Citations

Abstract INTRODUCTION Greater white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) are seen with transactive response DNA‐binding protein 43 (TDP‐43) pathology in frontotemporal lobar degeneration (FTLD‐TDP). WMH associations with TDP‐43 pathology in Alzheimer's disease (AD‐TDP) remain unclear. METHODS A total of 157 participants from Mayo Clinic Rochester with autopsy‐confirmed AD, known TDP‐43 status, and antemortem fluid‐attenuated inversion recovery (FLAIR) MRI were included. Vascular risk factors were assessed. A semi‐automated WMH segmentation‐quantification process produced total and regional WMH volumes. Penalized linear regression models adjusting for age at MRI analyzed TDP‐43 associations (status and typing) with WMHs. RESULTS TDP‐43‐positive status was not associated with WMH burden overall because opposite effects were seen based on AD‐TDP typing. Despite similar antemortem vascular risk factors and postmortem vascular pathologies, AD‐TDP type‐ α showed greater total and regional WMH burden (particularly in subcortical frontotemporal and basal ganglia regions) than TDP‐43 negatives and AD‐TDP type‐ β . DISCUSSION AD‐TDP types may have different WMH pathomechanisms, with type‐ α having associations more like FTLD‐TDP than AD. Highlights In transactive response DNA‐binding protein 43 (TDP‐43) pathology in Alzheimer's disease (AD‐TDP), TDP‐43 status alone is not associated with total or regional WMH burden AD‐TDP type‐ α shows greater total, frontotemporal subcortical, and basal ganglia white matter hyperintensities (WMHs) AD‐TDP type‐ β shows less total and subcortical occipital WMHs AD‐TDP type‐ α effect on WMH burden closely mimics the effects of frontotemporal lobar degeneration with TDP‐43 (FTLD‐TDP) rather than AD Different relationships of AD‐TDP types with WMHs suggest different pathomechanisms

Abstract Purpose: Two randomized clinical trials (STOMP and ORIOLE) demonstrated that stereotactic ablative radiotherapy (SABR) can prolong androgen-deprivation therapy–free survival or progression-free survival (PFS) in patients with metachronous oligometastatic castration-sensitive prostate cancer (omCSPC). Although most patients with omCSPC have a more modest delay in progression, a small subset achieves a durable response following SABR. We investigated the prognostic and predictive value of circulating prostate-specific membrane antigen-positive (PSMA+) extracellular vesicles (EV) and PSA in a biomarker correlative study using blood samples from three independent patient cohorts. Experimental Design: Plasma samples from 46 patients with omCSPC on the ORIOLE trial and 127 patients with omCSPC on the STOMP trial protocol treated with SABR were included in the study. Pre-SABR PSMA+EV levels (EV/mL) were measured by nanoscale flow cytometry. Kaplan–Meier curves and logistic regression models were used to determine the association of PSMA+EV and PSA levels with clinical outcomes. Results: In the pooled cohorts, the median biochemical PFS were 26.1 and 15.0 months (P = 0.005), and the median radiographic PFS were 36.0 and 25.0 months (P = 0.003) for PSMA+EV-low and -high groups, respectively. The combination of pre-SABR low levels of both PSMA+EV and PSA was associated with a lower risk of radiographic progression (HR, 0.34, 95% confidence interval, 0.18–0.58; P = 0.0002). In the ORIOLE cohort, which included both an SABR arm and an observation arm, low PSMA+EV was predictive of benefit from SABR (P = 0.012). Conclusions: PSMA+EV is a novel prognostic and predictive biomarker of radiographically occult tumor burden in omCSPC. PSMA+EV may inform clinical decisions about identifying patients who will achieve a durable benefit from consolidative SABR alone.

