Mielke, Michelle M.

Abstract Background Opioids are frequently prescribed to alleviate pain in older adults, yet the relationships between prescription opioids and long‐term cognitive function are unclear. Methods In this analysis of the Mayo Clinic Study of Aging, a longitudinal population‐based cohort study of older adults with formal neuropsychological testing and cognitive evaluations performed every 15 months, the associations between prescription opioids, global and domain‐specific cognitive function, and mild cognitive impairment were evaluated through time‐dependent linear mixed effects and Cox proportional hazards models. Results Four thousand two hundred eighteen participants (51% male) were included with enrollment between 11/1/2004 and 4/1/2019 and median age of 76 (interquartile range 72, 82) years. Two thousand nine hundred seventy‐seven subjects (71%) received at least 1 opioid prescription during a median follow‐up of 7.5 (5.0, 10.7) years. Overall, there was an estimated 0.096 reduction in the global cognitive Z ‐score per year, including decreases of 0.050 in memory, 0.080 in language, 0.044 in visual–spatial cognition, and 0.112 in attention. In multivariable analyses, each receipt of an opioid prescription resulted in an additional −0.007 (95% CI −0.009, −0.005) change in global cognitive Z ‐score ( p < 0.001), with significant effects seen in the domains of memory (−0.005, 95% CI −0.007, −0.003; p < 0.001), language (−0.002, 95% CI −0.003, 0.000; p = 0.024) and attention (−0.004, 95% CI −0.006, −0.002; p < 0.001) but not visual–spatial function (0.000, 95% CI −0.001, 0.001; p = 0.897). Opioid prescriptions were associated with incident mild cognitive impairment (MCI) in adjusted analysis (hazard ratio 1.21, 95% CI 1.04, 1.42; p = 0.014). Conclusion Prescription opioids are associated with small but statistically significant declines in long‐term cognitive function in older adults, which may represent effects of opioids or other related factors.

Background: Preeclampsia (PE) is a pregnancy-specific hypertensive disorder which affects up to 7% of all pregnancies. It is associated with increased risk for cardiovascular disease later in life. We have recently reported increased senescence and accelerated aging in women with PE. We hypothesize that senescence burden remains after PE. The aim of this study was to compare senescence profiles, and history of individual chronic conditions and multimorbidity, a marker of accelerated aging, in women with and without a history of PE. Methods: Forty women with histories of PE and 40 with histories of normotensive pregnancy confirmed by manual chart review were age- and parity-matched. None of the women had a history of CVD at the time of recruitment. Markers of senescence (p16, p21 and Klotho) and metabolic syndrome (leptin, adiponectin) were measured and compared between women with and without histories of preeclampsia using conditional logistic regression. The rates of chronic conditions and multimorbidity between the groups were also compared. Results: Urinary Klotho/creatinine levels were significantly lower (median [IQR]: 117 [87.4, 224] vs. 205 [101, 359], respectively, p=0.042), while leptin/adiponectin ratio was significantly higher (median [IQR]: 0.25 [0.13, 0.45] vs. 0.05 [0.02, 0.12], p=0.027) among women with histories of PE compared to controls. There were no significant differences observed in plasma p21 or p16 concentrations. Women with histories of PE experienced a higher prevalence of two or more co-morbidities compared to women with normotensive pregnancies [67.5% (27/40) vs. 22.5% (9/40), p<0.05]. Results were similar after removing hypertension as a comorbidity [45% (18/40) vs. 20.0% (8/40), p<0.05]. Conclusion: Women with a history of PE had altered markers of senescence, metabolic syndrome and multimorbidity decades after PE.

