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The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterised by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in two Kii cases. We also identified a novel Type III CTE tau filament, where protofilaments pack against each other in an anti-parallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.SIGNIFICANCEA neurodegenerative disease of unknown cause on the island of Guam and the Kii peninsula of Japan has been widely studied, because patients can suffer from the combined symptoms of motor neuron disease, parkinsonism and dementia. Abnormal filamentous inclusions made of tau protein characterise this amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) and their formation closely correlates with neurodegeneration. Here we have used electron cryo-microscopy (cryo-EM) to show that tau filaments from ALS/PDC are identical to those from chronic traumatic encephalopathy (CTE), a disease caused by repetitive head impacts or blast waves. CTE tau filaments are also found in subacute sclerosing panencephalitis, which is a rare consequence of measles infection. ALS/PDC may therefore also be caused by environmental factors.

Clinical Practice Points • Immune checkpoint inhibitor (ICI) therapy could exacerbate preexisting active autoimmune diseases (AIDs), and the presence of preexisting AIDs might be associated with a greater risk of developing new immune-related adverse events (irAEs). • The safety of ICIs for patients with Lambert-Eaton myasthenic syndrome (LEMS), a neuromuscular autoimmune disease known as a paraneoplastic syndrome mainly associated with small-cell lung cancer (SCLC), is fully unknown. • We experienced an extensive-stage (ES)-SCLC patient with LEMS successfully treated with chemotherapy in combination with ICI without a flare-up of LEMS. • Phase III trials have shown that ICIs in combination with platinum doublet therapy significantly improved the overall survival of patients with ES-SCLC in first-line settings, therefore, patients diagnosed with ES-SCLC with the complication of LEMS have the widespread opportunity to receive ICIs as standard care. This report suggests that treatment using ICIs may be a treatment option to consider for ES-SCLC patients with LEMS.

Background and Objectives:To examine the association of the apolipoprotein E gene (APOE) ε4 and ε2 alleles with the pathological features of patients with amyotrophic lateral sclerosis and Parkinsonism-dementia complex cases in the Kii peninsula of Japan (Kii ALS/PDC)Methods:We analyzed APOE polymorphisms in 18 autopsy patients with ALS/PDC, consisting of nine, eight, and one patient with PDC, ALS, and PDC followed by ALS, respectively. Moreover, we revealed the relationship between APOE polymorphisms and Aβ and tau pathologies, respectively.Results:The frequency of the ε4 allele was not different between patients with Kii ALS/PDC and control participants. APOE ε4 was associated with increased Aβ pathology (p=0.005 by χ2 test) but not with increased tau pathology (p=0.984). The frequency of the ε2 allele was apparently higher than that of control participants (p=0.254). APOE ε2 allele was associated with increased tau pathology (p=0.009) and not with reduced Aβ pathology (p=0.383) in patients with Kii ALS/PDC.Discussion:Although there was no overrepresentation of the frequency of the ε4 or ε2 allele, our findings suggest that the ε2 allele is associated with increased tau pathology and not with reduced Aβ pathology in patients with Kii ALS/PDC.

Objectives Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a unique endemic on Guam island of the USA, the Kii Peninsula of Japan, and Papua state of Indonesia. The pathomechanism of ALS/PDC remains to be solved, although interaction between some environmental factors and genetic background is plausible. This is the first autopsy-proven immigrant family of ALS/PDC of the Kii Peninsula. Methods A daughter and her father immigrated to the high incident area from outside the Kii Peninsula. The father developed ALS 18 years later after immigration, and his daughter also developed ALS 65 years after immigration. They showed pure ALS phenotype without parkinsonism and dementia. Results The daughter was diagnosed neuropathologically with Kii ALS/PDC with multiple proteinopathies: tauopathy, α-synucleinopathy, and TDP-43 proteinopathy. Gene analysis of familial ALS-related genes, including C9orf72, showed no mutation. Discussion The findings in an immigrant family established that certain environmental factors play a critical role in the pathogenesis of Kii ALS/PDC.

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a unique endemic on Guam island of the USA, the Kii Peninsula of Japan, and Papua state of Indonesia. The pathomechanism of ALS/PDC remains to be solved, although interaction between some environmental factors and genetic background is plausible. This is the first autopsy-proven immigrant family of ALS/PDC of the Kii Peninsula.A daughter and her father immigrated to the high incident area from outside the Kii Peninsula. The father developed ALS 18 years later after immigration, and his daughter also developed ALS 65 years after immigration. They showed pure ALS phenotype without parkinsonism and dementia.The daughter was diagnosed neuropathologically with Kii ALS/PDC with multiple proteinopathies: tauopathy, α-synucleinopathy, and TDP-43 proteinopathy. Gene analysis of familial ALS-related genes, including C9orf72, showed no mutation.The findings in an immigrant family established that certain environmental factors play a critical role in the pathogenesis of Kii ALS/PDC.

ObjectiveTo characterize the distribution of tau pathology in patients with amyotrophic lateral sclerosis/parkinsonism dementia complex on the Kii Peninsula (Kii ALS/PDC) by tau PET using [11C]PBB3 as ligand.MethodsThis is a cross-sectional study of 5 patients with ALS/PDC and one asymptomatic participant with a dense family history of ALS/PDC from the Kii Peninsula who took part in this study. All were men, and their age was 76 ± 8 (mean ± SD) years. Thirteen healthy men (69 ± 6 years) participated as healthy controls (HCs). Dynamic PET scans were performed following injection of [11C]PBB3, and parametric PET images were generated by voxel-by-voxel calculation of binding potential (BP*ND) using a multilinear reference tissue model. [11C] Pittsburgh compound B (PiB) PET, MRI, and cognitive tests were also performed.ResultsA voxel-based comparison of [11C]PBB3 BP*ND illustrated PET-detectable tau deposition in the cerebral cortex and white matter, and pontine basis including the corticospinal tract in Kii ALS/PDC patients compared with HCs (uncorrected p < 0.05). Group-wise volume of interest analysis of [11C]PBB3 BP*ND images showed increased BP*ND in the hippocampus and in frontal and parietal white matters of Kii ALS/PDC patients relative to HCs (p < 0.05, Holm-Sidak multiple comparisons test). BP*ND in frontal, temporal, and parietal gray matters correlated with Mini-Mental State Examination scores in Kii ALS/PDC patients (p < 0.05). All Kii ALS/PDC patients were negative for [11C]PiB (β-amyloid) except one with marginal positivity.Conclusion[11C]PBB3 PET visualized the characteristic topography of tau pathology in Kii ALS/PDC, corresponding to clinical phenotypes of this disease.

Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder that is endemic to the Kii peninsula of Japan. The disorder is clinically characterized by a variable combination of parkinsonism, dementia, and motor neuron symptoms. Despite extensive investigations, the etiology and pathogenesis of ALS/PDC remain unclear. At the neuropathological level, Kii ALS/PDC is characterized by neuronal loss and tau-dominant polyproteinopathy. Here, we report the accumulation of several proteins involved in protein homeostasis pathways, that is, the ubiquitin-proteasome system and the autophagy-lysosome pathway, in postmortem brain tissue from a number of Kii ALS/PDC cases (n = 4). Of particular interest is the presence of a mutant ubiquitin protein (UBB+1), which is indicative of disrupted ubiquitin homeostasis. The findings suggest that abnormal protein aggregation is linked to impaired protein homeostasis pathways in Kii ALS/PDC.

Amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC) is a unique endemic neurodegenerative disease, with high-incidence foci in Kii Peninsula, Japan. To gather new insights into the pathological mechanisms underlying Kii ALS/PDC, we performed transcriptome analyses of patient brains. We prepared frozen brains from three individuals without neurodegenerative diseases, three patients with Alzheimer&rsquo, s disease, and 21 patients with Kii ALS/PDC, and then acquired microarray data from cerebral gray and white matter tissues. Microarray results revealed that expression levels of genes associated with heat shock proteins, DNA binding/damage, and senescence were significantly altered in patients with ALS/PDC compared with healthy individuals. The RNA expression pattern observed for ALS-type brains was similar to that of PDC-type brains. Additionally, pathway and network analyses indicated that the molecular mechanism underlying ALS/PDC may be associated with oxidative phosphorylation of mitochondria, ribosomes, and the synaptic vesicle cycle, in particular, upstream regulators of these mechanisms may be found in synapses and during synaptic trafficking. Furthermore, phenotypic differences between ALS-type and PDC-type were observed, based on HLA haplotypes. In conclusion, determining the relationship between stress-responsive proteins, synaptic dysfunction, and the pathogenesis of ALS/PDC in the Kii peninsula may provide new understanding of this mysterious disease.

OBJECTIVE: To characterize the distribution of tau pathology in patients with amyotrophic lateral sclerosis/parkinsonism dementia complex on the Kii Peninsula (Kii ALS/PDC) by tau PET using [11C]PBB3 as ligand. METHODS: This is a cross-sectional study of 5 patients with ALS/PDC and one asymptomatic participant with a dense family history of ALS/PDC from the Kii Peninsula who took part in this study. All were men, and their age was 76 ± 8 (mean ± SD) years. Thirteen healthy men (69 ± 6 years) participated as healthy controls (HCs). Dynamic PET scans were performed following injection of [11C]PBB3, and parametric PET images were generated by voxel-by-voxel calculation of binding potential (BP* ND) using a multilinear reference tissue model. [11C] Pittsburgh compound B (PiB) PET, MRI, and cognitive tests were also performed. RESULTS: A voxel-based comparison of [11C]PBB3 BP* ND illustrated PET-detectable tau deposition in the cerebral cortex and white matter, and pontine basis including the corticospinal tract in Kii ALS/PDC patients compared with HCs (uncorrected p < 0.05). Group-wise volume of interest analysis of [11C]PBB3 BP* ND images showed increased BP* ND in the hippocampus and in frontal and parietal white matters of Kii ALS/PDC patients relative to HCs (p < 0.05, Holm-Sidak multiple comparisons test). BP* ND in frontal, temporal, and parietal gray matters correlated with Mini-Mental State Examination scores in Kii ALS/PDC patients (p < 0.05). All Kii ALS/PDC patients were negative for [11C]PiB (β-amyloid) except one with marginal positivity. CONCLUSION: [11C]PBB3 PET visualized the characteristic topography of tau pathology in Kii ALS/PDC, corresponding to clinical phenotypes of this disease.

The high incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) has been previously known in the Kii Peninsula of Japan and in Guam. Recently, the accumulation of various proteins, such as tau, trans-activation response DNA binding protein 43 kDa (TDP-43), and alpha-synuclein (αSyn), was reported in the brains of patients with ALS/PDC in Guam. To confirm whether similar findings are present in Kii ALS/PDC, we neuropathologically examined the brains and spinal cords of 18 patients with ALS/PDC (clinical diagnoses: eight ALS and 10 PDC) in Hohara Village, which is the eastern focus of Kii ALS. The average age at death was 71.6 years, and 16 patients (88.9%) had a family history of ALS/PDC. Autopsy specimens were immunohistochemically examined with antibodies against four major proteins. Neurofibrillary tangles, including ghost tangles, and tau-positive astrocytes were distributed widely in all of the brains examined, and TDP-43-positive neuronal cytoplasmic inclusions were observed mainly in the limbic system. Synuclein pathology was present in 14 patients (77.8%). These patients were classified into three pathological subtypes according to the most prominent proteinopathy: the tauopathy-dominant type, the TDP-43 proteinopathy-dominant type, and the synucleinopathy-dominant type. Five patients with severe tau deposition showed clinical features of atypical parkinsonism and dementia with or without motor neuron disease. Eight patients were predominated by phosphorylated TDP-43 inclusions and clinically showed ALS, and five patients were predominated by synuclein pathology and clinically showed signs of PDC. Based on the common characteristic tau pathology, three subtypes seemed to be pathologically continuous on a spectrum of a single disease. Thus, we conclude that ALS/PDC in the Hohara focus of the Kii Peninsula is a single disease characterized neuropathologically by a multiple proteinopathy, even though the clinical manifestations of the three subtypes differed from each other. It remains unclear whether the coexistence of the three proteinopathies was incidental or pathogenetically related.

Amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) is an endemic disease observed in the Kii peninsula, Guam, and Papua. We report a case of a 76-year old man with ALS/PDC of the Kii peninsula of Japan (Kii ALS/PDC). The patient was born and grew up in the Kii peninsula. He moved out at age three, and developed symptoms 73 years later. He showed pyramidal sign, parkinsonian symptoms, and mildly impaired cognitive function. 131I-metaiodobenzylguanidine myocardial scintigraphy showed decreased cardiac sympathetic nerve function, and dopamine transporter single photon emission computed tomography imaging showed decreased 123I-N-x-fluoropropyl-2b-carbomethoxy3b-(4-iodo phenyl) nortropane accumulation. Cerebral blood flow showed hypoperfusion. Positron emission tomography showed widespread tau deposition in his brain. This is a migration case of Kii ALS/PDC with the shortest stay in the endemic area and the longest delay to develop the disease, indicating a genetic factor for the disease development in a considerable degree.

[Objective] Lifestyle changes may play an important role in the incidence reduction and delay of onset age of amyotrophic lateral sclerosis (ALS) in the Koza/Kozagawa/Kushimoto (K) area. The aim of this study was to evaluate recent lifestyle changes in the K area and to investigate the relationships between lifestyle and oxidative stress among the residents. [Methods] We conducted a medical checkup for elderly residents in the K area and the control area and evaluated the urinary 8-OHdG levels, cognitive function test scores and metal contents in serum and scalp hair, coupled with a lifestyle questionnaire survey between 2010 and 2015. [Results] Recent lifestyle changes among the K residents, including a decrease in the Japanese pickle consumption, increase in fresh vegetable consumption and decrease in farm work, were evaluated in this study. Low consumption of Japanese pickles, high consumption of fresh vegetables, rare farm work and low levels of 8-OHdG/creatinine were all associated with high scores in the cognitive function tests. Frequent farm work and consumption of Japanese pickles was associated with high contents of transition metals, such as Mn, Al and V, in the scalp hair. [Conclusion] These lifestyle changes among residents in the K area may be associated with their oxidative stress.

Recent papers of amyotrophic lateral sclerosis/parkinsonism-dementia complex in the Kii peninsula, Japan (Kii ALS/PDC), published since 2015, were reviewed The studies included transition element of scalp hair analysis, dopaminergic PET study, review of life style changes in the high incident area, neurotoxic BMAA analysis, a clinical report of a migration case, comprehensive neuropathological study, cerebellar tau pathology, nitrative stress in the central nervous system study, optinurin pathology in the spinal cord, and tau PET study. Tau PET was advocated to be a new useful tool for diagnosis, even in the early stage of ALS/PDC with tauopathy. The etiology of Kii ALS/PDC remainds unknown. There are patients and healthy residents within the same environment in the high incidence foci, therefore it is difficult to explain this result by exposure to environmental factors alone. From the genetic viewpoint, rare-disease and rare-variant model may be applied to Kii ALS/PDC. Because there was an immigrant who was diagnosed neuropathologically, and a drastic decrease of the prevalence in the past several decades in the high incident area, it is feasible that Kii ALS/PDC is a multifactorial disease caused by both risk genes and environmental factors. Identifying risk genes and environmental factors for Kii ALS/PDC may contribute to the prevention of neurodegenerative diseases.

Summary Background Identification of causative genes in mendelian forms of Parkinson's disease is valuable for understanding the cause of the disease. We did genetic studies in a Japanese family with autosomal dominant Parkinson's disease to identify novel causative genes. Methods We did a genome-wide linkage analysis on eight affected and five unaffected individuals from a family with autosomal dominant Parkinson's disease (family A). Subsequently, we did exome sequencing on three patients and whole-genome sequencing on one patient in family A. Variants were validated by Sanger sequencing in samples from patients with autosomal dominant Parkinson's disease, patients with sporadic Parkinson's disease, and controls. Participants were identified from the DNA bank of the Comprehensive Genetic Study on Parkinson's Disease and Related Disorders (Juntendo University School of Medicine, Tokyo, Japan) and were classified according to clinical information obtained by neurologists. Splicing abnormalities of CHCHD2 mutants were analysed in SH-SY5Y cells. We used the Fisher's exact test to calculate the significance of allele frequencies between patients with sporadic Parkinson's disease and unaffected controls, and we calculated odds ratios and 95% CIs of minor alleles. Findings We identified a missense mutation ( CHCHD2 , 182C>T, Thr61Ile) in family A by next-generation sequencing. We obtained samples from a further 340 index patients with autosomal dominant Parkinson's disease, 517 patients with sporadic Parkinson's disease, and 559 controls. Three CHCHD2 mutations in four of 341 index cases from independent families with autosomal dominant Parkinson's disease were detected by CHCHD2 mutation screening: 182C>T (Thr61Ile), 434G>A (Arg145Gln), and 300+5G>A. Two single nucleotide variants (−9T>G and 5C>T) in CHCHD2 were confirmed to have different frequencies between sporadic Parkinson's disease and controls, with odds ratios of 2·51 (95% CI 1·48–4·24; p=0·0004) and 4·69 (1·59–13·83, p=0·0025), respectively. One single nucleotide polymorphism (rs816411) was found in CHCHD2 from a previously reported genome-wide association study; however, there was no significant difference in its frequency between patients with Parkinson's disease and controls in a previously reported genome-wide association study (odds ratio 1·17, 95% CI 0·96–1·19; p=0·22). In SH-SY5Y cells, the 300+5G>A mutation but not the other two mutations caused exon 2 skipping. Interpretation CHCHD2 mutations are associated with, and might be a cause of, autosomal dominant Parkinson's disease. Further genetic studies in other populations are needed to confirm the pathogenicity of CHCHD2 mutations in autosomal dominant Parkinson's disease and susceptibility for sporadic Parkinson's disease, and further functional studies are needed to understand how mutant CHCHD2 might play a part in the pathophysiology of Parkinson's disease. Funding Japan Society for the Promotion of Science; Japanese Ministry of Education, Culture, Sports, Science and Technology; Japanese Ministry of Health, Labour and Welfare; Takeda Scientific Foundation; Cell Science Research Foundation; and Nakajima Foundation.

