Synofzik, Matthis

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.

Objective Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a

ABSTRACT Neurodegenerative diseases are characterised by the assembly of a limited number of disease-specific proteins into amyloid filaments, which form intracellular inclusions or extracellular deposits in the central nervous system (CNS) 1,2 . We previously found that amyloid filaments of TATA-binding protein-associated factor 15 (TAF15) characterise a subtype of frontotemporal lobar degeneration with FET protein-immunoreactive inclusions (FTLD-FET) 3 , termed atypical FTLD with ubiquitin-positive inclusions (aFTLD-U) 4 , which causes early-onset, rapidly progressive behavioural variant frontotemporal dementia (FTD). However, it was not clear if TAF15 proteinopathy was more widespread in neurodegenerative diseases. Two additional FTLD-FET subtypes have been proposed, neuronal intermediate filament inclusion body disease (NIFID) and basophilic inclusion body disease (BIBD) 5,6 , which have more heterogenous clinical presentations including FTD, motor neuron diseases (MND) and movement disorders. Here, we used electron cryo-microscopy (cryo-EM) to determine a total of 32 amyloid filament structures from the brains of 17 individuals encompassing all three proposed subtypes of FTLD-FET and their diverse clinical presentations. All cases were characterised by TAF15 filaments, in the absence of filaments of the other FET proteins, fused in sarcoma (FUS) and Ewing’s sarcoma (EWS). All three aFTLD-U cases had the previously-reported TAF15 fold 3 . Unexpectedly, we found four distinct TAF15 folds among 11 NIFID cases. Eight of these cases shared a common fold, while the remaining three were each distinct. Furthermore, we found distinct TAF15 folds for each of the three BIBD cases. Neuropathological reassessment of the neocortical TAF15 inclusion pathology of these cases distinguished the NIFID cases with the common fold from the others. Thus, TAF15 filament structures form the basis of a new, expanded classification of FTLD-FET subtypes. Moreover, we discovered a TAF15 Y38C variant in the filament fold of one of the individuals with BIBD. The structure is unable to incorporate wild-type TAF15, despite the individual being heterozygous, suggesting that this variant drives TAF15 filament assembly. This study provides structural and genetic evidence that TAF15 amyloid filaments underlie the diverse group of neurodegenerative diseases currently termed FTLD-FET, which we therefore rename FTLD-TAF15.

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.

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.

AbstractBackground and purposeClinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.MethodsTo evaluate total tau (t‐tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy‐terminal hydrolase L1 (UCHL1) and neurofilament light‐chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD‐1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t‐tau and phosphorylated tau (p‐tau181). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t‐tau levels.ResultsPlasma t‐tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non‐Ataxia Signs was associated with t‐tau in ataxic patients (p = 0.004). Pre‐ataxic carriers showed higher cerebrospinal fluid t‐tau and p‐tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t‐tau was elevated in MJDTg mice compared to wild‐type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001).ConclusionOur results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.

4-Aminopyridine is a potential therapeutic option for a subgroup of patients with KCNA2 -encephalopathy and gain-of-function variants.

ObjectivePerirolandic atrophy occurs in corticobasal syndrome (CBS) but is not specific versus progressive supranuclear palsy (PSP). There is heterogeneity in the locations of atrophy outside the perirolandic cortex and it remains unknown why atrophy in different locations would cause the same CBS‐specific symptoms. In prior work, we used a wiring diagram of the brain called the human connectome to localize lesion‐induced disorders to symptom‐specific brain networks. Here, we use a similar technique termed “atrophy network mapping” to localize single‐subject atrophy maps to symptom‐specific brain networks.MethodsSingle‐subject atrophy maps were generated by comparing cortical thickness in patients with CBS versus controls. Next, we performed seed‐based functional connectivity using a large normative connectome to determine brain regions functionally connected to each patient's atrophied locations.ResultsPatients with CBS had perirolandic atrophy versus controls at the group level, but locations of atrophy in CBS were heterogeneous outside of the perirolandic cortex at the single‐subject level (mean spatial correlation = 0.04). In contrast, atrophy occurred in locations functionally connected to the perirolandic cortex in all patients with CBS (spatial correlation = 0.66). Compared with PSP, patients with CBS had atrophy connected to a network of higher‐order sensorimotor regions beyond perirolandic cortex, matching a CBS atrophy network from a recent meta‐analysis. Finally, atrophy network mapping identified a symptom‐specific network for alien limb, matching a lesion‐induced alien limb network and a network associated with agency in healthy subjects.InterpretationWe identified a syndrome‐specific network for CBS and symptom‐specific network for alien limb using single‐subject atrophy maps and the human connectome. ANN NEUROL 2020;88:1118–1131