Mielke, Michelle M.

AbstractBackgroundPreeclampsia (PE), a pregnancy specific hypertensive disorder, has been associated with elevated risk for strokes, cognitive decline, and smaller brain volumes later in life. As severe PE has been associated with the highest risks for cerebrovascular disease, we hypothesized that circulating extracellular vesicles (EVs) of neurovascular origin will be detectable in women years after severe PE as a marker of persistent neurovascular damage and amyloid‐β.MethodA cohort of 40 women with histories of normotensive pregnancies (control group) and age‐ and parity‐matched to 40 women with history of mild (n = 33) and severe (n = 7) PE were identified using the Rochester Epidemiology Project. Diagnosis of severe PE was ascertained based on clinical criteria (Table). While none of the women had any major cardiovascular events, our previous study of this cohort has demonstrated that total gray matter volumes were smaller in women with a history of preeclampsia and late‐life hypertension compared with the other groups. Blood‐borne EVs derived from neurovascular cellular activation were determined by standardized digital flow cytometry. Plasma concentration of amyloid‐β was measured by ELISA. Differences among the groups were tested by ANOVA, with the least difference test for pos hoc analysis. The association between EVs and MRI brain imaging was assessed by Pearson correlation coefficient.ResultWomen with history of severe PE had a significantly higher concentration of amyloid‐β carrying EVs compared to controls (p = 0.003). EVs positive for the markers of blood‐brain barrier‐ endothelial damage (LDL‐R) and inflammatory coagulation pathway activator (tissue factor), were significantly higher in women with history of severe PE compared to controls (p = 0.008 and p = 0.002, respectively), as well as to the women with history of mild PE. Plasma concentration of total amyloid‐β was also significantly greater in women with history of severe vs. mild PE (p = 0.037) (Table). The number of tissue factor positive EVs was negatively correlated with total gray matter volume (cm3) (p<0.05).ConclusionWomen with a history of severe PE demonstrate elevated levels of markers of neuroinflammation and neurovascular damage, as well as greater amyloid‐β secretion. Excessive inflammation may contribute to previously described brain atrophy in these women.

AbstractBackgroundThe effect of an intensive lifestyle intervention (ILI) on Alzheimer’s disease (AD) blood‐based biomarker levels and cognitive outcomes among individuals with type 2 diabetes (T2D) is unknown. We examined AD biomarkers and cognitive outcomes in the Look AHEAD Study.MethodParticipants aged 45‐76 years were randomized at baseline to a 10‐year ILI or a diabetes support and education (DSE) condition. Cognitive assessments at years 8‐18 included measures of attention, executive function, global function, and memory. Mild cognitive impairment (MCI) and probable dementia were adjudicated by an expert panel. Stored baseline and end‐of‐intervention plasma samples were analyzed with the Quanterix Simoa HD‐X Analyzer. Changes in Aβ42/Aβ40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic characteristics, and cognitive outcomes. Cognitive scores and biomarker levels were converted to z‐scores. Cognitive trajectories were evaluated using mixed models to account for repeated measures; logistic regression was used for a composite outcome of MCI/dementia. Models were adjusted for baseline characteristics (age, sex, education, race/ethnicity, body mass index (BMI), CVD history, hypertension, diabetes duration, eGFR), APOE‐ε4, randomization arm, time from randomization, and time between blood draw and cognitive testing.ResultThe mean age of 779 participants was 61.4 years; 56% = female, 22.8% = APOE ε4+, mean BMI = 34.8, baseline diabetes duration >5 years = 57%, 16.7% Black, 12.5% Hispanic, 66.2% White, and 4.7% other racial and ethnic groups. There were no associations between the intervention and biomarker levels at baseline or biomarker change over time. Increases in NfL levels significantly predicted lower memory (‐0.04 ±0.01; p = 0.002), global cognition scores (‐0.05 ±0.02; p = 0.011), executive function (‐0.04 ±0.01; p = 0.01), as well as increased risk of MCI/probable dementia (odds ratio [OR] 1.10, 95% CI 1.02‐1.19). Increases in GFAP predicted lower memory (‐0.10 ±0.03; p = 0.0001), global cognition (‐0.09 ±0.03; p = 0.009), executive function scores (‐0.12 ±0.03; p<0.0001), and increased risk of MCI/probable dementia (OR 1.24, 95% CI 1.09‐1.41).ConclusionThere was no association between the intervention and changes in biomarker levels. Increasing levels of NfL and GFAP over the ∼10 year period were associated with reduced cognitive performance and increased risk of MCI/probable dementia.

