BACKGROUND AND OBJECTIVES:Patients with antibody-associated movement disorders sometimes lack specific features of autoimmune diseases and can therefore be misdiagnosed, for example, as neurodegenerative diseases. A well-known example is anti-IgLON5 disease, which may mimic atypical parkinsonian (AP) syndromes. Our objectives were (1) to test different cohorts of patients with suspected AP for anti-IgLON5 and other neuronal antibodies and (2) to describe the characteristics of AP in anti-IgLON5 disease. METHODS:We performed a retrospective observational cohort study in which we screened 5 cohorts of patients with AP syndromes for antibodies by immunohistochemistry. Positive results were evaluated with additional techniques including human live neurons. We also reviewed all Dutch patients with anti-IgLON5 disease for parkinsonian features. RESULTS:We identified 719 patients with AP syndromes, of which 532 had available serum or CSF. Seven (1.3%) had antibody-associated disorders (2 anti-IgLON5, 1 anti-IgLON5/anti-NMDAR, 1 anti-Caspr2, 1 anti-CV2, 1 anti-Hu, and 1 anti-CV2/anti-Hu). All but 1 of these patients were already suspected of an autoimmune cause.Furthermore, we identified 30 Dutch patients with anti-IgLON5 disease. Twelve (40%) had AP features, but 11 of the 12 patients also had additional features that differentiated them from classical AP (prominent sleep apnea in 10, neuromuscular symptoms in 6, and chorea in 3). The phenotype of the last patient was clinically indistinguishable from idiopathic Parkinson disease (with probable concurrent mild anti-IgLON5 disease). We also found 8 patient cases falsely identified as anti-IgLON5 positive using a commercial cell-based assay. DISCUSSION:Routine testing for anti-IgLON5 or other neuronal antibodies in AP is not recommended. Rather, careful clinical phenotyping is essential to uncover additional features that might suggest an underlying antibody-associated disease in selected patient cases.

Prior research on genetic frontotemporal dementia (FTD) has examined the psychological impact of predictive testing, leaving other effects of genetic awareness largely unexplored. This study examined whether genetic awareness is associated with cognitive, behavioral, and neuropsychiatric outcomes in individuals from genetic FTD families. From a longitudinal genetic cohort study, we included 228 individuals (age 18–70 years) from families with different underlying pathogenic variants. 99 individuals were aware of their genetic status, of which 75 pathogenic variant carriers and 24 non-carriers. 129 individuals were unaware of their genetic status, of which 56 carriers and 73 non-carriers. 26 individuals became aware of their genetic status mid-study. We compared baseline and longitudinal cognitive, behavioral, and neuropsychiatric outcomes between the aware and unaware groups, and explored differences in longitudinal slopes before and after becoming aware of the genetic status. Cross-sectionally, genetic awareness is associated with the anxiety subdomain of the NPI-Q, but not after FDR correction. Longitudinally, awareness of genetic status was associated with decline in verbal learning, recall, and semantic fluency in carriers. Non-carriers who learned their status mid-study reported fewer depressive symptoms post-disclosure, but depressive symptoms increased over time. Awareness of genetic status is associated with faster cognitive decline and greater behavioral and neuropsychiatric symptoms in aware carriers of FTD variants. These findings suggest that genetic awareness is an important factor to consider during personalized guidance and monitoring in clinical trials. Future studies should aim for larger sample sizes to further explore potential effects in genetic subgroups.

Iron accumulation is known to be involved in frontotemporal lobar degeneration (FTLD) and possibly with a different spatial pattern in FTLD with tau (FTLD-tau) versus TDP-43 (FTLD-TDP) pathology. In this study, we aimed to visualize the spatial distribution of iron in ex vivo brain tissue with FTLD and healthy controls using both histology and MRI. High resolution multi-echo T2*-weighted 7T MRI was performed on ex vivo tissue of the frontal and temporal cortex of 14 FTLD cases (6 FTLD-tau, 8 FTLD-TDP) and 11 healthy controls (HC) to obtain T2*-weighted images and quantitative susceptibility maps (QSM). These tissue blocks were then stained for iron. The spatial iron distribution was assessed visually by different scoring features on the three modalities (T2*-weighted MRI, QSM, and histology) and analyzing cortical layer profiles of the signal intensity. We found more iron accumulation in the temporal cortex of FTLD cases compared to HC, displayed by higher visual ratings and lower signal intensity values on cortical layer profiles. Histology showed a good correlation with T2*-weighted MRI. QSM offered complementary information compared to T2*-weighted MRI, particularly for identifying distinct histological features of iron accumulation within the subcortical U-fibers. We conclude that iron accumulation is involved in the disease process of FTLD and that T2*-weighted MRI and QSM can be used as a noninvasive imaging modality to study cortical and subcortical iron accumulation in FTLD.

