Citations

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates.ObjectiveThe objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD.MethodsAdvancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation.Results29% of respondents self‐reported as patients (63±10 years), 26% self‐reported as caregivers answering on behalf of patients (65±10 years), and 45% self‐reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (≧52%). Overall, respondents showed a positive attitude and support for research participation (≧77%) and trusted that their health information would remain confidential in a clinical trial (≧53%).ConclusionsFavorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation.

AbstractBackgroundClinical trials are underway to treat familial frontotemporal lobar degeneration (f‐FTLD). This is a rare disease, and a limited number of mutation carriers have been identified; thus, efficient trial design is critical. Multimodal, latent disease progression models (DPM) can estimate time to symptom onset and define the temporal ordering of biomarker changes. DPMs can also be leveraged to select endpoints and potentially supplement analyses by integrating historical data. Recent draft FDA guidance for gene therapy trials in neurological disease supports these novel approaches to clinical trials.MethodParticipants included 1,049 members of families affected by f‐FTLD, due to mutations in GRN, MAPT, or C9orf72 genes, who were enrolled in ALLFTD or GENFI. A Bayesian repeated measures model incorporated multimodal data to estimate disease progression, conditional on latent disease age (proximity to symptom onset), in 677 mutations carriers (GRN (n=233), MAPT (n=151) and C9orf72 (n=293)). Family members without pathogenic mutations were used as the reference group. Mean follow‐up was 1.1 (SD=1.1) years. Jointly modeled longitudinal variables included neuropsychological scores, CDR®+NACC‐FTLD Box Score, MRI volumes of brain regions affected by f‐FTLD, and plasma levels of neurofilament light chain (NfL).ResultDisease progression curves were similar across ALLFTD and GENFI cohorts. Plasma NfL elevations occurred earliest, up to 10 years before symptom onset, and NfL was the most powerful endpoint in the asymptomatic stage. MRI abnormalities occurred next, closer to symptom onset. The earliest MRI changes relative to symptom onset were observed in C9orf72+. GRN mutation carriers showed the most rapid acceleration in all biomarkers, and this acceleration occurred in close proximity to symptom onset. Neuropsychological measures and CDR®+NACC‐FTLD Box Score were among the most promising endpoints in the symptomatic stage. Trial simulations indicated that using latent disease age as an enrollment criterion would allow some asymptomatic mutation carriers to be enrolled without sacrificing power.ConclusionSimilarity in disease progression across ALLFTD and GENFI participants suggests these models will apply to international trials. Model‐derived estimates of disease progression curves indicate that endpoint selection should be specific to disease stage and mutation, and DPMs would facilitate greater participant enrollment.

AbstractBackgroundIn preparation for treatment trials in frontotemporal dementia (FTD), sensitive assessments to detect early clinical deficits and track longitudinal changes are needed. Remote digital data collection using smartphones may improve sensitivity to detect and follow abnormalities by allowing novel methods of data capture and more frequent assessments. Furthermore, remote evaluations can reduce patient and staff burden. Despite these benefits, little is known about the reliability and validity of self‐administered cognitive testing completed on smartphones.MethodWe investigated self‐administered smartphone cognitive tests from the ALLFTD Mobile App in a mixed sample of 45 participants, including 10 functionally intact older adults, 24 participants from families harboring pathogenic FTD mutations (asymptomatic n=14; mildly symptomatic n=10;), and 11 symptomatic FTD‐spectrum participants. A subset (n=15) was missing CDR®+NACC‐FTLD data but consensus diagnoses were available. Participants were asked to complete five tests that were repeated three times over eight days. Tests included versions of N‐back, Stroop, Flanker, and Go/No‐Go paradigms, and an adaptive spatial working memory test. Reliability was assessed using split‐half reliability (first testing session, 100 simulations) and intraclass correlations (ICC) across the three testing sessions. Linear models were fitted to evaluate the association of test performance with age and disease severity (CDR®+NACC‐FTLD Global and Box Scores), covarying for sex and education level. Models evaluating age associations excluded symptomatic participants.ResultParticipants completed 72.4% of available instruments. Split‐half reliability (range: 0.76 to 0.97) and ICCs (0.70 to 0.92) suggested adequate‐to‐excellent internal consistency and test‐retest reliability. Across the five tests, negative associations were observed with CDR®+NACC‐FTLD Box Scores (ßs = ‐0.24 to ‐0.77), and in clinically asymptomatic individuals, negative associations were observed with age (ßs = ‐0.43 to ‐0.88). Performance on all measures was worse in symptomatic participants compared to asymptomatic (p‐values<.05). Mildly symptomatic cases (CDR®+NACC‐FTLD=0.5) performed worse on Stroop, Flanker, and spatial working memory than asymptomatic participants (p‐values<.03). Flanker and Stroop tasks consistently showed the strongest reliability and validity findings.ConclusionSmartphone adaptations of common neuropsychological tests produced promising preliminary results. Strong associations with disease severity and age suggest these metrics may be valid for detecting clinically relevant cognitive changes, even in mildly symptomatic FTD.

