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Background: Glucose dysmetabolism is an important risk factor for dementia. Objective: We investigated the associations of diabetes mellitus, the levels of glycemic measures, and insulin resistance and secretion measures with dementia and its subtypes in a cross-sectional study. Methods: In this study, 10,214 community-dwelling participants were enrolled. Hemoglobin A1c (HbA1c), the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR), the HOMA of percent β-cell function (HOMA-β), and the glycated albumin (GA) was evaluated. The associations of each measure with Alzheimer’s disease (AD) and vascular dementia (VaD) were investigated. Results: The multivariable-adjusted odds ratios (ORs) of AD were significantly higher in participants with diabetes mellitus than in those without diabetes (1.46 [95% CI: 1.08–1.97]). Higher HbA1c levels were significantly associated with AD at diabetes (≥6.5%) and even at prediabetes (5.7 %–6.4 %) levels; multivariable-adjusted ORs for AD in participants at the diabetes level were 1.72 (95% CI: 1.19–2.49), and those in participants at the prediabetes level were 1.30 (95% CI: 1.00–1.68), compared with those in normal participants. Moreover, higher GA levels were associated with AD. No associations were observed between the diabetic status or the levels of glycemic measures and VaD. In addition, no significant relationships were observed between insulin resistance and secretion measurements and AD and VaD. Conclusion: Our findings indicate that diabetes mellitus and hyperglycemia are significantly associated with AD, even in individuals at the prediabetes level.

Background: Despite the significant palliative care needs for people living with amyotrophic lateral sclerosis (ALS), palliative medicine in Japan is mainly focused on oncologic disease. Objective: To compare the care provided to patients with ALS with and without intervention from the palliative care team (PCT and non-PCT groups, respectively). Design: This is a retrospective case–control study. Setting: One ALS center in Japan. Participants: Sixty patients with clinically definite ALS treated until death from January 2012 to December 2019. Measurements: We compared the two groups based on the presence of advance directives, patient age, use of noninvasive and invasive ventilation, maximum opioid dosage, and use of nonopioid palliative medications such as antidepressants and anxiolytics. We also compared the prescribing practices of the attending physicians. Results: There was no difference in the rate of advance directive completion between the PCT and non-PCT groups. Although all but one patient in the PCT group used opioids, only half of the patients in the non-PCT group used opioids (p

Background Rare neuromuscular diseases such as spinal muscular atrophy, spinal bulbar muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, distal myopathy, sporadic inclusion body myositis, congenital myopathy, and amyotrophic lateral sclerosis lead to incurable amyotrophy and consequent loss of ambulation. Thus far, no therapeutic approaches have been successful in recovering the ambulatory ability. Thus, the aim of this trial was to evaluate the efficacy and safety of cybernic treatment with a wearable cyborg Hybrid Assistive Limb (HAL, Lower Limb Type) in improving the ambulatory function in those patients. Results We conducted an open-label, randomised, controlled crossover trial to test HAL at nine hospitals between March 6, 2013 and August 8, 2014. Eligible patients were older than 18 years and had a diagnosis of neuromuscular disease as specified above. They were unable to walk for 10 m independently and had neither respiratory failure nor rapid deterioration in gait. The primary endpoint was the distance passed during a two-minute walk test (2MWT). The secondary endpoints were walking speed, cadence, and step length during the 10-m walk test (10MWT), muscle strength by manual muscle testing (MMT), and a series of functional measures. Adverse events and failures/problems/errors with HAL were also evaluated. Thirty patients were randomly assigned to groups A or B, with each group of 15 receiving both treatments in a crossover design. The efficacy of a 40-min walking program performed nine times was compared between HAL plus a hoist and a hoist only. The final analysis included 13 and 11 patients in groups A and B, respectively. Cybernic treatment with HAL resulted in a 10.066% significantly improved distance in 2MWT (95% confidence interval, 0.667–19.464; p = 0.0369) compared with the hoist only treatment. Among the secondary endpoints, the total scores of MMT and cadence at 10MWT were the only ones that showed significant improvement. The only adverse effects were slight to mild myalgia, back pain, and contact skin troubles, which were easily remedied. Conclusions HAL is a new treatment device for walking exercise, proven to be more effective than the conventional method in patients with incurable neuromuscular diseases. Trial registration: JMACTR, JMA-IIA00156

