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Background Mild parkinsonian signs are important clinical symptoms related to the decline of motor and cognitive functions. We aimed to identify predictors for the incidence of mild parkinsonian signs in older Japanese by conducting an 8-year longitudinal community-based cohort study. Methods Participants aged 65 years or older, living in Ama-cho, a rural island town in western Japan, underwent a baseline assessment of motor function, cognitive function, depression score, the Pittsburgh Sleep Quality Index (PSQI), the Tanner questionnaire, and cerebral white matter lesions on brain magnetic resonance imaging from 2008 to 2010, and then underwent a follow-up neurological examination from 2016 to 2017. Mild parkinsonian signs were defined according to a modified Unified Parkinson's Disease Rating Scale score. Results Of the 316 participants without mild parkinsonian signs at baseline, 94 presented with incident mild parkinsonian signs at follow-up. In addition to an absence of exercise habits, a higher score on the Tanner questionnaire, PSQI, and deep white-matter hyperintensity Fazekas scores were significant independent predictors for incidence of mild parkinsonian signs. Conclusion We suggest multiple factors related to incidence of mild parkinsonian signs. Vascular lesions and sleep disorders are associated with a pathogenesis of mild parkinsonian signs, the Tanner questionnaire is useful for early detection of subclinical mild parkinsonian signs, and exercise has a possibility of being associated with preventing onset of mild parkinsonian signs.

Objectives: Amyotrophic lateral sclerosis (ALS) patients may present with cognitive and behavioral abnormalities similar to frontotemporal dementia (FTD). In this multicenter study we examined Japanese ALS patients with and without FTD in order to characterize the full extent of cognitive and behavioral abnormalities, including associations with functional motor status, anxiety and depression. Methods: Patients were evaluated using the Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Hospital Anxiety and Depression Scale, ALS Functional Rating Scale-Revised, spirometry, and verbal fluency tests. Caregivers were asked to complete the ALS-FTD-Questionnaire (ALS-FTD-Q), a behavioral screen. We defined severe cognitive impairment (MoCA < 21 or FAB < 11), mild impairment (11 ≤ MoCA ≤ 25 or 11 ≤ FAB ≤ 15), and normal cognition (MoCA > 25 or FAB > 15). Severe and mild behavioral impairments and normal behavior were defined by the ALS-FTD-Q scores. Results: In 145 ALS patients, better cognitive scores were correlated with earlier age at onset, whereas a worse behavioral score was associated with a longer disease duration and higher level of anxiety and depression. Around seventy percent of all ALS patients showed mild (40–45%) or severe cognitive impairment with cognitive impairment outnumbering behavioral impairment fivefold. Cognitive functions were more impaired in patients with age of onset over 65 years, while behavioral scores were not related to age. Conclusions: Considering the high prevalence of in particular cognitive impairment, and the diversity of impairments, the cognitive and behavioral aspects of Japanese ALS patients should be given more attention clinically.

Background International reporting of epidemiological surveys of spinal muscular atrophy (SMA) in Japan has been limited to Shikoku, despite the epidemiology of the disease in countries worldwide becoming clearer. Treatments of 5q-SMA have been developed, and epidemiological studies are needed. Purpose This study aimed to conduct a nationwide epidemiological survey of SMA in Japan to clarify the actual situation of SMA in Japan. Method Patients with all clinical types of SMA, including neonates and adults, were selected from 1,005 medical facilities in Japan. Results As of December 2017, the actual number of reported patients with SMA was 658 and the genetic testing rate was 79.5%. The estimated number of patients was 1,478 (95% confidence interval (CI), 1,122–1,834), with a prevalence of 1.17 (95%CI, 0.89–1.45) per 100,000 people and an incidence of 0.51 (95%CI, 0.32–0.71) per 10,000 live births. Incidence rates of 5q-SMA by clinical type were 0.27 (95%CI, 0.17–0.38) and 0.08 (95%CI, 0.04–0.11) per 10,000 live births for type 1 and 2, respectively, in cases with a definitive diagnosis by genetic testing. We found that 363 cases (82.7%) occurred less than 2 years and 88 (20.0%) occurred age of 2 months old or under. Conclusion This study clarifies the prevalence and incidence of SMA in Japan. As infantile onset accounts for most cases of SMA, newborn screening and subsequent treatment are important to save lives.

Amyotrophic lateral sclerosis (ALS) patients might present with cognitive and behavioural abnormalities resembling frontotemporal dementia (FTD). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was developed as an easy to administer cognitive screen for detecting these symptoms. The aim of the present study was to develop and validate a Japanese version of the ECAS.In this single centre observational study, 35 ALS patients and 28 healthy controls were enrolled. Three patients in the ALS group fulfilled the criteria for behavioural variant FTD (ALS-FTD) and the rest were grouped as ALS without FTD. Participants were subjected to the Japanese version of the ECAS. ALS patients were also subjected to the Montreal Cognitive Assessment, Frontal Assessment Battery, ALS Functional Rating Scale-Revised, and respiratory function testing. Demographic and disease characteristics (e.g., sex, age at examination, and years of education) were also recorded.Internal consistency and correlations with general cognitive screenings were sufficient in the Japanese adaptation. Executive functions were the most commonly affected ECAS domain, followed by fluency and language. Compared to control subjects, ALS patients without FTD had low scores in the ECAS ALS-specific functions but not in ALS-nonspecific functions. Meanwhile ALS-FTD patients markedly underperformed both in the ECAS ALS-specific and ALS-nonspecific functions. Furthermore, the Japanese ECAS score correlated positively with years of education and negatively with age at onset.The Japanese version of the ECAS is a valid and useful screening tool to identify multiple types of cognitive impairment in ALS patients.

