Citations

AbstractBackgroundMany treatments targeting frontotemporal lobar degeneration (FTLD) are in the developmental pipeline, but the rarity of the disease, coupled with the behavioral and motor features of FTLD, make it challenging to identify sufficient trial participants who can attend frequent in‐person visits. Decentralized clinical trial designs with remote evaluations are attractive alternatives but require validated tools for symptom tracking. Our previous cross‐sectional analyses showed that cognitive tasks deployed via the ALLFTD Mobile App are reliable and sensitive to early stages of disease. The current study seeks to evaluate whether unsupervised smartphone cognitive tests are sensitive to longitudinal changes that occur with increasing FTLD disease stage.MethodThe study included 194 participants (mean baseline age 54.30, SD = 15.66; mean education = 16.52, SD = 2.31; 55.2% women) who were asymptomatic (Clinical Dementia Rating plus FTLD (CDR®+NACC‐FTLD) = 0 [n = 109; 43 carriers of FTLD‐associated genetic variants]), prodromal (CDR®+NACC‐FTLD = 0.5 [n = 39]), or symptomatic (CDR®+NACC‐FTLD>0.5 [n = 46]) at baseline. Participants completed ALLFTD Mobile App smartphone versions of Stroop, flanker, and 2‐back tasks, as well as an adaptive associative memory task, every six months for up to two years. Linear‐mixed effects models investigated the effect of disease severity on cognitive trajectories by testing the interaction of baseline CDR®+NACC‐FTLD box score and time on smartphone test scores. Analyses were repeated in the subsample of asymptomatic/prodromal CDR®+NACC‐FTLD<1) familial FTLD mutation carriers (C9orf72, n = 27; MAPT, n = 16). All models controlled for age, education, and sex.ResultGreater baseline disease severity was associated with lower cognitive scores across all tasks (β range: ‐0.28 to ‐0.13; p’s < 0.001), and faster rates of decline on the memory and 2‐back tasks (β range: ‐0.15 to ‐0.07; p’s<0.04). When the sample was restricted to asymptomatic and prodromal individuals (CDR®+NACC FTLD<1), greater baseline disease severity was still associated with lower scores across most tasks (β range: ‐0.48 to ‐0.27; p’s<0.002; 2‐back: β = ‐0.19, p = 0.26). When the sample was restricted to asymptomatic/prodromal mutation carriers, disease severity remained associated with the memory and flanker tasks (β range: ‐0.85 to ‐0.45; p’s<0.01).ConclusionThis study provides initial evidence that longitudinal smartphone‐based cognitive measurements capture the accelerated cognitive worsening that accompanies increasing disease progression in FTLD.

AbstractBackgroundSelf‐administered cognitive assessments demonstrate usability and ability to detect cognitive decline in Alzheimer’s disease, but usability in other neurodegenerative diseases is understudied. We investigated whether Mayo Test Drive (MTD), a self‐administered multi‐device compatible cognitive assessment platform, demonstrates usability and correlation with traditional neuropsychological tests in a pilot study of individuals with progressive supranuclear palsy (PSP).MethodEleven individuals with PSP (mean age = 69.6±7.2 years; mean education = 15.3±2.7 years; 72.7% male; 90.9% white; PSP Rating Scale [PSPRS] = 32.4±15.5) enrolled in a Neurodegenerative Research Group study at Mayo Clinic participated. Participants completed neurological evaluation, traditional neuropsychological assessment, in‐person self‐administered MTD comprised of the Stricker Learning Span and Symbols Test, and a MTD usability questionnaire with quantitative and qualitative questions. Participants received diagnoses of PSP clinical variants per Movement Disorders Society‐PSP criteria. Seven participants had PSP‐Richardson, two had PSP‐postural instability, and two had PSP‐parkinsonism. We used descriptive analyses to examine usability questions, qualitative analyses for free text responses, and Spearman correlations to analyze associations between MTD and traditional tests of global cognition and five cognitive domains.ResultTen of eleven patients completed MTD (average completion time [minutes] = 22.2±6.5). Study staff terminated one participant’s session early due to an appointment conflict; we excluded this participant from analyses. Six participants completed MTD with tablets and four used smartphones. Participants reported high ease completing MTD (9.00±1.76 on 0‐10 scale) and comfortability using their devices (9.40±1.58). All participants reported they could complete MTD independently, with one participant indicating need for assistance with hyperlinks and three reporting need for assistance with QR codes. Qualitative data suggested three participants had motoric difficulty using the tablets; these individuals had the greatest PSPRS symptom severity, although MTD performance was not correlated with the PSPRS (rho = ‐.122; p>.05). MTD performance significantly correlated with the MoCA (rho = 0.88) and tests of attention, executive, and visuospatial function (Table).ConclusionIn a MTD usability pilot for participants with PSP, participants reported high ease and comfort completing MTD independently; those with greater motor symptoms had more difficulty navigating technology. Additionally, performances on MTD were correlated with the MoCA and other in‐person assessments, demonstrating convergent validity.