The high incidence of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) has been previously known in the Kii Peninsula of Japan and in Guam. Recently, the accumulation of various proteins, such as tau, trans-activation response DNA binding protein 43 kDa (TDP-43), and alpha-synuclein (αSyn), was reported in the brains of patients with ALS/PDC in Guam. To confirm whether similar findings are present in Kii ALS/PDC, we neuropathologically examined the brains and spinal cords of 18 patients with ALS/PDC (clinical diagnoses: eight ALS and 10 PDC) in Hohara Village, which is the eastern focus of Kii ALS. The average age at death was 71.6 years, and 16 patients (88.9%) had a family history of ALS/PDC. Autopsy specimens were immunohistochemically examined with antibodies against four major proteins. Neurofibrillary tangles, including ghost tangles, and tau-positive astrocytes were distributed widely in all of the brains examined, and TDP-43-positive neuronal cytoplasmic inclusions were observed mainly in the limbic system. Synuclein pathology was present in 14 patients (77.8%). These patients were classified into three pathological subtypes according to the most prominent proteinopathy: the tauopathy-dominant type, the TDP-43 proteinopathy-dominant type, and the synucleinopathy-dominant type. Five patients with severe tau deposition showed clinical features of atypical parkinsonism and dementia with or without motor neuron disease. Eight patients were predominated by phosphorylated TDP-43 inclusions and clinically showed ALS, and five patients were predominated by synuclein pathology and clinically showed signs of PDC. Based on the common characteristic tau pathology, three subtypes seemed to be pathologically continuous on a spectrum of a single disease. Thus, we conclude that ALS/PDC in the Hohara focus of the Kii Peninsula is a single disease characterized neuropathologically by a multiple proteinopathy, even though the clinical manifestations of the three subtypes differed from each other. It remains unclear whether the coexistence of the three proteinopathies was incidental or pathogenetically related.

The Kii Peninsula of Japan and the island of Guam are known as high-incidence areas of amyotrophic lateral sclerosis and parkinsonism–dementia complex (ALS/PDC). The disorder is clinically characterized by a variable presentation of parkinsonism, dementia, and motor neuron symptoms and pathologically by tau protein deposits in the CNS.1 Both genetic and environmental factors are implicated in ALS/PDC pathogenesis. Exposure to β-N-methylamino-l-alanine (BMAA), a neurotoxin produced by cyanobacteria, has been proposed as a risk factor for ALS/PDC in Guam.2 It is not known whether Kii ALS/PDC shares the same etiology as Guam ALS/PDC. To address these issues, we conducted BMAA analyses of brain samples from 5 patients with Kii ALS/PDC using high-performance liquid chromatography (HPLC) and liquid chromatography–tandem mass spectrometry (LC/MS/MS). Acknowledgment: The authors thank Junko Karita for clerical assistance and Enago ( [ enago.jp ][1] ) for the English language review. The authors also thank the H.L. Castle Foundation, the W. F. Coulter Foundation, and the Margaret Q. Landenberger Foundation, as well as C. Childs, K. Farkas, and L. Atherton for research funding. [1]: http://www.enago.jp/

Background: Amyotrophic lateral sclerosis and parkinsonism-dementia complex in the Kii peninsula, Japan (Kii ALS/PDC) is an endemic and rare neurodegenerative disease. We conducted positron emission tomography (PET) study using C-11 CFT (2-b-carbomethoxy-3b-(4-fluorophenyl) tropane) and C-11 Raclopride for two patients with Kii ALS/PDC. Objective and methods: Patient #1 was 64 years old male having 12 years’ duration of the illness. Patient #2 was 68 years old female having 7 years’ duration of the illness. Results: In patient #1, CFT-PET showed marked decreased uptake in the bilateral corpus striatum, almost no signal in the posterior part of the putamen. RAC-PET showed mild decrease in the bilateral caudate nucleus and slight increase in the posterior part of the putamen. In patient #2, CFT-PET showed severe decrease in the bilateral corpus striatum, marked decrease in the posterior part of the putamen and in the caudate nucleus. RACPET showed the mild decrease in the bilateral corpus striatum. Conclusion: These results were compatible with L-dopa resistant Parkinsonism and similar to those of PSP.

