Longitudinal Associations Between Optimism and Objective Measures of Physical Functioning in Women.

Importance: Identifying factors contributing to sustained physical functioning is critical for the health and well-being of the aging population, especially as physical functioning may precede and predict subsequent health outcomes. Prior work suggests optimism may protect health, but less is known about the association between optimism and objective physical functioning measures as individuals age. Objective: To evaluate the longitudinal association between optimism and 3 physical functioning measures. Design, Setting, and Participants: This was a prospective cohort study using data from the Women's Health Initiative (WHI) with participants recruited from 1993 to 1998 and followed up over 6 years. Data analysis was conducted from January 2022 to July 2022. Participants included postmenopausal women older than 65 years recruited from 40 clinical centers in the US. Exposure: Optimism was assessed at baseline using the Life Orientation Test-Revised. Main Outcomes and Measures: Physical functioning was measured at 4 time points across 6 years by study staff evaluating performance in grip strength, timed walk, and chair stands. Results: The final analytic sample included 5930 women (mean [SD] age, 70 [4] years). Linear mixed-effects models controlling for demographics, depression, health status, and health behaviors showed that higher optimism was associated with higher grip strength (ß = 0.36; 95% CI, 0.21-0.50) and number of chair stands (ß = 0.05; 95% CI, 0.01-0.10) but not timed walk at baseline. Higher optimism was also associated with slower rates of decline in timed walk (ß = -0.09; 95% CI, -0.13 to -0.04) and number of chair stands (ß = 0.01; 95% CI, 0-0.03) but not grip strength over time. Cox proportional hazards models showed that higher optimism was associated with lower hazards of reaching clinically defined thresholds of impairment for all 3 outcomes over 6 years of follow-up. For example, in fully adjusted models, for a 1-SD increase in optimism, hazard ratios for reaching impairment thresholds were 0.86 (95% CI, 0.80-0.92) for grip strength, 0.94 (95% CI, 0.88-1.01) for timed walk, and 0.91 (95% CI, 0.85-0.98) for chair stands. Conclusion and Relevance: In this cohort study of postmenopausal women, at baseline, higher optimism was associated with higher grip strength and number of chair stands but not with the time it took to walk 6 m. Higher optimism at baseline was also associated with maintaining healthier functioning on 2 of the 3 performance measures over time, including less decline in walking speed and in number of chair stands women could perform over 6 years of follow-up. Given experimental studies suggesting that optimism is modifiable, it may be a promising target for interventions to slow age-related declines in physical functioning. Future work should explore associations of optimism with maintenance of physical functioning in diverse populations.

Purpose in Life and Its Association to Parkinsonism.

OBJECTIVES: Purpose in life has been associated with diverse health outcomes; however, few studies have examined its associations with progressive motor decline in older adults. We tested if higher purpose would be associated with lower likelihood of incident parkinsonism as well as with lower levels and slower rates of increase in parkinsonian signs. METHODS: Participants were 2,626 older adults from the Rush Memory and Aging Project and Minority Aging Research Study followed for an average of 7.2 years (standard deviation [SD] = 4.6). Purpose was measured using the purpose in life subscale of the modified Ryff's and Keyes's measure of psychological well-being. Four parkinsonian signs (i.e., parkinsonian gait, rigidity, bradykinesia, and tremor) were assessed using the United Parkinson's Disease Rating Scale. We examined purpose with risk of developing incident parkinsonism using Cox proportional hazards models. We also used linear mixed-effect models to assess the association between purpose and parkinsonian sign trajectories. RESULTS: After including demographics, health conditions, and health behaviors in the model, for a 1-SD increase in purpose, the hazards ratio for incident parkinsonism was 0.88 (95% confidence interval [CI] 0.80, 0.97). A 1-SD increase in purpose was associated with a -0.19 (95% CI -0.24, -0.15) point lower score in the global parkinsonian summary score at baseline but no differences in rate of change were evident. DISCUSSION: Higher purpose was associated with lower hazards of incident parkinsonism and lower levels of parkinsonian signs at baseline. Associations were seen even after adjustment for a wide range of covariates. Findings suggest higher purpose may contribute to maintenance of healthy physical function among older adults.

Everyday Discrimination is Associated with Higher Odds of Hospitalizations among Older African Americans.