Background Patients with non-demented Parkinson's disease (PD) sometime have mild cognitive impairment (MCI), and mild cognitive impairment in Parkinson's disease (PD-MCI) may convert to Parkinson's disease with dementia (PDD) within several years. Cognitive impairment also occurs in the early stages of the disease, gradually progressing to lower quality of life and instrumental activities of daily living. It is important to elucidate the predictors of progression from PD-MCI to PDD via longitudinal studies. Methods This was a single center, case-control study. We analysed data from 49 patients with PD-MCI diagnosed as level I using the Movement Disorder Society PD-MCI criteria at baseline who had completed 1.5 years of follow-up. We defined patients who progressed to PDD as patients with progressive PD-MCI and patients who did not progress to PDD as patients with non-progressive PD-MCI. Depression, apathy, sleep disorders, constipation, light-headedness, hallucinations, impulse control disorders (ICDs) and impulsive-compulsive behaviors (ICBs) at baseline were statistically analysed as predictors of progression. Results Of the 49 PD-MCI patients, 33 did not convert to PDD (non-progressive PD-MCI), and 16 converted to PDD (progressive PD-MCI). The Mini-Mental State Examination (MMSE) score, light-headedness and ICDs were elucidated as predictors of progressive PD-MCI via a multivariate logistic regression model. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for each item were MMSE score, OR 0.324, 95% CI 0.119-0.882, P = 0.027; light-headedness, OR 27.665, 95% CI 2.263-338.185, P= 0.009; and ICDs, OR 53.451, 95% CI 2.298-291.085, P = 0.010. Conclusion Cognitive function, ICDs and light-headedness may be risk factors for the development of PDD in PD-MCI patients.

Objective We conducted a study to obtain information that could be used to provide Parkinson's disease (PD) patients with appropriate advice on safe driving. Methods Consecutive PD patients who visited our office were studied. Among these patients, those who had experienced driving after being diagnosed with PD were interviewed by neurologists and a trained nurse to investigate their previous car accidents, motor function, cognitive function, sleepiness, levodopa equivalent dose (LED), and emotional dysregulation. The rates of major car accidents before and after the onset of PD were compared. Results Fifteen patients had experienced a major car accident resulting in human injury or serious property damage since the onset of PD. When the rates of major car accidents before and after the onset of PD were compared, the ratio was 4.3 [95% confidence interval (CI) 1.9-9.7]. The incidence of accidents after the onset of PD was correlated with age, disease duration, LED, the cognitive function Mini-Mental Scale Examination (MMSE), Japanese translation of the Montreal Cognitive Assessment (MoCA-J), but not the motor symptom score [Unified Pankinson's disease rating scale (UPDRS) part III at the time of the study]. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) score was also higher in patients with major car accidents. Conclusion The severity of symptoms (Hoehn-Yahr classification), cognitive function, and disease duration were expected to be risk factors for car accidents. However, the motor symptom score (UPDRS part III) was not associated with the incidence of major car accidents. In addition to a low cognitive function and the severity of symptoms, the QUIP score might be an independent factor that can be referenced when advising PD patients to refrain from driving.

Background and aims The relationship between exercise and subcortical gray matter volume is not well understood in the elderly population, although reports indicate that exercise may prevent cortical gray matter atrophy. To elucidate this association in the elderly, we measured subcortical gray matter volume and correlated this with volumes to exercise habits in a community-based cohort study in Japan. Methods Subjects without mild cognitive impairment or dementia (n = 280, 35% male, mean age 73.1 ± 5.9 years) were evaluated using the Mini-Mental State Examination (MMSE), an exercise habit questionnaire, and brain magnetic resonance imaging. Subcortical gray matter volume was compared between groups based on the presence/absence of exercise habits. The MMSE was re-administered 3 years after the baseline examination. Results Ninety-one subjects (32.5%) reported exercise habits (exercise group), and 189 subjects (67.5%) reported no exercise habits (non-exercise group). Volumetric analysis revealed that the volumes in the exercise group were greater in the left hippocampus (p = 0.042) and bilateral nucleus accumbens (left, p = 0.047; right, p = 0.007) compared to those of the non-exercise group. Among the 195 subjects who received a follow-up MMSE examination, the normalized intra-cranial volumes of the left nucleus accumbens (p = 0.004) and right amygdala (p = 0.014)showed significant association with a decline in the follow-up MMSE score. Conclusion Subjects with exercise habits show larger subcortical gray matter volumes than subjects without exercise habits in community-dwelling elderly subjects in Japan. Specifically, the volume of the nucleus accumbens correlates with both exercise habits and cognitive preservation.

A 30-year-old Vietnamese woman, about 19 weeks pregnant, was admitted for acute cerebral infarction with stenosis of the left middle cerebral artery (LMCA), tuberculous meningitis, and miliary tuberculosis. Treatment with heparin, quadruple anti-tuberculosis therapy, and dexamethasone afforded prompt symptomatic improvement. However, she delivered a stillbirth, after which there was recurrence of acute cerebral infarction with LMCA occlusion, sinus thrombosis, and cranial base inflammation. A thrice-weekly 100 mg dose of intrathecal isoniazid (INH) improved the signs of meningeal inflammation. The patient was discharged ambulatory after 7 months. In refractory tuberculous meningitis, multimodal therapy with intrathecal INH and steroids should be considered.

