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It is difficult to predict the development of carotid stenosis by means of the known risk factors. Using a computational fluid dynamics analysis, we examined the hemodynamic risks for carotid stenosis, focusing on wall shear stress (WSS) disturbances.In 59 patients with unilateral carotid stenosis, the plaque was removed from the original three-dimensional computed tomography angiographic images, and the vessel shape before stenosis was artificially reproduced. A multivariate regression analysis was performed to determine the associations between the degree of area stenosis and hemodynamic and morphologic factors after adjustment for 6 known risk factors.Metrics for WSS disturbances were higher at and distal to a bifurcation in the carotid arteries after plaque removal compared with the normal carotid arteries, and metrics for WSS magnitudes were lower. In the plaque-removed arteries, the degree of stenosis was significantly negatively correlated with the ratio of stenotic to distal values of metrics for WSS disturbances and the diameter ratio of the external to common carotid artery, and positively correlated with the ratio of proximal to stenotic values of metrics for WSS magnitudes.Rapid increases in WSS from the common carotid artery toward the bifurcation, rapid decreases in WSS disturbance from the bifurcation toward the internal carotid artery, and lower diameter ratio of the external to common carotid artery are more likely than other risk factors to cause future severe stenosis. In patients with these hemodynamic risks, underlying diseases should be controlled more strictly, with imaging examinations at shorter intervals.

This is the first Japanese autopsy case of Leucine-rich repeat kinase 2 (LRRK2) G2019S mutation with atypical TDP43 proteinopathy. Our case is important that presented clinically dysphagia and pathologically TDP-43 proteinopathy. TDP43 may play an important role of clinical presentation with LRRK2 G2019S mutation carriers.

We investigated the immunohistochemical localization of several proteins related to excitation-contraction coupling and ultrastructural alterations of the sarcotubular system in biopsied muscles from a father and a daughter in a family with permanent myopathy with hypokalemic periodic paralysis (PMPP) due to a mutation in calcium channel CACNA1S; p. R1239H hetero. Immunostaining for L-type calcium channels (LCaC) showed linear hyper-stained regions indicating proliferation of longitudinal t-tubules. The margin of vacuoles was positive for ryanodine receptor, LCaC, calsequestrin (CASQ) 1, CASQ 2, SR/ER Ca2+-ATPase (SERCA) 1, SERCA2, dysferlin, dystrophin, α-actinin, LC3, and LAMP 1. Electron microscopy indicated that the vacuoles mainly originated from the sarcoplasmic reticulum (SR). These findings indicate impairment of the muscle contraction system related to Ca2+ dynamics, remodeling of t-tubules and muscle fiber repair. We speculate that PMPP in patients with a CACNA1S mutation might start with abnormal SR function due to impaired LCaC. Subsequent induction of muscular contractile abnormalities and the vacuoles formed by fused SR in the repair process including autophagy might result in permanent myopathy. Our findings may facilitate prediction of the pathomechanisms of PMPP seen on morphological observation.

Objectives: Amyotrophic lateral sclerosis (ALS) patients may present with cognitive and behavioral abnormalities similar to frontotemporal dementia (FTD). In this multicenter study we examined Japanese ALS patients with and without FTD in order to characterize the full extent of cognitive and behavioral abnormalities, including associations with functional motor status, anxiety and depression. Methods: Patients were evaluated using the Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Hospital Anxiety and Depression Scale, ALS Functional Rating Scale-Revised, spirometry, and verbal fluency tests. Caregivers were asked to complete the ALS-FTD-Questionnaire (ALS-FTD-Q), a behavioral screen. We defined severe cognitive impairment (MoCA < 21 or FAB < 11), mild impairment (11 ≤ MoCA ≤ 25 or 11 ≤ FAB ≤ 15), and normal cognition (MoCA > 25 or FAB > 15). Severe and mild behavioral impairments and normal behavior were defined by the ALS-FTD-Q scores. Results: In 145 ALS patients, better cognitive scores were correlated with earlier age at onset, whereas a worse behavioral score was associated with a longer disease duration and higher level of anxiety and depression. Around seventy percent of all ALS patients showed mild (40–45%) or severe cognitive impairment with cognitive impairment outnumbering behavioral impairment fivefold. Cognitive functions were more impaired in patients with age of onset over 65 years, while behavioral scores were not related to age. Conclusions: Considering the high prevalence of in particular cognitive impairment, and the diversity of impairments, the cognitive and behavioral aspects of Japanese ALS patients should be given more attention clinically.

Lewy bodies (LBs) are usually detected in patients with idiopathic Parkinson's disease (PD), but there have been few reports of LBs in a familial form of early-onset PD associated with several mutations in parkin, a gene that encodes a ubiquitin E3 ligase involved in mitochondrial homeostasis, being also known as PARK2. Here, we report a case of PD with a PARK2 mutation characterized by a homozygous deletion of exon 2 and incidental LB pathology. A 60-year-old man developed tremor in the upper limbs. Although levodopa was initially effective, his symptoms slowly progressed. His cardiac uptake of 123 I-metaiodobenzylguanidine, as assessed by myocardial scintigraphy, decreased from an early stage after the onset. At the age of 81 years, he developed Legionella pneumonia and died of respiratory failure. Histopathological examination revealed a moderate loss of pigmented neurons, as well as gliosis in the substantia nigra and the locus coeruleus. Little LB-related pathology was found in the locus coeruleus, dorsal nucleus of vagal nerve, and basal nucleus of Meynert. The cardiac sympathetic nerve in the epicardium showed a reduction in the numbers of fibers immunoreactive for tyrosine hydroxylase and phosphorylated neurofilament protein. Genetic analysis of frozen brain materials revealed a homozygous deletion of exon 2 of parkin. To our knowledge, this is the first autopsy case with a homozygous deletion of exon 2 of parkin. The number of LBs was small, the age of disease onset was later than that in typical PARK2-associated PD patients, and cardiac sympathetic denervation was also present. Thus, we considered the LBs in our case as incidental and preclinical α-synucleinopathy.

