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

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 Cerebrospinal Fluid of Newly Diagnosed Multiple Sclerosis Patients and Their Link to Iron Deposition and Atrophy.

Oxidative stress has been implied in cellular injury even in the early phases of multiple sclerosis (MS). In this study, we quantified levels of biomarkers of oxidative stress and antioxidant capacity in cerebrospinal fluid (CSF) in newly diagnosed MS patients and their associations with brain atrophy and iron deposits in the brain tissue. Consecutive treatment-naive adult MS patients (n = 103) underwent brain MRI and CSF sampling. Healthy controls (HC, n = 99) had brain MRI. CSF controls (n = 45) consisted of patients with non-neuroinflammatory conditions. 3T MR included isotropic T1 weighted (MPRAGE) and gradient echo (GRE) images that were processed to quantitative susceptibility maps. The volume and magnetic susceptibility of deep gray matter (DGM) structures were calculated. The levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-iso prostaglandin F2α (8-isoPG), neutrophil gelatinase-associated lipocalin (NGAL), peroxiredoxin-2 (PRDX2), and malondialdehyde and hydroxyalkenals (MDA + HAE) were measured in CSF. Compared to controls, MS patients had lower volumes of thalamus, pulvinar, and putamen, higher susceptibility in caudate nucleus and globus pallidus, and higher levels of 8-OHdG, PRDX2, and MDA + HAE. In MS patients, the level of NGAL correlated negatively with volume and susceptibility in the dentate nucleus. The level of 8-OHdG correlated negatively with susceptibility in the caudate, putamen, and the red nucleus. The level of PRDX2 correlated negatively with the volume of the thalamus and both with volume and susceptibility of the dentate nucleus. From MRI parameters with significant differences between MS and HC groups, only caudate susceptibility and thalamic volume were significantly associated with CSF parameters. Our study shows that increased oxidative stress in CSF detected in newly diagnosed MS patients suggests its role in the pathogenesis of MS.

Age-related magnetic susceptibility changes in deep grey matter and cerebral cortex of normal young and middle-aged adults depicted by whole brain analysis.

BACKGROUND: Iron accumulates in brain tissue in healthy subjects during aging. Our goal was to conduct a detailed analysis of iron deposition patterns in the cerebral deep grey matter and cortex using region-based and whole-brain analyses of brain magnetic susceptibility. METHODS: Brain MRI was performed in 95 healthy individuals aged between 21 and 58 years on a 3T scanner. MRI protocol included T1-weighted (T1W) magnetization-prepared rapid acquisition with gradient echo images and 3D flow-compensated multi-echo gradient-echo images for quantitative susceptibility mapping (QSM). In the region-based analysis, QSM and T1W images entered an automated multi-atlas segmentation pipeline and regional mean bulk susceptibility values were calculated. The whole-brain analysis included a non-linear transformation of QSM images to the standard MNI template. For the whole-brain analysis voxel-wise maps of linear regression slopes ß and P values were calculated. Regional masks of cortical voxels with a significant association between susceptibility and age were created and further analyzed. RESULTS: In cortical regions, the highest increase of susceptibility values with age was found in areas involved in motor functions (precentral and postcentral areas, premotor cortex), in cognitive processing (prefrontal cortex, superior temporal gyrus, insula, precuneus), and visual processing (occipital gyri, cuneus, posterior cingulum, fusiform, calcarine and lingual gyrus). Thalamic susceptibility increased until the fourth decade and decreased thereafter with the exception of the pulvinar where susceptibility increase was observed throughout the adult lifespan. Deep grey matter structures with the highest increase of susceptibility values with age included the red nucleus, putamen, substantia nigra, dentate nucleus, external globus pallidus, caudate nucleus, and the subthalamic nucleus in decreasing order. CONCLUSIONS: Accumulation of iron in basal ganglia follows a linear pattern whereas in the thalamus, pulvinar, precentral cortex, and precuneus, it follows a quadratic or exponential pattern. Age-related changes of iron content are different in the pulvinar and the rest of the thalamus as well as in internal and external globus pallidus. In the cortex, areas involved in motor and cognitive functions and visual processing show the highest iron increase with aging. We suggest that the departure from normal patterns of regional brain iron trajectories during aging may be helpful in the detection of subtle neurodegenerative and neuroinflammatory processes.