Searching for neurodegeneration in multiple sclerosis at clinical onset: Diagnostic value of biomarkers

Abstract

BackgroundNeurodegeneration occurs during the early stages of multiple sclerosis. It is an essential, devastating part of the pathophysiology. Tools for measuring the degree of neurodegeneration could improve diagnostics and patient characterization.ObjectiveThis study aimed to determine the diagnostic value of biomarkers of degeneration in patients with recent clinical onset of suspected multiple sclerosis, and to evaluate these biomarkers for characterizing disease course.MethodsThis cross-sectional study included 271 patients with clinical features of suspected multiple sclerosis onset and was the baseline of a prospective study. After diagnostic investigations, the patients were classified into the following disease groups: patients with clinically isolated syndrome (n = 4) or early relapsing remitting multiple sclerosis (early RRMS; n = 93); patients with relapsing remitting multiple sclerosis with disease durations ≥2 years (established RRMS; n = 39); patients without multiple sclerosis, but showing symptoms (symptomatic controls; n = 89); and patients diagnosed with other diseases (n = 46). In addition, we included healthy controls (n = 51) and patients with progressive multiple sclerosis (n = 23). We analyzed six biomarkers of neurodegeneration: cerebrospinal fluid neurofilament light chain levels; cerebral spinal fluid glial fibrillary acidic protein; cerebral spinal fluid tau; retinal nerve fiber layer thickness; macula volume; and the brain parenchymal fraction.ResultsExcept for increased cerebral spinal fluid neurofilament light chain levels, median 670 ng/L (IQR 400–2110), we could not find signs of early degeneration in the early disease group with recent clinical onset. However, the intrathecal immunoglobin G production and cerebral spinal fluid neurofilament light chain levels showed diagnostic value. Moreover, elevated levels of cerebral spinal fluid glial fibrillary acidic protein, thin retinal nerve fiber layers, and low brain parenchymal fractions were associated with progressive disease, but not with the other phenotypes. Thin retinal nerve fiber layers and low brain parenchymal fractions, which indicated neurodegeneration, were associated with longer disease duration.ConclusionsIn clinically suspected multiple sclerosis, intrathecal immunoglobin G production and neurofilament light chain levels had diagnostic value. Therefore, these biomarkers could be included in diagnostic work-ups for multiple sclerosis. We found that the thickness of the retinal nerve fiber layer and the brain parenchymal fraction were not different between individuals that were healthy, symptomatic, or newly diagnosed with multiple sclerosis. This finding suggested that neurodegeneration had not reached a significant magnitude in patients with a recent clinical onset of multiple sclerosis.

Neurofilaments in progressive multiple sclerosis: a systematic review

“…A number of studies (including 312 PMS patients) have reported that CSF or blood NFL (cNFL/bNFL) is higher in PMS compared to RRMS [4,5,[10][11][12][13][14][15][16][17][18][19], or that it increases more quickly in PMS [20]. Others, however, report that NFL is lower in PMS compared to RRMS [21][22][23] or controls [24]. The majority of studies found no significant difference between disease stages [25][26][27][28][29][30][31][32][33][34][35][36][37][38].…”

Neurofilaments: The C-Reactive Protein of Neurology

“…While CSF has some obvious advantages in CNS disease, its use is often limited by the invasive nature of the procedure that precludes its use as a frequent longitudinal marker. In general, there are strong correlations between NF-L levels in CSF, serum, and plasma [97,101,166,167], but while specificity and sensitivity are high in CSF due to the higher levels of NF-L, sensitivity is often lower in plasma [101,164,166,168] and even lower in serum [97]. Finally, the test methods also affect the results.…”

“…Several studies have shown that NF-L is elevated in the blood and CSF of newly diagnosed MS patients and that this is correlated with disease severity and prognosis [21,[97][98][99]. NF-L is also elevated during disease activity such as a clinical relapse of new lesions on MRI [100,101]. This makes NF-L an attractive diagnostic biomarker in MS although its specificity does not allow differentiation from MS mimics like neuromyelitis optica spectrum disorders or other neuroinflammatory disorders [102,103].…”

Treatment Optimization in Multiple Sclerosis: Canadian MS Working Group Recommendations

“…57 For example, one database analysis found that men were more likely to have pyramidal, brain stem, and cerebellar relapses, which were associated with worse outcomes; women more commonly had sensory or visual symptoms, which showed better recovery; and older patients had poorer recovery from relapses. 58 Considerable progress has been made in researching the prognostic value of biomarkers of axonal damage and neurodegeneration, such as neurofilament-light chain in CSF or serum, glial fibrillary acidic protein in CSF, and retinal nerve fiber layer thickness on OCT. 59 While the results to date are promising, it is premature to recommend biomarker testing as a guide to clinical decision-making. 60,61 The initial clinical assessment will include a complete patient history, neurological examination and consideration of prognostic factors.…”