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INTRODUCTION: We tested whether changes in functional networks predict cognitive decline and conversion from the presymptomatic prodrome to symptomatic disease in familial frontotemporal dementia (FTD). METHODS: For hypothesis generation, 36 participants with behavioral variant FTD (bvFTD) and 34 controls were recruited from one site. For hypothesis testing, we studied 198 symptomatic FTD mutation carriers, 341 presymptomatic mutation carriers, and 329 family members without mutations. We compared functional network dynamics between groups, with clinical severity and with longitudinal clinical progression. RESULTS: We identified a characteristic pattern of dynamic network changes in FTD, which correlated with neuropsychological impairment. Among presymptomatic mutation carriers, this pattern of network dynamics was found to a greater extent in those who subsequently converted to the symptomatic phase. Baseline network dynamic changes predicted future cognitive decline in symptomatic participants and older presymptomatic participants. DISCUSSION: Dynamic network abnormalities in FTD predict cognitive decline and symptomatic conversion. HIGHLIGHTS: We investigated brain network predictors of dementia symptom onset Frontotemporal dementia results in characteristic dynamic network patterns Alterations in network dynamics are associated with neuropsychological impairment Network dynamic changes predict symptomatic conversion in presymptomatic carriers Network dynamic changes are associated with longitudinal cognitive decline.

Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioural variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). First, we identified distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally-connected neighbours, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicentre of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and antero-medial temporal areas. We found that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability, providing an explanation as to how heterogenous pathological entities can lead to the same clinical syndrome.

ObjectiveWe tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.MethodsBaseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables.ResultsIn both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.ConclusionsPlasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials.Trial registration informationClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.Classification of evidenceThis study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.

ObjectiveWe sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.MethodsWe evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.ResultsWe found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.ConclusionsOur results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

BackgroundFrontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.MethodsIn this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.FindingsData were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.InterpretationOur study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.FundingUK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.

IntroductionQuantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design.MethodsPittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally.ResultsGlobal amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers.DiscussionAlthough the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.

ObjectiveTo estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants.MethodsWe conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models.ResultsAmyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p

ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72-associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel-wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72-associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.