Abstract BACKGROUND Previous studies have demonstrated impaired expressive prosody in patients with frontotemporal dementia (FTD), but have been conducted in English‐speaking cohorts. To examine whether findings generalize across languages, we replicated prior work in Dutch patients. METHODS We examined expressive prosodic features in semi‐structured speech samples from patients with behavioral variant FTD (bvFTD; n = 17), primary progressive aphasia (PPA; n = 74) and controls (n = 45). We assessed group differences, classification abilities, and associations with neuropsychological tests and gray matter volume. RESULTS Patients with non‐fluent variant PPA (nfvPPA) showed the narrowest f0 range and shortest speech duration. f0 range separated patients with reduced prosody (nfvPPA/bvFTD) from those with relatively preserved prosody (semantic variant PPA/logopenic variant PPA). Lower f0 range correlated with reduced fluency and frontotemporal atrophy. DISCUSSION Viewing expressive prosody as a multidimensional system helps explain why FTD syndromes become dysprosodic in different ways and highlights its diagnostic relevance. Future studies with larger patient samples in less canonical subtypes are needed to replicate and extend our findings.

Introduction Frontotemporal lobar degeneration (FTLD) is the second most common early-onset dementia. Several studies demonstrated that neuroinflammation and iron accumulation occur in FTLD. However, the timing and relevance of these processes and whether these two are merely cause or consequence remains unclear. Elucidating the role is crucial to assess the rationale for using anti-inflammatory therapies in FTLD. Additionally, the process of glymphatic brain clearance has gained attention as a potential contributor in the disease pathophysiology.Methods and analysis In this multimodal biomarker study, we use a combination of ultra-high field (7T) MR, blood and cerebrospinal fluid (CSF) biomarkers to investigate the role of neuroinflammation, iron accumulation and brain clearance in FTLD, and to identify biomarkers to differentiate FTLD-TDP from FTLD-tau. We aim to include 25 patients with probable FTLD-tau, 25 with probable FTLD-TDP and 50 healthy individuals with 50% risk to develop FTLD. We will use several MRI techniques, including magnetic resonance spectroscopy, diffusion weighted spectroscopy and quantitative susceptibility mapping. In addition, we will assess the prevalence of perivascular spaces (PVS) and the mobility of CSF to address glymphatic brain clearance. We will compare quantitative MR markers between patients with FTLD-tau and FTLD-TDP, presymptomatic mutation carriers and healthy controls, and correlate these measures with clinical data and biomarkers in blood and CSF.Ethics and dissemination We obtained ethical approval from the Medical Ethics Committee Leiden Den Haag Delft (NL78272.058.21). The results will be disseminated through presentations at national and international conferences, open-access peer-reviewed publications, ClinicalTrials.gov and to the public through social media posts and annual newsletters.Study registration number NCT06870838; Pre-results.

BACKGROUND AND OBJECTIVES:Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by 3 core symptom complexes: parkinsonism, cerebellar syndrome, and dysautonomia. Recent Movement Disorder Society (MDS) criteria allow for the clinical diagnosis of MSA based solely on motor symptoms, without requiring dysautonomia. This study aimed to evaluate the frequency and disease trajectory of MSA patients without dysautonomia compared with those with autonomic involvement. METHODS:A multicenter cohort of autopsy-confirmed patients with MSA was analyzed for demographic characteristics, symptom onset, and progression of parkinsonism, cerebellar syndrome, and dysautonomia. Clinical data were collected through standardized chart reviews across participating centers and categorized using the MDS-MSA criteria. Patients were grouped according to their initial symptom complex and tracked for the evolution of additional symptoms. Analyses included time to development of further symptom complexes, age at symptom onset, disease duration, and phenotype at the last recorded visit. Patients with motor symptoms only were matched to patients with similar demographics but with dysautonomia. Statistical methods included ANOVA, t tests, Welch t tests, and χ2 tests, with significance set at p < 0.05. RESULTS:Among 140 patients (mean age at onset 62.3 ± 8.9 years; 44% female), 81 (58%) initially presented without dysautonomia (57 with parkinsonism only, 17 with cerebellar syndrome only, 7 with both). At final follow-up, 12 patients (9%) had not developed dysautonomia. These patients showed significantly longer disease duration (mean 8.1 ± 2.1 years) than matched patients with dysautonomia (mean 6.3 ± 2.6 years; p = 0.035). Overall, 51% of patients developed all 3 symptom complexes. Patients with cerebellar onset progressed more rapidly to multisystem involvement than those with parkinsonian onset (mean interval to second symptom: 2.0 vs 3.4 years; p < 0.05). DISCUSSION:The MDS-MSA criteria expand the diagnostic scope by identifying a motor-only subgroup with a distinct and potentially slower disease course. These findings underscore the importance of including motor-only patients in natural history and interventional studies. Limitations include retrospective data collection and potential variability in symptom documentation.

