Prescription Opioids and Brain Structure in Community-Dwelling Older Adults.

OBJECTIVE: To evaluate the associations between prescription opioid exposures in community-dwelling older adults and gray and white matter structure by magnetic resonance imaging. METHODS: Secondary analysis was conducted of a prospective, longitudinal population-based cohort study employing cross-sectional imaging of older adult (≥65 years) enrollees between November 1, 2004, and December 31, 2017. Gray matter outcomes included cortical thickness in 41 structures and subcortical volumes in 6 structures. White matter outcomes included fractional anisotropy in 40 tracts and global white matter hyperintensity volumes. The primary exposure was prescription opioid availability expressed as the per-year rate of opioid days preceding magnetic resonance imaging, with a secondary exposure of per-year total morphine milligram equivalents (MME). Multivariable models assessed associations between opioid exposures and brain structures. RESULTS: The study included 2185 participants; median (interquartile range) age was 80 (75 to 85) years, 47% were women, and 1246 (57%) received opioids. No significant associations were found between opioids and gray matter. Increased opioid days and MME were associated with decreased white matter fractional anisotropy in 15 (38%) and 16 (40%) regions, respectively, including the corpus callosum, posterior thalamic radiation, and anterior limb of the internal capsule, among others. Opioid days and MME were also associated with greater white matter hyperintensity volume (1.02 [95% CI, 1.002 to 1.036; P=.029] and 1.01 [1.001 to 1.024; P=.032] increase in the geometric mean, respectively). CONCLUSION: The duration and dose of prescription opioids were associated with decreased white matter integrity but not with gray matter structure. Future studies with longitudinal imaging and clinical correlation are warranted to further evaluate these relationships.

Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort.

INTRODUCTION: We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. METHODS: We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aß] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aß-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N = 299), mild cognitive impairment (MCI; N = 192), or dementia (DEM; N = 65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). RESULTS: Plasma biomarkers differed across diagnostic groups (DEM > MCI > CU), were altered in Aß-PET-positive individuals, and were associated with poorer brain health and kidney function. DISCUSSION: eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. HIGHLIGHTS: Plasma biomarkers differ across diagnostic groups (DEM > MCI > CU) and are altered in Aß-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.

A critical appraisal of blood-based biomarkers for Alzheimer's disease.

Biomarkers that predict the clinical onset of Alzheimer's disease (AD) enable the identification of individuals in the early, preclinical stages of the disease. Detecting AD at this point may allow for more effective therapeutic interventions and optimized enrollment for clinical trials of novel drugs. The current biological diagnosis of AD is based on the AT(N) classification system with the measurement of brain deposition of amyloid-ß (Aß) ("A"), tau pathology ("T"), and neurodegeneration ("N"). Diagnostic cut-offs for Aß1-42, the Aß1-42/Aß1-40 ratio, tau and hyperphosphorylated-tau concentrations in cerebrospinal fluid have been defined and may support AD clinical diagnosis. Blood-based biomarkers of the AT(N) categories have been described in the AD continuum. Cross-sectional and longitudinal studies have shown that the combination of blood biomarkers tracking neuroaxonal injury (neurofilament light chain) and neuroinflammatory pathways (glial fibrillary acidic protein) enhance sensitivity and specificity of AD clinical diagnosis and improve the prediction of AD onset. However, no international accepted cut-offs have been identified for these blood biomarkers. A kit for blood Aß1-42/Aß1-40 is commercially available in the U.S.; however, it does not provide a diagnosis, but simply estimates the risk of developing AD. Although blood-based AD biomarkers have a great potential in the diagnostic work-up of AD, they are not ready for the routine clinical use.

CSF biomarkers of immune activation and Alzheimer's disease for predicting cognitive impairment risk in the elderly.

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aß42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aß42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aß42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

Racial discrimination during middle age predicts higher serum phosphorylated tau and neurofilament light chain levels a decade later: A study of aging black Americans.

