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Previous studies have suggested that disease duration in Creutzfeldt–Jakob disease (CJD) may be related to the radiological findings or cerebrospinal fluid (CSF) tau levels; however, it is not yet established whether clinical, radiological, and laboratory findings at diagnosis can predict survival or have a prognostic value. The aim of this study was to examine whether the disease duration is correlated with clinical, radiological, and laboratory variables. The study population consisted of consecutive familial CJD (fCJD) patients that were assessed within 1 week from the diagnosis including the CJD neurological scale (CJD-NS), Minimental Status Examination, Frontal Assessment Battery, NIH Stroke Scale, and the expanded disability status scale. In addition, a single MRI study was done and measurements of the extent of the cortical and subcortical involvement were performed. CSF was examined as part of the workout, and tau levels were determined. Sixty-nine fCJD patients were included in the study (43 males, mean age 59.3 ± 8.4, range 44–79 years). The mean disease duration was 7.3 ± 6.9 months (median 5.6 months, range 2–20 months). A significant correlation was found between the disease duration and the CJD-NS, the disease burden as reflected by the degree of cortical involvement by DWI, and the CSF tau levels. The findings of the current study reveal that several findings at disease onset including the disease severity, the cortical changes, and the tau levels are each individually correlated with disease duration and can be used by the clinician as a tool to predict the disease course and prognosis. [ABSTRACT FROM AUTHOR]

Abstract The central nervous system (CNS) in neurodegenerative diseases is a battlefield in which microglia fight a highly atypical battle. During the inflammatory process microglia themselves become dysfunctional and even with all the available immune arsenal including cytokine or/and antibody production, the battle is eventually lost. A closer look into the picture will reveal the fact that this is mainly due to the atypical characteristics of the infectious agent. The supramolecular assemblies of misfolded proteins carry unique features not encountered in any of the common pathogens. Through misfolding, proteins undergo conformational changes which make them become immunogenic, neurotoxic and highly infective. The immunogenicity appears to be triggered by the exposure of previously hidden hydrophobic portions in proteins which act as damage-associated molecular patters (DAMPs) for the immune system. The neurotoxicity and infectivity are promoted by the small oligomeric forms of misfolded proteins/peptides. Oligomers adopt conformations such as tubular-like, beta-barrel-like, etc., that penetrate cell membranes through their hydrophobic surfaces, thus destabilizing ionic homeostasis. At the same time, oligomers act as a seed for protein misfolding through a prion/prion-like mechanism. Here, we propose the hypothesis that oligomers have catalytic surfaces and exercise their capacity to infect native proteins through specific characteristics such as hydrophobic, electrostatic and π-π stacking interactions as well as the specific surface area (SSA), surface curvature and surface chemistry of their nanoscale supramolecular assemblies. All these are the key elements for prion/prion-like mechanism of self-replication and disease spreading within the CNS. Thus, understanding the mechanism of prion's templating activity may help us in the prevention and development of novel therapeutic strategies for neurodegenerative diseases. Highlights • The atypical nature of infectious agent as main culprit behind the unorthodox inflammation in neurodegenerative diseases. • The presence of autoantibodies and the molecular mimicry point to an autoimmune component in neurodegenerative diseases. • The revealed hydrophobicity in proteins triggers inflammation, aggregation and perturbs the dynamic of water in the brain. • Oligomers and protofibrils in disease may have catalytic surfaces promoting protein destabilization onto their surfaces. [ABSTRACT FROM AUTHOR]

The use of diffusion MRI improved the accuracy of diagnosis in Creutzfeldt-Jakob disease (CJD) and expanded our knowledge of the changes occurring in the brain during the disease. The aim of this study was to test whether in patients with E200K familial CJD (fCJD) the clinical severity correlates with the disease burden as reflected by the extent of cortical involvement in DWI MRI. Consecutive fCJD patients were examined by a neurologist who performed several tests including the CJD neurological scale (CJD-NS), MiniMental status examination (MMSE), Frontal Assessment Battery (FAB), NIH Stroke Scale (NIHSS), and the expanded disability status scale (EDSS). A simultaneously acquired MRI was analyzed by measuring the extent of cortical involvement in the DWI axial sequence. Correlations were tested for using Pearson test. Fifty-two fCJD patients (35 males, mean age 59.4 ± 5.7 years) were recruited to the study. Significant negative correlation was found between the extent of cortical involvement and the cognitive performance of the patients as reflected by their MMSE and FAB scores. In addition, a significant positive correlation was found between the MRI and the clinical disease severity scales CJD-NS and EDSS. The correlation between clinical scales of severity and cognitive dysfunction and the disease burden confirms the reliability of the CJD-NS scale. Further studies are warranted to examine whether MRI may serve not only for diagnosis but also as a biomarker for follow-up of disease progression and the efficacy of potential treatments. [ABSTRACT FROM AUTHOR]

Familial Creutzfeldt-Jakob disease (fCJD) in Jews of Libyan ancestry is caused by an E200K mutation in the PRNP gene. While carriers are born with this mutation, they usually remain asymptomatic until middle age. Early detection of conversion is crucial for understanding and eventually for the treatment of the disease. The aim of this study was to report longitudinal MRI data in E200K individuals who eventually converted from healthy mutation carriers to clinically symptomatic CJD. As a part of a prospective study, asymptomatic E200K mutation carriers were scanned annually until their conversion to symptomatic disease. Standardized diffusion and anatomical MR sequences were performed before and after clinical conversion in the subjects and those were compared to 15 non-carrier siblings ('healthy controls'). Blinded radiological readings and region of interest analyses were performed. Radiological readings of individual cases failed to detect characteristic changes in the scans taken before the conversion. Region of interest analysis of diffusion changes in pre-symptomatic stage was inconclusive; however, ADC reduction was found in early and late stages of the disease. Computerized volumetric analysis revealed monotonic volume reductions in thalamus, putamen and caudate following conversion, and the lateral ventricles showed dilatation of up to 62 % after clinical conversion. Although the clinical manifestations at disease onset are variable, the diffusion abnormalities and/or volume changes in the thalamus and basal ganglia during conversion may indicate early involvement of the thalamostriatal neuronal circuit. [ABSTRACT FROM AUTHOR]

The largest cluster of E200K familial Creutzfeldt-Jakob disease (fCJD) which occurs is in Jews of Libyan origin in Israel. Insomnia is a very common early complaint in those patients and may even be the presenting symptom. The aim of this study was to assess and characterize sleep pathology in E200K fCJD patients. To do so, sleep studies of 10 consecutive fCJD patients were compared with those of 39 age and gender-matched controls. All patients presented pathological sleep characterized by fragmentation of sleep, loss of sleep spindles and reduced REM sleep amount. Respiration was characterized by irregular rhythm, periodic breathing, apneas and hypopneas, either central or obstructive. EMG recordings revealed repeated movements in sleep, with loss of REM atonia. Comparing to controls, a significant decrease of total sleep time, sleep efficacy and slow-wave sleep as well as a significant increase in the number of awakenings, apnea-hypopnea index and mixed and central apneas were evident in CJD patients. Comparison of two sequential sleep studies in one patient revealed a 40 % reduction of the total sleep time, a 40 % reduction in sleep efficacy and a 40-fold increase of the number of arousals in the second study. A significant correlation was found between the disease severity, as reflected by the CJD Neurological Scale and Periodic leg movement index. These definite and characteristic sleep pathologies in patients with fCJD associated with the E200K mutation may serve as a new diagnostic tool in the disease. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) tau was found to correlate with disease severity and cognitive status in E200K familial Creutzfeldt-Jakob disease (fCJD) patients. The objective of the present study was to test whether tau levels in the CSF also correlate with the disease burden as reflected by the degree of cortical involvement in DWI MRI. Forty-four consecutive E200K fCJD patients (25 males, mean age 58.6 ± 7.5, range 48–75 years) were recruited to the study and had a CSF tau examination as well as measurements of the extent of the cortical involvement in the DWI axial MRI. Correlation was tested using Pearson test. A significant correlation ( r = 0.617 p < 0.0001) was found between CSF tau levels and the extent of cortical involvement. This correlation between tau levels and the disease burden reinforce the notion that tau can be used as a biomarker reflecting the extent of disease in patients with E200K fCJD. [ABSTRACT FROM AUTHOR]