Medication non-adherence in the elderly population is a major problem, preventing them from obtaining optimal therapeutic effects. Identifying the factors affecting medication adherence is crucial for improving and maintaining health among the elderly population and enhance healthcare economy. The purpose of this study was to examine the prevalence of self-reported medication adherence, and identify the associated factors and the influence of health-related quality of life (HRQOL) in the Japanese community-dwelling elderly population. This cross-sectional study was part of the Nakajima study and targeted inhabitants aged ≥60 years who underwent health examinations in 2017. Data regarding medication adherence were acquired through interviews and self-administered questionnaires. Medication adherence were assessed using a visual analog scale, and HRQOL was assessed by EuroQol five-dimensional questionnaire with 3 levels. Among the 455 participants, low and high medication adherence were seen in 9.7% and 66.2% of the participants, respectively (visual analog scores

Close contact is unavoidable in the care of patients with neuromuscular diseases (NMD). In addition, respiratory physiotherapy and noninvasive ventilation generate massive amounts of aerosols. Caring for a patient suffering from coronavirus disease‐19 raises concerns about the risk of infection not only to the caregiver and/or medical staff but also to other individuals in contact with these personnel. We reviewed the points to be noted in infection control when a patient with neuromuscular diseases receiving respiratory care is infected with COVID‐19 and summarizes the recommendation. Infected patients must be isolated in a negative‐pressure or actively ventilated room. Clear zoning separating clean and infected areas should be performed for pathogen containment. Caregivers should wear appropriate personal protective equipment and thoroughly clean their hands. Leak‐prevention measures and the use of proper respiratory circuits and filters with virus‐removal performance are crucial to reducing aerosols in noninvasive ventilation. Although respiratory physiotherapy is essential, treatment should be minimized in consideration of the infection state and sputum status, and alternative therapies such as postural drainage should be carefully considered. Infection control is distinctly obligate; however, it impairs the quality of life and activity of daily living significantly. We should implement it with enough ethical consideration, adequate explanation, and patient consent. We hope that this paper will contribute to appropriate COVID‐19 infection control in patients with neuromuscular diseases requiring respiratory care.

Objective To determine the clinicopathological features of levodopa or dopamine agonist (DA) responders with multiple system atrophy (MSA), an autopsy-confirmed diagnosis is vital due to concomitant cases of MSA and Parkinson's disease (PD). We therefore aimed to investigate the effectiveness of levodopa and DA in autopsy cases of MSA without PD and thereby clarify the clinical course, magnetic resonance imaging (MRI) findings, and pathological features of levodopa-responsive MSA cases. Methods The medical records (clinical data, MRI findings, and pathological findings) of 12 patients with MSA were obtained, and the patients were pathologically confirmed to not have PD. The clinical diagnoses of the patients were MSA with predominant parkinsonism (MSA-P) (n=7), MSA with predominant cerebellar ataxia (MSA-C) (n=4), and progressive supranuclear palsy (PSP) with a concomitant pathology of MSA (n=1). Results Nine patients received a maximum dose of 300-900 mg of levodopa as treatment, which was effective in two MSA-P patients and mildly effective in another two MSA-P patients. DA was mildly effective in one MSA-C patient. The levodopa responders showed marked autonomic dysfunction relatively late and became bedridden after 10 years. Additionally, they exhibited bilateral hyperintense putaminal rims in MRIs after six and nine years, respectively, after disease onset. One levodopa responder and one DA mild responder showed relatively mild neurodegeneration of the putamen. Conclusion Levodopa responders, despite having MSA-P, may show a relatively slow progression in putaminal neurodegeneration, and might maintain prolonged daily life activities in cases without an early occurrence of autonomic dysfunction.

We describe an autopsy-proven case of Parkinson's disease with dementia showing early-onset delusions and hallucinations with limbic-type Lewy body pathology. A Japanese man 72 years old at time of death, developed hand tremor at the age of 45. On neurological examination at 47 years of age, parkinsonian symptoms and signs were present. Pergolide mesylate 1000 μg/day improved his motor symptoms. Then, delusional jealousy appeared and he consulted the psychiatric department in our hospital at the age of 50. Pergolide mesylate 2000 μg/day and trihexyphenidyl hydrochloride 6 mg/day were prescribed. His delusional jealousy made him hit his wife at the age of 63, and visual hallucinations were demonstrated. Brain magnetic resonance imaging (MRI) at the age of 65 revealed mild frontal lobe atrophy. At the age of 72, apparent dementia and dysphagia appeared. The total clinical course was 27 years. The brain showed mild frontal atrophy and weighed 1295 g before fixation. Depigmentation of the substantia nigra and locus ceruleus was macroscopically apparent. Neuronal loss with gliosis was noteworthy in the substantia nigra, locus ceruleus, dorsal vagal nucleus, nucleus basalis of Meynert (NBM), and intermediate lateral nuclei; however, cerebral neocortex and limbic systems were relatively preserved. Widespread occurrence of Lewy bodies with a few Lewy neurites were demonstrated (limbic-type). Noticeable Lewy body pathology in the NBM was shown in contrast to that in other limbic system structures, such as the amygdala and parahippocampal gyrus, and cerebral cortex. In vivo structural imaging studies revealed that cholinergic projections from the NBM could be responsible for generation of cholinergic deficiency syndrome, including delusions and hallucinations. Furthermore, basal forebrain volume is reduced in patients with Parkinson's disease showing visual hallucinations. Prominent Lewy body pathology in the NBM could be related to not only visual hallucinations but also delusions.