We aimed to clarify the longitudinal course of mild parkinsonian signs (MPS) and their association with dementia and functional disability by conducting a comprehensive epidemiological study, including brain MRI, and assessments of cognition, depression, and sleep, in people aged ≥65years living in Ama-cho. We diagnosed MPS and parkinsonism (PS) using a modified Unified Parkinson's Disease Rating Scale. The phase I study was conducted between 2008 and 2010 (n=729) and the phase II between 2011 and 2013 (n=436). By phase II, 8.5% of the phase I participants without PS had developed PS. In addition to older age, a lower Mini-Mental State Examination (MMSE) score, and lower body mass index, the MPS rigidity subtype was a significant independent predictor of PS onset. By phase II, 10.1% of the participants without dementia or PS at phase I had developed dementia. Older age, lower MMSE score, and the axial dysfunction and tremor MPS subtypes were significant independent predictors of dementia development. By phase II, 38.8% of participants with MPS at phase I showed no motor symptoms. Younger age and adequate sleep were significant predictors for this reversion. Periventricular and deep white matter hyperintensity Fazekas scores increased with the evolution of parkinsonian signs. MPS is therefore critically, although sometimes reversibly, associated with PS and dementia development in elderly people.

Aim An association between body mass index (BMI) and stroke outcome have been reported, but the results are controversial. The aim of the present study was to evaluate whether BMI is associated with ischemic stroke outcome. Methods Consecutive Japanese acute ischemic stroke patients were analyzed. BMI was categorized as underweight (BMI

Objective Melatonin is effective for treating patients with rapid eye movement sleep behavior disorder (RBD). Ramelteon, a novel hypnotic, acts as a melatonin receptor agonist. In the current study, we investigated the effects of ramelteon on sleep disorders, including RBD, in patients with Parkinson's disease (PD). Methods We evaluated 35 patients from multiple centers with idiopathic PD accompanied by sleep disturbances (age: 69.1±11.1 years; 17 men, 18 women; PD morbidity: 6.9±5.7 years; Hoehn & Yahr stage: 2.5±0.8; levodopa dose equivalent: 561±401 mg/day). The patients received 8 mg of ramelteon before sleep once daily for 12 weeks. Motor and sleep symptoms were evaluated both before and after ramelteon administration. Results Of the 35 patients enrolled in this study, 24 (68.6%) were diagnosed with probable RBD (pRBD) using the Japanese version of the RBD screening questionnaire. Ramelteon administration reduced the severity of sleep disturbances in patients with PD. It also lowered scores on the Japanese version of the RBD questionnaire in patients with PD and pRBD. Conclusion Ramelteon may have beneficial effects on sleep disturbances, especially on RBD in patients with PD.

We herein report a case of recurrent optic neuritis involving the cerebral white matter and brainstem in a patient positive for anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. The patient had an initial attack at 24 years of age. Optic neuritis recurred over 14 years, and she was admitted to our neurology unit at 38 years of age. She showed bilateral optic neuritis, high-intensity lesions in the cerebral white matter and brainstem on T2 MRI with contrast enhancement, and elevated serum anti-MOG antibodies. Immunotherapy improved the MRI lesions. Recurrent optic neuritis in patients with anti-MOG antibodies may thus involve the cerebral white matter and brainstem.

High plasma levels of brain natriuretic peptide (BNP) may also be observed in patients with non-cardioembolic infarction (CEI). We aimed to evaluate the relation between plasma BNP level, clinical parameters, and functional outcome in patients with and without CEI.This study analyzed consecutive Japanese patients with acute ischemic stroke. Correlations between plasma BNP level and conventional risk factors for ischemic stroke were examined. Values of P less than .05 were considered statistically significant.This study analyzed 718 acute ischemic stroke patients (445 men and 273 women; mean age, 73.9 years). Mean plasma level of BNP was significantly higher for CEI (366.6 pg/ml) than for non-CEI (105.6 pg/ml; P.01). Poor outcome (modified Rankin Scale score ≥3) at hospitalization and discharge were associated with significantly higher plasma BNP level than good outcome (modified Rankin Scale score ≤2) for both CEI and non-CEI. On multiple regression analysis, log-BNP was significantly associated with female sex, smoking, triglyceride, and creatinine clearance in CEI. In non-CEI, log-BNP was significantly associated with systolic/diastolic blood pressure, triglyceride, high-density lipoprotein cholesterol, and creatinine clearance.Irrespective of the presence of CEI, plasma BNP offers a marker of prognostic functional outcome. We clarified the characteristics and differences associated with plasma BNP in CEI and non-CEI, and our results suggest that plasma BNP can provide a useful marker of brain damage and neurohumoral dynamics in acute ischemic stroke.

International audience; Objective : Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case–control series.Methods : We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants.Results : In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel–Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14–5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15–5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10−3).Interpretation : The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

Lemierre syndrome is a clinical syndrome that presents with internal jugular thrombophlebitis, septicemia and systemic abscess formations. In general, the condition is preceded by oropharyngeal infections. We report a case of a 73-year-old man with Lemierre syndrome, clivus osteomyelitis and a steroid-responsive mass in the cavernous sinus-suprasellar region. He complained of fever, occipital pain, diplopia and right ptosis. Administration of oral steroids ameliorated the ophthalmic symptoms for a period before he was admitted to our hospital. After admission, the severity of his headache advanced, and his ophthalmic symptoms progressed bilaterally. Brain magnetic resonance imaging showed contrast enhancement of the clivus and revealed a mass lesion contrast-enhancement effect in the cavernous sinus-suprasellar region. Fusobacterium nucleatum was detected by blood culture, and computed tomography revealed multiple bacterial emboli in both lung fields and thrombosis of the left internal jugular vein; thus, he was diagnosed with Lemierre syndrome. After venous administration of antibiotics, his fever and headache markedly improved, but the ophthalmic symptoms did not. We prescribed an oral steroid because the cavernous sinus-suprasellar lesion was probably an inflammatory granuloma caused by a para-infectious mechanism rather than by infection. After the series of treatments, his ophthalmic symptoms improved, and the cavernous sinus-suprasellar region mass lesion decreased. He was eventually discharged in a fully ambulatory state and had no ophthalmic difficulties. We thought that the osteomyelitis of clivus was caused by Lemierre syndrome and its inflammatory processes formed the granuloma in the cavernous sinus-suprasellar region. This was a case of Lemierre syndrome with a rare combination of clivus osteomyelitis and a steroid-responsive tumour in the cavernous sinus-suprasellar region that was successfully treated.

