Plasma Metabolic Disturbances in Parkinson's Disease Patients.

Plasma from patients with Parkinson's disease (PD) is a valuable source of information indicating altered metabolites associated with the risk or progression of the disease. Neurotoxicity of dopaminergic neurons, which is triggered by aggregation of α-synuclein, is the main pathogenic feature of PD. However, a growing body of scientific reports indicates that metabolic changes may precede and directly contribute to neurodegeneration. Identification and characterization of the abnormal metabolic pattern in patients' plasma are therefore crucial for the search for potential PD biomarkers. The aims of the present study were (1) to identify metabolic alterations in plasma metabolome in subjects with PD as compared with the controls; (2) to find new potential markers, some correlations among them; (3) to identify metabolic pathways relevant to the pathophysiology of PD. Plasma samples from patients with PD (n = 25) and control group (n = 12) were collected and the gas chromatography-time-of-flight-mass spectrometry GC-TOFMS-based metabolomics approach was used to evaluate the metabolic changes based on the identified 14 metabolites with significantly altered levels using univariate and multivariate statistical analysis. The panel, including 6 metabolites (L-3-methoxytyrosine, aconitic acid, L-methionine, 13-docosenamide, hippuric acid, 9,12-octadecadienoic acid), was identified to discriminate PD from controls with the area under the curve (AUC) of 0.975, with an accuracy of 92%. We also used statistical criteria to identify the significantly altered level of metabolites. The metabolic pathways involved were associated with linoleic acid metabolism, mitochondrial electron transport chain, glycerolipid metabolism, and bile acid biosynthesis. These abnormal metabolic changes in the plasma of patients with PD were mainly related to the amino acid metabolism, TCA cycle metabolism, and mitochondrial function.

Unusual magnetic resonance imaging of the head in manganese and ephedrone intoxication - a case report.

Manganese intoxication leads to the accumulation of manganese in the brain, mostly in the globus pallidus, which clinically manifests as a L-DOPA - resistant parkinsonian syndrome with specific symptoms, such as spastic-hypokinetic dysarthria and postural instability. A new kind of manganese poisoning associated with drug abuse has been reported in Eastern European countries. A CASE REPORT: We present an adult patient with neurological abnormalities secondary to manganese intoxication related to the abuse of psychoactive substances. High serum levels of manganese, hyperintense lesions on T1-weighted magnetic resonance imaging (MRI), and parkinsonism in this case confirmed the diagnosis. MRI results showed accumulation of manganese in the basal ganglia which caused an increased signal in this area of the brain on T1 weighted sequence. This is the second case reported with diffuse high signal intensity of the entire white matter due to manganese and ephedron neurointoxication. To the best of our knowledge, this is the first time such extensive pathological changes to cerebellar white matter, located near the fourth ventricle, have been described. CONCLUSIONS: We suggest that chronic exposure to manganese and ephedron damaged the white matter in the cerebral hemispheres and continued to affect the periventricular area of the fourth ventricle, causing continuous changes to the white matter.

Diagnostic and therapeutic difficulties in patient with cerebral venous thrombosis - a case report.

Cerebral venous infarction also known as cerebral venous thrombosis (CVT) is a rare disease. It is more common in young adults, but three times more common in women than in men. The clinical picture of CVT may vary and non-specific manifestations often delay correct diagnosis. Headaches of various location, nature and severity occur in 90% of cases. Radiology findings in the central nervous system include bilateral cerebral involvement and foci location that does not correspond to arterial supply. More than 100 factors that may predispose to CVT have been identified. The aetiology of CVT remains unknown in about 20% of patients. A CARE REPORT: In this paper we present a case of 35-year-old woman at 27 weeks of gestation, who was admitted to the hospital after the first epileptic seizure in her life. The patient's history revealed the headaches that had lasted for about 3 months prior. The patient had no family history of hypercoagulability. The patient was diagnosed with CVT - a hemorrhagic lesion in the left hemisphere of the brain as a result of dural sinus thrombosis. Anticoagulant treatment according to current guidelines was started with good results.

