Publications by authors named "Kiyonobu Komai"

35 Publications

[Factors Associated with Self-reported Medication Adherence in Japanese Community-dwelling Elderly Individuals: The Nakajima Study].

Yakugaku Zasshi 2021 ;141(5):751-759

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences.

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 <80% and ≥95%, respectively). Medication adherence was significantly lower in participants taking medications ≥3 times daily than in those taking medications once or twice daily; a regimen involving drug administration ≥3 times daily had significantly lower odds of medication adherence. The use of a drug profile book and HRQOL had significant positive association with medication adherence. Our results suggest that low dosing frequency and using a drug profile book was positively associated with medication adherence among elderly persons, which in turn could enhance their QOL.
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http://dx.doi.org/10.1248/yakushi.20-00254DOI Listing
January 2021

An autopsy case of corticobasal degeneration with inferior olivary hypertrophy.

Neuropathology 2021 Jun 12;41(3):226-235. Epub 2021 Apr 12.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

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.
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http://dx.doi.org/10.1111/neup.12725DOI Listing
June 2021

Infection control in the respiratory care of coronavirus disease-19 patients with neuromuscular diseases.

Neurol Clin Neurosci 2021 Mar 1;9(2):159-165. Epub 2021 Feb 1.

Department of Neurology National Hospital Organization Hakone Hospital Odawara Japan.

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.
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http://dx.doi.org/10.1111/ncn3.12482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013339PMC
March 2021

A new computerized assessment battery for cognition (C-ABC) to detect mild cognitive impairment and dementia around 5 min.

PLoS One 2020 11;15(12):e0243469. Epub 2020 Dec 11.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243469PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732101PMC
January 2021

Effectiveness of Levodopa in Patients with Multiple System Atrophy and Associated Clinicopathological Features.

Intern Med 2021 Feb 19;60(3):367-372. Epub 2020 Sep 19.

Department of Neurology, National Hospital Organization Iou National Hospital, Hokuriku Brain and Neuromuscular Disease Center, Japan.

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.
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http://dx.doi.org/10.2169/internalmedicine.4836-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925269PMC
February 2021

Pharmacokinetics and tissue distribution of 3,4-diaminopyridine in rats.

Biopharm Drug Dispos 2019 Sep;40(8):294-301

Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan.

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.
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http://dx.doi.org/10.1002/bdd.2203DOI Listing
September 2019

Delusions and visual hallucinations in a patient with Parkinson's disease with dementia showing pronounced Lewy body pathology in the nucleus basalis of Meynert.

Neuropathology 2019 Aug 26;39(4):319-323. Epub 2019 Jun 26.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

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.
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http://dx.doi.org/10.1111/neup.12581DOI Listing
August 2019

The Japanese Early-Stage Trial of High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis (JETALS): Protocol for a Randomized Controlled Trial.

JMIR Res Protoc 2018 12 21;7(12):e12046. Epub 2018 Dec 21.

Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.

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.
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http://dx.doi.org/10.2196/12046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320396PMC
December 2018

Higher Blood Vitamin C Levels are Associated with Reduction of Apolipoprotein E E4-related Risks of Cognitive Decline in Women: The Nakajima Study.

J Alzheimers Dis 2018 ;63(4):1289-1297

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

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.
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http://dx.doi.org/10.3233/JAD-170971DOI Listing
June 2019

Contiguous and symmetrical disease expansion and massive necrosis of the cerebral white matter in a patient with neuromyelitis optica.

Mult Scler 2018 08 20;24(9):1258-1261. Epub 2018 Apr 20.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

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.
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http://dx.doi.org/10.1177/1352458518763086DOI Listing
August 2018

Differences in Dementia Beliefs between Non-Demented Public Screeners and In-Home Screeners and Their Potential Impact on Future Dementia Screening Intention: The Nakajima Study.

J Alzheimers Dis 2018 ;62(4):1651-1661

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan.

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.
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http://dx.doi.org/10.3233/JAD-171177DOI Listing
May 2019

Somatic sprouts of the Purkinje cells in a patient with multiple system atrophy.