Spinocerebellar ataxia type 31 (SCA31) is an autosomal dominant cerebellar ataxia commonly observed in Japan. However, few neuropathological examinations have been conducted. Here we report the case of a 76-year-old Japanese male SCA31 patient. He noticed dysarthria and difficulty walking at 65 years old. His symptoms subsequently deteriorated, although he could still walk with assistance at 70 years. At 73 years, when he could no longer walk, he was admitted to our hospital. He showed severe limb and truncal ataxia. His father and older brother had shown the same symptoms. Brain magnetic resonance imaging showed cerebellar atrophy of the anterior lobe and white matter hyperintensities. He was diagnosed with SCA31 by genetic analysis. Gradually, his cognitive functions and ability to communicate declined. He died of respiratory failure at the age of 76. Neuropathological examination revealed severe Purkinje cell loss that was accentuated in the anterior lobe of the cerebellum. Furthermore, the remaining Purkinje cells showed abnormal processes (that is, halo-like amorphous materials), as has been reported previously. Severe deposition of hyperphosphorylated tau-positive neurites, many senile plaques and amyloid angiopathy were observed in the neocortex. Our findings suggest that in SCA31, accelerated tau and amyloid pathology in the neocortex might induce dementia at the terminal stage.

Introduction The REM sleep behavior disorder (RBD) screening questionnaire (RBDSQ) has been used as a screening tool for RBD. We investigated the clinical characteristics of probable RBD (pRBD) using the RBDSQ in patients with Parkinson's disease (PD). Methods Seventy patients with PD (age: 69.2±8.9years old, 31 males and 49 females, length of PD morbidity: 7.4±6.4years, Hoehn and Yahr: 2.7±0.8) underwent examination including the RBDSQ and Mini-Mental State Examination (MMSE) in both 2011 and 2013. We assessed the changes and characteristics of pRBD associated with PD during the two year interval. Results Nineteen patients (27.1%) in 2011 and 27 patients (38.6%) in 2013 were diagnosed as having pRBD because they scored 6 or higher on the RBDSQ. During the 2year interval, twelve patients showed persistent pRBD, 15 developed pRBD, and 7 showed improved pRBD. In 2013, PD patients with pRBD took higher amounts of levodopa equivalents and scored lower on the MMSE than those without pRBD. Also, more PD patients with pRBD had dementia than those without pRBD. Similarly, more patients with persistent and developed pRBD had dementia than those without. Conclusion We found that RBD symptoms might fluctuate during the clinical course of PD, and RBD symptoms might temporarily affect cognitive impairment.

Documentation of the current status of specialty training to become a neurologist in Japan would represent an important basis for constructing better neurology training program in the planned reform of the specialty training system in Japan. The committee for future neurology specialty system of Japanese Society of Neurology (JSN) conducted a questionnaire survey on the process of specialty training of each trainee for neurology in board-certified educational facilities and semi-educational facilities throughout Japan. The response rate was 46.2% in all facilities and 87.5% in medical universities. The training process of 905 trainees over 5 grades was clarified, which was estimated to be about 80% of all the relevant subjects. Specialty training dedicated to neurology was started at the 3rd year of residency in 87.8% of subjects. During the 3 years following junior residency, 51.3% of subjects ran the rotation training between university and city hospital, whereas 36.5% was trained within the same institution throughout the 3 years of training period.

Background An association between serum uric acid and outcomes of ischemic stroke has been reported, but the results are controversial. The aim of this study is to clarify how uric acid may affect activities of daily living after acute ischemic stroke. Methods Consecutive Japanese patients with acute ischemic stroke were analyzed. Serum uric acid quartiles and activities of daily living at hospitalization and discharge in men and women were examined. Activities of daily living were evaluated using the modified Rankin scale score, and a score of 3 or higher was defined as poor activities of daily living. P values less than .05 were considered significant. Results A total of 987 patients with acute ischemic stroke (591 men; mean age, 72.3 years) were analyzed in this study. We observed a U-shaped relationship between serum uric acid and poor activities of daily living in both men and women at hospitalization and discharge. Multivariate analysis demonstrated that the first quartile group of serum uric acid was significantly associated with poor activities of daily living in both men and women, using the third quartile group as the reference. Conclusions Lower serum uric acid can be a marker for predicting poor activities of daily living in patients with acute ischemic stroke, irrespective of sex.

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. Results The 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.

In a prospective study, we recently discovered 8 clinical predictors of dementia in Parkinson's disease. Here, we validate these dementia predictors using two additional prospective cohorts (n = 134). After a 3.6-year follow-up, 35/134 developed dementia (7.2% per year). When confirming individual variables, 5/8 were significantly associated with dementia in the validation cohort. These included age, male sex, baseline RBD, orthostatic hypotension, and MCI. Bilateral onset, hallucinations and falls/freezing did not significantly predict dementia; however, point estimates of OR were all >1. In all cohorts, the strongest determinant for dementia development was the co-existence of RBD, MCI and orthostatic hypotension at baseline.

Objective To clarify the clinical features of freezing of gait (FOG) in Parkinson's disease (PD) patients by classification into two groups: Clinically observed FOG (CFOG) and self‐reported FOG (SFOG). Methods Two hundred twenty‐nine PD patients were medically examined in an examination room as well as subjected to a New Freezing of Gait Questionnaire (NFOG‐Q) and analysis of nonmotor symptoms including sleep, cognition, depression, and fatigue. Results The prevalence of CFOG was 17.9%, while 53.7% of the patients without CFOG reported the presence of FOG via the NFOG‐Q. Univariate analysis revealed that CFOG was associated with longer disease duration, motor dysfunction, sleepiness, fatigue, and cognitive dysfunction. These symptoms, excluding akinesia, apathy, rapid eye movement (REM) sleep Behavior Disorder, and cognitive dysfunction, were also associated with SFOG. Multivariate analysis revealed that long PD duration, postural instability, and gait difficulty (PIGD), along with fatigue, were independent factors for SFOG. Conclusions SFOG and CFOG have many common clinical features. Although the clinical relevance of SFOG remains unclear, careful attention should be paid to related features in clinical practice.