Abstract: Immune mediated neuropathies are uncommon but important to diagnose because they are potentially treatable. This chapter summarizes the clinical approach to diagnosis of Guillain Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and related neuropathies which are thought to be caused by direct autoimmune attack on peripheral nerves. [Copyright &y& Elsevier]

Thrombin and other proteases involved in coagulation also have the potential to stimulate inflammation in the brain to a large extent through the protease-activated receptors (PARs). Such exposure of the brain to increased levels of coagulation factors is more likely to occur during vasculitis and activation of intrinsic coagulation in the brain and may cause inflammatory diseases such as multiple sclerosis. There is growing evidence from animal models and human brain samples that links upregulation of coagulation factors to inflammatory central nervous system (CNS) disease. Evidence includes measures of thrombin-like activity, levels of its receptors, PARs, and inhibitors of the coagulation pathway. The major receptor for thrombin, PAR-1, has now been definitively located to the synapse and node of Ranvier and its excessive activation leads to blocks in long-term potentiation and in nerve conduction. There is growing evidence that modulating coagulation in models of CNS inflammatory disease has beneficial clinical effects. These findings suggest that coagulation-like pathways play a significant role in the pathogenesis of inflammatory diseases in the CNS and present a viable target for therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background/Aims: Large-scale population studies measuring rates and dynamics of cognitive decline in multiple sclerosis (MS) are lacking. In the current cross-sectional study we evaluated the patterns of cognitive impairment in MS patients with disease duration of up to 30 years. Methods: 1,500 patients with MS were assessed by a computerized cognitive battery measuring verbal and non-verbal memory, executive function, visual spatial perception, verbal function, attention, information processing speed and motor skills. Cognitive impairment was defined as below one standard deviation (SD) and severe cognitive impairment as below 2SD for age and education matched healthy population norms. Results: Cognitive performance in our cohort was poorer than healthy population norms. The most frequently impaired domains were information processing speed and executive function. MS patients with secondary-progressive disease course performed poorly compared with clinically isolated syndrome, relapsing-remitting and primary progressive MS patients. By the fifth year from disease onset, 20.9% of patients performed below the 1SD cutoff for impairment, p = 0.005, and 6.0% performed below the 2SD cutoff for severe cognitive impairment, p = 0.002. By 10 years from onset 29.3% and 9.0% of patients performed below the 1SD and 2SD cutoffs, respectively, p = 0.0001. Regression modeling suggested that cognitive impairment may precede MS onset by 1.2 years. Conclusions: The rates of cognitive impairment in this large sample of MS patients were lower than previously reported and severe cognitive impairment was evident only in a relatively small group of patients. Cognitive impairment differed significantly from expected normal distribution only at five years from onset, suggesting the existence of a therapeutic window during which patients may benefit from interventions to maintain cognitive health. [ABSTRACT FROM AUTHOR]

Decreased cortical thickness that signifies gray matter pathology and its impact on cognitive performance is a research field with growing interest in relapsing-remitting multiple sclerosis (RRMS) and needs to be further elucidated. Using high-field 3.0 T MRI, three-dimensional T1-FSPGR (voxel size 1 × 1 × 1 mm) cortical thickness was measured in 82 regions in the left hemisphere (LH) and right hemisphere (RH) in 20 RRMS patients with low disease activity and in 20 age-matched healthy subjects that in parallel underwent comprehensive cognitive evaluation. The correlation between local cortical atrophy and cognitive performance was examined. We identified seven regions with cortical tissue loss that differed between RRMS and age-matched healthy controls. These regions were mainly located in the frontal and temporal lobes, specifically within the gyrus rectus, inferior frontal sulcus, orbital gyrus, parahippocampal gyrus, and superior temporal gyrus, with preferential left asymmetry. Increased cortical thickness was identified in two visual sensory regions, the LH inferior occipital gyrus, and the RH cuneus, implicating adaptive plasticity. Correlation analysis demonstrated that only the LH superior temporal gyrus thickness was associated with cognitive performance and its thickness correlated with motor skills ( r = 0.65, p = 0.003), attention ( r = 0.45, p = 0.042), and information processing speed ( r = 0.50, p = 0.025). Our findings show that restricted cortical thinning occurs in RRMS patients with mild disease and that LH superior temporal gyrus atrophy is associated with cognitive dysfunction. [ABSTRACT FROM AUTHOR]

