Citations

Abstract INTRODUCTION We describe the reliability of remote self‐administered digital cognitive measures completed via the Mayo Test Drive (MTD) web‐based platform. METHODS A total of 1846 participants (mean age = 70, SD = 12, range 31–101; 48% male; 96% White; 99% non‐Hispanic; 97% cognitively unimpaired) with two to four complete MTD sessions at ∼7.5‐month intervals were included. Test‐retest reliability was assessed using single‐rating, absolute‐agreement, and two‐way mixed intraclass correlation coefficients (ICCs) with 95% confidence intervals. ICCs for in‐person‐administered traditional neuropsychological measures were compared to MTD for a subset of 244 participants. Analyses also compared reliability across demographic, residential, and session context subgroups. RESULTS Reliability was good for the MTD Composite (total ICC = 0.79 [0.77, 0.80]), and moderate‐to‐good for the primary outcome variables for each MTD subtest (total ICCs 0.70–0.83 for Stricker Learning Span and Symbols). The reliability of the remote self‐administered MTD was similar to in‐person‐administered cognitive measures. DISCUSSION MTD showed moderate‐to‐good reliability, supporting its use in longitudinal monitoring.

Abstract Introduction Isolated REM sleep behavior disorder (iRBD) is characterized by loss of normal REM sleep atonia and dream enactment behavior. iRBD is strongly associated with α-synucleinopathies and risk for developing Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), yet phenoconversion risk for long-term outcomes of younger women and men remains undefined. We aimed to ascertain longitudinal outcomes and phenoconversion risk in the Mayo Clinic iRBD cohort. Methods Eighty-nine of 165 registry participants with at least one-year follow-up were included. Retrospective chart review attained baseline demographics, age at presentation, baseline Timed Up and Go (TUG) and Montreal Cognitive Assessment (MoCA) scores, and phenoconversion status (iRBD, PD, DLB, mild cognitive impairment [MCI], MSA, or other). Kaplan–Meier survival analysis and Cox proportional hazards modeling were analyzed with alpha at p < 0.05. Results 68 men and 21 women had a mean age of 63 years at polysomnographic diagnosis. At follow-up, 64 (71.9%) remained iRBD; 7 (7.9%) developed PD, 11 (12.4%) developed DLB, 3 (3.4%) developed MCI, 1 (1.1%) developed MSA, and 3 (3.4%) developed another dementia. Abnormal TUG (>12 seconds) occurred in 5.9% and abnormal MoCA (< 24) in 23.3%. Phenoconversion rates were similar in women and men (p = 0.44). Older age at PSG predicted phenoconversion, corresponding to a two-fold increase in risk with each 10-year increase (HR 2.00, 95% CI 1.15–3.52). Neither abnormal TUG nor MoCA predicted conversion. Cumulative phenoconversion was approximately 1% at 1 year, 7% at 3 years, 10% at 5 years, 30% at 10 years, 34% at 12 years, and 49% at 15 years. Mean and median time to phenoconversion was 7 years (range, 1-18 years). Conclusion We found that iRBD phenoconversion rates were lower than historically reported. Only age at presentation predicted phenoconversion, with risk doubling per decade. At 12 years, cumulative phenoconversion rate was approximately 34%. Support (if any)

Abstract Introduction The relationship between sleep and brain metabolism remains unclear. This study aimed to examine whether overnight sleep features, using a home sleep apnea system based on peripheral arterial tonometry, are associated with regional FDG-PET changes in older adults. Methods We analyzed cognitively unimpaired adults (≥60 years) from the Mayo Clinic Study of Aging (MCSA) cohort who were not receiving sleep apnea treatment. Participants underwent overnight sleep assessment with the WatchPAT system, followed by FDG-PET imaging the next morning. FDG-PET data were co-registered to 3T MRI and automatically segmented into 122 anatomical regions. PET signal was referenced to the pons (SUVR). We computed voxel-weighted median FDG signal across 47 bilateral cortical and subcortical regions of interest (ROIs), excluding brainstem and cerebellum. Associations between sleep architecture and sleep apnea/hypoxemia burden and regional metabolism were assessed using partial Spearman’s rank correlation, adjusting for age. Results Thirty-seven participants were included (70.3% female; median [IQR] age: 72.0 [68.0–78.0] years). Wake after sleep onset (WASO) showed widespread negative associations with FDG uptake in cortical regions (p< 0.05), particularly the ventromedial/ventrolateral (rs=–0.47 to –0.33) prefrontal cortex, lateral temporal (rs=–0.38 to –0.33), and occipital (rs=–0.47 to –0.37) cortices. Total sleep time (TST) was positively associated with medial structures (p< 0.05), including the posterior cingulate (rs=0.39), retrosplenial cortex (rs=0.48), hippocampus/parahippocampal (rs=0.34 to 0.36), calcarine cortex (ρ=0.38), thalamus (rs=0.37), and caudate (rs=0.43). Hypoxic burden was positively associated with medial occipital regions (rs=0.35 to 0.39) and AHI-4% with cuneus (rs=0.33). Regional gray matter volume did not mediate these associations. WASO correlated with Insomnia Severity Index (rs=0.43, p=0.008) and self-reported refreshing sleep (rs=0.046). Conclusion Overnight sleep macrostructure features (WASO and TST) and hypoxic burden are significantly associated with brain metabolism, potentially underlying symptoms of sleep disturbance and cognitive aging. Support (if any) Mayo Clinic Alzheimer’s Disease Research Center Development Award (P30 AG062677), R01 AG056366, U01 AG006786, R01 AG056366, R01 AG034676, R37 AG011378, R01 AG041851, R01 NS097495, R01 AG068206, P30 AG062677, R01 HL065176. CLARA project work with funding from the European Union’s HORIZON EUROPE research and innovation programme (No 101136607).

