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BACKGROUND: White matter (WM) abnormalities have been implicated in clinically relevant functional decline in multiple system atrophy (MSA). OBJECTIVE: To identify the WM and gray matter (GM) abnormalities in MSA and assess the utility of longitudinal structural and diffusion changes as surrogate markers for tracking disease progression in MSA. METHODS: Twenty-seven participants with early MSA [15 with clinically predominant cerebellar (MSA-C) and 12 with clinically predominant parkinsonian features (MSA-P)] and 14 controls were enrolled as a part of our prospective, longitudinal study of synucleinopathies. Using structural magnetic resonance imaging (MRI) and diffusion MRI (diffusion tensor and neurite orientation and dispersion density imaging), we analyzed whole and regional brain changes in these participants. We also evaluated temporal imaging trajectories based on up to three annual follow-up scans and assessed the impact of baseline diagnosis on these imaging biomarkers using mixed-effect models. RESULTS: MSA patients exhibited more widespread WM changes than GM, particularly in the cerebellum and brainstem, with greater severity in MSA-C. Structural and diffusion measures in the cerebellum WM and brainstem deteriorated with disease progression. Rates of progression of these abnormalities were similar in both MSA subtypes, reflecting increasing overlap of clinical features over time. CONCLUSION: WM abnormalities are core features of MSA disease progression and advance at similar rates in clinical MSA subtypes. Multimodal MRI imaging reveals novel insights into the distribution and pattern of brain abnormalities and their progression in MSA. Selected structural and diffusion measures may be useful for tracking disease progression in MSA clinical trials.
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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.
Subject(s)
Arthritis , Sleep Apnea, Obstructive , Female , Humans , Aged , Middle Aged , Ovariectomy/adverse effects , Hysterectomy , Aging , Chronic DiseaseABSTRACT
BACKGROUND AND OBJECTIVES: Treatment options for Alzheimer disease (AD) are limited and have focused mainly on symptomatic therapy and improving quality of life. Recently, lecanemab, an anti-ß-amyloid monoclonal antibody (mAb), received accelerated approval by the US Food and Drug Administration for treatment in the early stages of biomarker-confirmed symptomatic AD. An additional anti-ß-amyloid mAb, aducanumab, was approved in 2021, and more will potentially become available in the near future. Research on the applicability and generalizability of the anti-ß-amyloid mAb eligibility criteria on adults with biomarkers available in the general population has been lacking. The study's primary aim was to apply the clinical trial eligibility criteria for lecanemab treatment to participants with early AD of the population-based Mayo Clinic Study of Aging (MCSA) and assess the generalizability of anti-amyloid treatment. The secondary aim of this study was to apply the clinical trial eligibility criteria for aducanumab treatment in MCSA participants. METHODS: This cross-sectional study aimed to apply the clinical trial eligibility criteria for lecanemab and aducanumab treatment to participants with early AD of the population-based MCSA and assess the generalizability of anti-amyloid treatment. RESULTS: Two hundred thirty-seven MCSA participants (mean age [SD] 80.9 [6.3] years, 54.9% male, and 97.5% White) with mild cognitive impairment (MCI) or mild dementia and increased brain amyloid burden by PiB PET comprised the study sample. Lecanemab trial's inclusion criteria reduced the study sample to 112 (47.3% of 237) participants. The trial's exclusion criteria further narrowed the number of potentially eligible participants to 19 (overall 8% of 237). Modifying the eligibility criteria to include all participants with MCI (instead of applying additional cognitive criteria) resulted in 17.4% of participants with MCI being eligible for lecanemab treatment. One hundred four participants (43.9% of 237) fulfilled the aducanumab clinical trial's inclusion criteria. The aducanumab trial's exclusion criteria further reduced the number of available participants, narrowing those eligible to 12 (5.1% of 237). Common exclusions were related to other chronic conditions and neuroimaging findings. DISCUSSION: Findings estimate the limited eligibility in typical older adults with cognitive impairment for anti-ß-amyloid mAbs.
Subject(s)
Alzheimer Disease , Cognitive Aging , Cognitive Dysfunction , Humans , Male , Aged , Child , Female , Cross-Sectional Studies , Quality of Life , Alzheimer Disease/complications , Cognitive Dysfunction/complications , Amyloid beta-Peptides , AmyloidABSTRACT
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.