The aim of the study was to examine the relationship between EEG abnormalities and the pattern of MRI changes in familial Creutzfeldt-Jakob Disease (fCJD) patients with E200K mutation. As part of a controlled, prospective study, 13 E200K fCJD patients underwent comprehensive evaluations, with EEG and an extensive MRI protocol that included one of the most prion-disease sensitive sequences, diffusion-weighted imaging (DWI). The relationship between EEG abnormalities and the pattern of DWI hyperintensities was examined. EEG demonstrated the classical CJD finding of PSWC (periodic sharp wave complexes) in five patients (38%) while in eight patients (62%) the EEG showed only slow activity. Six patients showed the typical cortical changes on MRI, and in five of them (83%) concordance between the MRI and the EEG was found. Five patients had isolated basal ganglia involvement per MRI, and in two of them (40%) concordance between the MRI and the EEG laterality was found. In the remaining two patients MRI did not show any changes suggesting CJD and EEG showed focal slow activity. The EEG of our E200K fCJD patients appears similar to that of the largest prion disease patient group, sporadic CJD (sCJD). EEG abnormalities in E200K fCJD appear to correlate mainly with cortical pathology, as revealed by DWI, rather than basal ganglia pathology. The observation that PSWC abnormalities reflect cortical rather than basal ganglia pathology is significant with respect to theories of the origins of EEG abnormalities in prion disease. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome (APS) is characterized by thromboses and neuropsychiatric manifestations possibly linked to brain inflammation. In order to examine the levels of proinflammatory and anti-inflammatory cytokines in experimental APS (eAPS) mice brains, we measured the levels of TNF-α, IFN-γ, and IL-10 in brain homogenates (cytosolic fractions) and in brain slices (secreted level) at 6, 15, and 24 weeks after immunization. We induced eAPS by immunization of Balb/c mice with β2-glycoprotein I (β2GPI), the major autoantigen in the disease and controls with adjuvant alone. We found increased levels of secreted TNF-α in eAPS mice for the entire experiment period. Cytosolic and secreted IL-10 and IFN-γ levels in eAPS mice were lower at 6 and 15 weeks and higher at 24 weeks after immunization. The results suggest that brain disease in APS is associated with significant and complex changes in proinflammatory and anti-inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome (APS) is characterized by thromboses and neuropsychiatric manifestations possibly linked to brain inflammation. In order to examine the levels of proinflammatory and anti-inflammatory cytokines in experimental APS (eAPS) mice brains, we measured the levels of TNF-α, IFN-γ, and IL-10 in brain homogenates (cytosolic fractions) and in brain slices (secreted level) at 6, 15, and 24 weeks after immunization. We induced eAPS by immunization of Balb/c mice with β2-glycoprotein I (β2GPI), the major autoantigen in the disease and controls with adjuvant alone. We found increased levels of secreted TNF-α in eAPS mice for the entire experiment period. Cytosolic and secreted IL-10 and IFN-γ levels in eAPS mice were lower at 6 and 15 weeks and higher at 24 weeks after immunization. The results suggest that brain disease in APS is associated with significant and complex changes in proinflammatory and anti-inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Pruritus, a common feature of animal prion diseases such as scrapie, is rarely reported in humans with Creutzfeldt-Jakob disease (CJD), and its anatomical background is not well defined. The present study was undertaken to carry out a methodical prospective search for the prevalence of pruritus in CJD patients and investigate its anatomical substrate by MRI. The study group included consecutive familial and sporadic CJD patients carrying the E200K PRNP mutation followed up in a longitudinal prospective study between the years 2005 and 2008. Pruritus was prospectively screened for and diffusion-weighted imaging (DWI) was used to correlate brain diffusion abnormalities with pruritus in CJD patients. Pruritus was present in 6/31 (19.35%) patients with familial disease (fCJD) and in none of the patients with sporadic disease (sCJD). Pruritus was a presenting symptom in one patient and evolved during the course of the disease in the other five patients. The pruritus was generalized in three patients, regional in two and localized in one patient. It was transient in one patient and continued throughout the disease in five patients. DWI showed that pruritus was significantly associated with reduced diffusion in the several areas known to be affected by CJD, but most significantly in the midbrain periaqueductal grey matter. Pruritus is relatively common in patients with familial CJD carrying the E200K mutation. Our findings point to a central origin that involves damage to the inhibitory gating mechanism for itch in the periaqueductal grey matter. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome (APS) is a multisystem disorder characterized by arterial and venous thrombosis, pregnancy morbidity, and neuropsychiatric manifestations. Antiphospholipid IgG injected intracerebro-ventricularly (ICV) cause behavioral hyperactivity in mice. In the present study we investigated the effects of APS whole-serum ICV administration in female Balb/C mice. Control mice were injected with serum derived from healthy subjects or saline solution. Behavior was assessed by the staircase apparatus which combines locomotor (stair-climbing) exploratory activities and rearing as a measure of anxiety. Mice injected with serum from APS patients or serum from normal subjects showed a trend to an increase in the number of stairs climbed in the APS group. The results suggest a differential effect of specific IgG and other serum components in the CNS manifestations of APS. [ABSTRACT FROM AUTHOR]

Oxidation of cerebrospinal fluid (CSF) causes differential unmasking of autoantibodies in control CSF vs. that obtained from postmortem CSF samples from autopsy confirmed Alzheimer's disease (AD) cases. This study demonstrates that normal CSF from both living patients and from non-demented autopsy cases contains redox-reactive autoantibodies with specificities that include antiphospholipid antibodies (aPL). In contrast, CSF from autopsy confirmed AD subjects contained little or no redox-reactive aPL autoantibodies. Tests using an in vitro rat synaptosome model showed that the oxidized CSF autoantibodies from a normal individual can cause ERK1/2 phosphorylation at a level consistent with reports of pathogenic changes found in brain tissues from AD patients. The decrease or absence of redox-reactive antibodies in CSF from Alzheimer's patients suggests that these antibodies may have been previously unmasked by the oxidative conditions that exist in the CNS in AD patients. These unmasked autoantibodies could then bind to neuronal tissues and possibly participate in the initial cascade leading to the dementia in Alzheimer's. To our knowledge, this is the first description of resident autoantibodies with the potential to cause brain cell damage documented in CSF without a breech in the blood-brain barrier. The untimely and inappropriate physiological unmasking of these redox-reactive autoantibodies in AD patients CSF may represent a valuable biomarker for diagnosis and progression of this and perhaps other neurodegenerative diseases which also have oxidative stress components. These novel autoantibody observations may stimulate thoughts about additional therapeutic approaches and warrant similar studies for other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Chronic fatigue syndrome (CFS) is characterized by severe disabling fatigue lasting for more than 6 months associated with physical and mental disturbances such as headache, arthralgia, myalgia, memory impairment, sore throat and tender lymph nodes. The exact pathogenesis is still unknown. Several models were proposed to explain its etiology including chronic infection, endocrine dysfunction, autonomic imbalance, depression, decreased immunity states and an aberrant reaction to infection. No convincing evidence was found to support any of the suggested pathogenic mechanisms. The current concept is that CFS pathogenesis is a multi factorial condition in which an infective agent cause an aberrant immune response characterized by a shift to Th-2 dominant response. When the response fails to be switched-off, a chronic immune activation occurs and clinically expressed as the symptomatology of CFS. Vaccinations are used in order to stimulate the immune system to induce a persistent immunity against the favorable antigens. Several syndromes that contain chronic fatigue as one of their symptoms, such as “Gulf war syndrome” and macrophagic myofasciitis were related to vaccinations. Can vaccinations induce the aberrant immune response of CFS? Little is known about this issue. There are some reports on CFS occurring after vaccination, but few prospective and retrospective studies failed to find such an association. A working group of the Canadian Laboratory Center for Disease Control (LCDC) that was founded in order to examine the suspected association between CFS and vaccinations concluded that there is no evidence that relates CFS to vaccination. Further studies are requested to examine this issue since it is very conceivable that if infection can lead to CFS, vaccination may also lead to it in the same immune-mediated pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Inflammatory brain diseases such as multiple sclerosis (MS) include hyperactivation of the coagulation pathway which includes thrombin. In the experimental autoimmune encephalomyelitis (EAE) model we have found significantly higher levels of thrombin inhibitors which include the very early elevation of protease nexin 1. The physiological importance of excess thrombin in neural tissue is demonstrated by recent experiments which link thrombin with conduction block in the sciatic nerve. [Copyright &y& Elsevier]

Abstract: Objective: To explore the diagnostic usefulness of high b-value diffusion magnetic resonance brain imaging (“q-space” imaging) in multiple sclerosis (MS). More specifically, we aimed at evaluating the ability of this methodology to identify tissue damage in the so-called normal-appearing white matter (NAWM). Design: In this study we examined the correlation between q-space diffusion imaging and magnetic resonance spectroscopy (MRS)-based two-dimensional 1H chemical shift imaging. Eight MS patients with different degree of disease severity and seven healthy subjects were scanned in a 1.5-T magnetic resonance imaging (MRI) scanner. The MRI protocol included diffusion tensor imaging (DTI) (with bmax of 1000 s/mm2), high b-value diffusion-weighted imaging (with bmax of 14,000 s/mm2) and 2D chemical shift imaging. The high b-value data set was analyzed using the q-space methodology to produce apparent displacement and probability maps. Results: We found that the q-space diffusion displacement and probability image intensities correlated well with N-acetylaspartate levels (r=.61 and .54, respectively). Furthermore, NAWM that was abnormal on MRS was also found to be abnormal using q-space diffusion imaging. In these areas, the q-space displacement values increased from 3.8±0.2 to 4.6±0.6 μm (P<.02), the q-space probability values decreased from 7.4±0.3 to 6.8±0.3 (P<.002), while DTI revealed only a small, but still significant, reduction in fractional anisotropy values from 0.40±0.02 to 0.37±0.02 (P<.05). Conclusion: High b-value diffusion imaging can detect tissue damage in the NAWM of MS patients. Despite the theoretical limitation of this method, in practice it provides additional information which is clinically relevant for detection of tissue damage not seen in conventional imaging techniques. [Copyright &y& Elsevier]