INTRODUCTION: Recent evidence suggests that exposure to the stress of racism may increase the risk of dementia for Black Americans. METHODS: The present study used 17 years of data from a sample of 255 Black Americans to investigate the extent to which exposure to racial discrimination predicts subsequent changes in serum Alzheimer's Disease Research Center (ADRC) biomarkers: serum phosphorylated tau181(p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). We hypothesized that racial discrimination assessed during middle age would predict increases in these serum biomarkers as the participants aged into their 60s. RESULTS: Our findings indicate that exposure to various forms of racial discrimination during a person's 40s and early 50s predicts an 11-year increase in both serum p-tau181 and NfL. Racial discrimination was not associated with subsequent levels of GFAP. DISCUSSION: These findings suggest that racial discrimination in midlife may contribute to increased AD pathology and neurodegeneration later in life. HIGHLIGHTS: A 17-year longitudinal study of Black Americans. Assessments of change in serum p-tau181, neurofilament light, and glial fibrillary acidic protein. Exposure to racial discrimination during middle age predicted increases in p-tau181 and neurofilament light. Education was positively related to both p-tau181 and exposure to racial discrimination.

County Rurality and Incidence and Prevalence of Diagnosed Diabetes in the United States.

OBJECTIVE: To examine differences in the incidence and prevalence of diagnosed diabetes by county rurality. PATIENTS AND METHODS: This observational, cross-sectional study used US Centers for Disease Control and Prevention data from 2004 through 2019 for county estimates of incidence and prevalence of diagnosed diabetes. County rurality was based on 6 levels (large central metro counties [most urban] to noncore counties [most rural]). Weighted least squares regression was used to relate rurality with diabetes incidence rates (IRs; per 1000 adults) and prevalence (percentage) in adults aged 20 years or older after adjusting for county-level sociodemographic factors (eg, food environment, health care professionals, inactivity, obesity). RESULTS: Overall, in 3148 counties and county equivalents, the crude IR and prevalence of diabetes were highest in noncore counties. In age and sex ratio-adjusted models, the IR of diabetes increased monotonically with increasing rurality (P<.001), whereas prevalence had a weak, nonmonotonic but statistically significant increase (P=.002). Further adjustment for sociodemographic factors including food environment, health care professionals, inactivity, and obesity attenuated differences in incidence across rurality levels, and reversed the pattern for prevalence (prevalence ratios [vs large central metro] ranged from 0.98 [95% CI, 0.97 to 0.99] for large fringe metro to 0.94 [95% CI, 0.93 to 0.96] for noncore). In region-stratified analyses adjusted for sociodemographic factors including inactivity and obesity, increasing rurality was inversely associated with incidence in the Midwest and West only and inversely associated with prevalence in all regions. CONCLUSION: The crude incidence and prevalence of diagnosed diabetes increased with increasing county rurality. After accounting for sociodemographic factors including food environment, health care professionals, inactivity, and obesity, county rurality showed no association with incidence and an inverse association with prevalence. Therefore, interventions targeting modifiable sociodemographic factors may reduce diabetes disparities by region and rurality.

Nonalcoholic Fatty Liver Disease and Longitudinal Change in Imaging and Plasma Biomarkers of Alzheimer Disease and Vascular Pathology.