AbstractBackgroundClinicopathologic studies reported that the NACC Uniform Dataset (UDS) 2.0 core measures do not adequately differentiate patients who ultimately died of Frontotemporal Lobar Degeneration (FTLD) from Alzheimer’s disease (AD). The FTLD Module (FTLD‐MOD) assesses core features of behavioral variant FTD (bvFTD) and primary progressive aphasia (PPA). Initial investigations suggest that the FTLD‐MOD improves discrimination between biomarker‐supported bvFTD and typical late‐onset AD, and that clinically diagnosed PPA participants performed worse than bvFTD on all FTLD‐MOD language tasks. However, the utility of these measures in the differential diagnosis of AD vs. major FTLD syndromes in young‐onset cases remains underexplored.MethodWe examined participants with age‐of‐onset < 65 years in the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) consortium and the Longitudinal Early Onset AD Study (LEADS). 115 bvFTD, 53 semantic variant PPA (svPPA), 29 non‐fluent variant PPA (nfvPPA) and 124 early‐onset AD (eoAD) cases completed the UDS3 and FLTD‐MOD. Linear regression analyses measured group differences in FLTD‐MOD raw scores and UDS3 neuropsychological z‐scores after accounting for group differences in demographic variables and global severity ratings. Alpha was 0.05 with Bonferroni corrections.ResultsParticipants with eoAD demonstrated the most impaired scores on tasks of attention, working memory, and processing speed, including Digit Span Backward (z=‐1.87) and Trails A (z=‐3.82). They also demonstrated difficulty on FTLD‐MOD language tasks with a working memory requirement (sentence repetition raw=3.68/5) and, as expected, memory (story delayed recall z=‐2.4z). svPPA performed the worst on FTLD‐MOD and UDS3 tasks assessing semantic memory, especially naming (all p’s ≤ 0.03). nfvPPA performed worst on sentence reading, sentence repetition, and letter fluency (all p’s ≤ 0.02). Consistent with previous work, these measures differentiate between bvFTD and PPA variants. However, relative to eoAD, bvFTD was equivalent (Trails B: bvFTDz=‐3.8, eoADz=‐3.82; p=0.12) or outperformed (sentence repetition: bvFTD=4.22/5, eoAD=3.68/5; p<0.001) the eoAD group on all tasks.ConclusionsWe undertook this analysis to compare performance of the major young‐onset sporadic AD and FTLD clinical syndromes in the ALLFTD and LEADS studies. Results demonstrate relatively distinct cognitive profiles among eoAD, svPPA, and nfvPPA, but not in bvFTD. Future analyses will include FTLD‐MOD behavioral symptom questionnaires to assess their utility in differentiating bvFTD.

