Mielke, Michelle M.

AbstractBackground: hearing loss has been associated with mild cognitive impairment (MCI) and dementia. Studies have not assessed whether hearing difficulties (HD) that interfere with daily activities as reported by partners can be a marker for increased risk for cognitive decline and impairment.Objective: to assess the cross-sectional and longitudinal associations between informant-based HD, which interfere with daily activities and the risk for MCI and dementia.Methods: the study included 4812 participants without dementia, enrolled in the Mayo Clinic Study of Aging (mean age (SD) 73.7 (9.6) years) with cognitive evaluation and informant-based report on participant’s HD that interfere significantly with daily activities at baseline and for every 15 months. Cox proportional hazards models (utilising time-dependent HD status and age as the time scale) were used to examine HD and the risk for MCI or dementia, and mixed-effects models (allowing for random subject-specific intercepts and slopes) were used to examine the relationship between HD and cognitive decline.Results: about, 981 participants had HD and 612 (12.7%) had prevalent MCI at baseline; 759 participants developed incident MCI and 273 developed incident dementia. In cognitively unimpaired participants at baseline, those with HD had higher risk for MCI (hazard ratio [HR] = 1.29, 95% confidence interval [CI] (1.10, 1.51), P = 0.002; adjusting for sex, years of education). In participants without dementia, those with HD had higher risk for dementia (HR: 1.39, 95% CI, (1.08–1.79), P = 0.011; adjusting sex and education). In individuals with MCI, HD was associated with modestly greater cognitive decline.Conclusions: informant-based HD was associated with increased risk for MCI and dementia.

Abstract Although white matter hyperintensities have traditionally been viewed as a marker of vascular disease, recent pathology studies have found an association between white matter hyperintensities and Alzheimer’s disease pathologies. The objectives of this study were to investigate the topographic patterns of white matter hyperintensities associated with Alzheimer’s disease biomarkers measured using PET. From the population-based Mayo Clinic Study of Aging, 434 participants without dementia (55% male) with FLAIR and gradient recall echo MRI, tau-PET (AV-1451) and amyloid-PET scans were identified. A subset had cerebral microbleeds detected on T2* gradient recall echo scans. White matter hyperintensities were semi-automatically segmented using FLAIR MRI in participant space and normalized to a custom template. We used statistical parametric mapping 12-based, voxel-wise, multiple-regression analyses to detect white matter hyperintense regions associated with Alzheimer’s biomarkers (global amyloid from amyloid-PET and meta-regions of interest tau uptake from tau-PET) after adjusting for age, sex and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Topographic patterns of amyloid-associated white matter hyperintensities included periventricular white matter hyperintensities (frontal and parietal lobes). White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex adjusted Cohen’s d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis. Among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities. The study did not support an association between increased tau burden and white matter hyperintense burden.

Abstract Introduction We evaluated whether incident mild cognitive impairment (MCI) subtypes could be empirically derived in the Mayo Clinic Study of Aging. Methods We performed cluster analysis on neuropsychological data from 506 participants with incident MCI. Results The 3‐cluster solution resulted in (1) amnestic, (2) dysexecutive, (3) dysnomic subtypes. The 4‐cluster solution produced these same three groups and a fourth group with subtle cognitive impairment (SCI). The SCI cluster was a subset of the amnestic cluster and distinct from well‐matched cognitively unimpaired participants based on memory and global z‐score area under the receiver operating characteristic curve analyses and probability of progression to MCI/dementia. Discussion We empirically identified three neuropsychological subtypes of MCI that share some features with MCI subtypes identified in the Alzheimer's Disease Neuroimaging Initiative. The fourth subtype with SCI in the Mayo Clinic Study of Aging differed from the fourth cluster‐derived normal group in Alzheimer's Disease Neuroimaging Initiative and could represent a group to target with early interventions.