Abstract Introduction Sleep-disordered breathing (SDB) is a potentially modifiable risk factor for the prevention of dementia, of which Alzheimer’s disease (AD) is the most common cause. However, there is a lack of longitudinal evidence relating SDB to AD pathology >20 years later. We examined the association between late-midlife SDB and late-life brain β-amyloid (Aβ) deposition—a hallmark of AD—assessed approximately 23 years later. Methods The Atherosclerosis Risk in Communities (ARIC) Study is an ongoing prospective cohort study initiated in 1987. Participants at two ARIC sites (Washington County, Maryland; Minneapolis, Minnesota) with primarily White participants also completed polysomnography (PSG) in the Sleep Heart Health Study (SHHS) in 1995-98. SDB measures included apnea-hypopnea index (AHI; number of apneas + hypopneas with ≥3% oxygen desaturation/hour of sleep), arousal index, and percentage of total sleep time in apnea, in hypopnea, and with oxygen saturation < 90%. A subset of participants completed florbetapir positron emission tomography (PET) scans through several ARIC ancillary studies (2011-2025 including the ARIC Sleep-PET study). We defined Aβ deposition as a global standardized uptake value ratio (SUVR) >1.2 (vs. SUVR ≤1.2). We used Poisson regression with robust standard errors to estimate relative risk (RR) of Aβ deposition by SDB, adjusting for demographics and vascular risk factors, and applied inverse probability attrition weighting to account for selective drop-out. Results Among 186 dementia-free participants (mean age=59 years at PSG and 82 years at PET scan, 58% female, 98% White), every 10% increase in total sleep time in hypopnea was associated with higher risk of Aβ deposition (RR=1.40, 95% confidence interval [CI]: 1.03, 1.91). When compared to no SDB (AHI < 5), moderate to severe SDB (AHI ≥15) was associated with elevated Aβ deposition (RR=2.36, 95% CI: 1.22, 4.57); mild SDB (AHI 5 to < 15) was not (RR=1.05, 95% CI: 0.53, 2.07). Conclusion SDB in late midlife was associated with greater risk of Aβ deposition approximately 23 years later. SDB may play a role in the early stages of AD pathogenesis. Future longitudinal studies are needed to optimize strategies for screening and treating SDB for dementia prevention. Support (if any) Supported in part by RF1AG050745.

Abstract INTRODUCTION Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission tomography (PET) scan indicates not/low ADNC and whether this autopsy finding can occur >10 years after a positive amyloid PET. METHODS Participants with positive amyloid PET scans were categorized by levels of ADNC at autopsy, grouped by time from initial positive amyloid PET to time of death (<5 years, 5 to <10 years, or 10+ years). RESULTS Among those with a positive amyloid PET scan, the majority had intermediate/high ADNC at autopsy (234/259, 90%). In the group with 10+ years between a positive amyloid PET and death ( n = 39) not/low ADNC occurred in 3/39 (8%). DISCUSSION Not/low ADNC is uncommon among those with positive amyloid PET scans. After 10+ years, it is possible but rare for a positive amyloid PET scan to represent an indolent state of neuropathology.

