Bayram, Ece

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.

AbstractINTRODUCTIONMales are disproportionately represented in dementia with Lewy bodies (DLB). Little is known regarding sex differences in cognitive, neuropsychiatric, and motor features of the prodromal stage of DLB.METHODSWe used National Alzheimer's Coordinating Center longitudinal data to examine cognitive, neuropsychiatric, and motor features in 120 males and 23 females 2 years prior to a clinical diagnosis of DLB.RESULTSMales were more likely than females to present with two or more core DLB clinical features 2 years prior to obtaining a diagnosis of dementia. Rapid eye movement sleep behavior disorder, cognitive fluctuations, bradykinesia, and rigidity were more common in males than females. Neuropsychological test performance was similar between groups.DISCUSSIONIn prodromal DLB, males exhibit a greater number of core features than females. Core DLB features may fall short in identifying females at risk. Additional work is needed to better understand the clinical profile of prodromal DLB in females.Highlights There are sex differences in the presentation and course of neurodegenerative disease. Findings from the National Alzheimer's Coordinating Center Uniform Data Set suggest there are sex differences in prodromal DLB symptoms. Females were less likely to demonstrate core clinical features of DLB prior to dementia diagnosis. This information can help inform clinical diagnostic criteria for prodromal DLB.

AbstractINTRODUCTIONHigher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females.METHODSWe included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex.RESULTSFemales with sporadic bvFTD showed worse compulsive behavior (p = 0.026) and language impairments (p = 0.024) compared to females with genetic bvFTD (n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe.DISCUSSIONFemales with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation.Highlights Sex ratio is equal in genetic behavioral variant of frontotemporal dementia (bvFTD), whereas more males are present in sporadic bvFTD. Distinct neuropsychiatric phenotypes exist between sporadic and genetic bvFTD in females. Phenotype might explain the sex ratio difference between sporadic and genetic cases.

Abstract INTRODUCTION Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. DISCUSSION In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations. Highlights Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

AbstractIntroductionClinicopathological correlations differ by sex in Lewy body dementia (LBD). However, previous studies have focused on pathological staging systems that place less emphasis on regional pathologies.MethodsWe included 357 people (131 female, 226 male) with a high likelihood of LBD based on pathology from the Brain Bank for Neurodegenerative (Jacksonville, FL). Sex differences for regional Lewy body, senile plaque, and neurofibrillary tangle counts and their associations with clinical LBD diagnosis were assessed.ResultsFemales were less likely to have a clinical LBD diagnosis; they had more Lewy bodies, neurofibrillary tangles, and senile plaques in various regions than males (all p’s < 0.05). A higher likelihood of clinical LBD diagnosis was associated with more middle frontal, cingulate, and entorhinal Lewy body pathology, and more so for males than for females (all p’s < 0.045).DiscussionSex differences for clinicopathological correlations in LBD also occur at the regional pathology level. Females have a higher frequency of clinical misdiagnosis than males.Highlights Females have a higher risk of clinical underdiagnosis for Lewy body dementia (LBD) than males. Regional pathology counts differ by sex for people with a high likelihood of LBD. Regional pathology association with clinical LBD diagnosis differs by sex. Regional Lewy body counts have a stronger association with LBD phenotype for males.

Abstract BACKGROUND We sought to characterize the cognitive profile among individuals with mild cognitive impairment with Lewy bodies (MCI‐LB) to help guide future clinical criteria. METHODS Systematic review and meta‐analysis included MCI‐LB studies with cognitive data from PubMed, Embase, Web of Science, and PsycINFO (January 1990 to March 2023). MCI‐LB scores were compared to controls, MCI due to Alzheimer's disease (MCI‐AD), and dementia with Lewy bodies (DLB) groups with random‐effects models. RESULTS We included 26 studies and 2823 participants. Across all domains, the MCI‐LB group performed worse than controls and better than DLB. Compared to MCI‐AD, the MCI‐LB group performed worse in attention/processing speed ( g = –0.24, 95% confidence interval [CI]: –0.35, –0.12), attention/executive ( g = –0.42, 95% CI: –0.56, –0.28); better in verbal immediate recall ( g = 0.37; 95% CI: 0.15, 0.59) and delayed memory ( g = 0.40; 95% CI: 0.22, 0.58). DISCUSSION The cognitive profiles in MCI‐LB and MCI‐AD are consistent with established profiles in DLB and AD. Neuropsychological assessment may be helpful in differential diagnosis, even in early disease states. Highlights We performed a systematic review and meta‐analysis for cognition in mild cognitive impairment with Lewy bodies (MCI‐LB). Compared to MCI due to Alzheimer's disease (MCI‐AD), MCI‐LB had worse attention, executive function, and processing speed. Compared to MCI‐AD, MCI‐LB had better verbal immediate and delayed recall. The MCI‐LB group was worse on all cognitive domains than controls, and better than dementia with Lewy bodies. Studies used different tests and there is a need for global efforts for harmonization.

AbstractBackgroundProdromal dementia with Lewy bodies (DLB) research criteria were recently published and further work is needed to characterize the neuropsychological profile and refine clinical criteria. We performed a meta‐analysis to compare the cognitive performance of mild cognitive impairment with Lewy bodies (MCI‐LB) groups to controls, MCI due to Alzheimer’s disease (MCI‐AD), and DLB.MethodFollowing PRISMA guidelines, we searched the literature for 1) English‐language studies on MCI‐LB; 2) published January 1990‐March 2023, 3) with ≥1 standardized cognitive measure; and 4) comparison data from controls, MCI‐AD, and/or DLB. Pooled means with 95% confidence intervals were calculated for demographics. Effect sizes were calculated for group comparisons on cognitive domains. Random effects meta‐analysis models were used for group comparisons.ResultThere were 3440 participants from 27 studies across 10 countries. Mean age did not differ between groups. The percentage of female subjects was lower in the MCI‐LB group than the MCI‐AD group. Mean years of education for the MCI‐LB group was lower than the controls, but similar to MCI‐AD and DLB groups (Table 1). Compared to controls, the MCI‐LB group had lower scores for the global screening, executive function, visuospatial, language, learning, and memory domains. Compared to MCI‐AD, MCI‐LB performed better on learning and delayed recall, but similarly across other domains. Compared to DLB, MCI‐LB had better scores for global screening, executive function, language, and delayed recall (Table 2). Recognition for MCI‐LB vs. MCI‐AD; visuospatial, learning, and recognition for MCI‐LB vs. DLB could not be assessed, as fewer than 3 studies reported this data.ConclusionCognitive measures can help differentiate MCI‐LB from controls and DLB. Neuropsychological measures of learning and memory may be required to discriminate MCI‐LB from MCI‐AD in clinical practice but global screening measure scores appear insufficient in this regard. High heterogeneity across MCI‐LB studies highlights the need for harmonized neuropsychological research protocols.

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

AbstractDespite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public‐health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public‐domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor.Highlights A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.