Subject(s)
Breast Neoplasms , Cognitive Dysfunction , Female , Humans , Middle Aged , Aged , Raloxifene Hydrochloride , Selective Estrogen Receptor Modulators , Cross-Sectional Studies , Tamoxifen , Cognition , Receptors, Estrogen/metabolism , Brain/metabolismABSTRACT
Blood pressure (BP) plays an important role in white matter integrity. We sought to determine the role of intra-individual BP changes on white matter and evaluate the impact on gait speed and imbalance by sex. We identified 990 eligible participants in the population-based Mayo Clinic Study of Aging and analyzed fractional anisotropy (FA) in white matter regions. Using structural equation models (SEM), we assessed the effect of BP slope on corticospinal tract (CST) FA and downstream effects on gait speed and imbalance after age and sex effects. Of 990 participants, 438 (44%) were female with mean age of 76 years. In linear models predicting CST FA, a greater change in BP slope (0.0004; p = 0.026) and female sex (0.017; p < 0.001) were significant predictors of lower CST FA. SEMs showed that older age, female sex, and higher BP slope predicted lower CST FA, and lower CST FA predicted worse downstream motor control. Therefore, intra-individual BP slope and variability impact corticospinal tract microstructural properties of white matter with females having increased susceptibility to damage.
Subject(s)
Diffusion Tensor Imaging , White Matter , Humans , Female , Aged , Male , Blood Pressure , White Matter/diagnostic imaging , Pyramidal Tracts/diagnostic imaging , Anisotropy , GaitABSTRACT
OBJECTIVE: To systematically evaluate structural MRI and diffusion MRI features for cross-sectional discrimination and tracking of longitudinal disease progression in early multiple system atrophy (MSA). METHODS: In a prospective, longitudinal study of synucleinopathies with imaging on 14 controls and 29 MSA patients recruited at an early disease stage (15 predominant cerebellar ataxia subtype or MSA-C and 14 predominant parkinsonism subtype or MSA-P), we computed regional morphometric and diffusion MRI features. We identified morphometric features by ranking them based on their ability to distinguish MSA-C from controls and MSA-P from controls and evaluated diffusion changes in these regions. For the top performing regions, we evaluated their utility for tracking longitudinal disease progression using imaging from 12-month follow-up and computed sample size estimates for a hypothetical clinical trial in MSA. We also computed these selected morphometric features in an independent validation dataset. RESULTS: We found that morphometric changes in the cerebellar white matter, brainstem, and pons can separate early MSA-C patients from controls both cross-sectionally and longitudinally (p < 0.01). The putamen and striatum, though useful for separating early MSA-P patients from control subjects at baseline, were not useful for tracking MSA disease progression. Cerebellum white matter diffusion changes aided in capturing early disease related degeneration in MSA. INTERPRETATION: Regardless of clinically predominant features at the time of MSA assessment, brainstem and cerebellar pathways progressively deteriorate with disease progression. Quantitative measurements of these regions are promising biomarkers for MSA diagnosis in early disease stage and potential surrogate markers for future MSA clinical trials.
Subject(s)
Multiple System Atrophy , Humans , Multiple System Atrophy/diagnostic imaging , Prospective Studies , Longitudinal Studies , Cross-Sectional Studies , Magnetic Resonance Imaging/methods , Cerebellum/diagnostic imaging , Disease Progression , Biomarkers , Diagnosis, DifferentialABSTRACT
OBJECTIVES: To report population-based, age-specific prevalence of infarctions as identified via 3D fluid-attenuated inversion recovery (FLAIR) imaging. MATERIALS AND METHODS: Participants without dementia in the Mayo Clinic Study of Aging (MCSA), a population-based study in Olmsted County, MN, age 50-89 who underwent 3D FLAIR imaging between 2017 and 2020 were included. Infarctions per participant were determined via visual interpretation. Inter- and intra-reader reliability were calculated. Infarction prevalence on 3D FLAIR was derived by standardization to the Olmsted County population and was compared to that previously reported on 2D FLAIR imaging. RESULTS: Among 580 participants (mean age 71 years, 46% female) the prevalence (95% confidence interval) of any infarction was 5.0% (0.0%-9.9%) at age 50-59 years and 38.8% (28.6%-49.0%) at 80-89 years. In addition to increasing with age, the prevalence varied by sex and type of infarction. Prevalence estimates of cortical infarcts were 0.9% (0.0%-2.7%) at age 50-59 years and 20.2% (10.7%-29.7%) at 80-89 years and lacunar infarcts 4.1% (0.0%-8.8%) at age 50-59 years and 31.2% (21.5%-41.0%) at 80-89 years. Prevalence estimates of any infarction by sex were: men, 8.7% (0.0%-18.7%) at 50-59 years and 54.9% (41.0%-68.8%) at 80-89 years and women, 2.4% (0.0%-7.3%) at age 50-59 years and 27.3% (12.9%-41.7%) at 80-89 years. Intra- and inter- reader reliability were very good (kappa = 0.85 and 0.82, respectively). After adjusting for age, sex and education, individuals imaged with 3D FLAIR were 1.5 times (95% CI 1.2-1.8, p<0.001) more likely to be identified as positive for infarction compared to those imaged with 2D FLAIR. CONCLUSIONS: Infarction prevalence increases with age and is greater in men than women. Infarction prevalence on 3D FLAIR imaging, which has become more widely implemented as an alternative to 2D FLAIR over the past several years, will be a useful reference in future work.
