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To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [123I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.

Motor function can be modulated by transcranial alternating current stimulation (tACS) in alpha, beta, and high-gamma frequencies. However, few studies have investigated tACS-induced behavioral changes in combination with endogenous oscillatory neural activity in detail. Herein, we investigated the effect of tACS on motor learning capacity and endogenous oscillatory neural activity. Fifty-two healthy volunteers were randomly assigned to four stimulation groups (10 Hz, 20 Hz, 70 Hz, or sham) and performed a visually cued button press motor learning task before and after tACS, which was delivered at the left primary motor area. Oscillatory neural activities during the motor learning task were measured using magnetoencephalography (MEG). Following tACS, the capacity for motor learning was significantly increased for 70 Hz tACS compared to sham stimulation. Oscillation analysis revealed a significant increase in beta-band power after 70-Hz tACS but not in the other stimulation groups. Our finding that capacity for motor learning and endogenous oscillatory beta activity were modulated in parallel after 70-Hz tACS suggests that 70-Hz tACS may increase the motor learning capacity by cross-modulating beta oscillatory activity. Because high gamma and beta oscillatory activity have been shown to reflect the activity of excitatory and inhibitory interneuron, our results may derive from the modulation of excitatory and inhibitory interneurons in M1 by 70-Hz tACS.

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10−9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10−18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

EEG findings in advanced Gerstmann-Sträussler-Scheinker syndrome (GSS) are shown. A 56-year-old woman developed GSS symptoms and was diagnosed as having GSS with the P102L mutation at age 58. During the early stage, there were no significant EEG findings. Her clinical condition worsened and she developed akinetic mutism at age 62. The patient died of pneumonia at age 65. EEGs were recorded annually from age 61 to 65. Bilateral independent periodic discharges (BIPDs) in both temporal areas appeared at age 64. No clinical seizures were noticed. MEG showed the sharp waves of BIPDs originated independently in each temporal lobe. Other causes of BIPDs were absent.

Background Many patients from Toroku, Japan, who have chronic arsenic exposure demonstrate whole-body sensory disturbance that is slightly more pronounced in the extremities. Although previous research in this population showed a mild peripheral neuropathy, it is unknown whether these patients have central nervous system impairment. To investigate the lesion sites underlying sensory disturbance related to chronic arsenic poisoning, we analyzed somatosensory evoked potentials (SEP). Methods Clinical features, nerve conduction study results, and median and/or tibial SEP were analyzed in patients with chronic arsenic exposure (total, 13 patients; median & tibial, 4; median, 5; tibial, 4) retrospectively. The SEP findings in patients were compared with those in normal controls. Results The median SEP results indicated a conduction delay between the proximal brachial plexus and the primary sensory cortex, and tibial SEP findings indicated a delay between the dorsal gray matter of the lumbosacral cord and the primary sensory cortex. Conclusion This is the first study to identify an impairment of the central somatosensory pathway in patients with chronic arsenic exposure. Sensory disturbance in these patients is related not only to peripheral neuropathy but also to impairment of the central nervous system.

It has been suggested that resting-state functional connectivity (rs-FC) between the primary motor area (M1) region of the brain and other brain regions may be a predictor of motor learning, although this suggestion is still controversial. In the work reported here, we investigated the relationship between M1 seed-based rs-FC and motor learning. Fifty-three healthy volunteers undertook random button-press and sequential motor learning tasks. Five-minute resting-state data acquisition was performed between the two tasks. Oscillatory neural activities during the random task and the rest period were measured using magnetoencephalography. M1 seed-based rs-FC was calculated for the alpha and beta bands using amplitude envelope correlation, in which the seed location was defined as an M1 position with peak event-related desynchronization value. The relationship between rs-FC and the performance of motor learning was examined using whole brain correlation analysis. The results showed that beta-band resting-state cross-network connectivity between the sensorimotor network and the core network, particularly the theory of mind network, affected the performance of subsequent motor learning tasks. Good learners could be distinguished from poor learners by the strength of rs-FC between the M1 and the left superior temporal gyrus, a part of the theory of mind network. These results suggest that cross-network connectivity between the sensorimotor network and the theory of mind network can be used as a predictor of motor learning performance.

We report a 33-year-old Japanese man who suffered from repetitive generalized tonic-clonic seizures which were medically intractable. Neurosyphilis was serologically diagnosed in blood and cerebrospinal fluid, and penicillin G (PcG) was consequently effective. The EEG during PcG pre-treatment showed frequent right occipital spikes and right frontocentral slow waves, which disappeared after treatment. During pre-treatment, positron emission tomography with 18-fluorodeoxyglucose and Tc-99m ethyl cysteinate dimer single-photon emission computed tomography revealed occipital hypermetabolism and hyperperfusion ("hot" area) and fronto-temporo-parietal hypometabolism and hypoperfusion ("cool" area) over the right hemisphere. The spike sources of magnetoencephalography during pre-treatment were localized to "hot" areas, and the slow activities were distributed to the fronto-temporo-parietal region, corresponding to "cool" areas. The inflammatory seizure focus and reversible dysfunctional zone associated with neurosyphilis were clearly delineated using these techniques.