BACKGROUND: Everyday discrimination-experiences of being treated unfairly based on background characteristics like race-is linked to poor physical and mental health throughout the lifespan. Whether more experiences of discrimination are associated with higher odds of being hospitalized in older African Americans has not been explored. METHODS: Community-dwelling participants from three longitudinal cohort studies (N=446, age 65+ years, with discrimination scores and ≥12 months of linked Medicare claims were included. Hospitalizations were identified using Medicare fee-for-service claims, available for an average of 6.2 (SD: 3.7) years follow-up after baseline. RESULTS: In mixed-effects ordinal logistic regression models (outcomes of 0, 1, or 2+ hospitalizations per year) adjusted for age, sex, education, and income, higher discrimination was associated with higher odds of total annual hospitalizations (OR per point higher=1.09, 95% CI: 1.02-1.17). Results were similar when accounting for depressive symptoms. CONCLUSIONS: Higher exposure to everyday discrimination is associated with higher odds of hospitalization among older African Americans. Mechanisms underlying associations should be explored further to understand how hospitalizations may be reduced in older African Americans.

Association of Age-Related Neuropathologic Findings at Autopsy With a Claims-Based Epilepsy Diagnosis in Older Adults.

BACKGROUND AND OBJECTIVES: Epilepsy is 1 of the 3 most common neurologic diseases of older adults, but few studies have examined its underlying pathologies in older age. We examined the associations of age-related brain pathologies with epilepsy in older persons. METHODS: Clinical and pathologic data came from 2 ongoing clinical pathologic cohort studies of community-dwelling older adults. Epilepsy was ascertained using Medicare fee-for-service Parts A and B claims data that were linked to data from the cohort studies. The postmortem pathologic assessment collected indices of 9 pathologies including Alzheimer disease, hippocampal sclerosis, macroinfarcts, and cerebral amyloid angiopathy. The fixed brain hemisphere was imaged using 3T MRI scanners before the pathologic assessments in a subgroup of participants. RESULTS: The participants (n = 1,369) were on average 89.3 (6.6) years at death, and 67.0% were women. Epilepsy was identified in 58 (4.2%) participants. Cerebral amyloid angiopathy (odds ratio [OR] = 2.21, 95% CI 1.24-3.95, p = 0.007) and cortical macroinfarcts (OR = 2.74, 95% CI 1.42-5.28, p = 0.003) were associated with a higher odds of epilepsy. Of note, hippocampal sclerosis and Alzheimer disease pathology were not associated with epilepsy (both p's > 0.25), although hippocampal sclerosis was not common and thus hard to examine with the modest number of epilepsy cases here. In 673 participants with MRI data, the association of cerebral amyloid angiopathy and cortical macroinfarcts with epilepsy did not change after controlling for cortical gray matter atrophy, which was independently associated with a higher odds of epilepsy (OR = 1.06, 95% CI 1.02-1.10, p = 0.003). By contrast, hippocampal volume was not associated with epilepsy. DISCUSSION: Cerebrovascular pathologies and cortical atrophy were associated with epilepsy in older persons.

Plasma metabolites of a healthy lifestyle in relation to mortality and longevity: Four prospective US cohort studies.

BACKGROUND: A healthy lifestyle is associated with a lower premature mortality risk and with longer life expectancy. However, the metabolic pathways of a healthy lifestyle and how they relate to mortality and longevity are unclear. We aimed to identify and replicate a healthy lifestyle metabolomic signature and examine how it is related to total and cause-specific mortality risk and longevity. METHODS: In four large cohorts with 13,056 individuals and 28-year follow-up, we assessed five healthy lifestyle factors, used liquid chromatography mass spectrometry to profile plasma metabolites, and ascertained deaths with death certificates. The unique healthy lifestyle metabolomic signature was identified using an elastic regression. Multivariable Cox regressions were used to assess associations of the signature with mortality and longevity. FINDINGS: The identified healthy lifestyle metabolomic signature was reflective of lipid metabolism pathways. Shorter and more saturated triacylglycerol and diacylglycerol metabolite sets were inversely associated with the healthy lifestyle score, whereas cholesteryl ester and phosphatidylcholine plasmalogen sets were positively associated. Participants with a higher healthy lifestyle metabolomic signature had a 17% lower risk of all-cause mortality, 19% for cardiovascular disease mortality, and 17% for cancer mortality and were 25% more likely to reach longevity. The healthy lifestyle metabolomic signature explained 38% of the association between the self-reported healthy lifestyle score and total mortality risk and 49% of the association with longevity. CONCLUSIONS: This study identifies a metabolomic signature that measures adherence to a healthy lifestyle and shows prediction of total and cause-specific mortality and longevity. FUNDING: This work was funded by the NIH, CIHR, AHA, Novo Nordisk Foundation, and SciLifeLab.

Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

A prospective study of the association of cognitive and motor function with odds of life space constriction in older adults.

BACKGROUND: Many studies indicate that smaller life space is related to worse cognitive and motor function. It is plausible that cognitive and motor function also predict life space constriction, thus long-term, prospective studies are needed of cognitive and motor function as predictors of life space. METHODS: A total of 1246 participants of the Rush Memory and Aging Project, who reported initial maximal life space and at least one follow-up assessment were included in this prospective study, with up to 19 years follow-up. The outcome of interest was the Modified version of the Life Space Questionnaire; which we categorized into large (beyond community), medium (neighborhood/community), and small (home/yard) life space. Participants also had detailed composite measures of global cognition and motor function as predictors and available at the first life space assessment. Life space transitions over one-year periods were modeled using multistate Markov modeling, including confounders and both predictors simultaneously. RESULTS: Better cognitive and motor function were broadly associated with lower odds of life space constriction (Cognitive: Large ➔ medium: OR = 0.91, 95% CI 0.83-1.00; Large ➔ small: OR = 0.85, 95% CI 0.74-0.97; Medium ➔ small: OR = 1.01, 95% CI 0.82-1.22. Motor: large ➔ medium: OR = 0.76, 95% CI 0.69-0.83; large ➔ small: OR = 0.58, 95% CI 0.51-0.67; medium ➔ small: OR = 0.71, 95% CI = 0.57-0.87). CONCLUSIONS: Combined with previous literature that life space predicts function, these results support the notion of complex inter-relations of cognitive function, motor function, and life space.

Post-traumatic stress disorder symptom remission and cognition in a large cohort of civilian women.

BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with cognitive impairments. It is unclear whether problems persist after PTSD symptoms remit. METHODS: Data came from 12 270 trauma-exposed women in the Nurses' Health Study II. Trauma and PTSD symptoms were assessed using validated scales to determine PTSD status as of 2008 (trauma/no PTSD, remitted PTSD, unresolved PTSD) and symptom severity (lifetime and past-month). Starting in 2014, cognitive function was assessed using the Cogstate Brief Battery every 6 or 12 months for up to 24 months. PTSD associations with baseline cognition and longitudinal cognitive changes were estimated by covariate-adjusted linear regression and linear mixed-effects models, respectively. RESULTS: Compared to women with trauma/no PTSD, women with remitted PTSD symptoms had a similar cognitive function at baseline, while women with unresolved PTSD symptoms had worse psychomotor speed/attention and learning/working memory. In women with unresolved PTSD symptoms, past-month PTSD symptom severity was inversely associated with baseline cognition. Over follow-up, both women with remitted and unresolved PTSD symptoms in 2008, especially those with high levels of symptoms, had a faster decline in learning/working memory than women with trauma/no PTSD. In women with remitted PTSD symptoms, higher lifetime PTSD symptom severity was associated with a faster decline in learning/working memory. Results were robust to the adjustment for sociodemographic, biobehavioral, and health factors and were partially attenuated when adjusted for depression. CONCLUSION: Unresolved but not remitted PTSD was associated with worse cognitive function assessed six years later. Accelerated cognitive decline was observed among women with either unresolved or remitted PTSD symptoms.

Identification of Dementia in Medicare Claims Compared to Rigorous Clinical Assessments in African Americans.