Background and ObjectivesWith upcoming clinical trials targeting preclinical stages of genetic frontotemporal dementia (FTD), early detection through cognitive screening is crucial. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) have potential as screening instruments for early-stage genetic FTD. However, no comparative evaluation has been performed. We aimed to compare MMSE and MoCA performance among presymptomatic, prodromal, and symptomatic pathogenic variant carriers to analyze which screening test has superior discriminative abilities. MethodsWe used cross-sectional and longitudinal data from 2 longitudinal genetic FTD cohort studies in the Netherlands and the United Kingdom, collected between 2021 and 2024. Participants were either presymptomatic, prodromal, or symptomatic pathogenic variant carriers or healthy controls (first-degree family members without pathogenic variants for FTD). Grouping was based on the global CDR-plus-NACC-FTLD score. Participants were assessed with both MoCA and MMSE. Statistical analyses compared total and subscores between groups and evaluated predictive and classification accuracy of both tests. ResultsA total of 243 participants (mean age 49.9 +/- 13.1 years, mean education 14.5 +/- 3.0 years, 56% female), 157 of whom were pathogenic variant carriers (MAPT, GRN, C9orf72, TARDBP, and TBK1) and 86 controls, were included. Carriers were classified as presymptomatic (n = 119), prodromal (n = 18), or symptomatic (n = 20). Both MoCA [F(3,239) = 16.565, p < 0.001] and MMSE [F(3,239) = 13.529, p < 0.001] total scores differed significantly between groups, with controls (median MoCA 28.5, 95% CI 28.0-29.0; median MMSE 30, 95% CI 30.0-30.0) outperforming prodromal (median MoCA 26, 95% CI 23.0-27.0; median MMSE 29, 95% CI 27.5-29.5) and symptomatic (median MoCA 20.5, 95% CI 17.0-24.0; median MMSE 26, 95% CI 23.5-29.0) carriers. MoCA distinguished between presymptomatic carriers and controls (median MoCA 28, 95% CI 27.0-29.0), but MMSE did not. MoCA demonstrated superior discriminative ability compared with MMSE (MoCA area under the curve [AUC] = 0.87, 95% CI 0.81-0.94; MMSE AUC = 0.80, 95% CI 0.72-0.89). DiscussionIts higher sensitivity and better discriminative power make MoCA a more valuable tool for cognitive screening in upcoming clinical trials targeting preclinical FTD. Future studies should aim for larger sample sizes from additional study centers.

BACKGROUND:Progressive Supranuclear Palsy (PSP) is a rare and severe neurodegenerative tauopathy characterized by diverse clinical phenotypes, including Richardson's syndrome (PSP-RS), PSP-parkinsonism (PSP-P), PSP-progressive gait freezing (PSP-PGF), and PSP-corticobasal syndrome (PSP-CBS). Significant geographic variation exists in prevalence, clinical presentations, and prognosis. OBJECTIVES:This global review aims to systematically evaluate the epidemiological variation, clinical phenotypes, diagnostic practices, and management strategies for PSP, focusing on regional disparities and identifying influencing genetic and environmental factors. METHODOLOGY:A comprehensive literature search following PRISMA guidelines was conducted, analyzing studies reporting PSP epidemiology, phenotypes, diagnostic criteria, risk factors, treatments, and prognoses. Data were categorized into epidemiology, risk factors, clinical presentations, diagnosis, treatment accessibility, and outcomes, considering geographic variation. RESULTS:Global PSP prevalence ranges between 5-6.4 per 100,000, influenced by diagnostic criteria and healthcare infrastructure. Clinical manifestations commonly include supranuclear gaze palsy, frequent falls, cognitive impairment, and motor dysfunction. Prognosis significantly varies with subtype; PSP-RS shows rapid progression and shorter survival (5-7 years), whereas PSP-P has a milder clinical course (8-12 years). Regional variations highlight differences in genetic predispositions, notably the MAPT H1 haplotype, environmental risk factors such as dietary neurotoxins and industrial pollutants, and accessibility to comprehensive healthcare services. Diagnostic accuracy has improved with the adoption of MDS-PSP criteria, facilitating recognition of diverse phenotypes. CONCLUSIONS:Regional disparities in PSP prevalence, phenotypic presentation, and healthcare accessibility underscore the importance of standardized diagnostic criteria, targeted genetic and environmental studies, and equitable healthcare strategies. Enhanced global collaboration is essential for improving PSP diagnosis, management, and patient outcomes worldwide.