To clarify the influence of coronavirus disease-19 (COVID-19) on the care of muscular dystrophy patients, we performed a questionnaire survey that was posted on the internet on May 11, 2020. By the end of July 2020, 542 responses had been collected. Approximately 30% of patients postponed regular consultations, and one-quarter of patients who received consultation more than once a month used telephone consultations. Two of 84 patients with Duchenne muscular dystrophy had reduced their steroid doses. A shortage of ventilator accessories and infection protection equipment occurred following the onset of COVID-19, and this shortage had a serious impact on medical care and infection prevention measures. Reductions in rehabilitation and other services, and avoidance of outings, led to a decrease in exercise and an increase in caregiver burden. Inpatients were restricted from going out and visiting family members. More than 20% of patients reported physical or mental complaints; however, few required treatment. COVID-19 has seriously affected the activities and quality of life of patients with muscular dystrophy. We will continue this survey and analyze the longitudinal changes.

Item does not contain fulltext Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share common clinical, genetic and neuropathological features. Some ALS patients have behavioral/personality changes, which could result in significant obstacles in the care provided by family members and caregivers. An easy screening tool would contribute greatly to the evaluation of these symptoms. We translated the ALS-FTD-Questionnaire, developed in the Netherlands, into Japanese (ALS-FTD-Q-J) and examined the clinimetric properties (internal consistency, construct and clinical validity). Patients with ALS and/or behavioral variant FTD (bvFTD) were evaluated alongside healthy controls in this multicenter study. All ALS patients, regardless of bvFTD status, were further evaluated by the frontal behavioral inventory (FBI) and for frontal/executive function, cognition, anxiety/depression, and motor functions. Data from 146 subjects were analyzed: ALS (92), ALS-bvFTD (6), bvFTD (16), and healthy controls (32). The internal consistency of the ALS-FTD-Q-J was good (Cronbach alpha=0.92). The ALS-FTD-Q-J showed construct validity as it exhibited a high correlation with the FBI (r=0.79). However, correlations were moderate with anxiety/depression and low with cognitive scales, in contrast to the original report, i.e. a moderate correlation with cognition and a low correlation with anxiety/depression. The ALS-FTD-Q-J discriminated ALS patients from (ALS-)bvFTD patients and controls. Thus, the ALS-FTD-Q-J is useful for evaluating Japanese ALS/FTD patients.

Spinocerebellar ataxia type 31 (SCA31) is an autosomal dominant cerebellar ataxia commonly observed in Japan. However, few neuropathological examinations have been conducted. Here we report the case of a 76-year-old Japanese male SCA31 patient. He noticed dysarthria and difficulty walking at 65 years old. His symptoms subsequently deteriorated, although he could still walk with assistance at 70 years. At 73 years, when he could no longer walk, he was admitted to our hospital. He showed severe limb and truncal ataxia. His father and older brother had shown the same symptoms. Brain magnetic resonance imaging showed cerebellar atrophy of the anterior lobe and white matter hyperintensities. He was diagnosed with SCA31 by genetic analysis. Gradually, his cognitive functions and ability to communicate declined. He died of respiratory failure at the age of 76. Neuropathological examination revealed severe Purkinje cell loss that was accentuated in the anterior lobe of the cerebellum. Furthermore, the remaining Purkinje cells showed abnormal processes (that is, halo-like amorphous materials), as has been reported previously. Severe deposition of hyperphosphorylated tau-positive neurites, many senile plaques and amyloid angiopathy were observed in the neocortex. Our findings suggest that in SCA31, accelerated tau and amyloid pathology in the neocortex might induce dementia at the terminal stage.

Cu, Zn superoxide dismutase (SOD) levels in the serum, cerebrospinal fluid (CSF) and skin fibroblasts of patients with dementia of the Alzheimer type (DAT) were estimated using enzyme immunoassay. The SOD mRNA level in the skin fibroblasts was also determined by the Northern blot analysis. As compared with the age-matched control groups of neurological patients without dementia, the AD group consisting of patients with DAT at ages under 65 years of age as well as the SDAT group of patients with DAT at ages over 65 years of age showed no significant changes in serum or CSF SOD levels. However, the skin fibroblast SOD- and SOD mRNA levels, which were correlate each other, were significantly higher in the AD group (p < 0.05), while lower in the SDAT group (p < 0.05). These results suggest that the determination of the SOD level of skin fibroblast may be useful for diagnosis of DAT and that the abnormality of SOD may play an important role in developing DAT.