BACKGROUND: Evidence indicates the health care system disproportionately misses dementia in African American compared to White individuals. In preliminary data, we examined factors related to dementia identification by the health care system among African Americans. METHODS: We leveraged linked Medicare fee-for-service claims and detailed annual cohort evaluations in African Americans from 4 cohorts at Rush Alzheimer's Disease Center. RESULTS: Among 88 African Americans with cognitive impairment (mean = 10 years follow-up), Medicare claims identified dementia <2 years from cohort diagnosis in 55%; 27% were identified 2-9.9 years after cohort diagnosis, and in 18% there was either no claims diagnosis during the study period, or claims identified dementia 10+ years after cohort diagnosis. Claims identification of dementia was related to older age at cohort diagnosis (eg, <2 years between cohort and claims: mean = 82 years; 10+ years/no diagnosis: mean = 77 years, p = .04), lower Mini-Mental State Examination (MMSE) score (<2 years: mean = 24; 10+ years/no diagnosis: mean = 26, p = .04), more depressive symptoms (<2 years: mean = 2.1 symptoms; 10+ years/no diagnosis: mean = 1.2, p = .04), and more comorbidity (<2 years: mean = 5.6 comorbidities; 10+ years/no diagnosis, mean = 3.0, p = .02). CONCLUSIONS: Among African Americans, preliminary data indicate the health care system most rapidly identifies dementia in older individuals, with worse cognitive and physical health. The health care system may miss opportunities for early support of African Americans with dementia, and caregivers.

A long and resilient life: the role of coping strategies and variability in their use in lifespan among women.

OBJECTIVES: Associations of stress-related coping strategies with lifespan among the general population are understudied. Coping strategies are characterized as being either adaptive or maladaptive, but it is unknown the degree to which variability in tailoring their implementation to different contexts may influence lifespan. METHOD: Women (N = 54,353; Mage = 47) completed a validated coping inventory and reported covariate information in 2001. Eight individual coping strategies (e.g., Acceptance, Denial) were considered separately. Using a standard deviation-based algorithm, participants were also classified as having lower, moderate, or greater variability in their use of these strategies. Deaths were ascertained until 2019. Accelerated failure time models estimated percent changes and 95% confidence intervals (CI) in predicted lifespan associated with coping predictors. RESULTS: In multivariable models, most adaptive and maladaptive strategies were associated with longer and shorter lifespans, respectively (e.g., per 1-SD increase: Active Coping = 4.09%, 95%CI = 1.83%, 6.41%; Behavioral Disengagement = -6.56%, 95%CI = -8.37%, -4.72%). Moderate and greater (versus lower) variability levels were similarly and significantly related to 8-10% longer lifespans. Associations were similar across age, racial/ethnic, residential income, and marital status subgroups. CONCLUSIONS: Findings confirm the adaptive and maladaptive nature of specific coping strategies, and further suggest benefits from both moderate and greater variability in their use for lifespan among women.

Risks and Benefits of Clinical Diagnosis Around the Time of Dementia Onset.

Diagnostic delay in dementia is common in the U.S. Drivers of diagnostic delay are poorly understood, but appear related to misconceptions about dementia, stigma, concerns about autonomy, the nature of the diagnostic process, and provider-related factors. There is little quantitative evidence underlying cited risks and benefits of receiving a diagnosis around the time of dementia onset, including impacts on physical health, impacts on mental health, care partner interactions, costs of care, increased time for care planning, or earlier access to treatment. While various groups continue to push for reductions in diagnostic delay, realization of benefits and mitigation of harms will require new research on potential benefits and harms. Workforce and resource constraints, coupled with the expected growth in the number of persons living with dementia, may be a barrier to realization of potential benefits and mitigation of identified harms, which will require adequate access to providers, services, and supports.

Navigating and diagnosing cognitive frailty in research and clinical domains.

While physical frailty has been recognized as a clinical entity for some time, the concept of cognitive frailty (CF) is now gaining increasing attention in the geriatrics research community. CF refers to the co-occurrence of physical frailty and cognitive impairment in older adults, which has been suggested as a potential precursor to both dementia and adverse physical outcomes. However, this condition represents a challenge for researchers and clinicians, as there remains a lack of consensus regarding the definition and diagnostic criteria for CF, which has limited its utility. Here, using insights from both the physical frailty literature and cognitive science research, we describe emerging research on CF. We highlight areas of agreement as well as areas of confusion and remaining knowledge gaps, and provide our perspective on fine-tuning the current construct, aiming to stimulate further discussion in this developing field.

Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer's disease.