AbstractBackgroundThe prognosis in patients with advanced cardiac amyloidosis (CA) remains poor.ObjectivesWe sought to describe survival post heart transplantation (HT) in amyloid compared with non‐amyloid recipients, highlight waitlist times within the new allocation system across three Organ Procurement and Transplantation Network (OPTN) regions, and describe multiorgan transplantation (MOT) in hereditary amyloidosis.MethodsThis is a retrospective review of end‐stage CA patients who underwent HT at Mayo Clinic from January 2007 to December 2020. Wait time was compared in the new versus old OPTN allocation era starting December 18, 2018 by Wilcoxon rank sum test. All‐cause mortality for those with and without CA was compared using Kaplan–Meier estimates with log rank analysis, censoring December 16, 2022.ResultsFifty‐five patients with CA underwent HT between 2007 and 2020, 8 light chain amyloidosis (AL) (14.5%), 28 hereditary transthyretin (ATTRv) (50.9%), 17 wildtype transthyretin (ATTRwt) (30.9%), and 2 hereditary apolipoprotein A1 (AApoA1) amyloidosis patients (3.6%). No significant difference in overall survival post‐transplant was seen in amyloid compared with non‐amyloid (p = 0.816). Median time to HT was shorter in the new system, 45 days (IQR 24, 78) versus 174 days (IQR 76.5, 483.5), p = 0.006. There was a decline in MOT in hereditary amyloidosis over time with the concomitant rise in disease‐targeted therapies.ConclusionsHT survival in CA patients was similar to non‐amyloid patients. The new allocation system benefits this cohort with shorter wait times. There is less MOT in hereditary amyloidosis with increased utilization of disease‐targeted therapy.

Abstract INTRODUCTION The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. METHODS The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered. A modified Delphi approach was used to rate each scenario by consensus as “rarely appropriate,” “uncertain,” or “appropriate.” Ratings were performed separately for amyloid and tau PET as stand‐alone modalities. RESULTS For amyloid PET, seven scenarios were rated as appropriate, two as uncertain, and eight as rarely appropriate. For tau PET, five scenarios were rated as appropriate, six as uncertain, and six as rarely appropriate. DISCUSSION AUC for amyloid and tau PET provide expert recommendations for clinical use of these technologies in the evolving landscape of diagnostics and therapeutics for Alzheimer's disease. Highlights A multidisciplinary workgroup convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging updated the appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. The goal of these updated AUC is to assist clinicians in identifying clinical scenarios in which amyloid or tau PET may be useful for guiding the diagnosis and management of patients who have, or are at risk for, cognitive decline These updated AUC are intended for dementia specialists who spend a significant proportion of their clinical effort caring for patients with cognitive complaints, as well as serve as a general reference for a broader audience interested in implementation of amyloid and tau PET in clinical practice.

Abstract High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the United States using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine &lt;1.5-fold baseline and without dialysis dependence. Key secondary end points were time to kidney recovery, neutropenia, and transaminitis on day 7, and time to death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% confidence interval [CI], 1.69–4.31) compared with no glucarpidase receipt. Patients treated with glucarpidase also had faster time to kidney recovery (adjusted hazard ratio [aHR], 1.88; 95% CI, 1.18–3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50; 95% CI, 0.28–0.91) and grade ≥2 transaminitis (aOR, 0.50; 95% CI, 0.28–0.91) on day 7. There was no difference in time to death (aHR, 0.76; 95% CI, 0.49–1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI.