A 34-year-old man was admitted with his unsteady gait, difficulty in speech and a paroxysmal severe headache accompanied with sensori-motor disturbance of the right extremities and aphasic symptom. His family history was unremarkable. His unsteadiness has progressed very slowly from childhood. He noted to be inarticulate at the age of 18 years. At the age of 33 years, he suddenly had an attack of severe throbbing headache, which was mainly left parietal, with nausea and photophobia. During the headache, his right extremities were paralyzed and he became aphasic. He had lost a partial memory of the event All these symptoms had gone within 24 hours. Thereafter, the same headache occurred about once a month. Neurological examination revealed a mild truncal ataxia and ataxic dysarthria. Electroencephalography (EEG) showed intermittent delta waves restricted over the left fronto-temporal region. Brain MRI showed a moderate atrophy of superior cerebellar vermis and anterior cerebellar lobe. The diagnosis of sporadic hemiplegic migraine (SHM) with cerebellar ataxia was made. Our case was very similar to familial hemiplegic migraine (FHM) 1, of which some families are accompanied with transient amnesia, cerebellar ataxia and EEG abnormality. Although we did not detect any mutations in CACNA1A gene previously reported in FHM1, our case might share same pathogenesis with FHM1.

Background: The increasing number of patients with dementia in Japan, together with the rapid aging of society, is currently considered to have a substantial impact on Japan's medical, economic and sociological systems. Therefore, the longitudinal estimation of changes in the prevalence of dementia based on accurate diagnostic evaluation has important implications. Methods: We undertook three separate epidemiological studies on long-term changes, 10 years apart (1980, 1990 and 2000), in the prevalence of dementia in an elderly population using identical methods (DSM-III and Hachinski's ischemic score) for the same rural area in Japan (Daisen-cho). Results: The percentage of the population that was elderly (over 65 years of age) increased steadily from 16.0% in 1980 to 21.7% in 1990 and 27.1% in 2000. The prevalence of dementia (cases/100 people aged 65 years or older, adjusted to the population structure of 1980) in 1980, 1990 and 2000 was 4.4, 4.5 and 5.9, respectively, for all types of dementia, 1.9, 2.5 and 3.6, respectively, for Alzheimer-type dementia (DAT) and 2.0, 1.7 and 2.2, respectively, for vascular dementia (VaD). Conclusions: These findings of an increase in the number of cases and prevalence of DAT and VaD in a Japanese rural community have important implications for interventional medicine.

Mutations in the parkin gene are a common cause of autosomal recessive, juvenile or early onset parkinsonism (PARK2). In this report, we use RT-PCR to detect compound heterozygous deletions of the parkin gene in fibroblasts from two cases of middle age-onset familial parkinsonism with lower extremities-dominant resting tremor and mild cogwheel rigidity. Although exonic amplification of the parkin gene showed a deletional mutation of exon 3-4, their family histories suggested that the deletional mutations were a compound heterozygous abnormality of discrete origin. Immunoblotting demonstrated that abundant Parkin protein was expressed in fibroblasts, but little expression was detected in lymphocytes. RT-PCR using RNA isolated from the patients' fibroblasts indicated a parkin mutation in this family that consisted of compound heterozygous deletions (del exon3-4/del exon3-5). These results suggest that RT-PCR using the patients' fibroblasts may be helpful for the detection of compound heterozygous abnormalities in the parkin gene.

Mutation of Cu/Zn superoxide dismutase (SOD1) contributes to a portion of the cases of familial amyotrophic lateral sclerosis (FALS). We previously reported on a FALS family whose members had a mutant form of SOD1 characterized by a 2-base pair (bp) deletion at codon 126 of the SOD1 gene. To investigate the cellular consequences of this mutation, we produced transgenic mice that expressed normal and mutated copies of human SOD1: wild-type SOD1 (W), wild-type SOD1 with a FLAG epitope at C-terminal (WF), mutated SOD1 with the 2-bp deletion (D), and SOD1 with the 2-bp deletion with FLAG (DF). The mice heterozygotic for the human mutated SOD1 (D and DF) showed distinct ALS-like motor symptoms, whereas the mice heterozygotic for the normal SOD1 (W and WF) mice did not. Homozygotes of D and DF lines showed the ALS symptoms at an earlier age and died earlier than the heterozygotes. By Northern blot analysis, the mRNAs for all human SOD1s were confirmed in these lines. All the human SOD1 proteins, except the D mutant, were detectable by immunoblot. The D protein was only confirmed when it was concentrated by immunoprecipitation. Neuropathologically, loss of spinal motor neurons and reactive gliosis were common features in the symptomatic lines. The remaining motor neurons in these mice also exhibited eosinophilic inclusions. The biochemical and pathological characteristics of these mice are quite similar to those of human FALS patients with same mutation. This intriguing model will provide an important source of information of the pathogenesis of FALS.

Methylenetetrahydrofolate reductase (MTHFR) is the only route for the synthesis of 5-methyltetrahydrofolate, which is utilized to convert homocysteine to methionine. In this study, we measured the enzyme activity of a mutant MTHFR that was detected in a patient with hyperhomocysteinemia. The 428C>T mutation in exon 2 of the MTHFR gene is a novel mutation, while the [458G>T+459C>T] mutation in exon 2 is a previously reported mutation. The activity of mutant enzymes containing the 428C>T, [458G>T+459C>T] and 677C>T mutations was 12.7±4.7%, 48.1±18.8%, and 43.6±14.4%, respectively, of that of the wild type enzyme. Our results suggest that these two variants each result in a severe MTHFR deficiency, which causes a developmental delay and cerebral vascular disease.

