Neurological Normal Controls Research Articles

Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations

Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions in C9orf72 are the two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration in FTD with GRN (FTD-GRN) or C9orf72 (FTD-C9orf72) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that GRN mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD-GRN cases, FTD-C9orf72 cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD-GRN cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD-C9orf72. FTD-GRN was distinguished from FTD-C9orf72 and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD-GRN and FTD-C9orf72 cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD-GRN. We conclude that both C9orf72 and GRN mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but GRN mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD-GRN. Since FTD-GRN is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD.

People with mild Parkinson's disease have impaired force production in upper limb muscles: A cross-sectional study.

There has been little examination of force production of the upper limb in people with Parkinson's disease (PD), despite its impact on activities of daily living and clear evidence that force production is significantly reduced in lower limb muscle groups. The aim of this study was to determine the force production of the major muscle groups of the upper limb in people with PD during the "on" phase after medication, compared with aged-matched neurologically-normal controls. A cross-sectional study was carried out. Thirty people with mild PD (Hoehn Yahr mean 1.1) and 24 age-matched neurologically-normal controls. Maximum isometric force production of the shoulder flexors, extensors, abductors, adductors, internal rotators and external rotators, elbow flexors and extensors, wrist flexors and extensors and hand grip using dynamometry. There was a significant impairment in force production in all upper limb muscle groups, compared with control participants, except in the wrist flexors. On average the deficit in force production was 22%, despite people with PD having mild disease, being physically active and being measured during the "on" phase of medication. The most severely affected muscle groups were the upper limb extensors. People with PD have a significant deficit in force production of the upper limb muscle groups compared with age-matched neurologically normal controls. Regular assessment of strength of the upper limb should be considered by clinicians and strengthening interventions could be implemented if a deficit is identified.

Quantitative detection of α-Synuclein and Tau oligomers and other aggregates by digital single particle counting

The pathological hallmark of neurodegenerative diseases is the formation of toxic oligomers by proteins such as alpha-synuclein (aSyn) or microtubule-associated protein tau (Tau). Consequently, such oligomers are promising biomarker candidates for diagnostics as well as drug development. However, measuring oligomers and other aggregates in human biofluids is still challenging as extreme sensitivity and specificity are required. We previously developed surface-based fluorescence intensity distribution analysis (sFIDA) featuring single-particle sensitivity and absolute specificity for aggregates. In this work, we measured aSyn and Tau aggregate concentrations of 237 cerebrospinal fluid (CSF) samples from five cohorts: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and a neurologically-normal control group. aSyn aggregate concentration discriminates PD and DLB patients from normal controls (sensitivity 73%, specificity 65%, area under the receiver operating curve (AUC) 0.68). Tau aggregates were significantly elevated in PSP patients compared to all other groups (sensitivity 87%, specificity 70%, AUC 0.76). Further, we found a tight correlation between aSyn and Tau aggregate titers among all patient cohorts (Pearson coefficient of correlation r = 0.81). Our results demonstrate that aSyn and Tau aggregate concentrations measured by sFIDA differentiate neurodegenerative disease diagnostic groups. Moreover, sFIDA-based Tau aggregate measurements might be particularly useful in distinguishing PSP from other parkinsonisms. Finally, our findings suggest that sFIDA can improve pre-clinical and clinical studies by identifying those individuals that will most likely respond to compounds designed to eliminate specific oligomers or to prevent their formation.

Abnormal B-Cell and Tfh-Cell Profiles in Patients With Parkinson Disease

Background and ObjectivesThere has been growing interest in potential roles of the immune system in the pathogenesis of Parkinson disease (PD). The aim of the current study was to comprehensively characterize phenotypic and functional profiles of circulating immune cells in patients with PD vs controls.MethodsPeripheral blood was collected from patients with PD and age- and sex-matched neurologically normal controls (NCs) in 2 independent cohorts (discovery and validation). Comprehensive multicolor flow cytometry was performed on whole blood leukocytes and peripheral blood mononuclear cells to characterize different immune subsets and their ex vivo responses.ResultsThe discovery cohort included 17 NCs and 12 participants with PD, and the validation cohort included 18 NCs and 18 participants with PD. Among major immune cell types, B cells appeared to be preferentially affected in PD. Proliferating B cell counts were decreased in patients with PD compared with controls. Proportions of B-cell subsets with regulatory capacity such as transitional B cells were preferentially reduced in the patients with PD, whereas proportions of proinflammatory cytokine-producing B cells increased, resulting in a proinflammatory shift of their B-cell functional cytokine responses. Unsupervised principal component analysis revealed increased expression of TNFα and GM-CSF by both B cells and T cells of patients with PD. In addition, levels of follicular T cells, an important B-cell helper T-cell population, decreased in the patients with PD, correlating with their B-cell abnormality.DiscussionOur findings define a novel signature of peripheral immune cells and implicate aberrant Tfh:B-cell interactions in patients with PD.