The interface between multiple sclerosis (MS) and the antiphospholipid syndrome (APS) is of great clinical relevance and may also shed some light on their pathogenesis. Although formal diagnostic criteria of these two immune syndromes are ostensibly mutually exclusive, many patients with subcortical white matter brain lesions share features of both MS and APS. The main diagnostic feature of APS, the antiphospholipid antibodies (aPLAb), is relatively common in multiple sclerosis and increased fibrin deposition is a feature of both APS lesions and MS plaques. A closer examination of the clinical and laboratory data reveals, however, fundamental differences between the syndromes: MS is a diffuse disease of white matter compared to a much more patchy disease in APS as demonstrated by recent studies in imaging and electrophysiology. Furthermore, a closer examination of the specific aPLAb profile reveals significant differences: we have found that although aPLAb were common in MS patients (32%), these antibodies did not depend on the presence of serum factors for binding to phospholipids and none of the MS patients had antibodies to β2-glycoprotein-I (β2-GPI), the major autoantigen in APS. Animal models of the two syndromes are induced by very different antigens and may serve to assess overlapping pathogenic mechanisms. The most common treatment used in MS are β-interferons which theoretically may exacerbate APS, while anticoagulation, the mainstay of APS treatment, is of unknown value in MS. The relationship of MS to APS remains to be clarified by focused large collaborative studies. [Copyright &y& Elsevier]

The increasing prevalence with age of antiphospholipid antibodies (aPL), of dementia and of stroke complicates the study of a causal relationship between antiphospholipid syndrome (APS) and dementia. Prolonged aPTT due to circulating anticoagulants (CAC) may serve as a more specific laboratory marker of APS. In a hospital-based study, we examined all patients with CAC and included 23 who fulfilled standard criteria for primary APS. These patients were assessed for dementia, vascular brain disease, autoimmune disease activity and dementia risk factors. Among CAC-positive APS patients, 13 of the 23 (56%) were demented and these were significantly older (mean age±S.E., 68±3 years) than the nondemented APS group (n=10, 51±4 years; p<0.01, Student''s t-test). The demented patients had significantly more pathology on computerized brain tomography (CT) and electroencephalography (EEG) studies but six of them had no clinical or CT evidence of vascular brain disease. Erythrocyte sedimentation rate was significantly lower in the dementia group, in which there was also a significant negative correlation between levels of aPL and age. CAC-positive APS patients seem to be at risk for developing dementia with age, suggesting a pathogenic role for prolonged exposure to elevated aPL. [Copyright &y& Elsevier]

Background: Creutzfeldt-Jacob disease (CJD) is a fatal neuro-degenerative disease, characterized by rapid and intense deterioration, mainly cognitive, leading to death. The typical onset of the disease is around the age of 67.Purpose: To characterize the demographic and clinical features of the population of CJD patients with late-onset disease.Methods: In this retrospective study, the Israeli national database of prion diseases was screened for CJD patients with disease age of onset > 80 years between 1960 and 2016. Patient's demographic and clinical data were collected including sex, type of disease (sporadic/ genetic), clinical presentation, lab results including tau protein level, imaging, and EEG characteristics. Then, the clinical and demographic data of patients with late onset (> 80 years) (L) and patients with usual age of onset (< 80 years) (U) were compared.Results: The study included 728 patients, 23 patients (3.3%) with late-onset disease (82.2.4±4 years, range 80-88) and 705 with usual disease onset (61.31 ± 9.47 years, range 34-80). Sporadic CJD was more common in the late-onset group (18/23 patients (78.2%) (L) vs. 256/705 patients (36.3%) (U)) (p = 0.0001, chi-square test). Classical EEG finding of periodic sharp wave activity were seen more often in the late-onset patients (55% (L) vs. 32.5% (U)) (p = 0.05, chi-square test). The rest of the demographic and clinical features were similar in both groups.Conclusion: Late- and usual-onset diseases are similar in most of demographic and clinical features suggesting a common disease type with normal distribution of age of onset. [ABSTRACT FROM AUTHOR]

Abstract: Neuromyelitis optica (NMO) is an autoimmune disorder, predominantly characterized by severe optic neuritis (ON) and transverse myelitis (TM). Historically considered a variant of Multiple sclerosis, the discovery that most NMO patients have autoantibodies against aquaporin-4 (AQP4) or NMO-IgG, dramatically changed our understanding of the disease. The finding of NMO-IgG revealed wider array of clinical presentations, including patients with recurrent ON of TM alone, now considered part of the NMO spectrum. Furthermore, symptoms other than optic-spinal involvement and the presence of brain lesions, do not exclude the diagnosis of NMO as traditionally accepted. We present an overview of the epidemiology, clinical manifestations and current diagnostic criteria for NMO and NMO spectrum disorders. [Copyright &y& Elsevier]

Abstract: We report a 36-year-old woman with the occurrence of painful focal seizures of her left hand and the left leg. She also had focal motor seizures at the left corner of her mouth. The duration and frequency of the episodes increased over four days from a few seconds once a day to frequent intervals lasting more than four hours at a time. The symptoms appeared one day after start of the treatment with fluvastatin (40 mg) administered in order to diminish the endothelial activation induced by antiphospholipid antibodies (aPL). The patient suffered from severe manifestations of the antiphospholipid syndrome (APS) including Catastrophic Antiphospholipid Syndrome (CAPS, Asherson''s syndrome). In this case a single 40 mg dose of oral fluvastatin was linked to seizures. After discontinuation of this treatment, the seizures immediately disappeared and the patient fully recovered without evidence of permanent neurological damage. This data links statins to seizures in patients with compromised blood brain barrier such as APS. [Copyright &y& Elsevier]

Background: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease characterized by rapidly progressive dementia, motor impairments, and psychiatric symptoms. Sensory disturbances were occasionally reported as well. The study aims to describe the sensory symptoms of the disease. Methods: The CJD Israeli National Database was screened for patients who presented sensory symptoms throughout the disease course. Symptoms, characteristics, and distribution were reviewed and the demographic and clinical data (sex, etiologies of the disease, age of onset, disease duration, neurological exam finding, tau protein level, EEG and MRI findings) were compared with the demographics and clinical data of CJD without sensory symptoms. Then, the patients with sensory symptoms were divided into patients with symptom distribution consistent with peripheral nervous system (PNS) involvement and central nervous system (CNS) involvement. The demographics and clinical data of the 2 groups were compared. Results: Eighty-four CJD patients with sensory symptoms and 645 CJD patients without sensory symptoms were included in the study. Sensory symptoms were more common in genetic E200K CJD patients (14.6% vs. 5.6% respectively, p = 0.0005) (chi-squared test). Numbness and neuropathic pain were the most common symptoms and distribution of symptoms of "stocking gloves" with decreased deep tendon reflexes suggesting peripheral neuropathy in 44% of the patients. In these patients, the classical EEG findings of Periodic Sharp Wave Complexes were less often found (58% vs. 22%, p = 0.02) (chi-squared test). Conclusions: Sensory symptoms are more common in E200K patients and often follow peripheral neuropathy distribution that suggests PNS involvement. [ABSTRACT FROM AUTHOR]