BACKGROUND:C9orf72 is one of the leading causes of genetic FTD. Although neuropsychiatric symptoms are considered a distinctive hallmark, no studies into maladaptive premorbid personality traits have been performed in C9orf72-FTD thus far. METHODS:We investigated differences in self-reported and informant-reported brief version of the Dutch Personality Inventory for the DSM (PID-5-NL) in symptomatic (n = 7) and presymptomatic C9orf72 repeat expansion carriers (C9orf72-REC) (n = 27), and controls (n = 18). We also explored relationships with cognitive performance and neuropsychiatric questionnaires (BDI-II-NL and NPI-Q). RESULTS:Informants of symptomatic C9orf72-REC reported higher total, Disinhibition and Psychoticism scores on the PID-5-NL than presymptomatic C9orf72-REC and controls. No significant differences were found between presymptomatic C9orf72 repeat expansion carriers and controls. There were no significant correlations between the Mini-Mental State Examination and Frontal Assessment Battery total scores and the PID-5-NL scores. In presymptomatic C9orf72-REC, PID-5-BF-NL total, Negative Affect, and Antagonism scores correlated with the BDI-II-NL. PID-5-IBF-NL total and Negative Affect, Antagonism, and Disinhibition scores correlated with the NPI-Q, Disinhibition correlated with the Frontal-Behavioural cluster, and Negative Affect, Antagonism, and Disinhibition correlated with the Mood and Psychotic clusters. CONCLUSION:Our findings suggests that the PID-5-BF-NL offers a valuable insight into the presence of maladaptive premorbid personality traits in the symptomatic phase of C9orf72-FTD.

Background:Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method:In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results:Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73×10-3) in PSP. Conclusions:Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

BACKGROUND:Multiple system atrophy is a neurodegenerative disease with α-synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia. OBJECTIVE:The aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers. METHODS:Diagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy-confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. RESULTS:We identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%-100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%-9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%-100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%-100% throughout). CONCLUSIONS:The International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Characterization of cognitive profiles across genetic FTD gene mutations is crucial for the identification of sensitive endpoints for clinical trials targeting specific pathologies. However, no systematic overview of the literature describing cognitive profiles in different FTD gene mutations has been made thus far. We performed a meta-analysis and systematic review to characterize cognitive profiles across the different FTD gene mutations and clinical disease stages of familial frontotemporal dementia (FTD). We included 27 studies comparing presymptomatic (n=1027), and/or symptomatic (n=574) mutation carriers (GRN, MAPT, C9orf72) with controls (n=1296). We extracted cognitive data and grouped them into six cognitive domains (language, attention and mental processing speed, executive function (EF), memory, social cognition, and visuospatial abilities). These domains were further subdivided into specific cognitive sub-processes. We calculated Hedges' g and performed multilevel meta-analyses per cognitive domain and FTD gene mutation comparing presymptomatic and symptomatic mutation carriers to controls. Moderator analyses were performed to the effect of age, education, sex, and cognitive subprocess. Eleven studies into rarer FTD mutations were included in the systematic review. Presymptomatic GRN mutation carriers showed deficits in EF, and presymptomatic C9orf72 mutation carriers in language, EF, and attention. Presymptomatic MAPT mutation carriers did not differ from controls on any of the cognitive domains. All symptomatic mutation carriers had deficits in language, EF, attention, and memory. Both in the presymptomatic and symptomatic stage cognitive sub-processes for language, attention and mental processing speed, EF, and memory were differentially affected in GRN, MAPT, and C9orf72. Cognitive decline was present in the presymptomatic stage of GRN and C9orf72 mutation carriers, but not MAPT mutation carriers. Unique cognitive sub-processes were affected in GRN, MAPT, and C9orf72. This study increased our knowledge of the cognitive deficits in familial FTD, which can aid in differential diagnosis and selection of endpoints for clinical trials.