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

We report autopsy results of a female patient who was confirmed pathologically as having corticobasal degeneration (CBD). This patient presented with progressive gait disturbance at the age of 66 years, and subsequently showed parkinsonism with a right-sided predominance and dementia. She was clinically diagnosed as having possible corticobasal syndrome without palatal myoclonus throughout the disease course. An autopsy at 72 years of age revealed that neuronal loss with gliosis was severe in the substantia nigra and the portion from hippocampal cornu ammonis (CA1) region to the parahippocampal gyrus, and mild-to-moderate in the basal ganglia, thalamus, red nucleus, dentate nucleus, and cerebral cortices, predominantly in the frontal lobe. Myelin pallor was observed in the pyramidal tract of the brainstem and central tegmental tract. Neurodegenerative or axonal degenerative findings were observed predominantly on the left side, except for the dentate nucleus, which was more affected on the right side. The inferior olivary nucleus exhibited hypertrophic degeneration predominantly on the left side. The topography of neurodegeneration was likely to correspond to the dentate nucleus and inferior olivary nucleus. Phosphorylated tau-immunoreactive pretangles, neurofibrillary tangles, coiled bodies, and threads were diffusely observed in the whole brain. The distribution of tau deposits was prominent in the deeper affected lesions of the dentate nucleus and inferior olivary nucleus. Inferior olivary hypertrophy is unusual in patients with CBD. It is highly possible that the neurodegeneration of the inferior olivary nucleus followed that of the dentate nucleus in our patient. Moreover, these results indicate not only the severity of neurodegenerative changes, but also that of tau deposition that could be related to the topography of the projections of the dentato-olivary pathway. Tau propagation and subsequent neurodegeneration along the fiber connections may have occurred. Our results support the possibility that progression of CBD lesions can be mediated by tau propagation.

This study aimed to develop a new computerized assessment battery for cognition (C-ABC) to detect mild cognitive impairment (MCI) and dementia. We performed C-ABC in subjects with dementia (n = 422), MCI (n = 145), and normal cognition (NC; n = 574), and analyzed by age stratum (50s, 60s, and 70–85 years). To distinguish MCI from NC, the C-ABC total combined score, which were calculated by dividing the C-ABC total score by the C-ABC required time, revealed the best area under the curves (AUC) at 0.838 and 0.735 in the 50s and 60s age groups, respectively; notably, this entire procedure took approximately 5 min. To distinguish dementia from NC and MCI, the partial items of C-ABC (items 3 + 6 combined score) revealed the best AUCs at 0.910, 0.874, and 0.882 in the 50s, 60s, and 70–85 age groups, respectively. Furthermore, the items 3 + 6 combined score established the best AUC at 0.794 in the 70–85 age group to distinguish MCI from NC; this entire procedure took around 2 min. Hence, this study suggests that C-ABC could be a useful tool for detecting dementia or MCI in a short time.

Background Antioxidants like vitamins C and E may minimize the risk for Alzheimer's disease. Objective We examined whether vitamins C and E modify the apolipoprotein E (APOE) E4-related risks for developing cognitive decline. Methods We conducted a population-based prospective study including Japanese residents aged 65 years from Nakajima, Japan. The participants received an evaluation of cognitive function and underwent blood tests including tests for vitamins C and E levels and APOE phenotypes. The APOE E4-by-gender-by-vitamin C or E interactions on developing cognitive decline were analyzed. Results Of 606 participants with normal cognitive function determined using a baseline survey (2007-2008), 349 completed the follow up survey between 2014 and 2016. In women with APOE E4, significantly reduced risk for cognitive decline was observed for the highest blood vitamin C concentration tertile [multivariate OR 0.10 (95% CI 0.01-0.93)] compared with the lowest tertile. In men without APOE E4, significantly reduced risk for cognitive decline was observed for the highest blood vitamin E concentration tertile [multivariate OR 0.19 (0.05-0.74)] as compared with the lowest tertile. Conclusion Our results demonstrate significant beneficial effects of vitamins C and E in reducing the risk of cognitive decline in women with APOE E4 and men without APOE E4, respectively.