Abstract Introduction Gastrointestinal bleeding (GIB) is often encountered among patients with atrial fibrillation (AF) due to the use of anticoagulation. This study assesses disparities in GIB‐related mortality among decedents with AF in the United States. Methods GIB mortality data in patients with AF from 1999 to 2020 was queried from the CDC database. Decedent demographic information (age, sex, race and ethnicity, and geographic residence) was obtained from death certificates. We calculated age‐adjusted mortality rates (AAMRs) through the direct method and estimated the annual percentage change (APC) in mortality using log‐linear regression models. Results From 11,209 GIB‐related deaths among AF decedents, we observed an increase in AAMR from 0.12 in 1999 to 0.21 in 2020, particularly during the 2009 to 2020 period (APC +4.8, p < .001). Disproportionate mortality rates were noted in males (AAMR 0.18) and White populations (AAMR 0.15) as compared to females (AAMR 0.13) and Black populations (AAMR 0.10), respectively. Rural regions also reported higher mortality (AAMR 0.18) than urban areas (AAMR 0.14). Mortality shifts in urban regions remained stagnant from 1999 to 2009 (APC –0.15, p = .806) followed by an increase from 2009 to 2020 (APC +4.83, p < .001). However, mortality increased consistently from 1999 to 2020 in rural regions (APC +4.08, p < .001). The Northeast US exhibited the highest mortality rate (AAMR 0.18), followed by the Midwest (AAMR 0.16), West (AAMR 0.14), and South (AAMR 0.13). Conclusions Disparities in GIB mortality among AF decedents were identified. These findings accentuate the need for targeted interventions to mitigate GIB risks in vulnerable subgroups.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

Importance Although 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a well-established cross-sectional biomarker of brain metabolism in dementia with Lewy bodies (DLB), the longitudinal change in FDG-PET has not been characterized. Objective To investigate longitudinal FDG-PET in prodromal DLB and DLB, including a subsample with autopsy data, and report estimated sample sizes for a hypothetical clinical trial in DLB. Design, Setting, and Participants Longitudinal case-control study with mean (SD) follow-up of 3.8 (2.3) years. Cases were recruited consecutively between 2007 and 2022 at a referral center and among the population. Patients with probable DLB or mild cognitive impairment with Lewy bodies (MCI-LB) were included. Individuals without cognitive impairment were included from a population-based cohort balanced on age and sex for comparison. All participants completed at least 1 follow-up assessment by design. Exposure Patients with MCI-LB and DLB. Main Outcomes and Measures Rate of change in FDG-PET was assessed as standardized uptake value ratios (SUVr). Clinical progression was assessed with the Clinical Dementia Rating Sum of Boxes (CDR-SB) score. Results Thirty-five patients with probable DLB, 37 patients with MCI-LB, and 100 individuals without cognitive impairment were included. The mean (SD) age of the DLB and MCI-LB groups combined (n = 72) was 69.6 (8.2) years; 66 patients (92%) were men and 6 (8%) were women. At follow-up, 18 participants (49%) with MCI-LB had progressed to probable DLB. Patients with MCI-LB had a faster decline in FDG-SUVr, compared with that of participants without cognitive impairment, in the posterior cingulate, occipital, parietal, temporal, and lateral frontal cortices. The same regions showed greater metabolic decline in patients with DLB than in participants without cognitive impairment, with the addition of anterior-middle cingulate, insula, and medial frontal orbital cortices. Rates of change in FDG-PET in these brain regions were combined into a region of interest (ROI) labeled longitudinal FDG-PET LB meta-ROI. The rate of change in FDG-SUVr in the meta-ROI correlated with the rate of change in CDR-SB, and sample size estimates were reported for potential clinical trials in DLB. Findings were confirmed in the subsample with neuropathologic confirmation (n = 20). Conclusions and Relevance This study found that brain hypometabolism begins to evolve during the prodromal stages of DLB with changes paralleling symptomatic progression. These data may inform clinical practice and trials planning to use FDG-PET for biologic staging, monitoring disease progression, and potentially assessing treatment response.

Background The aim of this study was to examine the potential added value of including neuropsychiatric symptoms (NPS) in machine learning (ML) models, along with demographic features and Alzheimer's disease (AD) biomarkers, to predict decline or non-decline in global and domain-specific cognitive scores among community-dwelling older adults. Objective To evaluate the impact of adding NPS to AD biomarkers on ML model accuracy in predicting cognitive decline among older adults. Methods The study was conducted in the setting of the Mayo Clinic Study of Aging, including participants aged ≥ 50 years with information on demographics (i.e., age, sex, education), NPS (i.e., Neuropsychiatric Inventory Questionnaire; Beck Depression and Anxiety Inventories), at least one AD biomarker (i.e., plasma-, neuroimaging- and/or cerebrospinal fluid [CSF]-derived), and at least 2 repeated neuropsychological assessments. We trained and tested ML models using a stepwise feature addition approach to predict decline versus non-decline in global and domain-specific (i.e., memory, language, visuospatial, and attention/executive function) cognitive scores. Results ML models had better performance when NPS were included along with a) neuroimaging biomarkers for predicting decline in global cognition, as well as language and visuospatial skills; b) plasma-derived biomarkers for predicting decline in visuospatial skills; and c) CSF-derived biomarkers for predicting decline in attention/executive function, language, and memory. Conclusions NPS, added to ML models including demographic and AD biomarker data, improves prediction of downward trajectories in global and domain-specific cognitive scores among community-dwelling older adults, albeit effect sizes are small. These preliminary findings need to be confirmed by future cohort studies.

AbstractBackgroundEvidence for abnormal amyloid‐β (Aβ) plaque accumulation is necessary prior to initiating anti‐amyloid therapy in early symptomatic Alzheimer’s disease (AD). While the clinical trials for lecanemab and related drugs utilized positron emission tomography (PET) to demonstrate brain amyloidosis, current appropriate use recommendations for clinical practice consider PET or cerebrospinal fluid (CSF) biomarkers as satisfactory for this purpose. Here, we present four clinical cases where CSF biomarker results were discordant from amyloid PET, with the potential to result in erroneous treatment targeting.MethodPatients were seen at a tertiary care subspecialty clinic in consideration for lecanemab therapy. All patients had office examination, neuropsychological assessment, structural magnetic resonance imaging (MRI), amyloid PET (with either 11C‐Pittsburgh compound B or 18F‐florbetapir), CSF AD biomarkers (Roche Elecsys p‐tau181/Aβ42 and Fujirebio Lumipulse Aβ42/Aβ40 ratios), and apolipoprotein E (APOE) allele testing. Amyloid PET interpretations were made by consensus visual review from experienced readers.ResultAll four patients had clinical diagnoses of mild cognitive impairment or mild dementia (Table 1). Two patients had positive CSF p‐tau181/Aβ42 and Aβ42/40 ratios with negative amyloid PET (indicating sparse to no neuritic plaques). Case 1 displayed aphasia (characterized by anomia and deep dysgraphia) and imaging findings possibly compatible with semantic dementia. Case 2 displayed a gait abnormality and imaging signs of abnormal CSF dynamics. Two other patients had negative CSF p‐tau181/Aβ42 measures with positive amyloid PET (indicating moderate to frequent neuritic plaques). In those instances, the clinical syndrome and imaging studies were strongly supportive of AD and the CSF Aβ42/40 ratio was “likely positive” (Table 1). For one patient (Case 4), tau PET and Lumipulse plasma p‐tau217 concentration were both positive.ConclusionClinicians prescribing anti‐amyloid therapies should be aware of the possibility for CSF biomarkers to be discordant from amyloid PET status in select scenarios. These cases highlight the value of considering PET imaging in the presence of clinically atypical features, concern for mixed etiology, or strong clinical suspicion for AD despite negative CSF biomarkers. Larger series are needed to identify broader patterns contributing to biomarker discordance by assay, modality (PET versus CSF/plasma measures), and medical/neurologic comorbidities.