Frontotemporal lobar degeneration (FTLD) is one of the leading causes of early onset dementia. Pathogenic variants in GRN have been reported to cause 5–25

AbstractObjectiveMethylation of plasma cell‐free DNA (cfDNA) has potential as a marker of brain damage in neurodegenerative diseases such as frontotemporal dementia (FTD). Here, we study methylation of cfDNA in presymptomatic and symptomatic carriers of genetic FTD pathogenic variants, next to healthy controls.MethodscfDNA was isolated from cross‐sectional plasma of 10 presymptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), 10 symptomatic carriers (4 C9orf72, 4 GRN, and 2 MAPT), and 9 healthy controls. Genome‐wide methylation of cfDNA was determined using a high‐resolution sequencing technique (MeD‐seq). Cumulative scores based on the identified differentially methylated regions (DMRs) were estimated for presymptomatic carriers (vs. controls and symptomatic carriers), and reevaluated in a validation cohort (8 presymptomatic: 3 C9orf72, 3 GRN, and 2 MAPT; 26 symptomatic: 7 C9orf72, 6 GRN, 12 MAPT, and 1 TARDBP; 13 noncarriers from genetic FTD families).ResultsPresymptomatic carriers showed a distinctive methylation profile compared to healthy controls and symptomatic carriers. Cumulative DMR scores in presymptomatic carriers enabled to significantly differentiate presymptomatic carriers from healthy controls (p < 0.001) and symptomatic carriers (p < 0.001). In the validation cohort, these scores differentiated presymptomatic carriers from symptomatic carriers (p ≤ 0.007) only. Transcription‐start‐site methylation in presymptomatic carriers, generally associated with gene downregulation, was enriched for genes involved in ubiquitin‐dependent processes, while gene body methylation, generally associated with gene upregulation, was enriched for genes involved in neuronal cell processes.InterpretationA distinctive methylation profile of cfDNA characterizes the presymptomatic stage of genetic FTD, and could reflect neuronal death in this stage.

Importance:The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, β, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective:To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, β, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants:Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, β, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures:The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results:The copy numbers of α and β were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1β1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1β1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1β1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1β1γ4. Moreover, H1β1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1β1γ1 to 77% in H1β1γ4. Conclusions and relevance:This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.

BACKGROUND AND OBJECTIVES:Elevated serum neurofilament light chain (NfL) is used to identify carriers of genetic frontotemporal dementia (FTD) pathogenic variants approaching prodromal conversion. Yet, the magnitude and timeline of NfL increase are still unclear. Here, we investigated the predictive and early diagnostic value of longitudinal serum NfL for the prodromal conversion in genetic FTD. METHODS:In a longitudinal observational cohort study of genetic FTD pathogenic variant carriers, we examined the diagnostic accuracy and conversion risk associated with cross-sectional and longitudinal NfL. Time periods relative to prodromal conversion (>3, 3-1.5, 1.5-0 years before; 0-1.5 years after) were compared with values of participants who did not convert. Next, we modeled longitudinal NfL and MRI volume trajectories to determine their timeline. RESULTS:We included 21 participants who converted (5 chromosome 9 open-reading frame 72 [C9orf72], 10 progranulin [GRN], 5 microtubule-associated protein tau [MAPT], and 1 TAR DNA-binding protein [TARDBP]) and 61 who did not (20 C9orf72, 30 GRN, and 11 MAPT). Participants who converted had higher NfL levels at all examined periods before prodromal conversion (median values 14.0-18.2 pg/mL; betas = 0.4-0.7, standard error [SE] = 0.1, p < 0.046) than those who did not (6.5 pg/mL) and showed further increase 0-1.5 years after conversion (28.4 pg/mL; beta = 1.0, SE = 0.1, p < 0.001). Annualized longitudinal NfL change was only significantly higher in participants who converted (vs. participants who did not) 0-1.5 years after conversion (beta = 1.2, SE = 0.3, p = 0.001). Diagnostic accuracy of cross-sectional NfL for prodromal conversion (vs. nonconversion) was good-to-excellent at time periods before conversion (area under the curve range: 0.72-0.92), improved 0-1.5 years after conversion (0.94-0.97), and outperformed annualized longitudinal change (0.76-0.84). NfL increase in participants who converted occurred earlier than frontotemporal MRI volume change and differed by genetic group and clinical phenotypes. Higher NfL corresponded to increased conversion risk (hazard ratio: cross-sectional = 6.7 [95% CI 3.3-13.7]; longitudinal = 13.0 [95% CI 4.0-42.8]; p < 0.001), but conversion-free follow-up time varied greatly across participants. DISCUSSION:NfL increase discriminates individuals who convert to prodromal FTD from those who do not, preceding significant frontotemporal MRI volume loss. However, NfL alone is limited in predicting the exact timing of prodromal conversion. NfL levels also vary depending on underlying variant-carrying genes and clinical phenotypes. These findings help to guide participant recruitment for clinical trials targeting prodromal genetic FTD.