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Objectives: Frontotemporal Degeneration (FTD) is a common cause of early onset dementia with symptoms often presenting before 65 years of age and adding tremendous burden on caregivers. FTD caregiving research describes patient behavioral symptoms such as apathy and disinhibition as primary sources of poor caregiver psychological health; however, little attention has been paid to other common patient behaviors, such as loss of empathy. To better understand the relationship between empathy loss and FTD caregiver outcomes, this integrative review aimed to address the question: How does the loss of empathy in a person living with FTD (PLwFTD) impact the caregiver?, Method: Quantitative and qualitative articles were found in PubMed, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Scopus and were assessed for quality using the Crowe Critical Appraisal Tool (CCAT). Through constant comparative analysis, articles were assessed to abstract common themes in the literature., Results: From 333 citations, 8 qualitative and 8 quantitative studies published between 2010 and 2022 were included. Three main themes were uncovered: 1) caregiver emotional reactions to the PLwFTD; 2) caregiver psychological distress; 3) changes in the relationship., Conclusion: This review emphasizes the detrimental impact of empathy loss on FTD caregivers. Understanding these underexplored consequences is critical in understanding the well-being of caregivers and promoting ways to support caregivers.

Racial disparities in neuropsychological test performance are well documented in Alzheimer's Disease (AD) but have received little attention in frontotemporal degeneration (FTD). Identification of potential disparities in neuropsychological performance is critical to identify ways to improve inclusivity in clinical research and care of representative FTD populations. We evaluated disparities in neuropsychological performance among individuals with clinically diagnosed FTD (behavioral variant FTD [bvFTD] or primary progressive aphasia [PPA]) using data from the National Alzheimer's Coordinating Center (NACC) collected between September 2005 and November 2023. Only 10% of NACC FTD cases are from racially/ethnically minoritized groups. Black (n=56), Hispanic (n=77) and White (n=1301) individuals were evaluated in the cognitive domains of episodic memory, working memory, processing speed, cognitive flexibility, attention, category fluency and lexical retrieval, in addition to global cognition across Uniform Data Set versions 1 to 3. Linear regressions examined the association between racial/ethnic group and cognitive scores covarying for disease stage, age, sex, and education. After adjusting for age, sex, and education using NACC established normative correction, binary logistic regression examined group differences in the proportion of participants classified as impaired (<=-1.5 normative z-score) for each cognitive test. Minoritized individuals, on average, had lower scores and/or greater likelihood of impairment (odds ratio; OR) on measures of global cognition (Black: β = -3.63; OR = 2.74; Hispanic: β = -2.50), lexical retrieval (Black: β = -4.31; OR = 3.28; Hispanic: β = -2.90; OR = 3.81), processing speed (Black: β = 26.80; OR = 4.07; Hispanic: β = 21.31; OR = 2.37), cognitive flexibility (Black: β = 46.65; OR = 3.35), attention (Hispanic: β = -0.39), working memory (Black: β = -0.79; Hispanic: β = -0.42), episodic memory (Hispanic: β = -1.67), and category fluency (Hispanic: β = -1.28). We did not identify any neuropsychological tests where White individuals performed worse than minoritized individuals. These findings indicate racial/ethnic differences in neuropsychological test performance on measures of global cognition, executive function, and lexical retrieval. Critically, these tests are used in diagnosis and monitoring of FTD. Future efforts must focus on increasing research participation in underrepresented populations with FTD to support the diverse needs of individuals, and an understanding of social determinants of health in FTD to evaluate potential sources of the observed differences across racial and ethnic groups.

Objectives: Dimensions of religion and spirituality are associated with better emotional, physical, and cognitive health. However, the underlying physiological mechanisms are not well known. We investigated the relationship between dimensions of religion and spirituality with levels of C-reactive protein (CRP), a biomarker of systematic inflammation, in middle-aged and older adults in the United States. Methods: In this descriptive longitudinal study using secondary data, we used proportional odds models of the generalized estimating equation (GEE) to assess the association between religious beliefs and values and religious service attendance with CRP levels from respondents ( n  = 2,385) aged 50 years and older in the Health and Retirement Study from 2006 to 2014. Results: Middle-aged to older adults who reported higher religious beliefs and values had lower levels of CRP, controlling for age, sex, education, marital status, race, household income, and health, such as hypertension, diabetes, cancer, and body mass index (BMI). Conclusion: Religious beliefs and values are associated with lower CRP levels among middle-aged and older adults in the U.S. This study adds to the understanding of biological processes underlying the relationship between dimensions of religion and spirituality with better cognitive and physical health, potentially through inflammation.

In behavioral-variant frontotemporal degeneration (bvFTD) and amyotrophic lateral sclerosis (ALS), secondary motor or cognitive-behavioral symptoms, respectively, are associated with shorter survival. However, factors influencing secondary symptom development remain largely unexplored. We performed a retrospective evaluation of the entire disease course of individuals with ALS (n=172) and bvFTD (n=69). Only individuals who had neuropathological confirmation of TDP-43 proteinopathy at autopsy or a C9orf72 hexanucleotide repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether each was modified by the presence of a C9orf72 expansion or initial clinical syndrome. Binary logistic regression and Cox proportional hazard analyses revealed increased odds (OR=4.25 [95% CI 1.97-9.14], p<0.001) and an increased hazard (HR= 4.77 [95% CI 2.33-9.79], p<0.001) for developing secondary symptoms in those with a C9orf72 expansion compared to those without. Initial clinical syndrome (bvFTD or ALS), age at symptom onset, and sex were not associated with development of secondary symptoms. These data highlight the need for clinician vigilance to detect the onset of secondary motor and cognitive-behavioral symptoms in patients carrying a C9orf72 expansion, regardless of initial clinical syndrome. C9orf72 clinical care can be enhanced through coordination between cognitive and neuromuscular clinics.

Objective: Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative condition featuring variable degrees of motor and cognitive impairment. We assessed the impact of specific, empirically derived occupational skills and requirements on cognitive and motor functioning in ALS., Methods: Individuals with ALS (n = 150) were recruited from the University of Pennsylvania's Comprehensive ALS Clinic. The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) measured cognition, and the Penn Upper Motor Neuron (PUMNS) and ALS Functional Rating Scales (ALSFRS-R) measured motor symptoms. We derived 17 factors representing distinct occupational skills and requirements from the Occupational Information Network (O*NET), which were related to cognitive and motor scores using multiple linear regression., Results: Occupational roles involving greater reasoning ability (β = 2.12, p  < .05), social ability (β = 1.73, p  < .05), analytic skills, (β = 3.12, p  < .01) and humanities knowledge (β = 1.83, p <.01) were associated with better performance on the ECAS, while jobs involving more exposure to environmental hazards (β=-2.57, p  < .01) and technical skills (β=-2.16, p <.01) were associated with lower ECAS scores. Jobs requiring more precision skills (β = 1.91, p  < .05) were associated with greater motor dysfunction on the PUMNS., Conclusions: Occupational histories involving more cognitively complex skills and activities were related to preserved cognitive functioning in ALS consistent with the cognitive reserve hypothesis, while jobs with greater exposure to environmental hazards and technical demands were linked to poorer cognitive functioning. Jobs involving more repetitive movements were associated with worse motor functioning, possibly due to overuse. Occupational history provides insight into protective and risk factors for variable degrees of cognitive and motor dysfunction in ALS.

Cortical atrophy in behavioral variant frontotemporal degeneration (bvFTD) exhibits spatial heterogeneity across genetic subgroups, potentially driven by distinct biological mechanisms. Using an integrative imaging-transcriptomics approach, we identified disparate and shared transcriptomic signatures associated with cortical thickness in C9orf72 , GRN or MAPT -related bvFTD. Genes associated with cortical thinning in GRN -bvFTD were implicated in neurotransmission, further supported by mapping synaptic density maps to cortical thickness maps. Previously identified genes linked to TDP-43 positive neurons were significantly overlapped with genes associated with C9orf72 -bvFTD and GRN -bvFTD, but not MAPT -bvFTD providing specificity for our associations. C9orf72 -bvFTD and GRN -bvFTD shared genes displaying consistent directionality of correlations with cortical thickness, while MAPT -bvFTD displayed more pronounced differences in transcriptomic signatures with opposing directionality. Overall, we identified disparate and shared genes tied to regional vulnerability with increased biological interpretation including overlap with synaptic density maps and pathologically-specific gene expression, illuminating intricate molecular underpinnings contributing to heterogeneities in bvFTD.