We report disseminated cysticercosis concurrent with taeniasis in a 31-year-old male Japanese, who had visited India three times and stayed for 1 month each time during the previous 1 year. The patient presented increasing numbers of subcutaneous nodules and expelled proglottids, although numerous cysts were also found in the brain in imaging findings, though no neurological symptoms were observed. Histopathological and serological findings strongly indicated cysticercosis. We found taeniid eggs in his stool by microscopic examination and revealed them as the Indian haplotype of Taenia solium by mitochondrial DNA analysis. We concluded that disseminated cysticercosis was caused by the secondary autoinfection with eggs released from the tapeworm carrier himself. After confirming the absence of adult worms in the intestine by copro-polymerase chain reaction, the patient was successfully treated with albendazole at a dose of 15 mg/kg/day for 28 days. Subcutaneous and intracranial lesions had completely disappeared by the end of the treatment period.

Objective Although Oshima, in the Kii Peninsula of Japan, is located within a high incidence area of amyotrophic lateral sclerosis (ALS) (Koza/Kozagawa/Kushimoto area, K area), no patients with ALS were detected between 1960 and 1999. However, the incidence recently increased between 2000 and 2009. On Oshima, the source of drinking water was changed from a regional river/wells to the Kozagawa River in the K area in 1975. We speculate that this change in water source may have played a role in the recent increase in the incidence of ALS. The aim of this study is to find contributing factors that may have triggered the locally high incidence of ALS. Methods We investigated a possible association between the mineral content of drinking water and serum and oxidative stress markers among patients with ALS in the K area (K-ALS), residents of Oshima and controls. Results We found that the levels of Ca and Zn in the recent drinking water in Oshima are low and that the serum levels of Ca and Zn in the Oshima residents and patients with K-ALS were significantly lower, while the oxidative stress markers were significantly higher, than those of the controls. The serum Zn and urinary 8-OHdG/creatinine levels explained 60% and 58% of the variations among the three groups, respectively. The serum Zn levels were negatively correlated with the serum Cu levels in the patients with K-ALS, and the serum Cu levels exhibited a tendency to be positively correlated with the 8-OHdG/creatinine levels in both the patients with K-ALS (r: 0.64) and the residents free from K-ALS (r: 0.32, p

Background Mutations in the microtubule associated protein tau ( MAPT ) and progranulin ( PGRN ) have been identified in several neurodegenerative disorders, such as frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). Recently, C9orf72 repeat expansion was reported to cause FTLD and amyotrophic lateral sclerosis (ALS). To date, no comprehensive analyses of mutations in these three genes have been performed in Asian populations. The aim of this study was to investigate the genetic and clinical features of Japanese patients with MAPT , PGRN , or C9orf72 mutations. Methods MAPT and PGRN were analyzed by direct sequencing and gene dosage assays, and C9orf72 repeat expansion was analyzed by repeat-primed PCR in 75 (48 familial, 27 sporadic) Japanese patients with FTLD, PSP, or CBS. Results We found four MAPT mutations in six families, one novel PGRN deletion/insertion, and no repeat expansion in C9orf72 . Intriguingly, we identified a de novo MAPT p.S285R mutation. All six patients with early-onset PSP and the abnormal eye movements that are not typical of sporadic PSP had MAPT mutations. The gene dosages of MAPT and PGRN were normal. Discussion MAPT p.S285R is the first reported de novo mutation in a sporadic adult-onset patient. MAPT mutation analysis is recommended in both familial and sporadic patients, especially in early-onset PSP patients with these abnormal eye movements. Although PGRN and C9orf72 mutations were rare in this study, the PGRN mutation was found in this Asian FTLD. These genes should be studied further to improve the clinicogenetic diagnoses of FTLD, PSP, and CBS.

We report an autopsy case of globular glial tauopathy (GGT) presenting clinically with amyotrophic lateral sclerosis (ALS) with dementia. A 79-year-old female developed weakness in the right upper limb, which progressed gradually. She developed apathy and speech disorder at 80 years of age. On neurological examination, she showed signs of upper and lower motor neuron disorder and dementia, but no extrapyramidal signs. The clinical diagnosis was ALS with dementia. The autopsy revealed left predominant marked atrophy of the frontal lobe due to severe neuronal loss and Gliosis. Immunohistochemistry using anti-4-repeat tau antibody revealed numerous globular glial inclusions. Severe neurodegeneration in the primary motor cortex and corticospinal tract was observed. There were distinctive tau-positive inclusions in both Betz and anterior horn cells. TDP-43-positive inclusions in motor neurons were not detected. Sequence analysis of the tau gene revealed no mutations in exons 1-5, 7, 9-13, or the adjacent intronic sequences. GGT can cause a clinical phenotype of ALS with dementia. (Received December 28, 2015; Accepted February 23, 2016; Published August 1, 2016).

Vacuolar protein sorting 35 (VPS35) was recently reported to be a pathogenic gene for late- onset autosomal dominant Parkinson's disease (PD), using exome sequencing. To date, VPS35 mutations have been detected only in whites with PD. The aim of the present study was to determine the incidence and clinical features of Asian PD patients with VPS35 muta- tions. We screened 7 reported nonsynonymous mis- sense variants of VPS35, including p.D620N, known as potentially disease-associated variants of PD, in 300 Japanese index patients with autosomal dominant PD and 433 patients with sporadic PD (SPD) by direct sequencing or high-resolution melting (HRM) analysis. In addition, we screened 579 controls for the p.D620N mutation by HRM analysis. The p.D620N mutation was detected in 3 patients with autosomal dominant PD (1.0%), in 1 patient with SPD (0.23%), and in no con- trols. None of the other reported variants of VPS35 were detected. Haplotype analysis suggested at least 3 independent founders for Japanese patients with p.D620N mutation. Patients with the VPS35 mutation showed typical tremor-predominant PD. We report Asian PD patients with the VPS35 mutation. Although VPS35 mutations are uncommon in PD, the frequency of such mutation is relatively higher in Japanese than reported in other populations. In VPS35, p.D620N sub- stitution may be a mutational hot spot across different ethnic populations. Based on the clinical features, VPS35 should be analyzed in patients with PD, espe- cially autosomal dominant PD or tremor-predominant PD. V C 2012 Movement Disorder Society