AbstractBackgroundMayo Test DRIVE (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based multi‐device (smartphone, tablet, personal computer) platform optimized for remote self‐administered cognitive assessment that includes a computer‐adaptive word list memory test (Stricker Learning Span; SLS), a measure of processing speed/executive functioning (Symbols Test) and a score combining both the memory and processing speed/executive functioning measures (MTD Composite). We aimed to determine the reliability of MTD measures across follow‐up sessions.MethodIndividuals participating in this ancillary study who completed at least two and up to four complete MTD sessions were included, resulting in 1,293 participants (mean age = 70.6, SD = 11.6; mean education = 15.6, SD = 2.3; 48.6% male; 96.9% White; 99.1% non‐Hispanic; 97.1% cognitively unimpaired) from parent studies (see Table 1). MTD raw scores were winsorized at 1% and 99% to minimize the impact of outliers. Test‐retest reliability was assessed using single‐rating, absolute‐agreement, and two‐way mixed ICCs and results are described using descriptives from Koo et al. (2016). ICCs for in‐person‐administered traditional neuropsychological measures are also reported alongside MTD for a subset of participants newly enrolled into the MCSA (to ensure participants were test naïve to both MTD and in‐person tests).ResultReliability was good for the MTD Composite raw [total ICC = 0.78; see Table 2 for session‐to‐session ICCs and 95% CIs], and moderate‐to‐good for the primary outcome variables for each subtest [total ICC = 0.74 for both SLS and Symbols]. Weighting by accuracy negatively impacted reliability of Symbols and the Composite; without this weighting, MTD Composite and Symbols variables showed higher reliability (MTD Composite z total ICC = 0.80; Symbols response time total ICC = 0.84; see Table 2). Alternative methods of defining response time on Symbols showed nearly identical reliability values. SLS sum of trials (primary variable) had subtly higher reliability than separate measures of learning (1‐5 correct, max span) or delay. Reliability of remote MTD and in‐person‐administered measures and select comparisons are provided in Table 3.ConclusionMTD showed moderate to good reliability, similar to in‐person‐administered traditional neuropsychological tests. Future work will examine the effect of demographics, device type, and session interference on reliability.

AbstractBackgroundThe NIA Health Disparities Research (NIA‐HD) Framework organizes factors in four domains (i.e., environmental, sociocultural, behavioral, and biological), which work together over the lifetime to influence health and health disparities.MethodIn previous work, we employed a 2‐stage approach using factor and principal component (PC) analyses to identify patterns of factors in the domains of the NIA‐HD Framework. We found three PCs that identified related groupings from more than one NIA‐HD domain. PC1: retirement status, residence type, multivitamin use, heart disease, Charlson comorbidity index, walking/balance difficulties, and Beck Depression Inventory (BDI)‐II questions – mainly from the somatic dimension; PC2: physical activity/exercise, social and group activities, education, occupation, cardiometabolic risk factors, and self‐rated health; PC3: national and state area deprivation index ranking and BDI‐II questions – mainly in the cognitive dimension. Age and sex‐adjusted linear regression models were used to assess the cross‐sectional association of each PC with AD‐plasma biomarkers measured using the Quanterix Simoa platform in the Mayo Clinic Study of Aging (MCSA) participants. AD‐plasma biomarkers included Aβ 42/40, phosphorylated‐tau 181 (p‐tau181), plasma glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). All analyses were considered statistically significant at a p <0.05.ResultThere were 1300 cognitively unimpaired participants, 50 years old or older, with available plasma biomarkers (mean age (SD) 68.6 (9.5) years; 49.1% were female) at the current study baseline. PC1 and PC3 were associated with higher NfL and p‐tau 181 values (p<0.05). PC1 and PC2 were associated with higher GFAP values (p<0.05). No PCs were associated with the Aβ 42/40 ratio. Findings were mostly similar after additionally adjusting for global cognitive performance and chronic kidney disease.ConclusionWe found that patterns in a wide range of environmental, sociocultural, behavioral, and biological factors were associated with AD plasma biomarkers. Longitudinal studies are warranted to validate findings and support multi‐faceted approaches to address health disparities and achieve disease delay and prevention.