Rankin, Katherine P.

AbstractBackgroundAutonomic dysfunction has been linked to empathy deficits in symptomatic frontotemporal degeneration (FTD), but less is known about pre‐symptomatic FTD mutation carriers (preFTD+). Our prior work found that increasing resting heart rate (RHR) over time predicts decline in emotional empathy in preFTD+. Here, we replicate previous findings in a large, multi‐site consortium sample and assess relationships between RHR and empathy loss across disease stages.MethodRHR and Interpersonal Reactivity Index (IRI) were obtained serially for up to 7 years in 348 preFTD+, 202 symptomatic FTD mutation carriers (FTD+), and 311 non‐carrier family members (FTD‐) enrolled in ALLFTD. IRI Perspective Taking (IRI‐PT) and Empathic Concern (IRI‐EC) subscales measured cognitive and emotional empathy, respectively. Separate multiple linear regressions related mutation status and annualized change in RHR to annualized change in IRI subscales and assessed interactions between RHR change and phenoconversion status among mutation carriers. Logistic regression was used to assess the association between change in RHR and phenoconversion among mutation carriers, and Wilcoxon signed‐rank tests were used to examine differences in change in RHR between all study groups.ResultIn asymptomatic participants (preFTD+ and FTD‐), increase in RHR over time was associated with greater decline in IRI‐EC (ß = ‐0.07, p<.001) and IRI‐PT (ß = ‐0.03, p = .011), regardless of mutation status. Among mutation carriers (preFTD+ and FTD+), increase in RHR was associated with greater decline in IRI‐EC (ß = ‐0.04, p = .041), and this effect was stronger in FTD+ compared to PreFTD+ (ß = ‐0.07, p = .038), while an increase in RHR was associated with decline in IRI‐PT only in FTD+ (ß = ‐0.07, p = .046). Change in RHR did not predict phenoconversion in mutation carriers (PreFTD+ and FTD+), but PreFTD+ showed less change in RHR over time relative to FTD+.ConclusionChanges in empathy in asymptomatic preFTD+ and FTD‐ are linked to variability in RHR regardless of genetic status, likely reflecting a non‐specific impact of autonomic functioning on empathy and prosocial behavior. In contrast, increasing RHR predicts decline in cognitive and emotional empathy in FTD mutation carriers but primarily after phenoconversion, suggesting that autonomic contributions to empathy in familial FTD increase with disease progression and could be an early marker of manifest disease.

AbstractBackgroundFrontotemporal dementia (FTD) presents with heterogeneous neuropsychiatric symptoms (NPS). These symptoms often begin prior to the onset of FTD, and progress throughout the prodromal stages of FTD. Particularly, familial FTD due to autosomal dominant genetic mutations might display mutation‐specific NPS profiles. We hypothesized distinct NPS trajectories for chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule‐associated protein tau (MAPT) mutation carriers during their transition from presymptomatic to symptomatic stages of FTD.MethodIn this study, we analyzed N = 1662 participants from the ARTFL‐LEFFTDS Longitudinal FTLD (ALLFTD) Study, with 342 C9orf72, 148 GRN, 168 MAPT mutation carriers, and 1004 noncarriers. We used the CDR plus NACC FTLD global scores to define the conversion status, and stratified participants into four stages of progression: 1) Presymptomatic (CDR = 0 throughout the follow‐up), 2) Early conversion (began with CDR = 0, then increased to 0.5), 3) Advanced conversion (began with CDR = 0.5, then increased to 1.0 or above), and 4) Symptomatic (CDR>1.0 throughout). Over up to seven visits, the Neuropsychiatric Inventory Questionnaire (NPI‐Q) assessed changes in NPS. We analyzed total NPI‐Q score trajectories using a generalized linear mixed‐effects model, adjusting for age and baseline NPI‐Q scores.ResultOur findings showed similar NPS trajectories among carriers and noncarriers during presymptomatic stages. However, in the early conversion stage, C9orf72 and GRN carriers exhibited significantly higher NPI‐Q score increases compared to MAPT carriers, primarily in the psychosis and hyperactivity domains. In the advanced and symptomatic stages, the rate of increase in NPS was not significantly different across groups.ConclusionThis study suggests that people with familial FTD, particularly those predicted to have underlying TDP‐43 pathology, may experience more severe neuropsychiatric symptoms like psychosis or hyperactivity as they progress from presymptomatic to prodromal phases. This trajectory appears distinct from those with tau pathology or sporadic FTD. Further studies are warranted to understand these unique progression patterns and their implications for FTD management.

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.

ImportanceFrontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD.ObjectiveTo evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations.Design, Setting, and ParticipantsIn this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)–based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes.ExposureParticipants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests.Main Outcomes and MeasuresInternal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy.ResultsIn the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized β range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, −2.49 [95% CI, −0.19 to −0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back β = −0.49 [95% CI, −0.72 to −0.25]; P &amp;lt; .001) but not a composite of traditional neuropsychological measures (β = −0.14 [95% CI, −0.42 to 0.14]; P = .32).Conclusions and RelevanceThe findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

AbstractBackgroundNeuropsychiatric symptoms (NPS) often occur during the prodromal stage of frontotemporal dementia (FTD), as evidenced by the presence of early psychiatric diagnosis in approximately 50% of bvFTD patients prior to their dementia diagnosis. We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased baseline burden and rates of progression of NPS compared to non‐carrier individuals prior to onset of dementia symptoms based on the Clinical Dementia Rating (CDR) scale.MethodParticipants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. NPS were assessed with Neuropsychiatric Inventory‐Questionnaire (NPI‐Q), Geriatric Depression Scale (GDS), Interpersonal Reactivity Index (IRI), Social Behaviour Checklist (SBOCL), and Behavioral Inhibition Scale (BIS) annually for up to five years. We selected participants with CDR scores of 0 and 0.5. If a participant’s CDR changed to above 0.5 during the follow‐up, we only analyzed observations collected before the conversion. We used mixed effects models to compare the baseline burden and the longitudinal progression of NPS measures between carriers and controls, adjusted for baseline age, sex, education, and baseline Montreal Cognitive Assessment (MoCA) scores.ResultWe analyzed data from 607 participants (111 C9orf72+, 47 GRN+, 67 MAPT+ and 382 non‐carrier controls). There were no significant group differences in baseline demographic features, except that MAPT+ was significantly younger than other groups (average age: C9orf72+ = 45, GRN+ = 53, MAPT+ = 41, controls = 54). Baseline NPS scores were not significantly different between carriers and controls, except that C9orf72+ had significantly lower GDS compared to controls (p = 0.002). Longitudinally, GRN+ (p = 0.02) and MAPT+ (p = 0.009) had significantly higher rates of NPI‐Q increases compared to controls, while the progression of NPI‐Q in C9orf72+ was comparable to controls. The rates of GDS, IRI, SBOCL and BIS progression were not significantly different between carriers and controls.ConclusionPrior to the onset of dementia, GRN+ and MAPT+ have a faster progression of NPS, as measured by NPI‐Q, compared to controls. Future work will investigate whether different mutation carriers are affected by specific type/cluster of symptoms.

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.