Huntington's Disease-like 2 (HDL2) is a progressive, autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntington's disease (HD). The causal mutation is a CTG/CAG expansion mutation on chromosome 16q24.3, in a variably spliced exon of junctophilin-3. The frequency of HDL2 was determined in nine independent series of patients referred for HD testing or selected for the presence of an HD-like phenotype in North America or Japan. The repeat length, ancestry, and age of onset of all North American HDL2 cases were determined. The results show that HDL2 is very rare, with a frequency of 0 to 15% among patients in the nine case series with an HD-like presentation who do not have the HD mutation. HDL2 is predominantly, and perhaps exclusively, found in individuals of African ancestry. Repeat expansions ranged from 44 to 57 triplets, with length instability in maternal transmission detected in a repeat of r2=0.29, p=0.0098). The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of HDL2 and provide preliminary guidelines for the genetic testing of patients with an HD-like phenotype.

Objective – We report on a Japanese family with Charcot–Marie–Tooth disease (CMT) with the Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene. Material and methods – Based on the clinical study, we investigated MPZ gene by direct sequence analysis and polymerase chain reaction–restriction fragment length polymorphism analysis. Results – Genotyping of four symptomatic family members showed that one family member with severe disease symptoms was homozygous, while the other three were heterozygous. The heterozygous cases were clinicopathologically determined to be the axonal type, which is characterized by late-onset and slow progression associated with Adie's pupil and deafness. The homozygous case was the demyelinating type, which showed earlier onset, rapid progression, sural nerve demyelination, and cranial nerve demyelination at autopsy. Conclusions – We suggest that axonal and demyelinating forms of CMT are not two distinct classes, but rather parts of a spectrum of genotypically related conditions, particularly with some MPZ mutations.

Migraine is considered to be a polygenic multifactorial disease with various environmental and genetic etiologies. We investigated glutathione S-transferase (GST) P1 Ile105Val, T1 and M1 polymorphisms in 174 Japanese headache sufferers and 372 Japanese controls. The headache group consisted of 38 cases of migraine with aura, 95 migraine without aura (MWOA) and 41 tension-type headache sufferers. The M1 homozygous deletion genotype was significantly higher in MWOA (64%) compared with controls (46%; p < 0.01; odds ratio = 2.18, 95% confidence interval: 1.32–3.61, adjusted for age and gender). In a comparison of the current smokers, the M1 null frequencies in MWOA were further increased. GSTM1 may be one of the genetic risk factors for MWOA in the Japanese population.

Here we report a female patient with elderly-onset cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). At age 71, she developed gait disturbance, followed by memory disturbance 1 year later. She had been treated for hypertension and diabetes mellitus for 19 years. There apparently was low penetrance of disease. Magnetic resonance imaging (MRI) findings showed typical features of CADASIL, and the R607C mutation was detected in exon 11 in NOTCH3. This case strongly indicates that CADASIL should be considered when typical findings are observed on MRI even in cases of elderly onset with multiple cerebrovascular risk factors.

To determine whether treatment with branched-chain amino acids (BCAA) can improve the condition of patients with ataxia, a double-blind crossover study of BCAA therapy was performed in 16 patients with spinocerebellar degeneration (SCD). The patients were treated with BCAA in oral doses of 1.5, 3.0, or 6.0 g or with placebo daily for 4 weeks in each study phase. The order of treatment phases (placebo or BCAA) was assigned randomly. An International Cooperative Ataxia Rating Scale (ICARS) was used to quantify the severity of symptoms of SCD. The mean ICARS score improved significantly with BCAA treatment compared with the mean pretreatment score (p

A 36-year-old man had been treated by thoracoscopic bullectomy because of left pneumothorax at another hospital. 2 weeks post-surgery, he was transferred to our hospital because of recurrent left pneumothorax. Chest computed tomography (CT) revealed multiple, irregular-shaped pulmonary cysts of various sizes predominating in the apex of both lungs. Thoracoscopy showed diffuse multiple thinwalled small cysts on the visceral pleura. Small cyst with air leakage was sutured and other cysts were cauterized. He was diagnosed as having Birt-Hogg-Dubé (BHD) syndrome by DNA sequence analysis of his FLCN gene.

In order to study progressive dementia in Alzheimer’s disease (AD) patients, we analyzed the gene expression of apolipoprotein E (apoE). ApoE mRNA level in the brains of patients with AD was determined by the reverse transcriptase-polymerase chain reaction (RT-PCR) method. ApoE genotype and the promoter polymorphisms (–491A/T, Th1/E47cs) were determined by the PCR restriction fragment length polymorphism method. The apoE mRNA level was significantly higher in the AD group than the control group (p < 0.05). ApoE mRNA in the AD group with apoE Ε4 was also significantly higher than that in the control group with apoE Ε4 (p < 0.05). Our result did not indicate the possibility that the promoter polymorphisms modulate the apoE mRNA level. The higher level of apoE mRNA in AD with apoE Ε4 may play an important role in the development of AD.

This report describes an autopsied Alzheimer's disease (AD) patient with primary progressive aphasia (PPA) as an early symptom. The patient developed a progressive speech disturbance at the age of 70 years, and difficulty in comprehension became apparent 2 years later. Magnetic resonance imaging scan disclosed asymmetrical brain atrophy, predominantly on the left temporal lobe. At the age of 74 years, the patient's dementia rapidly progressed with parkinsonism and he died after a disease duration of 6 years. At autopsy, the brain showed a marked temporo-frontal lobe atrophy, predominantly on the left side. There was severe neuronal loss with gliosis and tissue rarefaction in the atrophied cerebral cortex and amygdala. Many neurofibrillary tangles with neuropil threads were found in the cerebral cortex. Numerous amyloid deposits were distributed throughout the cerebral cortex, accompanied by amyloid angiopathies. This patient was clinically diagnosed with temporal lobe-dominant Pick's disease, although the possibility of corticobasal degeneration was made. The neuropathological diagnosis was AD with asymmetrical brain atrophy and widespread amyloid angiopathies.