Abstract INTRODUCTION Prospective studies of blood‐based biomarkers reflecting pathogenic processes, other than Alzheimer‐specific pathologies, that contribute to dementia in diverse cohorts are lacking. METHODS We jointly fitted linear mixed‐effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble cluster of differentiation‐14 (sCD14), neurofilament light chain (NfL), total tau (t‐tau), and ubiquitin C‐terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community‐based Atherosclerosis Risk in Communities Study. sCD14 and YKL‐40 were measured in 3082 participants and the other four biomarkers in 1766 participants. RESULTS Higher serum GFAP, YKL‐40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log‐base2 YKL‐40 was associated with −0.11SD faster 25‐year cognitive decline (95% confidence interval [CI]: −0.15,−0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t‐tau and UCHL1 were also associated with faster cognitive decline. DISCUSSION Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.

Cytomegalovirus (CMV) establishes lifelong latency following primary infection and can reactivate to cause severe illness in immunocompromised hosts. CMV DNAemia in non-HIV-infected, non-solid organ/bone marrow transplant (NHNT) hosts is poorly characterized, with limited clinical insights. We aim to describe the clinical presentation, prognostic indicators, and outcomes of CMV DNAemia among NHNT patients. We used the TriNetX international patient database to identify adult patients diagnosed with CMV DNAemia from 2016 until March 2023. We evaluated hospitalization, intensive care unit (ICU) level care, and all-cause mortality at 30 days and 1 year. We also completed a post-propensity score analysis comparing clinical characteristics of survivors versus non-survivors at 90 days. We identified 1123 NHNT patients with CMV DNAemia, most of whom had neoplasms (63%). Venous thromboembolism occurred in 31% of the population. The 30-day hospitalization and all-cause mortality rates were 35% and 14%, respectively. After propensity score matching and Bonferroni correction, weakness, purpura, acute respiratory failure, malnutrition, encephalopathy, and hypotension were associated with increased 90-day all-cause mortality. NHNT patients with CMV DNAemia carry a substantial morbidity and all-cause mortality. Further studies are warranted to clarify whether CMV DNAemia is a causative factor or an incidental finding in this population.

Summary Functional high‐risk (FHR) multiple myeloma (FHRMM) is often defined as progression within 12–24 months of front‐line autologous hematopoietic stem cell transplantation (AHSCT). For patients with early progression after suboptimal front‐line therapies, it is challenging to assign the disease progression to a true FHR phenotype versus less effective front‐line therapy. In this study, we combined data from three Center for International Blood and Marrow Transplant Research studies (MM18‐02, MM19‐01 and MM20‐03). We included patients who received front‐line AHSCT between 2008 and 2018 and had progression <12 (FHR12, n = 465), <18 (FHR18, n = 672) or <24 months (FHR24, n = 853) after AHSCT. We classified induction therapy as standard lenalidomide‐containing triplets (bortezomib, lenalidomide, dexamethasone [VRD]/carfilzomib, lenalidomide, dexamethasone [KRD]) versus other (bortezomib, thalidomide, dexamethasone [VTD]/bortezomib, cyclophosphamide, dexamethasone [VCD]/bortezomib, dexamethasone [VD]/lenalidomide, dexamethasone [RD]) and studied the impact of front‐line therapy on post‐FHR overall survival (OS). In the FHR12 cohort (follow‐up 48 months), the OS after VRD/KRD ( n = 238) was 21 versus 17 months with other regimens ( n = 227, hazard ratio [HR] = 1.2, 95% confidence interval [CI]: 0.6–1.06). In a multivariable model, the HR for OS was 0.94 (95% CI: 0.7–1.3, p = 0.69) for VRD/KRD versus other regimens. There was no significant interaction between type of first‐line (1L) therapy and time from 1L AHSCT to first relapse in predicting OS. Similar results were seen for FHR18 and FHR24. FHRMM remains a negative prognostic factor irrespective of front‐line therapy and warrants consideration of T‐cell engagers' second‐line therapy.

Abstract In 2011, a workgroup of the Alzheimer's Association Research Roundtable introduced recommendations for detecting and monitoring amyloid‐related imaging abnormalities (ARIA) in Alzheimer's disease (AD) clinical trials. Since then, anti‐amyloid immunotherapies have received regulatory approval for AD treatment and are beginning to enter clinical practice, underscoring the importance of informing healthcare providers, researchers, and patients about ARIA's implications in real‐world settings. In response, the Alzheimer's Association convened a new workgroup to review current knowledge of ARIA, including underlying mechanisms, clinical presentations, associated risk factors, mitigation strategies, radiologic detection methods, patients’ perspectives in treatment decision‐making, and outstanding challenges. Here, we outline key insights from this workgroup, highlighting that effective ARIA detection and monitoring in clinical practice requires adherence to robust protocols to mitigate risks and enhance patient safety. Limited availability of clinical and pathologic data on predictors of symptomatic and severe ARIA underscores the importance of continued real‐world data collection.