BACKGROUND AND OBJECTIVES: Prospective measures of plasma and cerebral MRI biomarkers of Alzheimer disease (AD) and vascular neuropathology provide an opportunity to investigate possible mechanisms linking liver disease and dementia. We aimed to quantify the association of midlife nonalcoholic fatty liver disease (NAFLD) with change in plasma and brain MRI biomarkers of AD and vascular neuropathology. METHODS: We included participants from the Atherosclerosis Risk in Communities Study with brain MRI measurements of white matter hyperintensity (WMH) volume and temporal-parietal lobe cortical thickness meta region of interest (ROI) at up to 2 different visits, in 2011-13 and 2016-19, and plasma biomarkers of ß-amyloid (Aß)42:40, phosphorylated tau at threonine 181, and neurofilament light (NfL) were measured up to 3 times in 1993-95, 2011-13, and 2016-19. NAFLD was categorized using the fatty liver index in 1990-92. Multivariate linear regression was performed for associations between midlife NAFLD and change in plasma and brain MRI biomarkers of AD and vascular neuropathology. The primary models adjusted for demographics, Apolipoprotein E, alcohol use, and kidney function. RESULTS: Among 1,706 participants (mean age 56 years, 62% female, 28% Black), midlife NAFLD vs no NAFLD was associated with greater late-life WMH volume (difference per SD 0.19, 95% CI 0.06-0.31) and faster late-life WMH increase over 6 years (difference in annual change, SD 0.28, 95% CI 0.05-0.51), suggesting accumulating vascular pathology. Midlife NAFLD vs no NAFLD was also associated with AD biomarkers in midlife (lower Aß42:40 [SD -0.21, 95% CI -0.39 to -0.04] measured in 1993-95) and late life (lower Aß42:40 [SD -0.13, 95% CI -0.23 to -0.03] and lower temporal-parietal lobe cortical thickness meta ROI [SD -0.16, 95% CI -0.28 to -0.05] measured in 2011-13). Although midlife NfL was lower in individuals with vs without midlife NAFLD, those with NAFLD exhibited a faster rate of NfL increase that accelerated over time. DISCUSSION: Midlife NAFLD shows associations with AD and accumulating vascular pathology, revealing potential pathways linking liver function to dementia. Plasma biomarkers of neuropathology and neuronal injury may serve as easily measurable and dynamic indicators for monitoring the impacts of impaired liver function on brain health.

Plasma glial fibrillary acidic protein in the visual and language variants of Alzheimer's disease.

INTRODUCTION: Glial fibrillary acidic protein (GFAP) in plasma is a proxy for astrocytic activity and is elevated in amyloid-ß (Aß)-positive individuals, making GFAP a potential blood-based biomarker for Alzheimer's disease (AD). METHODS: We assessed plasma GFAP in 72 Aß-positive participants diagnosed with the visual or language variant of AD who underwent Aß- and tau-PET. Fifty-nine participants had follow-up imaging. Linear regression was applied on GFAP and imaging quantities. RESULTS: GFAP did not correlate with Aß- or tau-PET cross-sectionally. There was a limited positive correlation between GFAP and rates of tau accumulation, particularly in the language variant of AD, although associations were weaker after removing one outlier patient with the highest GFAP level. DISCUSSION: Among Aß-positive AD participants with atypical presentations, plasma GFAP did not correlate with levels of AD pathology on PET, suggesting that the associations between GFAP and AD pathology might plateau during the advanced phase of the disease.

Comparison of plasma biomarkers and amyloid PET for predicting memory decline in cognitively unimpaired individuals.

BACKGROUND: We compared the ability of several plasma biomarkers versus amyloid positron emission tomography (PET) to predict rates of memory decline among cognitively unimpaired individuals. METHODS: We studied 645 Mayo Clinic Study of Aging participants. Predictor variables were age, sex, education, apolipoprotein E (APOE) ε4 genotype, amyloid PET, and plasma amyloid beta (Aß)42/40, phosphorylated tau (p-tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and p-tau217. The outcome was a change in a memory composite measure. RESULTS: All plasma biomarkers, except NfL, were associated with mean memory decline in models with individual biomarkers. However, amyloid PET and plasma p-tau217, along with age, were key variables independently associated with mean memory decline in models combining all predictors. Confidence intervals were narrow for estimates of population mean prediction, but person-level prediction intervals were wide. DISCUSSION: Plasma p-tau217 and amyloid PET provide useful information about predicting rates of future cognitive decline in cognitively unimpaired individuals at the population mean level, but not at the individual person level.

Associations of reproductive factors and exogenous estrogens with global and domain-specific cognition in later life.

INTRODUCTION: Few studies have comprehensively examined the impact of reproductive factors (i.e., reproductive window, parity, hormonal contraception [HC], and menopausal hormone therapy [MHT]) on global and domain-specific cognition in later life. METHODS: We studied a population-based sample of 2458 women (median age 74.2 years) residing in Olmsted County, Minnesota; participants underwent a clinical evaluation and comprehensive cognitive testing. RESULTS: The length of a woman's reproductive window was not associated with cognition. Higher parity was associated with greater cognitive decline in all domains. Ever HC use was associated with less decline in all domains. Ever MHT use was associated with greater decline in global cognition and all domain-specific z-scores except visuospatial; results were driven by women who initiated MHT 5 or more years after menopause. Additional adjustments for APOE and vascular-related covariates did not attenuate the results. DISCUSSION: Multiple reproductive risk factors are associated with cognitive decline in later life. HIGHLIGHTS: The length of a woman's reproductive window was not associated with cognition longitudinally. Greater parity was associated with greater cognitive decline longitudinally. Ever HC use was associated with less decline in global cognition and all domain-specific z-scores longitudinally (all p < 0.01). Ever MHT use was associated with greater decline in global cognition and all domain-specific z-scores except visuospatial longitudinally (all p < 0.01). The greatest cognitive decline was among women who initiated MHT more than 5 years after menopause.

Stricker Learning Span criterion validity: a remote self-administered multi-device compatible digital word list memory measure shows similar ability to differentiate amyloid and tau PET-defined biomarker groups as in-person Auditory Verbal Learning Test.

OBJECTIVE: The Stricker Learning Span (SLS) is a computer-adaptive digital word list memory test specifically designed for remote assessment and self-administration on a web-based multi-device platform (Mayo Test Drive). We aimed to establish criterion validity of the SLS by comparing its ability to differentiate biomarker-defined groups to the person-administered Rey's Auditory Verbal Learning Test (AVLT). METHOD: Participants (N = 353; mean age = 71, SD = 11; 93% cognitively unimpaired [CU]) completed the AVLT during an in-person visit, the SLS remotely (within 3 months) and had brain amyloid and tau PET scans available (within 3 years). Overlapping groups were formed for 1) those on the Alzheimer's disease (AD) continuum (amyloid PET positive, A+, n = 125) or not (A-, n = 228), and those with biological AD (amyloid and tau PET positive, A+T+, n = 55) vs no evidence of AD pathology (A-T-, n = 195). Analyses were repeated among CU participants only. RESULTS: The SLS and AVLT showed similar ability to differentiate biomarker-defined groups when comparing AUROCs (p's > .05). In logistic regression models, SLS contributed significantly to predicting biomarker group beyond age, education, and sex, including when limited to CU participants. Medium (A- vs A+) to large (A-T- vs A+T+) unadjusted effect sizes were observed for both SLS and AVLT. Learning and delay variables were similar in terms of ability to separate biomarker groups. CONCLUSIONS: Remotely administered SLS performed similarly to in-person-administered AVLT in its ability to separate biomarker-defined groups, providing evidence of criterion validity. Results suggest the SLS may be sensitive to detecting subtle objective cognitive decline in preclinical AD.

Modeling the temporal evolution of plasma p-tau in relation to amyloid beta and tau PET.

INTRODUCTION: The timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co-evolution of plasma and positron emission tomography (PET) Alzheimer's disease (AD) biomarkers. METHODS: We included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aß) PET, tau PET, plasma p-tau217, p-tau181, and glial fibrillary acidic protein (GFAP) as endpoints. RESULTS: Individual timing of plasma p-tau progression was strongly associated with Aß PET and GFAP progression. In the population, GFAP became abnormal first, then Aß PET, plasma p-tau, and tau PET temporal meta-regions of interest when applying cut points based on young, cognitively unimpaired participants. DISCUSSION: Plasma p-tau is a stronger indicator of a temporally linked response to elevated brain Aß than of tau pathology. While Aß deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p-tau and Aß PET was the strongest. HIGHLIGHTS: Plasma p-tau progression was more strongly associated with Aß than tau PET. Progression on plasma p-tau was associated with Aß PET and GFAP progression. P-tau181 and p-tau217 become abnormal after Aß PET and before tau PET. GFAP became abnormal first, before plasma p-tau and Aß PET.

Biomarkers of Cellular Senescence Predict the Onset of Mobility Disability and Are Reduced by Physical Activity in Older Adults.

