Miller, Bruce L.

Introduction: Frontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform. Methods: Participants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing. Results: Passive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85). Discussion: Passive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.

Abstract INTRODUCTION Similarities between frontotemporal lobar degeneration with transactive response DNA‐binding protein of 43 kDa (TDP‐43) (FTLD‐TDP) and limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) raise questions about whether they represent distinct entities or a single disease spectrum. The literature mostly examined series with disproportionate numbers of LATE‐NC over FTLD‐TDP. METHODS Leveraging a clinicopathological collection of FTLD‐TDP ( N = 148) from the University of California, San Francisco, we compared demographic, clinical, genetic, and neuropathological features of FTLD‐TDP, particularly FTLD‐TDP type A ( N = 39), and LATE‐NC ( N = 42). RESULTS FTLD‐TDP type A cases were younger at onset and death, had shorter disease duration, and frequent genetic causes ( GRN , C9ORF72 ) compared to LATE‐NC, which were mostly sporadic and older. Blinded evaluation of middle frontal gyrus (MFG) TDP‐43 immunostaining alone proved insufficient to reliably differentiate FTLD‐TDP type A from LATE‐NC stage 3. However, factoring in all neuropathologic features, FTLD type A and LATE‐NC could be differentiated with >95% confidence. DISCUSSION These overall findings support distinct diagnostic entities for FTLD‐TDP and LATE‐NC.

Abstract Background Frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominant atrophy is an emerging area of interest. Recent findings by the International Working Group (IWG) have identified this subtype as having a distinct clinical profile within the FTD spectrum (Ulugut et al., 2024, A&D). However, its genetic and pathological underpinnings remain unexplored in large, multicultural cohorts. Methods Retrospective analyses encompassing clinical, genetic, pathological, and neuroimaging data from 23 IWG sites across 13 countries in Asia, Middle East, Europe, North and South America were conducted. The study included 444 patients with FTD exhibiting predominant RATL atrophy. Results Genetic screening was performed on 51% ( n = 225) of the cohort for at least the major frontotemporal lobar degeneration (FTLD) mutations including microtubule‐associated protein tau ( MAPT ), progranulin ( GRN ), and chromosome 9 open reading frame 72 ( C9orf72 ), or dementia panels encompassing extended sets of genes. Of these, 81% were sporadic, showing negative results for the screened genes and a modified Goldman Score of ≥ 3, indicating a negative family history for dementia. The MAPT mutation was the most common genetic variant, identified in 7% of the screened cases (Figure 1). Pathological confirmation was available for 63 patients. Among the sporadic cases, transactive response DNA‐binding protein 43 type C (TDP‐C) pathology was most prevalent (60%, n = 32), while tau‐MAPT pathology was most common in the genetic cases (38%, n = 16). Fifteen cases did not fit neatly into genetic or sporadic categories, displaying heterogeneous pathologies (Figure 2). At the initial visit, compared to genetic cases, patients with TDP‐C pathology were older, and more frequently exhibited semantic deficits, with less frequent attention difficulties and executive dysfunction. No differences were observed in sex distribution, symptom duration or disease severity between genetic and sporadic TDP‐C cases. However, left handedness was more common in TDP‐C cases (14%) compared to genetic cases (5%). Conclusion While FTD with RATL atrophy primarily appears sporadic, a significant proportion of cases exhibit genetic variants. These sporadic and genetic subtypes display distinct neuropathological features and clinical manifestations. Given the implications for therapeutic strategies, precise clinical and molecular subtyping is critical for enhancing patient management and ensuring appropriate enrollment in clinical trials.

Abstract Objectives There are striking differences among caregivers of people with dementia in their health and well-being during active caregiving and after caregiving has ended. A key factor influencing caregiver health is the emotional quality of the caregiver–care recipient relationship, which may be reflected in the emotional language caregivers use when describing this relationship. The present study assessed whether caregivers’ positive and negative language is associated with their current and future depression trajectories. Methods Active caregivers responded to an open-ended question about a recent time they felt connected to the care recipient. We summed the number of positive and negative emotion words and divided them by the total words in the response. We evaluated whether caregivers’ emotional language (a proxy for the emotional quality of the caregiver–care recipient relationship) was associated with their depression assessed both concurrently (N = 347 active caregivers) and longitudinally (N = 224 former caregivers). Results Neither positive nor negative emotional language significantly correlated with caregiver depression during active caregiving. Structural equation modeling revealed caregivers’ greater positive emotional language (accounting for baseline depression) was associated with less steep increases in depression after the care recipient’s death. Results were robust when accounting for negative emotional language and covariates. Negative emotional language was not significantly associated with changes in caregiver depression. Discussion Caregivers who use more positive words when describing their connection with the care recipient may be more resilient, underscoring the potential role of positive emotional qualities of the caregiving relationship in preserving caregivers’ mental health after caregiving ends.

