N-Acetylaspartate and neurofilaments as biomarkers of axonal damage in patients with progressive forms of multiple sclerosis

Abstract

Primary and secondary progressive forms of multiple sclerosis (PPMS and SPMS) have different pathological characteristics. However, it is unknown whether neurodegenerative mechanisms are shared. We measured cerebrospinal fluid (CSF) levels of neurofilament (Nf) light and heavy isoforms and N-acetylaspartic acid (NAA) in 21 PP, 10 SPMS patients and 15 non-inflammatory neurological disease controls (NINDC). Biomarkers were related to Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) over a long period of follow-up [median (interquartile range) 9 (5.5-12.5) years] in 19 PPMS and 4 SPMS patients, and to T2 lesion load, T1 lesion load, and brain parenchymal fraction at the time of lumbar puncture. Nf light was higher in PPMS (p < 0.005) and Nf heavy was increased in both SPMS and PPMS (p < 0.05 and p < 0.01) compared to NINDC, but were comparable between the two MS subtypes. Nf heavy was a predictor of the ongoing disability measured by MSSS (R(2) = 0.17, β = 0.413; p < 0.05). Conversely, Nf light was the only predictor of the EDSS annual increase (R(2) = 0.195, β = 0.441; p < 0.05). The frequency of abnormal biomarkers did not differ between the two MS progressive subtypes. Our data suggest that PP and SPMS likely share similar mechanisms of axonal damage. Moreover, Nf heavy can be a biomarker of ongoing axonal damage. Conversely, Nf light can be used as a prognostic marker for accumulating disability suggesting it as a good tool for possible treatment monitoring in the progressive MS forms.

Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis

“…NfL levels are increased in the cerebrospinal fluid (CSF) of MS patients as well as in degenerative and traumatic neurological diseases (eg, dementia, amyotrophic lateral sclerosis, and spinal cord injury) 4, 5, 6, 7, 8, 9. CSF NfL levels are further increased during relapses and are positively associated with magnetic resonance imaging (MRI) lesion load and disability scores in MS 10, 11, 12.…”

“…3 NfL levels are increased in the cerebrospinal fluid (CSF) of MS patients as well as in degenerative and traumatic neurological diseases (eg, dementia, amyotrophic lateral sclerosis, and spinal cord injury). [4][5][6][7][8][9] CSF NfL levels are further increased during relapses and are positively associated with magnetic resonance imaging (MRI) lesion load and disability scores in MS. [10][11][12] Noteworthy, CSF NfL levels have also been shown to be a marker of treatment response in this disease. [13][14][15][16][17] However, lumbar punctures are relatively invasive procedures, limiting the value of CSF NfL in routine clinical settings.…”

Blood Biomarkers as Outcome Measures in Inflammatory Neurologic Diseases

“…In another cohort of patients with RRMS followed up for a median of 14 years, CSF NfL levels at diagnosis correlated with the MS Severity Score in the long term, while cases with high NfL levels (>386 ng/l) were more likely to convert into SPMS than those with low levels (<60 ng/ l) [74]. In a cohort of patients with progressive MS, NfH was a predictor of continuing disability, and NfL was a predictor of EDSS annual increase [75]. There is currently a new promising sensitive immunoassay for quantification of NfL in serum [76].…”

“…CSF IgG [15] Anti-natalizumab Abs [121,122] Anti-JCV Abs [132][133][134] Emerging Epidermal and hepatocyte growth factors, CCL4, and CCL11 [23] Anti-MOG Abs [56] Anti-MOG Abs [31][32][33][34] FasandMIF [66] Fas, FasL [79][80][81][82][83][84][85][86] miR-26a-5p [108][109][110] Anti-MOG Abs [30,57] Anti-MBP Abs [56] Anti-Nf Abs [69][70][71] sPECAM-1 [88] T R A I L [ 128,129] miR-223 [25] C H I 3 L 1 [ 58,59] N f L [ 37,68] sP-selectin and sE-selectin [88] L-selectin [135,137] miR-15b [26] C H I 3 L 2 [ 59] N f H [73][74][75][76]…”

A Personalized Approach in Progressive Multiple Sclerosis: The Current Status of Disease Modifying Therapies (DMTs) and Future Perspectives

“…In the PMS, neurofilament proteins and increased levels of antibodies to the neurofilaments light subunit have been found in PP and SPMS CSF showing good correlations with clinical disability and brain atrophy. Neurofilaments, the major axonal cytoskeleton proteins, represent biomarkers for monitoring axonal damage [46,47]. Moreover, antibodies to various gangliosides [48], and other neuronal antigens have been described as being associated with disease progression in PMS patients [49].…”