β = -0.560 standard deviation (SD) units, 95% confidence interval (CI): -0.874, -0.246), executive function (β = -0.624 SD units, 95% CI: -0.916, -0.332), and memory (β = -0.560 SD units, 95% CI: -0.907, -0.213) at age 70 years but not with rates of cognitive change. Late-life (age 70 years) elevated CHD risk, however, was associated with somewhat better levels of general cognitive performance and memory. There were associations between duration of elevated CHD risk during midlife and levels (but not trajectories) of later-life cognitive outcomes. Associations were not modified by APOE-ɛ4 status. These findings suggest that midlife elevated CHD risk is associated with lower cognition, independently of APOE-ɛ4 status, suggesting that risk of vascular disease may not contribute a "second hit" to AD risk., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.)