The present report discusses the case of a woman with neuromyelitis optica (NMO) who exhibited bilateral optic neuritis, longitudinally extensive myelitis, serum anti-aquaporin-4 antibodies, and a unique pattern of white matter involvement. The disease duration was 26 years, and the patient died at the age of 65 years. Sequential magnetic resonance images obtained during the last 6 years of life revealed leukoencephalopathy-like lesions extending symmetrically and contiguously from the periventricular regions, which had begun to transform into multiple cavities with semi-annular partitions. This unique pattern of white matter abnormalities should thus be considered among those associated with NMO.

We describe the post mortem case of a 71-year-old Japanese woman diagnosed as having multiple system atrophy (MSA), showing somatic sprouting formation of Purkinje cells. The patient had suffered from frequent falling episodes and clumsiness of the left hand since the age of 67 years. Orthostatic hypotension and parkinsonism subsequently emerged. Typical neuropathological features of MSA, including degeneration of the striatum, pontine base and cerebellum with abundance of phosphorylated α-synuclein-positive neuronal and glial cytoplasmic and nuclear inclusions in the brain, were observed. In addition to gliosis of the cerebellar white matter and notable loss of Purkinje cells, several Purkinje cells showed somatic sprouting. Somatic sprouting of Purkinje cells has been demonstrated in several specific conditions, such as developing brains and several neurodegenerative disorders, including Menkes kinky hair disease, familial spinocerebellar ataxia, acute encephalopathy linked to familial hemiplegic migraine, and Huntington's disease; however, no MSA cases have been reported with sprouting from the soma of Purkinje cells. Axonal damage caused by oligodendroglial dysfunction could be crucial in the development of Purkinje cell loss in MSA. Moreover, no apparent α-synuclein accumulation has been described in the Purkinje cells of MSA. We propose that MSA is another degenerative disorder associated with somatic sprouts of Purkinje cells.

Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain (SLC2A1, SLC2A3, and SLC23A2) on APOE4-associated risk of developing cognitive decline. This case–control study involved 393 Japanese subjects: 252 cognitively normal and 141 cognitively impaired individuals (87 mild cognitive impairment and 54 dementia). Database searches revealed that rs1279683 of SLC23A2, and rs710218 and rs841851 of SLC2A1 are functional variants that are significantly associated with the altered expression of the respective genes and genotyped as three single nucleotide variants (SNVs). When stratified by SNV genotype, we found a significant association between APOE4 and cognitive decline in minor allele carriers of rs1279683 (odds ratio [OR] 2.02, 95% CI, 1.05–3.87, p = 0.035) but not in the homozygote carriers of the major allele. Significant associations between APOE4 and cognitive decline were also observed in participants with major allele homozygotes of rs710218 (OR 2.35, 95% CI, 1.05–5.23, p = 0.037) and rs841851 (OR 3.2, 95% CI, 1.58–6.46, p = 0.0012), but not in minor allele carriers of the respective SNVs. In contrast, the three functional SNVs showed no significant effect on cognitive decline. Our results imply that functional SNVs of VC transporter genes can affect APOE4-associated risk of developing cognitive decline via altered VC levels in the brain.

Lambert-Eaton myasthenic syndrome (LEMS) is characterized by muscle weakness, amyotrophy, easy fatigability, and depressed tendon reflexes. 3,4-Diaminopyridine (3,4-DAP) is the recommended therapy for the treatment of LEMS. However, estimations of 3,4-DAP pharmacokinetics in human and animals, such as rats, are rarely reported because 3,4-DAP is an orphan drug for the treatment of a very rare disease (LEMS). In particular, little is known about its tissue distribution. Therefore, the pharmacokinetics of 3,4-DAP were studied, with particular focus on tissue distribution, in rats. After intravenous administration of 3,4-DAP to rats, the half-life of 3,4-DAP was 15.9 ± 3.9 min and the volume of distribution at steady-state was 2.8 ± 0.7 L/kg. The tissue-to-plasma partition coefficient (Kp) was high in the kidney, heart, and muscle. In addition, with increased steady state plasma concentration (Css), a tendency toward increased Kp was found in most tissues. In the muscle, a likely target region of 3,4-DAP in LEMS patients, the Kp was higher than in the plasma. Furthermore, more than 68% of 3,4-DAP was distributed to the muscle as determined by the ratio of 3,4-DAP distribution calculated from the apparent volumes of distribution. Hence, 3,4-DAP may provide for more effective and long-lasting effects.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months. Objective: This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset. Methods: The Japanese early-stage trial of high-dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase III study conducted at 24 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 128 ALS patients within one year of onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 16 weeks. If patients wish to receive E0302 50 mg after the double-blind administration period, E0302 will be provided to them until March 2020 during the continuous administration period. Results: This study began in October 2017 and is being conducted at 24 participating institutions in Japan. The study is in progress and the patient enrollment period is scheduled to end in August 2019, with follow-up scheduled to end in March 2020. Conclusions: This study is being performed to revalidate the efficacy and safety of E0302 in patients with early-stage ALS in the first year of symptom onset. If positive results are obtained, the aim is to apply for E0302 approval as a new drug for the treatment of ALS. Trial Registration: ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb) International Registered Report Identifier (IRRID): PRR1-10.2196/12046