The aim of this study was to assess the efficacy of early phase washout rate (early WR) and area under the time-activity curve (AUTAC) by (123)I-metaiodobenzylguanidine (MIBG) dynamic chest imaging for distinguishing Lewy body-related diseases (LBRD) from Parkinson's syndrome (PS) and reducing examination time.Sixty-two patients with suspected LBRD who underwent (123)I-MIBG dynamic imaging in early phase were retrospectively selected. The early WR and AUTAC were calculated from (123)I-MIBG dynamic data of the heart. We evaluated the relationships between proposed and conventional parameters by using Spearman's rank correlation coefficient. Differences in parameters between LBRD and PS groups were tested for statistical significance using the Mann-Whitney U test. The diagnostic performance of all parameters for distinguishing LBRD from PS was assessed in terms of receiver operating characteristic (ROC) analysis. Additionally, combination diagnostic performance and concordance rate between early phase parameters and late H/M ratio by kappa statistics were also assessed.The early WR and AUTAC showed a positive and negative correlation with conventional parameters. Both the early WR and AUTAC of LBRD group were significantly distinguishable from those of the PS group (p0.001). Area under the ROC curve of the early WR (0.98) was greater than that of AUTAC (0.91). The diagnostic performance of combination of the early phase parameters was 93 % sensitivity and 100 % specificity. Moreover, the early phase parameters showed excellent agreement with late H/M ratio (k = 0.93).The early WR and AUTAC showed high performance for distinguishing LBRD from PS, and the combination diagnosis with early H/M ratio and early WR contribute to improve the diagnostic performance. Thus, these parameters would be useful for reducing the examination time of myocardial (123)I-MIBG scintigraphy to diagnose LBRD.

AIM It is well known that patients with Parkinson's disease (PD) prominently experience difficulty in smelling, a nonmotor symptom, without any signs or symptoms from an early stage. However, no study on the classification of the reduced sense of smell has been performed. We compared the classification of reduced sense of smell (bromine) between PD patients and healthy subjects to clarify the disorder profile. METHODS The subjects were 14 female neurology outpatients clinically diagnosed with PD (mean age: 71.6 ± 6.1 years) and 11 female elderly healthy subjects without any psychiatric or neurological disorders (mean age: 68.9 ± 6.9 years). In this study, the Japanese odor stick identification test was used. RESULTS Both the PD patients and the healthy subjects showed a reduced sense of smell for the bromine of lumber, orange, and domestic gas. The PD patients preserved a sense of smell for perfume, but they showed a significantly lower sense of smell than the healthy subjects for the bromine of China ink, menthol, curry, rose, cypress, sweaty socks, and condensed milk; this indicates that bromine can be a supportive diagnostic index for PD. CONCLUSION It was considered important to evaluate the reduced sense of smell in PD patients to avoid hazards in their daily lives and to conduct an effective rehabilitation program.

The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders. To date, at least 11 genes and 13 additional loci have been identified in ADCAs. Despite phenotypic differences, spinocerebellar ataxia 4 (SCA4) and Japanese 16q-linked ADCA type III map to the same region of 16q22.1. We report four Japanese families with pure cerebellar ataxia and a disease locus at 16q22.1. Our families yielded a peak lod score of 6.01 at marker D16S3141. To refine the candidate region, we carried out genetic linkage studies in four pedigrees with a high density set of DNA markers from chromosome 16q22.1. Our linkage data suggest that the disease locus for 16q-ADCA type III is within the 1.25-Mb interval delineated by markers 17msm and CTTT01. We screened for mutations in 36 genes within the critical region. Our critical region lies within the linkage interval reported for SCA4 and for Japanese 16q-ADCA type III. These data suggest that the ADCA that we have characterized is allelic with SCA4 and Japanese 16q-linked ADCA type III.

Objective From 1920 to 1962, a mining company at a small mountainous village called Toroku in Japan intermittently produced arsenic trioxide. Although many patients had severe whole-body surface and deep sensory disturbances, previous studies reported only slight axonal degeneration based on nerve conduction studies or sural nerve biopsy. Methods Subjects were six patients with chronic arsenic exposure in Toroku. All patients had moderate to severe whole-body surface and deep sensory impairments without any motor disturbances. Peripheral nerve conduction study and bilateral median nerve somatosensory evoked potentials were performed in all patients. Results In nerve conduction study, two patients showed mild decrease of sensory nerve action potentials. In somatosensory evoked potentials, the N9 was delayed in two patients. The N11 was not detected in any patients, while the P13/14 was detected only in two patients. The N20 was detected in all patients. Patients with chronic arsenic poisoning had a significantly longer central sensory conduction time (latency between N9 and N20) compared to normal subjects (p Conclusions Sensory disturbances in patients with chronic arsenic poisoning are related to not only peripheral neuropathy but also central nervous system impairment. Key message Chronic arsenic exposure may affect the central nervous system.