Neuropathology 2018 Mar 25. Epub 2018 Mar 25.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

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.
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http://dx.doi.org/10.1111/neup.12464DOI Listing
March 2018

Tooth loss-related dietary patterns and cognitive impairment in an elderly Japanese population: The Nakajima study.

PLoS One 2018 15;13(3):e0194504. Epub 2018 Mar 15.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

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 <-0.2. In a multivariate regression analysis, the adjusted odds ratios regarding the prevalence of cognitive impairment for the lowest, middle and highest tertiles of the DP1 score were 1.00 (reference), 1.224 (95% confidence interval [CI]: 0.611-2.453) and 0.427 (95% CI: 0.191-0.954), respectively. To our knowledge, this is the first report to show that tooth loss-related dietary patterns are associated with a high prevalence of cognitive impairment. These results may motivate changes in dental treatment and the dietary behaviours and thereby lower the risk of cognitive impairment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194504PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854423PMC
July 2018

Effectiveness of electric toothbrushing in patients with neuromuscular disability: A randomized observer-blind crossover trial.

Spec Care Dentist 2016 Jan 21;36(1):13-7. Epub 2015 Sep 21.

Department of Dentistry, National Hospital Organization Iou Hospital, Kanazawa, Japan.

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.
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http://dx.doi.org/10.1111/scd.12141DOI Listing
January 2016

Pharmacokinetics and safety of 3,4-diaminopyridine base in healthy Japanese volunteers.

Int J Clin Pharmacol Ther 2015 Aug;53(8):674-80

Objective: 3,4-diaminopyridine (3,4-DAP) is commonly used for treating neuromuscular diseases, such as the Lambert-Eaton myasthenic syndrome, but the pharmacokinetics of 3,4-DAP base have not been investigated. We therefore studied 3,4-DAP base pharmacokinetics in healthy Japanese volunteers.

Materials And Methods: In this crossover study, we administered a single oral dose of 10 or 20 mg 3,4-DAP base to healthy Japanese volunteers (n = 5) after food intake, or 10 mg 3,4-DAP to fasting individuals. We measured serum 3,4-DAP concentrations, performed electrocardiography (ECG), and administered questionnaires.

Results: After administration of 10 or 20 mg 3,4-DAP following food intake, the maximum serum concentrations (Cmax) were 8.09 ± 4.47 ng/mL and 35.8 ± 15.7 ng/mL, respectively (mean ± standard deviation; SD), and the areas under the serum concentration-time curve (extrapolated to infinity) were 639 ± 213 ng x min/mL and 2,097 ± 936 ng x min/mL (mean ± SD), respectively. Administration to fasted individuals indicated that food intake did not significantly alter 3,4-DAP pharmacokinetics. ECG showed no clinically significant changes, but PR intervals were prolonged in all cases. Two out of 5 subjects showed perioral paresthesia symptoms after administration of 20 mg 3,4-DAP.

Conclusion: This study indicated that 3,4-DAP base pharmacokinetics were non-linear. Although no clinically significant changes in ECG were observed, it is advisable to perform ECG periodically during 3,4-DAP administration in order to monitor cardiac function. Moreover, the development of perioral paresthesia may be dependent on the dose of 3,4-DAP used.
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http://dx.doi.org/10.5414/CP202133DOI Listing
August 2015

Aspiration pneumonia and bronchopneumonia in progressive supranuclear palsy treated with qing fei tang: two case reports.

J Med Case Rep 2015 Mar 26;9:67. Epub 2015 Mar 26.

Department of Neurology, National Hospital Organization Iou Hospital, Ni-73-1, Iwade-machi, Kanazawa, 920-0192, Japan.

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.
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http://dx.doi.org/10.1186/s13256-015-0538-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403770PMC
March 2015

Retinitis pigmentosa and macular degeneration in a patient with ataxia with isolated vitamin E deficiency with a novel c.717 del C mutation in the TTPA gene.