LC-MS/MS Determination of Modified Nucleosides in The Urine of Parkinson's Disease and Parkinsonian Syndromes Patients.

Epigenetic modifications play a key role in gene regulation and expression and are involved in numerous cellular processes. Due to the limited research on nucleosides in Parkinson's disease (PD), it is very important to consider epigenetic factors and their role in the development of PD. The aim of this study was to investigate and compare the levels of modified nucleosides, such as O-methylguanosine, N6-methyl-2'-deoxyadenosine, 1-methyladenosine, 1-methylguanine, 7-methylguanine, 3-methyladenine and 7-methylguanosine in the urine of Parkinson's disease (PD) patients and the control group, and to verify that the results obtained differ in a subgroup of patients with parkinsonian syndromes. The study group comprised 18 patients with diagnosed idiopathic Parkinson's disease and four parkinsonian syndromes. The control group consisted of 30 age- and sex-matched neurological patients without confirmation by neuroimaging brain damage and extrapyramidal symptoms. The levels of nucleosides were determined by validated liquid chromatography coupled with the mass spectrometry (LC-MS/MS) method using the multiple reaction monitoring (MRM) mode. Lower levels of O-methylguanosine, 3-methyladenine, 1-methylguanine, N6-methyl-2'-deoxyadenosine and a higher level of 7-methylguanine in the urine of 22 PD patients were observed. Moreover, elevated levels of 1-methyladenosine, 7-methylguanine, and O-methylguanosine were observed in the parkinsonian syndrome subgroup. These preliminary results may indicate that modified nucleosides describe metabolic disturbances in the metabolism of purine, which was the most severely affected pathway that mediated the detrimental effects of neuroinflammation on PD.

Brain MRI features and scoring of leukodystrophy in adult-onset Krabbe disease.

OBJECTIVE: To perform a systematic analysis and scoring of brain MRI white matter hyperintensities (WMH) in adult-onset Krabbe disease. METHODS: We retrospectively collected basic clinical data and the first available brain MRI from patients with confirmed Krabbe disease with first clinical manifestations beyond 10 years of age. Data were obtained from our reference center for lysosomal diseases (n = 6) and from contacted authors of published articles describing patients with adult-onset Krabbe disease (n = 15). T2-weighted fluid-attenuated inversion recovery images of each patient were analyzed and scored using a radiologic score of WMH in a single center. RESULTS: The corticospinal tract was always affected by WMH (100% of patients), however, with some distinctions along the tract: the precentral gyrus (100%), corona radiata (95%), and posterior internal capsule (81%) were highly abnormal, whereas the mesencephalon (57%), pons (52%), and medulla oblongata (5%) were less affected. WMH were also frequently present in the posterior lateral periventricular white matter (95%), optic radiations (86%), postcentral gyrus (71%), medial lemniscus (62%), and corpus callosum, especially in the isthmus (71%), whereas the genu was always normal. A few patients did not have the classical MRI pattern but extensive hyperintensities (n = 3), or patchy distribution of hyperintensities mimicking an acquired etiology (n = 2), or very subtle hyperintensities of the corticospinal tract (n = 1). CONCLUSIONS: We specified the main locations of WMH, which were observed in the earliest stages of the disease and were also present in patients with atypical MRI pattern, highlighting the importance of radiologic features to guide the diagnosis.

66034T/C polymorphism of the human pregnane X receptor (hPXR) as potential risk factor for drug resistance in epilepsy - Preliminary study.

