Environmental challenges for the nervous system and the brain in Japan.

Japan provides many lessons for the Environmental Neurology's issues. Drama and disasters have paved the recent history of Japan. The Japanese people have been intoxicated by chemical compounds (methylmercury, sulfur dioxide, cadmium, PCBs and other dioxin-related compounds) and were the victims of several dramatic disasters (atomic bombing, nuclear disaster, sarin gas attack). They are still exposed to air pollution. Prion diseases including dura-graft-associated CJD are still an issue. In addition, continuously spreading chronic wasting disease is a worldwide challenge .

Glycaemic control boosts glucosylated nanocarrier crossing the BBB into the brain.

Recently, nanocarriers that transport bioactive substances to a target site in the body have attracted considerable attention and undergone rapid progression in terms of the state of the art. However, few nanocarriers can enter the brain via a systemic route through the blood-brain barrier (BBB) to efficiently reach neurons. Here we prepare a self-assembled supramolecular nanocarrier with a surface featuring properly configured glucose. The BBB crossing and brain accumulation of this nanocarrier are boosted by the rapid glycaemic increase after fasting and by the putative phenomenon of the highly expressed glucose transporter-1 (GLUT1) in brain capillary endothelial cells migrating from the luminal to the abluminal plasma membrane. The precisely controlled glucose density on the surface of the nanocarrier enables the regulation of its distribution within the brain, and thus is successfully optimized to increase the number of nanocarriers accumulating in neurons.There are only a few examples of nanocarriers that can transport bioactive substances across the blood-brain barrier. Here the authors show that by rapid glycaemic increase the accumulation of a glucosylated nanocarrier in the brain can be controlled.

Specific clinical signs and symptoms are predictive of clinical course in sporadic Creutzfeldt-Jakob disease.

BACKGROUND AND PURPOSE: Akinetic mutism is thought to be an appropriate therapeutic end-point in patients with sporadic Creutzfeldt-Jakob disease (sCJD). However, prognostic factors for akinetic mutism are unclear and clinical signs or symptoms that precede this condition have not been defined. The goal of this study was to identify prognostic factors for akinetic mutism and to clarify the order of clinical sign and symptom development prior to its onset. METHODS: The cumulative incidence of akinetic mutism and other clinical signs and symptoms was estimated based on Japanese CJD surveillance data (455 cases) collected from 2003 to 2008. A proportional hazards model was used to identify prognostic factors for the time to onset of akinetic mutism and other clinical signs and symptoms. RESULTS: Periodic synchronous discharges on electroencephalography were present in the majority of cases (93.5%). The presence of psychiatric symptoms or cerebellar disturbance at sCJD diagnosis was associated with the development of akinetic mutism [hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.14-1.99, and HR 2.15, 95% CI1.61-2.87, respectively]. The clinical course from cerebellar disturbance to myoclonus or akinetic mutism was classified into three types: (i) direct path, (ii) path via pyramidal or extrapyramidal dysfunction and (iii) path via psychiatric symptoms or visual disturbance. CONCLUSIONS: The presence of psychiatric symptoms or cerebellar disturbance increased the risk of akinetic mutism of sCJD cases with probable MM/MV subtypes. Also, there appear to be sequential associations in the development of certain clinical signs and symptoms of this disease.

Significance of Development and Reversion of Collaterals on MRI in Early Neurologic Improvement and Long-Term Functional Outcome after Intravenous Thrombolysis for Ischemic Stroke.

BACKGROUND AND PURPOSE: Predicting response to rtPA is essential in the era of endovascular therapy for stroke. The purpose of this study was to elucidate prognostic factors of early neurologic improvement and long-term outcome with respect to the development and reversion of leptomeningeal collaterals in recanalization therapy after acute ischemic stroke. MATERIALS AND METHODS: We analyzed consecutive patients with proximal MCA occlusion treated with rtPA from 2007 to 2012 at 2 hospital stroke centers. All patients routinely underwent brain MR imaging before rtPA. To assess the reversion of collateral signs, we included patients who underwent follow-up MR imaging. We assessed the development and reversion of collaterals by using a combination of 2 MR imaging collateral markers, the hyperintense vessel sign and the posterior cerebral artery laterality sign. Early neurologic improvement was defined as a decrease in the NIHSS score of ≥10 or a score of ≤2 at 24 hours of treatment. RESULTS: Early neurologic improvement was observed in 22 of 48 eligible patients. The development of collaterals at arrival (15/22 versus 9/26, P = .042) was significantly associated with early neurologic improvement. Multivariate analysis adjusting for other variables showed that the development of collaterals at arrival (OR, 4.82; 95% CI, 1.34-19.98; P = .015) was independently associated with early neurologic improvement. Reversion of collaterals was significantly associated with successful recanalization (P < .001), and multivariate analysis showed that the reversion of collaterals was an independent prognostic factor of long-term functional outcome (OR, 5.07; 95% CI, 1.38-22.09; P = .013). CONCLUSIONS: Our results indicate that the development of leptomeningeal collaterals plays a crucial role in achieving early neurologic improvement, and reversion of collaterals predicts a favorable outcome via arterial recanalization after rtPA treatment for acute stroke.