AbstractBackgroundGenome‐wide association studies (GWAS) in Alzheimer’s disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.MethodWe conducted a meta‐analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.67% female, age = 71) and an autopsy GWAS of brain amyloidosis (N = 6,519, 63.08% amyloid positive, 51.34% female, age at death = 83), both adjusted for covariates including age, sex and principal components of genetic ancestry. All participants in both GWAS were unrelated individuals of European descent. We defined amyloid positivity as moderate or frequent neuritic plaques using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores within each autopsy cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET imaging cohort to identify the cohort and tracer‐specific cut‐offs that differentiate amyloid positive and negative populations.ResultThe genome‐wide significant results from the meta‐analysis identified three known AD loci (APOE, CR1, and BIN1) and a novel chromosome 17 locus (rs35635959, intergenic, MAF = 0.27, OR = 1.18, p = 1.47 × 10‐8). The MAGMA gene‐level analysis excluding the APOE region suggests significant associations between rs35635959 and COASY, PLEKHH3, and TUBG2 on chromosome 17, implying the potential roles of these genes on amyloidosis. Functional annotations of rs35635959 leveraging brain eQTL databases indicate its association with differential gene expression of COASY and TUBG2 in AD brains. ROSMAP bulk and single‐nucleus RNAseq analyses link TUBG2 downregulation to the higher amyloid burden and AD diagnosis while suggesting such observations are enriched in excitatory and inhibitory neurons, reaching FDR significance.ConclusionThis study is the most extensive European GWAS of brain amyloidosis, and our findings replicate known AD loci and identify a possible novel locus (index SNP rs35635959) on chromosome 17. Functional annotations of the novel variant indicate TUBG2, implicating in microtubule organization, warrants further assessment. Ongoing efforts aim to validate these novel effects using independent datasets.

AbstractBackgroundLate Onset Alzheimer’s Disease (LOAD) is the most common neurodegenerative disorder. Carriers of an ɛ4 allele of the apolipoprotein E gene (APOE) have significantly increased risk of developing LOAD. LOAD is also strongly sex biased. Besides the well‐established role of sex hormones, the impact of genetic sex combined with APOE genotypes has not been studied. Sex chromosome dosage (SCD) is the main genetic difference between females (XX) and males (XY). Despite dosage compensation by X chromosome inactivation (XCI), some X‐linked genes remain expressed from the inactive X (Xi) and are female biased in expression. Many of these genes are related to neurological and immune functions and could contribute to neuroinflammation in AD.MethodTo understand the genetic interactions between autosomal risk (APOE) and sex‐bias in AD, we are generating isogenic sets of hiPSCs with various sex chromosome complements and APOE genotypes. We have derived XXY/XY, XY/X, and XX/X isogenic pairs by reprogramming cells from naturally mosaic individuals or by selective removal of the Xi in vitro. These lines uniquely position us to differentiate the effects of X chromosome dosage and/or presence of a Y chromosome, while minimizing genetic variability and environmental or hormonal confounders. Currently, we are also constructing APOE ɛ3 and ɛ4 alleles in our paired hiPSC lines with differing sex chromosome content using gene editing.ResultStarting from an XXY/XY isogenic pair, we have generated an hiPSC series with six different genotypes of APOE ɛ3/ɛ3, ɛ3/ɛ4 or ɛ4/ɛ4 alleles with either the XXY or XY genotype. Preliminary results in differentiated neural precursor cells show differential expression of sex‐linked genes in relation to SCD. We also observed genome‐wide changes in gene expression and DNA methylation. Subsets of autosomal sex‐biased genes were differentially affected either by X chromosome dosage, presence of a Y, or both.ConclusionThe new hiPSC lines are being differentiated to AD‐relevant cell types, including neurons, microglia, and cortical organoids, for transcriptomic and functional analyses to elucidate how APOE alleles and genetic sex interact to modulate risk in LOAD pathology.

