Rosen, Howard J.

Abstract Background Agitation is a clinically significant symptom contributing to behavioral and psychological symptoms of dementia (BPSD) but is poorly understood across the different syndromes related to Frontotemporal Lobar Degeneration (FTLD). This study investigates sex differences in agitation across FTLD‐related syndromes and its relationship to various neuropsychiatric symptoms (NPS). Method We analyzed data from 1,654 participants (916 males, 738 females; average ages 65.8 and 65.9, respectively) from the National Alzheimer's Coordinating Center (NACC) and ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study with a FTLD‐related syndrome: behavioral variant FTD (bvFTD), Primary Progressive Aphasia (non‐fluent variant (nfvPPA), semantic variant (svPPA)), Corticobasal syndrome (CBS) and Progressive Supranuclear Palsy (PSP). Participants’ symptoms were assessed using the Neuropsychiatric Inventory (NPI). Prevalence ratios and odds ratios were computed to assess the likelihood of NPS comorbidities when agitation was present in males and females. Principal Component Analysis (PCA) was performed to identify NPS associated with agitation and how they varied by sex. Result Males were more likely to experience anxiety (bvFTD: p <0.001, CBS: p <0.01, PSP: p <0.0001), apathy (nfvPPA: p <0.01, PSP: p <0.01), depression (bvFTD: p <0.0001, PSP<0.01), disinhibition (nfvPPA: p <0.0001), PSP: p <0.001), and motor symptoms (bvFTD: p <0.01, CBS: p <0.01) when agitation was present. In contrast, females had a higher likelihood of experiencing disinhibition in svPPA ( p <0.001). These findings suggest that agitation is associated with a wider range of NPS in males than in females. Agitation and NPS are especially prominent in males with PSP. Conclusion This study reveals significant sex differences in NPS in FTLD‐related syndromes when agitation is present. Males and especially PSP, are more likely to experience a broader range of NPS in association with agitation. These findings underscore the need for further investigation into the underlying mechanisms driving these sex differences, particularly focusing on the neurobiological impact of agitation, the recognition of symptoms in the presence of greater behavioral disturbances, and potential variations from informant reports. Understanding these factors will provide valuable insights into the role of agitation in the presentation of NPS across FTLD‐related syndromes. Ultimately, addressing these gaps will enhance our ability to effectively treat and manage agitation in both male and female patients with FTLD‐related syndromes.

Abstract Background Motor disturbances are common in neurodegenerative disorders. Digital health technologies can be a tool for remote, accessible, and low‐burden motor assessments. The ALLFTD Mobile App includes a finger‐tapping test (mApp‐FTT) to assess dexterity. We evaluated the reliability and construct validity of smartphone‐based measures of finger tapping in an in‐person sample. Methods Participants ( n = 33; mean age=68.2 [SD=8.6]) completed the mobile finger‐tapping test (mApp‐FTT) on iOS and Android devices (two counterbalanced 20‐second trials per hand) and the mechanical finger‐tapping test (FTT). The sample included cognitively unimpaired participants (22.2%) and those diagnosed with frontotemporal dementia‐spectrum disorders (41.7%), Alzheimer's dementia (22.2%), and progressive supranuclear palsy or corticobasal syndrome (13.9%). A motor domain was calculated based on neurological exam and added to the Clinical Dementia Rating® plus National Alzheimer's Coordinating Center–Frontotemporal Lobar Degeneration (CDR®+NACC‐FTLD). Pearson's correlations assessed associations between mApp‐FTT performance and FTT performance, clinical severity (CDR®+NACC‐FTLD Box Score), motor rating scales (Progressive Supranuclear Palsy Rating Scale [PSPRS] and Unified Parkinson's Disease Rating Scale [UPDRS]), and cognitive function. Due to small sample size, PSPRS subdomains were dichotomized, and t‐tests were performed to evaluate group differences based on symptom presence. Results Total mApp‐FTT taps on iOS and Android were strongly correlated ( r = 0.86, 95% CI [0.76, 0.92], p < .001). mApp‐FTT was associated with manual FTT on iOS ( r = 0.70, 95% CI [0.52, 0.82], p < .001) and Android ( r = 0.62, 95% CI [0.41, 0.77], p < .001). Among iOS users, total PSPRS score was negatively correlated with mApp‐FTT ( r = ‐0.60, 95% CI [‐0.75, ‐0.39], p < .001). Worse mApp‐FTT performance was observed in participants with higher limb rigidity (mean difference=15.46, 95% CI [3.40, 27.52], p < .001), limb dystonia (mean difference=19.22, 95% CI [5.67, 32.77], p < .001), and finger tapping (mean difference=12.74, 95% CI [3.42, 22.06], p < .001). Total UPDRS score correlated with lower mApp‐FTT ( r = ‐0.48, 95% CI [‐0.66, ‐0.28], p < .001), as did disease severity (CDR®+NACC‐FTLD Box Score; r=‐0.46, 95% CI [‐0.66, ‐0.22], p < .001). Conclusion Smartphone‐based finger‐tapping assessments effectively detect motor and cognitive impairment, with stronger associations for motor function. Findings in iOS users highlight the need to assess operating system‐related biases and validate in Android. Remote smartphone assessments offer a scalable tool for tracking disease progression, warranting larger longitudinal studies.