Clinical and demographic characteristics of patients with NMOSD: a longitudinal retrospective analysis of a Slovak cohort of 63 patients.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are autoantibody-mediated inflammatory diseases of the central nervous system predominantly targeting optic nerves and the spinal cord. Two distinct phenotypes are recognized based on the presence of serum aquaporin-4 (AQP4-IgG) antibodies. However, contrasting clinical course patterns have been identified between AQP4-IgG-positive and AQP4-IgG-negative patients. AIMS: This study aimed to present demographic and clinical characteristics of patients with NMOSD in Slovakia and to evaluate the significance of differences between AQP4-IgG-seropositive and AQP4-IgG-seronegative patients. METHODS: We performed a longitudinal multi-centric retrospective study and analysed the clinical and demographic characteristics of a cohort of 63 Slovak NMOSD patients. RESULTS: Eighty-six percent of patients were women, and ninety-four patients were Caucasian. The median age at diagnosis was 37 years. The most frequent initial manifestations were optic neuritis (47.6% of patients) and transverse myelitis (39.7% of patients). The median EDSS score deteriorated from the initial 3.0 to 4.0 at the last follow-up. Sixty-eight percent of patients were AQP4-IgG positive; 10% of patients were MOG-IgG positive; 27% of patients had no NMOSD-specific antibodies detected. There was a higher prevalence of autoimmune thyroiditis among AQP4-IgG-positive patients (25.6%) compared to AQP4-IgG-negative patients (0%) (p = 0.01). CONCLUSION: This study provides a detailed overview of the clinical and demographic characteristics of NMOSD based on a retrospective analysis of a Slovak cohort of 63 NMOSD patients and extends information provided by similar recently published studies. The most important finding is that there is a high prevalence of autoimmune thyroiditis among AQP4-IgG-negative patients (25%).

Analysis of Cdx2 VDR gene polymorphism rs11568820 in association with multiple sclerosis in Slovaks.

Vitamin D deficiency is involved in the pathogenesis of multiple sclerosis (MS), a severe autoimmune demyelinating disease of the central nervous system. The gene polymorphism Cdx-2 (rs11568820, G/A) seriously influences the trancriptional activity of the vitamin D receptor (VDR) that binds the vitamin D responsive elements of target genes including HLA-DRB1*15. The aim of the present study in Slovaks was to analyse the association of Cdx-2 variants with the risk of MS and disability progression, and to assess the DRB1*15:01 allele as a possible confounding factor. In total, 493 MS patients and 417 healthy controls were involved in this study. The genotyping of Cdx-2 was performed using restriction analysis; DRB1*15:01 positivity was determined by a high-resolution melting analysis of its surrogate marker rs3135388 (G/A). Our results did not prove any allelic association between Cdx-2 and a risk of MS (minor allele A - 0.181 in patients vs. 0.161 in controls, OR = 1.15, .95 CI = 0.90-1.47, p = 0.289). The logistic regression analysis, adjusted for sex and age, showed no differences in Cdx-2 genotype counts when using an additive, dominant or recessive genetic model (p = 0.351, 0.150, 0.240 respectively). The Cdx-2 variants were also not associated with disease disability progression, evaluated using the Multiple Sclerosis Severity Score. The HLA-DRB1*15:01 allele was found to strongly increase the risk of MS in our study (0.300 in patients vs. 0.101 in controls, OR = 3.83, .95 CI = 2.94-4.99, p = 1.016 × 10-26, dominant genetic model OR = 4.62, .95 CI = 3.40-6.26, p = 9.1 × 10-23). In summary, we found the Cdx-2 as a single genetic marker not to be associated with MS development or progression in Slovaks, independently of HLA-DRB1*15:01 status.

Safety and efficacy of simple training protocol in patients after mild traumatic brain injury.

AIMS: Mild Traumatic Brain Injury (mTBI) is the most common type of craniocerebral injury. Proper management appears to be a key factor in preventing post-concussion syndrome. The aim of this prospective study was to evaluate the effect and safety of selected training protocol in patients after mTBI. METHODS: This was a prospective study that included 25 patients with mTBI and 25 matched healthy controls. Assessments were performed in two sessions and included a post-concussion symptoms questionnaire, battery of neurocognitive tests, and magnetic resonance with tractography. Participants were divided into two groups: a passive subgroup with no specific recommendations and an active subgroup with simple physical and cognitive training. RESULTS: The training program with slightly higher initial physical and cognitive loads was well tolerated and was harmless according to the noninferiority test. The tractography showed overall temporal posttraumatic changes in the brain. The predictive model was able to distinguish between patients and controls in the first (AUC=0.807) and second (AUC=0.652) sessions. In general, tractography had an overall predictive dominance of measures. CONCLUSION: The results from our study objectively point to the safety of our chosen training protocol, simultaneously with the signs of slight benefits in specific cognitive domains. The study also showed the capability of machine learning and predictive models in mTBI patient recognition.

