Neurofilaments can differentiate ALS subgroups and ALS from common diagnostic mimics

Arvin Behzadi,Anton E Tjust,Henrik Zetterberg,Kaj Blennow,Peter Munch Andersen,Fani Pujol-Calderón,Karin Forsberg,Anna Wuolikainen,Erik Portelius,Kina Höglund

doi:10.1038/s41598-021-01499-6

Arvin Behzadi, Anton E Tjust + Show 8 more

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https://doi.org/10.1038/s41598-021-01499-6

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Delayed diagnosis and misdiagnosis are frequent in people with amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease (MND). Neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) are elevated in ALS patients. We retrospectively quantified cerebrospinal fluid (CSF) NFL, CSF pNFH and plasma NFL in stored samples that were collected at the diagnostic work-up of ALS patients (n = 234), ALS mimics (n = 44) and controls (n = 9). We assessed the diagnostic performance, prognostication value and relationship to the site of onset and genotype. CSF NFL, CSF pNFH and plasma NFL levels were significantly increased in ALS patients compared to patients with neuropathies & myelopathies, patients with myopathies and controls. Furthermore, CSF pNFH and plasma NFL levels were significantly higher in ALS patients than in patients with other MNDs. Bulbar onset ALS patients had significantly higher plasma NFL levels than spinal onset ALS patients. ALS patients with C9orf72HRE mutations had significantly higher plasma NFL levels than patients with SOD1 mutations. Survival was negatively correlated with all three biomarkers. Receiver operating characteristics showed the highest area under the curve for CSF pNFH for differentiating ALS from ALS mimics and for plasma NFL for estimating ALS short and long survival. All three biomarkers have diagnostic value in differentiating ALS from clinically relevant ALS mimics. Plasma NFL levels can be used to differentiate between clinical and genetic ALS subgroups.

Highlights

Amyotrophic lateral sclerosis (ALS) is an adult onset fatal neurodegenerative syndrome characterized by the insidious onset of progressive motor symptoms and signs secondary to the loss of upper and lower motor neurons and their tracts[1]
Participants in the study were categorized as patients with amyotrophic lateral sclerosis (ALS) (n = 234) or ALS mimics (n = 44); the latter group consisted of patients with other types of motor neuron diseases (n = 13), neuropathies & myelopathies (n = 24) or myopathies (n = 7)
ALS patients were stratified into spinal onset ALS (n = 148), bulbar onset ALS (n = 72), truncal onset ALS (n = 11) and frontotemporal dementia (FTD) onset ALS (n = 1)

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Introduction

Amyotrophic lateral sclerosis (ALS) is an adult onset fatal neurodegenerative syndrome characterized by the insidious onset of progressive motor symptoms and signs secondary to the loss of upper and lower motor neurons and their tracts[1]. ALS is heterogeneous, misdiagnoses are frequent, and it is a challenge in clinical practice to determine an ALS d iagnosis[4] It is essential in the diagnostic process to exclude a number of conditions termed ALS mimics that present with symptoms similar to ALS and may be difficult to differentiate[5,6,7]. The rarity of SOD1 mutations and the finding that seven SOD1 mutants have preserved enzymatic activity limit the clinical use of SOD1 enzymatic analysis, the finding of reduced SOD1 enzymatic activity may be critical for correctly diagnosing ALS in patients who had been on diagnostic odysseys[10,12,13]. We retrospectively investigated the diagnostic and prognostic value of assaying CSF NFL, CSF pNFH and plasma NFL in samples collected from patients during the diagnostic procedure performed at a specialized university clinic for ALS evaluation and examined whether these biomarkers differed between clinical and genotypic subtypes of ALS

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