Subject(s)
Aging , Magnetic Resonance Imaging , Aged , Aged, 80 and over , Female , Humans , Imaging, Three-Dimensional/methods , Infarction , Magnetic Resonance Imaging/methods , Male , Middle Aged , Prevalence , Reproducibility of ResultsABSTRACT
Importance: While amyloidosis is an early event in the Alzheimer disease (AD) biomarker cascade, a complex interplay among the apolipoprotein E (APOE) É4 allele, educational levels, and sex may be associated with an individual's resilience to dementia. Objective: To assess whether APOE É4, educational levels, and sex are associated with regional tau deposition and tau-mediated metabolic dysfunction in older adults. Design, Setting, and Participants: Population-based cohort study of individuals aged 65 years and older enrolled between January 1, 2004, and May 1, 2018, in the Mayo Clinic Study of Aging, a prospective longitudinal study of cognitive aging in Olmsted County, Minnesota. Main Outcomes and Measures: The primary outcomes were cross-sectional tau burden and the fluorodeoxyglucose (FDG) to tau ratio (as a measure of tau-mediated metabolic dysfunction) assessed by positron emission tomography for 43 atlas-defined regions, with specific focus on the entorhinal, inferior temporal, and posterior cingulate cortices. Exposures: Using linear regression, APOE É4 status and years of education were the primary exposure variables, with sex additionally investigated through interaction models. Results: The sample included 325 individuals (173 [53%] male; mean [SD] age, 76.1 [7.2] years; 291 [90%] cognitively unimpaired). Although APOE É4 was nominally associated with higher tau deposition (ß = 0.05 [95% CI, 0.02-0.09]; P = .001; Cohen d = 0.40) and lower FDG to tau ratio (ß = -0.05 [95% CI, -0.08 to -0.01]; P = .008; Cohen d = 0.33) in the entorhinal cortex, these associations were completely attenuated after controlling for global amyloid burden. Education was not associated with regional tau burden or FDG to tau ratio. In the 3 regions of interest, global amyloid burden accounted for the largest proportion of variance in tau deposition among the candidate variables assessed. In the entorhinal cortex, significant interactions were identified between APOE É4 and global amyloid burden on tau (ß = 0.25; SE = 0.06; P < .001) and between sex and tau burden on FDG metabolism (ß = 0.10; SE = 0.05; P = .049). Conclusions and Relevance: These results suggest that (1) tau deposition is most significantly associated with amyloidosis; (2) in the presence of abundant amyloidosis, APOE É4 may be associated with accelerated entorhinal cortex tau deposition; and (3) women may have lower resilience to tau, manifested by a higher degree of metabolic dysfunction in the entorhinal cortex in response to tau pathology.
Subject(s)
Amyloid beta-Peptides/metabolism , Apolipoprotein E4/metabolism , Educational Status , Positron-Emission Tomography , Tauopathies/diagnostic imaging , Tauopathies/metabolism , tau Proteins/metabolism , Aged , Aged, 80 and over , Biomarkers/metabolism , Female , Fluorodeoxyglucose F18 , Humans , Male , Minnesota , Radiopharmaceuticals , Sex FactorsABSTRACT
BACKGROUND: Statins have been proposed to reduce the risk of Alzheimer's disease (AD). OBJECTIVE: Assess whether long-term statin use was associated with neuroimaging biomarkers of aging and dementia. METHODS: Methods: We analyzed neuroimaging biomarkers in 1,160 individuals aged 65+ from the Mayo Clinic Study of Aging, a population-based prospective longitudinal study of cognitive aging. RESULTS: Statin-treated (5+ years of therapy) individuals had greater burden of mid-and late-life cardiovascular disease (pâ<â0.001) than statin-untreated (≤3 months) individuals. Lower fractional anisotropy in the genu of the corpus callosum, an early marker of cerebrovascular disease, was associated with long-term statin exposure (pâ<â0.035). No significant associations were identified between long-term statin exposure and cerebral amyloid or tau burden, AD pattern neurodegeneration, or white matter hyperintensity burden. CONCLUSIONS: Long-term statin therapy was not associated with differences in AD biomarkers. Individuals with long-term statin exposure had worse white matter integrity in the genu of the corpus callosum, consistent with the coexistence of higher cerebrovascular risk factor burden in this group.