ObjectiveTo evaluate cerebrospinal fluid (CSF) and serum neurofilament light chain (NfL) levels in genetic frontotemporal dementia (FTD) as a potential biomarker in the presymptomatic stage and during the conversion into the symptomatic stage. Additionally, to correlate NfL levels to clinical and neuroimaging parameters.MethodsIn this multicenter case–control study, we investigated CSF NfL in 174 subjects (48 controls, 40 presymptomatic carriers and 86 patients with microtubule‐associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) mutations), and serum NfL in 118 subjects (39 controls, 44 presymptomatic carriers, 35 patients). In 55 subjects both CSF and serum was determined. In two subjects CSF was available before and after symptom onset (converters). Additionally, NfL levels were correlated with clinical parameters, survival, and regional brain atrophy.Results CSF NfL levels in patients (median 6762 pg/mL, interquartile range 3186–9309 pg/mL) were strongly elevated compared with presymptomatic carriers (804 pg/mL, 627–1173 pg/mL, P < 0.001), resulting in a good diagnostic performance to discriminate both groups. Serum NfL correlated highly with CSF NfL (r s= 0.87, P < 0.001) and was similarly elevated in patients. Longitudinal samples in the converters showed a three‐ to fourfold increase in CSF NfL after disease onset. Additionally, NfL levels in patients correlated with disease severity, brain atrophy, annualized brain atrophy rate and survival.InterpretationNfL in both serum and CSF has the potential to serve as a biomarker for clinical disease onset and has a prognostic value in genetic FTD.

BackgroundIn patients with frontotemporal dementia, it has been shown that brain atrophy occurs earliest in the anterior cingulate, insula and frontal lobes. We used visual rating scales to investigate whether identifying atrophy in these areas may be helpful in distinguishing symptomatic patients carrying different causal mutations in the microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame (C9ORF72) genes. We also analysed asymptomatic carriers to see whether it was possible to visually identify brain atrophy before the appearance of symptoms.MethodsMagnetic resonance imaging of 343 subjects (63 symptomatic mutation carriers, 132 presymptomatic mutation carriers and 148 control subjects) from the Genetic Frontotemporal Dementia Initiative study were analysed by two trained raters using a protocol of six visual rating scales that identified atrophy in key regions of the brain (orbitofrontal, anterior cingulate, frontoinsula, anterior and medial temporal lobes and posterior cortical areas).ResultsIntra- and interrater agreement were greater than 0.73 for all the scales. Voxel-based morphometric analysis demonstrated a strong correlation between the visual rating scale scores and grey matter atrophy in the same region for each of the scales. Typical patterns of atrophy were identified: symmetric anterior and medial temporal lobe involvement for MAPT, asymmetric frontal and parietal loss for GRN, and a more widespread pattern for C9ORF72. Presymptomatic MAPT carriers showed greater atrophy in the medial temporal region than control subjects, but the visual rating scales could not identify presymptomatic atrophy in GRN or C9ORF72 carriers.ConclusionsThese simple-to-use and reproducible scales may be useful tools in the clinical setting for the discrimination of different mutations of frontotemporal dementia, and they may even help to identify atrophy prior to onset in those with MAPT mutations.

IntroductionMutations in the TANK-binding kinase 1 (TBK1) gene have recently been shown to cause frontotemporal dementia (FTD). However, the phenotype of TBK1-associated FTD is currently unclear.MethodsWe performed a single case longitudinal study of a patient who was subsequently found to have a novel A705fs mutation in the TBK1 gene. He was assessed annually over a 7-year period with a series of clinical, cognitive, and magnetic resonance imaging assessments. His brain underwent pathological examination at postmortem.ResultsThe patient presented at the age of 64 years with an 18-month history of personality change including increased rigidity and obsessiveness, apathy, loss of empathy, and development of a sweet tooth. His mother had developed progressive behavioral and cognitive impairment from the age of 57 years. Neuropsychometry revealed intact cognition at first assessment. Magnetic resonance imaging showed focal right temporal lobe atrophy. Over the next few years his behavioral problems progressed and he developed cognitive impairment, initially with anomia and prosopagnosia. Neurological examination remained normal throughout without any features of motor neurone disease. He died at the age of 72 years and postmortem showed TDP-43 type A pathology but with an unusual novel feature of numerous TAR DNA-binding protein 43 (TDP-43)–positive neuritic structures at the cerebral cortex/subcortical white matter junction. There was also associated argyrophilic grain disease not previously reported in other TBK1 mutation cases.DiscussionTBK1-associated FTD can be associated with right temporal variant FTD with progressive behavioral change and relatively intact cognition initially. The case further highlights the benefits of next-generation sequencing technologies in the diagnosis of neurodegenerative disorders and the importance of detailed neuropathologic analysis.