Imaging Methods Applicable in the Diagnostics of Alzheimer's Disease, Considering the Involvement of Insulin Resistance.

Alzheimer's disease (AD) is an incurable neurodegenerative disease and the most frequently diagnosed type of dementia, characterized by (1) perturbed cerebral perfusion, vasculature, and cortical metabolism; (2) induced proinflammatory processes; and (3) the aggregation of amyloid beta and hyperphosphorylated Tau proteins. Subclinical AD changes are commonly detectable by using radiological and nuclear neuroimaging methods such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Furthermore, other valuable modalities exist (in particular, structural volumetric, diffusion, perfusion, functional, and metabolic magnetic resonance methods) that can advance the diagnostic algorithm of AD and our understanding of its pathogenesis. Recently, new insights into AD pathoetiology revealed that deranged insulin homeostasis in the brain may play a role in the onset and progression of the disease. AD-related brain insulin resistance is closely linked to systemic insulin homeostasis disorders caused by pancreas and/or liver dysfunction. Indeed, in recent studies, linkages between the development and onset of AD and the liver and/or pancreas have been established. Aside from standard radiological and nuclear neuroimaging methods and clinically fewer common methods of magnetic resonance, this article also discusses the use of new suggestive non-neuronal imaging modalities to assess AD-associated structural changes in the liver and pancreas. Studying these changes might be of great clinical importance because of their possible involvement in AD pathogenesis during the prodromal phase of the disease.

Lesion-Specific Metabolic Alterations in Relapsing-Remitting Multiple Sclerosis Via 7 T Magnetic Resonance Spectroscopic Imaging.

BACKGROUND: Magnetic resonance spectroscopic imaging (MRSI) of the brain enables in vivo assessment of metabolic alterations in multiple sclerosis (MS). This provides complementary insights into lesion pathology that cannot be obtained via T1- and T2-weighted conventional magnetic resonance imaging (cMRI). PURPOSE: The aims of this study were to assess focal metabolic alterations inside and at the periphery of lesions that are visible or invisible on cMRI, and to correlate their metabolic changes with T1 hypointensity and the distance of lesions to cortical gray matter (GM). METHODS: A 7 T MRSI was performed on 51 patients with relapsing-remitting MS (30 female/21 male; mean age, 35.4 ± 9.9 years). Mean metabolic ratios were calculated for segmented regions of interest (ROIs) of normal-appearing white matter, white matter lesions, and focal regions of increased mIns/tNAA invisible on cMRI. A subgroup analysis was performed after subdividing based on T1 relaxation and distance to cortical GM. Metabolite ratios were correlated with T1 and compared between different layers around cMRI-visible lesions. RESULTS: Focal regions of, on average, 2.8-fold higher mIns/tNAA than surrounding normal-appearing white matter and with an appearance similar to that of MS lesions were found, which were not visible on cMRI (ie, ~4% of metabolic hotspots). T1 relaxation was positively correlated with mIns/tNAA ( P ≤ 0.01), and negatively with tNAA/tCr ( P ≤ 0.01) and tCho/tCr ( P ≤ 0.01). mIns/tCr was increased outside lesions, whereas tNAA/tCr distributions resembled macroscopic tissue damage inside the lesions. mIns/tCr was -21% lower for lesions closer to cortical GM ( P ≤ 0.05). CONCLUSIONS: 7 T MRSI allows in vivo visualization of focal MS pathology not visible on cMRI and the assessment of metabolite levels in the lesion center, in the active lesion periphery and in cortical lesions. This demonstrated the potential of MRSI to image mIns as an early biomarker in lesion development.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) syndrome: Treatment approach depends on disease course.