AbstractBackgroundThe 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).ObjectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.MethodsUtilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP.ResultsWe found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub‐haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up‐regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down‐regulating KANSL1. Single‐nucleus RNA‐seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up‐regulates LRRC37A/LRRC37A2 in neuronal cells.ConclusionsThe copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

AbstractBackgroundAs new anti‐amyloid immunotherapies emerge for Alzheimer’s disease (AD), it is clear that early diagnosis of AD pathology is crucial for treatment success. This can be challenging in atypical presentations of AD and, together with our reliance on CSF or PET scans, can, at times, lead to delayed diagnosis. Here, we further explore the possible role of plasma tau phosphorylated at threonine 217 (P‐tau217) for the detection of primary AD or AD co‐pathology when frontotemporal dementia spectrum disorders are the main clinical presentation.MethodParticipants were recruited through ALLFTD, a North American multisite research consortium for the longitudinal assessment of frontotemporal lobar degeneration. After excluding cases with known FTD‐causing mutations, 573 participants with sporadic disease, mild cognitive/behavioral impairment, or healthy familial controls evaluated between 2014 and 2023 were included in this analysis (45.8% female, median age 66 years). 39 of those cases underwent neuropathological evaluation. Plasma P‐tau217 was measured with the Eli Lilly electrochemiluminescence‐based assay. P‐tau217 concentrations were compared by phenotype, disease severity, genotype, and, when available, neuropathological diagnosis with non‐parametric tests. Its diagnostic performance was tested with ROC curves. Associations between plasma P‐tau217 concentrations and clinical scales of global cognition, memory, executive function, motor function, and social cognition with linear regressions and non‐parametric tests.ResultPlasma P‐tau217 concentrations were higher in logopenic variant primary progressive aphasia (lvPPA) and amnestic dementia (AmDem), compared to participants with normal cognition or other FTD phenotypes. P‐tau217 concentrations were higher in APOE e4 carriers, compared to non‐carriers, regardless of phenotype, but were not affected by disease severity. P‐tau217 concentrations showed associations with clinical measures of global cognition, memory, and executive function, but had no associations with measures of motor function or social cognition. Plasma P‐tau217 concentrations were elevated in high and intermediate ADNC scoring, or more advanced Braak stages, even when AD was not the primary pathology.ConclusionEven when FTD is suspected, high plasma p‐tau 217 concentrations are strongly associated with underlying AD as primary pathology or contributing co‐pathology. Plasma P‐tau217 could be a tool to support the development of disease‐modifying therapies for atypical Alzheimer’s disease presentations or for FTD cases with Alzheimer’s disease co‐pathology.