Electroencephalogram (EEG) pattern in Creutzfeldt-Jakob disease (CJD) is characterized by diffuse abnormal activity, although lateralization to one hemisphere has been described in the first stages of the disease. This study aimed to determine whether abnormal EEG activity predominantly occurs in anterior versus posterior brain regions. As part of a prospective study, the demographics, clinical features and MRI findings of genetic E200K CJD patients were collected. EEG was performed and the recordings reviewed for the typical periodic sharp wave complex (PSWC) and non-specific slow activity. Data were analyzed using the qEEG tool, and the activity in anterior and posterior regions of the brain compared. Eleven genetic E200K CJD patients were included in the study (67% women). The average age was 59.1 ± 8.4 SD years and the average disease duration was 2.4 ± 2.1 months. EEG showed the classic PSWC pattern in 5/11 (45%) of the patients, and slow activity was seen in 9/11 (82%). EEG was normal in 2 patients. PSWC activity was diffuse in 2/5 patients and unilateral in 3/5 patients; slow activity was diffuse in 9 patients. Quantitative analysis of PSWC and slow activity showed no significant difference between anterior and posterior distribution. The abnormal EEG activity in CJD is diffuse with no clear spatial predominance in anterior or posterior brain regions. [ABSTRACT FROM AUTHOR]

Objective: To characterize the demographic, clinical features and disease course of familial Creutzfeldt–Jakob disease (fCJD) patients homozygous to the E200K mutation. Methods: The Israeli National CJD Database was screened for patients homozygous to the E200K mutation. Patients' demographic data, clinical presentation and neurological findings, tau protein levels in the cerebrospinal fluid (CSF) and EEG, were assessed. Results: Ten homozygous E200K patients were identified (80% males). Average age of onset was 47.5 ± 6.1 years (range 40–56) and the average age of death was 49.3 ± 7. 7 years (range 42–63) with average disease duration of 27.7 ± 9.7 months (range 2–97). Initial clinical presentation included behavioral change in 4/10 patients, cognitive decline in 3/10 patients and focal neurological deficits in 2/10 patients. Throughout the disease course, the clinical signs in descending order of prevalence included cerebellar (70%), brainstem (60%), extrapyramidal (50%), pyramidal (50%), frontal lobe signs (30%), and disturbances of ocular motility (30%) Compared to the 228 heterozygous E200K fCJD patients, the 10 homozygous patients were significantly younger at disease onset (47.5 vs 59.7 years, p < 0.001), had a longer disease duration (27.7 vs 8.5 months, p < 0.001) and presented more frequently with behavioral changes as initial manifestation (4/10 vs. 34/228, p = 0.05). Conclusions: Homozygous E200K fCJD patients are characterized by a relatively younger age of onset and longer disease duration. Behavioral changes as a presenting symptom were more common in homozygous patients and cerebellar dysfunction was the most common neurological manifestation throughout the disease course. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies showed concordance between the typical Periodic Sharp Wave Complex (PSWC) activity in EEG of Creutzfeldt‐Jakob Disease (CJD) patients and the MRI findings, while the concordance with slow activity in EEG is less established. The aim of this study was to better characterize the association between MRI findings and EEG changes using quantitative EEG (qEEG) analysis. Methods: The demographics, clinical features, and the MRI findings of 12 familial E200K patients with CJD were gathered. EEG test was done and reviewed for the typical PSWC and for the non‐specific slow activity. A possible association between the MRI findings and the EEG activity was examined. Then, EEG was analyzed using qEEG tool, and the association between the qEEG finding and the MRI was examined. Results: Twelve patients were included in the study (67% women). Cortical MRI lesions finding were seen in 6/12 (50%) of the patients, and deep gray mater lesions were seen in 8/12 patients (67%). EEG showed the classic PSWC in 6/12 (50%) of the patients where slow activity was seen in 10/12 (83%). Slow activity and cortical MRI findings were associated in only 2/6 (33%) where deep gray matter findings and the slow activity had concordance of 4/8 (50%). qEEG analysis improved this concordance between slow activity and cortical findings to 3/6 (50%) and with the deep gray matter findings to 5/8 (63%). Conclusions: Quantitative EEG analysis modesty but not significantly, improves the association of EEG slow activity in familial E200K CJD patients with MRI findings. [ABSTRACT FROM AUTHOR]

Background and purpose: Intramuscular blood flow increases during physical activity and may be quantified immediately following exercise using power Doppler sonography. Post‐exercise intramuscular blood flow is reduced in patients with muscular dystrophy, associated with disease severity and degenerative changes. It is not known if intramuscular blood flow is reduced in patients with neuropathy, nor if it correlates with muscle strength and structural changes. The aim was to determine whether blood flow is reduced in patients with polyneuropathy due to Charcot–Marie–Tooth disease type 1 (CMT1) and to compare more affected distal to less affected proximal muscles. Methods: This was a cross‐sectional study including 21 healthy volunteers and 17 CMT patients. Power Doppler ultrasound was used to quantify post‐exercise intramuscular blood flow in distal (gastrocnemius) and proximal (elbow flexor) muscles. Intramuscular blood flow was compared to muscle echo intensity, muscle strength, disease severity score, patient age and electromyography. Results: Polyneuropathy patients showed reduced post‐exercise blood flow in both gastrocnemius and elbow flexors compared to controls. A more prominent reduction was seen in the gastrocnemius (2.51% vs. 10.34%, p < 0.0001) than in elbow flexors (4.48% vs. 7.03%, p < 0.0001). Gastrocnemius intramuscular blood flow correlated with muscle strength, disease severity and age. Receiver operating characteristic analysis showed that quantification of intramuscular blood flow was superior to echo intensity for detecting impairment in the gastrocnemius (area under the curve 0.962 vs. 0.738, p = 0.0126). Conclusion: Post‐exercise intramuscular blood flow is reduced in CMT1 polyneuropathy. This reduction is present in both impaired distal and minimally affected proximal muscles, indicating it as an early marker of muscle impairment due to neuropathy. [ABSTRACT FROM AUTHOR]

Specific inflammatory pathways and specifically Tumor Necrosis Factor alpha (TNF-α) have been associated with the neurodegeneration in Parkinson’s disease (PD). TNFα is also known to play an important role in the pathogenesis of sarcoidosis and TNF blockers can ameliorate the disease. In contrast, multiple sclerosis (MS) is clearly exacerbated by anti- TNF-α medications. We have therefore hypothesized that Parkinson-like disease would be more common in neurosarcoidosis (NS) compared to MS. The aim of this case-control study was therefore to assess the frequency of extrapyramidal signs in patients with NS compared to MS patients. In order to do so the medical records of NS patients and of age and gender matched MS patients were reviewed and data regarding the clinical features, ancillary tests performed, treatment, and outcome were documented. Patients were then examined in a uniform manner for the presence of extrapyramidal signs. We found that in the NS group 8 patients had minor signs, one had mild functional disability and 3 subjects had significant extrapyramidal signs compatible with the diagnosis of Parkinson's disease. All extrapyramidal signs found in 5 of the MS group were minor. The proportional severity of extrapyramidal signs was significantly higher ( p = 0.045, chi square test) in the NS group compared to the MS group. We conclude that the specificity of extrapyramidal to NS raises the intriguing question of whether specific inflammatory pathways involving TNF-α play a role in the pathogenesis of PD and therefore may be a therapeutic target. [ABSTRACT FROM AUTHOR]

