Mielke, Michelle M.

AbstractINTRODUCTIONCorticobasal syndrome (CBS) can result from underlying Alzheimer's disease (AD) pathologies. Little is known about the utility of blood plasma metrics to predict positron emission tomography (PET) biomarker‐confirmed AD in CBS.METHODSA cohort of eighteen CBS patients (8 amyloid beta [Aβ]+; 10 Aβ−) and 8 cognitively unimpaired (CU) individuals underwent PET imaging and plasma analysis. Plasma concentrations were compared using a Kruskal–Wallis test. Spearman correlations assessed relationships between plasma concentrations and PET uptake.RESULTSCBS Aβ+ group showed a reduced Aβ42/40 ratio, with elevated phosphorylated tau (p‐tau)181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentrations, while CBS Aβ− group only showed elevated NfL concentration compared to CU. Both p‐tau181 and GFAP were able to differentiate CBS Aβ− from CBS Aβ+ and showed positive associations with Aβ and tau PET uptake.DISCUSSIONThis study supports use of plasma p‐tau181 and GFAP to detect AD in CBS. NfL shows potential as a non‐specific disease biomarker of CBS regardless of underlying pathology.Highlights Plasma phosphorylated tau (p‐tau)181 and glial fibrillary acidic protein (GFAP) concentrations differentiate corticobasal syndrome (CBS) amyloid beta (Aβ)− from CBS Aβ+. Plasma neurofilament light concentrations are elevated in CBS Aβ− and Aβ+ compared to controls. Plasma p‐tau181 and GFAP concentrations were associated with Aβ and tau positron emission tomography (PET) uptake. Aβ42/40 ratio showed a negative correlation with Aβ PET uptake.

AbstractINTRODUCTIONFemale‐specific reproductive factors and exogeneous estrogen use are associated with cognition in later life. However, the underlying mechanisms are not understood. The present study aimed to investigate the effect of reproductive factors on neuroimaging biomarkers of Alzheimer's disease (AD) and cerebrovascular pathologies.METHODSWe evaluated 389 females (median age of 71.7 years) enrolled in the Mayo Clinic Study of Aging with reproductive history data and longitudinal magnetic resonance imaging (MRI) scans. We used linear mixed effect models to examine the associations between reproductive factors and changes in neuroimaging measures.RESULTSEver hormonal contraception (HC) use was longitudinally associated with higher fractional anisotropy across the corpus callosum, lower white matter hyperintensity (WMH) volume, and greater cortical thickness in an AD meta‐region of interest (ROI). The initiation of menopausal hormone therapy (MHT) > 5 years post menopause was associated with higher WMH volume.DISCUSSIONHC use and initiation of MHT >5 years post menopause were generally associated with neuroimaging biomarkers of cerebrovascular pathologies.Highlights Hormonal contraception use was associated with better brain white matter (WM) integrity. Initiation of menopausal hormone therapy >5 years post menopause was associated with worsening brain WM integrity. Hormonal contraception use was associated with greater cortical thickness. Ages at menarche and menopause and number of pregnancies were not associated with imaging measures. There were few associations between reproductive factors or exogenous estrogens and amyloid or tau PET.

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 Aβ42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aβ42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aβ42, 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.

AbstractINTRODUCTIONGlial fibrillary acidic protein (GFAP) in plasma is a proxy for astrocytic activity and is elevated in amyloid‐β (Aβ)‐positive individuals, making GFAP a potential blood‐based biomarker for Alzheimer's disease (AD).METHODSWe assessed plasma GFAP in 72 Aβ‐positive participants diagnosed with the visual or language variant of AD who underwent Aβ‐ and tau‐PET. Fifty‐nine participants had follow‐up imaging. Linear regression was applied on GFAP and imaging quantities.RESULTSGFAP did not correlate with Aβ‐ 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.DISCUSSIONAmong Aβ‐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.

Background: Little is known about the association between physical activity (PA) and cognitive trajectories in older adults. Objective: To examine the association between PA and change in memory, language, attention, visuospatial skills, and global cognition, and a potential impact of sex or Apolipoprotein E (APOE) ε4 status. Methods: Longitudinal study derived from the population-based Mayo Clinic Study of Aging, including 2,060 cognitively unimpaired males and females aged ≥70 years. Engagement in midlife (ages 50–65) and late-life (last year) PA was assessed using a questionnaire. Neuropsychological testing was done every 15 months (mean follow-up 5.8 years). We ran linear mixed-effect models to examine whether mid- or late-life PA at three intensities (mild, moderate, vigorous) was associated with cognitive z-scores. Results: Light intensity midlife PA was associated with less decline in memory function compared to the no-PA reference group (time x light PA; estimate [standard error] 0.047 [0.016], p = 0.004). Vigorous late-life PA was associated with less decline in language (0.033 [0.015], p = 0.030), attention (0.032 [0.017], p = 0.050), and global cognition (0.039 [0.016], p = 0.012). Females who were physically inactive in midlife experienced more pronounced cognitive decline than females physically active in midlife and males regardless of PA (p-values for time interaction terms with midlife PA levels and sex were all p < 0.05 for global cognition). APOE ε4 carriership did not moderate the association between PA and cognition. Conclusion: Engaging in PA, particularly of vigorous intensity in late-life, was associated with less pronounced decline in global and domain-specific cognition. This association may differ by sex.