Telomere length (TL) attrition, epigenetic age acceleration, and mitochondrial DNA copy number (mtDNAcn) decline are established hallmarks of aging. Each has been individually associated with Alzheimer's dementia, cognitive function, and pathologic Alzheimer's disease (AD). Epigenetic age and mtDNAcn have been studied in brain tissue directly but prior work on TL in brain is limited to small sample sizes and most studies have examined leukocyte TL. Importantly, TL, epigenetic age clocks, and mtDNAcn have not been studied jointly in brain tissue from an AD cohort. We examined dorsolateral prefrontal cortex (DLPFC) tissue from N = 367 participants of the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP). TL and mtDNAcn were estimated from whole genome sequencing (WGS) data and cortical clock age was computed on 347 CpG sites. We examined dementia, MCI, and level of and change in cognition, pathologic AD, and three quantitative AD traits, as well as measures of other neurodegenerative diseases and cerebrovascular diseases (CVD). We previously showed that mtDNAcn from DLPFC brain tissue was associated with clinical and pathologic features of AD. Here, we show that those associations are independent of TL. We found TL to be associated with ß-amyloid levels (beta = - 0.15, p = 0.023), hippocampal sclerosis (OR = 0.56, p = 0.0015) and cerebral atherosclerosis (OR = 1.44, p = 0.0007). We found strong associations between mtDNAcn and clinical measures of AD. The strongest associations with pathologic measures of AD were with cortical clock and there were associations of mtDNAcn with global AD pathology and tau tangles. Of the other pathologic traits, mtDNAcn was associated with hippocampal sclerosis, macroscopic infarctions and CAA and cortical clock was associated with Lewy bodies. Multi-modal age acceleration, accelerated aging on both mtDNAcn and cortical clock, had greater effect size than a single measure alone. These findings highlight for the first time that age acceleration determined on multiple genomic measures, mtDNAcn and cortical clock may have a larger effect on AD/AD related disorders (ADRD) pathogenesis than single measures.

Plasma metabolomic profiles associated with mortality and longevity in a prospective analysis of 13,512 individuals.

Experimental studies reported biochemical actions underpinning aging processes and mortality, but the relevant metabolic alterations in humans are not well understood. Here we examine the associations of 243 plasma metabolites with mortality and longevity (attaining age 85 years) in 11,634 US (median follow-up of 22.6 years, with 4288 deaths) and 1878 Spanish participants (median follow-up of 14.5 years, with 525 deaths). We find that, higher levels of N2,N2-dimethylguanosine, pseudouridine, N4-acetylcytidine, 4-acetamidobutanoic acid, N1-acetylspermidine, and lipids with fewer double bonds are associated with increased risk of all-cause mortality and reduced odds of longevity; whereas L-serine and lipids with more double bonds are associated with lower mortality risk and a higher likelihood of longevity. We further develop a multi-metabolite profile score that is associated with higher mortality risk. Our findings suggest that differences in levels of nucleosides, amino acids, and several lipid subclasses can predict mortality. The underlying mechanisms remain to be determined.

Association Between Bowel Movement Pattern and Cognitive Function: Prospective Cohort Study and a Metagenomic Analysis of the Gut Microbiome.

BACKGROUND AND OBJECTIVES: Little is known regarding the association between intestinal motility patterns and cognitive function in individuals who are baseline cognitively healthy. The gut microbiome may contribute to the association. We examined the association between bowel movement (BM) pattern and cognitive function and explored the role of the gut microbiome in explaining this association. METHODS: In this prospective study, we leveraged 3 cohort studies, Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS). Participants reported BM frequency and subjective cognitive function. In a subset of NHSII participants, we assessed cognitive function using an objective neuropsychological battery. We profiled the gut microbiome in a subset of participants using whole-genome shotgun metagenomics. General linear models, Poisson regression, and logistic regression were used to quantify the association of BM frequency with different cognitive measurements. RESULTS: We followed 112,753 men and women (women: 87.6%) with a mean age of 67.2 years at baseline (NHS: 76 years, NHSII: 59 years, HPFS: 75 years) for a median follow-up of 4 years (NHSII and HPFS: 4 years, NHS: 2 years). Compared with those with BM once daily, participants with BM frequency every 3+ days had significantly worse objective cognitive function, equivalent to 3.0 (95% confidence interval [CI],1.2-4.7) years of chronological cognitive aging. We observed similar J-shape dose-response relationships of BM frequency with the odds of subjective cognitive decline and the likelihood of having more subsequent subjective cognitive complaints (both p nonlinearity < 0.001). BM frequencies of every 3+ days and ≥twice/day, compared with once daily, were associated with the odds ratios of subjective cognitive decline of 1.73 (95% CI 1.60-1.86) and 1.37 (95% CI 1.33-1.44), respectively. BM frequency and subjective cognitive decline were significantly associated with the overall gut microbiome configuration (both p < 0.005) and specific microbial species in the 515 participants with microbiome data. Butyrate-producing microbial species were depleted in those with less frequent BM and worse cognition, whereas a higher abundance of proinflammatory species was associated with BM frequency of ≥twice/day and worse cognition. DISCUSSION: Lower BM frequency was associated with worse cognitive function. The gut microbial dysbiosis may be a mechanistic link underlying the association.