INTRODUCTION: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare inflammatory central nervous system (CNS) disorder, chiefly involving the brainstem, especially the pons. The diagnosis is challenging, requires careful exclusion of alternative diagnoses and a targeted therapeutic approach. CLIPPERS is known to respond well to corticosteroids, but the treatment needs to be long-term and can cause significant side-effects. Moreover, subsequent corticosteroid withdrawal often leads to a relapse. It has been suggested that anti-CD20 molecules could benefit several antibody-mediated CNS inflammatory diseases, including CLIPPERS. CASE REPORT: This paper describes two cases of CLIPPERS. The first demonstrates the benefit of early introduction of corticosteroids with side effects in cases of long-term use. The second demonstrates the efficacy of ocrelizumab (anti-CD20 molecule) in a severe course of CLIPPERS. CONCLUSION: These two cases bring attention to this rare, often misdiagnosed but treatable disease.

Information-processing speed in mildly disabled relapsing-remitting multiple sclerosis patients correlates with volumetry of optic chiasma and subcortical grey matter nuclei.

INTRODUCTION: Multiple sclerosis (MS) is an inflammatory demyelinating disease leading not only to physical disability but also to cognitive dysfunction. The aim of our study was to test cognitive functions of MS patients with mild relapsing-remitting form and to find out the relationship between cognitive functions and brain volumetry. METHODS: 52 patients (RRMSp) and 23 age-related healthy participants (CON) were enrolled. Mild disability was defined by mean EDSS 2.4 (≤ 4.0), and by median of disease duration 5.2 years. Cognitive status was tested using Single Digit Modality Test (SDMT). Brain volumetry was processed in FreeSurfer 2.0.0. RESULTS: RRMSp patients showed significantly lower SDMT score than CON. SDMT results correlated positively with volume of thalamus, putamen and nc. caudate, and negatively with optic chiasma volume. Compared with CON, RRMSp presented with significantly lower volume in left and right nc. accumbent, cuneus and insular GM, right putamen, total brain cortical grey matter (GM), white matters hypointensities, and 3rd ventricular widths. CONCLUSION: To our best knowledge, this is the first study that presents results showing a correlation of lower SDMT with higher optic chiasma volume, due to its subclinical chronic demyelination. We confirmed that GM atrophy is involved in cognitive functions in MS (Tab. 3, Fig. 2, Ref. 73).

Extensive Brain Pathologic Alterations Detected with 7.0-T MR Spectroscopic Imaging Associated with Disability in Multiple Sclerosis.

Background MR spectroscopic imaging (MRSI) allows in vivo assessment of brain metabolism and is of special interest in multiple sclerosis (MS), where morphologic MRI cannot depict major parts of disease activity. Purpose To evaluate the ability of 7.0-T MRSI to depict and visualize pathologic alterations in the normal-appearing white matter (NAWM) and cortical gray matter (CGM) in participants with MS and to investigate their relation to disability. Materials and Methods Free-induction decay MRSI was performed at 7.0 T. Participants with MS and age- and sex-matched healthy controls were recruited prospectively between January 2016 and December 2017. Metabolic ratios were obtained in white matter lesions, NAWM, and CGM regions. Subgroup analysis for MS-related disability based on Expanded Disability Status Scale (EDSS) scores was performed using analysis of covariance. Partial correlations were applied to explore associations between metabolic ratios and disability. Results Sixty-five participants with MS (mean age ± standard deviation, 34 years ± 9; 34 women) and 20 age- and sex-matched healthy controls (mean age, 32 years ± 7; 11 women) were evaluated. Higher signal intensity of myo-inositol (mI) with and without reduced signal intensity of N-acetylaspartate (NAA) was visible on metabolic images in the NAWM of participants with MS. A higher ratio of mI to total creatine (tCr) was observed in the NAWM of the centrum semiovale of all MS subgroups, including participants without disability (marginal mean ± standard error, healthy controls: 0.78 ± 0.04; EDSS 0-1: 0.86 ± 0.03 [P = .02]; EDSS 1.5-3: 0.95 ± 0.04 [P < .001]; EDSS ≥3.5: 0.94 ± 0.04 [P = .001]). A lower ratio of NAA to tCr was found in MS subgroups with disabilities, both in their NAWM (marginal mean ± standard error, healthy controls: 1.46 ± 0.04; EDSS 1.5-3: 1.33 ± 0.03 [P = .03]; EDSS ≥3.5: 1.30 ± 0.04 [P = .01]) and CGM (marginal mean ± standard error, healthy controls: 1.42 ± 0.05; EDSS ≥3.5: 1.23 ± 0.05 [P = .006]). mI/NAA correlated with EDSS (NAWM of centrum semiovale: r = 0.47, P < .001; parietal NAWM: r = 0.43, P = .002; frontal NAWM: r = 0.34, P = .01; frontal CGM: r = 0.37, P = .004). Conclusion MR spectroscopic imaging at 7.0 T allowed in vivo visualization of multiple sclerosis pathologic findings not visible at T1- or T2-weighted MRI. Metabolic abnormalities in the normal-appearing white matter and cortical gray matter were associated with disability. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Barker in this issue.

