Centres of Excellence in Neurodegeneration.

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.

Background: Frontotemporal dementia (FTD) is frequently caused by genetic mutations in GRN, C9orf72 and MAPT. Neurofilament light chain (NfL) is a promising blood biomarker in genetic FTD, with elevated levels in symptomatic mutation carriers. A better understanding of NfL dynamics is essential for its use in upcoming therapeutic trials. We investigated longitudinal serum NfL trajectories in presymptomatic and symptomatic genetic FTD. over time was associated with atrophy rate in several grey matter regions, but not with rate of change in clinical parameters. Interpretation: This study confirms the value of blood NfL as a disease progression biomarker in genetic FTD and indicates that longitudinal NfL measurements could help identify mutation carriers approaching symptom onset and capture the rate of brain atrophy. The stable levels in C9orf72-and MAPT-associated FTD offer potential for NfL as a marker of treatment effect in therapeutic trials.

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.

See Boeve and Rosen (doi:) for a scientific commentary on this article.Jiskoot et al. present evidence of presymptomatic reduction in white matter integrity and grey matter volume in familial FTD, with the largest declines in the uncinate fasciculus, genu corpus callosum, and frontotemporal, cingulate and insular cortex. Multimodal MRI parameters may be valuable prognostic biomarkers in familial FTD.