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AbstractIntroductionRemote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD‐mApp).MethodsA diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC‐FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD‐mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys.ResultsIt was feasible for participants to complete the ALLFTD‐mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests.DiscussionThese findings suggest that the ALLFTD‐mApp study protocol is feasible and acceptable for remote FTD research.HIGHLIGHTS The ALLFTD Mobile App is a smartphone‐based platform for remote, self‐administered data collection. The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities. Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders. Remote digital data collection was well accepted by participants with a variety of diagnoses.

AbstractIntroductionEmpathy relies on fronto‐cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress.MethodsFour hundred thirty‐one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non‐carrier controls were enrolled. In sub‐samples, we investigated empathy measured by the informant‐based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51).ResultsEmpathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy.DiscussionLoss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials.

ImportancePhysical activity is associated with cognitive health, even in autosomal dominant forms of dementia. Higher physical activity is associated with slowed cognitive and functional declines over time in adults carrying autosomal dominant variants for frontotemporal lobar degeneration (FTLD), but whether axonal degeneration is a potential neuroprotective target of physical activity in individuals with FTLD is unknown.ObjectiveTo examine the association between physical activity and longitudinal neurofilament light chain (NfL) trajectories in individuals with autosomal dominant forms of FTLD.Design, Setting, and ParticipantsThis cohort study included individuals from the ALLFTD Consortium, which recruited patients from sites in the US and Canada. Symptomatic and asymptomatic adults with pathogenic variants in one of 3 common genes associated with FTLD (GRN, C9orf72, or MAPT) who reported baseline physical activity levels and completed annual blood draws were assessed annually for up to 4 years. Genotype, clinical measures, and blood draws were collected between December 2014 and June 2019; data were analyzed from August 2021 to January 2022. Associations between reported baseline physical activity and longitudinal plasma NfL changes were assessed using generalized linear mixed-effects models adjusting for baseline age, sex, education, functional severity, and motor symptoms.ExposuresBaseline physical activity levels reported via the Physical Activity Scale for the Elderly. To estimate effect sizes, marginal means were calculated at 3 levels of physical activity: 1 SD above the mean represented high physical activity, 0 SD represented average physical activity, and 1 SD below the mean represented low physical activity.Main Outcomes and MeasuresAnnual plasma NfL concentrations were measured with single-molecule array technology.ResultsOf 160 included FTLD variant carriers, 84 (52.5%) were female, and the mean (SD) age was 50.7 (14.7) years. A total of 51 (31.8%) were symptomatic, and 77 carried the C9orf72 variant; 39, GRN variant; and 44, MAPT variant. Higher baseline physical activity was associated with slower NfL trajectories over time. On average, NfL increased 45.8% (95% CI, 22.5 to 73.7) over 4 years in variant carriers. Variant carriers with high physical activity demonstrated 14.0% (95% CI, −22.7 to −4.3) slower NfL increases compared with those with average physical activity and 30% (95% CI, −52.2 to −8.8) slower NfL increases compared with those with low physical activity. Within genotype, C9orf72 and MAPT carriers with high physical activity evidenced 18% to 21% (95% CI, −43.4 to −7.2) attenuation in NfL, while the association between physical activity and NfL trajectory was not statistically significant in GRN carriers. Activities associated with higher cardiorespiratory and cognitive demands (sports, housework, and yardwork) were most strongly correlated with slower NfL trajectories (vs walking and strength training).Conclusions and RelevanceIn this study, higher reported physical activity was associated with slower progression of an axonal degeneration marker in individuals with autosomal dominant FTLD. Physical activity may serve as a primary prevention target in FTLD.

AbstractBackgroundFrontotemporal dementia spectrum disorders (FTD) display complex neuropathological substrates and poor clinicopathological correlations, which hinders therapy development. Plasma P‐tau217 is an emerging tool to screen for Alzheimer’s disease (AD) pathology and may have diagnostic value in FTD.MethodPlasma P‐tau217 was measured cross‐sectionally by electrochemiluminescence in FTD patients referred to ALLFTD from ARTFL (n = 628, 45.7% female, median age 66 ± 12 years). P‐tau217 differences by baseline phenotype, disease severity and genotype were determined with non‐parametric tests and general linear models. Associations between P‐tau217 and measures of disease severity and neuropsychological performance were determined with linear regressions corrected for age, sex, phenotype and APOE.ResultThe sample included 33% behavioral variant FTD, 23.6% primary progressive aphasia (PPA), 28.5% atypical parkinsonism, 1.6% amnestic dementia (AmDem), 2.8% FTD/motoneuron disease, 3% mild cognitive/behavioral impairment and 7.5% healthy controls. Only 1.6% carried FTD‐causing mutations. P‐tau217 was not related to age (r = 0.034, 95%CI ‐0.03 – 0.12, p = 0.4). Compared to controls (0.18 ± 0.07 pg/mL), P‐tau217 was elevated only in AmDem (0.58 ± 0.9 pg/mL, p = 0.001) and logopenic PPA (lvPPA, 0.71 ± 0.62 pg/mL p < 0.001). P‐tau217 ≥ 0.42 pg/mL effectively discriminated AmDem and lvPPA from all other phenotypes (AUC 0.87, 95%CI 0.77 – 0.96, p = 0.001, 77% sensitivity, 92% specificity). AmDem (60%) and lvPPA (91.7%) had the highest prevalence of high (≥ 0.42 pg/mL) P‐tau217, and the highest prevalence of APOE4 (AmDem 40%, lvPPA 63.6%). APOE4 carriers (0.23 ± 0.22 pg/mL) had higher P‐tau217, than non‐carriers (0.19 ± 0.09 pg/mL), regardless of phenotype (APOE effect p = .002, APOE x phenotype, p = 0.44). P‐tau217 was associated with worse clinical severity, mood, memory and executive function, but not with worse motor symptoms or social cognition.ConclusionWhen FTD is suspected, high plasma P‐tau217 is strongly associated with amnestic dementia and logopenic PPA phenotypes. Pending completion of ongoing neuropathological, CSF and molecular neuroimaging analyses, the data support the use of plasma P‐tau217 to identify atypical AD as a cause or AD as a co‐pathology contributing to FTD clinical presentation.

