APOE Alleles With Tau and Aß Pathology in Patients With Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex in the Kii Peninsula.

BACKGROUND AND OBJECTIVES: To examine the association of the APOE ε4 and ε2 alleles with the pathologic 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 variants in 18 autopsy patients with ALS/PDC, consisting of 9, 8, and 1 patient with PDC, ALS, and PDC followed by ALS, respectively. Moreover, we revealed the relationship between APOE variants and Aß and tau pathologies. 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 Aß pathology (p = 0.005 by the χ 2 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). The APOE ε2 allele was associated with increased tau pathology (p = 0.009) and not with reduced Aß 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 Aß pathology in patients with Kii ALS/PDC.

An immigrant family with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex.

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.

"Endemic paraplegia of Koza in Kii" in Honcho Koji Innen Shu published in 1689 is probably the earliest description of amyotrophic lateral sclerosis of Kii Peninsula: Presentation of the original and investigation of factuality.

High prevalence of amyotrophic lateral sclerosis (ALS) in Kii Province (Kii) located in southern Kii Peninsula was first pointed out by Kinnosuke Miura in 1911, and epidemiological studies by Kiyoshi Kimura et al. verified extremely high incidence after World War II. In 1970s, Yoshiro Yase pointed out that "endemic paraplegia of Koza in Kii" in Honcho Koji Innen Shu published in 1689 would mean the same disorder as that of ALS and be the earliest description of Kii ALS although he gave no clear grounds. In this study, the original of the article was presented with an English translation, and factuality of it was investigated from the viewpoints of geography, geology, culture and history of Kii. As a result, it was shown that the article was probably written based on historical events and that the "endemic paraplegia" meant the same disorder as Kii ALS. The author has concluded that "endemic paraplegia of Koza in Kii" is likely to be the earliest description of Kii ALS since ALS is included in the causes of paraplegias of these kinds.

[Recurrent myelitis in a case of IgG4-related respiratory disease].

We report an 80-year-old man with IgG4-related pleuritis who had been treated with a low dose oral steroid for two years and developed recurrent myelitis. He was admitted to our hospital with gradually worsening numbness in the lower body and difficulty in walking due to mild weakness and loss of proprioception in the legs. T2-weighted MR images of the spinal cord showed a high signal intensity lesion, located centrally in the spinal cord at the Th2-4 spine levels. Laboratory data revealed an elevated serum IgG4 level and cerebrospinal fluid protein level. Anti-aquaporin 4 antibody, anti-myelin oligodendrocyte glycoprotein antibody and other autoantibodies were negative. He showed a good response to the administration of steroid pulse therapy with almost resolution of the neurological symptoms and MRI findings. He was followed with the maintenance therapy with a low dose oral steroid. After one year, he developed recurrence of myelitis in the lower end of the medulla oblongata and in the central to dorsal area at the C2 spine level. Each lesion of recurrent myelitis was located within 3 vertebral segments length and improved without focal spinal atrophy. Recently, IgG4-related disease (IgG4-RD)-associated inflammation involving brain parenchyma and spinal cord were reported. Further investigations are needed to elucidate the relationship between IgG4-RD and seronegative recurrent myelitis.

Expression of Mutant Ubiquitin and Proteostasis Impairment in Kii Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex Brains.

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.

Brain Transcriptome Analysis Links Deficiencies of Stress-Responsive Proteins to the Pathomechanism of 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'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.

[Lessons from the 116 years (1902-2018) of history of the Japanese Society of Neurology in establishing its identity].

The Japanese Society of Neurology and Psychiatry was founded in 1902 as a joint society of Neurology and Psychiatry, but was renamed the Japanese Society of Psychiatry and Neurology in 1935 because of the stagnation of activities of Neurology and the rise of those of Psychiatry. After World War II, activities of Neurology were restored and the Japanese Society of Neurology (JSN) independent from the Societies of Internal Medicine and Psychiatry was established in 1960 after overcoming many difficulties. In 1975, neurology was approved by law as one of the specialized fields of medicine. After that, neurology and JSN developed dramatically, both in research and medical practices. As of 2018, JSN had 9,000 members and more than 5,500 board-certified neurology specialists. JSN successfully hosted the World Congress of Neurology twice in 1981 and 2017. In 2002, JSN accepted the offer to join the Japanese Board of Medical Specialties as one of the subspecialties of Internal Medicine. In 2018 JSN enacted a new policy to upgrade the neurology specialist from a subspecialty of Internal Medicine to an independent major medical field. Lessons of the 116 years of history of the Society would teach us a sensible way to achieve the goals.

Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study.

OBJECTIVE: To evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS). METHODS: 373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration ≤36 months) were randomly assigned to placebo, 25 mg or 50 mg of methylcobalamin groups. The primary endpoints were the time interval to primary events (death or full ventilation support) and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to week 182. Efficacy was also evaluated using post-hoc analyses in patients diagnosed early (entered ≤12 months after symptom onset). RESULTS: No significant differences were detected in either primary endpoint (minimal p value=0.087). However, post-hoc analyses of methylcobalamin-treated patients diagnosed and entered early (≤12 months' duration) showed longer time intervals to the primary event (p<0.025) and less decreases in the ALSFRS-R score (p<0.025) than the placebo group. The incidence of treatment-related adverse events was similar and low in all groups. CONCLUSION: Although ultra-high-dose methylcobalamin did not show significant efficacy in the whole cohort, this treatment may prolong survival and retard symptomatic progression without major side effects if started early. TRIAL REGISTRATION NUMBER: NCT00444613.