Abstract 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 ) ε 4 genotype, amyloid PET, and plasma amyloid beta (Aβ)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.

AbstractBackgroundSeveral studies suggest that premenopausal bilateral oophorectomy (PBO) is associated with an increased risk of cognitive impairment and dementia; however, the underlying brain changes are not well understood. Animal studies suggest that long‐term ovarian hormone deprivation in rats is associated with reduced white matter integrity, but few studies have been conducted among women. We assessed the impact of age at PBO before age 50 years on white matter integrity in a community‐based cohort of older women.MethodParticipants included 1,011 women enrolled in the Mayo Clinic Study on Aging (MCSA; 22 with PBO<40 years; 43 with PBO 40‐45 years; 39 with PBO 46‐49 years and 907 referent women). MCSA is a population‐based study of aging in Olmsted County, MN. PBO was abstracted from the medical records. Regional DTI metrics of fractional anisotropy (FA) and mean diffusivity (MD) were investigated using the Johns Hopkins University Atlas. Linear regression was used to examine the association between PBO age group and z‐scores of either FA or MD after adjusting for age at imaging and APOE.ResultThere were no differences in age at study visit (median = 72 years), education, APOE E4 frequency, or vascular comorbidities between the 3 groups of women with a history of PBO or referent women. Women with PBO<40 years, compared to referent women, had lower FA and higher MD in the anterior corona radiata, genu of the corpus collosum, inferior fronto‐occipital fasciculus, superior occipital, and superior temporal white matter. Women with PBO<40 years also had lower inferior frontal white matter FA and higher posterior thalamic radiation MD. Women who underwent PBO between 40‐44 years or 45‐49 generally did not have significant changes in white matter integrity compared to referent women.ConclusionWomen who underwent premenopausal bilateral oophorectomy prior to the age of 40 years had reduced white matter integrity across multiple regions in later‐life. These results are important for the education of women at a low risk for ovarian cancer who are considering PBO for benign conditions.

AbstractBackgroundEasily accessible and self‐administered cognitive assessments that can aide early identification of individuals at risk for Alzheimer’s disease (AD) dementia are critical for timely intervention. Mayo Test Drive (MTD) is a remote, self‐administered, multi‐device compatible, web‐based cognitive assessment (Stricker et al., 2022). We investigated continuous associations between MTD and amyloid and tau PET biomarkers and compared the strength of association to PET biomarkers and in‐person cognitive measures.Method556 adults from the Mayo Clinic Study of Aging participated (mean age = 70.6; mean education = 16.0 years; 50.7% female; 97.5% white). Participants were predominantly cognitively unimpaired (95.3%; 4.7% had a consensus diagnosis of mild cognitive impairment). Participants completed (1) brain amyloid and tau PET scans, (2) in‐person neuropsychological assessment including Mayo Preclinical Alzheimer’s disease Cognitive Composite (Mayo‐PACC) and Global‐z, and (3) remote MTD comprised of the Stricker Learning Span (SLS) and the Symbols test, which are combined into an MTD composite. Multiple regressions adjusted for age, sex, and education queried associations between imaging biomarkers [amyloid meta‐region of interest (ROI), tau meta‐ROI, and tau entorhinal cortex (EC)‐ROI)] and composite and subtest scores from remote and in‐person measures. Davidson‐Mackinnon J‐test compared R‐squared values of models with remote versus in‐person composites.ResultLower performances on MTD composite and Mayo‐PACC were associated with higher amyloid meta‐ROI (p’s<.05; Table 1). MTD composite was also negatively associated with tau meta‐ROI and EC‐ROI (p’s<.05). For memory measures, SLS sum of trials was negatively associated with tau meta‐ROI (p = .01) and EC‐ROI (p<.001) with no associations between AVLT sum of trials and PET (p’s≥.06; Table 2). Among processing speed/executive function measures, worse Trails B performance was associated with higher amyloid meta‐ROI (p<.001). Symbols and Digit Symbol Coding were not associated with PET (p’s≥.29). A multivariable model with MTD explained significantly less variance (p = .04) for amyloid meta‐ROI (adjusted R‐squared = 0.165) than a multivariable model with Mayo‐PACC (adjusted R‐squared = 0.176); remote and in‐person composite measures were comparable for other associations (p’s>.05).ConclusionMTD is associated with continuous measures of amyloid and tau PET biomarkers of AD, demonstrating criterion validity for MTD. Several associations were comparable to relationships between gold‐standard in‐person neuropsychological tests and imaging biomarkers.