In many cohort studies of dementia, while differences in sociodemographic characters between responders and non-responders of dementia screening have been reported, differences in dementia beliefs have been relatively less known. The aims of this study were to clarify dementia beliefs and to explore potential impacts on an intention to attend a future dementia screening in public screeners and in-home screeners, respectively. We performed a cross-sectional population-based study using a question about an intention to attend a future dementia screening and a questionnaire on dementia beliefs. Subjects were all residents aged 65 years or older in the north area of Nakajima, Japan (n = 385). All subjects were asked to attend a public dementia screening first. An in-home dementia screening was subsequently conducted in subjects with non-responders to a public screening. The questionnaire consisted of four dementia beliefs: "perceived susceptibility," "perceived severity," "perceived barriers," and "perceived benefits." Public screeners significantly expressed an intention to attend a future dementia screening more than in-home screeners (p = 0.002). In in-home screeners, low "perceived severity" were significantly associated with an intention to attend a future dementia screening [adjusted OR (95% CI) = 0.51 (0.32-0.80)]. In both public and in-home screeners, high "perceived benefits" were significantly associated with an intention to attend a future dementia screening [adjusted OR (95% CI) = 2.13 (1.46-3.10); adjusted OR (95% CI) = 2.56 (1.22-5.35), respectively]. It is necessary to reduce "perceived severity" among in-home screeners to increase dementia screening participants.

Supplemental material, MSJ763086_supplementary_appendix for Contiguous and symmetrical disease expansion and massive necrosis of the cerebral white matter in a patient with neuromyelitis optica by Chiho Ishida, Tokuhei Ikeda, Kiyonobu Komai, Kazuya Takahashi, Moeko Noguchi-Shinohara and Masahito Yamada in Multiple Sclerosis Journal

Objective To evaluate the effectiveness of an electric toothbrush for oral care in patients with neuromuscular disability. Methods In this randomized observer-blind crossover trial, 30 patients with neuromuscular disease performed either electric or manual toothbrushing each for 4 weeks. Plaque status (plaque control record), periodontal pocket depth, oral status (oral assessment guide), salivary bacterial count, and toothbrushing time were assessed after each period and compared between the two groups by Wilcoxon signed-rank test. Results Twenty-eight patients completed the study, including 18 communicative patients. Periodontal pockets were significantly shallower and toothbrushing time was significantly shorter with electric toothbrush use than with manual toothbrush use. No significant differences in oral status and salivary bacterial counts were noted between the approaches, but plaque status significantly improved after electric toothbrushing in communicative patients. Conclusions Electric toothbrushing is beneficial for maintaining oral health in patients with neuromuscular disability and reducing the caregivers’ oral care burden.

Objective: To examine whether there are clinical features in Japanese patients with both neurodegenerative diseases and cancers. Methods: We analyzed the clinical characteristics of consecutive Japanese patients with neurodegenerative diseases during the past 5 years, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), dementia with Lewy bodies, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). Results: Out of 292 patients, 39 patients had cancers, including a past history, as follows: ALS, n = 16; PD, n = 8; PSP, n = 7; CBD, n = 1, and MSA, n = 7. About 10% of patients with neurodegenerative diseases developed cancer after onset of the disease; about 30% of patients with ALS, PD, or PSP occurring with cancers died of cancer. Gastric cancer was most common before the onset of ALS (62.5%) but did not develop after the onset of ALS. Conversely, PD patients frequently developed gastric cancers after the onset of neurological signs (60.0%) in spite of no cancer before the onset of PD. The proportion of breast cancer in MSA (45.5%) was significantly higher than in other neurodegenerative diseases. Conclusion: ALS, PD, or MSA patients with cancer showed clinical characteristics unique to each neurodegenerative disease in Japan compared to other countries.