AbstractBackgroundHigher brain amyloid PET is associated with slower gait speed and has been hypothesized to play a role in age‐related mobility decline. With the development of blood‐based biomarkers of Alzheimer’s disease pathology, we examined whether plasma levels of amyloid‐beta (Aβ)40, Aβ42, the Aβ42/Aβ40 ratio, phosphorylated tau 181 (p‐tau181) and 217 (p‐tau217), total tau, and neurofilament light chain (NfL) were associated with gait speed.MethodThis study included 779 cognitively unimpaired participants (median age 75, 54.8% male, median follow‐up 6.8 years) in the Mayo Clinic Study of Aging with concurrent measurement of plasma biomarkers and gait speed. Individuals with chronic kidney disease or a history of stroke were excluded. The plasma markers (pg/mL) were measured on the Quanterix Simoa® HD‐1 analyzer (total tau, Aβ42, Aβ40, NfL) and the Meso Scale Discovery platform (p‐tau181, p‐tau217). Gait speed (m/s) was obtained by timing a self‐paced walk across 25 ft using a stopwatch. Linear mixed effects models, with subject‐specific intercepts and slopes for time since baseline, with z‐scored baseline plasma markers were used to predict cross‐sectional and longitudinal gait speed. All models adjusted for baseline age and sex.ResultAt baseline, higher Aβ42 [Beta = ‐0.019; 95%CI = (‐0.035, ‐0.004)], total‐tau [‐0.026; (‐0.041, ‐0.011)], and p‐tau181 [‐0.021; (‐0.036, ‐0.006)] were associated with slower gait speed. Gait speed decreased, on average, by about 0.015 m/s annually for those in this study. Each one standard deviation (SD) increase in baseline level of plasma Aβ40 [‐0.005; (‐0.007, ‐0.002)], NfL [‐0.006; (‐0.009, ‐0.004)], and p‐tau217 [‐0.004; (‐0.007, ‐0.001)] accelerated this decline over time. In contrast, each one SD increase in Aβ42/Aβ40 ratio [0.003; (0.001, 0.006)] mitigated decline. Additional analyses adjusting for Charlson comorbidity index, Beck Depression Inventory, body mass index, and APOE E4 allele status gave similar results.ConclusionBoth cross‐sectional and longitudinal associations of plasma markers of amyloid and tau pathology and neurodegeneration with gait speed among cognitively unimpaired individuals were present. Therefore, not only are these markers of cognitive changes, they are also related to motor changes such as those affecting gait speed.

AbstractBackgroundTamoxifen is used as a selective estrogen receptor modifier (SERM) to treat hormone receptor‐positive breast cancer. Raloxifene, another SERM, has been used for the treatment of osteoporosis in post‐menopausal women. The aim of this cross‐sectional study was to examine whether a history of tamoxifen or raloxifene use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or structural neurodegenerative MRI markers.MethodThe study included women with and without a personal history of breast cancer enrolled in the Mayo Clinic Study of Aging (MCSA). A history of breast cancer and use of SERMs before the MCSA enrollment visit was abstracted using the Rochester Epidemiology Project medical‐linkage system. Participants had a diagnosis of MCI (prevalent) at the time of enrollment into the MCSA. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive measures z‐scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), hippocampal volume, and Alzheimer’s disease signature cortical thickness.ResultAmong the women aged ≥ 50 at enrollment in the MCSA, 151 had a history of breast cancer, and 2235 had no prior history of any cancer. Of the 151 women with a history of breast cancer, 42 (28%) had taken tamoxifen and 109 (72%) had not at enrollment in the MCSA; 54 had neuroimaging data (tamoxifen = 16; no tamoxifen = 38). Among the women without prior history of cancer at enrollment in the MCSA, 76 (3%) had taken raloxifene and 2159 (97%) had not; 755 had neuroimaging data (raloxifene = 25; no raloxifene = 730). No significant associations between tamoxifen with global or domain‐specific cognition or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders (Table 1). Likewise raloxifene was not significantly associated with global or domain‐specific cognition or odds of MCI in women without a history of cancer after adjusting for confounders (Table 2). We did not find significant associations between SERMs and any neuroimaging outcome (Table 3).ConclusionOur results suggest use of tamoxifen or raloxifene is not significantly associated with cognition in postmenopausal women.