Cerebrospinal Fluid Profiles in Parkinson's Disease: No Accumulation of Glucosylceramide, but Significant Downregulation of Active Complement C5 Fragment.

As mutations in glucocerebrosidase 1 (GBA1) are a major risk factor for Parkinson's disease (PD), decreased GBA1 activity might play an important role in the pathogenesis of the disease. However, there are currently no reports on glucosylceramide levels in the cerebrospinal fluid (CSF) in PD. We investigated whether glucosylceramide accumulation and abnormal immune status in the brain are associated with PD. We measured glucosylceramide by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) as well as levels of the active fragment of complement C5, C5a, in the CSF of 33 PD, 15 amyotrophic lateral sclerosis (ALS) and 22 neurologically normal control (NNC) subjects. Serum C5a levels in all PD and ALS cases and in a limited number of NNC subjects (n = 8) were also measured. C5a levels in CSF were significantly downregulated in PD compared with NNC. Moreover, CSF C5a/serum C5a ratio showed pronounced perturbations in PD and ALS patients. LC-ESI-MS/MS revealed a statistically significant accumulation of a specific subspecies of glucosylceramide (d18 : 1/C23 : 0 acyl chain fatty acid) in ALS, but not in PD. Interestingly, CSF glucosylceramide (d18 : 1/C23 : 0) exhibited a significant correlation with CSF C5a levels in PD, but not ALS. No correlation was observed between C5a levels or glucosylceramide subspecies content and disease duration, levodopa equivalent daily dose or Hoehn & Yahr staging in PD. Our findings demonstrate complement dysregulation without glucosylceramide accumulation in PD CSF. Furthermore, we found an association between a specific glucosylceramide subspecies and immune status in PD.

Exosomes from patients with Parkinson's disease are pathological in mice.

Cell-to-cell transport of risk molecules is a highly anticipated pathogenic mechanism in the initiation and progression of various neurodegenerative diseases. Extracellular exosome-mediated neuron to neuron transport of α-synuclein (α-syn) is increasingly recognized as a potential etiologic mechanism in Parkinson's disease (PD). Exosomal inflammation has also been increasingly implicated in PD pathogenesis and could trigger, facilitate, or aggravate disease development. However, these mechanisms have not been verified systematically, especially in vivo. Since serum contains abundant exosomes, the correlation between serum exosomes and PD pathogenesis remains unknown. Here, we show that exosomes from PD patient serum contain more α-syn and inflammatory factors such as IL-1β and TNF-α than neurological normal controls, eventually cause α-syn, ubiquitin, and P62 aggregation in recipient cells. More importantly, the intravenous or intrastriatal treatment of mice with exosomes from PD patient serum could evoke protein aggregation, trigger dopamine neuron degeneration, induce microglial activation, and cause apomorphine-coaxed rotation and movement defects. All these findings imply the exosome pathway as a new pathogenesis mechanism for PD, and therefore may present new targets for therapeutics. KEY MESSAGES: We have presented the evidence for a relationship between PD (Parkinson's disease) patients' serum exosomes and pathogenesis. PD patients' serum-derived exosomes could induce α-syn, ubiquitin and P62 aggregation in recipient cells. Intravenous or intrastriatal treatments of mice with PD exosomes were able to recapitulate the molecular, cellular and behavioral phenotypes of PD.

Neuroinflammation and Myelin Status in Alzheimer's Disease, Parkinson's Disease, and Normal Aging Brains: A Small Sample Study.