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.

Background Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that is sometimes confused with Parkinson's disease, multiple system atrophy, and other disorders. The typical clinical features are categorized as Richardson's syndrome (RS), but other clinical subtypes include PSP-parkinsonism (PSP-P) and PSP-pure akinesia with gait freezing (PSP-PAGF). In this study, we determined the prevalence of PSP in a Japanese rural area compared to our previous 1999 report. Methods We collected data in Yonago City from 2009 to 2014 using a service-based study of PSP. We collected case history data from PSP patients in the area from our hospital. The crude prevalence and 95% confidence interval (CI) were calculated using the population demographics on the prevalence day of 1 October 2010. Age- and sex-adjusted prevalence was calculated by direct standardization to the population demographics in Yonago City on the prevalence day of 1 April 1999. Material and Results We identified 25 patients: 16 with probable RS, 4 with possible RS, 3 with clinical PSP-P, and 2 with clinical PSP-PAGF. The prevalence per 100,000 was 17.90 (male = 18.05; female = 17.76). The prevalence of PSP in Yonago in 2010 increased compared to the measurements from 1999. Conclusion The prevalence of PSP in Japan increased from 1999 to 2010.

A patient with xerostomia and xerophthalmia due to Sjogren's syndrome presented with acute motor-dominant polyneuropathy and multiple mononeuropathy with antiganglioside antibodies. Nerve conduction studies and a sural nerve biopsy revealed the neuropathy as a mixture of segmental demyelination and axonal degeneration. Positive results were obtained for several antiganglioside antibodies. Corticosteroid treatment proved effective. The neuropathy was considered to represent a mixture of polyneuropathy as Guillain-Barre syndrome and multiple mononeuropathy via Sjogren's syndrome. We speculate that Guillain-Barre syndrome occurred in the patient and Guillain-Barre syndrome itself activated multiple mononeuropathy via Sjogren's syndrome.

Objective Rapid eye movement (REM) sleep behavior disorder (RBD) is important not only as a preclinical symptom of Parkinson's disease (PD), but also as an aggravating symptom of PD. However, it is not known whether the onset of RBD in relation to PD affects the clinical characteristics of PD. A cross-sectional study comparing clinical characteristics of PD between patients with RBD occurring before and after the onset of PD was conducted. Methods Interviews regarding RBD symptoms were conducted and polysomnography was performed on 136 patients with PD. Patients with PD were divided into a group with RBD and a group without RBD. Moreover, the group with RBD was subdivided into those with RBD before the onset of PD (RBD → PD) and those with RBD after the onset of PD (PD → RBD). Clinical characteristics of the patients with and without RBD, and PD with RBD → PD and PD → RBD were compared. Results Patients with RBD (47 PD patients) had more severe parkinsonian symptoms, autonomic dysfunction, and cognitive impairment than those without RBD (89 PD patients). Moreover, 38 PD patients with PD → RBD had greater cognitive impairment including Mini-metal examination than 9 with RBD → PD in spite of similar motor and autonomic dysfunction with similar dopaminergic agents. Conclusion The occurrence of RBD after the onset of PD might be an important factor aggravating cognitive function.

Background: The prevalence of frontotemporal lobar degeneration (FTLD) in Japan is unknown. An epidemiological survey study of FTLD was undertaken in Tottori Prefecture, a district in the western region of Japan. Methods: Hospitals in Tottori Prefecture were surveyed by a two-step questionnaire in 2010, and the prevalence of FTLD per 100,000 inhabitants was calculated using the actual number of patients and inhabitants in Tottori Prefecture on the prevalence day of October 1, 2010. Results: In this survey, 66 patients were diagnosed with FTLD. The subtypes of FTLD were as follows: 62 cases of frontotemporal dementia (FTD), 3 cases of progressive nonfluent aphasia, and 1 case of semantic dementia. Among the FTD cases, 5 cases were FTD with motor neuron disease and 1 case was FTD with parkinsonism linked to chromosome 17. The prevalence of FTD in the total population of Tottori Prefecture was 11.2 per 100,000 inhabitants. Based on these results, the prevalence of FTLD in Japan in 2008 was estimated to be 9.5 per 100,000 individuals. Conclusions: Our epidemiological survey results suggest that there are at least 12,000 FTLD patients in Japan, indicating that FTLD is not a rare disease.

