Kenji Nakashima

Tottori University, TTJ, Tottori, Japan

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Publications (332)822.65 Total impact

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    ABSTRACT: Background Only a few prospective studies have determined which clinical symptoms and factors are associated with the disease severity of spinocerebellar ataxia type 6 (SCA6). A multicenter longitudinal cohort study was conducted to clarify both the natural history of SCA6 in Japan and the factors influencing disease progression.Methods Patients were consecutively recruited between 2007 and 2008. Scores from the Scale for the Assessment and Rating of Ataxia (SARA) and Barthel Index (BI) were collected prospectively each year. Additionally, data from the Japan intractable diseases research (IDR) registry were collected both retrospectively, from 2003 to 2006, and prospectively, from 2007 to 2010. As a result, we were able to collect 3 years of retrospective data and 4 years of prospective data during the course of 3 yearly visits.ResultsForty-six patients were registered. The follow-up rate of the third year was 93%. The SARA scores worsened significantly each year. Over 3 years, the decline of the SARA scores was 1.33¿±¿1.40 points/year. The results of multivariate analysis of the decline of the SARA score were not significant. The IDR scores correlated well with the SARA and BI scores. Kaplan-Meier curves of 7 years of data from the IDR registry illustrated the correlation between the ability to walk and the time course of the disease.Conclusions Information regarding the progression of ataxia and the decline in the activities of daily living (ADL) in patients with SCA6 was obtained by a 3-year cohort study and a 7-year IDR study. The decline of the SARA score of patients with SCA6 was 1.33¿±¿1.40 points/year. The results elucidate the natural history of SCA6, factors influencing disease severity, and utility of data from the IDR registry of Japan.
    Orphanet Journal of Rare Diseases 07/2014; 9(1):118. · 4.32 Impact Factor
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    ABSTRACT: Background Fatigue is a common nonmotor symptom of Parkinson's disease (PD). Although the causes of fatigue were estimated in the previous reports, fatigue is not fully understood. To determine the frequency of and factors related to fatigue in patients with PD, we carried out clinical assessments in our university hospital.Methods We used the Japanese version of the Parkinson Fatigue Scale (J-PFS). The J-PFS was administered to 110 patients with PD, and a cutoff point of 3.3 was used for the diagnosis of fatigue. Subsequently, demographic characteristics, clinical features, and medications utilized were evaluated to elucidate the factors related to fatigue. In particular, we focused on the relationship between fatigue and gait disorder assessed via the portable gait rhythmogram.ResultsThe frequency of fatigue in patients with PD was 52.7%. Univariate analysis revealed that factors significantly associated with fatigue were many motor symptoms and nonmotor symptoms. In addition, multivariate analysis revealed that gait disorder and constipation were independent factors related to fatigue. Furthermore, short-step walking and bradykinesia in gait disorder had especially a relationship with fatigue.Conclusions More than half of our patients were judged having fatigue. Several factors, including motor and nonmotor symptoms, might be related to fatigue in patients with PD.
    Brain and Behavior. 07/2014;
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    ABSTRACT: Rare non-synonymous variants of TREM2 have recently been shown to be associated with Alzheimer's disease (AD) in Caucasians. We here conducted a replication study using a well-characterized Japanese sample set, comprising 2,190 late-onset AD (LOAD) cases and 2,498 controls. We genotyped 10 non-synonymous variants (Q33X, Y38C, R47H, T66M, N68K, D87N, T96K, R98W, H157Y, and L211P) of TREM2 reported by Guerreiro et al. (2013) by means of the TaqMan and dideoxy sequencing methods. Only three variants, R47H, H157Y, and L211P, were polymorphic (range of minor allele frequency [MAF], 0.0002-0.0059); however, no significant association with LOAD was observed in these variants. Considering low MAF of variants examined and our study sample size, further genetic analysis with a larger sample set is needed to firmly evaluate whether or not TREM2 is associated with LOAD in Japanese.
    Journal of Alzheimer's disease: JAD 04/2014; · 4.17 Impact Factor
  • Internal medicine (Tokyo, Japan). 01/2014; 53(19):2261.
  • Kenji Wada, Mikie Yamamoto, Kenji Nakashima
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    ABSTRACT: Physical function was declined in aging as well as sensory function in human. Motor slowness and unbalance gait occur as well as decline of ability visual acuity and hearing let elderly people live in limited daily activity. Psychological functions are also thought to be decline in aging. In International Classification of Functioning, Disability and Health(ICF), psychological functions are classified into attention, memory, psychomotor, emotion, perception, thought, higher-level cognitive functions, language, calculation, sequencing complex movements, experience of self and time functions and unspecified functions. It is difficult to assess an individual psychological function itself, because some functions may affect each other and results of evaluations of a psychological function may not represent the meaning of the function. There were numerous reports on physical function in aging in a cross sectional or a longitudinal study design. In this article, we review changes of psychological function in aging.