Studies in mice and cross-sectional studies in humans support the premise that cellular senescence is a contributing mechanism to age-associated deficits in physical function. We tested the hypotheses that circulating proteins secreted by senescent cells are (i) associated with the incidence of major mobility disability (MMD), the development of persistent mobility disability (PMMD), and decrements in physical functioning in older adults, and (ii) influenced by physical activity (PA). Using samples and data obtained longitudinally from the Lifestyle Interventions in Elders Study clinical trial, we measured a panel of 27 proteins secreted by senescent cells. Among 1 377 women and men randomized to either a structured PA intervention or a healthy aging (HA) intervention, we observed significant associations between several senescence biomarkers, most distinctly vascular endothelial growth factor A (VEGFA), tumor necrosis factor receptor 1 (TNFR1), and matrix metallopeptidase 7 (MMP7), and the onset of both MMD and PMMD. Moreover, VEGFA, GDF15, osteopontin, and other senescence biomarkers were associated with reductions in short physical performance battery scores. The change in senescence biomarkers did not differ between PA and HA participants. In the whole cohort, higher levels of PA were associated with significantly greater reductions in 10 senescence-related proteins at 12 and/or 24 months. These data reinforce cellular senescence as a contributing mechanism of age-associated functional decline and the potential for PA to attenuate this hallmark of aging. Clinical Trials Registration Number: NCT01072500.

Mayo normative studies: regression-based normative data for ages 30-91 years with a focus on the Boston Naming Test, Trail Making Test and Category Fluency.

OBJECTIVE: Normative neuropsychological data are essential for interpretation of test performance in the context of demographic factors. The Mayo Normative Studies (MNS) aim to provide updated normative data for neuropsychological measures administered in the Mayo Clinic Study of Aging (MCSA), a population-based study of aging that randomly samples residents of Olmsted County, Minnesota, from age- and sex-stratified groups. We examined demographic effects on neuropsychological measures and validated the regression-based norms in comparison to existing normative data developed in a similar sample. METHOD: The MNS includes cognitively unimpaired adults ≥30 years of age (n = 4,428) participating in the MCSA. Multivariable linear regressions were used to determine demographic effects on test performance. Regression-based normative formulas were developed by first converting raw scores to normalized scaled scores and then regressing on age, age2, sex, and education. Total and sex-stratified base rates of low scores (T < 40) were examined in an older adult validation sample and compared with Mayo's Older Americans Normative Studies (MOANS) norms. RESULTS: Independent linear regressions revealed variable patterns of linear and/or quadratic effects of age (r2 = 6-27% variance explained), sex (0-13%), and education (2-10%) across measures. MNS norms improved base rates of low performance in the older adult validation sample overall and in sex-specific patterns relative to MOANS. CONCLUSIONS: Our results demonstrate the need for updated norms that consider complex demographic associations on test performance and that specifically exclude participants with mild cognitive impairment from the normative sample.

Liver integrity and the risk of Alzheimer's disease and related dementias.

INTRODUCTION: We examined midlife (1990-1992, mean age 57) and late-life (2011-2013, mean age 75) nonalcoholic fatty liver disease (NAFLD) and aminotransferase with incident dementia risk through 2019 in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: We characterized NAFLD using the fatty liver index and fibrosis-4, and we categorized aminotransferase using the optimal equal-hazard ratio (HR) approach. We estimated HRs for incident dementia ascertained from multiple data sources. RESULTS: Adjusted for demographics, alcohol consumption, and kidney function, individuals with low, intermediate, and high liver fibrosis in midlife (HRs: 1.45, 1.40, and 2.25, respectively), but not at older age, had higher dementia risks than individuals without fatty liver. A U-shaped association was observed for alanine aminotransferase with dementia risk, which was more pronounced in late-life assessment. DISCUSSION: Our findings highlight dementia burden in high-prevalent NAFLD and the important feature of late-life aminotransaminase as a surrogate biomarker linking liver hypometabolism to dementia. Highlights Although evidence of liver involvement in dementia development has been documented in animal studies, the evidence in humans is limited. Midlife NAFLD raised dementia risk proportionate to severity. Late-life NAFLD was not associated with a high risk of dementia. Low alanine aminotransferase was associated with an elevated dementia risk, especially when measured in late life.