Amyotrophic lateral sclerosis and parkinsonism-dementia complex of the Hohara focus of the Kii Peninsula: A multiple proteinopathy?

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.

A migration case of Kii amyotrophic lateral sclerosis/parkinsonism dementia complex with the shortest stay in the endemic area and the longest incubation to develop the disease.

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 73years 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-ω-fluoropropyl-2ß-carbomethoxy3ß-(4-iodophenyl) 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.

Nitrative Stress and Tau Accumulation in Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC) in the Kii Peninsula, Japan.

Objective: The Kii Peninsula of Japan is known to be a high incidence area of amyotrophic lateral sclerosis/parkinsonism-dementia complex (Kii ALS/PDC) with tauopathy. Nitrative stress and oxidative stress on ALS/PDC and their relationship to tau pathology were clarified. Methods: Seven patients with Kii ALS/PDC (3 males and 4 females, average age 70.7 years, 3 with ALS, 2 with ALS with dementia, and 2 with PDC) were analyzed in this study. Five patients with Alzheimer's disease and five normal aged subjects were used as controls. Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded temporal lobe sections (the hippocampal area including hippocampus, prosubiculum, subiculum, presubiculum, and parahippocampal gyri) using antibodies to detect phosphorylated tau (anti-AT-8), nitrated guanine (anti-8-NG), anti-iNOS, anti-NFκB, and oxidized guanine (anti-8-OHdG) antibodies. Results: Most hippocampal neurons of Kii ALS/PDC patients were stained with anti-8-NG, anti-iNOS, anti-NFκB, and anti-8-OHdG antibodies and some AT-8 positive neurons were co-stained with anti-8-NG antibody. The numbers of 8-NG positive neurons and 8-OHdG positive neurons were greater than AT-8 positive neurons and the number of 8-NG positive neurons was larger in patients with Kii ALS/PDC than in controls. Conclusion: Nitrative and oxidative stress may take priority over tau accumulation and lead to the neurodegeneration in Kii ALS/PDC.

CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study.

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.

Neutron activation analysis of scalp hair from ALS patients and residents in the Kii Peninsula, Japan.

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.

[Robert Wartenberg: the neurologist, the teacher, and the man].

Wartenberg was born in 1887 in Grodno, old Lithuania (present-day Belarus). He received his medical degree from the University of Rostock in 1919, and worked at the University of Freiburg until 1935, when he immigrated to the United States to escape Nazi Germany. He then worked at the University of California, San Francisco, and was appointed Clinical Professor of Neurology in 1952. He died of a heart illness in 1956. Wartenberg wrote more than 150 papers on clinical neurology in German and English, especially on reflexes and signs. His books, "Examination of Reflex" and "Diagnostic Tests in Neurology" were translated into many languages, including Japanese. His contribution to the study of reflexes includes Wartenberg's reflex of the thumb, head dropping test in Parkinson's disease, necessity of differentiating abdominal muscle and abdominal skin muscle reflexes, and many others. He had knowledge, skill, art and ability enough to translate difficult problems into tangible methods of diagnosis and treatment. He tried to diagnose and treat patients quickly, with minimum laboratory tests, and avoided invasive tests and expense of time and money. His efforts to provide patients with the best treatment in terms of time, safety, and cost, is the essence of medicine and is still worth practicing in modern neurology using advanced technology.

Neuropsychological study of amyotrophic lateral sclerosis and parkinsonism-dementia complex in Kii peninsula, Japan.

BACKGROUND: The Kii peninsula of Japan is one of the foci of amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) in the world. The purpose of this study is to clarify the neuropsychological features of the patients with ALS/PDC of the Kii peninsula (Kii ALS/PDC). METHODS: The medical interview was done on 13 patients with Kii ALS/PDC, 12 patients with Alzheimer's disease, 10 patients with progressive supranuclear palsy, 10 patients with frontotemporal lobar degeneration and 10 patients with dementia with Lewy bodies. These patients and their carer/spouse were asked to report any history of abulia-apathy, hallucination, personality change and other variety of symptoms. Patients also underwent brain magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and neuropsychological tests comprising the Mini Mental State Examination, Raven's Colored Progressive Matrices, verbal fluency, and Paired-Associate Word Learning Test and some of them were assessed with the Frontal Assessment Battery (FAB). RESULTS: All patients with Kii ALS/PDC had cognitive dysfunction including abulia-apathy, bradyphrenia, hallucination, decrease of extraversion, disorientation, and delayed reaction time. Brain MRI showed atrophy of the frontal and/or temporal lobes, and SPECT revealed a decrease in cerebral blood flow of the frontal and/or temporal lobes in all patients with Kii ALS/PDC. Disorientation, difficulty in word recall, delayed reaction time, and low FAB score were recognized in Kii ALS/PDC patients with cognitive dysfunction. CONCLUSIONS: The core neuropsychological features of the patients with Kii ALS/PDC were characterized by marked abulia-apathy, bradyphrenia, and hallucination.

EIF4G1 gene mutations are not a common cause of Parkinson's disease in the Japanese population.

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.

Amyotrophic lateral sclerosis and parkinsonism in Papua, Indonesia: 2001-2012 survey results.

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.