AbstractBackgroundTwo pathways that help explain cognitive health are 1) brain maintenance – referring to the relative absence of brain changes over time; 2) cognitive reserve – a property of the brain that allows for sustained cognitive ability in the presence of brain pathology. Both pathways influence cognitive aging and are best understood using longitudinal data. Our goal was to assess the effect of modifiable vascular/metabolic and lifestyle enrichment factors on these pathways using longitudinal brain changes measured on structural magnetic resonance imaging (MRI) and longitudinal cognitive decline. Lastly, we combined these pathways and their relationships in the same model.MethodWe identified 1250 participants from a well‐characterized sample of older adults from the Mayo Clinic Study of Aging with both longitudinal MRI and cognitive data. Linear mixed models were performed to assess the impact of modifiable factors on brain maintenance and cognitive reserve. Latent growth curve models (SEM) were used to assess the impact of brain structure and cognitive reserve on longitudinal cognition.ResultThe mean age of our sample was 78.8 years, with 45.4% female, and 27.1% APOE4 carriers. Mean follow‐up time was 4.0 years with a mean of 3.2 MRI scans per participant. Linear mixed models showed that poorer vascular/metabolic health (presence of vascular/metabolic conditions) was associated with lower cross‐sectional temporal region cortical thickness (‐0.014 (0.003), p<0.001) and lower global cognition (‐0.042 (0.018), p = 0.024). Higher estimated cognitive reserve at baseline as assessed by education/occupation composite (0.103 (0.01), p<0.001) was associated with higher global cognition. Unexpectedly, late‐life physical activities were related to lower global cognition (‐0.05 (0.007), p = 0.004). Our final latent growth curve SEM fit the data well showing temporal associations between unmodifiable characteristics, cognitive reserve, and brain structural pathways, as well as the influence of modifiable vascular/metabolic factors.ConclusionWe found that brain maintenance and cognitive reserve pathways were related to better cognition over time. We further showed that vascular/metabolic health impacts long‐term cognitive outcomes (i.e. cognitive aging) primarily through the brain maintenance pathway. These data provide a modeling scheme for future studies and can aid in assessing the pathways by which individual factors may influence cognitive aging.