Significant differences exist in demographic characteristics between responders and non-responders in population-based studies on mental health and cognitive status, but much less is known regarding differences in the prevalence of dementia and cognitive dysfunction between them. Here we compared the prevalence of dementia and mild cognitive impairment between early responders of a mass brain function examination and delayed responders (non-responders of the mass brain function examination) in a survey of elderly Japanese citizens (≥65 years) to evaluate non-responder bias. All residents in an area of Nakajima, Japan, were considered as potential candidates (n = 783). Participants of a mass brain function examination were considered as "early responders." The cognitive functions of delayed responders were assessed by home visits. To assess the correlation between sociodemographic characteristics and cognitive functions, the early and delayed responders completed the same questionnaires and neuropsychological tests. Delayed responders (n = 320) were significantly older and less educated than the early responders (n = 307). The delayed responders also exhibited a higher frequency of dementia and mild cognitive impairment than the early responders, even when the groups were restricted to the age group 65-89 years. Our results suggest that population-based studies likely underestimate the prevalence of dementia and mild cognitive impairment, especially if the participation rate is low.

We report the case of a woman who developed limb clumsiness in her fifties and gait disturbance in her sixties. She was bedridden after bone fractures at age 75 and showed disorientation, slow eye movement, gaze palsy, ataxic speech, muscle atrophy and weakness, and areflexia with pathological reflex. She died of respiratory failure at age 85. This patient was diagnosed genetically as having spinocerebellar ataxia type 2 (SCA2), and the number of expanded CAG repeats was 41. At autopsy, the brain weighed 965 g, and the brainstem, cerebellum, frontal convexity and spinal cord were atrophic. Neuronal loss and gliosis were severe in the pontine nucleus, inferior olivary nucleus, cerebellar cortex, gracile and cuneate nuclei and moderate in the substantia nigra, cerebellar dentate nucleus, anterior horns of the spinal cord and dorsal root ganglia. Axonal loss was observed in the middle and inferior cerebellar peduncles, pyramidal tract and posterior column of the spinal cord. Senile plaques and neurofibrillary tangles (NFTs) were diffusely found in the cerebrum (plaque stage C; NFT stage IV). Expanded polyglutamine-immunoreactive inclusions in the neuronal cytoplasm were widely distributed in the CNS, and neuronal intranuclear inclusions were observed in the pontine nucleus and cerebral cortex. This patient in this autopsy case is a late-onset and aged patient with SCA2, and this is the first report of SCA2 combined with Alzheimer's disease (AD) pathology. Neuropathological findings in this patient, except for AD pathology, were consistent with those of reported SCA2 cases. However, the olivo-ponto-cerebellar system of this patient was relatively preserved and the cerebellar dentate nucleus was more involved as compared with previously reported cases. These results suggest that age at onset or the number of CAG repeat expansions could correlate with the distribution pattern of SCA2 neurodegeneration.

Although several studies have demonstrated a potential correlation of dietary patterns with cognitive function, the relationship between tooth loss and dietary patterns and cognitive function have not been identified. In this cross-sectional study, we used a reduced rank regression (RRR) analysis, a technique used previously to observe dietary patterns based on the intakes of nutrients or levels of biomarkers associated with the condition of interest, to identify tooth loss-related dietary patterns and investigate the associations of such patterns with cognitive impairment in 334 community-dwelling Japanese subjects aged ≥ 60 years. According to Pearson correlation coefficients, the intakes of six nutrients (ash content, sodium, zinc, vitamin B1, α- and β-carotene) correlated significantly with the number of remaining teeth. Using RRR analysis, we extracted four dietary patterns in our subject population that explained 86.67% of the total variation in the intakes of these six nutrients. Particularly, dietary pattern 1 (DP1) accounted for 52.2% of the total variation. Food groups with factor loadings of ≥ 0.2 included pickled green leafy vegetables, lettuce/cabbage, green leaves vegetables, cabbage, carrots/squash; by contrast, rice had a factor loading of

金沢大学医学部附属病院神経内科, A family with familial amyloid polyneuropathy (FAP) due to a transthyretin (TTR) Leu58Arg mutation was investigated clinicopathologically. The proband presented with sensorimotor-autonomic polyneuropathy and autopsy demonstrated massive amyloid deposition in the peripheral nerves and heart. However, the mother was characterized by carpal tunnel syndrome and ocular vitreous opacities. Thus, there was considerable phenotypic heterogeneity among family members despite the identical TTR genotype. © 2007 Elsevier B.V. All rights reserved.