We examined the expression of presenilin 1 (PS-1) mRNA in cultured skin fibroblasts taken from living patients with Alzheimer’s disease (AD) and human brains taken postmortem from AD patients by RT-PCR analysis. The donors of fibroblasts consisted of 28 cases with AD and 19 neurological patient without dementia (CTL). The brains came from 17 cases with AD and 23 cases with CTL. We found that PS-1 mRNA levels in skin fibroblasts of AD patients were significantly higher than those of CTL patients (p < 0.0001). Moreover, we found that PS-1 mRNA levels in human brains with AD were significantly higher than in those with CTL (p < 0.0001). These findings suggest that high levels of PS-1 mRNA in AD may play an important role in developing AD and that the examination of PS-1 mRNA in skin fibroblasts may be helpful for the diagnosis of AD.

An autopsied case of a 49-year-old man with Down syndrome is described. The patient developed mental deterioration and parkinsonism at the age of 44 years. The brain revealed Alzheimer's disease (AD) pathology in addition to anomalies and lesions of premature senility. In the substantia nigra, many neurofibrillary tangles (NFT) and some Lewy bodies (LB) were found, suggesting that a limited degree of Parkinson's disease (PD) pathology may combine with AD pathology to develop parkinsonism. However, spongiform change and ubiquitin-positive spheroids in the central nucleus of the amygdala, which are peculiar to dementia with Lewy bodies (DLB), were observed, suggesting that the substantia nigra lesion is similar to that of DLB rather than that of PD. In addition, α-synuclein-positive neurons in the limbic areas, predominantly in the amygdala, were found. Their incidence and distribution did not fulfill the criteria of DLB. These neurons did not show the typical features of cortical type LB, and were mostly accompanied by tau-positive NFT. These findings suggest that the presence of α-synuclein-positive neurons does not always indicate the presence of LB, and that the present case should not be regarded as the complication of DLB in Down syndrome.

Parkinson's disease (PD) is a common cause of dementia in the elderly. Dementia in Alzheimer's disease (AD) and PD share common biologic and clinical features. The estrogen receptor (ER) gene is one of the susceptibility genes for AD. In order to test the hypothesis that the overlap between AD and PD may have a genetic basis, we determined ER gene polymorphisms in 13 PD patients with dementia (PDD) (age +/- SD; 71.9 +/- 5.5 years), 71 PD patients without dementia (PDND) (68.4 +/- 7.5 years), 86 AD patients (76.8 +/- 8.0 years) and 51 control subjects (CTL) (74.9 +/- 6.9 years). ER genotypes were classified as a P or p allele on the basis of a Pvu II-RFLP, and X and x on the basis of a Xba I-RFLP. The frequency of the P allele in the PDD group as well as the AD group was higher than that in CTL. There was no significant difference in the distribution of the P allele between CTL and PDND. There were no significant differences in the distribution of the X allele among the PDD, PDND and CTL groups, whereas a higher incidence was found in AD. We conclude that the ER gene may be a common susceptibility gene for dementia in PD as well as AD.

Object: The potential effects of branched-chain ammo acids (BCAAs) on spinocerebellar degeneration (SCD) were explored in eleven patients. Methods: The patients received 200 ml of BCAA-rich solution, 2 mg of thyrotropin-releasing hormone (TRH; protirelin), or a placebo daily for 7 days each in a random order. An SCD score was used to quantify the severity of symptoms. Patients: Eleven patients with SCD (7 male, 4 female; mean age 60±11; mean disease duration 5.5 years) participated in this study. Results: The mean SCD score of the eleven patients improved significantly by the BCAA treatment compared with the baseline. The conditions of five of the eleven patients (45%) were clearly improved by the BCAA treatment. All of the responders manifested predominantly cerebellar symptoms, but no prominent parkinsonian symptoms. Two patients with marked rigidity and akinesia did not respond to the treatment. Conclusion: We concluded that BCAAs do have a beneficial effect on functional improvement in patients with SCD, and that further large scale studies are needed.(Internal Medicine 38: 401-406, 1999)

We carried out two separate epidemiological studies on long-term changes, 10 years apart, on the prevalence rate of dementia in the elderly by the same method for the same area in Japan. We also performed a genetic study of patients with dementia of the Alzheimer type (DAT) based on the epidemiological studies. The number of patients with dementia was much larger in 1990 than in 1980. Especially, the number of mildly demented patients was significantly larger in 1990 than in 1980. The 35 patients with DAT did not show any mutations of amyloid-β protein precursor, presenilin 1 and presenilin 2 genes. The frequency of apolipoprotein E (apo E) σ4 allele in DAT was significantly higher than that in control subjects (p < 0.005). This study suggests that the frequency of DAT may increase by aging of the population in the future and we confirm the close association between apoE σ4 allele and DAT in a community-based study in Japan.

Therapy for Parkinson's disease (PD) has been progressing. However, the prognosis for patients with PD is still unclear. We studied the course of PD in patients in the San-in Area of Japan over a long time period. The main purpose of this study was to see whether there was a difference in survival between PD patients and the general population. Information on 114 deceased PD patients, who died between 1989 and 1996, was collected from hospitals belonging to the Tottori University Parkinson's Disease Epidemiology Study Group. Although the duration of illness was prolonged, the survival of PD patients was still poorer than that of the general population. The most common cause of death was pneumonia. The main cause of death in young PD patients was also pneumonia. In order to improve the survival of PD patients, PD-related conditions should be treated more extensively, especially pneumonia.