Abstract The aim of this cross‐sectional study was to examine whether a history of selective estrogen receptor modifiers (SERMs), tamoxifen and raloxifene, use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or magnetic resonance imaging (MRI) markers of neurodegeneration associated with Alzheimer's disease. We included women with prior history of breast cancer or no prior history of any cancer at enrollment in the Mayo Clinic Study of Aging (MCSA). This information was abstracted using the Rochester Epidemiology Project medical‐linkage system. 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 z‐scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), and MRI markers. Among 2840 women aged 50 and older in the MCSA, 151 had a history of breast cancer, and 42 (28%) of these had a history of tamoxifen treatment. A total of 2235 women had no prior history of any cancer, and 76 (3%) of these had a history of raloxifene use. No significant associations between tamoxifen use and cognition, or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders. Similarly, raloxifene use was not significantly associated with cognition, or odds of MCI in women without a history of cancer after adjusting for confounders. We did not find significant associations between the use of either SERM and MRI markers. Use of tamoxifen or raloxifene was not significantly associated with cognition in postmenopausal women.

Background: Observational studies suggested that dementia risk in patients with rheumatoid arthritis (RA) is higher than in the general population. Objective: To examine the associations of RA with cognitive decline and dementia, and neuroimaging biomarkers of aging, Alzheimer’s disease, and vascular pathology in adult participants in the Mayo Clinic Study of Aging (MCSA). Methods: Participants with RA were matched 1:3 on age, sex, education, and baseline cognitive diagnosis to participants without RA. RA cases with MRI were also matched with non-cases with available MRI. All available imaging studies (i.e., amyloid and FDG PET, sMRI, and FLAIR) were included. The study included 104 participants with RA and 312 without RA (mean age (standard deviation, SD) 75.0 (10.4) years, 33% male and average follow-up (SD) 4.2 (3.8) years). Results: Groups were similar in cognitive decline and risk of incident dementia. Among participants with neuroimaging, participants with RA (n = 33) and without RA (n = 98) had similar amyloid burden and neurodegeneration measures, including regions sensitive to aging and dementia, but greater mean white matter hyperintensity volume relative to the total intracranial volume (mean (SD)% : 1.12 (0.57)% versus 0.76 (0.69)% of TIV, p = 0.01), and had higher mean (SD) number of cortical infarctions (0.24 (0.44) versus 0.05 (0.33), p = 0.02). Conclusion: Although cognitive decline and dementia risk were similar in participants with and without RA, participants with RA had more abnormal cerebrovascular pathology on neuroimaging. Future studies should examine the mechanisms underlying these changes and potential implications for prognostication and prevention of cognitive decline in RA.

Abstract Introduction Alzheimer's disease (AD) biomarkers are increasingly more reliable in predicting neuropathology. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, we sought to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) are recognized. Methods We queried the Florida Autopsied Multi‐Ethnic (FLAME) cohort for cases ranging from Braak stages I through VI, excluding non‐AD neuropathologies and tauopathies. Thioflavin‐S staining was compared to immunohistochemical measures of phosphorylated threonine (pT) 181, pT205, pT217, and pT231 in two hippocampal subsectors across n = 24 cases. Results Each phosphorylated tau site immunohistochemically labeled early neurofibrillary tangle maturity levels compared to advanced levels recognized by thioflavin‐S. Hippocampal burden generally increased with each Braak stage. Discussion These results provide neurobiologic evidence that these phosphorylated tau fluid biomarker sites are present during early neurofibrillary tangle maturity levels and may explain why these fluid biomarker measures are observed before symptom onset. Highlights Immunohistochemical evaluation of four phosphorylated tau fluid biomarker sites. Earlier neurofibrillary tangle maturity levels recognized by phosphorylated tau in proline‐rich region. Advanced tangle pathology is elevated in the subiculum compared to the cornu ammonis 1 of the hippocampus. Novel semi‐quantitative frequency to calculate tangle maturity frequency.