Microglia and astrocytes play important roles in mediating the immune processes and nutritional support in the central nervous system (CNS). Neuroinflammation has been indicated in the progression of neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD). Chronic neuroinflammation with sustained activation of microglia and astrocytes may affect white matter tracts and disrupt communication between neurons. Recent studies indicate astrogliosis may inhibit remyelination in demyelinating disorders such as multiple sclerosis. In this study, we investigated the relationship between neuroinflammation and myelin status in postmortem human brain tissue (n = 15 including 6 AD, 5 PD, and 4 age-matched, neurologically normal controls (NC)). We conducted systematic and quantitative immunohistochemistry for glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1), amyloid beta, and highly phosphorylated tau (tauopathy). White matter intactness was evaluated by myelin and axon staining in adjacent brain tissue sections. Eight of 15 cases (4 AD, 3 PD, and 1 NC) showed increased immunoreactivity for microglia and astrocytes in the white matter that connects striatum and cortex. Quantitative analysis of these 8 cases showed a significant negative correlation between GFAP (but not Iba-1) and myelin (but not axon) staining in white matter (r2 = 0.78, p < 0.005). Tau, but not amyloid beta plaques, is significantly higher in AD vs. PD and NC. Tau burden increases with age in AD cases. These observations indicate that astrocytosis in white matter is associated with loss of myelin in AD, PD, and normal aging and that tau is a potent biomarker for AD.

Pre-movement planning processes in people with congenital mirror movements

ObjectivePre-movement processes were investigated in people with Congenital mirrormovement (CMM), a rare disorder in which bilateral movement (mirroring) occurs in the upper distal extremities (primarily the hands and fingers) during intended unilateral movements. Abnormal density of ipsilateral corticospinal projections is an established hallmark of CMM. This study tested whether the Lateralised Readiness Potential (LRP), which reflects movement planning and readiness, is also abnormal in people with CMM. MethodsTwenty-eight neurologically-normal controls and 8 people with CMM were tested on a unimanual Go/No-go task while electroencephalography (EEG) was recorded to assess the LRP. ResultsNo significant group differences were found in reaction time (RT). However, significantly smaller LRP amplitudes were found, on average, in the CMM group compared to Controls at central-motor (C3,C4) sites in stimulus-locked and response-locked epochs; similar group differences were also found at further frontal sites (F3,F4) during response-locked epochs. ConclusionsAbnormal brain activity in pre-movement processes associated with response planning and preparation is present in people with CMM. SignificanceAberrant bilateral activity during pre-movement processes is clearly implicated; whether part of the etiology of CMM, or as a mechanism of neuro-compensation, is not yet known.

Micronutrient levels and antioxidant status in pediatric cerebral palsy patients

Background: Micronutrients such as coper, zinc and selenium are essential to the functioning of the nervous system and their deficiencies is a critical concern for cerebral palsy children. The aim of this study was to investigate micronutrient levels and antioxidant status in pediatric cerebral palsy patients and compare them to neurologically normal children in Accra, Ghana. Method: Twenty seven patients with cerebral palsy (0-14 years) and 17 age-bracket matched neurological normal controls were recruited. Three milliliters of venous blood was drawn from each participant into an EDTA tube and transferred on ice to the laboratory. Activity of the antioxidant enzyme superoxide dismutase (SOD) as well as micronutrient status for copper, zinc and selenium were analyzed. Results: About 86.2% of cases (n = 25/29) compared to 11.7% of controls (n= 2/17) had copper concentrations below the normal physiologic range; mean copper concentration was significantly lower in cases than in control. Serum zinc levels were normal in only 20.1% (n = 6/29) of cases, but in 59% (n = 10/17) of controls; however, mean concentration of zinc was not statistically different among. Selenium concentration below normal physiologic range was recorded to be about 94% in both cases (n = 27/29) and controls (n = 16/17); but the mean selenium concentration was significantly higher in cases compared to control. Also, the mean SOD activity was significantly lower in cases than in controls. Moreover, negative correlation was observed between the age of children with cerebral palsy and SOD levels. Conclusion: Copper, zinc and selenium deficiencies contributed disproportionately to oxidative stress and this may be a common feature in Ghanaian children with cerebral palsy. There is the need for micronutrient supplementation.