α-Synuclein pathology was examined in the brains and spinal cords of 10 patients with amyotrophic lateral sclerosis (ALS)/parkinsonism-dementia complex (PDC) in the Kii Peninsula, Japan. Various types of phosphorylated α-synuclein-positive structures including neuronal cytoplasmic inclusions, dystrophic neurites, and glial cytoplasmic inclusions were found in all ALS/PDC cases. There were phosphorylated α-synuclein-positive neurons in 8 cases (80%), and the amygdala was most severely affected. Phosphorylated α-synuclein was distributed mainly in the limbic system and brainstem; tau pathology was more prevalent than α-synuclein pathology in most affected areas. In the substantia nigra, periaqueductal gray, locus coeruleus, raphe nuclei, dorsal nucleus of the vagus nerve, hypoglossal nucleus or ventral horn, and intermediolateral nucleus of the spinal cord, α-synuclein pathology was more predominant than tau pathology in only 1 or 2 patients. Phosphorylated α-synuclein- positive structures were not found in the molecular layer of the cerebellum. Phosphorylated α-synuclein frequently colocalized with tau in neuron cell bodies, neurites, and glia. Immunoblots of sarkosyl-insoluble fractions extracted from the brain of 1 patient showed a triplet of α-synuclein-immunoreactive bands that were ubiquitinated. These results suggest that interaction between tau and α-synuclein be involved in the pathogenesis of Kii ALS/PDC.

Our objective was to elucidate the genetic epidemiology of familial amyotrophic lateral sclerosis (FALS) and sporadic ALS (SALS) with OPTN mutations in the Japanese population. Mutational analysis of OPTN was conducted in 18 FALS pedigrees in whom mutations in other causative genes have been excluded and in 218 SALS patients by direct nucleotide sequence analysis. Novel non-synonymous variants identified in ALS patients were further screened in 271 controls. Results showed that although no mutations were identified in the FALS pedigrees, a novel heterozygous non-synonymous variant c.481G > A (p.V161M) was identified in one SALS patient, who originated from the southernmost part of the Kii Peninsula. The mutation was not present in 271 controls. As the clinical feature, the patient carrying V161M showed predominantly upper motor neuron signs with slow progression. This study suggests that mutations in OPTN are not the main cause of ALS in the Japanese population.

We investigated changes in the incidence of amyotrophic lateral sclerosis (ALS) in the Koza/Kozagawa/Kushimoto area (K. area) in the Kii Peninsula, Japan in 1960 – 2009. Probable and defi nite ALS cases diagnosed using El Escorial criteria were collected during a fi ve-decade period: period I – V, 1960 – 2009. Forty-three ALS patients matched the selection criteria in the overall K. area, including three patients on Oshima, a small island opposite the mainland K. area. The age- and gender-adjusted incidence of ALS in the overall K. area (standardized for the 2005 Japanese population) decreased from 5.47/100,000 (95% CI 1.86–9.08) in period I to 0.61/100,000 (95% CI 0.28 1.50) in period III, and then increased to 4.39/100,000 (95% CI 1.70–7.07) in period V. On Oshima, the age- and gender-adjusted incidence of ALS was 9.45/100,000 (95% CI 7.39 26.29) in period V. The present research indicates an increase of ALS incidence in the K. area, especially on Oshima. A limitation of this study was the small population.

Amyotrophic lateral sclerosis and Parkinsonism-dementia complex of the Kii peninsula (Kii ALS/PDC) is an endemic and a tauopathy, which shows clinical symptoms of amyotrophy, parkinsonism, and dementia. The objective of this study was to report the role of oxidative stress on Kii ALS/PDC using biochemical analysis. Urinary 8-hydroxydeoxyguanosine (8-OHdG)/creatinine ratio was analyzed in 11 patients with Kii ALS/PDC and 8 normal controls. The mean level of urinary 8-OHdG/creatinine ratio of the patients with Kii ALS/PDC was significantly higher than that of control subjects. Oxidative stress may be implicated in pathogenesis of Kii ALS/PDC. © 2008 Movement Disorder Society

Non-herpetic acute limbic encephalitis (NHALE) is a cause-unknown, inflammatory disease entity that affects the limbic system restrictedly. Neuropathological changes of NHALE have been described in only one report. A 53-year-old Japanese woman developed high fever, disturbance of consciousness and intractable generalized convulsions. Her symptoms were resistant to aggressive therapy including corticosteroid, acyclovir, gamma-globulin and anticonvulsants, and progressed acutely, leading to status epilepticus at 6 days after the onset. Brain MRI revealed inflammatory changes restricted to the limbic system. Herpes encephalitis was excluded by laboratory tests. Although paraneoplastic limbic encephalitis could not be excluded completely, no tumor lesions were detected on chest CT and abdominal ultrasonography. The patient died of multiple organ failure at 34 days after the onset of the disease. Histologically, there were neuronal loss and severe gliosis with an increase in hypertrophic astrocytes and with perivascular cuffings around several small blood vessels restricted to the hippocampus and the amygdala. Immunohistochemically, macrophages and activated astrocytes were distributed more widely over the limbic system, namely internal capsule, thalamus, caudate nucleus and substantia nigra. Herpes simplex virus I(1) and II(2) were negative immunohistochemically. The neuropathological findings of this case were similar to that of the previous report. NHALE is supposed to be a distinct disease entity neuropathologically and the fulminant form of NHALE exists.