To evaluate the effectiveness of an electric toothbrush for oral care in patients with neuromuscular disability.In this randomized observer-blind crossover trial, 30 patients with neuromuscular disease performed either electric or manual toothbrushing each for 4 weeks. Plaque status (plaque control record), periodontal pocket depth, oral status (oral assessment guide), salivary bacterial count, and toothbrushing time were assessed after each period and compared between the two groups by Wilcoxon signed-rank test.Twenty-eight patients completed the study, including 18 communicative patients. Periodontal pockets were significantly shallower and toothbrushing time was significantly shorter with electric toothbrush use than with manual toothbrush use. No significant differences in oral status and salivary bacterial counts were noted between the approaches, but plaque status significantly improved after electric toothbrushing in communicative patients.Electric toothbrushing is beneficial for maintaining oral health in patients with neuromuscular disability and reducing the caregivers' oral care burden.

uated from the medical records and autopsy findings if available. Differences between the two groups were assessed by nonparametric analysis. The characteristics of the patients are shown in table 1 . There were no significant differences in gender, age at onset and age at death between the two groups; however, disease duration was significantly longer in patients with TPPV than without TPPV (Wilcoxon’s test, p ! 0.05). The hospitalization period until death was also significantly longer in patients with TPPV (Wilcoxon’s test, p ! 0.05). All patients with TPPV died in hospital, whereas a few patients without TPPV died at home. Twenty-two patients underwent autopsy and the diagnosis of ALS was confirmed in all patients by pathologic study. The causes of death in this study are shown in table 2 . The most frequent cause of death in patients with TPPV was respiratory failure (46.2%), as well as in patients without TPPV (89.6%). It was previously reported that 81.3% of ALS patients without TPPV died of respiratory failure [4] . Taken together with a previous report [4] and our study, the frequency of respiratory failure as a cause of death in patients with TPPV seems to be lower than in patients without TPPV. In addition, it is notable that all patients with TPPV developed reDear Sirs, Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of upper and lower motor neurons, leading to weakness and wasting of the affected muscles [1] . Previous reports have shown that the most common cause of death in patients with ALS is respiratory failure followed by other causes, including cardiac problems (myocardial infarction, arrhythmia), sepsis and malignancies [2– 5] ; however, knowledge about the causes of death in patients treated with tracheostomy-positive pressure ventilation (TPPV) is very limited. In this study, we investigated the causes of death of ALS patients on TPPV. We retrospectively reviewed the medical records of 112 consecutive patients with ALS referred to our hospital between April 2006 and September 2011. Diagnosis of ALS was made according to El Escorial diagnostic criteria [6] and clinically probable or definite patients were evaluated in this study. We identified 51 patients who died in this period and divided them into two groups: 13 patients who had been assisted with TPPV at the time of death and 38 patients who had not (9 patients had been assisted with noninvasive positive pressure ventilation, and 29 patients had not received any mechanically assisted ventilation). The causes of death were evalReceived: March 14, 2012 Accepted: June 24, 2012 Published online: September 21, 2012

Introduction Qing fei tang, which is used for various respiratory diseases, is useful for reducing relapse of aspiration pneumonia and bronchopneumonia in stroke, but the effect remains unknown in Parkinson's syndrome. We report two cases of Japanese patients with progressive supranuclear palsy and relapsing aspiration pneumonia and bronchopneumonia, which was successfully prevented by qing fei tang. Case presentation Two Japanese men with progressive supranuclear palsy and receiving total enteral feeding (patient one (66-years-old) and patient two (76-years-old)) had experienced recurrent aspiration pneumonia and bronchopneumonia, which was unresponsive to conventional therapy. The respiratory infection developed twice at intervals of two months in patient one, and nine times at almost monthly intervals in patient two. Thereafter, they were given qing fei tang. After administration of qing fei tang, the respiratory infection reoccurred only once; after 5.5 months for patient one, and six months for patient two. Both of our patients clearly showed a reduced incidence of respiratory infection. Conclusions Both of our patients clearly showed a reduced incidence of respiratory infection after the administration of qing fei tang. Qing fei tang could be useful for the prevention of recurrent aspiration pneumonia and bronchopneumonia in progressive supranuclear palsy.