Diabetic encephalopathy (DE) is an inflammation-associated diabetes mellitus (DM) complication. Inflammation and coagulation are linked and are both potentially modulated by inhibiting the thrombin cellular protease-activated receptor 1 (PAR1). Our aim was to study whether coagulation pathway modulation affects DE. Diabetic C57BL/6 mice were treated with PARIN5, a novel PAR1 modulator. Behavioral changes in the open field and novel object recognition tests, serum neurofilament (NfL) levels and thrombin activity in central and peripheral nervous system tissue (CNS and PNS, respectively), brain mRNA expression of tumor necrosis factor α (TNF-α), Factor X (FX), prothrombin, and PAR1 were assessed. Subtle behavioral changes were detected in diabetic mice. These were accompanied by an increase in serum NfL, an increase in central and peripheral neural tissue thrombin activity, and TNF-α, FX, and prothrombin brain intrinsic mRNA expression. Systemic treatment with PARIN5 prevented the appearance of behavioral changes, normalized serum NfL and prevented the increase in peripheral but not central thrombin activity. PARIN5 treatment prevented the elevation of both TNF-α and FX but significantly elevated prothrombin expression. PARIN5 treatment prevents behavioral and neural damage in the DE model, suggesting it for future clinical research. [ABSTRACT FROM AUTHOR]

Background: The largest cluster of genetic Creutzfeldt‐ Jakob Disease (CJD) exists in Libyan Jews carrying the E200K mutation in the PRNP gene. However, there is another cluster of genetic CJD with E200K mutation in families of Turkish–Jewish origin. Aims: In this retrospective study, we aim to describe the demographic and clinical features of this population of patients. Material and Methods: The Israeli National CJD database was searched for demographic, clinical, imaging, and laboratory data of genetic CJD patients of Libyan and Turkish ancestry with the E200K mutation. The data of Libyan and Turkish patients were compared with notice similar or different demographic or clinical courses. Results: Four hundred and twenty‐three patients with CJD of Libyan (L) ancestry and 27 patients with CJD of Turkish (T) ancestry were identified. There were no significant differences in demographic and clinical data between the two populations (age of onset: T = 62 ± 8.8, L = 60 ± 9.7; age of death: T = 63 ± 8.6, L = 61 ± 9.7; and disease duration: T = 7.8 ± 8.4 months, L = 9.6 ± 13.6 months). Rapidly progressive dementia was the most common presentation in both groups, followed by pure cerebellar onset. The levels of tau protein in CSF did not differ between groups (T = 1290 ± 397.6 pg/ml, L = 1276 ± 594.2 pg/ml). MRI and EEG showed classical CJD features in most patients in both groups. Discussion: The E200K mutation is the most common mutation among gCJD patients and was reported in different ethnical populations, suggesting several independent haplotypes of the mutation. The Turkish‐Jew cluster, first described in this study, shares similar demographic and clinical features with the bigger cluster of Libyan‐Jews CJD patients. Conclusion: E200K gCJD patients of Turkish ancestry share similar demographic and clinical features to patients of Libyan descent, suggesting a common origin of both populations. [ABSTRACT FROM AUTHOR]

Background. Due to the interactions between neuroinflammation and coagulation, the neural effects of lipopolysaccharide (LPS)-induced inflammation (1 mg/kg, intraperitoneal (IP), n = 20) and treatment with the anti-thrombotic enoxaparin (1 mg/kg, IP, 15 min, and 12 h following LPS, n = 20) were studied in C57BL/6J mice. Methods. One week after LPS injection, sensory, motor, and cognitive functions were assessed by a hot plate, rotarod, open field test (OFT), and Y-maze. Thrombin activity was measured with a fluorometric assay; hippocampal mRNA expression of coagulation and inflammation factors were measured by real-time-PCR; and serum neurofilament-light-chain (NfL), and tumor necrosis factor-α (TNF-α) were measured by a single-molecule array (Simoa) assay. Results. Reduced crossing center frequency was observed in both LPS groups in the OFT (p = 0.02), along with a minor motor deficit between controls and LPS indicated by the rotarod (p = 0.057). Increased hippocampal thrombin activity (p = 0.038) and protease-activated receptor 1 (PAR1) mRNA (p = 0.01) were measured in LPS compared to controls, but not in enoxaparin LPS-treated mice (p = 0.4, p = 0.9, respectively). Serum NfL and TNF-α levels were elevated in LPS mice (p < 0.05) and normalized by enoxaparin treatment. Conclusions. These results indicate that inflammation, coagulation, neuronal damage, and behavior are linked and may regulate each other, suggesting another pharmacological mechanism for intervention in neuroinflammation. [ABSTRACT FROM AUTHOR]

Background: Inflammation and coagulation are linked and pathogenic in neuroinflammatory diseases. Protease-activated receptor 1 (PAR1) can be activated both by thrombin, inducing increased inflammation, and activated protein C (aPC), inducing decreased inflammation. Modulation of the aPC-PAR1 pathway may prevent the neuroinflammation associated with PAR1 over-activation. Methods: We synthesized a group of novel molecules based on the binding site of FVII/aPC to the endothelial protein C receptor (EPCR). These molecules modulate the FVII/aPC-EPCR pathway and are therefore named FEAMs—Factor VII, EPCR, aPC Modulators. We studied the molecular and behavioral effects of a selected FEAM in neuroinflammation models in-vitro and in-vivo. Results: In a lipopolysaccharide (LPS) induced in-vitro model, neuroinflammation leads to increased thrombin activity compared to control (2.7 ± 0.11 and 2.23 ± 0.13 mU/ml, respectively, p = 0.01) and decreased aPC activity (0.57 ± 0.01 and 1.00 ± 0.02, respectively, p < 0.0001). In addition, increased phosphorylated extracellular regulated kinase (pERK) (0.99 ± 0.13, 1.39 ± 0.14, control and LPS, p < 0.04) and protein kinase B (pAKT) (1.00 ± 0.09, 2.83 ± 0.81, control and LPS, p < 0.0002) levels indicate PAR1 overactivation, which leads to increased tumor necrosis factor-alpha (TNF-α) level (1.00 ± 0.04, 1.35 ± 0.12, control and LPS, p = 0.02). In a minimal traumatic brain injury (mTBI) induced neuroinflammation in-vivo model in mice, increased thrombin activity, PAR1 activation, and TNF-α levels were measured. Additionally, significant memory impairment, as indicated by a lower recognition index in the Novel Object Recognition (NOR) test and Y-maze test (NOR: 0.19 ± 0.06, -0.07 ± 0.09, p = 0.03. Y-Maze: 0.50 ± 0.03, 0.23 ± 0.09, p = 0.02 control and mTBI, respectively), as well as hypersensitivity by hot-plate latency (16.6 ± 0.89, 12.8 ± 0.56 s, control and mTBI, p = 0.01), were seen. FEAM prevented most of the molecular and behavioral negative effects of neuroinflammation in-vitro and in-vivo, most likely through EPCR-PAR1 interactions. Conclusion: FEAM is a promising tool to study neuroinflammation and a potential treatment for a variety of neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome (APS) affects the brain by both hypercoagulation and immunological mechanisms. APS is characterized by several autoantibodies binding to a thrombolytic complex including beta-2-glycoprotein I (β2-GPI) and annexin A2 (ANXA2). Teriflunomide, an oral drug for the treatment of multiple sclerosis (MS), has a cytostatic effect on B cells and is therefore a potential antibody-targeting treatment for APS. In this study, we assessed the effect of teriflunomide in two APS mouse models by inducing autoantibody formation against β2-GPI and ANXA2 in female BALB/c mice. The ANXA2 model displayed a behavioral change suggesting an anti-anxiety effect in open field and forced swim tests, early in the course of the disease. This effect was normalized following teriflunomide treatment. Conversely, behavioral tests done later during the study demonstrated depression-like behavior in the ANXA2 model. No behavioral changes were seen in the β2-GPI model. Total brain IgG levels were significantly elevated in the ANXA2 model but not in the teriflunomide treated group. No such change was noted in the brains of the β2-GPI model. High levels of serum autoantibodies were induced in both models, and their levels were not lowered by teriflunomide treatment. Teriflunomide ameliorated behavioral changes in mice immunized with ANXA2 without a concomitant change in serum antibody levels. These findings are compatible with the effect of teriflunomide on neuroinflammation. Teriflunomide ameliorated behavioral and brain IgG levels in mice immunized with ANXA2 without a concomitant change in serum antibody levels. These findings are compatible with an effect of teriflunomide on the IgG permeability to the brain and neuroinflammation. Graphical Abstract [ABSTRACT FROM AUTHOR]