Purpose: Distal radius fractures (DRFs) represent up to 18% of all fractures in the elderly population, yet studies on the rate of complications following surgery are lacking in the literature. This systematic review aimed to quantify the rate of complications and reinterventions in patients treated with volar plate for distal radius fractures, and analyze if there was any predisposing factor., Methods: A comprehensive literature search was performed on three databases up to January 2023, following PRISMA guidelines. Studies describing volar plate complications and hardware removal were included. A systematic review was performed on complications and rate of reintervention. Assessment of risk of bias and quality of evidence was performed with the 'Down and Black's Checklist for measuring quality'., Results: About112 studies including 17 288 patients were included. The number of complications was 2434 in 2335 patients; the most frequent was carpal tunnel syndrome (CTS), representing 14.3% of all complications. About 104 studies reported the number of reinterventions, being 1880 with a reintervention rate of 8.5%. About 84 studies reported the reason of reintervention; the most common were patient's will (3.0%), pain (1.1%), CTS (1.2%), and device failure (1.1%)., Conclusion: The complication rate after DRFs is 13.5%, with the main complication being CTS (14.3%), followed by pain and tendinopathy. The reintervention rate is 8.5%, mainly due to the patient's willingness, and all these patients had plate removal. Correct positioning of the plate and correct information to the patient before surgery can reduce the number of hardware removal, thereby reducing costs and the risk of complications associated with VLP for distal radius fractures.

With the increasing availability of predictive genetic testing for adult-onset neurodegenerative conditions, it is imperative that we better understand the impact of learning one's risk status. Frontotemporal degeneration (FTD) is the second most prevalent cause of early-onset dementia. About one-third of patients have an identifiable genetic etiology, and some genetic variants that cause FTD can also cause amyotrophic lateral sclerosis (ALS). To understand individuals' risk perception and broader experience of living at risk, we completed semi-structured telephone interviews with 14 asymptomatic adults who tested positive for a variant known to cause risk for FTD and/or ALS. We conducted a thematic analysis, and within the core topic of identity, we derived three themes: conceptualization of FTD and ALS as a threat to identity, enduring uncertainty and dread, and varying centrality of risk status to identity. FTD and ALS risk raised fundamental issues for participants related to the essence of personhood, challenged them to confront Cartesian dualism (the philosophy of mind-body separation), and exposed how time, relationships, and social roles have affected their understanding of the nature of the self. Our findings provide important insight into how being at genetic risk shapes an individual's identity. We conclude that genetic counseling interventions that allow for identity exploration, anticipatory guidance, and uncertainty management should be utilized when supporting persons at risk., (© 2023 National Society of Genetic Counselors.)

Objective: Personality change in Alzheimer's disease and related dementias (ADRD) is complicated by the patient and informant factors that confound accurate reporting of personality traits. We assessed the impact of caregiver burden on informant report of Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness) and investigated the regional cortical volumes associated with larger discrepancies in the patient and informant report of the Big Five personality traits., Method: Sixty-four ADRD participants with heterogeneous neurodegenerative clinical phenotypes and their informants completed the Big Five Inventory (BFI). Caregiver burden was measured using the Zarit Burden Interview. Discrepancy scores were computed as the difference between patient and informant ratings for the BFI. Regional gray matter volumes from T1-weighted 3T MRI were normalized to intracranial volume and related to global Big Five discrepancy scores using linear regression., Results: Higher levels of caregiver burden were associated with higher informant ratings of patient neuroticism (ß = 0.08, p = .012) and with lower informant ratings of patient agreeableness (ß = 0.11, p = .021) and conscientiousness (ß = 0.04, p = .034) independent of disease severity. Patients with greater Big Five discrepancy scores showed smaller cortical volumes in the right medial prefrontal cortex (β = -5.24, p = .045) and right superior temporal gyrus (β = -7.91, p = .028)., Conclusions: Informant ratings of personality traits in ADRD can be confounded by the caregiver burden, highlighting the need for more objective measures of personality and behavior in dementia samples. Discrepancies between informant and patient ratings of personality may additionally reflect loss of insight secondary to cortical atrophy in the frontal and temporal structures., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

This study aims to design and pilot an empirically based mobile application ( ActiviDaily ) to increase daily activity in persons with apathy and ADRD and test its feasibility and preliminary efficacy. ActiviDaily was developed to address impairments in goal-directed behaviour, including difficulty with initiation, planning, and motivation that contribute to apathy. Participants included patients with apathy and MCI, mild bvFTD, or mild AD and their caregivers. In Phase I, 6 patient-caregiver dyads participated in 1-week pilot testing and focus groups. In Phase II, 24 dyads completed 4 weeks of at-home ActiviDaily use. Baseline and follow-up visits included assessments of app usability, goal attainment, global cognition and functioning, apathy, and psychological symptoms. App use did not differ across diagnostic groups and was not associated with age, sex, education, global functioning or neuropsychiatric symptoms. Patients and care-partners reported high levels of satisfaction and usability, and care-partner usability rating predicted app use. At follow-up, participants showed significant improvement in goal achievement for all goal types combined. Participant goal-directed behaviour increased after 4 weeks of ActiviDaily use. Patients and caregivers reported good usability and user satisfaction. Our findings support the feasibility and efficacy of mobile-health applications to increase goal-directed behaviour in ADRD.

Objectives: This review aimed to assess characteristics of telehealth in pain management for adult patients with chronic pain and their family care partners and review current evidence of the effectiveness of telehealth for pain management. Based on the Revised Symptom Management model, this review identified types of chronic pain management strategies and symptom management outcomes delivered by telehealth. Methods: We conducted a systematic review of four electronic databases, PubMed, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, and Embase, using combinations of keywords, including "telehealth," "caregivers," and "pain." Only interventions delivered online, including websites, mobile applications, phone calls, and videoconferencing, were included. To accurately characterize the features of each telehealth pain intervention, we employed a standardized checklist. Additionally, a summary table of the evidence was created. Results: We analyzed 17 studies that met the inclusion criteria, of which 14 were randomized controlled trials, 1 was a cohort study, and 2 were qualitative cohort studies. We grouped interventions based on content of the intervention for pain management (education, psychotherapy, reporting and consultation, and multicomponent intervention). The quality rating of studies was mostly moderately strong. Findings of interventions' effectiveness were showing heterogenous effects on variables, possibly due to different pain measurements and varying follow-up times. Significance of Results: Telehealth interventions can potentially increase access to care for patients with chronic pain and their families in a limited resource area. Telehealth technology is a feasible tool that may enhance clinicians' pain management efforts for patients with chronic pain and their family care partners. The results of this review can be used to guide telehealth pain assessment and evaluation for care partners, clinicians, and researchers and inform the design of future telehealth systems.

Objective: To evaluate automated digital speech measures, derived from spontaneous speech (picture descriptions), in assessing bulbar motor impairments in patients with ALS-FTD spectrum disorders (ALS-FTSD)., Methods: Automated vowel algorithms were employed to extract two vowel acoustic measures: vowel space area (VSA), and mean second formant slope (F2 slope). Vowel measures were compared between ALS with and without clinical bulbar symptoms (ALS + bulbar (n = 49, ALSFRS-r bulbar subscore: x¯ = 9.8 (SD = 1.7)) vs. ALS-nonbulbar (n = 23), behavioral variant frontotemporal dementia (bvFTD, n = 25) without a motor syndrome, and healthy controls (HC, n = 32). Correlations with bulbar motor clinical scales, perceived listener effort, and MRI cortical thickness of the orobuccal primary motor cortex (oral PMC) were examined. We compared vowel measures to speaking rate, a conventional metric for assessing bulbar dysfunction., Results: ALS + bulbar had significantly reduced VSA and F2 slope than ALS-nonbulbar (|d|=0.94 and |d|=1.04, respectively), bvFTD (|d|=0.89 and |d|=1.47), and HC (|d|=0.73 and |d|=0.99). These reductions correlated with worse bulbar clinical scores (VSA: R = 0.33, p  = 0.043; F2 slope: R = 0.38, p  = 0.011), greater listener effort (VSA: R=-0.43, p  = 0.041; F2 slope: p  > 0.05), and cortical thinning in oral PMC (F2 slope: β = 0.0026, p  = 0.017). Vowel measures demonstrated greater sensitivity and specificity for bulbar impairment than speaking rate, while showing independence from cognitive and respiratory impairments., Conclusion: Automatic vowel measures are easily derived from a brief spontaneous speech sample, are sensitive to mild-moderate stage of bulbar disease in ALS-FTSD, and may present better sensitivity to bulbar impairment compared to traditional assessments such as speaking rate.

Importance: Frontotemporal 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., Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations., Design, Setting, and Participants: In 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., Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests., Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy., Results: In 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 < .001) but not a composite of traditional neuropsychological measures (β = -0.14 [95% CI, -0.42 to 0.14]; P = .32)., Conclusions and Relevance: The 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.

Background: Impairment in goal-directed behavior (GDB) contributes to apathy, a prevalent syndrome in Parkinson's disease (PD). The Philadelphia Apathy Computerized Task (PACT) is a performance-based measure of GDB that may be less confounded by reduced patient insight, cognitive impairment, and care partner burnout., Objective: To examine how the PACT is related to patient function and care partner burden., Methods: PD patients with normal cognition (n = 19) or mild cognitive impairment (n = 14) and their care partners were recruited. Participants completed the PACT, a computerized paradigm consisting of subtasks specific to each component of GDB: initiation, motivation, and planning. Care partners completed the Zarit Burden Interview (ZBI) and the Penn Parkinson's Daily Activities Questionnaire (PDAQ-15). The associations between mean latency on each PACT subtask and ZBI and PDAQ-15 scores, respectively, were tested using Spearman's rank correlation coefficients. Significant associations were further delineated using multivariate regression with the following covariates: age, years of education, MoCA score, daily levodopa equivalency dose, UPDRS Part III score, and GDS-15 score., Results: Worse performance on the planning subtask of the PACT related to higher ZBI scores and lower PDAQ-15 scores when adjusting for covariates. Decreased initiation was associated with higher ZBI and decreased motivation with lower PDAQ-15., Conclusions: Specific components of the PACT are related to patient and care partner outcomes in PD. The main advantage of this measure is to minimize the confounds of poor insight and care partner distress. We propose future research directions to refine the PACT for potential use in research and clinical practice., Competing Interests: Declaration of competing interest The authors of this manuscript do not have competing interests to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Objectives: Clinical trials developing therapeutics for frontotemporal degeneration (FTD) focus on pathogenic variant carriers at preclinical stages. Objective, quantitative clinical assessment tools are needed to track stability and delayed disease onset. Natural speech can serve as an accessible, cost-effective assessment tool. We aimed to identify early changes in the natural speech of FTD pathogenic variant carriers before they become symptomatic., Methods: In this cohort study, speech samples of picture descriptions were collected longitudinally from healthy participants in observational studies at the University of Pennsylvania and Columbia University between 2007 and 2020. Participants were asymptomatic but at risk for familial FTD. Status as "carrier" or "noncarrier" was based on screening for known pathogenic variants in the participant's family. Thirty previously validated digital speech measures derived from automatic speech processing pipelines were selected a priori based on previous studies in patients with FTD and compared between asymptomatic carriers and noncarriers cross-sectionally and longitudinally., Results: A total of 105 participants, all asymptomatic, included 41 carriers: 12 men [30%], mean age 43 ± 13 years; education, 16 ± 2 years; MMSE 29 ± 1; and 64 noncarriers: 27 men [42%]; mean age, 48 ± 14 years; education, 15 ± 3 years; MMSE 29 ± 1. We identified 4 speech measures that differed between carriers and noncarriers at baseline: mean speech segment duration (mean difference -0.28 seconds, 95% CI -0.55 to -0.02, p = 0.04); word frequency (mean difference 0.07, 95% CI 0.008-0.14, p = 0.03); word ambiguity (mean difference 0.02, 95% CI 0.0008-0.05, p = 0.04); and interjection count per 100 words (mean difference 0.33, 95% CI 0.07-0.59, p = 0.01). Three speech measures deteriorated over time in carriers only: particle count per 100 words per month (β = -0.02, 95% CI -0.03 to -0.004, p = 0.009); total narrative production time in seconds per month (β = -0.24, 95% CI -0.37 to -0.12, p < 0.001); and total number of words per month (β = -0.48, 95% CI -0.78 to -0.19, p = 0.002) including in 3 carriers who later converted to symptomatic disease., Discussion: Using automatic processing pipelines, we identified early changes in the natural speech of FTD pathogenic variant carriers in the presymptomatic stage. These findings highlight the potential utility of natural speech as a digital clinical outcome assessment tool in FTD, where objective and quantifiable measures for abnormal behavior and language are lacking.

Background: Anxiety is common in older adults and social isolation is one of the leading factors associated with their anxiety. However, what is unknown is how the relationship between social isolation and anxiety differs by cognitive status. Therefore, this study was conducted to (1) compare the level of social isolation and anxiety in older adults who developed probable dementia and mild cognitive impairment (MCI) to those who maintained normal cognitive function over 5 years; and (2) determine if cognitive impairment moderates the relationship between changes in social isolation and changes in anxiety over 5 years., Methods: A secondary data analysis was conducted using the National Social Life, Health, and Aging Project (NSHAP): Wave 2 (2010-2011) and Wave 3 (2015-2016). The participants were categorized into three groups: Participants who developed probable dementia over 5 years (4.3%), developed probable MCI (19.1%), or maintained normal cognitive function (76.6%). Weighted linear regression analyses with a group interaction were used to examine the moderating effect of cognitive impairment on the relationship between changes in social isolation and anxiety., Results: At the 5-year follow up, there were statistically significant differences in social isolation between the three groups (p = 0.043). Regression analyses showed that increased social isolation over time was related to increased anxiety over 5 years regardless of cognitive status after controlling for covariates (p = 0.017)., Conclusions: The relationship between social isolation and anxiety was a universal phenomenon regardless of cognitive status. Tailored interventions targeting both people with or without cognitive impairment are needed to lessen social isolation and anxiety., (© 2024. The Author(s).)

Background: TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum., Methods: We used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS-FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease., Results: SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King's stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology., Conclusions: Our findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns., (© 2023. The Author(s).)

Importance: Prior research suggests there are racial disparities in the presentation of dementia, but this has not been investigated in the context of frontotemporal dementia (FTD)., Objective: To explore racial disparities in dementia severity, functional impairment, and neuropsychiatric symptoms in individuals with a diagnosis of FTD., Design, Setting, and Participants: This exploratory cross-sectional study of National Alzheimer's Coordinating Center (NACC) data collected between June 2005 to August 2021 evaluated Asian, Black, and White individuals with a diagnosis of FTD (behavioral variant FTD or primary progressive aphasia). Excluded were races with limited data, including American Indian or Alaska Native (n = 4), Native Hawaiian or other Pacific Islander (n = 3), other (n = 13), and unknown (n = 24), and participants with symptom duration more than 4 SDs above the mean., Main Outcomes and Measures: Racial differences at initial NACC visit were examined on Clinical Dementia Rating Dementia Staging Instrument plus NACC Frontotemporal Lobar Degeneration Behavior & Language Domains (FTLD-CDR), Functional Assessment Scale, and Neuropsychiatric Inventory using regression models. Matching was also performed to address the imbalance between racial groups., Results: The final sample comprised 2478 individuals, of which 59 (2.4%) were Asian, 63 (2.5%) were Black, and 2356 (95.1%) were White. The mean (SD) age at initial visit was 65.3 (9.4) years and symptom duration at initial visit was 67.5 (35.6) months. Asian and Black individuals were considerably underrepresented, comprising a small percent of the sample. Black individuals had a higher degree of dementia severity on FTLD-CDR (β = 0.64; SE = 0.24; P = .006) and FTLD-CDR sum of boxes (β = 1.21; SE = 0.57; P = .03) and greater functional impairment (β = 3.83; SE = 1.49; P = .01). There were no differences on FTLD-CDR and Functional Assessment Scale between Asian and White individuals. Black individuals were found to exhibit a higher frequency of delusions, agitation, and depression (delusions: odds ratio [OR], 2.18; 95% CI, 1.15-3.93; P = .01; agitation: OR, 1.73; 95% CI, 1.03-2.93; P = .04; depression: OR, 1.75; 95% CI, 1.05-2.92; P = .03). Asian individuals were found to exhibit a higher frequency of apathy (OR, 1.89; 95% CI, 1.09-3.78; P = .03), nighttime behaviors (OR, 1.72; 95% CI, 1.01-2.91; P = .04), and appetite/eating (OR, 1.99; 95% CI, 1.17-3.47; P = .01) compared to White individuals., Conclusions and Relevance: This exploratory study suggests there are racial disparities in dementia severity, functional impairment, and neuropsychiatric symptoms. Future work must address racial disparities and their underlying determinants as well as the lack of representation of racially minoritized individuals in nationally representative dementia registries.

Respite care provides alternative care for persons living with dementia (PLWD) and is intended to alleviate the burden of caregiving. However, the evaluation of respite programs is limited. Time Out Weekly Smile (TOWS) is a virtual intergenerational respite care program designed to meet the needs of PLWD and their care partners and provide allied health students opportunities to serve as respite volunteers. This multi-method pilot study aimed to evaluate the experience of TOWS participation for all (i.e., care partners, PLWD, students) and identify outcomes of interest for future efficacy studies. Semi-structured interviews with all participants after experiencing TOWS were analyzed using conventional content analysis methods and student surveys of dementia attitudes were summarized. Results demonstrated lasting mutual benefits for all participants including social connection and creating meaning. Our findings suggest that including all respite care participants in future efficacy studies will elucidate the wide impact of respite care programs., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Frontotemporal dementia (FTD) is a spectrum of clinically and pathologically heterogenous neurodegenerative dementias. Clinical and anatomical variants of FTD have been described and associated with underlying frontotemporal lobar degeneration (FTLD) pathology, including tauopathies (FTLD-tau) or TDP-43 proteinopathies (FTLD-TDP). FTD patients with predominant degeneration of anterior temporal cortices often develop a language disorder of semantic knowledge loss and/or a social disorder often characterized by compulsive rituals and belief systems corresponding to predominant left or right hemisphere involvement, respectively. The neural substrates of these complex social disorders remain unclear. Here, we present a comparative imaging and postmortem study of two patients, one with FTLD-TDP (subtype C) and one with FTLD-tau (subtype Pick disease), who both developed new rigid belief systems. The FTLD-TDP patient developed a complex set of values centered on positivity and associated with specific physical and behavioral features of pigs, while the FTLD-tau patient developed compulsive, goal-directed behaviors related to general themes of positivity and spirituality. Neuroimaging showed left-predominant temporal atrophy in the FTLD-TDP patient and right-predominant frontotemporal atrophy in the FTLD-tau patient. Consistent with antemortem cortical atrophy, histopathologic examinations revealed severe loss of neurons and myelin predominantly in the anterior temporal lobes of both patients, but the FTLD-tau patient showed more bilateral, dorsolateral involvement featuring greater pathology and loss of projection neurons and deep white matter. These findings highlight that the regions within and connected to anterior temporal lobes may have differential vulnerability to distinct FTLD proteinopathies and serve important roles in human belief systems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ohm, Rhodes, Bahena, Capp, Lowe, Sabatini, Trotman, Olm, Phillips, Prabhakaran, Rascovsky, Massimo, McMillan, Gee, Tisdall, Yushkevich, Lee, Grossman and Irwin.)

Frontotemporal dementia is the second most common form of early onset dementia (<65 years). Despite this, there are few known disease-modifying factors. The anterior cingulate is a focal point of pathology in behavioural variant frontotemporal dementia. Sulcation of the anterior cingulate is denoted by the presence of a paracingulate sulcus, a tertiary sulcus developing, where present during the third gestational trimester and remaining stable throughout life. This study aims to examine the impact of right paracingulate sulcal presence on the expression and prognosis of behavioural variant frontotemporal dementia. This retrospective analysis drew its population from two clinical samples recruited from memory clinics at university hospitals in the USA and The Netherlands. Individuals with sporadic behavioural variant frontotemporal dementia were enrolled between 2000 and 2022 and followed up for an average of 7.71 years. T 1 -MRI data were evaluated for hemispheric paracingulate sulcal presence in accordance with an established protocol by two blinded raters. Outcome measures included age at onset, survival, cortical thickness and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating determined clinical disease progression. The study population consisted of 186 individuals with sporadic behavioural variant frontotemporal dementia (113 males and 73 females), mean age 63.28 years (SD 8.32). The mean age at onset was 2.44 years later in individuals possessing a right paracingulate sulcus [60.2 years (8.54)] versus individuals who did not [57.76 (8.05)], 95% confidence interval > 0.41, P = 0.02. Education was not associated with age at onset ( β = -0.05, P = 0.75). The presence of a right paracingulate sulcus was associated with an 83% increased risk of death per year after age at onset (hazard ratio 1.83, confidence interval [1.09-3.07], P < 0.02), whilst the mean age at death was similar for individuals with a present and absent right paracingulate sulcus ( P = 0.7). Right paracingulate sulcal presence was not associated with baseline cortical thickness. Right paracingulate sulcal presence is associated with disease expression and survival in sporadic behavioural variant frontotemporal dementia. Findings provide evidence of neurodevelopmental brain reserve in behavioural variant frontotemporal dementia that may be important in the design of trials for future therapeutic approaches., Competing Interests: O.H. has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Fujirebio, Genentech, Novartis, Novo Nordisk, Roche and Siemens., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Cognitive reserve (CR) is the ability to maintain cognitive performance despite brain pathology. CR is built through lifecourse experiences (e.g., education) and is a key construct in promoting healthy aging. However, the operationalization of CR and its estimated association with late-life cognition varies. The purpose of this study was to systematically examine the operationalization of CR and the relationship between its operationalization and late-life cognition., Methods: We performed a comprehensive review of experiences (proxies) used to operationalize CR. The review informed quantitative analyses using data from 1366 participants of the Memory and Aging Project to examine 1) relationships between proxies and 2) the relationship between operationalization and late-life cognition. We also conducted a factor analysis with all identified CR experiences to create a composite lifecourse CR score. Generalized linear mixed models examined the relationship between operationalizations and global cognition, with secondary outcomes of five domains of cognition to examine consistency., Results: Based on a review of 753 articles, we found the majority (92.3%) of the 28 commonly used proxies have weak to no correlation between one another. There was substantial variability in the association between operationalizations and late-life global cognition (median effect size: 0.99, IQR: 0.34 to 1.39). There was not strong consistency in the association between CR operationalizations and the five cognitive domains (mean consistency: 56.1%). The average estimate for the 28 operationalizations was 0.91 (SE = 0.48), compared to 2.48 (SE = 0.40) for the lifecourse score and it was associated with all five domains of cognition., Conclusions: Inconsistent methodology is theorized as a major limitation of CR research and barrier to identification of impactful experiences for healthy cognitive aging. Based on the weak associations, it is not surprising that the relationship between CR and late-life cognition is dependent on the experience used to operationalize CR. Scores using multiple experiences across the lifecourse may help overcome such limitations. Adherence to a lifecourse approach and collaborative movement towards a consensus operationalization of CR are imperative shifts in the study of CR that can better inform research on risk factors related to cognitive decline and ultimately aid in the promotion of healthy aging., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative condition featuring variable degrees of motor decline and cognitive impairment. We test the hypothesis that cognitive reserve (CR), defined by occupational histories involving more complex cognitive demands, may protect against cognitive decline, while motor reserve (MR), defined by working jobs requiring complex motor skills, may protect against motor dysfunction., Methods: Individuals with ALS (n=150) were recruited from the University of Pennsylvania's Comprehensive ALS Clinic. Cognitive performance was evaluated using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), and motor functioning was measured using Penn Upper Motor Neuron (PUMNS) scale and ALS Functional Rating Scales (ALSFRS-R). The Occupational Information Network (O*NET) Database was used to derive 17 factors representing distinct worker characteristics, occupational requirements, and worker requirements, which were related to ECAS, PUMNS, and ALSFRS-R scores using multiple linear regression., Results: A history of working jobs involving greater reasoning ability (β=2.12, p<.05), social ability (β=1.73, p<.05), analytic skills, (β=3.12, p<.01) and humanities knowledge (β=1.83, p<.01) was associated with better performance on the ECAS, while jobs involving more exposure to environmental hazards (β=-2.57, p<.01) and technical skills (β=-2.16, p<.01) were associated with lower ECAS Total Scores. Jobs involving greater precision skills (β=1.91, p<.05) were associated with greater disease severity on the PUMNS. Findings for the ALSFRS-R did not survive correction for multiple comparisons., Discussion: Jobs requiring greater reasoning abilities, social skills, and humanities knowledge were related to preserved cognitive functioning consistent with CR, while jobs with greater exposure to environmental hazards and technical demands were linked to poorer cognitive functioning. We did not find evidence of MR as no protective effects of occupational skills and requirements were found for motor symptoms, and jobs involving greater precision skills and reasoning abilities were associated with worse motor functioning. Occupational history provides insight into protective and risk factors for variable degrees of cognitive and motor dysfunction in ALS.

Despite well-articulated hypotheses of spreading pathology in animal models of neurodegenerative disease, the basis for spreading neurodegenerative pathology in humans has been difficult to ascertain. In this study, we used graph theoretic analyses of structural networks in antemortem, multimodal MRI from autopsy-confirmed cases to examine spreading pathology in sporadic frontotemporal lobar degeneration. We defined phases of progressive cortical atrophy on T 1 -weighted MRI using a published algorithm in autopsied frontotemporal lobar degeneration with tau inclusions or with transactional DNA binding protein of ∼43 kDa inclusions. We studied global and local indices of structural networks in each of these phases, focusing on the integrity of grey matter hubs and white matter edges projecting between hubs. We found that global network measures are compromised to an equal degree in patients with frontotemporal lobar degeneration with tau inclusions and frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions compared to healthy controls. While measures of local network integrity were compromised in both frontotemporal lobar degeneration with tau inclusions and frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions, we discovered several important characteristics that distinguished between these groups. Hubs identified in controls were degraded in both patient groups, but degraded hubs were associated with the earliest phase of cortical atrophy (i.e. epicentres) only in frontotemporal lobar degeneration with tau inclusions. Degraded edges were significantly more plentiful in frontotemporal lobar degeneration with tau inclusions than in frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions, suggesting that the spread of tau pathology involves more significant white matter degeneration. Weakened edges were associated with degraded hubs in frontotemporal lobar degeneration with tau inclusions more than in frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions, particularly in the earlier phases of the disease, and phase-to-phase transitions in frontotemporal lobar degeneration with tau inclusions were characterized by weakened edges in earlier phases projecting to diseased hubs in subsequent phases of the disease. When we examined the spread of pathology from a region diseased in an earlier phase to physically adjacent regions in subsequent phases, we found greater evidence of disease spreading to adjacent regions in frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions than in frontotemporal lobar degeneration with tau inclusions. We associated evidence of degraded grey matter hubs and weakened white matter edges with quantitative measures of digitized pathology from direct observations of patients' brain samples. We conclude from these observations that the spread of pathology from diseased regions to distant regions via weakened long-range edges may contribute to spreading disease in frontotemporal dementia-tau, while spread of pathology to physically adjacent regions via local neuronal connectivity may play a more prominent role in spreading disease in frontotemporal lobar degeneration-transactional DNA binding protein of ∼43 kDa inclusions., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Patients with ALS-FTD spectrum disorders (ALS-FTSD) have mixed motor and cognitive impairments and require valid and quantitative assessment tools to support diagnosis and tracking of bulbar motor disease. This study aimed to validate a novel automated digital speech tool that analyzes vowel acoustics from natural, connected speech as a marker for impaired articulation due to bulbar motor disease in ALS-FTSD., Methods: We used an automatic algorithm called Forced Alignment Vowel Extraction (FAVE) to detect spoken vowels and extract vowel acoustics from 1 minute audio-recorded picture descriptions. Using automated acoustic analysis scripts, we derived two articulatory-acoustic measures: vowel space area (VSA, in Bark 2 ) which represents tongue range-of-motion (size), and average second formant slope of vowel trajectories (F2 slope) which represents tongue movement speed. We compared vowel measures between ALS with and without clinically-evident bulbar motor disease (ALS+bulbar vs. ALS-bulbar), behavioral variant frontotemporal dementia (bvFTD) without a motor syndrome, and healthy controls (HC). We correlated impaired vowel measures with bulbar disease severity, estimated by clinical bulbar scores and perceived listener effort, and with MRI cortical thickness of the orobuccal part of the primary motor cortex innervating the tongue (oralPMC). We also tested correlations with respiratory capacity and cognitive impairment., Results: Participants were 45 ALS+bulbar (30 males, mean age=61±11), 22 ALS-nonbulbar (11 males, age=62±10), 22 bvFTD (13 males, age=63±7), and 34 HC (14 males, age=69±8). ALS+bulbar had smaller VSA and shallower average F2 slopes than ALS-bulbar (VSA: | d |=0.86, p =0.0088; F2 slope: | d |=0.98, p =0.0054), bvFTD (VSA: | d |=0.67, p =0.043; F2 slope: | d |=1.4, p <0.001), and HC (VSA: | d |=0.73, p =0.024; F2 slope: | d |=1.0, p <0.001). Vowel measures declined with worsening bulbar clinical scores (VSA: R=0.33, p =0.033; F2 slope: R=0.25, p =0.048), and smaller VSA was associated with greater listener effort (R=-0.43, p =0.041). Shallower F2 slopes were related to cortical thinning in oralPMC (R=0.50, p =0.03). Neither vowel measure was associated with respiratory nor cognitive test scores., Conclusions: Vowel measures extracted with automatic processing from natural speech are sensitive to bulbar motor disease in ALS-FTD and are robust to cognitive impairment.

Introduction: A tremendous burden is placed on frontotemporal degeneration (FTD) caregivers who sacrifice their own self-care to manage the functional impairments of their loved one, contributing to high levels of stress and depression. Health coaching provides support for coping with stress while fostering self-care behaviors. We report on preliminary evidence for efficacy of a virtual health coach intervention aimed at increasing self-care., Methods: Thirty-one caregivers of persons with behavioral variant FTD (bvFTD) were assigned randomly to an intervention group, which included 10 coaching sessions over 6 months plus targeted health information or the control group receiving standard care augmented with the health information. Caregiver self-care (primary outcome), stress, depression, coping, and patient behavioral symptoms were collected at enrollment and 3 and 6 months. Change over time was evaluated between the intervention and control groups using linear mixed-effects models., Results: There was a significant group-by-time interaction for self-care monitoring ( t 58 = 2.37, p = 0.02 and self-care confidence ( t 58 = 2.32, p = 0.02) on the Self-Care Inventory, demonstrating that caregivers who received the intervention improved their self-care over time. Behavioral symptoms were reduced in bvFTD patients whose caregivers received the intervention ( t 54 = -2.15, p = 0.03)., Discussion: This randomized controlled trial (RCT) shows promise for health coaching as a way to increase support that is urgently needed to reduce poor outcomes in FTD caregivers., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: The aim of this study is to report an Italian multicenter experience analyzing the incidence and the risk factors associated with spinal cord ischemia (SCI) in a large cohort of thoracoabdominal aortic aneurysms (TAAAs) treated by fenestrated-branched endovascular aneurysm repair (F-/B-EVAR)., Materials and Methods: All consecutive patients undergoing F-/B-EVAR in 4 Italian university centers between 2008 and 2019 were prospectively recorded and retrospectively analyzed. Spinal cord ischemia, 30 day/in-hospital adverse events, and mortality were assessed as early outcomes. Risk factors for SCI were determined by multivariable analysis., Results: A total of 351 patients received F-/B-EVAR for a TAAA. Twenty-eight (8.0%) patients died within 30 postoperative days or during the hospitalization. Regarding SCI, 47 patients (13.4%) developed neurological symptoms related to spinal cord impaired perfusion. Among them, 17 (4.8%) had a major permanent impairment. The multivariable analysis identified that SCI was associated with Crawford extent I to III (odds ratio [OR]: 20.90, p=0.004, 95% confidence interval [CI]=2.69-162.57), and with endovascular procedures performed for ruptured TAAA (OR: 5.74, p=0.010, 95% CI=1.53-21.57). Spinal cord ischemia was also significantly associated with a grade 3 bleeding during the visceral stage (OR: 4.34, p=0.005, 95% CI=1.55-12.16) and a grade 2 renal insufficiency at 30 days (OR: 7.45, p=0.002, 95% CI=2.12-26.18)., Conclusion: The present study indicates that SCI is still an open issue after extent I to III TAAA endovascular repair, while its incidence in extent IV TAAA and pararenal/juxtarenal aneurysms is rare. Thoracoabdominal aortic aneurysms extension, urgent TAAA repair for rupture, severe bleeding, and 30 day renal insufficiency have been identified as significant risk factors for SCI. In the presence of such factors, adjunctive strategies may be considered to reduce SCI rates, while in low-risk patients invasive or potentially-risky maneuvers might not be justified.

Background: Assessment of personality change in Alzheimer's disease and related dementias (ADRD) is clinically meaningful but complicated by patient (i.e., reduced insight) and informant (i.e., caregiver burden) factors that confound accurate reporting of personality traits. This study assessed the impact of caregiver burden on informant report of Big Five personality traits (Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness) and investigated regional cortical volumes associated with larger discrepancies in patient and informant report of Big Five personality traits., Methods: Sixty-four ADRD participants with heterogeneous neurodegenerative clinical phenotypes and their informants completed the Big Five Inventory (BFI). Caregiver burden was measured using the Zarit Burden Interview (ZBI). Discrepancy scores were computed as the absolute value of the difference between patient and informant ratings for all BFI trait scores and summed to create a global score. Regional grey matter volumes from T1-weighted 3T MRI were normalized to intracranial volume and related to global Big Five discrepancy scores using linear regression., Results: Higher levels of caregiver burden were associated with higher informant ratings of patient Neuroticism (ß =0.27, p =.016) and lower informant ratings of patient Agreeableness (ß =-0.32, p =.002), Conscientiousness (ß =-0.3, p =.002), and Openness (ß =-0.34, p =.003) independent of disease severity. Patients with greater Big Five discrepancy scores showed smaller cortical volumes in right medial PFC (β = -0.00015, p = .002), right superior temporal gyrus (β = -0.00028, p = .025), and left inferior frontal gyrus (β = -0.00006 p = .013)., Conclusions: Informant ratings of personality traits in ADRD can be confounded by caregiver burden, highlighting the need for more objective measures of personality and behavior in dementia samples. Discrepancies between informant and patient ratings of personality may additionally reflect loss of insight secondary to cortical atrophy in frontal and temporal structures.

Background: In previous studies of patients with frontotemporal lobar degeneration due to tau (FTLD-tau) and FTLD due to TDP (FTLD-TDP), cortical volumes derived from T1-weighted MRI have been used to identify a sequence of volume loss according to arbitrary volumetric criteria. Event-based modeling (EBM) is a probabilistic, generative machine learning model that determines the characteristic sequence of changes, or "events", occurring during disease progression. EBM also estimates an individual patient's disease "stage" by identifying which events have already occurred. In the present study, we use an EBM analysis to derive stages of regional anatomic atrophy in FTLD-tau and FTLD-TDP, and validated these stages against pathologic burden., Methods: Sporadic autopsy-confirmed patients with FTLD-tau (N = 42) and FTLD-TDP (N = 21), and 167 healthy controls with available T1-weighted images were identified. A subset of patients had quantitative digital histopathology of cortex performed at autopsy (FTLD-tau = 30, FTLD-TDP = 17). MRI images were processed, producing regional measures of cortical volumes. K-means clustering was used to find cortical regions with similar amounts of GM volume changes (n = 5 clusters). EBM was used to determine the characteristic sequence of cortical atrophy of identified clusters in autopsy-confirmed FTLD-tau and FTLD-TDP, and estimate each patient's disease stage by cortical volume biomarkers. Linear regressions related pathologic burden to EBM-estimated disease stages., Results: EBM for cortical volume biomarkers generated statistically robust characteristic sequences of cortical atrophy in each group of patients. Cortical volume-based EBM-estimated disease stage was associated with pathologic burden in FTLD-tau (R2 = 0.16, p = 0.017) and FTLD-TDP (R2 = 0.51, p = 0.0008)., Conclusions: We provide evidence that EBM can identify sequences of pathologically-confirmed cortical atrophy in sporadic FTLD-tau and FTLD-TDP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: There are limited studies exploring the support and education needs of individuals at-risk for or diagnosed with hereditary frontotemporal degeneration (FTD) and/or amyotrophic lateral sclerosis (ALS). This study evaluated a novel conference for this population to assess conference efficacy, probe how participants assessed relevant resources, and identify outstanding needs of persons at-risk/diagnosed., Methods: We implemented a post-conference electronic survey that probed participants' satisfaction, prior experience with resources, and unmet needs. Along with multiple-choice, free-text items were included to gather qualitative context., Results: Survey completion rate was 31% (115/376 attendees who were emailed the survey). There was positive interest in pursuing genetic counseling among eligible responders: 61% indicated they planned to seek genetic counseling because of the conference, which was significantly more than those who were undecided (21%) or did not plan to seek genetic counseling (18%). Qualitative data demonstrated need for additional education, support, and research opportunities., Conclusion: Conference reactions indicate this is a valued resource. Results indicated the importance of raising awareness about existing resources, and the need for further resource development, especially for at-risk communities., Innovation: While most resources are developed for caregivers' needs, this unique program targets at-risk individuals and unites ALS and FTD communities., Competing Interests: Laynie Dratch receives consulting fees from Passage Bio and has received honoraria from the Muscular Dystrophy Association (MDA) and NSGC. Cynthia Clyburn has received honoraria from the MDA. Tanya Bardakjian is employed by Sarepta, a gene therapy company, and has financial relationships with Novartis, Invitae, Vigil Therapeutics, and Genome Medical. Murray Grossman participates in treatment trials sponsored by Passage Bio, Alector, and Prevail, and is a member of the Medical and Scientific Advisory Board of AFTD; he also receives funding from NIH and Department of Defense. Brianna Morgan receives funding support from the NIH and P.E.O. International. David J. Irwin is on the scientific advisory board of Denali Therapeutics. None of these sources of funding represent a conflict of interest. Katheryn A. Q. Cousins, Weiyi Mu, Elisabeth McCarty Wood, and Lauren Massimo declare no conflicts of interest., (© 2022 The Authors.)

Interferon beta (IFNβ) is a well-known cytokine, belonging to the type I family, that exerts antiviral, immunomodulatory, and antiproliferative activity. It has been reported that the artificially deamidated form of recombinant IFNβ-1a at Asn25 position shows an increased biological activity. As a deepening of the previous study, the molecular mechanism underlying this biological effect was investigated in this work by combining experimental and computational techniques. Specifically, the binding to IFNAR1 and IFNAR2 receptors and the canonical pathway of artificially deamidated IFNβ-1a molecule were analyzed in comparison to the native form. As a result, a change in receptor affinity of deamidated IFNβ-1a with respect to the native form was observed, and to better explore this molecular interaction, molecular dynamics simulations were carried out. Results confirmed, as previously hypothesized, that the N25D mutation can locally change the interaction network of the mutated residue but also that this effect can be propagated throughout the molecule. In fact, many residues not involved in the interaction with IFNAR1 in the native form participate to the recognition in the deamidated molecule, enhancing the binding to IFNAR1 receptor and consequently an increase of signaling cascade activation. In particular, a higher STAT1 phosphorylation and interferon-stimulated gene expression was observed under deamidated IFNβ-1a cell treatment. In conclusion, this study increases the scientific knowledge of deamidated IFNβ-1a, deciphering its molecular mechanism, and opens new perspectives to novel therapeutic strategies.

Background: Bimatoprost 0.03% is an intraocular pressure (IOP) lowering prostaglandin analog with different adverse side effects such as potential ocular inflammatory effect and ocular hyperemia., Case Presentation: We report a case of 80-year-old woman diagnosed with bilateral glaucomatous uveitis, and choroidal detachment in the left eye after topical bimatoprost administration. During the patient's hospitalization, Bimatoprost treatment was discontinued and local steroid therapy was administrated. After 1 week we reported a marked improvement of visual acuity, IOP measurement was 12 mmHg in both eyes. Anterior segment examination showed complete resolution of conjunctival and pericheratic hyperemia with significant reduction of endothelial precipitates in both eyes., Conclusions: In our case, the anterior granulomatous uveitis occurred in both pseudophakic eyes and the choroidal detachment (CD) in the eye that previously had trabeculectomy. Probably the scar tissue of the trabeculectomy allowed a better penetration of the Bimatoprost or a greater sensitivity due to an altered trabecular tissue. This work confirms that the onset physiopathology mechanism of granulomatous uveitis and CD following instillation of Bimatoprost remains uncertain.

Frontotemporal lobar degeneration (FTLD) includes clinically similar FTLD-tau or FTLD-TDP proteinopathies which lack in vivo markers for accurate antemortem diagnosis. To identify early distinguishing sites of cortical atrophy between groups, we retrospectively analyzed in vivo volumetric MRI from 42 FTLD-Tau and 21 FTLD-TDP patients and validated these findings with postmortem measures of pathological burden. Our frequency-based staging model revealed distinct loci of maximal early cortical atrophy in each group, including dorsolateral and medial frontal regions in FTLD-Tau and ventral frontal and anterior temporal regions in FTLD-TDP. Sørenson-Dice calculations between proteinopathy groups showed little overlap of phases. Conversely, within-group subtypes showed good overlap between 3R- and 4R-tauopathies, and between TDP-43 Types A and C for early regions with subtle divergence between subtypes in subsequent phases of atrophy. Postmortem validation found an association of imaging phases with pathologic burden within FTLD-tau (F (4, 238)  = 17.44, p < 0.001) and FTLD-TDP (F (4,245)  = 42.32, p < 0.001). These results suggest that relatively early, distinct markers of atrophy may distinguish FTLD proteinopathies during life., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Neurology is one of Africa's central and noble specialties due to the frequency of its related diseases. Through this study we: -1-described the status of neurologists in Africa in terms of numbers,-2-listed the reasons and discussed how to increase their number, and how to get the most benefit of them in healthcare coverage., Methods: The distribution and number of neurologists in the African continent was acquired from many participants in different African countries using a survey sent between March 2020 and August 2020 by email. Further, data from the World health organization on the number of neurologists was added for the countries, from which we didn't receive answers by the survey., Results: Surveys' answers were received from representatives of 50 (92%) of the 54 African nations. Authors suggest a ranking into four levels according to the number of neurologists per nation. Level A [more than 201 neurologists per country] included 2 nations. Level B [31 to 200 neurologists per country] included six nations. Level C [1 to 30 neurologists per country] including the majority of African countries (36 nations). Level D includes 10 nations without any neurologists., Conclusion: The need for reliable and competent neurologists with a sufficient number is considered as a crucial element to enhance the care of neurological diseases in Africa. For this, all African countries should establish new centers of excellence in neurology, by developing good south-south collaboration with supports from governmental and non-governmental institutions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Frontotemporal lobar degeneration (FTLD) with either tau (FTLD-tau) or TDP-43 (FTLD-TDP) inclusions are distinct proteinopathies that frequently cause similar frontotemporal dementia (FTD) clinical syndromes. FTD syndromes often display macroscopic signatures of neurodegeneration at the level of regions and networks, but it is unclear if subregional laminar pathology display patterns unique to proteinopathy or clinical syndrome. We hypothesized that FTLD-tau and FTLD-TDP accumulate pathology in relatively distinct cortical layers independent of clinical syndrome, with greater involvement of lower layers in FTLD-tau. The current study examined 170 patients with either FTLD-tau (n = 73) or FTLD-TDP (n = 97) spanning dementia and motor phenotypes in the FTD spectrum. We digitally measured the percent area occupied by tau and TDP-43 pathology in upper layers (I-III), lower layers (IV-VI), and juxtacortical white matter (WM) from isocortical regions in both hemispheres where available. Linear mixed-effects models compared ratios of upper to lower layer pathology between FTLD groups and investigated relationships with regions, WM pathology, and global cognitive impairment while adjusting for demographics. We found lower ratios of layer pathology in FTLD-tau and higher ratios of layer pathology in FTLD-TDP, reflecting lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology, respectively (p < 0.001). FTLD-tau displayed lower ratios of layer pathology related to greater WM tau pathology (p = 0.002) and to earlier involved/severe pathology regions (p = 0.007). In contrast, FTLD-TDP displayed higher ratios of layer pathology not related to either WM pathology or regional severity. Greater cognitive impairment was associated with higher ratios of layer pathology in FTLD-tau (p = 0.018), but was not related to ratios of layer pathology in FTLD-TDP. Lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology are proteinopathy-specific, regardless of clinical syndromes or regional networks that define these syndromes. Thus, patterns of laminar change may provide a useful anatomical framework for investigating how degeneration of select cells and corresponding laminar circuits influence large-scale networks and clinical symptomology in FTLD., (© 2022. The Author(s).)

Objectives: Social isolation among older adults with cognitive impairment is understudied. The purpose of this study is to examine the relationship between social isolation and anxiety in people with cognitive impairment in the United States., Methods/design: Secondary data analyses were conducted using the National Social Life, Health, and Aging Project (NSHAP) Wave 2 (2010-2011) dataset which includes a nationally representative sample of American older adults living at home. A total of 1343 people who had probable cognitive impairment measured by a Montreal Cognitive Assessment (MoCA) score of 22 or less were selected. Anxiety was measured using the anxiety measure of Hospital Anxiety and Depression Scale (HADS-A) and social isolation was measured using Perceived Social Isolation Scale. A weighted multivariable linear regression analysis and weighted F tests were used to examine the relationship between social isolation and anxiety., Results: We observed that greater social isolation was related to increased anxiety in people with cognitive impairment (coefficients = 0.7242, t = 2.51, p = 0.015), adjusting for severity of cognitive impairment, race, pain, depression, activities of daily living, and instrumental activities of daily living. Weighted F tests showed that persons with clinically significant anxiety (HADS-A ≥ 8) had higher levels of loneliness, including feeling a lack of companionship, feeling left out, and greater social isolation., Conclusions: The results of our study suggest that people with cognitive impairment can feel social isolation and it may contribute to their anxiety. Health care professionals, family, and friends of people with cognitive impairment should pay greater attention to social isolation of their loved ones., (© 2022 John Wiley & Sons Ltd.)

The T allele in rs1768208 located in or near the myelin oligodendrocyte basic protein gene (MOBP) is a risk factor for frontotemporal degeneration pathology. We evaluated the hypothesis that the presence of a T allele in rs1768208 will be associated with rate of cognitive decline in behavioral variant frontotemporal degeneration (bvFTD) related to compromised frontal networks. We studied 81 individuals clinically diagnosed with bvFTD who were genotyped for rs1768208 and coded using a dominant model reflecting the presence (i.e., MOBP +) or absence (MOBP -) of the T risk allele. Linear mixed-effects models assessed the association of genotype on neuropsychological performance over time. Regression analyses examined differences in network structure by MOBP genotype. We found a genotype by time interaction for declining cognitive performance, whereby MOBP + individuals demonstrated faster rates of decline in executive function. The presence of a MOBP risk allele was associated with degradation of white matter network features in the frontal lobe. These findings suggest that individual genetic variation may contribute to heterogeneity in clinical progression., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau. While Gosuranemab passive immunotherapy trials for PSP failed to demonstrate clinical benefit, Gosuranemab reduced N-terminal tau in the cerebrospinal fluid of transgenic mouse models and PSP patients. However, the neuropathologic sequelae of Gosuranemab have not been described. In this present study, we examined the brain tissue of three individuals who received Gosuranemab. Post-mortem human brain tissues were studied using immunohistochemistry to identify astrocytic and microglial differences between immunized cases and a cohort of unimmunized PSP, CBD and aging controls. Gosuranemab immunotherapy was not associated with clearance of neuropathologic FTLD-tau inclusions. However, treatment-associated changes were observed including the presence of perivascular vesicular astrocytes (PVA) with tau accumulation within lysosomes. PVAs were morphologically and immunophenotypically distinct from the tufted astrocytes seen in PSP, granular fuzzy astrocytes (GFA) seen in aging, and astrocytic plaques seen in CBD. Additional glial responses included increased reactive gliosis consisting of bushy astrocytosis and accumulation of rod microglia. Together, these neuropathologic findings suggest that Gosuranemab may be associated with a glial response including accumulation of tau within astrocytic lysosomes., (© 2021. The Author(s).)

Objective: Accurate diagnosis and prognosis of frontotemporal lobar degeneration (FTLD) during life is an urgent concern in the context of emerging disease-modifying treatment trials. Few CSF markers have been validated longitudinally in patients with known pathology, and we hypothesized that CSF neurofilament light chain (NfL) would be associated with longitudinal cognitive decline in patients with known FTLD-TAR DNA binding protein ~43kD (TDP) pathology., Methods: This case-control study evaluated CSF NfL, total tau, phosphorylated tau, and β-amyloid 1-42 in patients with known FTLD-tau or FTLD-TDP pathology (n = 50) and healthy controls (n = 65) and an extended cohort of clinically diagnosed patients with likely FTLD-tau or FTLD-TDP (n = 148). Regression analyses related CSF analytes to longitudinal cognitive decline (follow-up ∼1 year), controlling for demographic variables and core AD CSF analytes., Results: In FTLD-TDP with known pathology, CSF NfL is significantly elevated compared with controls and significantly associated with longitudinal decline on specific executive and language measures, after controlling for age, disease duration, and core AD CSF analytes. Similar findings are found in the extended cohort, also including clinically identified likely FTLD-TDP. Although CSF NfL is elevated in FTLD-tau compared with controls, the association between NfL and longitudinal cognitive decline is limited to executive measures., Conclusion: CSF NfL is associated with longitudinal clinical decline in relevant cognitive domains in patients with FTLD-TDP after controlling for demographic factors and core AD CSF analytes and may also be related to longitudinal decline in executive functioning in FTLD-tau., (© 2020 American Academy of Neurology.)

We implemented an automated analysis of lexical aspects of semi-structured speech produced by healthy elderly controls (n = 37) and three patient groups with frontotemporal degeneration (FTD): behavioral variant FTD (n = 74), semantic variant primary progressive aphasia (svPPA, n = 42), and nonfluent/agrammatic PPA (naPPA, n = 22). Based on previous findings, we hypothesized that the three patient groups and controls would differ in the counts of part-of-speech (POS) categories and several lexical measures. With a natural language processing program, we automatically tagged POS categories of all words produced during a picture description task. We further counted the number of wh-words, and we rated nouns for abstractness, ambiguity, frequency, familiarity, and age of acquisition. We also computed the cross-entropy estimation, where low cross-entropy indicates high predictability, and lexical diversity for each description. We validated a subset of the POS data that were automatically tagged with the Google Universal POS scheme using gold-standard POS data tagged by a linguist, and we found that the POS categories from our automated methods were more than 90% accurate. For svPPA patients, we found fewer unique nouns than in naPPA and more pronouns and wh-words than in the other groups. We also found high abstractness, ambiguity, frequency, and familiarity for nouns and the lowest cross-entropy estimation among all groups. These measures were associated with cortical thinning in the left temporal lobe. In naPPA patients, we found increased speech errors and partial words compared to controls, and these impairments were associated with cortical thinning in the left middle frontal gyrus. bvFTD patients' adjective production was decreased compared to controls and was correlated with their apathy scores. Their adjective production was associated with cortical thinning in the dorsolateral frontal and orbitofrontal gyri. Our results demonstrate distinct language profiles in subgroups of FTD patients and validate our automated method of analyzing FTD patients' speech., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Frontotemporal lobar degeneration proteinopathies with tau inclusions (FTLD-Tau) or TDP-43 inclusions (FTLD-TDP) are associated with clinically similar phenotypes. However, these disparate proteinopathies likely differ in cellular severity and regional distribution of inclusions in white matter (WM) and adjacent grey matter (GM), which have been understudied. We performed a neuropathological study of subcortical WM and adjacent GM in a large autopsy cohort (n = 92; FTLD-Tau = 37, FTLD-TDP = 55) using a validated digital image approach. The antemortem clinical phenotype was behavioral-variant frontotemporal dementia (bvFTD) in 23 patients with FTLD-Tau and 42 with FTLD-TDP, and primary progressive aphasia (PPA) in 14 patients with FTLD-Tau and 13 with FTLD-TDP. We used linear mixed-effects models to: (1) compare WM pathology burden between proteinopathies; (2) investigate the relationship between WM pathology burden and WM degeneration using luxol fast blue (LFB) myelin staining; (3) study regional patterns of pathology burden in clinico-pathological groups. WM pathology burden was greater in FTLD-Tau compared to FTLD-TDP across regions (beta = 4.21, SE = 0.34, p < 0.001), and correlated with the degree of WM degeneration in both FTLD-Tau (beta = 0.32, SE = 0.10, p = 0.002) and FTLD-TDP (beta = 0.40, SE = 0.08, p < 0.001). WM degeneration was greater in FTLD-Tau than FTLD-TDP particularly in middle-frontal and anterior cingulate regions (p < 0.05). Distinct regional patterns of WM and GM inclusions characterized FTLD-Tau and FTLD-TDP proteinopathies, and associated in part with clinical phenotype. In FTLD-Tau, WM pathology was particularly severe in the dorsolateral frontal cortex in nonfluent-variant PPA, and GM pathology in dorsolateral and paralimbic frontal regions with some variation across tauopathies. Differently, FTLD-TDP had little WM regional variability, but showed severe GM pathology burden in ventromedial prefrontal regions in both bvFTD and PPA. To conclude, FTLD-Tau and FTLD-TDP proteinopathies have distinct severity and regional distribution of WM and GM pathology, which may impact their clinical presentation, with overall greater severity of WM pathology as a distinguishing feature of tauopathies.

Objective: Cognitive reserve is a concept that explains individual differences in resilience to brain pathology and susceptibility to poor late-life cognitive outcomes. We evaluate the analogous concept of "Functional Reserve," defined as the difference between observed functional abilities and those predicted by brain structure, cognitive performance, and demographics. This study aims to validate the construct of functional reserve by testing its utility in predicting clinical outcomes and exploring its predictors., Method: Longitudinal data collected annually for up to 7 years from 1,084 older adults (ndementia = 163; nMCI = 333; nCN = 523) were analyzed. Functional reserve was operationalized as the residual variance in the Lawton-Brody Instrumental Activities of Daily Living (IADL) Scale after accounting for demographics (sex/gender, race, ethnicity, education), neuropathology (gray matter, hippocampal, and white matter hyperintensity volumes), and cognition (executive function, verbal episodic memory, semantic memory, and spatial function). Structural equation models estimated (a) functional reserve's associations with 7-year changes in clinical diagnosis and disease severity and (b) predictors of functional reserve., Results: Functional reserve was lower in dementia versus cognitively normal individuals. Higher baseline functional reserve was associated with lower concurrent dementia severity and slower clinical progression and attenuated the association of cognition with concurrent dementia severity. Physical function and apathy were the strongest predictors of functional reserve., Conclusions: Results provide preliminary validation of functional reserve for explaining individual differences in susceptibility to IADL dysfunction independent of neuropathology, cognition, and demographics. Physical functioning and apathy are promising modifiable intervention targets to enhance functional reserve in the context of brain atrophy and cognitive decline. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Behavioral variant frontotemporal degeneration (bvFTD) is clinically characterized by progressive decline in social and executive domains. Previous work suggests that early lifestyle factors such as education and occupational attainment may relate to structural integrity and moderate the rate of cognitive decline in bvFTD, but the role of other cognitively stimulating activities is understudied. We sought to investigate the effect of such activities on cortical thickness (CT) in bvFTD. bvFTD patients (n = 31) completed a baseline MRI scan, and informants for the patients completed the Lifetime of Experiences Questionnaire (LEQ), which measures specific activities considered to be undertaken primarily within one particular life phase, such as education (young-life), occupation (mid-life), and social/leisure activity (late-life). At baseline, linear models assessed the effect of LEQ scores from each life phase on regional CT. A subset (n = 19) of patients completed longitudinal MRI, and to evaluate the association of LEQ with longitudinal rates of CT decline, we derived individualized slopes of decline using linear mixed effects models and these were related to LEQ scores from each life phase. At baseline, a higher late-life LEQ score was associated with less atrophy in left superior and inferior anterior temporal regions as well as right middle temporal gyrus. Longitudinally, we observed that higher late-life LEQ scores were associated with an attenuated rate of CT loss in insular cortex. Late-life LEQ score was positively associated with both relatively preserved CT early in bvFTD and a slower rate of cortical loss in regions important for social functioning. These findings suggest that social and leisure activities may contribute to a form of resilience against pathologic effects of disease., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Neurodegeneration in Alzheimer's disease (AD) is closely associated with the accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in VCP (valosin-containing protein) was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro, which was impaired by the p.Asp395Gly mutation. Additionally, intracerebral microinjection of pathologic tau led to increased tau aggregates in mice in which p.Asp395Gly VCP mice was knocked in, as compared with injected wild-type mice. These findings suggest that p.Asp395Gly VCP is an autosomal-dominant genetic mutation associated with neurofibrillary degeneration in part owing to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

We implemented an automated analysis of lexical aspects of semi-structured speech produced by healthy elderly controls (n=37) and three patient groups with frontotemporal degeneration (FTD): behavioral variant FTD (n=74), semantic variant primary progressive aphasia (svPPA, n=42), and nonfluent/agrammatic PPA (naPPA, n=22). Based on previous findings, we hypothesized that the three patient groups and controls would differ in the counts of part-of-speech (POS) categories and several lexical measures. With a natural language processing program, we automatically tagged POS categories of all words produced during a picture description task. We further counted the number of wh -words, and we rated nouns for abstractness, ambiguity, frequency, familiarity, and age of acquisition. We also computed the cross-entropy estimation, which is a measure of word predictability, and lexical diversity for each description. We validated a subset of the POS data that were automatically tagged with the Google Universal POS scheme using gold-standard POS data tagged by a linguist, and we found that the POS categories from our automated methods were more than 90% accurate. For svPPA patients, we found fewer unique nouns than in naPPA and more pronouns and wh -words than in the other groups. We also found high abstractness, ambiguity, frequency, and familiarity for nouns and the lowest cross-entropy estimation among all groups. These measures were associated with cortical thinning in the left temporal lobe. In naPPA patients, we found increased speech errors and partial words compared to controls, and these impairments were associated with cortical thinning in the left middle frontal gyrus. bvFTD patients' adjective production was decreased compared to controls and was correlated with their apathy scores. Their adjective production was associated with cortical thinning in the dorsolateral frontal and orbitofrontal gyri. Our results demonstrate distinct language profiles in subgroups of FTD patients and validate our automated method of analyzing FTD patients' speech.