Ewa Papuć

Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes.

Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10(-9) using Poser criteria; P = 5.6 × 10(-11) for McDonald criteria) and more rapid development of disability (P = 1.8 × 10(-10)). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis.

Decreased cerebrospinal fluid hypocretin‐1 (orexin A) in patients after repetitive generalized tonic–clonic seizures

The effects of seizures on the hypocretin/orexin system have not yet been investigated in epileptic patients. The present study aimed to assay hypocretin‐1 in the cerebrospinal fluid (CSF) of patients after generalized tonic–clonic (GTC) seizures. Study groups consisted of 21 patients after GTC seizures and 19 controls. Diagnostic lumbar puncture was performed in control and epileptic patients within 48 h after the GTC seizures. Hypocretin‐1 levels were measured in unextracted CSF samples, using a standardized commercial radioimmunoassay. There was a significant overall difference in median CSF hypocretin‐1 concentrations between controls and patients with GTC patients (p < 0.001). The lowest concentrations were noted in a subgroup of patients with repetitive GTC seizures (RS) compared to those with a single GTC seizure (SS) (p > 0.05) or controls (p < 0.001). The current results suggest that the hypocretin‐1 system deficiency contributes to the complex pathophysiology of repetitive GTC seizures and status epilepticus (SE) and could be associated with typical somnolence after seizure attacks.

Neurofilament heavy chain and heat shock protein 70 as markers of seizure-related brain injury.

Purpose:  Status epilepticus (SE) has deleterious effects on brain tissue, but whether brief recurrent seizures may also damage neurons represents a matter of controversy. Therefore, it remains a central area of epilepsy research to identify individuals at risk where disease progression can be potentially prevented. Biomarkers may serve as tools for such identification. Thus the present study aimed at analyzing the levels of heat shock protein 70 (HSP‐70, also designated as HSPA1A) and neurofilament heavy chain protein (NfHSMI35) in cerebrospinal fluid (CSF) of patients with seizures of different severity.

CSF hypocretin-1 concentrations correlate with the level of fatigue in multiple sclerosis patients

Considering the multiplicity of symptoms associated with multiple sclerosis (MS), there is possibility that hypocretin system function might be involved in the pathogenesis of the disease. The current study aimed to investigate the hypocretin-1 levels in cerebrospinal fluid (CSF) of MS patients in relation to different neurological deficit measures including: Ambulation Index (AI), Expanded Disability Status Scale (EDSS), Fatigue Severity Scale (FSS), and Epworth Sleepiness Scale (ESS) in relapse-onset MS patients. 53 subjects were included into the study: 38 patients with a diagnosis of MS and 15 healthy controls. Among MS patients, 25 had relapsing-remitting and 13 secondary progressive MS. CSF hypocretin-1 levels did not differ between MS patients and healthy controls (p>0.05). A positive correlation between hypocretin-1 level and fatigue level was found in MS patients (p<0.05) and this effect was even stronger in the MS subgroup suffering from fatigue (p=0.01). Hypocretin system seems to be generally unchanged in MS but a positive correlation between hypocretin-1 level and fatigue may indicate involvement of some compensatory mechanisms stimulating the production of the neuropeptide in MS patients.

Atypical symptomatology of myoclonus dystonia (DYT-11) with positive response to bilateral pallidal deep brain stimulation.

