Julie A. Fields

Background and ObjectivesClinical trials in REM sleep behavior disorder (RBD) to delay or prevent the development of Parkinson disease (PD), dementia with Lewy bodies (DLBs), and multiple system at...

Background and ObjectivesIdiopathic REM sleep behavior disorder (iRBD) is a marker of early neurodegenerative synucleinopathy. Nigrostriatal dopaminergic dysfunction is often considered the primary...

Cognitive fluctuations are reported in 90% of individuals with dementia with Lewy bodies (DLB) and along with dysautonomia, are a key source of disability. Through this effort, we sought to investigate the relationship between autonomic burden and cognitive fluctuations, neuropsychiatric burden and quality of life in moderate-advanced DLB. This multicenter, prospective, observational, longitudinal cohort study, Predicting ACcurately End-of-Life in Dementia With Lewy Bodies and Promoting Quality End-of-Life Experiences (PACE-DLB), was conducted in the United States to study individuals with moderate-advanced DLB. The primary exposure for the current analysis was time-varying total autonomic burden, as measured by the autonomic symptom checklist (ASC) at baseline and follow-up visits. The primary outcomes were cognitive fluctuations measured by Clinician Assessment of Fluctuations (CAF) scores and neuropsychiatric burden as measured by Neuropsychiatric Inventory Questionnaire (NPI-Q) scores. Secondary outcomes included quality of life (QoL) captured through the Quality of Life-Alzheimer's Disease scale. Mixed-effects regression analyses were conducted to assess the effect of autonomic burden on each primary outcome, with age, sex, education, Charlson Comorbidity Index, anticholinergic burden, levodopa equivalent daily dosage, and EPWORTH sleepiness scale scores adjusted as potential confounders. We additionally conducted modified graphical network model analyses. A total of 189 patients with 745 longitudinal observations were included in the analysis. Mean age of the cohort was 74.92 years (SD 7.77 years) with 22% female participants. At baseline, ASC was directly associated with CAF (RC = 0.16; 95% CI 0.01-0.31; p = 0.032) and NPI-Q (RC = 3.27; 95% CI 2.37-4.18; p < 0.001). In longitudinal analysis, ASC remained directly associated with CAF (RC = 0.18; 95% CI 0.11-0.24; p < 0.001) and NPI-Q (RC = 2.10; 95% CI 1.49-2.71; p < 0.001). ASC scores were inversely associated with QoL of the caregiver (RC = -0.04; 95% CI -0.06 to -0.02) in longitudinal adjusted analysis. Graphical network modeling incorporating possible relationships across characteristics showed that autonomic burden was directly and stably associated with cognitive fluctuations (weight = 0.15) and neuropsychiatric burden (weight = 0.47). Autonomic burden correlates with severity of cognitive fluctuations and neuropsychiatric burden in moderate-advanced DLB. It also correlates with the QoL of the caregiver over time. These results encourage investigation into novel potential therapeutic avenues in moderate-advanced DLB.

Engagement in physical and cognitive activities is associated with a decreased risk of mild cognitive impairment (MCI) and dementia, but the association with Alzheimer disease (AD) neuroimaging biomarkers is less clear. We thus examined associations of physical and cognitive activities with longitudinal trajectories of AD neuroimaging biomarkers among older adults free of dementia. We conducted a longitudinal study within the population-based Mayo Clinic Study of Aging (mean follow-up durations 1.3-3.4 years). Participants were aged 50 years or older and were cognitively unimpaired or had MCI at baseline. Engagement in physical and cognitive activities during 12 months before baseline was assessed through questionnaires. Participants underwent AD neuroimaging biomarker assessments at 1 or more time points. We ran linear mixed-effect models to examine associations between physical and cognitive activity composite scores and trajectories of individual yearly change in amyloid deposition (Pittsburgh compound B [PiB]-PET centiloid), tau burden (tau-PET standardized uptake value ratio [SUVR]), and regional glucose hypometabolism (fluorodeoxyglucose [FDG]-PET SUVR), adjusted for age, sex, APOE ɛ4 carrier status, and medical comorbidity. We included 1,176 participants (47% female; mean [SD] age, 68.7 [9.6] years) for PiB-PET trajectories, 399 participants (49% female; mean [SD] age, 71.9 [11.0] years) for tau-PET trajectories, and 983 participants (46% female; mean [SD] age, 67.9 [9.2] years) for FDG-PET trajectories. PiB-PET and tau-PET measures increased during follow-up (3.4 [SD 4.0] and 1.3 [SD 2.1] years, respectively), whereas FDG-PET values decreased over 2.9 (SD 3.5) years of follow-up. Participants with higher total physical activity (interaction estimate 0.0017; 95% CI 0.0003-0.0031; p = 0.021) and higher moderate-to-vigorous physical activity (interaction estimate 0.0015; 95% CI 0.0001-0.0029; p = 0.040) had a less pronounced decrease in FDG-PET over time. Participants with higher cognitive activity experienced a less pronounced increase in PiB-PET (interaction estimate -0.2253; 95% CI -0.4437 to -0.0070; p = 0.043) and a smaller decrease in FDG-PET (interaction estimate 0.0015; 95% CI 0.0001-0.0028; p = 0.038) over time. Physical activity was associated with less synaptic dysfunction and cognitive activity with less synaptic dysfunction and lower amyloid burden over time, albeit effect sizes were small. Further research is needed to validate findings and clarify causal inference between physical and cognitive activities and AD neuroimaging biomarkers.