Aims: In order to determine the prevalence of dementia and mild cognitive impairment (MCI), we conducted a population-based study in Japan. Methods: Participants included 924 subjects aged 65 years or older who resided in the town of Ama-cho. In phase 1 of the study, the Mini-Mental State Examination and Clinical Dementia Rating were administered for screening purposes. In phase 2 of the study, the subjects who screened positive were further examined by neurologists. Dementia and MCI were diagnosed by means of DSM-IV and International Working Group on MCI criteria, respectively. Results: By the prevalence date of June 1, 2010, 24 subjects had deceased or lived outside the town. In total, 723 of the remaining 900 subjects received a phase 1 test. In phase 2, 98 subjects were diagnosed with amnestic MCI, 113 subjects with non-amnestic MCI, and 82 subjects with dementia. Of the subjects who did not receive the phase 1 test, 66 subjects were diagnosed as having dementia according to data from their town medical card or the Long-term Care Insurance System. The crude prevalence of amnestic MCI, non-amnestic MCI, and dementia were 10.9, 12.6, and 16.4%, respectively. Conclusion: Consistent with the striking increase in the number of elderly individuals, we report higher prevalence of MCI and dementia in Japan than previously described.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by serious muscle atrophy and weakness. The purpose of this study was to find prognostic factors in patients with mild ALS using application forms for the Specified Disease Treatment Research Program in Japan. We classified ALS as mild, moderate and severe. The subjects consisted of 363 patients with mild ALS who underwent needle electromyography at registration and were followed for more than one year. Time to progression to severe ALS and time to deterioration of activities of daily living such as speech dysfunction, upper limb dysfunction, and walking disability were used as outcomes. Cox proportional hazards model analysis was performed to identify prognostic factors. Of the patients with initially mild ALS, 38.3% (139/363) had progressed severe ALS at the last follow-up. In multivariate analysis of time to progression to severe ALS, bulbar onset (hazard ratio [95% confidence interval]: 1.68 [1.13-2.49], p = 0.010), tongue atrophy (1.69 [1.14-2.51], p = 0.009), dyspnea (1.57 [1.02-2.41], p = 0.042) and active denervation findings (ADFs) of the cervical-upper limb area (1.81 [1.25-2.63], p = 0.002) emerged as prognostic factors. Furthermore ADFs in the trunk area were prognostic factors for upper limb dysfunction and walking disability (1.72 [1.05-2.81], p = 0.031, and 1.97 [1.09-3.59], p = 0.026). In conclusion ADFs of the cervical-upper limb area and trunk area were prognostic factors in ALS patients.

Persistent infection with hepatitis C virus (HCV) is closely correlated with type 2 diabetes. In this study, replication of HCV at different glucose concentrations was investigated by using J6/JFH1-derived cell-adapted HCV in Huh-7.5 cells and the mechanism of regulation of HCV replication by AMP-activated protein kinase (AMPK) as an energy sensor of the cell analyzed. Reducing the glucose concentration in the cell culture medium from 4.5 to 1.0 g/L resulted in suppression of HCV replication, along with activation of AMPK. Whereas treatment of cells with AMPK activator 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) suppressed HCV replication, compound C, a specific AMPK inhibitor, prevented AICAR's effect, suggesting that AICAR suppresses the replication of HCV by activating AMPK in Huh-7.5 cells. In contrast, compound C induced further suppression of HCV replication when the cells were cultured in low glucose concentrations or with metformin. These results suggest that low glucose concentrations and metformin have anti-HCV effects independently of AMPK activation.

Objective This study was set out to identify the population with restless legs syndrome (RLS) developing a chronic course and the impact of long-term morbidity of RLS on disorder related dysfunctions. Methods Two population-based epidemiological surveys were performed in 2005 and 2007 on the same cohort in Japan. Questionnaires including demographics, measurement scales for depression, quality of life, subjective sleep disturbances, and the NIH/IRLSSG consensus questionnaire for RLS diagnosis, were distributed to participants, and then telephone interviews were performed to determine the diagnosis and severity of RLS. Results Among 1592 valid respondents, only 20 (40%) of 50 RLS-positive subjects at the first survey were repeatedly RLS-positive at the second survey. The frequency of RLS symptoms at the first survey was associated with the repeated appearance of RLS symptoms (odds ratio 8.70, p =0.0302). The chronic morbidity of RLS seemed to be associated with the existence of depression and subjective sleep disturbance. Conclusions RLS may not be persistent in more than 50% of the affected population. The frequency of RLS symptoms, but not the severity, may predict the persistence of this disorder.

Background We studied the relationship between survival prognosis and the functional outcome at discharge from acute-care hospitals in each subtype of ischemic stroke patients. Methods A total of 853 consecutive patients with first-ever ischemic stroke, recruited from December 1999 to November 2002, were followed for 725.8 ± 430.0 days. Functional outcome was scored using the modified Rankin scale (mRS). Survival analysis was performed using Kaplan-Meier curves, log rank test, and Cox regression model. Results The respective mortality of the groups with mRS scores of 0-2, 3, 4, and 5 were 13.1%, 25.0%, 47.2% (p

Aim: To elucidate the factors associated with insomnia symptoms and the use of sleep medication, and the correlations among insomnia symptoms, sleep medication use and depressive symptoms in the general population. Methods: This survey was conducted in a rural community of Japan. Questionnaires consisted of basic information, the Pittsburgh Sleep Quality Index, and a 12-item version of the Center for Epidemiological Studies Depression scale, and were administered to all community members aged 20 years or over. A total of 2822 respondents with valid answers were subjected to analysis. Results: Occurrence of insomnia symptoms appeared to be associated with advancing age and existence of depressive symptoms. The extent of sleep medication use in the entire sample was 9%, and the value in the subjects with insomnia symptoms was 26%. Sleep medication use in insomniacs was associated with female sex and advancing age as well as higher scores in subcomponents of both poor subjective sleep quality and prolonged delay of sleep onset. Depressive symptoms were worst in the group with insomnia symptoms using sleep medication, and were significantly lower in the group without insomnia symptoms using sleep medication. Conclusions: Our study revealed that female sex, advancing age, depressive symptoms, poor sleep quality, and prolonged delay of sleep onset appeared as risk factors for sleep medication use. Insomnia symptoms were suspected to act as an exacerbating factor for depressive symptoms. However, our findings suggested that appropriate use of sleep medication could reduce depressive symptoms in the subjects with insomnia symptoms. Language: en