Myoclonus-dystonia (M-D) is a childhood onset movement disorder characterized by a combination of brief myoclonic jerks and dystonia. Myoclonic jerks are usually triggered by complex motor tasks like writing and drawing. We report an atypical clinical manifestation of M-D with positive response to bilateral stimulation of the globus pallidus. A 31-year-old patient with myoclonic jerks and dystonia affecting predominantly the lower limbs was referred to our Department of Neurosurgery. Disease onset was at age 4, when he developed difficulties with walking because of pain in the left limb that required frequent rest. Over the subsequent years he had a slowly progressing deterioration of gait. On attempting to walk, the patient presented negative myoclonus, causing frequent jerks in the lower limbs, which resulted in poor balance. At age 18, difficulties with articulation occurred caused by myoclonic movements of laryngeal muscles, which produced vocal myoclonus. The patient reported dramatic improvement of his symptoms after alcohol ingestion. The diagnosis of DYT-11 was established by genetic testing. As the patient had not responded to previous trials with levodopa, baclofen, or clonazepam, he was referred for surgical procedure. After fulfilling the selection criteria for deep brain stimulation in dystonia, the patient was qualified for bilateral GPi stimulation, which led to considerable improvement in gait, by reduction of both myoclonus and lower limb dystonia, as evidenced by lower score on the Burke-Fahn-Marsden Dystonia Scale (preoperative score was 37; 6 months after, the score was 14). The patient also experienced improvement in speech, achieved by reduction of laryngeal myoclonus. Our patient is unusual as he had persistent predominance of lower limb dystonia in adulthood. Another rare feature observed in the patient was laryngeal myoclonus, rarely observed in patients with M-D. GPi-DBS is an efficacious treatment for primary dystonias, but the effects for secondary dystonias are unequivocal. There is emerging evidence that for some secondary dystonias like tardive dystonia, secondary generalized dystonia and M-D results may be satisfying.

Humoral response against glial derived antigens in Parkinson's disease

To check whether glial cells have the ability to elicit adaptive immune response in Parkinsons disease and whether a change in this immune response can be observed over time. There is an increasing evidence that glial cells are involved in the neurodegenerative process in PD, in addition to neuronal structures. Measurement of autoantibodies against proteins of oligodendrocytes may serve as an indirect method to assess the level of glial cells activation or degeneration under in vivo conditions. Serum samples from 26 PD patients were collected twice, at baseline and after mean of 13 months. In addition, serum samples from 13 healthy controls matched for age and gender were assessed at one time point. IgG and IgM autoantibodies against myelin-oligodendrocyticglycoprotein (MOG), myelin basic protein (MBP), myelin-associated glycoprotein (MAG) and proteolipoprotein (PLP) were measured in all investigated subjects by a commercially available ELISA system (Mediagnost, Germany). In a group of PD significant decrease of IgG titers was observed for anti-MAG autoantibodies over the investigated time period (p<0.05). For IgM antibodies, we observed statistically significant decrease in anti-MAG autoantibodies in the follow-up period (p<0.05) and increase in anti-MBP and anti-PLP autoantibodies (p<0.05). All antibody titers differed significantly between healthy control subjects and PD patients. Our study provides the evidence for the presence of humoral response against some glial derived antigens in PD. The increasing levels of anti MBP IgG and IgM might point to the value of this marker for monitoring disease progression.

Can Antibodies Against Glial Derived Antigens be Early Biomarkers of Hippocampal Demyelination and Memory Loss in Alzheimer’s Disease?

BACKGROUND Alzheimers disease (AD) is known to exhibit well characterized pathologies including the extracellular accumulation of amyloid plaques, intra-axonal presence of neurofibrillary tangles, and glial hypertrophy. Nevertheless, the nature of myelin pathology in AD has not been well studied. Recent studies on animal models of AD, however, revealed focal demyelination within amyloid-β plaques in hippocampus. OBJECTIVES In a view of this finding, we decided to assess humoral response against proteins of myelin sheath in AD, in the hope of identifying early biomarkers of memory loss and neuropathological process characteristic of AD. METHODS We assessed antibodies levels against proteins of the myelin sheath: myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), myelin-associated glycoprotein (MAG), and proteolipoprotein (PLP) in sera of 26 AD patients and 26 healthy controls, using commercially available ELISA system (Mediagnost, Germany). RESULTS In the AD patient subgroup, significantly higher titers were observed for all types of assessed IgG autoantibodies compared to healthy control subjects (anti-MOG, anti-MAG, anti-MBP, anti-PLP). The titers of most of the investigated IgM antibodies were also higher in AD patients (p <  0.05), with the exception of anti-MAG IgM antibodies (p >  0.05). CONCLUSION The study provides the evidence for the significantly increased production of autoantibodies against proteins of myelin sheath in AD. These results can be of importance in the light of emerging data from animal models of AD, indicating early demyelination of hippocampal region. Further studies on larger population are necessary to confirm whether these autoantibodies could serve as early biomarkers of AD in humans.