Background: Neuro-Sweet disease is a rare condition of central nervous involvement accompanied by cutaneous Sweet lesions. Neuropathological changes in neuro-Sweet disease are unknown. Objective: To describe post-mortem findings of the first case of neuro-Sweet disease. Results: A 44-year-old Japanese man developed recurrent episodes of cerebral and brainstem encephalitis with cutaneous Sweet lesions from the age of 34 years. His HLA typing was B54 and Cw1, and the symptoms and MRI abnormalities markedly subsided following corticosteroid therapy. Histologically, there were multiple lesions of perivascular cuffing of small venules by macrophages without vasculitis in the thalamus, temporal lobe, basal ganglia, pons, leptomeninges or ventricular ependym. Conclusions: The core neuropathological findings were: perivascular cuffing around particularly small veins; absence of granulomatous or necrotic angitis; mainly macrophage infiltration; and the thalamus being most affected. In the present case, the diagnosis of neuro-Sweet disease was made by skin biopsy 5 years after the onset of the central neuron system symptoms. We should pay more attention to skin lesions in steroid responsive recurrent encephalitis in patients who are HLA-B54 or Cw1 positive.

Growing evidence documents oxidative stress involvement in ALS. We previously demonstrated accumulation of a protein-bound form of the highly toxic lipid peroxidation product crotonaldehyde (CRA) in the spinal cord of sporadic ALS patients. In the present study, to the determine the role for CRA in the disease processes of superoxide dismutase-1 (SOD1) mutation-associated familial ALS (FALS), we performed immunohistochemical and semi-quantitative cell count analyses of protein-bound CRA (P-CRA) in the spinal cord of SOD1-mutated FALS and its transgenic mouse model. Immunohistochemical analysis revealed increased P-CRA immunoreactivity in the spinal cord of the FALS patients and the transgenic mice compared to their respective controls. In the FALS patients, P-CRA immunoreactivity was localized in almost all of the chromatolytic motor neurons, neurofilamentous conglomerates, spheroids, cordlike swollen axons, reactive astrocytes and microglia, and the surrounding neuropil in the affected areas represented by the anterior horns. In the transgenic mice, P-CRA immunoreactivity was localized in only a few ventral horn glia in the presymptomatic stage, in almost all of the vacuolated motor neurons and cordlike swollen axons and some of the ventral horn reactive astrocytes and microglia in the onset stage, and in many of the ventral horn reactive astrocytes and microglia in the advanced stage. Cell count analysis on mouse spinal cord sections disclosed a statistically significant increase in the density of P-CRA-immunoreactive glia in the ventral horns of the young to old G93A mice compared to the age-matched control mice. The present results indicate that enhanced CRA formation occurs in motor neurons and reactive glia in the spinal cord of SOD1-mutated FALS and its transgenic mouse model as well as sporadic ALS, sug- gesting implications for CRA in the pathomechanism common to these forms of ALS.

The diagnostic criteria for amyotrophic lateral sclerosis/parkinsonism-dementia complex in the Kii peninsula of Japan (Kii ALS/PDC) have been proposed. Muro disease has been considered an endemic neurodegenerative disease in the southern part of the Kii peninsula. Recent intensive and comprehensive research has revealed it to be a complex and genetically heterogeneous disease. At present, there are four subtypes of Muro disease: sporadic amyotrophic lateral sclerosis (ALS), Kii ALS/PDC with tauopathy, ALS with C9orf72 gene mutation, and ALS with optineurin gene mutation. The present criteria are applicable to only one of these subtypes, Kii ALS/PDC with tauopathy, which is quite similar to ALS/PDC in Guam.

Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower limbs. HSP is caused by failure of development or selective degeneration of the corticospinal tracts, which contain the longest axons in humans. The most common form of HSP is caused by mutations of the spastin gene (SPAST), located on chromosome 2p21-p22, which encodes spastin, one of the ATPases associated with diverse cellular activities (AAA). In this study, we detected four causative mutations of SPAST among 14 unrelated patients with spastic paraplegia. Two missense mutations (1447A-->G, 1207C-->G) and two deletion mutations (1465delT, 1475-1476delAA) were located in the AAA cassette region. Three of these four mutations were novel. Previous reports and our results suggest that the frequency of SPAST mutations is higher among Japanese patients with autosomal dominant HSP, although SPAST mutations are also observed in patients with sporadic spastic paraplegia.

An update of the endemic parkinsonism-dementia complex (PDC) frequently associated with amyotrophic lateral sclerosis (ALS) in the high prevalence ALS focus of the Kii peninsula of Japan is presented. The initial symptom was parkinsonian gait or hypobulia/amnesia, which was followed by akinesia, rigidity, occasional tremor, bradyphrenia, abulia and amnesia, and finally by akinetic mutism. In several years, most of the patients developed ALS symptoms such as muscle atrophy, bulbar palsy, and upper motor neuron signs. Magnetic resonance imaging and computed tomography of the brain showed marked atrophy of the temporal and frontal lobes and the cerebral blood flow reduction on single-photon emission computed tomography. Marked loss of nerve cells associated with abundant neurofibrillar tangles (NFTs) in the entire central nervous system, most predominantly in the brainstem and temporal lobe was characteristic. Concomitant ALS pathology involving the upper and lower motor neurons was common, and senile plaques were absent in most cases. NFTs consisted of twisted tubules on electron microscopy. Western blot of tau protein showed three bands consisting of six tau isoforms, similar to those of Alzheimer's disease. A family history of ALS/PDC was recorded in more than 70% of patients, but no abnormal mutation or polymorphism was found in the genes of SOD1, tau, and apolipoprotein E. Familial nature and continuing morbidity of Kii ALS/PDC suggest that genetic factors may be more likely in its pathogenesis.