INTRODUCTION AND OBJECTIVES: Recent research has suggested that genetic factors may play an important role in the development of drug resistance in epilepsy. It is not clear which gene loci are responsible for the drug-resistant phenotype. Studying certain nuclear receptors may be helpful in predicting drug response, as they regulate drug transporting proteins and enzymes involved in their metabolism. This study focuses on one of these receptors, the human pregnane X receptor (hPXR). The objective was to examine the link between selected single nucleotide polymorphisms (SNPs) 69789A/G rs 7643645 and 66034T/C rs 13059232 hPXR and the lack of response to epilepsy treatment. MATERIALS AND METHODS: 73 patients diagnosed with drug-resistant epilepsy were included in the study. The diagnoses were made according to the criteria published by The International League Against Epilepsy (ILAE) in 2010. The control group was comprised of a group of 122 healthy volunteers. Genetic material isolated from the peripheral blood of the participants was analyzed with TagMan Genotyping Assays in search of the selected hPXR polymorphisms. RESULTS: The distribution of genotypes of the 66034T/C rs 13059232 hPXR polymorphism was significantly different in the group with drug-resistant epilepsy and the control group. In the drug-resistant group the CC genotype was significantly more common compared to the control group (50.7% vs 35.2%) p=0.0339. The distribution of 69789 A/G rs 7643645 hPXR genotypes was comparable in both groups. CONCLUSIONS: There is potential association between hPXR and drug resistance but its relevance for the development of drug-resistant phenotype remains to be studied.

The impact of multiple sclerosis relapse treatment on migration of effector T cells--Preliminary study.

UNLABELLED: Migration of inflammatory cells from the blood to the central nervous system (CNS) is crucial for development of multiple sclerosis (MS). Inhibition of this process would allow to control disease activity. The first step confirming this approach would be the analysis of the impact of effective MS relapse therapy on migration of effector T cells. The aim of the study was to analyze the influence of methylprednisolone (MP) on the migratory activity of effector CD4+ T cells from MS patients. Moreover, to study the potential mechanism of this process we studied expression of chemokine receptors on migrating cells. MATERIAL AND METHODS: Peripheral blood samples were obtained from relapsing-remitting MS (RR-MS) patients during relapse (n=23) and from control group (n=23). After isolation CD4+ T cells were incubated with various concentrations of MP. Then they were stimulated in chemotaxis assay with chemokines CCL3 or CXCL10 or were used to CCR1 and CXCR3 expression analysis. RESULTS: CXCL10- and CCL3-stimulated migration of CD4+ T cells was significantly increased in MS. MP was able to reduce in vitro migration of effector T cells induced by CXCL10, but not by CCL3. Inhibition by MP was dose-dependent. Expression of analyzed chemokine receptors was unaltered after MP incubation. CONCLUSIONS: MP reduced CD4+ T cells migration induced by CXCL10 without affecting CXCR3 expression. These observations demonstrate one of the potential mechanisms of MP action in MS, distinct from inducing cell apoptosis, and suggests the new targets for development of more effective MS treatments.

Hemorrhagic stroke, cerebral amyloid angiopathy, Down syndrome and the Boston criteria.

A stroke, or a cerebrovascular accident (CVA) is a life-threatening condition which often results in permanent or significant disability in the adult population. Several classifications of CVAs exist, one of them being based on the mechanism of injury of brain tissue: ischemic (85-90%) and hemorrhagic (10-15%). In a hemorrhagic stroke an intercranial bleeding occurs, leading to the formation of a focal hematoma typically located in the basal ganglia of the brain (approx. 45% of cases). A common yet underestimated cause of intracerebral hemorrhage is cerebral small vessel disease with microhemorrhages, including the cerebral amyloid angiopathy (CAA). This condition is associated with the deposition of amyloid-beta in arterial walls (in soft meninges, subcortical areas and the cerebral cortex). Research has shown that causes of hemorrhagic changes in the brain include genetic disorders, such as Down syndrome. The association is caused by the so-called 'gene dosage effect', as the gene for the precursor protein for amyloid-beta is located in chromosome 21. We wish to present the case of a 60 year old patient with Down syndrome who suffered a hemorrhagic stroke without antecedent hypertension. Based on the history taken, diagnostic imaging and the source literature, a diagnosis of cerebral amyloid angiopathy as the source of the bleeding was made (however it must be noted that without a full post-mortem examination, the Boston criteria allow only for a 'probable cerebral amyloid angiopathy' diagnosis to be made). The authors hereby also report the need to modify the Boston criteria for cerebral amyloid angiopathy.