Risk of dementia and psychiatric or sleep disorders after diagnosis of adrenal adenomas: a population-based cohort study.

OBJECTIVE: Adrenal adenomas are commonly encountered in clinical practice. To date, population-based data on their impact on cognition, mental health, and sleep are lacking. We aimed to study possible associations between adrenal adenomas and dementia, psychiatric or sleep disorders. DESIGN: Population-based cohort study, Olmsted County, MN, 1995-2017. METHODS: Patients with adrenal adenoma and absent overt hormone excess were age- and sex-matched 1:1 to a referent person without adrenal adenoma. Outcomes were baseline and incident diagnoses of dementia, psychiatric or sleep disorders, assessed using ICD codes. RESULTS: Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years. At baseline, and after adjusting for age, sex, education, BMI, and tobacco use, patients with adenoma had higher odds of depression (adjusted odds ratio, aOR: 1.3, 95% CI, 1.1-1.6), anxiety (aOR: 1.4, 95% CI, 1.1-1.8), and substance abuse (aOR: 2.4, 95% CI, 1.7-3.4) compared to referents. During a median follow-up of 6.8 years, and after adjusting for age, sex, socioeconomic status, BMI, tobacco, and substance abuse, patients demonstrated a higher risk of psychiatric and sleep disorders [adjusted hazard ratio (95% CI)]: depression [1.7 (1.3-2.2)], anxiety [1.4, CI (1.1-1.7)], insomnia [1.4 (1.0-1.9)], sleep-related breathing disorders [1.5 (1.1-1.9)], hypersomnias [2.1 (1.0-4.2)], parasomnias [2.1 (1.0-4.2)], and sleep-related movement disorders [1.5 (1.0-2.1)], but not dementia. CONCLUSIONS: Patients with adenomas demonstrate a higher incidence of psychiatric and sleep disorders, possibly due to the underlying subtle increase in cortisol secretion.

Biomarkers of cellular senescence and risk of death in humans.

A robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age-related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults. We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow-up of 6.3 years in 1923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c-statistic for risk of death (0.79, 95% confidence interval (CI): 0.76-0.82) than the covariates alone (0.70, CI: 0.67-0.74) (p < 0.001). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death.

Plasma ceramides relate to mild cognitive impairment in middle-aged men: The Maastricht Study.

Introduction: There is an urgent need for biomarkers identifying individuals at risk of early-stage cognitive impairment. Using cross-sectional data from The Maastricht Study, this study included 197 individuals with mild cognitive impairment (MCI) and 200 cognitively unimpaired individuals aged 40 to 75, matched by age, sex, and educational level. Methods: We assessed the association of plasma sphingolipid and ceramide transfer protein (CERT) levels with MCI and adjusted for potentially confounding risk factors. Furthermore, the relationship of plasma sphingolipids and CERTs with magnetic resonance imaging brain volumes was assessed and age- and sex-stratified analyses were performed. Results: Associations of plasma ceramide species C18:0 and C24:1 and combined plasma ceramide chain lengths (ceramide risk score) with MCI were moderated by sex, but not by age, and higher levels were associated with MCI in men. No associations were found among women. In addition, higher levels of ceramide C20:0, C22:0, and C24:1, but not the ceramide risk score, were associated with larger volume of the hippocampus after controlling for covariates, independent of MCI. Although higher plasma ceramide C18:0 was related to higher plasma CERT levels, no association of CERT levels was found with MCI or brain volumes. Discussion: Our results warrant further analysis of plasma ceramides as potential markers for MCI in middle-aged men. In contrast to previous studies, no associations of plasma sphingolipids with MCI or brain volumes were found in women, independent of age. These results highlight the importance of accounting for sex- and age-related factors when examining sphingolipid and CERT metabolism related to cognitive function.

Long-term effects of premenopausal bilateral oophorectomy with or without hysterectomy on physical aging and chronic medical conditions.

