CSF Markers of Oxidative Stress Are Associated with Brain Atrophy and Iron Accumulation in a 2-Year Longitudinal Cohort of Early MS

Abstract

In this prospective longitudinal study, we quantified regional brain volume and susceptibility changes during the first two years after the diagnosis of multiple sclerosis (MS) and identified their association with cerebrospinal fluid (CSF) markers at baseline. Seventy patients underwent MRI (T1 and susceptibility weighted images processed to quantitative susceptibility maps, QSM) with neurological examination at the diagnosis and after two years. In CSF obtained at baseline, the levels of oxidative stress, products of lipid peroxidation, and neurofilaments light chain (NfL) were determined. Brain volumetry and QSM were compared with a group of 58 healthy controls. In MS patients, regional atrophy was identified in the striatum, thalamus, and substantia nigra. Magnetic susceptibility increased in the striatum, globus pallidus, and dentate and decreased in the thalamus. Compared to controls, MS patients developed greater atrophy of the thalamus, and a greater increase in susceptibility in the caudate, putamen, globus pallidus and a decrease in the thalamus. Of the multiple calculated correlations, only the decrease in brain parenchymal fraction, total white matter, and thalamic volume in MS patients negatively correlated with increased NfL in CSF. Additionally, negative correlation was found between QSM value in the substantia nigra and peroxiredoxin-2, and QSM value in the dentate and lipid peroxidation levels.

Oxidative Stress Markers in Multiple Sclerosis

“…Table S1 summarizes the results of studies related to markers of oxidative stress in the CSF from MS patients compared to controls [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ]. Most of these studies found increased CSF levels of markers of lipid peroxidation, such as malonyl-dialdehyde, hydroxyalkenals, diene conjugates, 4-hydroxy-nonenal, oxidized phosphatidylcholine, and isoprostanes in patients diagnosed with MS compared to controls [ 13 , 32 , 33 , 34 , 35 , 37 , 38 , 39 , 40 , 45 , 46 , 47 ], with some exceptions [ 36 ]. CSF levels of certain prostaglandins were increased in patients with MS in most studies [ 35 ,…”

“…The CSF human serum albumin (HAS), mercaptoalbumin (HMA), and non-mercaptoalbumins 1 and 2 (HNA1 and HNA2) [ 65 ] levels were reported to be similar in MS patients and controls. CSF neutrophil gelatinase-associated lipocalin (NGAL) was increased [ 39 ] or similar [ 38 ] compared to controls in two studies by the same group. Finally, DJ-1 [ 66 ], periredoxins 2 (PRX2) [ 38 , 39 ], and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) [ 67 ] were increased in the CSF of patients with MS compared to controls.…”

“…CSF neutrophil gelatinase-associated lipocalin (NGAL) was increased [ 39 ] or similar [ 38 ] compared to controls in two studies by the same group. Finally, DJ-1 [ 66 ], periredoxins 2 (PRX2) [ 38 , 39 ], and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) [ 67 ] were increased in the CSF of patients with MS compared to controls.…”