AbstractBackgroundPreclinical Alzheimer’s cognitive composites (PACC) are designed to detect subtle cognitive changes in clinical trials. PACCs often include measures of memory, attention, and semantic fluency, with variations based on available measures. We created a Mayo Clinic PACC (Mayo‐PACC) to address limitations of existing PACCs by prioritizing parsimony, non‐proprietary measures, clinical applicability, and psychometric properties. We developed a Mayo‐PACC and examined sensitivity to detecting longitudinal cognitive change in amyloid positive (A+) older adults relative to the Preclinical Alzheimer’s Cognitive Composite‐Revised (PACC‐R). Exploratory analyses included comparison to other composites.MethodParticipants included 614 individuals in the Mayo Clinic Study of Aging (428 A‐ and 186 A+) age 65‐85 who were cognitively unimpaired at baseline with 7 years mean follow‐up. A+ was defined as PiB‐PET meta‐ROI SUVR ≥ 1.48 (centiloid 22). The Mayo‐PACC included the AVLT sum of trials (trials 1‐5, short delay, long delay), Trails B and Animal fluency. Measures included in the PACC‐R and other comparison composites are listed in Table 1. We calculated study‐specific z‐scores and examined psychometric properties of component measures including test‐retest reliability, practice effects, and distributional properties (ceiling/floor effects, skew, kurtosis). We examined sensitivity to preclinical cognitive change using slope estimates (difference in annualized change across A+ and A‐ groups) from linear mixed models (LMMs) for each composite. A jackknife procedure was used to calculate the standard error and subsequent confidence intervals of differences in rates of change (A+>A‐ indicating more significant decline in A+). Significance was determined based on whether the 95% Confidence Interval (CI) contained 0 (alpha = .05).ResultAll composites showed sensitivity to amyloid‐related longitudinal cognitive decline (A+>A‐ annualized change p<.05; see Table 2). Jack‐knife comparisons revealed comparable utility of Mayo‐PACC and PACC‐R (CI contained 0, see Table 3). Exploratory analyses revealed Mayo‐PACC performed similarly to an adaptation of the ADCS‐PACC, Global‐z, Memory‐z and Attention‐z. The Mayo‐PACC performed better than a 2‐measure Mayo‐PACC‐remote and a single memory measure.ConclusionThe Mayo‐PACC provides a parsimonious composite score that has comparable utility for detecting A+>A‐ cognitive decline compared to the PACC‐R and other composites and can be widely used in both research and clinical settings.

Abstract Blood-based biomarkers offer strong potential to revolutionize diagnosis, trial enrolment and treatment monitoring in Alzheimer’s disease (AD). However, further advances are needed before these biomarkers can achieve wider deployment beyond selective research studies and specialty memory clinics, including the development of frameworks for optimal interpretation of biomarker profiles. We hypothesized that integrating Alzheimer’s disease genetic risk score (AD-GRS) data would enhance the diagnostic value of plasma AD biomarkers by better capturing extant disease heterogeneity. Analysing 962 individuals from a population-based sample, we observed that an AD-GRS was independently associated with amyloid PET levels (an early marker of AD pathophysiology) over and above APOE ε4 or plasma p-tau181, amyloid-β42/40, glial fibrillary acidic protein or neurofilament light chain. Among individuals with a high or moderately high plasma p-tau181, integrating AD-GRS data significantly improved classification accuracy of amyloid PET positivity, including the finding that the combination of a high AD-GRS and high plasma p-tau181 outperformed p-tau181 alone in classifying amyloid PET positivity (88% versus 68%; P = 0.001). A machine learning approach incorporating plasma biomarkers, demographics and the AD-GRS was highly accurate in predicting amyloid PET levels (90% training set; 89% test set) and Shapley value analyses (an explainer method based in cooperative game theory) indicated that the AD-GRS and plasma biomarkers had differential importance in explaining amyloid deposition across individuals. Polygenic risk for AD dementia appears to account for a unique portion of disease heterogeneity, which could non-invasively enhance the interpretation of blood-based AD biomarker profiles in the population.

Objective Ceramides have been associated with several ageing-related conditions but have not been studied as a general biomarker of multimorbidity (MM). Therefore, we determined whether ceramide levels are associated with the rapid development of MM. Design Retrospective cohort study. Setting Mayo Clinic Biobank. Participants 1809 persons in the Mayo Clinic Biobank ≥65 years without MM at the time of enrolment, and with ceramide levels assayed from stored plasma. Primary outcome measure Persons were followed for a median of 5.7 years through their medical records to identify new diagnoses of 20 chronic conditions. The number of new conditions was divided by the person-years of follow-up to calculate the rate of accumulation of new chronic conditions. Results Higher levels of C18:0 and C20:0 were associated with a more rapid rate of accumulation of chronic conditions (C18:0 z score RR: 1.30, 95% CI: 1.10 to 1.53; C20:0 z score RR: 1.26, 95% CI: 1.07 to 1.49). Higher C18:0 and C20:0 levels were also associated with an increased risk of hypertension and coronary artery disease. Conclusions C18:0 and C20:0 were associated with an increased risk of cardiometabolic conditions. When combined with biomarkers specific to other diseases of ageing, these ceramides may be a useful component of a biomarker panel for predicting accelerated ageing.