Spinal cord ring enhancement in patients with neuromyelitis optica.

OBJECTIVES: Clinical and pathological significance of gadolinium (Gd)-enhancing pattern on magnetic resonance imaging (MRI), including ring enhancement (RE), is well documented in multiple sclerosis but not in neuromyelitis optica (NMO), especially in the spinal cord. The purpose of this study is to examine the prevalence of spinal cord RE in NMO and to determine the association between clinical characteristics and spinal cord RE. MATERIALS AND METHODS: We retrospectively examined Gd-enhanced spinal cord MRI scans, during the acute phase, in patients with anti-aquaporin 4-positive NMO, including NMO spectrum disorder. We then analysed their clinical features and MRI imaging characteristics of spinal cord lesions. RESULTS: Of the 30 patients with NMO, we enrolled 12 patients with 16 Gd-enhanced spinal cord MRI scans in this study. Five scans revealed RE (31.2%). Male ratio, as well as myelin basic protein (MBP) levels, in the cerebrospinal fluid (CSF) of patients with RE was significantly higher than those of patients without RE (P = 0.018, P = 0.026, respectively). CONCLUSIONS: Spinal cord RE is common in patients with NMO. Higher MBP levels in the CSF of patients with RE can be associated with a higher degree of myelin damage.

Relationship and factor structure in multisystem neurodegeneration in Parkinson's disease.

OBJECTIVES: Parkinson's disease (PD) is a multisystem neurodegenerative disease. We aimed to identify the relationship and factor structure among its different features. MATERIALS & METHODS: Motor, olfactory and cognitive function, and cardiac sympathetic denervation were evaluated in 125 patients with PD using the Unified Parkinson's Disease Rating Scale (UPDRS) part III score, odor stick identification test for the Japanese (OSIT-J), Mini-Mental State Examination (MMSE), and [(123) I] meta-iodobenzylguanidine (MIBG) cardiac scintigraphy (heart-to-mediastinum (H/M) ratio). Pearson's correlation and multiple regression analysis were used to evaluate the association among the four measures with age, gender, and disease duration as the covariates. Exploratory factor analysis was used to identify the underlying factor structure among the measures and covariates. RESULTS: Pearson's correlation and multiple regression analysis showed correlations between OSIT-J score and MIBG H/M ratio, OSIT-J and MMSE scores, UPDRS part III score and MIBG H/M ratio, UPDRS part III score and disease duration, and MMSE score and age. Factor analysis identified three factors: (i) age and MMSE score; (ii) MIBG H/M ratio and OSIT-J score; and (iii) UPDRS part III score and disease duration. CONCLUSIONS: Our results suggest that aging, PD-related pathogenesis, and disease duration underlie the multisystem neurodegeneration present in PD. Moreover, age and disease duration are the major risk factors for cognitive impairment and motor symptoms, respectively. Olfactory impairment and cardiac sympathetic denervation are strongly associated in PD.

Different patterns of fornix damage in idiopathic normal pressure hydrocephalus and Alzheimer disease.

BACKGROUND AND PURPOSE: The fornix contains efferent fibers of the hippocampus and is in close contact with the corpus callosum. Part of the fornix is directly attached to the corpus callosum, and another part is suspended from the corpus callosum via the septum pellucidum. DTI can be used to evaluate the morphology and microstructural integrity of the fornix. We examined the pattern of fornix damage in patients with iNPH or AD. MATERIALS AND METHODS: We enrolled 22 patients with iNPH, 20 with AD, and 20 healthy controls. DTI data were obtained. The morphology (volume, length, and mean cross-sectional area) and FA values of the fornix were evaluated by using tract-specific analysis and compared among groups. RESULTS: The volume, cross-sectional area, and FA value of the fornix were significantly smaller in patients with iNPH than in controls, whereas the length was significantly greater. In patients with AD, the volume, mean cross-sectional area, and FA value of the fornix were significantly smaller than those in controls, whereas the length was not altered. The fornix was significantly longer in patients with iNPH than in patients with AD, whereas the volume and cross-sectional areas were significantly smaller. CONCLUSIONS: Our results suggest that the different pathogeneses of these diseases lead to fornix damage through different mechanisms: through mechanical stretching due to lateral ventricular enlargement and corpus callosum deformation in patients with iNPH, and through degeneration secondary to hippocampal atrophy in patients with AD.

White matter alteration in idiopathic normal pressure hydrocephalus: tract-based spatial statistics study.

BACKGROUND AND PURPOSE: White matter alteration in iNPH has not been well-investigated. TBSS is a voxelwise statistical analysis developed for DTI data. We aimed to elucidate the cerebral white matter alteration in patients with iNPH by using DTI and to test the accuracy of TBSS analysis. MATERIALS AND METHODS: DTI data were obtained from 20 patients with iNPH and 20 age- and sex-matched controls. The FA values were evaluated by using TBSS, region-of-interest and tract-specific analysis of the CST. The accuracy of TBSS analysis was tested by using "back-projection" of TBSS results and by comparing the TBSS analysis results with those of region-of-interest and tract-specific analysis. RESULTS: Back-projection of the TBSS results showed accurate registration of the whole brain, with the exception of parts of the thalamus, fornix, and white matter around the posterior body of the lateral ventricle. The TBSS analysis results were consistent with those of the region-of-interest analysis and tract-specific analysis. In patients with iNPH compared with control subjects, the FA values were significantly decreased in parts of the corpus callosum, periventricular white matter, and juxtacortical white matter in the frontal and parietal lobes. In contrast, FA values were significantly increased in the internal capsule, extending to the white matter in the centrum semiovale. CONCLUSIONS: Our results suggest that patients with iNPH have various patterns of white matter damage and that TBSS analysis is a promising tool for performing accurate voxelwise statistical analysis of the iNPH brain, with the exception of misregistered areas.

Amnesia in frontotemporal dementia with amyotrophic lateral sclerosis, masquerading Alzheimer's disease.

A 68-year-old man with a clinical diagnosis of Alzheimer's disease (AD) later developed amyotrophic lateral sclerosis (ALS), which was confirmed at autopsy at age 72 years. Because neuronal loss and AD-type pathologies (Braak stage II for neurofibrillary tangles) were scant, TDP-43-positive intracytoplasmic inclusions in hippocampal dentate granular cells and in neurons in the subiculum and amygdala, even though small in amount, may represent the earliest lesions of ALS-related dementia and could be the cause of dementia in this patient. Although the persistent elevation of creatine kinase from the onset could be a pointer to the presence of motor involvement, more accurate characterization of dementia, which may differentiate ALS-related dementia and AD, is necessary.

Altered microstructure in corticospinal tract in idiopathic normal pressure hydrocephalus: comparison with Alzheimer disease and Parkinson disease with dementia.

BACKGROUND AND PURPOSE: Previous neuropathologic studies in chronic hydrocephalus have suggested the presence of white matter damage, presumably from mechanical pressure due to ventricular enlargement and metabolic derangement. This study aimed to investigate the diffusional properties of the CST in patients with iNPH by using DTI and to determine whether this method could be used as a new diagnostic tool to differentiate patients with iNPH from those with AD and PDD and control subjects. MATERIALS AND METHODS: We enrolled 18 patients with iNPH, 11 patients with AD, 11 patients with PDD, and 19 healthy control subjects. Diffusion tensor metrics of the segmented CST, including FA values, axial eigenvalues, and radial eigenvalues, were evaluated by using tract-specific analysis. The anisotropy color-coding tractography of the CST was visually evaluated. The DTI findings were compared among groups. RESULTS: Tract-specific analysis of the CST showed that FA values and axial eigenvalues were significantly increased (P < .001), whereas radial eigenvalues were not significantly altered, in patients with iNPH compared with other subjects. The CST tractographic images in patients with iNPH was visually different from those in other subjects (P < .001). In discriminating patients with iNPH from other subjects, the CST FA values had a sensitivity of 94% and specificity of 80% at a cutoff value of 0.59. CONCLUSIONS: Our results suggest that patients with iNPH have altered microstructures in the CST. Quantitative and visual CST evaluation by using DTI may be useful for differentiating patients with iNPH from patients with AD or PDD or healthy subjects.