We examined amyloid precursor protein (APP) mRNAs expression in skin fibroblasts from Down''s Syndrome (DS) patients of different ages to deter-mine the time of occurrence of abnormal splicing. The ratio of APP770 + 751 mRNA to APP695 mRNA (APP770 + 751/695) was significantly increased in the young DS group and adult DS group compared with the age-matched con-trol groups (p < 0.01, p < 0.05), but no significant increase was observed in the aged DS group compared with the age-matched control group. These findings suggest that metabolic abnormalities of the APP gene occur at a very early stage of DS, at a mean age of about 5 years. Therefore, metabolic abnormalities of the APP gene are considered to appear at a very young age also Alzheimer''s disease (AD). In this study, we confirmed that examination of the APP gene in skin fibroblasts might be useful for early diagnosis of AD.

The prevalence of all neurological disorders in a Japanese town was calculated, with a result of 91.1 per 1,000 population. The prevalence of cerebrovascular disease was 28.8; myelopathy and/or radiculopathy caused by deformity of the spine or disc herniation, 23.9; neuralgia, 11.5; dementia, 10.4; peripheral nerve disturbance, 5.5; epilepsy, 4.4; Parkinson's disease, 2.0; mental retardation, 2.9; brain/spinal tumor, 1.4; headache, 10.8, and vertigo/dizziness, 4.4. The prevalence of headache and vertigo/dizziness was also calculated from the results of the questionnaires sent to inhabitants: headache, 79.6, and vertigo/dizziness, 60.8. Neurological disorders are common in Japan and likely to continue to increase.

Objectives – The goal of this study is to clarify the association between migraine and Serotonin 2C receptor Cys23Ser polymorphism in Japanese population. Materials and method – This study included 37 individuals with migraine with aura (MWA), 80 with migraine without aura, 43 with tension type headache (TH) and 360 with controls. The genotypes of Cys23Ser polymorphism were confirmed by polymerase chain reaction-restriction fragment length polymorphism techniques. Results – The Ser allele frequency in control subjects is much less than that in Caucasian population. The Ser allele frequency in patients with MWA was higher than that in control subjects. Conclusion – The present study provides that 5HTR2c Cys23Ser polymorphism may be associated with MWA in Japanese population.

The ALS/parkinsonism-dementia complex (PDC) of Kii is an endemic disease with a diverse phenotypic expression characteristic of classical ALS, parkinsonism and dementia. Its clinical and neuropathological manifestations are similar to a syndrome found in Guam, sharing classical ALS pathology together with many neurofibrillary tangles in the brain. The incidence rates of ALS declined dramatically between the 1950s and 1980s. In the 1990 s, Kuzuhara found a high incidence of PDC with abundant neurofibrillary tangles, similar to Guamanian PDC. The incidence rates of PDC dramatically rose during the 1980s and 1990 s, and PDC replaced ALS. More than 70% of patients in the endemic region had a family history of ALS or PDC. We recently found a new gene OPTN causing ALS, and have extended its clinical survey in Japan. Two autopsied cases showed involvement of basal ganglia and/or cerebral cortex with neurofibrillary tangles. A few family members also showed dementia and parkinsonism without evidence of motor neuron disease. Moreover the penetrance seems to be incomplete. Despite these similarities, OPTN mutations were not found in the Kii patients. We speculate that the Kii/ALS-PDC could primarily be a genetic disease, and its clinical manifestation is modified by other genes or environmental factors.

BackgroundzzLeber’s hereditary optic neuropathy (LHON) is a mitochondrial disorder with optic nerve atrophy. Although there are no other associated neurological abnormalities in most cases of LHON, cases of “LHON plus” have been reported. Case ReportzzThe proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dys arthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. ConclusionszzThese results suggest that the combination of G11778A and T3394C mutations leads to an atypical LHON phenotype. J Clin Neurol 2012;8:230-234

Summary: We administrated WEB 1881, 800 mg/day (400 mg twice a day), nine patients with dementia of the Alzheimer type for 8 weeks, and undertook an open study to investigate the clinical effects of the distribution into the cerebrospinal fluid (CSF) as well as the influence on the neurotransmitter-related substances in the CSF. These were outpatients living at home with caregivers. Significant clinical improvement was shown by means of the Gottfries, Brane, and Steen Scale and by Hasegawa's dementia scale. Unchanged WEB 1881 was identified in the CSF. The mean concentration of which was 198.7 ng/ml, this corresponded to 19.0% of the plasma concentration. Of several neurotransmitter-related substances measured in the CSF, a marked rise of AChE activity was observed. Adverse effects consisted of a slight skin eruption in one case and alterations in a clinical laboratory test in another case. These were, however, not significant from a clinical viewpoint. It is suggested that the mechanisms of action of WEB 1881 are based on its transit into the CSF as well as the activation of intracerebral acetylcholinergic systems.

Familial hypokalemic periodic paralysis is an autosomal dominant disorder. Recently, three predominant mutations were found in the muscle dihydropyridine-sensitive calcium channel alpha 1-subunit gene. We present a Japanese family that displays one of these, the Arg1239His mutation. All the affected individuals of this family displayed this mutation. Two cases had a history of recurrent episodes of muscle weakness and difficulty in running before their first paralytic attack. It is suggested that there are no racial differences with this mutation, and that mild muscle weakness occurs not only after but also preceding the first attack.

