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Science News: Three Article Summaries on Recent Amyotrophic Lateral Sclerosis (ALS) Research Findings

Submitted by Shan (Sarah) Chen, MD, PhD, News Science Editorial Board
Edited by Benn E. Smith, MD, News Science Editorial Board
Gille B, De Schaepdryver M, Goossens J, Dedeene L, et al. Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 2018 Jun 16. doi: 10.1111/nan.12511. [Epub ahead of print]
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive motor neuron disease affecting both the upper and lower motor neurons. It was found that in ALS, blood neurofilament light chain (NfL) levels are elevated. The mechanism and diagnostic values of this finding have been elusive. NfL and phosphorylated neurofilament heavy chain (pNfC) have been found to be elevated in CSF samples of ALS patients compared to the ALS mimics and healthy controls.  
This Belgian research group previously showed there is correlation of the CSF NfL level with the serum level. In this article, they did the study based on a cohort of 149 serum samples of patients with ALS, 19 serum samples of patients with a disease mimicking ALS and 82 serum samples of disease control patients. The serum NfL levels were correlated with the number of regions (thoracic, bulbar, upper limb and lower limb) displaying upper and/or lower motor neuron degeneration. The prognostic performances of serum NfL were investigated based on a Cox regression analysis. They showed that serum NfL was associated with motor neuron degeneration driven by upper motor neuron degeneration and was independently associated with survival in patients with ALS. 
Comment: ALS is the most common motor neuron disease and the diagnosis is still based on clinical history and neurological examination as well as ruling out other ALS mimics. EMG/NCS is the diagnostic test that assesses the denervation in the lower motor neurons. There are no existing validated biomarkers for upper motor neuron dysfunction. On average, there is a 10-12 months delay in diagnosing ALS after the first onset of ALS symptoms. An early and timely diagnosis is desirable both for initiation of the therapy and also for the clinical trial enrollment. This work showed that elevated serum NfL levels in ALS are driven by UMN degeneration and the disease progression rate and are independently associated with survival at time of diagnosis. It’s worth noting that elevated CSF and serum NfL have been shown in other neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, and frontal temporal dementia, thus making this biomarker less specific. Nevertheless, this study provided a potentially useful biomarker for ALS diagnosis and research.
Submitted by John C. Kincaid, MD, News Science Editorial Board 
Edited by Benn E. Smith, MD, News Science Editorial Board
Thompson AG, Gray D, Thezenas M, et al. Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis. Ann Neurol 2018; 83:258-268. 
The paper reports about elevated CSF levels of chitinase proteins which are biomarkers of macrophage activation. Elevation of CSF levels of these proteins also correlate with CSF level of a neurofilament protein pNFH which is a marker of axonal degeneration. The degree of elevation correlated with the rate of disease progression. Immune activation has been considered a potential contributor to the pathogenesis of ALS for many years. Two of the 3 proteins studies did not showed elevated levels in patients with primary lateral sclerosis. Unanswered questions include whether macrophage activation influences disease progression/survival independent of the primary degenerative process.
Submitted by Rocio Carolina Garcia Santibanez, MD, News Science Editorial Board 
Edited by Leigh Maria K. Ramos-Platt, MD, News Science Editorial Board
Zambelis T, Koutsoudaki P, Anagnostou E, Kokotis P, Karandreas N. Electromyography study of the thoracic paraspinal and rectus abdominis muscles in amyotrophic lateral sclerosis. Journal of Clinical Neurophysiology. May 2018.
The investigators in this study sought to describe the EMG findings in the rectus abdominis (RA) muscles in patients with clinically definite ALS by El Escorial criteria to see if this could be a suitable muscle to evaluate for denervation of the thoracic region (and thus be an alternative way to evaluate for the third denervated region). Ninety-five consecutive patients were recruited over 5 years. The thoracic paraspinal and RA muscles were sampled at the level of T9. Active denervation was seen in the thoracic paraspinal muscles in 75 patients (79%) and in the RA in 62 (65.3%). Nineteen patients had thoracic paraspinal and not RA denervation. Six patients had RA and thoracic paraspinal denervation. Denervation in RA was more common in older patients.
Comment: RA sampling could be an alternative for evaluation of thoracic region denervation in ALS. Though the RA seems to be less commonly involved than the thoracic paraspinals, it is more easily accessible and easier to relax but there is a risk of perinoteum puncture. The significance of the more frequent denervation of the RA in older patients needs further investigation.

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