AbstractBackgroundAt present, no research criteria exist for the diagnosis of prodromal behavioral variant frontotemporal dementia (bvFTD). Leveraging data from carriers of pathogenic genetic mutations as a proxy for frontotemporal lobar degeneration pathology, we sought to develop and test a proposed set of research criteria for prodromal bvFTD, termed “Mild Behavioral and/or Cognitive Impairment in bvFTD” (MBCI‐FTD).MethodParticipants included 68 carriers of a pathogenic mutation in microtubule‐associated protein tau (MAPT), or progranulin (GRN), or a repeat expansion in chromosome 9 open reading frame 72 (C9orf72), with mild behavioral and/or cognitive changes. Based on extensive clinical workup, the prodromal mutation carrier group was divided into a Development Group (N=22) and a Test Group (N=46). The Development Group was selected to be the subset of the prodromal mutation carriers for whom we had longitudinal evidence of conversion to a bvFTD phenotype, and were used to develop the criteria. The Test Group was the remainder of the prodromal mutation carriers (e.g., single visits only) and was used to validate the criteria. Familial non‐carriers were included as controls (N=165).ResultFrequencies of behavioral and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in prodromal mutation carriers and non‐carrier controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate‐severe dysphoria, behavioral disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviors (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioral changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of Possible MBCI‐FTD; Probable MBCI‐FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI‐FTD criteria correctly classified 95% of the Development Group of prodromal mutation carriers, and 41% of the Test Group, with a false positive rate of <10%.ConclusionWe present the first diagnostic criteria for prodromal bvFTD. Future research should prioritize establishing generalizability to non‐genetic cases, and testing the specificity of these criteria against psychiatric, neurologic and other neurodegenerative diseases.

AbstractIntroductionCaregivers of patients with frontotemporal lobar degeneration (FTLD) spectrum disorders experience tremendous burden, which has been associated with the neuropsychiatric and behavioral features of the disorders.MethodsIn a sample of 558 participants with FTLD spectrum disorders, we performed multiple‐variable regressions to identify the behavioral features that were most strongly associated with caregiver burden, as measured by the Zarit Burden Interview, at each stage of disease.ResultsApathy and disinhibition, as rated by both clinicians and caregivers, as well as clinician‐rated psychosis, showed the strongest associations with caregiver burden, a pattern that was consistent when participants were separated cross‐sectionally by disease stage. In addition, behavioral features appeared to contribute most to caregiver burden in patients with early dementia.DiscussionCaregivers should be provided with early education on the management of the behavioral features of FTLD spectrum disorders. Interventions targeting apathy, disinhibition, and psychosis may be most useful to reduce caregiver burden.

Abstract At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed ‘mild behavioural and/or cognitive impairment in bvFTD’ (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of &lt;10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer’s disease, and the false positive rate of diagnosis was 11–16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence.

AbstractStudies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau‐related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first‐ever Tau2020 Global Conference in Washington, DC, co‐organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research‐advancing tools and insights that are now rapidly accelerating the pace of tau research.

Abstract Introduction The Frontotemporal Lobar Degeneration Module (FTLD‐MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility. We investigated FTLD‐MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring. Methods Linear regressions compared baseline performances in 1655 National Alzheimer's Coordinating Center participants (behavioral variant frontotemporal dementia (bvFTD, n = 612), semantic variant primary progressive aphasia (svPPA, n = 185), non‐fluent/agrammatic variant PPA (nfvPPA, n = 168), logopenic variant PPA (lvPPA, n = 109), and controls (n = 581)). Sample sizes to detect treatment effects were estimated using longitudinal data. Results Among PPAs, the FTLD‐MOD language tasks and UDS Multilingual Naming Test accurately discriminated svPPA. Number Span Forward best discriminated lvPPA; Phonemic:Semantic Fluency ratio was excellent for nfvPPA classification. UDS fluency and naming measures required the smallest sample size to detect meaningful change. Discussion The FTLD‐MOD and UDS differentiated among PPA subtypes. UDS 3.0 measures performed best for longitudinal monitoring.