Hemiconvulsion-hemiplegia-epilepsy syndrome involves sudden and prolonged unilateral seizures, followed by transient or permanent hemiplegia and epilepsy during infancy or early childhood. Some patients with familial hemiplegic migraine and demonstrating the S218L mutation in CACNA1A experience severe attacks with unilateral cerebral edema after trivial head trauma. We report on a 5-year-old Japanese girl presenting with hemiconvulsion-hemiplegia-epilepsy syndrome after infection with parvovirus B19. Magnetic resonance imaging performed 2 days after admission revealed cerebellar atrophy and marked hyperintensity in the left hemisphere on T(2)-weighted and diffusion-weighted imaging. Magnetic resonance angiography performed 7 days after admission demonstrated obliteration of the left proximal middle cerebral artery in the acute phase. However, this finding was not evident on brain angiography performed 25 hours after magnetic resonance angiography. Genetic analysis of familial hemiplegic migraine revealed a heterozygous S218L mutation in CACNA1A. Taken together, these results suggest that vasospasms of cerebral vascular smooth muscle, with possible cortical spreading depression, may have caused the hemiconvulsions and hemiplegia in the left hemisphere. This case report is the first, to the best of our knowledge, to associate CACNA1A with hemiconvulsion-hemiplegia-epilepsy syndrome and familial hemiplegic migraine, and to suggest that similar pathogenic mechanisms may underlie these two disorders.

Background: With the striking increase in the number of elderly people in Japan, dementia has not only become a medical but also a social issue. Methods: We studied the prevalence of dementing disorders in a rural island town of Japan (Ama-cho), using a door-to-door 2-phase design. Results: Of the 120 persons screened as having cognitive impairment, 104 people were diagnosed as having dementia. The prevalence (cases/100 persons aged 65 years and older) was 11.0 for all types of dementia, 7.0 for Alzheimer’s disease, 1.7 for vascular dementia, 0.53 for dementia with Lewy bodies, 0.74 for Parkinson’s disease dementia, 0.21 for progressive supranuclear palsy, 0.11 for frontotemporal lobar degeneration and 0.74 for other dementia. The overall prevalence was higher in women for Alzheimer’s disease and Parkinson’s disease dementia, and in men, for vascular dementia and dementia with Lewy bodies. Conclusion: We confirmed the overall prevalence of dementia in the elderly population aged 65 years and older to be 11.0. This finding is higher compared with previous reports in Japan.

Objective – Autosomal dominant cerebellar ataxia (ADCA) is a heterogeneous neurodegenerative disorder. A single nucleotide substitution in the puratrophin-1 gene is associated with 16q22.1-linked ADCA showing pure cerebellar ataxia. We screened patients with spinocerebellar degeneration (SCD) to investigate the frequency and clinical features of 16q22.1-linked ADCA. Materials and methods – We examined 91 SCD patients from a 1998 community-based prevalence study of Tottori Prefecture in western Japan. We also analyzed samples from 176 patients with SCD collected from a 1996 to 2006 laboratory-based study. Results – In the community-based study, the prevalence of spinocerebellar ataxia 6 (SCA6) and 16q22.1-linked ADCA was 2.4 and 1.12 per 100,000 individuals, respectively. In the laboratory-based study, the frequency of SCA6 and 16q22.1-linked ADCA was 28% and 17%, respectively. We found two cases of 16q22.1-linked ADCA among 26 SCD patients with no family history. Conclusion – In this area in Japan, 16q22.1-linked ADCA was the second most common type of hereditary SCD.

Apolipoprotein E sigma4 allele (ApoE sigma4) is associated with Alzheimer's disease (AD) in familial and sporadic cases, but the associations of ApoE sigma4 allele and vascular dementia (VD) and/or ischemic cerebrovascular disease (ICVD) are still controversial. To clarify the associations of ApoE polymorphism with AD, VD and ICVD in Japanese, we examined ApoE polymorphism in samples of 255 patients with AD, 87 patients with VD, and 123 patients with ICVD, as compared with 117 age-matched healthy control subjects (CTL). The frequency of the ApoE sigma4 allele was significantly higher in the VD group (0.21), the ICVD group (0.15) as well as in the AD group (0. 26) than in the CTL subjects (0.08). These findings suggest that the genotype of ApoE sigma4 is associated with not only AD but also VD and ICVD, and that ApoE sigma4 plays an important role in the development of dementia and ICVD.