    Nippon rinsho. Japanese journal of clinical medicine 10/2013; 71(10):1713-9.
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    ABSTRACT: To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10(-9)) and rs3781834 (P = 1.04×10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10(-5)) and rs744373 near BIN1 (P = 1.39×10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.
    PLoS ONE 07/2013; 8(4):e58618. · 3.53 Impact Factor
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    ABSTRACT: Background Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components. Methods In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography. Results We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population. Conclusions Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.).
    New England Journal of Medicine 06/2013; 369(3):233-44. · 54.42 Impact Factor
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    ABSTRACT: BACKGROUND: In order to evaluate impulsive compulsive behaviors (ICBs), such as pathological gambling, compulsive sexual behavior, compulsive buying, compulsive eating, punding, and dopamine dysregulation syndrome (DDS) in Japanese Parkinson's disease (PD) patients, we constructed a Japanese version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (J-QUIP) and evaluated the utility of the J-QUIP in Japanese PD patients. METHODS: J-QUIP was administered to 121 PD patients. Diagnoses of ICBs were made via interview of patients or their caregivers. Subsequently, in order to evaluate risk factors related to these conditions, we evaluated demographic and clinical characteristics, clinical features, and medications utilized. RESULTS: We were able to administer the J-QUIP to 118 of 121 PD patients (97.5%). Sensitivity and specificity of J-QUIP were similar to that reported for the original version of QUIP. In our study, the actual prevalence of each disorder diagnosed via interview was as follows: pathological gambling (6.5%), compulsive sexual behavior (3.2%), compulsive buying (3.2%), compulsive eating (3.2%), punding (6.5%), and DDS (2.2%). Significantly risk factors for these conditions were younger age (p=0.047), earlier age of disease onset (p=0.015), longer PD duration (p=0.001), total levodopa equivalent dose (p=0.006), and dosage of levodopa (p=0.019). CONCLUSIONS: We evaluated the prevalence of ICBs in Japanese PD patients along with factors associated with these behaviors via J-QUIP.
    Journal of the neurological sciences 06/2013; · 2.32 Impact Factor
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    Takashi Nomura, Yuichi Inoue, Kenji Nakashima
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    ABSTRACT: Rapid eye movement sleep behavior disorder (RBD) frequently occurs in synucleinopathies including multiple system atrophy, Parkinson's disease, and dementia with Lewy bodies despite the clinical course of RBD being different between these disorders. Comparatively, the existence of RBD symptoms is relatively rare in patients with progressive supranuclear palsy, a tauopathy showing atypical parkinsonism compared with Parkinson's disease. Moreover, in patients with Alzheimer's disease, which is another tauopathy, RBD symptoms are less frequent than dementia with Lewy bodies, although both disorders share commonalities in terms of the existence of cortical dementia. Thus, RBD is thought to be relatively specific to synucleinopathies.
    Sleep and Biological Rhythms 06/2013; 11(S1). · 1.05 Impact Factor
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    ABSTRACT: Parkinson's disease (PD) patients frequently develop obstructive sleep apnea (OSA). In order to clarify the clinical significance of OSA in PD, we compared descriptive variables between PD patients with OSA (PD+OSA) and without (PD-OSA), and between the PD+OSA group and a group of OSA patients without PD (control OSA). The apnea hypopnea index (AHI) cutoff of 15 episodes/hour on polysomnogram (PSG) was used to assign 107 PD patients to groups; OSA-related symptoms and PSG findings were then compared. Demographic and PSG variables were compared between PD+OSA patients and 31 OSA controls. Twenty-four patients with PD (22.4%) were classified as PD+OSA. There were no significant differences in descriptive variables between the PD+OSA and PD-OSA groups. The PD+OSA group had a higher arousal index on PSG than the PD-OSA group, although the two groups had similar ESS scores. The PD+OSA patients had a lower respiratory arousal index and a smaller decrease in oxygen saturation than the control OSA group, despite having a similar AHI. The prevalence of OSA in PD did not differ from that in the general elderly population, indicating that the clinical significance of OSA as a contributor to daytime sleepiness in PD is low.