Neurocognitive performance in relapsing-remitting multiple sclerosis patients is associated with metabolic abnormalities of the thalamus but not the hippocampus- GABA-edited 1H MRS study.

OBJECTIVES: Multiple sclerosis (MS) is an inflammatory demyelinating disease that may cause physical disabling as well as cognitive dysfunction. The presented study investigated how the neuropsychological status depends on the thalamus and hippocampus's metabolic processes, using γ-aminobutyric acid-edited magnetic resonance spectroscopy (GABA-edited 1H MRS) in patients with early MS, and how the results differ from healthy volunteers. METHODS: We recruited 36 relapsing-remitting (RRMS) MS patients and 22 controls (CON). In addition to common 1H MRS metabolites, such as N-acetyl-aspartate (tNAA), myoinositol (mIns), total choline and creatine (tCr, tCho), we also evaluated GABA and glutamate/glutamine (Glx). Metabolite ratios were correlated with the results of Single-Digit Modality Test (SDMT) and Expanded Disability Status Score (EDSS). RESULTS: In the thalamus, GABA ratios (GABA/tCr, GABA/tNAA) were significantly lower in RRMS patients than in CON. Both tCho- and mIns-ratios correlated with lower scores of SDMT but not with EDSS. Metabolic ratios in the hippocampus did not differ between RRMS and CON and did not correlate with any of performed tests. DISCUSSION: This study is the first to provide GABA-edited 1H MRS evidence for MS-related metabolic changes of the thalamus and hippocampus. The findings underline the importance of evaluating subcortical grey matter in MS patients to improve understanding of the clinical manifestations of MS and as a potential future target for treatment.

Incidence and prevalence of neuromyelitis optica spectrum disorders in Slovakia.

OBJECTIVE: : Neuromyelitis optica spectrum disorders (NMOSDs) are a group of rare, inflammatory, demyelinating diseases that affect the central nervous system. Neither the incidence nor the prevalence of NMOSD has been determined in Slovakia thus far. The aim of this study was to determine both the incidence and the prevalence of NMOSD in Slovakia using the 2015 International Panel of NMOSD diagnosis (IPND) criteria. METHODS: : We performed a population-based study in Slovakia to estimate both the incidence and the prevalence of NMOSD during the period from 1 January 2006 through 31 December 2019. NMOSD cases were reported from multiple sources and the diagnosis was subsequently verified using the IPND criteria by a joint commitee of three neurologists. The prevalence is reported as number of cases per 100,000 inhabitans and the incidence as number of new cases per 1,000,000 person-years. Age-adjusted rates to the WHO standard population 2005-2025 were also calculated. RESULTS: : We identified 63 NMOSD cases. The crude point-prevalence rate was 1.37 (95% CI 1.03-1.71) per 100,000 inhabitants. The crude indidence rate was 0.88 (95% CI 0.65-1.12) per 1,000,000 person-years. The age-adjusted point-prevalence rate was 1.42 (95% CI 1.07-1.84) per 100,000 persons and the age-adjusted incidence rate was 0.96 (95% CI 0.72-1.25) per 1,000,000 person-years. CONCLUSION: : The NMOSD epidemiological situation in Slovakia is comparable to those reported from other Caucasian populations.

Proton magnetic resonance spectroscopy changes in the brainstem in patients after mild traumatic brain injury with loss of consciousness.