This analysis used clinical data from prospectively followed participants meeting criteria for probable dementia with Lewy bodies (DLB) in the Mayo Clinic Alzheimer's Disease Research Center (ADRC) between 1998 and 2024. DLB is characterized by unique core features of visual hallucinations (VHs), parkinsonism, REM sleep behavior disorder, and cognitive fluctuations with a variable disease course. DLB is associated with a poor prognosis, but whether these unique DLB core clinical features influence survival is unknown. We aimed to determine whether core clinical features are associated with survival in patients with probable DLB. Patients followed in the Mayo Clinic ADRC between 1998 and 2024 underwent annual clinical assessments. Those who met clinical criteria for probable DLB were analyzed. Time-dependent Cox proportional hazard models using age as the time scale determined associations between the individual and cumulative number of core clinical DLB features and survival. The prognostic significance of core features present at the time DLB criteria were met was assessed in separate models. Models were adjusted for sex and duration from the onset of cognitive symptoms to DLB diagnosis. Of 488 patients with probable DLB meeting inclusion criteria, 118 (24%) were women with a mean age of 71.9 ± 8.4 years at the time of meeting probable DLB criteria. Shorter survival was associated with the development of VHs (hazard ratio [HR] 3.25, 95% CI 2.46-4.29) and parkinsonism (HR 2.28, 95% CI 1.54-3.39) during the disease course and VHs at the time of DLB diagnosis (HR 1.60, 95% CI 1.18-2.16). All four core features were also associated with shorter survival (4 core features vs 2 core features, HR 3.58 95% CI 2.66-4.80, 4 core features vs 3 core features, HR 2.46, 95% CI 1.86-3.25). In 191 patients (45 women (24%) with a mean age of 71.2 ± 8.6 years at probable DLB diagnosis) with autopsy-confirmed DLB, VHs, parkinsonism, and all four core features were associated with shorter survival. Sex was not associated with survival. VHs, parkinsonism, and the development of all 4 core features were associated with shorter survival in probable and in autopsy-confirmed DLB. These findings have important prognostic and management implications for patients with DLB and their caregivers.

Objectives: To assess the long-term effects of 4 years of menopausal hormone therapy (mHT) on the brain’s white matter architecture in women who initiated mHT within 3 years of menopause onset. Methods: The Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, double-blind, randomized, placebo-controlled 4-year mHT trial with treatment arms of oral conjugated equine estrogens (oCEE), transdermal 17β-estradiol (tE2), and placebo in recently postmenopausal women. KEEPS Continuation was an observational follow-up of KEEPS participants. White matter integrity was evaluated in KEEPS Continuation participants 10 years after KEEPS completion using white matter hyperintensity volume, diffusion magnetic resonance imaging (dMRI) techniques, and cerebral infarcts. Linear regression models were fitted for each brain region to evaluate if there were differences in white matter between KEEPS treatment arms. Results: There was no evidence to suggest the long-term effects of 4 years of mHT on brain white matter in KEEPS Continuation participants [n=266, mean age 67 (58-73)]. No differences in dMRI metrics were found in each of the treatment arms (oCEE n=70; tE2 n=79) when compared to placebo (n=94), following a false discovery rate adjustment for multiple comparisons. There were no statistically significant differences in white matter hyperintensity volume or infarct occurrence when comparing each of the treatment arms to placebo. Conclusions: We found no evidence of the long-term effect of 4-year mHT on white matter integrity when compared to placebo, consistent with emerging evidence of the safety of short-term use of mHT in recently postmenopausal women.

