Diagnostic-prognostic value and electrophysiological correlates of CSF biomarkers of neurodegeneration and neuroinflammation in amyotrophic lateral sclerosis

Abstract

Neurofilament light chain protein (NfL) is currently the most accurate cerebrospinal fluid (CSF) biomarker in amyotrophic lateral sclerosis (ALS) in terms of both diagnostic and prognostic values, but the mechanism underlying its increase is still a matter of debate. Similarly, emerging CSF biomarkers of neurodegeneration and neuroinflammation showed promising results, although further studies are needed to clarify their clinical and pathophysiological roles. In the present study we compared the diagnostic accuracy of CSF NfL, phosphorylated (p)-tau/total (t)-tau ratio, chitinase-3like protein 1 (YKL-40) and chitotriosidase 1 (CHIT1), in healthy controls (n = 43) and subjects with ALS (n = 80) or ALS mimics (n=46). In ALS cases, we also investigated the association between biomarker levels and clinical variables, the extent of upper motor neuron (UMN) and lower motor neuron (LMN) degeneration, and denervation activity through electromyography (EMG). ALS patients showed higher levels of CSF NfL, YKL-40, CHIT1, and lower values of p-tau/ttau ratio compared to both controls and ALS mimics. Among all biomarkers, NfL yielded the highest diagnostic performance (> 90% sensitivity and specificity) and was the best predictor of disease progression rate and survival in ALS. NfL levels showed a higher correlation with the extent of LMN involvement, whereas YKL-40 levels increased together with the number of areas showing both UMN and LMN damage. EMG denervation activity did not correlate with any CSF biomarker change. These findings confirm the highest value of NfL among currently available CSF biomarkers for the diagnostic and prognostic assessment of ALS and contribute to the understanding of the pathophysiological and electrophysiological correlates of biomarker changes.

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

“…At the moment, however, the apparent lack of change of NFs concentration with advancing stages of diseases would indicate that the first measured value of NF would be informative about the rate of disease progression along the entire course of MND. The observation that baseline NF levels, i.e., at the first diagnostic visit, mostly in CSF [67,70,84], but also in serum [71,83,90] inversely correlated with survival in regression models support this conclusion. In univariate regression models, NF levels retain a high hazard risk for death [57,70,81].…”

“…However, subsequent larger studies provided controversial results on this issue, and, overall, did not confirm the correlation between NFs and DTI findings of corticospinal tract integrity [64,70,81]. Finally, in a recent study [67], CSF NfL concentration significantly correlated with the extent of LMN degeneration and not to that of UMN involvement, suggesting that the damaged motor neurons in the anterior horn of the spinal cord, which is rich in large axons, also significantly contribute to the release of NfL in CSF.…”

“…An ideal disease-progression or pharmaco-dynamic biomarker (see text for explanation) would change with the progression of the disease. Doubts on the possible use of NFs as disease-progression biomarkers have been raised, but only few studies have thoroughly investigated their longitudinal behaviour studies, holding for both NfL and NfH, in CSF and blood [57,58,[67][68][69]. On the other hand, other known prognostic indicators as bulbar-onset, and cognitive involvement did not correlate as expected with NF levels [58,70], possibly because the effect of neurodegenerative changes on NF levels is relatively independent of the brain region involved.…”

“…On the other hand, other known prognostic indicators as bulbar-onset, and cognitive involvement did not correlate as expected with NF levels [58,70], possibly because the effect of neurodegenerative changes on NF levels is relatively independent of the brain region involved. Moreover, when patients were stratified in fast, intermediate and slow progressors by tertiles, according to the ALSFRS-r progression rate, baseline levels of NFs variably discriminated between these categories between studies [58,67,69,83].…”

“…ALS mimic disorders, which initially could not be reliably differentiated from ALS, can now be identified with a significant degree of confidence [57,58,67,69] In the largest case series of MND mimics reported to date, the highest levels of NFs involved pathologies such as CIDP, myopathies, and polyneuropathies [57,64]. For a more detailed overview of studies analysing differential specificities of NFs in serum and CSF see Table 1.…”