AbstractBackgroundAlthough the rate of Alzheimer’s disease (AD) in African‐ancestry (AA) Americans is higher than that of persons from European‐ancestry (EA) populations, AA participants have been underrepresented in AD neuropathological studies.MethodUtilizing the AD Research Centers (ADRC) infrastructure, we obtained AA donor pre‐frontal cortex (PFC) tissue from brain repositories of 12 ADRC and generated bulk RNA sequencing (RNA‐seq) data for 179 samples that met QC and inclusion criteria. Previously generated PFC RNAseq data were obtained for 28 additional AA donors from the Columbia University ADRC. Differential gene expression was evaluated among 125 donors with a neuropathological diagnosis of AD (NIA‐Reagan intermediate or high likelihood) and 82 neuropathologically confirmed controls using regression models including covariates for age at death, sex, cell‐type frequencies, and RNA integrity number (RIN) calculated with Limma. FDR‐corrected p‐values (padj) were calculated to control for the 33,611 genes examined.ResultA total of 482 genes surpassed the multiple‐testing threshold. The most significant, ADAMTS2 (p = 2.96 × 10‐8, padj = 0.001), showed increased expression in AD cases (see Table/Figure). We note that ADAMTS2 was differentially expressed in a prior EA study of neuropathologically confirmed AD cases and controls (Panitch et al. Molecular Psychiatry 2021). Additionally, a recent analysis of cognitive resilience in EA neuropathological AD cases identified a strong association with ADAMTS2 (See Li et al. AAIC2024 abstract). Of the differentially expressed genes observed in the Panitch et al. EA study, 385 (35%) were nominally significant,65 (5.8%) were corrected significant, and most (89%) of these genes had the same effect direction in the AA cohort. Some of the observed associations appear to be AA specific (e.g., EFR3B, IRS4, and CA12; see Table). Additionally, we found nominally significant (p<0.05) associations with expression of APOE (Log2 fold change [L2FC = ‐0.20, p = 0.012) and several other established AD genes including SORL1 (L2FC = ‐0.10, p = 0.014) and IGF1R(L2FC = 0.11, p = 0.0013).ConclusionThis largest‐ever (to our knowledge) gene expression study of AD in postmortem brain tissue from AA donors implicates many more genes as having a role in AD in this population than previously identified in genome‐wide association studies and provides insight into trans‐ancestry differences risk for AD.

AbstractBackgroundSelf‐administered cognitive assessments demonstrate usability and ability to detect cognitive decline in Alzheimer’s disease, but usability in other neurodegenerative diseases is understudied. We investigated whether Mayo Test Drive (MTD), a self‐administered multi‐device compatible cognitive assessment platform, demonstrates usability and correlation with traditional neuropsychological tests in a pilot study of individuals with progressive supranuclear palsy (PSP).MethodEleven individuals with PSP (mean age = 69.6±7.2 years; mean education = 15.3±2.7 years; 72.7% male; 90.9% white; PSP Rating Scale [PSPRS] = 32.4±15.5) enrolled in a Neurodegenerative Research Group study at Mayo Clinic participated. Participants completed neurological evaluation, traditional neuropsychological assessment, in‐person self‐administered MTD comprised of the Stricker Learning Span and Symbols Test, and a MTD usability questionnaire with quantitative and qualitative questions. Participants received diagnoses of PSP clinical variants per Movement Disorders Society‐PSP criteria. Seven participants had PSP‐Richardson, two had PSP‐postural instability, and two had PSP‐parkinsonism. We used descriptive analyses to examine usability questions, qualitative analyses for free text responses, and Spearman correlations to analyze associations between MTD and traditional tests of global cognition and five cognitive domains.ResultTen of eleven patients completed MTD (average completion time [minutes] = 22.2±6.5). Study staff terminated one participant’s session early due to an appointment conflict; we excluded this participant from analyses. Six participants completed MTD with tablets and four used smartphones. Participants reported high ease completing MTD (9.00±1.76 on 0‐10 scale) and comfortability using their devices (9.40±1.58). All participants reported they could complete MTD independently, with one participant indicating need for assistance with hyperlinks and three reporting need for assistance with QR codes. Qualitative data suggested three participants had motoric difficulty using the tablets; these individuals had the greatest PSPRS symptom severity, although MTD performance was not correlated with the PSPRS (rho = ‐.122; p>.05). MTD performance significantly correlated with the MoCA (rho = 0.88) and tests of attention, executive, and visuospatial function (Table).ConclusionIn a MTD usability pilot for participants with PSP, participants reported high ease and comfort completing MTD independently; those with greater motor symptoms had more difficulty navigating technology. Additionally, performances on MTD were correlated with the MoCA and other in‐person assessments, demonstrating convergent validity.