Risk factors for idiopathic dystonia in Queensland, Australia

It is currently hypothesised that a combination of genetic and environmental factors underlies the development of idiopathic isolated dystonia (IID). In this study, we examined several possible environmental or other non-genetic factors that may influence the risk for IID in Queensland, Australia. We surveyed several environmental exposures, lifestyle factors, medical and family histories to investigate potential risk factors for IID. Associations between putative risk factors and IID were assessed using a total of 184 dystonia patients and 1048 neurologically-normal control subjects sampled from Queensland between 2005 and 2012. Our analyses revealed that anxiety disorders, depression, tremor, cigarette smoking and head injuries with a loss of consciousness were associated with increased risk for IID (p<0.05), all of which remained statistically significant following an adjustment for multiple hypothesis testing except for depression. We also observed that the risk for dystonia increased with higher cigarette smoking pack-year quartiles in our analyses. Our results suggest possible environmental factors that influence the development of IID and complement the findings of similar dystonia risk factor studies. Further investigation defining the environmental and other non-genetic risk factors for IID may provide insight into the development of the disorder in genetically-susceptible individuals.

Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum

BackgroundThe cellular mechanism(s) underlying autism spectrum disorders (ASDs) are not completely understood, but ASDs are thought to ultimately result from disrupted synaptogenesis. However, studies have also shown that glial cell numbers and function are abnormal in post-mortem brain tissue from autistic patients. Direct assessment of glial cells in post-mortem human brain tissue is technically challenging, limiting glial research in human ASD studies. Therefore, we attempted to determine if glial cell-type specific markers may be altered in autistic brain tissue in a manner that is consistent with known cellular findings, such that they could serve as a proxy for glial cell numbers and/or activation patterns.MethodsWe assessed the relative expression of five glial-specific markers and two neuron-specific markers via qRT-PCR. We studied tissue samples from the prefrontal cortex (PFC) and cerebellum of nine post-mortem autistic brain samples and nine neurologically-normal controls. Relative fold-change in gene expression was determined using the ΔΔCt method normalized to housekeeping gene β-actin, with a two-tailed Student’s t-test P <0.05 between groups considered as significant.ResultsBoth astrocyte- and microglial-specific markers were significantly more highly expressed in autistic PFC as compared to matched controls, while in the cerebellum only astrocyte markers were elevated in autistic samples. In contrast, neuron-specific markers showed significantly lower expression in both the PFC and cerebellum of autistic patients as compared to controls.ConclusionsThese results are in line with previous findings showing increased glial cell numbers and up-regulation of glial cell gene expression in autistic post-mortem brain tissue, particularly in the PFC, as well as decreased number of neurons in both the PFC and cerebellum of autistic patients. The concordance of these results with cell-level studies in post-mortem autistic brain tissue suggests that expression of glial cell-type specific markers may serve as a useful alternative to traditional cellular characterization methods, especially when appropriately-preserved post-mortem tissue is lacking. Additionally, these results demonstrate abnormal glial-specific gene expression in autistic brains, supporting previous studies that have observed altered glial cell numbers or activation patterns in ASDs. Future work should directly assess the correlation between cell-type specific marker levels and cell number and activation patterns.

Dystonia, facial dysmorphism, intellectual disability and breast cancer associated with a chromosome 13q34 duplication and overexpression of TFDP1: case report

BackgroundDystonia is a movement disorder characterized by involuntary sustained muscle contractions causing twisting and repetitive movements or abnormal postures. Some cases of primary and neurodegenerative dystonia have been associated with mutations in individual genes critical to the G1-S checkpoint pathway (THAP1, ATM, CIZ1 and TAF1). Secondary dystonia is also a relatively common clinical sign in many neurogenetic disorders. However, the contribution of structural variation in the genome to the etiopathogenesis of dystonia remains largely unexplored.Case presentationCytogenetic analyses with the Affymetrix Genome-Wide Human SNP Array 6.0 identified a chromosome 13q34 duplication in a 36 year-old female with global developmental delay, facial dysmorphism, tall stature, breast cancer and dystonia, and her neurologically-normal father. Dystonia improved with bilateral globus pallidus interna (GPi) deep brain stimulation (DBS). Genomic breakpoint analysis, quantitative PCR (qPCR) and leukocyte gene expression were used to characterize the structural variant. The 218,345 bp duplication was found to include ADPRHL1, DCUN1D2, and TMCO3, and a 69 bp fragment from a long terminal repeat (LTR) located within Intron 3 of TFDP1. The 3' breakpoint was located within Exon 1 of a TFDP1 long non-coding RNA (NR_026580.1). In the affected subject and her father, gene expression was higher for all three genes located within the duplication. However, in comparison to her father, mother and neurologically-normal controls, the affected subject also showed marked overexpression (2×) of the transcription factor TFDP1 (NM_007111.4). Whole-exome sequencing identified an SGCE variant (c.1295G > A, p.Ser432His) that could possibly have contributed to the development of dystonia in the proband. No pathogenic mutations were identified in BRCA1 or BRCA2.ConclusionOverexpression of TFDP1 has been associated with breast cancer and may also be linked to the tall stature, dysmorphism and dystonia seen in our patient.

Long-term cognitive complaint and post-concussive symptoms following mild traumatic brain injury: The role of cognitive and affective factors

Primary objective: To determine whether neuropsychological test performance or affective factors predict long-term post-concussive symptoms and cognitive complaint following mild traumatic brain injury.Methods and procedures: Participants included 21 individuals with mild traumatic brain injury, 19 individuals with spinal injury but no injury to the brain and 20 neurologically-normal controls. All participants completed measures of post-concussive symptoms, cognitive complaint, depression, anxiety, and personality and were administered a variety of neuropsychological tests.Main outcomes and results: The hypothesis that depression, anxiety and neuroticism would be better predictors of post-concussive symptoms than neuropsychological test performance for all three groups was supported. Contrary to expectations, however, neuropsychological test performance was a unique predictor of cognitive complaint for the mild traumatic brain injury group.Conclusions: It was concluded that long-term post-concussive symptoms are largely representative of psychological symptoms and not brain damage, but that genuine, albeit subtle, cognitive deficits also may be present for long-term periods following mild traumatic brain injury.

Error-related processing following severe traumatic brain injury: An event-related functional magnetic resonance imaging (fMRI) study

Continuous monitoring of one's performance is invaluable for guiding behavior towards successful goal attainment by identifying deficits and strategically adjusting responses when performance is inadequate. In the present study, we exploited the advantages of event-related functional magnetic resonance imaging (fMRI) to examine brain activity associated with error-related processing after severe traumatic brain injury (sTBI). fMRI and behavioral data were acquired while 10 sTBI participants and 12 neurologically-healthy controls performed a task-switching cued-Stroop task. fMRI data were analyzed using a random-effects whole-brain voxel-wise general linear model and planned linear contrasts. Behaviorally, sTBI patients showed greater error-rate interference than neurologically-normal controls. fMRI data revealed that, compared to controls, sTBI patients showed greater magnitude error-related activation in the anterior cingulate cortex (ACC) and an increase in the overall spatial extent of error-related activation across cortical and subcortical regions. Implications for future research and potential limitations in conducting fMRI research in neurologically-impaired populations are discussed, as well as some potential benefits of employing multimodal imaging (e.g., fMRI and event-related potentials) of cognitive control processes in TBI.

Rare Deletions at 16p13.11 Predispose to a Diverse Spectrum of Sporadic Epilepsy Syndromes

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.

A genome-wide analysis of brain DNA methylation identifies new candidate genes for sporadic amyotrophic lateral sclerosis

Genetic variants may underlie sporadic amyotrophic lateral sclerosis (SALS), but in only a few percent of patients have causative mutations been found. This is possibly because SALS is more often due to a variation in DNA methylation, an epigenetic phenomenon involved in gene silencing. Methylation across the whole genome was examined in brain DNA of 10 SALS patients and 10 neurologically-normal controls. Methylated DNA was immunoprecipitated and interrogated by Affymetrix GeneChip Human Tiling 2.0R Arrays. Methylation levels were compared between SALS patients and controls at each region of methylation across the genome. SALS patients had either hypo- or hyper-methylation at 38 methylation sites (p </= 0.01). Of these, 23 were associated with genes and three with CpG islands. Pathway analysis showed that genes with different methylation in SALS were particularly involved in calcium homeostasis, neurotransmission and oxidative stress. In conclusion, a number of genes, either unsuspected in SALS or in potential cell death pathways, showed altered methylation in SALS brains. The possibility of epigenetic therapy for SALS should encourage confirmation of these initial results in a future larger whole-genome DNA methylation study.

Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy

Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for epilepsy. We screened a consecutive cohort of 18 children with cryptogenic partial epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q substitutes glutamine for an evolutionarily conserved lysine residue in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood epilepsy.

