Projekt je zaměřen na zkoumání prediktivní síly multiparametrické MRI (kvantitativní mapování susceptibility – QSM a R1, R2* relaxometrie), zejména parametrů odrážejících akumulaci železa v mozku, na predikci prognózy pacientů v časné fázi roztroušené sklerózy (RS). Prediktivní hodnota biomarkerů ve vztahu k progresi onemocnění a klinickému stavu bude hodnocena 12 a 24 měsíců po stanovení diagnózy. Dále budeme zkoumat biochemické a imunologické parametry v krvi a likvoru, které souvisí s metabolismem železa, oxidativním stresem a feroptózou a hledat markery, které korelují s akumulací železa v mozku mezi měsícem 0 a 24. Pomocí MRI-histopatologické studie používající obdobný MR protokol, jako u pacientů, plánujeme potvrdit validitu QSM (ve spojení s R2*/R1 relaxometrií) ve stanovení koncentrace železa v lézích v bílé hmotě. Identifikace nových MRI parametrů, které predikují rychlost progrese onemocnění může přinést nové biomarkery aktivity nemoci, přispět k lepšímu porozumění patofyziologie nemoci a zlepšit léčebnou strategii u pacientů s RS (tzv. theranostics).; This project is aimed at examining the prognostic value of multi-parametric MRI (quantitative susceptibility mapping - QSM, R1, R2*relaxometry) focusing on iron content in early multiple sclerosis (MS). The ability of these biomarkers to predict disease progression defined as change in Expanded Disability Status Scale and cognitive status at 12 and 24 months from baseline will be assessed in a cohort of de novo MS patients. Additionally, blood/CSF parameters related to immune activation, iron metabolism, oxidative stress, and ferroptosis will be investigated and determinants of cerebral iron accumulation will be sought for. Post-mortem MRI-histopathology correlation will be performed with similar MRI protocol as the in vivo study to validate QSM in conjunction with R2*/R1 relaxometry for measuring iron concentration. Identifying new MRI approaches that predict disease progression can provide new biomarkers of disease activity, contribute to a better understanding of the disease pathophysiology, and improve the therapeutic strategy in MS patients and thus have a theranostic value.

• Klíčová slova
• biomarkers, magnetická rezonance, magnetic resonance imaging, roztroušená skleróza, biomarkry, železo v mozku, multiple sclerosis, brain iron, quantitative susceptibility mapping, kvantitativní mapování susceptibility,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

BACKGROUND: Although there is evidence that shows worse cognitive functioning in male patients with multiple sclerosis (MS), the role of brain pathology in this context is under-investigated. OBJECTIVE: To investigate sex differences in cognitive performance of MS patients, in the context of brain pathology and disease burden. METHODS: Brain MRI, neurological examination, neuropsychological assessment (Brief International Cognitive Assessment in MS-BICAMS, and Paced Auditory Verbal Learning Test-PASAT), and patient-reported outcome questionnaires were performed/administered in 1052 MS patients. RESULTS: Females had higher raw scores in the Symbol Digit Modalities Test (SDMT) (57.0 vs. 54.0; p < 0.001) and Categorical Verbal Learning Test (CVLT) (63.0 vs. 57.0; p < 0.001), but paradoxically, females evaluated their cognitive performance by MS Neuropsychological Questionnaire as being worse (16.6 vs 14.5, p = 0.004). Females had a trend for a weaker negative correlation between T2 lesion volume and SDMT ([Formula: see text] = - 0.37 in females vs. - 0.46 in men; interaction p = 0.038). On the other hand, women had a trend for a stronger correlation between Brain Parenchymal Fraction (BPF) and a visual memory test (Spearman's [Formula: see text] = 0.31 vs. 0.21; interaction p = 0.016). All these trends were not significant after correction for false discovery rate. CONCLUSIONS: Although, females consider their cognition as worse, males had at a group level slightly worse verbal memory and information processing speed. However, the sex differences in cognitive performance were smaller than the variability of scores within the same sex group. Brain MRI measures did not explain the sex differences in cognitive performance among MS patients.

• MeSH
• kognice MeSH
• kognitivní dysfunkce * MeSH
• kognitivní poruchy * diagnóza   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mozek diagnostické zobrazování   MeSH
• neuropsychologické testy MeSH
• pohlavní dimorfismus MeSH
• roztroušená skleróza * komplikace   diagnostické zobrazování   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

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.

• MeSH
• atrofie patologie   MeSH
• lidé MeSH
• longitudinální studie MeSH
• magnetická rezonanční tomografie metody   MeSH
• mozek diagnostické zobrazování   patologie   MeSH
• nemoci centrálního nervového systému * patologie   MeSH
• oxidační stres MeSH
• prospektivní studie MeSH
• roztroušená skleróza * diagnostické zobrazování   patologie   MeSH
• šedá hmota patologie   MeSH
• železo MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

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.

• Publikační typ
• časopisecké články MeSH