J Neurol Sci 2014 Oct 9;345(1-2):228-30. Epub 2014 Jul 9.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Japan. Electronic address:

Ataxia with isolated vitamin E deficiency (AVED) is a neurodegenerative disease caused by a mutation in the α-tocopherol transfer protein gene (TTPA). The clinical features of the disease resemble Friedreich's ataxia. However, AVED is associated with low plasma vitamin E levels, which results in compromised antioxidant function. Dysregulation of this lipid-soluble antioxidant vitamin plays a major role in the neurodegeneration observed in AVED. Some AVED patients experience decreased visual acuity. Retinitis pigmentosa is thought to be the main cause of this visual impairment. Although antioxidant levels are important for the prevention of macular degeneration, there have been no reports of macular degeneration in AVED. Here, we describe a patient with AVED with progressive macular degeneration, who carried a novel truncating mutation-c.717 del C (p.D239EfsX25)-in exon 5 of the TTPA gene. These findings suggest that this newly identified mutation results in severely low serum vitamin E levels, which may be associated with the development of retinitis pigmentosa and macular degeneration.
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http://dx.doi.org/10.1016/j.jns.2014.07.001DOI Listing
October 2014

Neuroleptic malignant syndrome induced by combination therapy with tetrabenazine and tiapride in a Japanese patient with Huntington's disease at the terminal stage of recurrent breast cancer.

Intern Med 2014 1;53(11):1201-4. Epub 2014 Jun 1.

Department of Neurology, National Hospital Organization Iou National Hospital, Japan.

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.
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http://dx.doi.org/10.2169/internalmedicine.53.1717DOI Listing
May 2015

Consumption of green tea, but not black tea or coffee, is associated with reduced risk of cognitive decline.

PLoS One 2014 14;9(5):e96013. Epub 2014 May 14.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0096013PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020750PMC
December 2014

Clinical features in association with neurodegenerative diseases and malignancies.

Eur Neurol 2014 10;71(3-4):99-105. Epub 2013 Dec 10.

Department of Neurology, National Hospital Organization Iou National Hospital, Kanazawa, Japan.

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.
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http://dx.doi.org/10.1159/000353995DOI Listing
November 2014

Differences in the prevalence of dementia and mild cognitive impairment and cognitive functions between early and delayed responders in a community-based study of the elderly.

J Alzheimers Dis 2013 ;37(4):691-8

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

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.
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http://dx.doi.org/10.3233/JAD-130398DOI Listing
July 2014

Winged scapula in patients with myotonic dystrophy type 1.

Neuromuscul Disord 2012 Aug 8;22(8):755-8. Epub 2012 Jun 8.

Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Fukui, Japan.

We report two patients with myotonic dystrophy type 1 (DM1) showing winged scapula in a single family. Genomic analysis revealed a marked expansion of CTG repeats in the 3' untranslated region; 1100 in patient 1 and 667 in patient 2. Muscle MRI revealed marked atrophy in the serratus anterior muscle in both patients. Muscle biopsy findings showed central nuclei and variations in fiber size. One of the patients showed ragged red fibers in muscles of the biceps brachii. To our knowledge, this is the first report of typical winged scapula in DM1.
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http://dx.doi.org/10.1016/j.nmd.2012.04.010DOI Listing
August 2012

Effect of cognitive and aerobic training intervention on older adults with mild or no cognitive impairment: a derivative study of the nakajima project.

Dement Geriatr Cogn Dis Extra 2012 Jan 20;2(1):69-80. Epub 2012 Mar 20.

Department of Occupational Therapy, Faculty of Health Sciences, Bukkyo University, Kyoto, Japan.

Background: An increasing elderly population in Japan requires effective cognitive intervention programs for dementia. This study demonstrates the effectiveness of such programs for older adults.

Methods: The participants were local community-dwelling non-demented older adults and adults with mild cognitive impairment who underwent executive function and group aerobic training. In addition, a non-intervention group participated in activity sessions involving handicraft, Skutt ball matches, and cooking. The four criteria for assessment were cognitive function, instrumental activities of daily living, human relationships, and physical function.

Results: The participants in both intervention groups showed a significant improvement in their memory function compared with the non-intervention group.

Conclusion: Early rehabilitation intervention using executive function and aerobic training programs may improve memory.
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http://dx.doi.org/10.1159/000337224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350345PMC
January 2012

An autopsy case of an aged patient with spinocerebellar ataxia type 2.