INTRODUCTION: Loss of consciousness (LOC) is used as a diagnostic feature of mild traumatic brain injury (MTBI). However, only 10% of concussions result in LOC. There are only a limited number of in-vivo studies dealing with unconsciousness and structural and functional integrity of the brainstem in patients with MTBI. The aim of our pilot study was to assess the sensitivity of proton magnetic resonance spectroscopy (1H-MRS) to detect metabolic changes in the brainstem in patients after MTBI with unconscioussness. METHODS: Twenty-four patients (12 with LOC, and 12 without LOC) within 3 days of MTBI and 19 healthy controls were examined. All subjects underwent single-voxel 1H-MRS examination of the upper brainstem. Spectra were evaluated using LCModel software. Ratios of total N-acetylaspartate (tNAA), total choline-containing compounds (tCho) and glutamate plus glutamine (Glx) to total creatine (tCre) were used for calculations. RESULTS: We found a significant decrease in tNAA/tCre and tCho/tCre ratios in the patient group with LOC when compared with the control group of healthy volunteers (P=0.002 and P=0.041, respectively), and a significant decrease in the tNAA/tCre ratio in the LOC group when compared with patients without LOC (P=0.04). Other metabolite ratios in the brainstem did not show any significant group differences. CONCLUSION: Our findings indicate that decrease of tNAA/tCre ratio in the upper brainstem using single-voxel 1H-MRS may provide a potential biomarker for MTBI associated with LOC.

Fatigue as the limiting factor for vaginal birth in patients with multiple sclerosis.

OBJECTIVES: Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease. This study evaluated pregnancy-related issues in patients with MS in one perinatological centre. MATERIAL AND METHODS: A single-centre, retrospective study of the perinatal period in patients with MS admitted at the Dpt. of Gynaecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University and the University Hospital in Martin, Slovak Republic, European Union from January 1, 2015 to December 1, 2020 was performed. Selected parameters from personal, obstetric, and neurological histories were analysed. RESULTS: A cohort of 15 patients (32.5±5.3 years) with a relapsing-remitting form of MS gave birth to 16 children. The mean length of MS at the time of delivery was 9±3.6 years. The severity of the Expanded Disability Status Scale score was 2.0±1.5. Caesarean section (CS) was indicated in 14 deliveries (87.5%). It was elective CS in 10 patients. The most common indication for elective CS was a combination of significant chronic fatigue syndrome and neurological deficit (paresis). CONCLUSIONS: The basis for the management of pregnancy, childbirth, and the postpartum period in women with MS is a planned pregnancy based on close cooperation among patients, gynaecologists, and neurologists. Vaginal delivery is not primarily contraindicated. Indications for CS should be considered individually. One way to minimise the indications for CS is a more accurate diagnosis and personalised treatment of fatigue in pregnant women with MS. Presumably, both obstetricians and neurologists prefer vaginal delivery as the first choice in patients with fatigue syndrome.

Atypical presentation of Charcot-Marie-Tooth disease type 1C with a new mutation: a case report.

BACKGROUND: Charcot-Marie-Tooth 1C (CMT1C) is a rare form of dominantly inherited CMT1 neuropathy caused by a mutated gene encoding lipopolysaccharide-induced tumour necrosis alpha factor (LITAF). CASE PRESENTATION: We report a 56-year-old patient with an atypical clinical phenotype of CMT1C, which started as progressive weakness of a single upper limb resembling acquired inflammatory neuropathy. Nerve conduction studies (NCS) and temporarily limited and partial effects of immunotherapy supported the diagnosis of inflammatory neuropathy. Significant progression of polyneuropathy, despite intensive long-lasting immunotherapy, together with repeatedly negative auxiliary investigations (CSF, MRI and antibodies) and genetic testing results finally led to the diagnosis of CMT1C neuropathy. CONCLUSIONS: CMT1C should be added to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy.

Positivity of oligoclonal bands in the cerebrospinal fluid predisposed to metabolic changes and rearrangement of inhibitory/excitatory neurotransmitters in subcortical brain structures in multiple sclerosis.

BACKGROUND: The latest diagnostic criteria for multiple sclerosis (MS) have revitalized the role of oligoclonal bands synthesis in the cerebrospinal fluid (CSF-OCB). This study identifies predictors of CSF-OCB-positivity among in vivo metabolic markers in the subcortical gray/white matter in MS patients after their first episode (CIS) and in patients with relapsing-remitting course (RRMS). METHODS: The study enrolled 13 CIS and 23 RRMS patients. Metabolism was evaluated using Mescher-Garwood-edited proton-magnetic resonance spectroscopy on a 3T MR scanner. In addition to N-acetyl-aspartate (tNAA), myoinositol (mIns), and choline- and creatine compounds (tCho, tCr) were also evaluated γ-aminobutyric acid (GABA) and glutamate-glutamine (Glx) ratios. RESULTS: CSF-OCB-positivity was found in 76.9% of CIS and 78.2% of RRMS patients. GABA and Glx ratios in putamen and corpus callosum strongly determined CSF-OCB-positive CIS patients. Other essential predictors of CSF-OCB-positive CIS were mIns and Glx ratios in the putamen, and tCho/tNAA in the corpus callosum. In RRMS, GABA ratios in the right thalamus and Glx ratios in the left hippocampus strongly predicted CSF-OCB-positive patients. tCho/tNAA and tNAA/tCr in the left hippocampus were also identified as essential predictors of CSF-OCB-positive RRMS patients. CONCLUSION: This is the first in vivo evidence of GABA-Glx rearrangement in CSF-OCB-positive patients since its early stages of MS.