    Journal of the neurological sciences 02/2013; · 2.32 Impact Factor
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    ABSTRACT: OBJECTIVES: Mild parkinsonian signs (MPS) are reported to be associated with increased risk of dementia, Parkinson's disease, parkinsonism, and vascular lesions of white matter and are also a significant predictor of mortality. Although more than 20% of subjects aged 60 years and older suffer from MPS in Japan, it is often unrecognized and underestimated by patients and medical physicians. We used neuropsychological methods to examine cognitive function and depressive symptoms in subjects with MPS. METHODS: We performed a population-based study in Ama-cho, a rural island town in western Japan. Participants included 951 subjects aged 65 years and older, 613 of whom completed all questionnaires, neurological examinations, and neuropsychological assessments and were included in the data analysis. Subjects were assessed for depression and subjective cognitive impairment using the Geriatric Depression Scale (GDS-15), Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and modified Unified Parkinson's Disease Rating Scale (mUPDRS). RESULTS: Of the 613 participants, 143 were diagnosed with MPS. GDS scores were significantly higher in the MPS group compared with the motor control group, while MMSE scores were significantly lower. CONCLUSIONS: We demonstrated that MPS correlate with both depressive symptoms and cognitive impairment.
    Acta Neurologica Scandinavica 02/2013; · 2.47 Impact Factor
  • Clinical neurology and neurosurgery 02/2013; · 1.30 Impact Factor
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    ABSTRACT: We used ramelteon to treat two patients with secondary REM sleep behavior disorder (RBD) complications along with neurodegenerative diseases including multiple system atrophy and Parkinson's disease. These two patients not only improved in terms of their clinical RBD symptoms but also exhibited a decrease in the proportion of REM sleep without atonia (from 8.5% to 3.5% and from 10.9% to 3.9% in the two patients). Although clonazepam is the standard first-line therapy for the treatment of RBD, ramelteon might be an effective treatment alternative in patients with RBD who cannot take clonazepam due to either ineffectiveness or adverse effects.
    Internal Medicine 01/2013; 52(18):2123-6. · 0.97 Impact Factor
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. Many recent studies focused on the interaction between α-synuclein (α-syn) and dopamine in the pathogenesis of PD, and fluorescent anisotropy suggested that the C-terminal region of α-syn may be a target for modification by dopamine. However, it is not well understood why PD-related pathogenesis occurs selectively in dopaminergic neurons. We investigated the interaction between dopamine and α-syn with regard to cytotoxicity. A soluble oligomer was formed by co-incubating α-syn and dopamine . To clarify the effect of dopamine on α-syn in cells, we generated PC12 cells expressing human α-syn, as well as the α-syn mutants, M116A, Y125D, M127A, S129A, and M116A/M127A, in a tetracycline-inducible manner (PC12-TetOFF-α-syn). Overexpression of wildtype α-syn in catecholaminergic PC12 cells decreased cell viability in long-term cultures, while a competitive inhibitor of tyrosine hydroxylase blocked this vulnerability, suggesting that α-syn-related cytotoxicity is associated with dopamine metabolism. The vulnerabilities of all mutant cell lines were lower than that of wildtype α-syn-expressing cells. Moreover, α-syn containing dopamine-mediated oxidized methionine (Met(O)) was detected in PC12-TetOFF-α-syn. Met(O) was lower in methionine mutant cells, especially in the M127A or M116A/M127A mutants, but also in the Y125D and S129A mutants. Co-incubation of dopamine and the YEMPS peptide enhanced the production of HO, which may oxidize methionine residues and convert them to Met(O). Y125- or S129-lacking peptides did not enhance the dopamine-related production of HO. Our results suggest that M127 is the major target for oxidative modification by dopamine, and that Y125 and S129 may act as enhancers of this modification. These results may describe a mechanism of dopaminergic neuron-specific toxicity of α-syn in the pathogenesis of PD.
    PLoS ONE 01/2013; 8(2):e55068. · 3.53 Impact Factor
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    ABSTRACT: OBJECTIVE: Rapid eye movement (REM) sleep behavior disorder (RBD) may be a risk factor for dementia development in patients with Parkinson's disease (PD); however, the role of subclinical RBD remains unknown. Patients with PD and clinical RBD, subclinical RBD, or with normal REM sleep were examined in a cross sectional study and a longitudinal follow-up. METHODS: Interviews regarding RBD symptoms and polysomnographies were performed on 82 PD patients divided into RBD subcategories based on the presence/absence of REM sleep without atonia (RWA) and/or RBD symptoms. Descriptive variables were compared and patients were followed-up longitudinally for 21.4±10.8months. RESULTS: The existence of RBD, but not subclinical RBD, was associated with orthostatic hypotension and levodopa dose equivalents (LDEs) in patients with PD. Kaplan-Myer curves indicated that the occurrence of dementia in the PD group with clinical RBD was significantly faster than in the PD group with normal REM sleep (p=0.013). A Cox hazard regression analysis revealed that development to PD with dementia was only significantly associated with the presence of clinical RBD (hazard ratio: 14.1, p=0.017). CONCLUSION: Clinical RBD symptoms, but not subclinical RBD, were associated with the development of dementia in PD.
