BACKGROUND AND OBJECTIVES: Noninvasive and accurate biomarkers of neurologic Wilson disease (NWD), a rare inherited disorder, could reduce diagnostic error or delay. Excessive subcortical metal deposition seen on susceptibility imaging has suggested a characteristic pattern in NWD. With submillimeter spatial resolution and increased contrast, 7T susceptibility-weighted imaging (SWI) may enable better visualization of metal deposition in NWD. In this study, we sought to identify a distinctive metal deposition pattern in NWD using 7T SWI and investigate its diagnostic value and underlying pathophysiologic mechanism. METHODS: Patients with WD, healthy participants with monoallelic ATP7B variant(s) on a single chromosome, and health controls (HCs) were recruited. NWD and non-NWD (nNWD) were defined according to the presence or absence of neurologic symptoms during investigation. Patients with other diseases with comparable clinical or imaging manifestations, including early-onset Parkinson disease (EOPD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and neurodegeneration with brain iron accumulation (NBIA), were additionally recruited and assessed for exploratory comparative analysis. All participants underwent 7T T1, T2, and high-resolution SWI scanning. Quantitative susceptibility mapping and principal component analysis were performed to illustrate metal distribution. RESULTS: We identified a linear signal intensity change consisting of a hyperintense strip at the lateral border of the globus pallidus in patients with NWD. We termed this feature "hyperintense globus pallidus rim sign." This feature was detected in 38 of 41 patients with NWD and was negative in all 31 nNWD patients, 15 patients with EOPD, 30 patients with MSA, 15 patients with PSP, and 12 patients with NBIA; 22 monoallelic ATP7B variant carriers; and 41 HC. Its sensitivity to differentiate between NWD and HC was 92.7%, and specificity was 100%. Severity of the hyperintense globus pallidus rim sign measured by a semiquantitative scale was positively correlated with neurologic severity (ρ = 0.682, 95% CI 0.467-0.821, p < 0.001). Patients with NWD showed increased susceptibility in the lenticular nucleus with high regional weights in the lateral globus pallidus and medial putamen. DISCUSSION: The hyperintense globus pallidus rim sign showed high sensitivity and excellent specificity for diagnosis and differential diagnosis of NWD. It is related to a special metal deposition pattern in the lenticular nucleus in NWD and can be considered as a novel neuroimaging biomarker of NWD. CLASSIFICATION OF EVIDENCE: The study provides Class II evidence that the hyperintense globus pallidus rim sign on 7T SWI MRI can accurately diagnose neurologic WD.

• MeSH
• ATPasy transportující měď metabolismus   genetika   MeSH
• dospělí MeSH
• globus pallidus diagnostické zobrazování   metabolismus   MeSH
• hepatolentikulární degenerace * diagnostické zobrazování   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie * metody   MeSH
• měď metabolismus   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mozek diagnostické zobrazování   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ATP7B protein, human MeSH Prohlížeč
• ATPasy transportující měď MeSH
• měď 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.

• Klíčová slova
• cerebrospinal fluid, iron, magnetic resonance imaging, multiple sclerosis, oxidative stress, susceptibility,
• 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
• Názvy látek
• železo 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.

• Klíčová slova
• cerebrospinal fluid, magnetic resonance imaging, multiple sclerosis, neutrophil gelatinase-associated lipocalin, oxidative stress, peroxiredoxin,
• Publikační typ
• časopisecké články MeSH

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson's disease, Friedreich's disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood-brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.

• Klíčová slova
• MRI, NBIA, chelation, ferroptosis, iron accumulation, neurodegeneration, siderosis,
• MeSH
• lidé MeSH
• mozek patologie   MeSH
• neuroaxonální dystrofie * patologie   MeSH
• neurodegenerativní nemoci * patologie   MeSH
• poruchy metabolismu železa * patologie   MeSH
• železo farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• železo MeSH