Total and free 25-hydroxyvitamin D concentrations and risk of urinary incontinence in women participating in Nurses Health Studies I & II.

BACKGROUND: Urgency urinary incontinence (UUI) occurs in >40% of older women. Our objective was to examine the relationship of total and free plasma 25-hydroxyvitamin D (25(OH)D) and UUI to evaluate vitamin D status as a novel target for prevention of UUI. METHODS: We conducted a nested case control study using the Nurses' Health Study (NHS) and NHS II. Using stored plasma samples from 2000, we measured total 25(OH)D, free 25(OH)D, and intact parathyroid hormone (PTH) levels and examined their relationship to incident UUI from 2000 to 2013. Plasma biomarker levels were categorized as quartiles. Multivariable-adjusted odds ratios of UUI were estimated by conditional logistic regression models (with matching by age) across categories of each biomarker and covariates. RESULTS: The analytic sample included 398 cases of incident UUI and 398 matched controls with a mean age of 50 years. We found a strong correlation of plasma levels of total 25(OH)D with free 25(OH)D (r=0.5). Plasma total 25(OH)D and free 25(OH)D concentrations were negatively correlated with PTH (r=-0.08 AND -0.09, respectively). Overall, we found no evidence that levels of total plasma 25(OH)D, free 25(OH)D, or PTH were related to incident UUI after adjustment for obesity, physical activity, cigarette smoking, menopausal status, hypertension, and type 2 diabetes. CONCLUSIONS: Free plasma 25(OH)D by quartile, as well as total plasma 25(OH)D, was not associated with incident UUI in women. We found that plasma total and free 25(OH)D were highly correlated with each other and inversely correlated with PTH. Plasma free 25(OH)D did not provide additional predictive value in determining risk of UUI.

The MIND diet, brain transcriptomic alterations, and dementia.

Identifying novel mechanisms underlying dementia is critical to improving prevention and treatment. As an approach to mechanistic discovery, we investigated whether MIND diet (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), a consistent risk factor for dementia, is correlated with a specific profile of cortical gene expression, and whether such a transcriptomic profile is associated with dementia, in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). RNA sequencing (RNA-Seq) was conducted in postmortem dorsolateral prefrontal cortex tissue from 1,204 deceased participants; neuropsychological assessments were performed annually prior to death. In a subset of 482 participants, diet was assessed ~6 years before death using a validated food-frequency questionnaire; in these participants, using elastic net regression, we identified a transcriptomic profile, consisting of 50 genes, significantly correlated with MIND diet score (P=0.001). In multivariable analysis of the remaining 722 individuals, higher transcriptomic score of MIND diet was associated with slower annual rate of decline in global cognition (ß=0.011 per standard deviation increment in transcriptomic profile score, P=0.003) and lower odds of dementia (odds ratio [OR] =0.76, P=0.0002). Cortical expression of several genes appeared to mediate the association between MIND diet and dementia, including TCIM, whose expression in inhibitory neurons and oligodendrocytes was associated with dementia in a subset of 424 individuals with single-nuclei RNA-seq data. In a secondary Mendelian randomization analysis, genetically predicted transcriptomic profile score was associated with dementia (OR=0.93, P=0.04). Our study suggests that associations between diet and cognitive health may involve brain molecular alterations at the transcriptomic level. Investigating brain molecular alterations related to diet may inform the identification of novel pathways underlying dementia.

Nutritional redundancy in the human diet and its application in phenotype association studies.

Studying human dietary intake may help us identify effective measures to treat or prevent many chronic diseases whose natural histories are influenced by nutritional factors. Here, by examining five cohorts with dietary intake data collected on different time scales, we show that the food intake profile varies substantially across individuals and over time, while the nutritional intake profile appears fairly stable. We refer to this phenomenon as 'nutritional redundancy' and attribute it to the nested structure of the food-nutrient network. This network enables us to quantify the level of nutritional redundancy for each diet assessment of any individual. Interestingly, this nutritional redundancy measure does not strongly correlate with any classical healthy diet scores, but its performance in predicting healthy aging shows comparable strength. Moreover, after adjusting for age, we find that a high nutritional redundancy is associated with lower risks of cardiovascular disease and type 2 diabetes.

