Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia

Abstract

Objective:To investigate serum neurofilament light chain (NfL) concentrations in frontotemporal dementia (FTD) and to see whether they are associated with the severity of disease.Methods:Serum samples were collected from 74 participants (34 with behavioral variant FTD [bvFTD], 3 with FTD and motor neuron disease and 37 with primary progressive aphasia [PPA]) and 28 healthy controls. Twenty-four of the FTD participants carried a pathogenic mutation in C9orf72 (9), microtubule-associated protein tau (MAPT; 11), or progranulin (GRN; 4). Serum NfL concentrations were determined with the NF-Light kit transferred onto the single-molecule array platform and compared between FTD and healthy controls and between the FTD clinical and genetic subtypes. We also assessed the relationship between NfL concentrations and measures of cognition and brain volume.Results:Serum NfL concentrations were higher in patients with FTD overall (mean 77.9 pg/mL [SD 51.3 pg/mL]) than controls (19.6 pg/mL [SD 8.2 pg/mL]; p < 0.001). Concentrations were also significantly higher in bvFTD (57.8 pg/mL [SD 33.1 pg/mL]) and both the semantic and nonfluent variants of PPA (95.9 and 82.5 pg/mL [SD 33.0 and 33.8 pg/mL], respectively) compared with controls and in semantic variant PPA compared with logopenic variant PPA. Concentrations were significantly higher than controls in both the C9orf72 and MAPT subgroups (79.2 and 40.5 pg/mL [SD 48.2 and 20.9 pg/mL], respectively) with a trend to a higher level in the GRN subgroup (138.5 pg/mL [SD 103.3 pg/mL). However, there was variability within all groups. Serum concentrations correlated particularly with frontal lobe atrophy rate (r = 0.53, p = 0.003).Conclusions:Increased serum NfL concentrations are seen in FTD but show wide variability within each clinical and genetic group. Higher concentrations may reflect the intensity of the disease in FTD and are associated with more rapid atrophy of the frontal lobes.

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

“…Patients with high NfL experienced the steepest annual decline in both clinical rating scales and MRI measurements. These findings are consistent with previous studies establishing the prognostic value of both CSF7, 8, 36 and plasma7, 9 NfL in genetic FTD syndromes. Within our bvFTD and nfvPPA cohorts, median CSF NfL levels (4.1 × 10 3  pg/mL and 5.17 × 10 3  pg/mL, respectively) separated patients into subgroups with clinically significant annual change and clinically negligible annual change.…”

“…Recent studies in FTD suggest that serum and CSF neurofilament‐light chain (NfL), an intermediate cytoskeletal element that elevates upon neuronal injury,6 is a reliable marker of disease onset,7 clinical severity,7, 8, 9 disease prognosis,7, 10 and brain atrophy rates 7, 9. Few studies, however, have addressed the relative value of NfL in prediction of disease progression in different FTD cohorts.…”

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

“…Consequently, surrogate endpoints reflecting neurodegeneration are critical for assessing disease onset and the efficacy of therapeutic interventions. Our data show that NfL is elevated during the symptomatic phase of C9orf72 ‐associated dementia and correlate with indicators of disease severity (i.e., MMSE, CDR, and CDR‐SB), survival, and grey matter atrophy, consistent with other studies of NfL in sporadic and genetic FTD 18, 38, 39. In mouse models, NfL also correlates with disease severity, specifically with the burden of α‐synuclein, tau, or β ‐amyloid inclusions, and NfL levels are attenuated with treatment 40.…”

Plasma neurofilament light chain levels in Alzheimer’s disease

“…Further longitudinal studies are needed to confirm the utility of plasma NFL as a neuropathological or prognostic biomarker for AD. It also should be noted that abnormal NFL levels in blood were not only found in AD but also in other neurological disorders, such as multiple sclerosis [8], clinically isolated syndrome [2], amyotrophic lateral sclerosis [3], frontotemporal dementia [12], Guillain Barré syndrome [3], spinal cord injury [9], and others, suggesting that blood NFL levels may not be disease-specific. Finally, the increase could be related with the aggravated neuronal damages associated with cognitive impairment severity, rather than a diagnostic biomarker.…”