AbstractBackgroundBlood neurofilament light chain (NfL) is a robust predictor of phenoconversion in familial frontotemporal lobar degeneration (fFTLD). The comparative value of CSF NfL and other CSF markers of degeneration in fFTLD remains unexplored.MethodFLTD‐causing mutation carriers were recruited through ALLFTD (n = 113, 56.6% female, mean age 48.1 ± 13 years; 29 C9orf72, 16 GRN, 34 MAPT, 34 mutation non‐carriers) and prospectively evaluated for 3 years. Baseline CSF was analyzed for NfL, phosphorylated neurofilament heavy chain (p‐NfH), tau, phosphorylated tau181 (p‐tau) and neurogranin using fit‐for‐purpose immunoassays. Mixed effect linear models, with random slopes, corrected for age, sex, genotype and total intracranial volume related CSF biomarkers to longitudinal clinical variables.ResultNfL (β = 0.64, p < 0.001), p‐NfH (β = 0.68, p < 0.001) and tau (β = 0.46, p < 0.001) correlated with age. There were no differences in biomarker concentrations by phenotype or severity, except for higher NfL and p‐NfH in full phenotype, compared to prodromal disease and asymptomatic carriers. Low neurogranin (β = ‐0.39, p < 0.001), low p‐tau (β = ‐0.33, p < 0.001) and high NfL (β = 0.42, p < 0.001) correlated with worse baseline disease severity measured by the CDR® Dementia Staging Instrument plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center FTLD module sum of boxes (CDR®+NACC‐FTLDsb), and with other measures of global cognition, instrumental and daily function, and frontal and temporal brain volumes. Regardless of genotype, the predicted annualized rate of CDR®+NACC‐FTLDsb score worsenings per higher baseline CSF biomarker Log pg/mL were tau: 3.0 ± 0.2, NfL: 2.8 ± 0.2 and p‐NfH: 2.8 ± 0.2. High tau, NfL and p‐NfH also predicted worsening in other measures of global cognition and instrumental and daily function. Neurogranin and p‐tau did not predict clinical decline.ConclusionCSF tau, p‐tau, neurogranin, NfL and p‐NfH reflect important aspects of disease severity in fFTLD. In contrast to Alzheimer’s disease, low p‐tau and neurogranin are inversely related to clinical severity, which suggests a distinctive pathophysiological process and has implications for therapeutic development. CSF NfL, p‐NfH and tau have strong prognostic value in fFTLD.

AbstractBackgroundUp to 30% of frontotemporal dementia (FTD) cases are due to known pathogenic mutations (f‐FTD). Little is known about the factors that predict who will choose to learn their results. Upcoming clinical trials in f‐FTD may require disclosure prior to enrollment, even before symptom onset, and thus characterizing this sample is important. Furthermore, understanding the mood impacts of genetic disclosure may guide genetic counseling practice.MethodF‐FTD participants (n=568) from families with a known pathogenic mutation (MAPT, C9orf72, GRN) were enrolled through the ARTFL/LEFFTDS Longitudinal FTD Study (ALLFTD) and provided the opportunity for disclosure. Independent‐sample t‐tests compared demographic and psychosocial factors between participants who did and did not receive their results. In participants who were asymptomatic at baseline and follow up (n=199,177 with follow‐up), linear mixed effects modeling was used to investigate pre‐ to post‐disclosure changes in the 15‐item Geriatric Depression Scale (GDS).ResultOf participants from families with a known pathogenic genetic mutation, 47% received genetic disclosure. Of the asymptomatic subset (n=386), 36% know their mutation status. Of these asymptomatic learners, 46% received disclosure through the study, and the remainder learned their genetic status prior to study enrollment. None of the analyzed demographic or psychosocial factors (i.e., sex, age, education, having children) differed between learners and non‐learners (p’s > 0.05). In the longitudinal analysis of asymptomatic participants, learners showed a pre‐ to post‐increase of 0.31 GDS points/year (95%CI: ‐0.08, 0.69, p = 0.12), whereas non‐learners showed a slight decline (‐0.15 points/year, 95%CI: ‐0.36, 0.06, p = 0.16). This difference between slopes was statistically significant (0.46, 95%CI: 0.02, 0.89, p=0.04) but represents a small clinical effect. In asymptomatic learners, slopes did not differ based on mutation status (0.28, 95%CI: ‐0.66, 1.20, p=0.55). Conclusions were based on the estimates and full range of confidence intervals.ConclusionThe majority of asymptomatic research participants do not know their genetic status, which will be a consideration for clinical trials that require disclosure. No considered demographic factors were strongly associated with the decision to receive disclosure. The findings suggest that disclosure in asymptomatic participants has minimal impact on depressive symptoms regardless of genetic results.

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.

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.