Importance Parkinson disease dementia dramatically increases mortality rates, patient expenditures, hospitalization risk, and caregiver burden. Currently, predicting Parkinson disease dementia risk is difficult, particularly in an office-based setting, without extensive biomarker testing. Objective To appraise the predictive validity of the Montreal Parkinson Risk of Dementia Scale, an office-based screening tool consisting of 8 items that are simply assessed. Design, Setting, and Participants This multicenter study (Montreal, Canada; Tottori, Japan; and Parkinson Progression Markers Initiative sites) used 4 diverse Parkinson disease cohorts with a prospective 4.4-year follow-up. A total of 717 patients with Parkinson disease were recruited between May 2005 and June 2016. Of these, 607 were dementia-free at baseline and followed-up for 1 year or more and so were included. The association of individual baseline scale variables with eventual dementia risk was calculated. Participants were then randomly split into cohorts to investigate weighting and determine the scale’s optimal cutoff point. Receiver operating characteristic curves were calculated and correlations with selected biomarkers were investigated. Main Outcomes and Measures Dementia, as defined by Movement Disorder Society level I criteria. Results Of the 607 patients (mean [SD] age, 63.4 [10.1]; 376 men [62%]), 70 (11.5%) converted to dementia. All 8 items of the Montreal Parkinson Risk of Dementia Scale independently predicted dementia development at the 5% significance level. The annual conversion rate to dementia in the high-risk group (score, >5) was 14.9% compared with 5.8% in the intermediate group (score, 4-5) and 0.6% in the low-risk group (score, 0-3). The weighting procedure conferred no significant advantage. Overall predictive validity by the area under the receiver operating characteristic curve was 0.877 (95% CI, 0.829-0.924) across all cohorts. A cutoff of 4 or greater yielded a sensitivity of 77.1% (95% CI, 65.6-86.3) and a specificity of 87.2% (95% CI, 84.1-89.9), with a positive predictive value (as of 4.4 years) of 43.90% (95% CI, 37.76-50.24) and a negative predictive value of 96.70% (95% CI, 95.01-97.85). Positive and negative likelihood ratios were 5.94 (95% CI, 4.08-8.65) and 0.26 (95% CI, 0.17-0.40), respectively. Scale results correlated with markers of Alzheimer pathology and neuropsychological test results. Conclusions and Relevance Despite its simplicity, the Montreal Parkinson Risk of Dementia Scale demonstrated predictive validity equal or greater to previously described algorithms using biomarker assessments. Future studies using head-to-head comparisons or refinement of weighting would be of interest.

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease, and the etiology of sporadic ALS is generally unknown. The TANK-binding kinase 1 (TBK1) gene was identified as an ALS gene contributing to a predisposition toward ALS. To reveal the frequency and characteristics of variants of the TBK1 gene in sporadic ALS patients in Japan, we analyzed the TBK1 gene by exome sequencing in a large Japanese cohort of 713 sporadic ALS patients and 800 controls. We identified known or potentially toxic rare variants of TBK1 gene in 9 patients (1.26%) with sporadic ALS, including 4 novel missense variants (p.V23I, p.H322R, p.R358C, and p.T478I) and 3 loss-of-function variants (p.R357X, p.P378_I379del, and p.T419_G420del). The odds ratio between sporadic ALS patients and controls was 10.2 (p = 0.008, 95% confidence interval = 1.67–62.47). These findings support the contribution of TBK1 to the etiology of sporadic ALS in Japanese patients.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. alpha-Synuclein is a major component of Lewy bodies. Recently, many studies have focused on the interaction between alpha-synuclein and catecholamine in the pathogenesis of PD. However, no detailed relationship between cathecholamine and alpha-synuclein cytotoxicity has been elucidated. Therefore, this study established PC12 cell lines which overexpress human alpha-synuclein in a tetracycline-inducible manner. The overexpression of human alpha-synuclein increased the number of apoptotic cells in a long-term culture. Moreover, human alpha-synuclein expressing PC12 cells demonstrated an increased vulnerability to several stressors in a short culture period. Thapsigargin increased the SDS soluble oligomers of alpha-synuclein associated with catecholamine-quinone. The unfolded protein response (UPR) study showed that thapsigargin increased eIF2alpha phosphorylation and nuclear GADD153/CHOP induction under alpha-synuclein overexpressed conditions. The activities of the ATF6alpha and IRE1alpha pathways decreased. These findings suggest that an overexpression of alpha-synuclein partly inactivates the UPR. alpha-Methyltyrosine inhibited the dysfunction of the UPR caused by an overexpression of human alpha-synuclein. Therefore, these findings suggest that the coexistence of human alpha-synuclein with catecholamine enhances the endoplasmic reticulum stress-related toxicity in PD pathogenesis.

Background and purpose: We investigated dementia in patients with multiple system atrophy (MSA) in order to characterize the prevalence and nature of impairments in these patients. Methods: Fifty-eight MSA patients were recruited in our institution between April 1996 and December 2006 and investigated. Results: Of 58 patients, 10 were diagnosed with dementia. There were no significant differences in age at onset, gender, duration of disease, or severity of cerebellar dysfunction between patients with and without dementia. The early and delayed heart to mediastinum (H/M) ratios obtained with 123I-metaidobenylguanidine (MIBG) cardiac scintigraphy were significantly decreased in patients with dementia compared with those without dementia. Of the 10 patients with dementia, three were found to have cognitive decline that preceded onset of motor symptoms. White matter lesions were evident in these patients, whilst frontal atrophy was prominent in patients whose cognitive decline was preceded by onset of motor symptoms. Conclusions: Dementia in patients with MSA may be more common than previously thought, furthermore, we speculate that clinical features of dementia in these patients might be heterogeneous.