Neurofilament protein light in multiple sclerosis

To determine if neurofilament protein light (NF-L) and anti-NF-L antibody can be used as biologic markers in diagnosing multiple sclerosis (MS) and assessing prognosis thereof. Samples of cerebrospinal fluid (CSF) and serum were corrected from 63 MS patients, 15 patients with neuromyelitis optica (ONM), 31 patients with other inflammatory neurological disease (OIND), 18 patients with noninflammatory neurological disease (NIND), and 46 neurological normal controls (NC group), all age- and sex- matched. ELISA was used to detect the concentrations of NF-L, anti-NF-L antibody, anti-myelin basic protein (MBP) antibody, and anti-myelin oligo-dendroglia glycoprotein (MOG) antibody in serum and cerebral spinal fluid. And the IgG level was tested. The CSF levels of NF-L of the MS, ONM, OIND, and NIND groups were 26 ng/L (33), 20 ng/L (92), 19 ng/L (82), and 30 ng/L (194) respectively, without significant differences among these different groups, but all significantly higher than that of the NC group (10 ng/L, all P < 0.01). No NF-L was detected in the serum specimens of all groups. The CSF NF-L antibody level of the MS group was significantly lower than that of the OIND group (P < 0.01), and significantly higher than those of the NIND and NC groups (both P < 0.05). The CSF anti-NF-L antibody level of the MS patients was positively correlated with the MBP antibody level (r = 0.784, P < 0.01) and the IgG level (r = 0.675, P < 0.01). Neither the NF-L nor the anti-NF-L antibody can be used as reliable biological markers for the diagnosis of MS. Strongly increased levels of NF-L were observed in patients with MS, ONM, OIND, and NIND, suggesting the occurrence of axonal injury in these conditions. Inflammation may not lead to the generation of anti-NF-L antibody which links to the axonal injury.

High frequency of allergic conjunctivitis in myasthenia gravis without thymoma

Objectives To investigate the frequency of allergic disorders in myasthenia gravis (MG) patients and characterize the features of MG associated with allergic disorders. Methods Frequencies of past and present common allergic disorders in 160 MG patients who visited the Department of Neurology, Kyushu University Hospital from April 2000 to July 2003 and in 81 neurological normal controls were studied. Results Among various allergic disorders, the frequency of allergic conjunctivitis (AC) was significantly higher in MG patients (39/160, 24.4%, p corr=0.0112), especially with MG without thymoma (36/123, 29.3%, p corr=0.0016), in comparison to the controls (6/81, 7.4%). MG patients with AC showed a significantly higher rate of seronegative MG (43.6% vs. 17.4%, p=0.008) and a higher tendency of ocular MG (43.6% vs. 28.1%, p=0.071). Moreover, MG with AC had significantly lower anti-acetylcholine receptor antibody titers (median 6.8 nmol/l vs. median 23.6 nmol/l, p=0.0359) as well as a lower rate of coexisting thymoma (7.7% vs. 17.4%, p=0.016). The incidence of myasthenic crisis was also lower in MG with AC than without AC, yet the difference was not significant (7.7% vs. 15.7%). Conclusion There was a significant association of AC with MG especially for ocular or seronegative MG in cases without thymoma.

Interhemispheric depth judgement

Interhemispheric depth comparisons were studied by requiring subjects to align in depth two textured plates, one presented to the left hemifield and the other to the right. Callosal agenesis subjects and neurologically-normal control subjects adjusted the plates so that they appeared to be at the same distance. Subjects viewed the plates monocularly or binocularly while keeping their head still, moving it side-to-side or moving it up and down. Subjects fixated a target located between the two plates while performing the task. For all subjects, the results showed that the deviations from veridical settings were significantly smaller for the binocular than for the monocular viewing conditions. Moreover, there were no significant differences among the three binocular viewing conditions (horizontal, vertical or no head movement), indicating that neither vertical nor horizontal motion parallax improves the precision of depth judgement when binocular disparity is available. These results further suggest that the precision of interhemispheric comparison for binocular depth is not affected by the absence of the corpus callosum. Looking at the plates monocularly, the control subjects judge the relative depth between the plates more precisely when they moved their head than when they kept it still. These results show that motion parallax is a useful depth cue when relative motion is extracted from different hemifields. Unlike the control subjects, the callsal agenesis subjects did not judge the relative depth between the plates more precisely when they moved their head when they kept it still. These results show that interhemispheric comparison of depth using relative motion is not possible without the corpus callosum.