Page 32 - Read Online

Page 28 Toscano et al. Neuroimmunol Neuroinflammation 2021;8:14-41 I http://dx.doi.org/10.20517/2347-8659.2020.12

medium (NF-M) and light (NF-L) chains [211] , their detection in CSF and blood samples has been the subject
of interest for years. Several studies investigated the increase in NFs in several neurological diseases [212] ,
such as amyotrophic lateral sclerosis [213] , Alzheimer’s disease [214] , frontotemporal dementia [215] , stroke [216] ,
MS [211] , Huntington disease [217] , atypical parkinsonian syndromes and neurocognitive impairment in HIV-
positive individuals [218] .

In most cases, NFs have been investigated as a potential prognostic and disease activity marker related to
axonal damage, speculating a relation between the quantitative amount of CSF and serum NFs and the rate
of neurodegeneration [218] .

In MS, NFs have also been extensively examined as a diagnostic, disease activity and drug response
biomarker. Moreover, serum NF-L levels, detected through a single molecule array (Simoa), appear
strictly related to CSF levels [219-222] , despite being approximately 42-fold lower [223] . Cut-off values have not
been unequivocally established as for CSF ones. However, serum NF-L values between 16-20 pg/mL have
been identified as a normal range among a heterogeneous group of healthy controls enrolled in various
studies [211] , without gender difference and with a trend to increase along with age-related physiological
axonal damage [223] .

Particularly, while the detection of higher CSF NF-H levels in SPMS patients suggests a major correlation
with chronic axonal damage and is accordingly age-related [224,225] , CSF NF-L seem to be better related to
acute axonal damage due to inflammation. Indeed, increased levels of NF-L were found in CSF of MS
patients compared with controls, with greater concentrations during exacerbations. Moreover, such high
concentrations were associated with progression in both clinically stable patients and relapsing ones [226,227] .
A recent meta-analysis confirmed these results, finding higher CSF NF-L levels in RRMS patients compared
with PMS and double concentrations in relapsing patients compared with remitting ones [228] .

In a longitudinal study involving 22 IFNβ-1a- and riluzole-treated patients and 20 IFNβ-1a- and placebo-
treated ones with early MS, serum NF-L concentrations were assessed over a 24-month period, correlating
well with EDSS changes, Gd+ lesions and the development of brain atrophy. Moreover, increased
serum NF-L levels were associated with worse results in neuropsychological tests assessing visuospatial
functioning, recall and both verbal and non-verbal episodic learning [229] .

Similar results concerning the association between serum NF-L levels and cognitive impairment in early
[231]
stages of MS [230] and between serum NF-L concentrations and EDSS changes were confirmed by other
studies, though not all agreed [232] . Despite correlating with EDSS in PMS patients, serum NF-L levels failed
to correlate with EDSS progression in the previous year and during a median follow-up of 27 months.
Particularly, serum NF-L increased in all PMS patients, including those who did not exhibit changes in
EDSS or an increase in disability [232] .

In patients with RIS, increased CSF NF-L levels were found to be an independent risk factor for the
conversion to CIS and MS. Matute-Blanch and coworkers considered a cut-off value equal to 619 ng/L,
[32]
since greater values were related to shorter times of conversion . CSF NF-L concentrations have been
found to be increased in patients with CIS as well [233] , with greater ones in those who converted to clinically
definite MS [224,234] . Despite these promising results, their role as prognostic biomarker for CIS conversion is
[3]
still weak, and replication in larger cohorts is needed to confirm it .
In 86 CIS patients with optic neuritis as the first clinical event, CSF NF-L levels also predicted long-term
cognitive and physical disability over a follow-up period ranging between 9 and 19 years [235] .