Treatment for Urinary Incontinence in Women Older Than 65 Years.

IMPORTANCE: Urinary incontinence (UI) is common among women older than 65 years and negatively affects quality of life. However, the prevalence of UI treatment and determinants of treatment are largely unknown. OBJECTIVES: The aim of this study was to identify rates of UI treatment and factors associated with treatment in older women with self-reported UI. STUDY DESIGN: This is a retrospective cohort analysis of a data set linking UI symptoms from the Nurses' Health Study to Medicare claims. We evaluated use of pharmacotherapy, noninvasive, and procedural treatments for UI within 1 year before symptom survey. For pharmacotherapy, we used multivariable logistic regression to estimate odds ratios (ORs) of UI treatment. RESULTS: Of the 67,587 Nurses' Health Study respondents, 15,088 had linkage to Medicare, subscribed to part D, and answered UI questions. Of these, 8,332 (55.2%) women reported UI, and 10.9% with UI had a Medicare claim for treatment; pharmacotherapy represented 94.6% of all treatments.On regression analysis, women with more severe and longer-term UI had higher odds of treatment (severe vs slight UI: OR, 3.1; 95% confidence interval [CI], 2.2-4.3) (longer vs new UI: OR, 1.9; 95% CI, 1.5-2.3). Women with mixed (OR, 2.5; 95% CI, 1.9-3.2) or urgency UI (OR, 3.0; 95% CI, 2.2-3.9) had greater odds of treatment compared with women with stress UI. CONCLUSIONS: We estimate that only approximately 1 in 9 older women with self-reported UI underwent treatment within the year before reporting symptoms, of which pharmacotherapy was the most common UI intervention, and women with more severe and longer duration of symptoms were most often treated.

Trial of the MIND Diet for Prevention of Cognitive Decline in Older Persons.

BACKGROUND: Findings from observational studies suggest that dietary patterns may offer protective benefits against cognitive decline, but data from clinical trials are limited. The Mediterranean-DASH Intervention for Neurodegenerative Delay, known as the MIND diet, is a hybrid of the Mediterranean diet and the DASH (Dietary Approaches to Stop Hypertension) diet, with modifications to include foods that have been putatively associated with a decreased risk of dementia. METHODS: We performed a two-site, randomized, controlled trial involving older adults without cognitive impairment but with a family history of dementia, a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 25, and a suboptimal diet, as determined by means of a 14-item questionnaire, to test the cognitive effects of the MIND diet with mild caloric restriction as compared with a control diet with mild caloric restriction. We assigned the participants in a 1:1 ratio to follow the intervention or the control diet for 3 years. All the participants received counseling regarding adherence to their assigned diet plus support to promote weight loss. The primary end point was the change from baseline in a global cognition score and four cognitive domain scores, all of which were derived from a 12-test battery. The raw scores from each test were converted to z scores, which were averaged across all tests to create the global cognition score and across component tests to create the four domain scores; higher scores indicate better cognitive performance. The secondary outcome was the change from baseline in magnetic resonance imaging (MRI)-derived measures of brain characteristics in a nonrandom sample of participants. RESULTS: A total of 1929 persons underwent screening, and 604 were enrolled; 301 were assigned to the MIND-diet group and 303 to the control-diet group. The trial was completed by 93.4% of the participants. From baseline to year 3, improvements in global cognition scores were observed in both groups, with increases of 0.205 standardized units in the MIND-diet group and 0.170 standardized units in the control-diet group (mean difference, 0.035 standardized units; 95% confidence interval, -0.022 to 0.092; P = 0.23). Changes in white-matter hyperintensities, hippocampal volumes, and total gray- and white-matter volumes on MRI were similar in the two groups. CONCLUSIONS: Among cognitively unimpaired participants with a family history of dementia, changes in cognition and brain MRI outcomes from baseline to year 3 did not differ significantly between those who followed the MIND diet and those who followed the control diet with mild caloric restriction. (Funded by the National Institute on Aging; ClinicalTrials.gov number, NCT02817074.).