Objective: The National Institutes of Health (NIH) Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) is a validated laptop-based battery of executive functioning tests. A modified tablet version of the EXAMINER was developed on the UCSF Tablet-based Cognitive Assessment Tool (TabCAT-EXAMINER). Here we describe the battery and investigate the reliability and validity of a composite score. Methods: A diagnostically heterogeneous sample of 2135 individuals (mean age = 65.58, SD = 16.07), including controls and participants with a variety of neurodegenerative syndromes, completed the TabCAT-EXAMINER. A composite score was developed using confirmatory factor analysis and item response theory. Validity was evaluated via linear regressions that tested associations with neuropsychological tests, demographics, clinical diagnosis, and disease severity. Replicability of cross-sectional results was tested in a separate sample of participants ( n = 342) recruited from a frontotemporal dementia study. As this separate sample also collected longitudinal TabCAT-EXAMINER measures, we additionally assessed test-retest reliability and associations between baseline disease severity and changes in TabCAT-EXAMINER scores. Results: The TabCAT-EXAMINER score was normally distributed, demonstrated high test-retest reliability, and was associated in the expected directions with independent tests of executive functioning, demographics, disease severity, and diagnosis. Greater baseline disease severity was associated with more rapid longitudinal TabCAT-EXAMINER decline. Conclusions: The TabCAT-EXAMINER is a tablet-based executive functioning battery developed for observational research and clinical trials. Performance can be summarized as a single composite score, and results of this study support its reliability and validity in cognitive aging and neurodegenerative disease cohorts.

Objective: To assess the association of systolic and diastolic blood pressure (SBP and DBP) in recently menopausal women with white matter hyperintensity (WMH) volume later in life and determine whether short-term menopausal hormone therapy (mHT) modifies these associations. Methods: Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, randomized, double-blinded, placebo-controlled 4-year mHT trial (oral conjugated equine estrogens or transdermal 17β-estradiol). KEEPS continuation was an observational follow-up of the participants 10 years after the end of mHT. The associations between KEEPS baseline blood pressure (BP) with KEEPS continuation WMH volume were examined adjusting for covariates in model 1 (age, total intracranial volume, study site, mHT type) and model 2 (additionally conventional CVD risk factors). Interaction terms (BP × mHT type) were added into the linear regression models. Results: The mean ± SD ages of participants were 53 (±2) years at KEEPS baseline and 67 (±2) years at KEEPS continuation. Elevated BP at KEEPS baseline was associated with greater WMH volume measured 14 years later (model 1: SBP: β = 0.01 [95% CI, 0.001‐0.01] and DBP: β = 0.01 [95% CI, 0.003‐0.03]) and after additionally adjusting for CVD risk factors (model 2). We did not find any evidence that mHT versus placebo modified these associations. Topographically, higher BP was associated with greater periventricular WMH in the frontal and parietal lobes. Conclusion: Our findings suggest the importance of maintaining normal BP in recently postmenopausal women with low CVD risk, irrespective of short-term mHT usage, to potentially reduce the risk of WMH later in life.

Idiopathic/isolated REM sleep behavior disorder (iRBD) has been strongly linked to neurodegenerative synucleinopathies such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. However, there have been increasing reports of RBD as a presenting feature of serious and treatable autoimmune syndromes, particularly IGLON5. This study's objective was to investigate the frequency of autoantibodies in a large cohort of participants with iRBD. Participants were enrolled in the North American Prodromal Synucleinopathy cohort with polysomnography-confirmed iRBD, free of parkinsonism and dementia. Plasma samples were systematically screened for the autoantibodies IGLON5, DPPX, LGI1, and CASPR2 using plasma IgG cell-based assay. Positive or equivocal results were confirmed by repeat testing, plus tissue-based indirect immunofluorescence assay for IGLON5. Of 339 samples analyzed, 3 participants (0.9%) had confirmed positive IGLON5 autoantibodies in the cell-based assay, which were confirmed by the tissue-based assay. An additional participant was positive for CASPR2 with low titer by cell-based assay only (of lower clinical certainty). These cases exhibited a variety of symptoms including dream enactment, cognitive decline, autonomic dysfunction, and motor symptoms. In 1 IGLON5 case and the CASPR2 case, evolution was suggestive of typical synucleinopathy, suggesting the possibility that findings were incidental. However, 2 participants with IGLON5 died before diagnosis was clinically suspected, with a final clinical picture highly suggestive of autoimmune disease. Our finding that nearly 1% of a large iRBD cohort may have a serious but potentially treatable autoantibody syndrome has important clinical implications. In particular, it raises the question of whether autoantibody testing for IGLON-5-IgG should be widely implemented for participants with iRBD, considering the difficulty in diagnosis of autoimmune diseases, their response to treatment, and the potential for rapid disease progression. However, any routine testing protocol will also have to consider costs and potential adverse effects of false-positive findings. NCT03623672.