    Sleep Medicine 12/2012; · 3.49 Impact Factor
  • Kenji Wada, Kenji Nakashima
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    ABSTRACT: Abstract Parkinson's disease (PD), a neurodegenerative disease, has been traditionally defined by its characteristic motor symptoms. Non-motor symptoms, including mood disorder, psychosis, sleep disturbance, autonomic dysfunction, and cognitive impairment, have being recently recognized as symptoms of PD. Cognitive impairment or dementia is one of the critical symptoms during the advanced stages of PD and is associated with increased disability and reduced quality of life of both patients and caregivers. The point prevalence of dementia in PD is about 30%, and its incidence rate in PD patients is 4-6 times higher than that in age-matched controls. The term mild cognitive impairment (MCI) has been adopted to describe the potential prodromal stage of dementia in PD, which has been gaining increasing attention. Several studies have reported the clinical features, epidemiology, biomarkers, and neuropathology of MCI in PD; however, neither the precise definitions nor the employed criteria were consistent across these studies. Recently, the Movement Disorder Society Task Force proposed new diagnostic criteria for MCI in PD to allow clinicians to identify PD patients with increased risk of dementia. Further studies are needed to validate the proposed criteria in daily clinical practice.
    Brain and nerve = Shinkei kenkyū no shinpo 12/2012; 64(12):1365-75.
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    ABSTRACT: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder with optic nerve atrophy. Although there are no other associated neurological abnormalities in most cases of LHON, cases of "LHON plus" have been reported. The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. These results suggest that the combination of G11778A and T3394C mutations leads to an atypical LHON phenotype.
    Journal of Clinical Neurology 09/2012; 8(3):230-4. · 1.69 Impact Factor
  • Takashi Nomura, Yuichi Inoue, Kenji Nakashima
    Clinical Neurophysiology. 09/2012; 123(9):e96–e97.
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    ABSTRACT: This study attempts to identify changes in the symptoms of sleep disturbances/insomnia over a two-year course and their effects on daytime functioning. We administered two population-based epidemiological surveys in 2005 and 2007 to participants from rural Japan. In the first survey, 30.7% of the subjects reported sleep disturbances/insomnia. Among them, 60.9% reported sleep problems at the two-year follow-up. A comparison of sleep disturbances/insomnia, and subjective daytime functioning measures between the new incident cases and persistent poor sleepers revealed that the total score of persistent poor sleepers was significantly lower than that of new incident cases on the Pittsburgh Sleep Quality Index and physical quality of life (QoL) but not mental QoL. Longitudinal comparisons of the symptoms of sleep disturbances/insomnia in persistent poor sleepers revealed that sleep efficiency was significantly worse at follow-up. Exacerbation of the symptoms of sleep disturbances/insomnia at follow-up was observed in mild but not severe cases. Sleep efficiency progressively worsens over time, and physical QoL can deteriorate as sleep disturbances/insomnia become chronic. Since the symptoms of sleep disturbances/insomnia and their daytime effects are exacerbated even in mild cases, early intervention and treatment are necessary.
    Sleep Medicine 07/2012; 13(9):1115-21. · 3.49 Impact Factor

Publication Stats

5k Citations
822.65 Total Impact Points


  • 1992–2014
    • Tottori University
      • • Department of Brain and Neurosciences
      • • Faculty of Medicine
      • • Division of Urology
      • • Institute of Neurological Sciences
      TTJ, Tottori, Japan
  • 2013
    • Niigata University
      • Department of Molecular Genetics
      Niahi-niigata, Niigata, Japan
  • 2011–2012
    • Tokyo Medical University
      • Department of Somnology
      Edo, Tōkyō, Japan
  • 2005
    • Macalester College
      • Department of Mathematics, Statistics, and Computer Science
      Saint Paul, Minnesota, United States
  • 1999
    • Shimane University
      • Faculty of Life and Environmental Science
      Izumo, Shimane-ken, Japan