We herein describe the case of an 81-year-old Japanese woman with neuroleptic malignant syndrome that occurred 36 days after the initiation of combination therapy with tiapride (75 mg/day) and tetrabenazine (12.5 mg/day) for Huntington's disease. The patient had been treated with tiapride or tetrabenazine alone without any adverse effects before the administration of the combination therapy. She also had advanced breast cancer when the combination therapy was initiated. To the best of our knowledge, the occurrence of neuroleptic malignant syndrome due to combination therapy with tetrabenazine and tiapride has not been previously reported. Tetrabenazine should be administered very carefully in combination with other neuroleptic drugs, particularly in patients with a worsening general condition.

Our objective was to determine whether the consumption of green tea, coffee, or black tea influences the incidence of dementia and mild cognitive impairment (MCI) in older people. We conducted a population-based prospective study with Japanese residents aged >60 years from Nakajima, Japan (the Nakajima Project). Participants received an evaluation of cognitive function and blood tests. The consumption of green tea, coffee, and black tea was also evaluated at baseline. Of 723 participants with normal cognitive function at a baseline survey (2007-2008), 490 completed the follow up survey in 2011-2013. The incidence of dementia during the follow-up period (mean ± SD: 4.9 ± 0.9 years) was 5.3%, and that of MCI was 13.1%. The multiple-adjusted odds ratio for the incidence of overall cognitive decline (dementia or MCI) was 0.32 (95% CI: 0.16-0.64) among individuals who consumed green tea every day and 0.47 (95% CI: 0.25-0.86) among those who consumed green tea 1-6 days per week compared with individuals who did not consume green tea at all. The multiple-adjusted odds ratio for the incidence of dementia was 0.26 (95% CI: 0.06-1.06) among individuals who consumed green tea every day compared with those who did not consume green tea at all. No association was found between coffee or black tea consumption and the incidence of dementia or MCI. Our results indicate that green tea consumption is significantly associated with reduced risk of cognitive decline, even after adjustment for possible confounding factors.

The study was undertaken to investigate by means of iodine-123-labelled metaiodobenzylguanidine (MIBG) scintigraphy the peripheral sympathetic function in patients with Parkinson’s disease (PD) without autonomic failure and in patients with related neurodegenerative diseases with parkinsonism. Seventy patients (33 men and 37 women, mean age 63±9.7 years) with parkinsonism and ten control subjects underwent MIBG scintigraphy. Of these 70 patients, 41 were diagnosed as having idiopathic PD, 9 multiple system atrophy (MSA), 6 progressive supranuclear palsy (PSP) and 2 corticobasal degeneration (CBD); the remaining 12 were diagnosed as having neurodegenerative disease with parkinsonism (P-nism) that did not meet the diagnostic criteria of any specific disease. Cardiac planar and tomographic imaging studies and subsequent whole-body imaging were performed 20 min and 3 h after the injection of 111 MBq MIBG. The early MIBG heart to mediastinum (H/M) ratio in PD (1.61±0.29) was significantly lower than that in the control group (2.24±0.14, P

In the Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disease that is often associated with lung cancer and characterized by reduced quantal release of acetylcholine from the motor nerve terminal, our studies to search for the target of LEMS antibodies have brought the voltage-gated calcium channel (VGCC) into relief. Among multiple types of VGCCs, the P/Q-type was highly recognized by LEMS antibodies. Using synthetic peptides or recombinant proteins as antigens, the study specified the S5-S6 linker regions in 3 of 4 domains as immunodominant sites in the molecular structure of P/Q-type VGCC alpha1 subunit. Synaptotagmin, one of the functionally VGCC-associated synaptic proteins, was also found to be an immunogen in the pathogenesis of LEMS.

Lambert–Eaton myasthenic syndrome (LEMS), often associated with small cell lung carcinoma (SCLC), is a disease of neuromuscular transmission in which antibodies directed against voltage-gated calcium channel (VGCC) in the motor nerve terminal play a crucial role in causing a deficient quantal release of acetylcholine. We focused attention on the P/Q-type VGCC, against which a majority of LEMS patients carry the specific antibody. Since the P/Q-type VGCC expresses in SCLC, the motor nerve terminal and SCLC may share a common VGCC antigen. In search for antigenic sites at the molecular level, We employed peptides or recombinant protein corresponding to the S5–S6 linker of each of four domains forming the α 1A subunit and tested their antigenicity. As the result, we specified the domain II, III and IV as immunodominant sites by the induction of an immune-mediated animal model of LEMS and the assay for antibodies in LEMS patients. Also, by use of peptides or recombinant protein corresponding to the synaptotagmin I, we found that in this VGCC-associated protein, the segment which exposes extracellularly during exocytosis can be antigenic for LEMS.