Cerebrospinal fluid metabolite and nigrostriatal dopaminergic function in Parkinson's disease.

OBJECTIVES: To evaluate the association between cerebrospinal fluid (CSF) homovanillic acid (HVA) concentrations and nigrostriatal dopaminergic function assessed by positron emission tomography (PET) imaging with carbon-11-labeled 2beta-carbomethoxy-3beta-(4-fluorophenyl)-tropane ((11)C-CFT), which can measure the dopamine transporter (DAT) density, in Parkinson's disease (PD). METHODS: (11)C-CFT PET scans and CSF examinations were performed on 21 patients with PD, and six patients with non-parkinsonian syndromes (NPS) as a control group. RESULTS: In the PD group, CSF HVA concentrations were significantly correlated with the striatal uptake of (11)C-CFT (r = 0.76, P < 0.01). However, in the NPS group, two indices were within the normal range. CONCLUSIONS: In PD, CSF HVA concentrations correlate with nigrostriatal dopaminergic function. Therefore, CSF HVA concentrations may be an additional surrogate marker for estimating the remaining nigrostriatal dopaminergic function in case that DAT imaging is unavailable.

Japanese encephalitis - serial CT findings and neuropathology in an autopsy case.

The patient was a 17-year-old man, who developed Japanese encephalitis in the autumn of 1990 in Japan. He was admitted to our hospital 4 days after onset because of consciousness disturbance. On admission, neurological examination demonstrated left hemiparesis, neck stiffness, and Kernig's sign. He developed generalized tonico-clonic seizure, and required a respirator on the next day of admission. Brain CT 10 days after onset demonstrated hypodensities in the right hippocampus, and the CT obtained 39 days after onset showed whole brain atrophy and hypodensities in the anterior portion of the bilateral thalamus. He died 40 days after onset. Postmortem examination demonstrated perivascular and parenchymal infiltration of lymphocytes and macrophages, proliferation of microglia and astrocytes, and necrosis in the gray matter of the brain. Involvement of the hippocampus and thalamus on CT seemed to reflect the severe lesions characterized by cellular infiltration and necrosis. We discussed for the first time the correlation of CT and neuropathological findings in a patient with Japanese encephalitis.

Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation.

Polyglutamine (polyQ) diseases, such as Huntington's disease and Machado-Joseph disease (MJD), are caused by gain of toxic function of abnormally expanded polyQ tracts. Here, we show that expanded polyQ of ataxin-3 (Q79C), a gene that causes MJD, stimulates Ku70 acetylation, which in turn dissociates the proapoptotic protein Bax from Ku70, thereby promoting Bax activation and subsequent cell death. The Q79C-induced cell death was significantly blocked by Ku70 or Bax-inhibiting peptides (BIPs) designed from Ku70. Furthermore, expression of SIRT1 deacetylase and the addition of a SIRT1 agonist, resveratrol, reduced Q79C toxicity. In contrast, mimicking acetylation of Ku70 abolished the ability of Ku70 to suppress Q79C toxicity. These results indicate that Bax and Ku70 acetylation play important roles in Q79C-induced cell death, and that BIP may be useful in the development of therapeutics for polyQ diseases.

Clinical features and diagnosis of dura mater graft associated Creutzfeldt Jakob disease.

BACKGROUND: A subset of patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) demonstrates atypical clinical features and plaque formation in the brain (plaque type). OBJECTIVE: To elucidate the frequency and clinical features of plaque type dCJD in comparison with the non-plaque type. METHODS: We analyzed clinicopathologic findings of 66 patients who had been registered as having dCJD by the Creutzfeldt-Jakob Disease Surveillance Committee, Japan, between April 1999 and February 2006. RESULTS: 1) Analysis of pathologically confirmed dCJD patients (n = 23) demonstrated plaque type dCJD in 11 patients (48%). In contrast to the non-plaque type with classic CJD features, the plaque type commonly presented with ataxic gait as an initial manifestation, relatively slow progression of neurologic symptoms, and no or late occurrence of periodic sharp-wave complexes (PSWCs) on EEG. MRI, especially diffusion-weighted images, and CSF 14-3-3 protein and neuron specific enolase (NSE) showed high diagnostic sensitivities for plaque as well as non-plaque types. 2) Analysis of clinically diagnosed dCJD patients (n = 34) demonstrated that 7 patients (21%) had atypical clinical features without PSWCs, probably corresponding to plaque type dCJD. CONCLUSION: The frequency of the plaque type in dura mater graft-associated Creutzfeldt-Jakob disease is apparently higher than previously recognized. For the clinical diagnosis of the plaque type dura mater graft-associated Creutzfeldt-Jakob disease, MRI and CSF markers would be useful, in addition to the core features, i.e., onset with ataxic gait disturbance, relatively slow progression, and no or late occurrence of periodic sharp-wave complexes on EEG.