The present study was conducted to investigate the historical time-course changes and regional distribution of methylmercury concentrations in preserved umbilical cords collected from Minamata-area inhabitants born between 1947 and 1989. The data from Miyazaki, Tottori, Akita, Tsushima (Nagasaki), Fukuoka and Tokyo were used as controls. A total of 325 data were analyzed to estimate the temporal and spatial distribution of methylmercury among inhabitants born in the Minamata area. Elevated methylmercury concentrations (>or=1 microg/g) were mainly observed in inhabitants born between 1947 and 1968. That peak coincided with the peak of acetaldehyde production in Minamata. The methylmercury concentrations started to decrease in keeping with the decline of acetaldehyde production, which ceased in 1968, and thereafter the methylmercury levels gradually decreased to the control levels. Elevated methylmercury concentrations were first observed in the districts of Minamata, followed by Izumi, Tsunagi and Ashikita, indicating the time-course-dependent regional distributions of methylmercury pollution.

Yokukansan (YKS) is used frequently against behavioral and psychological symptoms of dementia (BPSD) together with donepezil in patients with Alzheimer's disease (AD). Here, we investigated the efficacy and safety of YKS in patients with AD in a non-blinded, randomized, parallel-group comparison study. Patients who had at least one symptom score of four or more on the Neuropsychiatric Inventory (NPI) subscales were enrolled in the study. The subjects were randomly assigned to the YKS-treated group (YKS/donepezil combination therapy group) and the non-YKS-treated group (donepezil monotherapy group). TSUMURA Yokukansan (TJ-54, 7.5g, t.i.d.) was administered in a four-week study treatment period. The subjects were evaluated twice at the start (Week 0) and completion (Week 4) of the study treatment in terms of NPI, Mini-Mental Status Examination (MMSE), Disability Assessment for Dementia (DAD), Zarit Burden Interview, and Self-rating Depression Scale (SDS). The efficacy analysis was performed in 29 patients (YKS-treated group) and 32 patients (non-YKS-treated group). The NPI total score improved significantly more in the YKS-treated group than in the non-YKS-treated group. In the NPI subscales of agitation/aggression and irritability/lability, the YKS-treated group showed significantly greater improvement than the non-YKS-treated group, but no statistically significant improvement was seen with YKS in the other subscales. There were no significant differences between the YKS-treated group and the non-YKS-treated group in MMSE, DAD, Zarit Burden Interview and SDS. No adverse reactions were noted in either group. The results of this study showed that YKS is safe and effective in the treatment of BPSD in AD patients.

A case of a 68-year-old female patient with hypokalemic myopathy is presented. Her persistent diarrhea due to radiation enteropathy with a total dose of 8,400 rad for the treatment of cervical cancer caused potassium loss in the stool. It finally induced generalized muscle weakness with hypokalemia as low as 1.6 mEq/l with elevated CK 3,845 IU/l. The muscle biopsy of the left vastus lateralis demonstrated typical findings of hypokalemic myopathy. Radiation to the pelvic space can cause damage of the terminal ileum. Hypokalemic myopathy associated with radiation enteropathy is very rare in the literature.

Posterior tibial somatosensory evoked potentials were recorded from 10 patients with Duchenne-type progressive muscular dystrophy (DMD). The results of the patients were compared with age-matched controls. The ratio of height to latency (H/P38 and H/N22-P38) decreased significantly in DMD, which indicated central conduction disturbances in DMD.

Sensory and autonomic polyneuropathy is a rare disease characterized by a sensory nerve disorder and postganglionic autonomic dysfunction. The etiology of this disease is unknown. We described a 51-year-old woman who had a chronic sensory dominant polyneuropathy and dysautonomia associated with hypergammaglobulinemia. In the previous reports of sensory and autonomic polyneuropathy, not much attention was given to coexisting hypergammaglobulinemia. By reviewing the literatures, hypergammaglobulinemia was frequently present in these case reports. This fact leads us to consider that an immunological mechanism may be playing a role in the pathogenesis of this disorder.

A 29-year-old single woman had recurrent stroke-like episodes. She developed loss of consciousness, myoclonic seizures, and lactic acidosis. She died at the age of 30. A muscle biopsy study revealed mitochondrial myopathy, and the postmortem biochemical analysis demonstrated decreased cytochrome c oxidase activity in the skeletal muscles by 20% of normal control. The brain had multiple ischemic lesions in the cerebral cortex without major vascular occlusions. We present this case as an autopsy case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with a partial deficiency of cytochrome c oxidase. The analytical electron microscopic study of the calcified small vessels in the globus pallidus revealed increased calcium, phosphorus and iron. No accumulation of chromium, nickel or zinc was noted in this case, which was different from the previously reported cases of basal ganglia calcification.

• Four male patients and one female patient of a new family with Joseph disease are reported. Their disease was characterized by autosomal dominant inheritance, bulging eyes, rigidity and spasticity of the lower extremities, dystonia, and bradykinesia. Cerebrospinal fluid homovanillic acid level was markedly reduced. Levodopa improved dystonia. Magnetic resonance imaging revealed mild atrophy of the frontal lobe and the cerebellum and marked atrophy of the lenticular nucleus and the brain stem. Polysomnographic studies revealed non-rapid eye movement stage central type sleep apnea syndrome. This is the first report using magnetic resonance imaging and sleep apnea studies of Joseph disease.