AbstractChronic pain is highly prevalent in older adults and is associated with poor functional outcomes. Furthermore, opioid analgesics are commonly utilized for the treatment of pain in older adults despite well-described adverse effects. Importantly, both chronic pain and opioid analgesics have been linked with impairments in cognitive function, though data are limited. In this manuscript we summarize the evidence and critical knowledge gaps regarding the relationships between pain, opioid analgesics, and cognition in older adults. Furthermore, we provide a conceptual framework to guide future research in the development, implementation, and evaluation of strategies to optimize analgesic outcomes in older adults while minimizing deleterious effects on cognition.

Abstract Introduction The aim of this study was to develop a conditional normative model for Rey's Auditory Verbal Learning Test (AVLT) that accounts for practice effects. Methods In our normative sample, robust conditional norms were derived from 1001 cognitively unimpaired (CU) adults ages 50 to 89 who completed the AVLT up to eight times. Linear mixed‐effects models adjusted for baseline performance, prior test exposures, time, demographics, and interaction terms. In our preliminary validation, mean performance on conditional and typical normative scores across two to four completed follow‐up tests in preclinical Alzheimer's disease participants at baseline with positive amyloid and tau positron emission ( n = 27 CU amyloid [A]+tau[T]+) was compared to biomarker negative individuals ( n = 269 CU A–T–). Results AVLT performance using typical norms did not differ across A+T+ and A–T– groups. Conditional norms z‐scores were lower in the A+T+ relative to the A–T– group for 30‐minute recall ( P = .033) and sum of trials ( P = .030). Discussion Conditional normative methods that account for practice effects show promise for identifying longitudinal cognitive decline.

Background: Brain accumulation of amyloid-β is a hallmark event in Alzheimer’s disease (AD) whose underlying mechanisms are incompletely understood. Case-control genome-wide association studies have implicated numerous genetic variants in risk of clinically diagnosed AD dementia. Objective: To test for associations between case-control AD risk variants and amyloid PET burden in older adults, and to assess whether a polygenic measure encompassing these factors would account for a large proportion of the unexplained variance in amyloid PET levels in the wider population. Methods: We analyzed data from the Mayo Clinic Study of Aging (MCSA) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Global cortical amyloid PET burden was the primary outcome. The 38 gene variants from Wightman et al. (2021) were analyzed as predictors, with PRSice-2 used to assess the collective phenotypic variance explained. Results: Known AD risk variants in APOE, PICALM, CR1, and CLU were associated with amyloid PET levels. In aggregate, the AD risk variants were strongly associated with amyloid PET levels in the MCSA ( p = 1.51×10 –50 ) and ADNI ( p = 3.21×10 –64 ). However, in both cohorts the non- APOE variants uniquely contributed only modestly (MCSA = 2.1%, ADNI = 4.4%) to explaining variation in amyloid PET levels. Conclusion: Additional case-control AD risk variants added only modestly to APOE in accounting for individual variation in amyloid PET burden, results which were consistent across independent cohorts with distinct recruitment strategies and subject characteristics. Our findings suggest that advancing precision medicine for dementia may require integration of strategies complementing case-control approaches, including biomarker-specific genetic associations, gene-by-environment interactions, and markers of disease progression and heterogeneity.

Objectives To study the association between multi-morbidity percentiles, which is a measure of clinical aging, and interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α. Methods Participants 50 to 95 years of age from the Mayo Clinic Study of Aging were assigned age- and sex-specific multi-morbidity percentiles using look-up tables that were reported previously (n = 1646). Percentiles were divided into quintiles for analysis. Plasma IL-6, IL-10, and TNF-α levels were measured in 1595 participants. Median inflammatory marker levels were compared across multi-morbidity quintiles using nonparametric tests. Results People with higher multi-morbidity percentiles had significantly higher IL-6 and TNF-α levels compared with those with lower multi-morbidity percentiles. Tests for trend across five multi-morbidity quintiles were significant among women for IL-6 and among participants 70 years of age or older for IL-6 and TNF-α. IL-10 was not associated with multi-morbidity percentiles. Conclusions Multi-morbidity percentiles may be a useful clinical index of biological age for future studies, particularly in women and people 70 years of age and older.