Migraine is a common form of the chronic headache syndromes. Although the pathogenesis of migraine still remains enigmatic, there have been remarkable progress in headache research. Point mutations of P/Q-type Ca2+ channel alpha 1 subunit (CACNA1A) gene have been identified in familial hemiplegic migraine (FHM), which linked to chromosome 19 (FHM-1, OMIM 141500). Na-K ATPase alpha2 gene has been identified as the causative gene for FHM linked to 1q21-23 (FHM-2, OMIM 602481). Common forms of migraine (i.e. migraine with and without aura) seems to be caused from multifactorial genetic factors and environmental factors. An association study of allelic variation at Codon 23 (Cys or Ser) of 5HT2C-R gene in Japanese samples revealed that the Ser allele frequency in migraine with aura was significantly higher than that in the non-headache controls. However, negative association of this polymorphism have been reported in Caucasian migrainures. The C677T allelic variation of 5,10-methylenetetrahydrofolate reductase (MTHFR) are focused on in association with the coronary heart diseases and the cerebrovascular diseases. The T allelic frequency in migraine sufferers was significantly higher than that in controls. The C677T mutation of MTHFR is one of the genetic risk factors for migraine. These observations are confirmed in Turkish, Australian and Spanish samples. Positive associations of angiotensin converting enzyme (ACE) gene, endotheline receptor-A (ET-A) gene, and insulin receptor gene have been reported. Using the genomewide screen technology, significant linkage between the migraine with aura and a marker on 4q24 has been reported in Finnish families. The genome wide screen analysis will be one of the powerful strategies on exploring migraine gene. Genetic study of migraine headache is a promised and fruitful field and will provide deep understanding to migraine headache. Discovery of new responsible or susceptible genes to migraine will also open an avenue to develop new therapeutic strategy of migraine.

Objective To establish further evidence that SCA6 may not be a pure cerebellar syndrome. Methods Seven patients with genetically confirmed SCA6 and 9 age-matched normal controls were studied. Recordings of the CMAP were obtained from the right first dorsal interosseus muscle. Transcranial magnetic stimulation of the left motor cortex was applied to the contralateral scalp with a plane figure-of-8 coil. Conventional transcranial magnetic stimulation (TMS), central motor conduction time (CMCT) by F-wave method and the triple stimulation technique (TST) amplitude ratio (TST test/TST control) were investigated. Results The mean resting motor threshold and mean CMCT did not show significant differences between normal controls and patients, but the mean TST amplitude ratio was significantly smaller in patients than in controls. Conclusions An abnormal TST represents upper motor neuron loss, central axon lesions or conduction blocks, or inexcitability in response to TMS. The lack of pathological changes in the corticospinal tract of patients with SCA6 indicates that this abnormality may be caused by crossed cerebellar diaschisis, or a functional disorder in the brain resulting from CACNA1A mutations. Significance TST is a useful method for quantifying corticospinal tract dysfunction.

The MPZ Thr124Met mutation is characterised by a late onset, pupillary abnormality, deafness, normal or moderate decreased motor nerve conduction velocity, and axonal damage in sural nerve biopsy.To investigate the clinical manifestations of the axonal or demyelinating forms of the Japanese MPZ Thr124Met mutation originating in four different areas: Tottori, Nara, Aichi, and Ibaragi.Genotyping with DNA microsatellite markers linked to the MPZ gene on chromosome 1q22-q23 showed shared allelic characteristics between 12.65 cM and revealed a common haplotype in all Tottori families. Aichi and Ibaragi families shared parts of the haplotype around the MPZ gene. However, there was no consistency with a Nara family.The high frequency of this peculiar genotype in the Tottori CMT population is presumably due to a founder effect, but in Thr124 it might constitute a mutation hotspot in the MPZ gene.

Objectives.—To determine prevalence and characteristics of migraine in Japan, and to investigate use of medical care and whether food preference is associated with risk of migraine. Methods.—Structured questionnaires were given to all adult residents (N = 5758; 2681 men and 3077 women) in Daisen, a rural community in western Japan. Second questionnaires, specific to headache, were given to 1628 residents with headache. A telephone survey was also carried out. Statistical Packages for the Social Sciences analyzed the data. Results.—The 1-year prevalence of migraine was 2.3% (migraine with aura, 0.4% and without aura, 1.9%) in men and 9.1% (migraine with aura, 1.0% and migraine without aura, 8.1%) in women. Overall prevalence of migraine in Daisen was 6.0% (95% confidence interval [CI], 5.4% to 6.6%). Women observed a 5.9-fold higher risk of migraine than men (odds ratio, 5.9; 95% CI, 4.5 to 8.0; P < .0001, after age adjustment, by logistic analysis). Fatigue and loss of vigor were predominant premonitory symptoms of migraine. Fatigue, mental stress, and lack of sleep were the main headache triggers. Over a 3-month period, 20.3% of migraineurs experienced time or days off work due to headache. Only 7.3% of those with migraine with aura and 5.3% of those with migraine without aura had consulted a physician, and of those with migraine, 61.0% with aura and 71.8% without aura had never visited a medical doctor for their headache. Consumption of alcohol and cigarette smoking did not influence the risk for migraine or tension-type headache, after age and gender adjustment (logistic analysis). Migraineurs consume significantly more fatty/oily foods, coffee, and tea than nonheadache subjects of the same community. Migraineurs consume significantly fewer fish than nonheadache residents. Conclusions.—Only a few Japanese migraineurs receive benefits of medical services and recent advances of headache medicine. Public education concerning headaches is one of the most urgent issues in Japan.

Methylenetetrahydrofolate reductase (MTHFR) is the only route for the synthesis of 5-methyltetrahydrofolate, which is utilized to convert homocysteine to methionine. In this study, we measured the enzyme activity of a mutant MTHFR that was detected in a patient with hyperhomocysteinemia. The 428CT mutation in exon 2 of the MTHFR gene is a novel mutation, while the [458GT+459CT] mutation in exon 2 is a previously reported mutation. The activity of mutant enzymes containing the 428CT, [458GT+459CT] and 677CT mutations was 12.7+/-4.7%, 48.1+/-18.8%, and 43.6+/-14.4%, respectively, of that of the wild type enzyme. Our results suggest that these two variants each result in a severe MTHFR deficiency, which causes a developmental delay and cerebral vascular disease.