OBJECTIVE: We examined the long-term effects of premenopausal bilateral oophorectomy (PBO) with or without concurrent or preceding hysterectomy on physical and cognitive function and on odds of chronic conditions. METHODS: We enrolled 274 women with PBO with or without concurrent or preceding hysterectomy and 240 referents aged 55 years and older who were residents of Olmsted County, MN as of the PBO or index date. Chronic conditions were assessed via medical record abstraction. Cognitive diagnoses were based on neurocognitive testing. A physical function assessment included measures of strength and mobility. Multivariable regression models compared characteristics for women with PBO <46 years, PBO 46-49 years, and referent women with adjustments for age and other confounders. RESULTS: The clinical visits (median age, 67 years) were a median of 22 years after the PBO or index date. Of 274 women with PBO, 161 (59%) were <46 years at PBO and 113 (41%) were 46-49 years. Compared with referents, women with a history of PBO <46 years had increased odds of arthritis (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.06-2.55), asthma (OR, 1.74; 95% CI, 1.03-2.93), obstructive sleep apnea (OR, 2.00; 95% CI, 1.23-3.26), and bone fractures (OR, 2.86; 95% CI, 1.17-6.98), and walked a shorter mean distance on a 6-minute walk test ( b = -18.43; P = 0.034). Compared with referents, women with a history of PBO at age 46-49 years had increased odds of arthritis (OR, 1.92; 95% CI, 1.16-3.18) and obstructive sleep apnea (OR, 2.21; 95% CI, 1.33-3.66). There were no significant differences in cognitive status in women with PBO compared with referents. CONCLUSIONS: Women with a history of PBO with or without concurrent or preceding hysterectomy, especially at age <46 years, have more chronic conditions in late mid-life compared with referents.

Association of Plasma Biomarkers of Alzheimer Disease With Cognition and Medical Comorbidities in a Biracial Cohort.

BACKGROUND AND OBJECTIVES: Recent advances in blood-based biomarkers offer the potential to revolutionize the diagnosis and management of Alzheimer disease (AD), but additional research in diverse populations is critical. We assessed the profiles of blood-based AD biomarkers and their relationships to cognition and common medical comorbidities in a biracial cohort. METHODS: Participants were evaluated through the Mayo Clinic Jacksonville Alzheimer Disease Research Center and matched on age, sex, and cognitive status. Plasma AD biomarkers (ß-amyloid peptide 1-42 [Aß42/40], plasma tau phosphorylated at position 181 [p-tau181], glial fibrillary acidic protein [GFAP], and neurofilament light) were measured using the Quanterix SiMoA HD-X analyzer. Cognition was assessed with the Mini-Mental State Examination. Wilcoxon rank sum tests were used to assess for differences in plasma biomarker levels by sex. Linear models tested for associations of self-reported race, chronic kidney disease (CKD), and vascular risk factors with plasma AD biomarker levels. Additional models assessed for interactions between race and plasma biomarkers in predicting cognition. RESULTS: The sample comprised African American (AA; N = 267) and non-Hispanic White (NHW; N = 268) participants, including 69% female participants and age range 43-100 (median 80.2) years. Education was higher in NHW participants (median 16 vs 12 years, p < 0.001) while APOE ε4 positivity was higher in AA participants (43% vs 34%; p = 0.04). We observed no differences in plasma AD biomarker levels between AA and NHW participants. These results were unchanged after stratifying by cognitive status (unimpaired vs impaired). Although the p-tau181-cognition association seemed stronger in NHW participants while the Aß42/40-cognition association seemed stronger in AA participants, these findings did not survive after excluding individuals with CKD. Female participants displayed higher GFAP (177.5 pg/mL vs 157.73 pg/mL; p = 0.002) and lower p-tau181 (2.62 pg/mL vs 3.28 pg/mL; p = 0.001) levels than male participants. Diabetes was inversely associated with GFAP levels (ß = -0.01; p < 0.001). DISCUSSION: In a biracial community-based sample of adults, we observed that sex differences, CKD, and vascular risk factors, but not self-reported race, contributed to variation in plasma AD biomarkers. Although some prior studies have reported primary effects of race/ethnicity, our results reinforce the need to account for broad-based medical and social determinants of health (including sex, systemic comorbidities, and other factors) in effectively and equitably deploying plasma AD biomarkers in the general population.