16q-linked autosomal dominant cerebellar ataxia: a clinical and genetic study.

The autosomal dominant cerebellar ataxias (ADCAs) comprise a genetically and clinically heterogenous group of neurodegenerative disorders. Very recently, a C-to-T single nucleotide substitution in the puratrophin-1 gene was found to be strongly associated with a form of ADCA linked to chromosome 16q22.1 (16q-linked ADCA; OMIM 600223). We found the C-to-T substitution in the puratrophin-1 gene in 20 patients with ataxia (16 heterozygotes and four homozygotes) and four asymptomatic carriers in 9 of 24 families with an unknown type of ADCA. We also found two cases with 16q-linked ADCA among 43 sporadic patients with late-onset cortical cerebellar atrophy (LCCA). The mean age at onset in the 22 patients was 61.8 years, and that of homozygous patients was lower than that of heterozygous ones in one family. Neurological examination revealed that the majority of our patients showed exaggerated deep tendon reflexes in addition to the cardinal symptom of cerebellar ataxia (100%), and 37.5% of them had sensorineural hearing impairment, whereas sensory axonal neuropathy was absent. The frequency of 16q-linked ADCA was about 1/10 of our series of 110 ADCA families, making it the third most frequent ADCA in Japan.

Time profile of eosinophilic neurons in the cortical layers and cortical atrophy.

Eosinophilic neurons (ENs) appear in the post-ischemic cortex; however, whether there are differences in the time profile for different cortical layers and the fate of the cortex with ENs is largely unknown. We examined the time profile of ENs in different cortical layers and evolution of cortical atrophy after transient cerebral ischemia in Mongolian gerbils. Unilateral forebrain ischemia was induced twice by 10-minute unilateral common carotid artery occlusions. Brains at 24 hours, 4 days, and 2, 4, and 16 weeks post-ischemia were prepared for morphometric analysis. Quantitative analysis of ENs in regions of interest in the rostral and caudal cortex showed the highest number of ENs at 4 days post-ischemia in layers 3 and 6. Reduction in ENs after this peak was slower in layer 6 than in layer 3 in both rostral and caudal cortex, and this difference was significant in layer 6 of the caudal cortex. Infarcts with significant atrophy appeared in the rostral cortex. In the caudal cortex, only selective neuronal death with mild but distinct atrophy was observed. We observed a significant difference between cortical layers in the time profile of ENs in the post-ischemic cortex. Selective neuronal death without infarction was sufficient to induce cortical atrophy after transient cerebral ischemia.

Long-term cognitive and neuropsychological symptoms after global cerebral ischemia in Mongolian gerbils.

The objective of this study was to establish a rodent model of vascular dementia that showed long-term cognitive and neuropsychological deficits, and to correlate those behavioral deficits with the patterns of ischemic lesions, thus providing a platform for future testing of potential therapeutic agents. In Mongolian gerbils, either 5-minute single bilateral common carotid artery occlusion (SBCCAO) or repetitive bilateral common carotid artery occlusion (two 7-minute occlusions, RBCCAO) was induced, and the behavioral deficits were evaluated using 2 tests: a modified open-field test with an escape zone to evaluate changes in anxiety and locomotor activity, and a T-maze test to assess cognitive dysfunction. SBCCAO did not induce anxiety changes but caused transient locomotor hyperactivity and mild cognitive deficits. Only pyramidal neuronal death was found in the bilateral CA1 sector of the hippocampus following SBCCAO. In contrast, RBCCAO induced persistent locomotor hyperactivity, reduced anxiety, and caused severe cognitive deficits at 4 weeks post-ischemia. RBCCAO caused significant atrophy associated with diffuse selective neuronal death in the bilateral cerebral cortex and caudate nucleus, as well as the CA1 region. The repetitive ischemia model appears to be a potentially useful platform for the long-term analysis of cognitive and neuropsychological symptoms associated with vascular dementia.