Serum neurofilament heavy chains as early marker of motor neuron degeneration

Abstract

ObjectiveTo determine whether serum phosphorylated neurofilament heavy chain (pNfH) levels are elevated before patients were diagnosed with sporadic or familial ALS, and what the prognostic value of these prediagnostic pNfH levels is.MethodspNfH was measured via ELISA in leftovers of serum drawn for routine purposes before the time of diagnosis. These prediagnostic samples were retrieved from the biobank of the University Hospitals Leuven for 95 patients who in follow‐up received a diagnosis of ALS. Additionally, 35 patients with mild cognitive impairment (MCI) and 85 healthy controls (HC) were included in this retrospective study.ResultsThe median disease duration (range) from onset to prediagnostic sampling and from onset to diagnosis was 6.5 (−71.9–36.1) and 9.9 (2.0–40.7) months, respectively. Fifty‐eight percent of the prediagnostic samples had serum pNfH levels above the 95th percentile of pNfH levels measured in HC. Serum pNfH levels (median (range)) were elevated up to 18 months before the diagnosis of ALS (91 pg/mL (6–342 pg/mL)) in comparison with HC (30 pg/mL (6–146 pg/mL); P = 0.05), and increased during the prediagnostic stage, which was not observed in patients with MCI. Furthermore, prediagnostic pNfH levels were a univariate predictor of survival in ALS (hazard ratio (95% CI): 2.16 (1.20–3.87); P = 0.01).InterpretationOur findings demonstrate that serum pNfH is elevated well before the time of diagnosis in mainly sporadic ALS patients. These results encourage to prospectively explore if pNfH has an added value to shorten the diagnostic delay in ALS.

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

“…However, the application of NF quantification at the general practitioner or first aid room may confuse rather than expedite the diagnosis of MND. On the other hand, a recent study proved that serum pNfH was already elevated above normative values in individuals admitted with early motor symptoms who only later satisfied the diagnosis of sporadic or familial ALS [108] . The lack of specificity of NFs towards neurodegenerative conditions should not alarm against their diagnostic value as far as their use is limited to experienced neurologists who can orient the diagnosis in the right direction.…”

Prognostic value of neurofilament light chain in chronic inflammatory demyelinating polyneuropathy

“…In various neurological diseases, blood-based biomarkers that reflect disease progression have recently been gaining attention, including serum neurofilament light chain (sNfL). 10–25 Neurofilaments are released into blood and cerebrospinal fluid of patients with neurodegenerative diseases in whom they have been shown to be associated with various clinical features. 10–25 For example, recent studies showed significant cross-sectional associations between sNfL and disability or therapy response in various peripheral neuropathies, including in CIDP.…”

“… 10–25 Neurofilaments are released into blood and cerebrospinal fluid of patients with neurodegenerative diseases in whom they have been shown to be associated with various clinical features. 10–25 For example, recent studies showed significant cross-sectional associations between sNfL and disability or therapy response in various peripheral neuropathies, including in CIDP. 19–23 However, these studies did not yet investigate the prognostic value of sNfL in CIDP with respect to disease progression or therapy response.…”

Proteostatic imbalance and protein spreading in amyotrophic lateral sclerosis

“…The identification of mutations in the C9orf72 gene by two independent groups was a groundbreaking discovery (Renton et al, 2011; Dejesus‐hernandez et al, 2011). This mutation is responsible for ~11% of all ALS cases and ~13% of all FTD cases (Abramzon et al, 2020).…”