AbstractBackgroundThe earliest cognitive manifestations of asymptomatic and prodromal familial frontotemporal dementia (f‐FTD) mutation carriers are still being characterized. Patients with symptomatic FTD are known to be error prone, particularly on tasks of executive function, but little is known about the frequency or predictive utility of these errors in the earliest stages of f‐FTD. The current study compared error rates on executive functioning tasks in controls and asymptomatic and prodromal mutation carriers and investigated whether errors predict worsening clinical status as follow up.MethodThis study included 90 participants (mean age = 48.57, SD = 13.30; 51.1% female; 86.67% white) with pathogenic FTD mutations (C9orf72, n = 45; GRN, n = 30; or MAPT, n = 15) who were asymptomatic or prodromal (Clinical Dementia Rating plus FTLD; CDR®+NACC‐FTLD ≤ 0.5). Propensity score matching identified (CDR®+NACC‐FTLD = 0) who did not carry pathogenic mutation but were matched on age, education, and sex. Regressions were used to compare controls and mutation carriers on error scores (rule violations and/or repetitions) from three executive functioning tasks: design fluency, lexical fluency, and Stroop inhibition. Mutation carriers with longitudinal data within 1.5 years were binarized as stable (n = 35) or progressors (n = 13) based on whether their CDR®+NACC‐FTLD sum of boxes score was worse at follow up (mean follow up = 1.07 years). Regressions were fit to evaluate the relationship between baseline error scores and group (i.e., stable vs. progressor).ResultMutation carriers committed significantly more errors than controls on the Stroop task (β = 0.67, p = 0.03) and lexical fluency (repetitions: β = 0.27, p = 0.02). The groups did not significantly differ in errors on the remaining tasks. A greater number of Stroop errors predicted mutation carriers who progressed at follow up (β = 1.04, p<0.001). When introducing the primary outcome from each task as a covariate (e.g., correct responses), the fluency task (repetitions: β = 0.10, p = 0.03) and Stroop task (errors: β = 0.82, p<0.001) were significantly associated with progression.ConclusionErrors on executive tasks may be early cognitive features in familial FTD. Importantly, errors were uniquely predictive above and beyond total scores. Research in larger samples will enable investigations of genetic differences in error rates.

AbstractBackgroundAutosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear.MethodUtilizing T1 and task‐free functional magnetic resonance imaging (tf‐fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel‐wise whole brain degree and GRN‐relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity.ResultNfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN‐FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers.ConclusionIn presymptomatic carriers, the co‐occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf‐fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

AbstractBackgroundThe Uniform Data Set (UDS) neuropsychological battery, administered across Alzheimer’s Disease Centers (ADC), includes memory tests but lacks a list‐learning paradigm. ADCs often supplement the UDS with their own preferred list‐learning task. Given the importance of list‐learning for characterizing memory, we aimed to develop a harmonized memory score that incorporates UDS memory tests while allowing centers to contribute differing list‐learning tasks.MethodWe applied item‐banking confirmatory factor analysis to develop a composite memory score in 5,287 participants (mean age 67.1; SD = 12.2) recruited through 18 ADCs and four consortia (DiverseVCID, MarkVCID, ALLFTD, LEADS) who completed UDS memory tasks (used as linking‐items) and one of five list‐learning tasks. All analyses used linear regression. We tested whether memory scores were affected by which list‐learning task was administered. To assess construct validity, we tested associations of memory scores with demographics, disease severity (CDR Box Score), an independent memory task (TabCAT Favorites, n = 675), and hippocampal volume (n = 811). We compared performances between cognitively unimpaired (n = 279), AD‐biomarker+ MCI (n = 26), and AD‐biomarker+ dementia (n = 98). In a subsample with amyloid‐ and tau‐PET (n = 49), we compared memory scores from participants with positive vs negative scans determined using established quantitative cutoffs.ResultModel fit indices were excellent (e.g., CFI = 0.998) and factor loadings were strong (0.43‐0.93). Differences in list‐learning task had a negligible effect on scores (average Cohen’s d = 0.11). Higher memory scores were significantly (p’s<.001) correlated with younger age (β = ‐0.18), lower CDR Box Scores (β = ‐0.63), female sex (β = 0.12), higher education (β = 0.19), larger hippocampal volume (β = 0.42), and an independent memory task (β = 0.71, p<0.001). The memory composite declined in a stepwise fashion by diagnosis (cognitively unimpaired>MCI>AD dementia, p<0.001). On average, amyloid‐PET positivity was associated with lower composite scores, but was not statistically significant (β = ‐0.34; p = 0.25; d = 0.40). Tau‐PET positivity was associated with worse performance, demonstrating a large effect size (β = ‐0.75; p<0.002; d = 0.91).ConclusionThe harmonized memory score developed in a large national sample was stable regardless of contributing list‐learning task and its validity for cross‐cohort ADRD research is supported by expected associations with demographics, clinical measures, and Alzheimer’s biomarkers. A processing script will be made available to enhance cross‐cohort ADRD research.

Abstract INTRODUCTION Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype. METHODS Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments. RESULTS Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word‐finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face‐recognition deficits (60%). Real‐life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations. DISCUSSION This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real‐life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients. Highlights This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses.