Brushaber, Danielle

Importance TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown. Objective To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD. Design, Setting, and Participants This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72 , GRN , or MAPT ; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls. Exposures CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]). Main Outcomes and Measures Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume. Results In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, −0.15; 95% CI, −0.24 to −0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P < .001), and faster clinical progression (β, −2.21; 95% CI, −3.70 to −0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD. Conclusions and Relevance Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.

ABSTRACT Background and Objectives Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm 3 , SE=317.0, p= 0.0046, f 2 =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm 3 , SE=29.9, p= 0.035, f 2 =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

Background Converging evidence hints at neurodevelopmental effects in people at risk of genetic frontotemporal dementia (FTD). Objective We investigated total intracranial volume (TIV), a neuroimaging marker of neurodevelopment, and years of education differences between adult mutation carriers and familial non-mutation carriers, as measures of the structural and functional neurodevelopmental effects of FTD-causing genetic mutations. Methods This cross-sectional cohort study, facilitated through the FTD Prevention Initiative (FPI), included 902 adult pathogenic mutation carriers of GRN , MAPT , or C9orf72 , and 532 familial non-carriers. ANCOVAs were computed to compare TIV and education between groups per gene. Pearson's correlations were used to examine associations between TIV and education. Results Mutation carriers (mean ± SD age = 50.0 ± 13.2 years, sex = 55% female, n ( GRN ) = 298, n( MAPT ) = 187, n ( C9orf72 ) = 417) were compared to familial non-carriers (age = 48.0 ± 12.9 years, sex = 58% female, n ( GRN ) = 201, n( MAPT ) = 114), n ( C9orf72 ) = 217). Consistent with prior findings in young adults, GRN carriers showed larger TIV, on average by 20531 mm 3 , compared to familial non-carriers (95% CI [85.4, 40977], p = 0.049, η 2 p = 0.008). Larger TIV correlated with higher years of education in GRN carriers (95% CI [0.01, 0.24], r (295) = 0.12, p = 0.03) and GRN non-carriers (95% CI [0.08, 0.34], r(198) = 0.21, p = 0.002). MAPT carriers demonstrated smaller TIV than non-carriers, on average by 29896 mm 3 (95% CI [–58248, −1545], p = 0.039, η 2 p = 0.02). Models with C9orf72 and education as outcome variables did not reveal significant differences. Conclusions In support of the neurodevelopmental hypothesis of FTD, GRN and MAPT mutations are linked to structural neurodevelopmental changes in TIV. Further research is needed to identify mechanisms underlying neurodevelopmental influences of FTD mutations and ascertain their suitability as intervention targets.

AbstractBackgroundAs new anti‐amyloid immunotherapies emerge for Alzheimer’s disease (AD), it is clear that early diagnosis of AD pathology is crucial for treatment success. This can be challenging in atypical presentations of AD and, together with our reliance on CSF or PET scans, can, at times, lead to delayed diagnosis. Here, we further explore the possible role of plasma tau phosphorylated at threonine 217 (P‐tau217) for the detection of primary AD or AD co‐pathology when frontotemporal dementia spectrum disorders are the main clinical presentation.MethodParticipants were recruited through ALLFTD, a North American multisite research consortium for the longitudinal assessment of frontotemporal lobar degeneration. After excluding cases with known FTD‐causing mutations, 573 participants with sporadic disease, mild cognitive/behavioral impairment, or healthy familial controls evaluated between 2014 and 2023 were included in this analysis (45.8% female, median age 66 years). 39 of those cases underwent neuropathological evaluation. Plasma P‐tau217 was measured with the Eli Lilly electrochemiluminescence‐based assay. P‐tau217 concentrations were compared by phenotype, disease severity, genotype, and, when available, neuropathological diagnosis with non‐parametric tests. Its diagnostic performance was tested with ROC curves. Associations between plasma P‐tau217 concentrations and clinical scales of global cognition, memory, executive function, motor function, and social cognition with linear regressions and non‐parametric tests.ResultPlasma P‐tau217 concentrations were higher in logopenic variant primary progressive aphasia (lvPPA) and amnestic dementia (AmDem), compared to participants with normal cognition or other FTD phenotypes. P‐tau217 concentrations were higher in APOE e4 carriers, compared to non‐carriers, regardless of phenotype, but were not affected by disease severity. P‐tau217 concentrations showed associations with clinical measures of global cognition, memory, and executive function, but had no associations with measures of motor function or social cognition. Plasma P‐tau217 concentrations were elevated in high and intermediate ADNC scoring, or more advanced Braak stages, even when AD was not the primary pathology.ConclusionEven when FTD is suspected, high plasma p‐tau 217 concentrations are strongly associated with underlying AD as primary pathology or contributing co‐pathology. Plasma P‐tau217 could be a tool to support the development of disease‐modifying therapies for atypical Alzheimer’s disease presentations or for FTD cases with Alzheimer’s disease co‐pathology.

AbstractBackgroundThe ALLFTD (ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration) study is an NIH‐funded effort to prepare for clinical trials in sporadic (s‐FTLD) and familial (f‐FTLD) FTLD syndromes by characterizing cohorts, developing new clinical trial outcome measures, and evaluating disease progression. To understand disease trajectories in the context of potential preventative or disease‐modifying therapeutic agents, comprehensive evaluation across multiple time‐points is crucial.MethodALLFTD evaluates participants with FTLD spectrum disorders (bvFTD, svPPA, nfvPPA, FTD‐ALS, CBS, PSP), with strong family histories of FTLD, or known FTLD‐associated genetic variants within the family. ALLFTD has expanded to include 28 expert sites in North America conducting clinical and neuropsychological evaluations, MR Imaging, blood draws, and CSF collection in willing participants, providing detailed data on participant status and disease progression. Participants are asked to return for annual evaluations. The central data management staff assist sites in retention efforts by providing monthly reports of follow‐up visits that are pending, due, or overdue, based on a 15‐month period from previous visit.ResultSince enrollment began in January 2020, ALLFTD has conducted 1363 baseline visits, including 339 participants previously enrolled in ALLFTD’s predecessor studies (ARTFL and LEFFTDS). Excluding individuals not anticipated to return due to disease progression (123), participant death (55), or recent enrollment (<15 months; 318), ALLFTD has a retention rate of 83% for a second visit despite early enrollment occurring during COVID restrictions. Retention rates for third and fourth visits are even higher (90% and 97% respectively), suggesting a high degree of engagement in longitudinal participants. Including historic data from ARTFL and LEFFTDS, >1000 participants have multiple visits.ConclusionLongitudinal assessment of clinical and biomarker profiles in f‐FTLD and s‐FTLD can inform models of disease onset and progression, allowing analysis of disease trajectories and identification of the most sensitive clinical outcome measures over time. ALLFTD has been successful at recruiting and retaining a large active cohort to obtain detailed clinical and biomarker characterizations; data are available by request.

Introduction Surgical site infections (SSI) continue to be a risk associated with surgery. The Centers for Disease Control (CDC) uses surgical wound class (SWC) to predict SSI postoperatively. Prior studies have shown that the current wound class definitions are unreliable for surgical subspecialties. Therefore, an alternative surgical wound classification (ASWC) was created to more accurately reflect risk of SSI following orthopedic procedures. The purpose of this study was to compare the two systems. Methods Seventy patients who developed 90-day SSI following total joint arthroplasty (TJA) were matched 1:1 to patients without postoperative SSI. The SWC was recorded from operative reports. Wounds were then retrospectively reclassified according to the ASWC based on preoperative history from the medical record. The degree of agreement and degree of association with occurrence of SSI was compared between the two systems. Results The proportion of agreement between the systems was poor (41.4%). The current SWC was associated with risk of SSI in both unadjusted (p=0.045) and multivariable analysis (p=0.050). Comparatively, the ASWC demonstrated a stronger association with SSI in both unadjusted (p=0.001) and multivariable analysis (p=0.001). Conclusion The results of this study suggest that the ASWC is more predictive for SSI following TJA than the current SWC definitions for total joint arthroplasty.

Abstract Purpose This study examines sense of belonging (belongingness) in a large population of medical students, residents, and fellows and associations with learner burnout, organizational recruitment retention indicators, and potentially modifiable learning environment factors. Method All medical students, residents, and fellows at Mayo Clinic sites were surveyed between October and November 2020 with items measuring sense of belonging in 3 contexts (school or program, organization, surrounding community), burnout (2 Maslach Burnout Inventory items), recruitment retention indicators (likelihood of recommending the organization and accepting a job offer), potentially modifiable learning environment factors, and demographics (age, gender, race and ethnicity, LGBTQ+ identification, disability, socioeconomic background). Results Of 2,257 learners surveyed, 1,261 (56%) responded. The percentage of learners reporting a somewhat or very strong sense of belonging was highest in the school or program (994 of 1,227 [81%]) followed by the organization (957 of 1,222 [78%]) and surrounding community (728 of 1,203 [61%]). In adjusted analyses, learners with very strong organization belongingness had lower odds of burnout (odds ratio [OR], 0.05; 95% CI, 0.02–0.12) and higher odds of being likely to recommend the organization (OR, 505.23; 95% CI, 121.54–2,100.18) and accept a job offer (OR, 38.68; 95% CI, 15.72–95.15; all P &lt; .001). School or program and community belongingness also correlated strongly with these outcomes. In multivariable analyses, social support remained associated with higher odds of belongingness in all 3 contexts; favorable ratings of faculty relationships and leadership representation remained associated with higher odds of belongingness in 2 contexts (school or program and organization); and favorable ratings of diversity, equity, and inclusion learning climate remained associated with belongingness in 1 context (community). Conclusions Sense of belonging among medical students, residents, and fellows varies across contexts, correlates strongly with burnout and organizational recruitment retention indicators, and is associated with multiple potentially modifiable learning environment factors.

Abstract Purpose To examine graduating medical student reports of burnout by sex, race and ethnicity, and sexual orientation and explore trends within intersectional demographic groups from 2019–2021 in a national sample. Method The authors obtained medical student responses to the 2019–2021 Association of American Medical Colleges (AAMC) Graduation Questionnaires (GQs) linked to data from other AAMC sources. The dataset included year of GQ completion, responses to a modified Oldenburg Burnout Inventory (exhaustion subscale range: 0–24; disengagement subscale range: 0–15), and demographics previously shown to relate to the risk of burnout in medical students, residents, or physicians. Multivariable linear regression analysis was performed to evaluate independent associations between demographics and burnout. Results Overall response rate was 80.7%. After controlling for other factors, mean exhaustion scores were higher among Asian (parameter estimate [PE] 0.38, 95% confidence interval [CI] 0.21, 0.54), bisexual (PE 0.97, 95% CI 0.76, 1.17), and gay or lesbian (PE 0.55, 95% CI 0.35, 0.75) students than those who did not identify with each of those respective groups. Mean disengagement scores were lower among female (PE −0.47, 95% CI −0.52, −0.42), Hispanic (PE −0.11, 95% CI −0.22, −0.01), and White (PE −0.10, 95% CI −0.19, 0.00) students and higher among Asian (PE 0.17, 95% CI 0.07, 0.27), Black or African American (PE 0.31, 95% CI 0.18, 0.44), bisexual (PE 0.54, 95% CI 0.41, 0.66), and gay or lesbian (PE 0.23, 95% CI 0.11, 0.35) students than those who did not identify with each of those respective groups. From 2019–2021, mean exhaustion and disengagement scores were relatively stable or improved across nearly all intersectional groups. Conclusions Male, Asian, Black or African American, and sexual minority students had a higher risk of burnout, while female, Hispanic, White, and heterosexual or straight students had a lower risk of burnout.