Neuropathology 2011 Oct 6;31(5):510-8. Epub 2010 Dec 6.

Department of Neurology, National Hospital Organization Iou Hospital, Kanazawa, Japan.

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.
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http://dx.doi.org/10.1111/j.1440-1789.2010.01176.xDOI Listing
October 2011

Progressive myelopathy with hyperintensity on T2-weighted spinal MRI.

J Clin Neurosci 2010 Jan 14;17(1):85, 155. Epub 2009 Dec 14.

Department of Neurology, National Hospital Organization Iou National Hospital, Ni73-1, Iwade-Cho, Kanazawa 920-0192, Japan.

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http://dx.doi.org/10.1016/j.jocn.2009.05.014DOI Listing
January 2010

Polyethylene glycol interferon alpha-2b-induced immune-mediated polyradiculoneuropathy.

Intern Med 2009 1;48(7):569-72. Epub 2009 Apr 1.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa.

Polyethylene glycol-interferon alpha (PEG-IFNalpha) has been used as the standard treatment for hepatitis C virus (HCV) infection. There have been no previous reports of polyradiculoneuropathy with anti-ganglioside antibodies induced by PEG-IFNalpha-2b. We report a 59-year-old man who developed polyradiculoneuropathy during treatment with PEG-IFN alpha-2b for chronic HCV infection. Serum levels of anti-asialo-GM1 (GA1) and anti-GM1 antibodies were elevated. Cessation of therapy with double filtration plasmapheresis resulted in marked improvement in his symptoms accompanied by a reduction in the antibody level. PEG-IFN alpha-2b may induce peripheral neuropathy mediated by anti-GA1 and anti-GM1 antibodies.
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http://dx.doi.org/10.2169/internalmedicine.48.1794DOI Listing
July 2009

Phenotypic heterogeneity in a family with FAP due to a TTR Leu58Arg mutation: a clinicopathologic study.

J Neurol Sci 2007 Sep 26;260(1-2):236-9. Epub 2007 Apr 26.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8641, Japan.

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.
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http://dx.doi.org/10.1016/j.jns.2007.03.021DOI Listing
September 2007

Microscopic polyangitis presenting with temporal arteritis and multiple cranial neuropathies.

J Neurol Sci 2007 May 26;256(1-2):81-3. Epub 2007 Mar 26.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Takaramachi 13-1, Kanazawa, Japan.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis affects vessels of various diameters in various tissues or organs, sometimes associated with neurological complications. A 77-year-old man developed dysphagia, hoarseness, dysgeusia, gait unsteadiness, and right temporalgia; neurological examination revealed multiple cranial neuropathies. Laboratory studies demonstrated severe inflammatory responses, elevation of perinuclear ANCA, and mild proteinuria. Magnetic resonance imaging of the brain showed dural enhancement in the cerebellar tentorium. Biopsy revealed necrotizing glomerulonephritis in the kidney, and temporal arteritis without giant cells in the temporal artery. The patient was diagnosed with microscopic polyangitis presenting with temporal arteritis and multiple cranial nerve involvement, and was treated with predonisolone, after which the symptoms and laboratory data showed improvement. This is the first case of ANCA-associated vasculitis with pathologically verified lesions in the temporal artery as well as in the kidney. Thus, ANCA-associated vasculitis may simultaneously affect large vessels such as temporal artery, as well as microvessels in the kidney, nerves and other organs.
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http://dx.doi.org/10.1016/j.jns.2007.01.009DOI Listing
May 2007

Myasthenia gravis presenting with unusual neurogenic muscle atrophy.

Muscle Nerve 2007 Sep;36(3):394-9

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8640, Japan.

We report a patient with myasthenia gravis who had neurogenic muscle atrophy in association with external ophthalmoplegia and weakness of the upper limbs. Neurogenic changes in the limb muscles were found on needle electromyography and histological studies. Symptoms improved and atrophy of the limbs diminished after intravenous immunoglobulin and oral corticosteroid therapy. We concluded that functional interruption of the neuromuscular junction caused the neurogenic muscle atrophy and that this was relieved by appropriate therapy.
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http://dx.doi.org/10.1002/mus.20757DOI Listing
September 2007