Objective Anti-ribosomal-phosphoprotein antibodies (anti-Ribos.P Abs) are detected in 10–45% of NPSLE patients. Intracerebroventricular administration of anti-ribosomal-P Abs induces depression-like behaviour in mice. We aimed to discern the mechanism by which anti-Ribos.P Abs induce behavioural changes in mice. Methods Anti-Ribos.P Abs were exposed to human and rat neuronal cell cultures, as well as to human umbilical vein endothelial cell cultures for a control. The cellular localization of anti-Ribo.P Abs was found by an immunofluorescent technique using a confocal microscope. Identification of the target molecules was undertaken using a cDNA library. Immunohistochemistry and an inhibition assay were carried out to confirm the identity of the target molecules. Neuronal cell proliferation was measured by bromodeoxyuridine, and Akt and Erk expression by immunoblot. Results Human anti-Ribos.P Abs penetrated into human neuronal cells and rat hippocampal cell cultures in vitro , but not to endothelial cells as examined. Screening a high-content human cDNA-library with anti-Ribos.P Abs identified neuronal growth–associated protein (GAP43) as a target for anti-Ribos.P Abs. Ex vivo anti-Ribos.P Abs bind to mouse brain sections of hippocampus, dentate and amygdala. Anti-Ribos.P Abs brain-binding was prevented by GAP43 protein. Interestingly, GAP43 inhibited in a dose-dependent manner the anti-Ribos.P Abs binding to recombinant-ribosomal-P0, indicating mimicry between the ribosomal-P0 protein and GAP43. Furthermore, anti-Ribos.P Abs reduced neuronal cell proliferation activity in vitro (P < 0.001), whereas GAP43 decreased this inhibitory activity by a factor of 7.6. The last was related to Akt and Erk dephosphorylation. Conclusion Anti-Ribos.P Abs penetrate neuronal cells in vitro by targeting GAP43. Anti -Ribos.P Abs inhibit neuronal-cell proliferation via inhibition of Akt and Erk. Our data contribute to deciphering the mechanism for anti-Ribos.P Abs' pathogenic activity in NPSLE. [ABSTRACT FROM AUTHOR]

Abstract: Neuromyelitis optica (NMO) is associated with antibodies to aquaporin 4 (AQP4). We hypothesized that antibodies to AQP4 can be triggered by exposure to environmental proteins. We compared human AQP4 to plant and bacterial proteins to investigate the occurrence of significantly similar structures and sequences. High similarity to a known epitope for NMO-IgG, AQP4(207–232), was observed for corn ZmTIP4-1. NMO and non-NMO sera were assessed for reactivity to AQP4(207–232) and the corn peptide. NMO patient serum showed reactivity to both peptides as well as to plant tissue. These findings warrant further investigation into the role of the environment in NMO etiology. [Copyright &y& Elsevier]

J. Neurochem. (2011) 119, 460-473. Abstract We studied the localization, activation and function of protease-activated receptor 1 (PAR-1) at the CNS synapse utilizing rat brain synaptosomes and slices. Confocal immunofluoresence and transmission electron microscopy in brain slices with pre-embedding diaminobenzidine (DAB) immunostaining found PAR-1 predominantly localized to the peri-synaptic astrocytic endfeet. Structural confocal immunofluorescence microscopy studies of isolated synaptosomes revealed spherical structures stained with anti-PAR-1 antibody which co-stained mainly for glial-filament acidic protein compared with the neuronal markers synaptophysin and PSD-95. Immunoblot studies of synaptosomes demonstrated an appropriate major band corresponding to PAR-1 and activation of the receptor by a specific agonist peptide (SFLLRN) significantly modulated phosphorylated extracellular signal-regulated kinase. A significant membrane potential depolarization was produced by thrombin (1 U/mL) and the PAR-1 agonist (100 μM) and depolarization by high K+ elevated extracellular thrombin-like activity in the synaptosomes preparation. The results indicate PAR-1 localized to the peri-synaptic astrocytic endfeet is most likely activated by synaptic proteases and induces cellular signaling and modulation of synaptic electrophysiology. A protease mediated neuron-glia pathway may be important in both physiological and pathological regulation of the synapse. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder which affects widespread areas of the brainstem, basal ganglia and cerebral cortex. A number of proteins are known to accumulate in parkinsonian brains including ubiquitin and a-synuclein. Prion diseases are sporadic, genetic or infectious disorders with various clinical and histopathological features caused by prion proteins as infectious proteinaceous particles transmitting a misfolded protein configuration through brain tissue. The most important form is Creutzfeldt-Jakob disease which is associated with a self-propagating pathological precursor form of the prion protein that is physiologically widely distributed in the central nervous system. Discussion: It has recently been found that α-synuclein may behave similarly to the prion precursor and propagate between cells. The post-mortem proof of α-synuclein containing Lewy bodies in embryonic dopamine cells transplants in PD patient suggests that the misfolded protein might be transmitted from the diseased host to donor neurons reminiscent of prion behavior. The involvement of the basal ganglia and brainstem in the degenerative process are other congruencies between Parkinson's and Creutzfeldt-Jakob disease. However, a number of issues advise caution before categorizing Parkinson's disease as a prion disorder, because clinical appearance, brain imaging, cerebrospinal fluid and neuropathological findings exhibit fundamental differences between both disease entities. Most of all, infectiousness, a crucial hallmark of prion diseases, has never been observed in PD so far. Moreover, the cellular propagation of the prion protein has not been clearly defined and it is, therefore, difficult to assess the molecular similarities between the two disease entities. Summary: At the current state of knowledge, the molecular pathways of transmissible pathogenic proteins are not yet fully understood. Their exact involvement in the pathophysiology of prion disorders and neurodegenerative diseases has to be further investigated in order to elucidate a possible overlap between both disease categories that are currently regarded as distinct entities. [ABSTRACT FROM AUTHOR]