Selected extracellular microRNA as potential biomarkers of multiple sclerosis activity--preliminary study.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). Four distinct disease courses are known, although approximately 90% of patients are diagnosed with the relapsing-remitting form (RRMS). The name "multiple sclerosis" pertains to the underlying pathology: the presence of demyelinating plaques in the CNS, in particular in the periventricular region, corpus callosum, cervical spine, and the cerebellum. There are ongoing efforts to discover biomarkers that would allow for an unequivocal diagnosis, assess the activity of inflammatory and neurodegenerative processes, or warn of disease progression. At present, small noncoding RNA particles-microRNA (miRNA, miR) seem to be particularly noteworthy, as they take part in posttranscriptional regulation of expression of various genes. Changes in composition as well as function of miRNA found in body fluids of MS patients are subjects of research, in the hope they prove accurate markers of MS activity. This preliminary study aims to evaluate the expression of selected extracellular microRNA particles (miRNA-let-7a, miRNA-92a, miRNA-684a) in patients experiencing MS relapse and remission, with healthy volunteers serving as a control group and to evaluate the correlation between miRNA expression and selected clinical parameters of those patients. Thirty-seven patients suffering from MS formed two examined groups: 20 patients undergoing relapse and 17 in remission. Thirty healthy volunteers formed the control group. All patients who were subjects to peripheral blood sampling had been hospitalized in the Department of Neurology and Stroke(1). Four milliliters of venous whole blood had been collected into EDTA tubes. The basis for the selection of the three particular miRNA investigated in this study (miRNA-let-7a, miRNA-92a, miRNA-684a) was a preliminary bioinformatic analysis of data compiled from several medical databases, including Ovid MEDLINE®, Embase, Cochrane Database of Systematic Reviews (CDSR), miRWalk, and miRBase. The isolation of extracellular microRNA from plasma was carried out using miRNeasy Mini Kit (Qiagen) reagents. The reverse transcription was carried out with TaqMan® MicroRNA Reverse Transcription Kit (Applied Biosystems), as per manufacturers' instructions. Standard microRNA TaqMan® tests (Applied Biosystems) were used for miRNA quantification. The qPCR were performed on a 7900 HT Fast Real-Time PCR System (Applied Biosystems) and analyzed using Sequence Detection System 2.3 software. In addition, all patients at the Department of Neurology and Stroke undergo a routine complete blood count with differential. The main objective of this study was to evaluate the expression of selected microRNA (has-miR-let-7a, miR-92a, and miR-648a) in the plasma of patients with MS during a relapse as well as in remission and attempt to correlate the acquired data with clinically relevant parameters of the disease. Finding such correlations may potentially lead to the use of miRNA as a biomarker of MS, which could help diagnose the disease and assess its severity and the efficacy of treatment. The difference in the expression of has-miR-let-7a in the remission group and the control group was statistically significant (p = 0.002). Similarly, the expression of miRNA-648a in patients in remission was significantly different from the expression in the control group (p = 0.02). Analysis of the correlation between the expression of miRNA-92a and the severity of the disease as measured by the EDSS scale in patients undergoing relapse showed significant negative linear correlation (r = -0.54, p = 0.01). Higher miR-648a expression correlated with more frequent flare-ups in the joint group of patients in remission and relapse (p = 0.03). This study is one of the few that demonstrate significantly changed expression of selected extracellular miRNA in plasma of MS patients and correlate those findings with clinical parameters. These observations may suggest that some miRNA subsets may be potential biomarkers for MS activity.

[Spinal cord diffusion tensor tractography as a diagnostic tool in difficult cases of spinal cord intramedullary tumours]. / Traktografia rdzenia jako metoda diagnostyczna w trudnych przypadkach guzów sródrdzeniowych.

Diffusion tensor-based spinal cord tractography is a technically complicated but rapidly evolving diagnostic method. The difficulties result from the volume of the spinal cord, the constant pulsing of the cerebrospinal fluid and respiratory movements. The method is being used more and more frequently to examine long spinal tracts in patients with intramedullary tumours. The method can be especially useful for ambiguous cases investigation. The presented case with coincidental intramedullary tumour and severe cervical spondylosis has been described by the authors to show their own experience with spinal cord tractography as a useful tool in determining an effective treatment method.