Humoral response against small heat shock proteins in Parkinson's disease.

Introduction In the light of evidence for the increased heat shock proteins (HSP) expression in neurodegenerative disorders, the presence of the adaptive humoral response of the immune system can be expected. The aim of the study was to check whether Parkinson’s disease (PD) has the ability to elicit immune response against small heat shock proteins. Methods IgG and IgM autoantibodies against alpha B-crystallin were assessed in 26 PD patients 26 healthy subjects. For the assessment of anti-HSP IgG autoantibodies serum samples from 31 parkinsonian patients and 31 healthy control subjects were collected. Serum samples from PD patients and healthy control subjects were collected twice, at baseline and after mean of 13 months follow up. Results Both IgM and IgG autoantibodies against alpha ß-crystallin in PD patients were significantly higher compared to healthy controls (p<0.05). We also found statistically significant increase in antibodies titers against alpha ß-crystallin over the time of 13 months, both for IgG (p = 0.021) and for IgM (p<0.0001). Additionally, PD patients presented higher levels of anti-HSP IgG autoantibodies than healthy controls (p = 0.02). Conclusions Increase of IgG and IgM autoantibodies against alpha B-crystallin in PD patients over time may suggest their involvement in the disease pathogenesis and progression. Further studies are required to confirm the role of this antibody as a biomarker of the disease progression.

Humoral response against myelin associated glycoprotein reflects oligodendroglial degeneration in Parkinson’s disease

UNLABELLED Identification of disease-specific diagnostic and prognostic biomarkers which would enable early detection and follow-up of Parkinsons disease (PD) is a crucial problem. Recently, we confirmed the presence of adaptive immune response against different glial-derived antigens in PD. OBJECTIVE The aim of the study was to assess humoral response against myelin-associated glycoprotein (MAG) on a larger group of PD patients. IgM autoantibodies against MAG were measured by an ELISA system in 66 PD patients and 66 control subjects. RESULTS The study confirmed a significantly increased production of anti-MAG IgM antibodies in parkinsonian patients (p<0.05). No correlations were found between anti-MAG IgM antibody titers and disease severity measured on the Hoehn-Yahr scale, MMSE or age of PD onset (p>0.05). The results provide evidence for activation of humoral response against MAG in PD patients, but argue against the utility of anti-MAG antibodies as biomarkers of disease severity. The results additionally indicate the potential protective role of autoimmunity in maintaining the bodys homeostasis, which may involve the clearance of abnormal proteins. Further studies are necessary to confirm the role of anti-MAG antibodies as biomarkers of PD, especially in relation to other neurodegenerative disorders.

Aggressive behavior as a rare side effect of subthalamic stimulation in Parkinson’s disease

Although deep brain stimulation (DBS) has a well-established position in the treatment of Parkinson’s disease (PD), it may be accompanied by different side effects including behavioral changes. We present a patient with advanced PD after bilateral stimulation of the subthalamic nucleus (STN) who developed attacks of aggressive behavior. The patient with a 12 year history of PD underwent the procedure of DBS with one-stage bilateral stereotactic approach using the Leksel G stereotactic frame. For STN identification microrecording technique was applied (5 microelectrodes). Four weeks after surgery STN stimulation was switched on. With increasing the amplitude of stimulation on the right (active contacts 1 and 2) the patient experienced transient episodes of aggression. Change of stimulation mode led to withdrawal of all side effects. We hypothesize that aggression episodes in the patient were caused by stimulation of limbic circuit probable within STN although we cannot exclude simultaneous stimulation of neighboring structures. Aggression episodes are rare side effect of STN-DBS, nevertheless they may be expected in more posteromedial placement of the electrode within STN. The presented case extends the evidence for non-motor functions of STN and highlights its role as an integrating structure within the basal ganglia system.