CSF neurofilament light chain reflects corticospinal tract degeneration in ALS

Abstract

ObjectiveDiffusion tensor imaging (DTI) is sensitive to white matter tract pathology. A core signature involving the corticospinal tracts (CSTs) has been identified in amyotrophic lateral sclerosis (ALS). Raised neurofilament light chain protein (NfL) in cerebrospinal fluid (CSF) is thought to reflect axonal damage in a range of neurological disorders. The relationship between these two measures was explored.MethodsCSF and serum NfL concentrations and DTI acquired at 3 Tesla on the same day were obtained from ALS patients (n = 25 CSF, 40 serum) and healthy, age-similar controls (n = 17 CSF, 25 serum). Within-group correlations between NfL and DTI measures of microstructural integrity in major white matter tracts (CSTs, superior longitudinal fasciculi [SLF], and corpus callosum) were performed using tract-based spatial statistics.ResultsNfL levels were higher in patients compared to controls. CSF levels correlated with clinical upper motor neuron burden and rate of disease progression. Higher NfL levels were significantly associated with lower DTI fractional anisotropy and increased radial diffusivity in the CSTs of ALS patients, but not in controls.InterpretationElevated CSF and serum NfL is, in part, a result of CST degeneration in ALS. This highlights the wider potential for combining neurochemical and neuroimaging-based biomarkers in neurological disease.

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

“…Similar to pNFH, increased levels of NFL were correlated with rate of progression, as monitored by the rate of decline in ALSFRS-R scores, as well as upper MN involvement [36,39]. A rapid time to generation (time of symptom spreading from bulbar or spinal localization to both) has also been noted with increased CSF NFL [37].…”

“…A rapid time to generation (time of symptom spreading from bulbar or spinal localization to both) has also been noted with increased CSF NFL [37]. Diffusion tensor imaging was recently used to evaluate the correlation between increased CSF NFL levels and white matter damage, where decreased fractional anisotropy and increased radial diffusivity were observed within the corticospinal tracts of patients with ALS but not in healthy controls, reflecting the degeneration of axons and subsequent release of NFL into the CSF [39].…”

“…One of the more interesting approaches to biomarker discovery is using combinations or ratios of biomarkers from different pathogenic pathways, which has been shown to increase the sensitivity and/or specificity of potential ALS biomarkers [31,39,116,168]. For example, as mentioned previously, studies from our group have shown that a ratio of pNFH/C3, which combines data representing both axonal degeneration and inflammatory processes, maintains the sensitivity and slightly increases the specificity for distinguishing ALS from controls compared with pNFH alone (see Table 5) [31].…”

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

“…To aid diagnostics, patient stratification and studies seeking to find further treatments for these diseases, there is a need to establish a way to reliably and objectively assess disease severity and the amount of ongoing neurodegeneration. Previous studies have suggested that cerebrospinal fluid (CSF) neurofilament light (NFL) may serve this purpose (Tortelli et al, 2012, Menke et al, 2015. NFL is part of a family of proteins with all members acting as important parts of the scaffolding of the neuronal and axonal cytoskeleton.…”

Finding Markers in Amyotrophic Lateral Sclerosis Diagnosis

“…Some researchers have been working looking forward markers for early diagnosis of the disease [4]. For example: Feneberg et al have showed increase of TDP-43 (it is a phosphorylated and ubiquinated cytoplasmic aggregated of neurons and glial cells) in bio fluids and tissues in early step of ALS [5].…”