Cystic echinococcosis causing thrombosis of the inferior vena cava in a patient with multiple sclerosis treated with alemtuzumab.

Alemtuzumab, one of the very effective immunomodulatory forms of treatment for patients with highly active multiple sclerosis, can also have unexpected side effects. We present a case of cystic echinococcosis causing thrombosis of the inferior vena cava in a female patient after two cycles of alemtuzumab.

Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease with expanding axonal and neuronal degeneration in the central nervous system leading to motoric dysfunctions, psychical disability, and cognitive impairment during MS progression. The exact cascade of pathological processes (inflammation, demyelination, excitotoxicity, diffuse neuro-axonal degeneration, oxidative and metabolic stress, etc.) causing MS onset is still not fully understood, although several accompanying biomarkers are particularly suitable for the detection of early subclinical changes. Magnetic resonance (MR) methods are generally considered to be the most sensitive diagnostic tools. Their advantages include their noninvasive nature and their ability to image tissue in vivo. In particular, MR spectroscopy (proton 1H and phosphorus 31P MRS) is a powerful analytical tool for the detection and analysis of biomedically relevant metabolites, amino acids, and bioelements, and thus for providing information about neuro-axonal degradation, demyelination, reactive gliosis, mitochondrial and neurotransmitter failure, cellular energetic and membrane alternation, and the imbalance of magnesium homeostasis in specific tissues. Furthermore, the MR relaxometry-based detection of accumulated biogenic iron in the brain tissue is useful in disease evaluation. The early description and understanding of the developing pathological process might be critical for establishing clinically effective MS-modifying therapies.

Altered hypothalamic metabolism in early multiple sclerosis - MR spectroscopy study.

Multiple sclerosis (MS) is a disease characterized by overlapping processes of neuroinflammation and neuro-axonal degeneration. Disturbances of the hypothalamo-pituitary axis in MS are supposed to modulate neuroinflammatory circuits, however, there is insufficient knowledge about the hypothalamic metabolism alterations in early MS. This 1H MRS study performed on a 1.5 T MR-scanner was focused on the hypothalamus of 31 pre-treatment patients after their first clinical MS episode/s, compared to 31 healthy controls. The metabolite ratios of N-acetyl-aspartate &N-acetyl-aspartyl-glutamate (tNAA), glutamate & glutamine (Glx), myo-Inositol (mIns), choline- and creatine-containing compounds (tCho, tCr) were further correlated with the Expanded Disability Status Scale (EDSS). In the hypothalamus of early MS patients compared to controls, we found decreased tNAA/tCr and increased tCho/tNAA, mIns/tNAA, Glx/tCr, and Glx/tNAA. In addition, tCho/tNAA, Glx/tNAA, and mIns/tNAA were positively and tNAA/tCr was negatively correlated with EDSS. Results suggest that the decline of the tNAA ratio, indicating neuro-axonal dysfunction in the hypothalamus, may be linked with glutamate excitotoxicity. Excessive glutamate concentrations may cause microglial activation and myelinated tracts degradation with subsequent gliosis, paralleled by increased mIns and tCho ratios. This indicates that glutamate excitotoxicity can play an important role in MS from its earliest stages.

Increased glutamate and deep brain atrophy can predict the severity of multiple sclerosis.