Objective : To evaluate the recovery function of the sensory cortex in patients with Kii amyotrophic lateral sclerosis/parkinsonism–dementia complex (Kii ALS/PDC) using somatosensory evoked potentials (SEPs) elicited by paired stimuli of the median nerve at the wrist. Methods : Five patients with Kii ALS/PDC were compared with 5 patients with classical ALS, 5 with Parkinson's disease (PD), and 7 healthy normal volunteers. SEPs were recorded from the hand sensory area contralateral to the side of stimulation. Recovery functions of N20-P25 and P25-N33 components were evaluated by comparing the second SEPs elicited by paired pulse stimuli at various interstimulus intervals (ISIs, 20–300ms) with the SEPs elicited by single stimuli. Results : Conventional SEPs to a single stimulus had a normal latency and size in all patients. The recovery function of the N20-P25 and P25-N33 components showed significantly less suppression at short ISIs without any facilitation at long ISIs in Kii ALS/PDC patients than in normal subjects, classical ALS or PD patients. Conclusions : In Kii ALS/PDC, the sensory cortex is disinhibited or hyperexcitable. These abnormalities may reflect cortical pathology in the sensory cortex and may be partly due to a secondary effect on the sensory cortex from the primary parkinsonian pathological changes.

The aim of this study was to evaluate the accumulation of transition metals in the scalp hair of amyotrophic lateral sclerosis (ALS) patients in the Koza/Kozagawa/Kushimoto (K) area (K-ALS) in the Kii Peninsula, Japan. Metal contents were measured in the unpermed, undyed hair samples of 88 K-residents, 20 controls, 7 K-ALS patients, and 10 sporadic ALS patients using neutron activation analysis at the Research Reactor Institute, Kyoto University. A human hair standard and elemental standards were used as comparative standards. The contents of Zn, Mn, and V were higher, while that of S was lower in K-ALS patients than in the controls. The content of Mn in K-ALS patients negatively correlated with clinical durations. The content of Al was significantly higher in K-residents than in the controls, with 15.9 % of K-residents having high Mn contents over the 75th percentile of the controls. The contents of Zn, Mn, and V were high in the scalp hair of K-ALS patients and correlated with the content of Al. The accumulation of these transition metals may chronically increase metal-induced oxidative stress, which may, in turn, trigger the neuronal degeneration associated with K-ALS.

Objective Only one previous follow-up study of amyotrophic lateral sclerosis (ALS) and parkinsonism in Papua, Indonesia has been carried out since a survey undertaken in 1962–1981 by Gajdusek and colleagues. Therefore, to clarify the clinical epidemiology of ALS and parkinsonism in the southern coastal region of Papua, the clinical characteristics and prevalence of the diseases in this region were examined and assessed. Methods Cases of ALS and parkinsonism were clinically examined during a 2001–2012 survey in Bade and other villages along the Ia, Edera, Dumut and Obaa rivers in Papua, Indonesia. Possible, probable and definite ALS was diagnosed clinically by certified neurologists based on El Escorial criteria. The criteria for a diagnosis of parkinsonism were the presence of at least two of the four following signs: tremor, rigidity, bradykinesia and postural impairment with a progressive course. Results During the survey, 46 cases of ALS and/or parkinsonism were diagnosed within a population range of 7000 (2001–2002) to 13 900 (2007–2012). The 46 cases consisted of 17 probable-definite cases of ALS, including three with cognitive impairment (CI), 13 cases of overlapping possible, probable or definite ALS and parkinsonism, including five with CI, and 16 cases of parkinsonism, including one with CI. The crude point prevalence rate of pure ALS was estimated to be at least 73 (95% CI 0 to 156) to 133 (27 to 240)/100 000 people and that of overlapping ALS and parkinsonism at least 53 (0 to 126) to 98 (2 to 193)/100 000 in 2007, or 2010 in some regions. Conclusions While the prevalence of ALS in Papua has decreased over the past ∼30–35 years, it remains higher than the global average. There was a high prevalence of overlapping ALS, parkinsonism and CI, which has also been previously reported in Guam and Kii.

BACKGROUND Juvenile muscular atrophy of the distal upper extremity (Hirayama disease) is a sporadic disorder, but very rarely occurs in a familial pattern. OBJECTIVE To describe the clinical features of Hirayama disease in 2 brothers, especially the look-alike anatomic physiques and magnetic resonance imaging (MRI) findings. DESIGN Case report. PATIENTS Two physically look-alike young brothers with Hirayama disease. RESULTS Clinical symptoms of the present brothers were consistent with those of sporadic cases. Their lanky physique, clinical features, and MRI findings looked alike to each other. CONCLUSIONS The pathogenesis of familial Hirayama disease is not well understood. The present brothers looked alike in terms of their physical frame and clinical symptoms. These findings suggest that similar mechanical damage against the cervical spinal cord by look-alike anatomic frame of the neck could be an important factor of familial Hirayama disease in the present brothers.

Pathogenic mutations in the EIF4G1 gene were recently reported as a cause of autosomal dominant parkinsonism. To assess the frequency of EIF4G1 mutations in the Japanese population we sequenced the entire gene coding region (31 exons) in 95 patients with an apparent autosomal dominant inherited form of Parkinson's disease. We detected three novel point mutations located in a poly-glutamic acid repeat within exon 10. These variants were screened through 224 Parkinson's disease cases and 374 normal controls from the Japanese population. We detected the poly-glutamic acid deletion in exon 10 in two additional patients with sporadic Parkinson's disease. Although the EIF4G1 variants identified in the present study were not observed in control subjects, co-segregation analyses and population-based screening data suggest they are not pathogenic. In conclusion, we did not identify novel or previously reported pathogenic mutations (including the p.A502V and p.R1205H mutants) within EIF4G1 in the Japanese population, thus future studies are warranted to elucidate the role of this gene in Parkinson's disease.