Abstract: EAE is a common animal model for multiple sclerosis (MS). Immunomodulatory treatments such as glatiramer acetate (GA, Copaxone) are beneficial in EAE but are not universally effective in the clinic. The Ras inhibitor farnesylthiosalycylic acid (FTS, Salirasib), efficiently ameliorate EAE as well. Here we demonstrate a synergistic beneficial effect of the combined GA and FTS treatment on EAE; 22.5% of the combined-treatment mice developed disease compared to 87.5%, 77.5% and 82.5% of mice treated with vehicle, GA and FTS, respectively, results supported by MRI, histological, immunological and biochemical data. Such a combined treatment may improve clinical outcome in MS patients. [ABSTRACT FROM AUTHOR]

Modern clinical research often involves multi-center studies, large and heterogeneous data flux, and intensive demands of collaboration, security and quality assurance. In the absence of commercial or academic management systems, we designed an open-source system to meet these requirements. Based on the Apache-PHP-MySQL platform on a Linux server, the system allows multiple users to access the database from any location on the internet using a web browser, and requires no specialized computer skills. Multi-level security system is implemented to safeguard the protected health information and allow partial or full access to the data by individual or class privilege. The system stores and manipulates various types of data including images, scanned documents, laboratory data and clinical ratings. Built-in functionality allows for various search, quality control, analytic data operations, visit scheduling and visit reminders. This approach offers a solution to a growing need for management of large multi-center clinical studies. [ABSTRACT FROM AUTHOR]

Human prion diseases present substantial scientific and public health challenges. They are unique in being sporadic, infectious and inherited, and their pathogen is distinct from all other pathogens in lacking nucleic acids. Despite progress in understanding the molecular structure of prions, their initial cerebral pathophysiology and the loci of cerebral injury are poorly understood. As part of a large prospective study, we analysed early diffusion MRI scans of 14 patients with the E200K genetic form of Creutzfeldt–Jakob Disease, 20 healthy carriers of this mutation that causes the disease and 20 controls without the mutation from the same families. Cerebral diffusion was quantified by the Apparent Diffusion Coefficient, and analysed by voxel-wise statistical parametric mapping technique. Compared to the mutation-negative controls, diffusion was significantly reduced in a thalamic-striatal network, comprising the putamen and mediodorsal, ventrolateral and pulvinar thalamic nuclei, in both the patients and the healthy mutation carriers. With disease onset, these diffusion reductions intensified, but did not spread to other areas. The caudate nucleus was reduced only after symptomatic onset. These findings indicate that cerebral diffusion reductions can be detected early in the course of Creutzfeldt–Jakob Disease, and years before symptomatic onset in mutation carriers, in a distinct subcortical network. We suggest that this network is centrally involved in the pathogenesis of Creutzfeldt–Jakob Disease, and its anatomical connections are sufficient to account for the common symptoms of this disease. Further, we suggest that the abnormalities in healthy mutation-carrying subjects may reflect the accumulation of abnormal prion protein and/or associated vacuolation at this time, temporally close to disease onset. [ABSTRACT FROM PUBLISHER]

Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease associated with more than 100 different autoantibodies, some of which may be associated with specific neuropsychiatric (NPSLE) manifestations. Injection of anti-P ribosomal antibodies (anti-P) directly to the brain ventricles of mice induces depression manifested by increased immobility time in the forced swim test (FST). Methods: Mice were injected intracerebroventricularily (ICV) with affinity-purified human anti-P antibodies or normal commercial IgG as control. Mice were examined for depression by the forced swimming test (FST) and for olfactory function by the smell threshold test. Treatments included the antidepressant drug fluoxetine or aroma therapy by exposure to lemon or cinnamon odor. Results: Mice injected with anti-P developed depression-like behavior, which improved significantly upon treatment with fluoxetine. Depressed mice had a significant deficit in olfactory function which was not reversed by fluoxetine. Exposure of anti-P-injected mice to lemon odor was associated with some improvement of the immobility time, a measure of depression. Conclusions: ICV injection of anti-P induces both depression-like behavior and impaired olfactory function in mice. Fluoxetine and possibly lemon odor exposure improve depressive behavior in these mice. [Copyright &y& Elsevier]

Many studies have used sural nerve action potential (NAP) as an electrophysiological marker for distal symmetrical polyneuropathy (DSP). We examined the role of medial plantar nerve testing for identifying DSP by comparing amplitudes from sural, superficial peroneal, and medial plantar nerves in 85 participants with symptoms and clinical signs of DSP and 204 participants without DSP. Receiver-operating characteristic curves were used to determine the sensitivity of all three sensory conduction studies for the diagnosis of DSP. All three nerves could be used to discriminate between subjects with and without DSP with an area under the curve of more than 85% of cases. Sural and superficial peroneal nerve testing sensitivities were about 55%, whereas medial plantar nerve testing sensitivity was more than 90%. These findings suggest that testing the medial plantar nerve may increase the diagnostic yield of nerve conduction studies for DSP. Muscle Nerve 38: 1595-1598, 2008 [ABSTRACT FROM AUTHOR]

The effects of thrombin, a blood coagulation serine protease, were studied in rat hippocampal slices, in an attempt to comprehend its devastating effects when released into the brain after stroke and head trauma. Thrombin acting through its receptor, protease-activated receptor 1 (PAR1), produced a long-lasting enhancement of the reactivity of CA1 neurons to afferent stimulation, an effect that saturated the ability of the tissue to undergo tetanus-induced long-term potentiation. This effect was mediated by activation of a PAR1 receptor, because it was shared by a PAR1 agonist, and was blocked by its selective antagonist. An independent effect of thrombin involved the lowering of the threshold for generating epileptic seizures in CA3 region of the hippocampus. Thus, the experiments in a slice mimicked epileptic and cognitive dysfunction induced by thrombin in the brain, and suggest that these effects are mediated by activation of the PAR1 receptor. [ABSTRACT FROM AUTHOR]

Abstract: Neuronal nicotinic acetylcholine receptors (nAChR), which modulate fast excitatory postsynaptic potentials (f-EPSP), are located on both pre- and postganglionic sites in the autonomic nervous system (ANS). The receptor subunits α3, α5, α7, β2 and β4 are present in autonomic ganglia in various combinations and modulate acetylcholine (ACh) transmission. In the present study, autonomic functions were systemically examined in mice lacking β2 subunits (β2−/−) to further understand the functional role of β2 subunits in modulating ganglionic transmission. The results show normal autonomic functions, both under physiological conditions and in perturbed conditions, on thermoregulation, pupillary size, heart rate responses and ileal contractile reactions. This suggests that the function of β2-containing receptors in ganglionic transmission is hidden by the predominant β4 containing receptors and confirms previous studies which suggest that α3α5β4 nAChRs are sufficient for autonomic transmission. On the other hand, β2-containing receptors have only a minor function on postsynaptic responses to ACh, but may modulate ACh release presynaptically, although there is no evidence for this. [Copyright &y& Elsevier]

Neuronal nicotinic acetylcholine receptors (nAChRs) are composed of 12 subunits (α2–α10 and β2–β4). α5 Subunits, expressed throughout the central nervous system (CNS) and the autonomic nervous system (ANS), possess unique pharmacological properties. The effects of oxotremorine (OXO) on autonomic functions and tremor were examined in mice lacking α5 nAChR subunits (α5-/-) and compared with those in wild-type (WT) control mice. The α5-/- mice showed significantly increased salivation and tremor responses to OXO. The hypothermia, bradycardia and defecation induced by OXO were of similar magnitudes in the two mouse strains. The enhanced OXO effects in α5-/- mice indicate inhibitory effects of α5 subunits in autonomic ganglia, and support the participation of these subunits in cholinergic transmission in autonomic ganglia. [Copyright &y& Elsevier]