OBJECTIVE: In multiple sclerosis (MS), deep grey matter (DGM) atrophy has been recognised as a crucial component of the disease that presents early and it has been associated with disability. Although the precise mechanism underlying grey matter atrophy is unknown, several hypotheses have been postulated. Our previous research pointed to correlations of hypothalamic metabolic alterations with clinical outcomes of MS, therefore we decided to further test the relationship of these alterations with DGM atrophy. METHODS: We used 1H-Magnetic Resonance spectroscopy (1H-MRS) of the hypothalamus to test its metabolites in 26 patients with RRMS and 22 healthy age-matched controls. DGM atrophy was evaluated by simple planimetry of third ventricular width on the hypothalamic level (3VW) in T1 weighted MRI pictures. Metabolite ratios of N-acetyl aspartate (NAA), choline (Cho), glutamate and glutamine (Glx), myo-inositol (mIns) and creatine (Cr) were correlated with Multiple Sclerosis Severity Scale (MSSS) and 3VW. RESULTS: Metabolite concentrations were compared between patients and controls using multiple regression models allowing for age, 3VW and metabolites. It revealed that the only relevant predictors of MSSS were 3VW and Glx/NAA. At a significance level of P<0.05, a unit increase of 3VW was associated with a 0.35 increase of MSSS, for a typical value of Glx/NAA; P value 0.0039. A unit increase of Glx/NAA was associated with a 0.93 increase of MSSS, for a typical value of atrophy; P value 0.090. There were significant linear correlations between Glx/Cr and MSSS, Glx/NAA and MSSS, and between mIns/NAA and 3VW. CONCLUSIONS: The results suggest that both NAA and Glx are associated with neurodegeneration of hypothalamic DGM and severe disease course. Glx related 1H-MRS parameters seem to be superior to other metabolites in determining disease burden, independently of otherwise powerful 3VW planimetry. Significantly increased mIns/NAA in MS patients compared to controls point to gliosis, which parallels the atrophy of hypothalamic DGM.

The HLA-DRB1 and HLA-DQB1 alleles are associated with multiple sclerosis disability progression in Slovak population.

OBJECTIVE: The aim of our present study was to analyse the association of HLA-DRB1 and -DQB1 alleles and genotypes with Multiple Sclerosis (MS) disability progression in a cohort of Central European Slovak population. METHODS: The allele and genotype variants were analyzed in 282 non-related MS patients. Rate of disease disability progression was evaluated using EDSS score in the 5th, 7th, 10th, and 15th year of disease duration, time to reach EDSS score 3 and 5, and MSSS score. Genotyping was performed by polymerase chain reaction with sequence-specific primers. RESULTS: We found that carriers of homozygous genotype for alleles DRB1*15 and DQB1*03 reached EDSS score 3 significantly earlier than non-carriers of these alleles (p = 0.0172; p = 0.00183, respectively). Genotype DQB1*03/03 carriage was also associated with significantly reduced time to reach EDSS score 5 (p = 0.00316). Lower EDSS score in the 5th year of disease duration was found in carriers of DRB1*07 allele (p cor = 0.028). When MSSS score was used, genotype DRB1*15/15 was found to be less frequent in slow progressing MS patients, when compared to MS patients with mid-rate and rapid disease disability progression (p cor = 0.0305). DISCUSSION: We showed for the first time that HLA-DRB1 and -DQB1 genotypes are genetic markers associated with disability progression in Slovak MS patients. Genotypes DRB1*15/15 and DQB1*03/*03 were identified as short-term clinical negative prognostic factors, while allele DRB1*07 carriage appeared to be a positive prognostic marker of better MS outcome.

Thalamic paramagnetic iron by T2* relaxometry correlates with severity of multiple sclerosis.

Iron can contribute to the pathogenesis and progression of multiple sclerosis (MS) due to its accumulation in the human brain. We focus on the thalamus as an information transmitter between various subcortical and cortical areas. Thalamic iron seems to follow different rules than iron in other deep gray matter structures and its relation to the clinical outcomes of MS is still indistinct. In our study, we investigated a connection between thalamic iron and patients' disability and course of the disease. The presence of paramagnetic substances in the tissues was tracked by T2* quantification. Twenty-eight subjects with definite MS and 15 age-matched healthy controls underwent MRI examination with a focus on gradient echo sequence. We observed a non-monotonous course of T2* values with age in healthy controls. Furthermore, T2* distribution in MS patients was significantly wider than that of age matched healthy volunteers (P<0.001). A strong significant correlation was demonstrated between T2* distribution spread and the expanded disability status scale (EDSS) (left thalamus:P<0.00005; right thalamus: P<0.005), and multiple sclerosis severity scale (MSSS) (left thalamus: P<0.05; right thalamus: P<0.005). The paramagnetic iron distribution in the thalamus in MS was not uniform and this inhomogeneity may be considered as an indicator of thalamic neurodegeneration in MS.