Cerebrospinal fluid neurofilament light chain protein levels in subtypes of frontotemporal dementia

Abstract

BackgroundFrontotemporal dementia (FTD) is recognised as a clinically and morphologically heterogeneous group of interrelated neurodegenerative conditions. One of the subtypes within this disease spectrum is the behavioural variant FTD (bvFTD). This is known to be a varied disorder with a mixture of tau-positive and tau-negative underlying pathologies. The other subtypes include semantic dementia (SD), which generally exhibits tau-negative pathology, and progressive non-fluent aphasia (PNFA), which is usually tau-positive. As the clinical presentation of these subtypes may overlap, a specific diagnosis can be difficult to attain and today no specific biomarker can predict the underlying pathology. Neurofilament light chain protein (NFL), a cytoskeletal constituent of intermediate filaments, is thought to reflect neuronal and axonal death when appearing in the cerebrospinal fluid (CSF). NFL has been shown to be elevated in CSF in patients with FTD compared with AD and controls. Our hypothesis was that the levels of NFL also differ between the subtypes of FTD and may indicate the underlying pathological subtype.MethodsWe retrospectively analysed data from previous CSF analyses in 34 FTD cases (23 bvFTD, seven SD, four PNFA), 20 AD cases, and 26 healthy controls. A separate group of 10 neuropathologically verified and subtyped FTD cases (seven tau-negative, three tau-positive) were also analysed.ResultNFL levels were significantly higher in FTD compared with both AD (p<0.001) and controls (p<0.001). The NFL levels of SD and bvFTD were significantly higher (p<0.001) compared with AD. The biomarker profiles of PNFA and AD were similar. In the neuropathologically verified FTD cases, NFL was higher in the tau-negative than in the tau-positive cases (exact p=0.017).ConclusionsThe marked NFL elevation in some but not all FTD cases is likely to reflect the different underlying pathologies. The highest NFL values found in the SD group as well as in the neuropathologically verified tau-negative cases may be of subtype diagnostic value, if corroborated in larger patient cohorts. In bvFTD, a mixture of tau-positive and tau-negative underlying pathologies could possibly explain the intermediate NFL values.

Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis

“…NfL is released from damaged neurons. Concentrations in CSF are increased in people with neurodegenerative diseases, including Alzheimer's disease, 13 amyotrophic lateral sclerosis, 13 and frontotemporal dementia 13, 14. Four small-scale cross-sectional studies found raised concentrations of NfL in the CSF of individuals with Huntington's disease,8, 15, 16, 17 and we have shown a close association between increased concentrations of NfL and mHTT in CSF 8 …”

Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration

“…This result is similar to another recent study of CSF NfL that demonstrated similar elevations in CSF NfL in SD. 39 Together, these data suggest that CSF NfL may be more prominently elevated in individuals with SD than other FTD subgroups. Whether these elevations reflect the association of SD with FTLD-TDP pathology, 40 or some other component of SD biology will require further study in a larger cohort of autopsy-confirmed cases.…”

Cerebrospinal fluid neurofilament light concentration in motor neuron disease and frontotemporal dementia predicts survival

“…This is unfortunate as MND mimics often display relatively low concentrations of CSF NFL . Also in FTD there are subtypes, such as progressive non-fluent aphasia, that do not have as markedly elevated CSF concentrations (Landqvist Waldö et al, 2013), as the common FTD variants. However, the main hypotheses of this study were clearly confirmed even though the influence of these subgroups might have hampered it.…”