Abstract
Biomarkers of neurodegeneration and neuronal injury have the potential to improve diagnostic accuracy, disease monitoring, prognosis, and measure treatment efficacy. Neurofilament proteins (NfPs) are well suited as biomarkers in these contexts because they are major neuron-specific components that maintain structural integrity and are sensitive to neurodegeneration and neuronal injury across a wide range of neurologic diseases. Low levels of NfPs are constantly released from neurons into the extracellular space and ultimately reach the cerebrospinal fluid (CSF) and blood under physiological conditions throughout normal brain development, maturation, and aging. NfP levels in CSF and blood rise above normal in response to neuronal injury and neurodegeneration independently of cause. NfPs in CSF measured by lumbar puncture are about 40-fold more concentrated than in blood in healthy individuals. New ultra-sensitive methods now allow minimally invasive measurement of these low levels of NfPs in serum or plasma to track disease onset and progression in neurological disorders or nervous system injury and assess responses to therapeutic interventions. Any of the five Nf subunits – neurofilament light chain (NfL), neurofilament medium chain (NfM), neurofilament heavy chain (NfH), alpha-internexin (INA) and peripherin (PRPH) may be altered in a given neuropathological condition. In familial and sporadic Alzheimer’s disease (AD), plasma NfL levels may rise as early as 22 years before clinical onset in familial AD and 10 years before sporadic AD. The major determinants of elevated levels of NfPs and degradation fragments in CSF and blood are the magnitude of damaged or degenerating axons of fiber tracks, the affected axon caliber sizes and the rate of release of NfP and fragments at different stages of a given neurological disease or condition directly or indirectly affecting central nervous system (CNS) and/or peripheral nervous system (PNS). NfPs are rapidly emerging as transformative blood biomarkers in neurology providing novel insights into a wide range of neurological diseases and advancing clinical trials. Here we summarize the current understanding of intracellular NfP physiology, pathophysiology and extracellular kinetics of NfPs in biofluids and review the value and limitations of NfPs and degradation fragments as biomarkers of neurodegeneration and neuronal injury.
Highlights
It is widely accepted that the pathophysiology underlying many neurodegenerative disorders, such as Alzheimer’s disease (AD), originates many years prior to clinical symptoms
Amyloid-beta and tau proteins are widely regarded as useful diagnostic biomarkers of AD, tau proteins increase only in specific neurodegenerative diseases such as AD and unaltered in other neurological diseases that are clearly neurodegenerative, such as tau-negative frontotemporal dementia (FTD) caused by granulin or C9orf72 mutations (Foiani et al, 2018) where, by contrast, CSF and serum neurofilament light chain (NfL) fragment levels are more than 8 times higher in patients than in pre-symptomatic carriers or healthy controls (Meeter et al, 2016)
Dementia With Lewy Bodies Plasma NfL levels in patients with dementia with Lewy bodies (DLB) were about 2-fold higher than in healthy controls (55.3 vs. 25.7 pg/ml) and the elevations correlate with disease severity and plasma NfL is the best predictor of cognitive decline compared to age, sex and baseline severity variables over a follow-up of 2 years (Pilotto et al, 2021)
Summary
It is widely accepted that the pathophysiology underlying many neurodegenerative disorders, such as Alzheimer’s disease (AD), originates many years prior to clinical symptoms. In addition to commonly used NfL and pNfH, some studies found potential values of other Nf subunits, i.e., NfM (Hu et al, 2002; Haggmark et al, 2014; Martinez-Morillo et al, 2014; Zucchi et al, 2018; Remnestal et al, 2020), INA (MartinezMorillo et al, 2014) and PRPH (Finderlater, 2010; Liang et al, 2019; Sabbatini et al, 2021) as biomarkers in CSF or serum in neurological diseases or injuries.
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