Objectives: Patients requiring admission to an ICU may subsequently experience cognitive decline. Our objective was to investigate longitudinal cognitive trajectories in older adults hospitalized in ICUs. We hypothesized that individuals hospitalized for critical illness develop greater cognitive decline compared with those who do not require ICU admission. Design: A retrospective cohort study using prospectively collected cognitive scores of participants enrolled in the Mayo Clinic Study of Aging and ICU admissions retrospectively ascertained from electronic medical records. A covariate-adjusted linear mixed effects model with random intercepts and slopes assessed the relationship between ICU admissions and the slope of global cognitive z scores and domains scores (memory, attention/executive, visuospatial, and language). Setting: ICU admissions and cognitive scores in the Mayo Clinic Study of Aging from October 1, 2004, to September 11, 2017. Patients: Nondemented participants age 50 through 91 at enrollment in the Mayo Clinic Study of Aging with an initial cognitive assessment and at least one follow-up visit. Interventions: None. Measurements and Main Results: Of 3,673 participants, 372 had at least one ICU admission with median (25–75th percentile) follow-up after first ICU admission of 2.5 years (1.2–4.4 yr). For global cognitive z score, admission to an ICU was associated with greater decline in scores over time compared with participants not requiring ICU admission (difference in annual slope = –0.028; 95% CI, –0.044 to –0.012; p < 0.001). ICU admission was associated with greater declines in memory (–0.029; 95% CI, –0.047 to –0.011; p = 0.002), attention/executive (–0.020; 95% CI, –0.037 to –0.004; p = 0.016), and visuospatial (–0.013; 95% CI, –0.026 to –0.001; p = 0.041) domains. ICU admissions with delirium were associated with greater declines in memory (interaction p = 0.006) and language (interaction p = 0.002) domains than ICU admissions without delirium. Conclusions: In older adults, ICU admission was associated with greater long-term cognitive decline compared with patients without ICU admission. These findings were more pronounced in those who develop delirium while in the ICU.

Background: Exercise prevents recurrent cardiovascular events and it may combat cognitive decline in coronary artery disease (CAD); however, evidence in type 2 diabetes (T2DM) has been mixed. T2DM and memory decline have been associated with differences in the plasma sphingolipidome. Objective: Here, we will investigate whether T2DM-related sphingolipids predict less memory improvement over an exercise intervention for CAD. Methods: Among participants with CAD entering a 6-month exercise intervention, we matched 20 with T2DM to 40 without T2DM for age, sex, and body mass index. We assessed 45 sphingolipid species using high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometry with multiple reaction monitoring. We assessed memory using the California Verbal Learning Test, 2nd Ed, and the revised Brief Visuospatial Learning Test. Results: Partial least squares discriminant analysis identified 8 species that distinguished T2DM from non-T2DM groups with 83% (95% confidence interval [70%, 95%]) accuracy in a receiver operator characteristic curve (validated by internal resampling, 1000 permutations, p = 0.01). At baseline, T2DM-associated sphingolipids (ceramide C22 : 0, monohexylceramide C16 : 1, and lactosylceramide C24 : 0) were associated with poorer memory, attention, and psychomotor processing speed performance. Among 50 completers, an indirect effect of T2DM on less improvement in verbal memory was mediated by monohexylceramide C16 : 1 (0.86 fewer words recalled, 95% bootstrap confidence interval [–2.32, –0.24]), and an indirect effect of T2DM on less visuospatial memory improvement was mediated by ceramide C22 : 0 concentrations (0.42 fewer points, 95% bootstrap confidence interval [–1.17, –0.05]). Conclusions: Ceramide species associated with T2DM predicted poorer cognitive responses to exercise in patients with CAD.

Objective. Autonomic symptoms are common in α-synuclein disorders: multiple system atrophy (MSA), Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Parkinson’s disease with dementia (PDD). These symptoms may precede the motor findings/clinical diagnosis by years. Erectile dysfunction (ED) is an autonomic symptom that has rarely been studied in these α-synuclein disorders. In this population-based, case-control study, we investigated the association between premonitory erectile dysfunction surfacing prior to the clinical-motor manifestations of these α-synucleinopathies. Methods. We used the medical record-linkage system of the Rochester Epidemiology Project to identify cases of α-synucleinopathies in Olmsted County from 1991 to 2010. Each male case was matched by age (±1 year) of symptom onset and sex to a control. We reviewed complete medical records of cases and controls to detect erectile dysfunction prior to the clinical-motor onset of α-synucleinopathies of any type. We used conditional logistic regression to calculate the odds ratio of all α-synucleinopathies, as well as by type, adjusting for diabetes, coffee, and smoking. Results. A history of male erectile dysfunction was associated with 1.5-fold increased odds of an α-synucleinopathy diagnosis of any type in univariate analyses (p=0.06). When stratifying α-synucleinopathies by type, early erectile dysfunction was most frequent in MSA cases than matched controls (45% vs. 9%). Premotor phase ED was next most frequent among the DLB cases (46% vs. 27% among the controls; OR = 2.83, p=0.03; when adjusted for diabetes, smoking, and coffee, OR = 2.98, p=0.04). Premotor phase ED was not significantly associated with PD or PDD. Conclusions. Early erectile dysfunction may be a premotor symptom of MSA and DLB, reflecting premonitory dysautonomia. It was not associated with premotor PD or PDD.