Aim: We assessed the long-term prognosis of patients with large subcortical infarctions (LSCI). Methods: We defined LSCI as lesions ≥15 mm confined to deep penetrating arteries without a cardioembolic or atherothrombotic source. Patients with acute ischemic strokes were consecutively registered and followed for 751 ± 441 days. The clinical characteristics and long-term prognoses of patients with LSCI were compared to those of patients with lacunar (LACI), atherothrombotic (ATI) and cardioembolic infarctions (CEI). Results: At discharge from the hospital, the proportion of good outcomes (modified Rankin Scale ≤2) for patients with LSCI (52.1%) was similar to that for ATIs (47.2%), but worse than that for LACIs (73.2%). After a 3-year follow-up period, the mortality rates from LSCI, LACIs, ATIs and CEIs were 8.4, 8.2, 22.3 and 41.1%, respectively; the recurrence rates were 9.3, 14.1, 16.6 and 23.8%, respectively. Conclusions: The short-term prognosis of functional outcomes for LSCI was worse than that for LACIs, but similar to acute-phase ATI outcomes. The long-term prognosis after a LSCI is good, and recurrence tends to be lower than for LACIs.

Background/Aim: To determine the prevalence and incidence of Parkinson’s disease (PD) and compare them with results from our previous studies. Methods: We examined epidemiological characteristics of PD patients using a service-based study in Yonago City, and a door-to-door study in Daisen Town. The prevalence days were April 1, 2004 in Yonago, and April 1, 2003 in Daisen. Results: In Yonago, we identified 254 PD patients. The crude prevalence was 180.3 (95% CI, 158.1–202.4) per 100,000 population. The adjusted prevalence was 145.8 (95% CI, 145.2–146.5) in 1980, 147.0 (95% CI, 146.3–147.6) in 1992, and 166.8 (95% CI, 166.1–167.5) in 2004, when calculated using the Japanese population in 2004. The crude incidence was 18.4 (95% CI, 11.3–25.5) per 100,000 population per year. The crude incidence in 1980 was 10.2 (95% CI, 4.6–15.8), and the adjusted incidence was 9.8 (95% CI, 4.3–15.3) in 1992, and 10.3 (95% CI, 4.7–15.9) in 2004, when calculated using the population in Yonago in 1980. In Daisen, there were 21 PD patients. The crude prevalence was 306.6 (95% CI, 175.7–437.6) and the adjusted prevalence was 192.6 (95% CI, 191.9–193.8). Conclusions: The prevalence of PD had increased, primarily because the population had aged. Differences in prevalence between these adjacent areas may have resulted from differences in the methods of investigation.

Background and purpose: To conduct an epidemiological survey of acute encephalitis focusing on non-herpetic acute limbic encephalitis (NHALE) in Tottori Prefecture, western area of Japan. Methods: A questionnaire survey on the annual number of patients aged 16 years or more with acute encephalitis from 2001 to 2005 was undertaken in 2006. Results: During the study period, 49 patients were diagnosed with acute encephalitis. The subtype of acute encephalitis was as follows: 10 patients with herpes simplex encephalitis (HSE), 12 patients with NHALE, 4 patients with paraneoplastic encephalitis, 2 patients with encephalitis associated with collagen disease, one patient with viral encephalitis other than HSE, 20 patients with encephalitis with unknown causes. The service-based incidence rate of acute encephalitis was 19.0 per million person-years. The incidence rate of NHALE subtype was 4.7 per million person-years. Conclusions: Our epidemiological survey indicated an estimated 550 patients would develop NHALE per year in Japan, suggesting that NHALE may not be a rare disorder.

Pramipexole, a dopamine D2/D3 receptor agonist used in the treatment of Parkinson's disease, has been reported to have neuroprotective potential. We investigated the effect of pramipexole against cell death induced by a proteasome inhibitor, lactacystin, using primary mecencephalic neuronal cultures and SH-SY5Y cells. In E14 rat primary mesencephalic cultures, the number of surviving tyrosine hydroxylase (TH)-positive neurons and microtubule associated protein 2 (MAP2)-positive neurons was decreased by exposure to 1-5 microM lactacystin in a dose-dependent manner. Pretreatment with 100 microM pramipexole rescued TH-positive neurons and MAP2-positive neurons from the toxicity of lactacystin. The protective effect of pramipexole was not selective for TH-positive dopaminergic neurons. However, the treatment with 100 microM pramipexole did not protect SH-SY5Y cells against lactacystin-induced cell toxicity and proteasome dysfunction. We hypothesized that the protective effect of pramipexole against the lactacystin-toxicity was not direct but a secondary effect mediated by astrocytes. Therefore, we investigated the efficacy of conditioned medium collected from mecencephalic astrocytes treated with pramipexole. The conditioned medium increased the viability of SH-SY5Y cells against the toxicity of lactacystin. Pramipexole increased the levels of brain derived neurotrophic factor (BDNF) in the conditioned medium of astrocyte cultures. These protective effects were not significantly inhibited by dopamine D2 or D3 receptor antagonists. We demonstrated that pramipexole had the protective effect against lactacystin toxicity, mediated by a neurotrophic effect of astrocyte-produced factors including BDNF.

The prevalence, clinical significance and awareness of restless legs syndrome (RLS) have not been well identified in Japan. We conducted an Internet-based survey on the general Japanese population. Using an Internet-linked questionnaire, we evaluated 8126 respondents, consisting of a cross-section of Japanese adults aged 20 to 59 years. The questionnaire items consisted of demographic variables, the National Institute of Health/International RLS Study Group (IRLSSG) consensus questionnaire, the IRLSSG rating scale (IRLS), the Pittsburgh sleep quality index (PSQI), and questions regarding diagnosis and treatment. Probable RLS was found in 326 participants (4.01%). The prevalence was significantly higher in women (4.9%) than in men (3.0%), but did not differ by age. Most of the probable participants had mild to moderate IRLS severity and their average PSQI score was significantly higher than in unaffected participants. No probable RLS participants had been diagnosed with RLS, and only 7.7% had sought medical assistance. The prevalence of probable RLS in Japan is higher than in previous reports in Asia and, despite its low severity, the disorder is also thought to contribute to sleep disturbances in affected individuals. RLS is not well recognized in Japan and so promoting RLS awareness is necessary.