[Show abstract][Hide abstract] ABSTRACT: A human artificial chromosome (HAC) is maintained as an episome within a cell and avoids random integration into the host genome. It can transfer multiple and/or large transgenes along with their regulatory elements thereby resembling native chromosomes. Using this HAC system, we established mesenchymal stem cells (MSCs) that simultaneously expressed hepatocyte growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor 1, termed HAC-MSCs. This cell line provides an opportunity for stable transplantation and thorough analyses. We then introduced the cells for the treatment of a neurodegenerative disorder, amyotrophic lateral sclerosis. The HAC-MSCs were transplanted via the fourth cerebral ventricle (CV) or intravenous (i.v.) infusion at various ages of recipient mice. Littermate- and sex-matched mice underwent a sham procedure. Compared to the controls, there was an encouraging trend of increased life span via CV transplantation and delayed onset in i.v. infusion 60 days after transplantation. Further, we confirmed a statistically significant increase in life span via CV transplantation at 100 days. This effect was not seen in mice transplanted with MSCs lacking the HAC. We successfully enhanced the trophic potential of the MSCs using the HAC. This strategy could be a promising direction for the treatment of neurodegenerative disorders.
[Show abstract][Hide abstract] ABSTRACT: A 30-year old man was admitted with right hip pain and gait disturbances. Neurological findings revealed muscular weakness in the lower limbs, hyporeflexia, dysesthesia in the sacral region, and bowel and bladder disturbances. Cerebrospinal fluid (CSF) examination indicated a white blood cell count of 371/μl (lymphocyte:polymorphonuclear leukocyte = 97:3), protein levels of 463 mg/dl and sugar of 20 mg/dl. Although CSF culture was negative, tuberculous infection was presumed. Magnetic resonance imaging revealed areas of enhancement in the intramedullary region surrounding the spinal cord and cauda equina. Enhanced computed tomography (CT) of the abdomen revealed lymph node swelling around the head of the pancreas. Biopsy of the lymph node swelling was culture-positive for Mycobacterium tuberculosis. Hence, assuming a diagnosis of tuberculous lymphadenitis of the abdomen, antitubercular drugs were started. Since antitubercular therapy had beneficial effects on the neurological symptoms and CSF findings, we diagnosed the patient with tuberculous myeloradiculitis. Systematic examinations including lymph node biopsy and cultures were useful for the diagnosis of tuberculous myeloradiculitis.
[Show abstract][Hide abstract] ABSTRACT: Objectives The pathogenesis of Alzheimer's disease (AD) is strongly correlated with the aggregation and deposition of the amyloid beta (Aβ1-42) peptide in fibrillar form, and many studies have shown that plant-derived polyphenols are capable of attenuating AD progression in various disease models. In this study, we set out to correlate the effects of anthocyanoside extracts (Vaccinium myrtillus anthocyanoside (VMA)) obtained from bilberry on the in vitro progression of Aβ fibril formation with the in vivo effects of this compound on AD pathogenesis. Methods Thioflavin T fluorescence assays and atomic force microscopy were used to monitor Aβ amyloid formation in in vitro assays. Effects of Aβ amyloids on cellular viability were assayed using cultured Neuro2a cells. Cognitive effects were probed using mice that simultaneously expressed mutant human Aβ precursor and mutant presenilin-2. Results Addition of VMA inhibited the in vitro formation of Aβ peptide fibrils and also reduced the toxicity of these aggregates toward Neuro2a cells. A diet containing 1% VMA prevented the cognitive degeneration in AD mice. Curiously, this diet-derived retention of cognitive ability was not accompanied by a reduction in aggregate deposition in brains; rather, an increase in insoluble deposits was observed compared with mice raised on a control diet. Discussion The paradoxical increase in insoluble deposits caused by VMA suggests that these polyphenols divert Aβ aggregation to an alternate, non-toxic form. This finding underscores the complex effects that polyphenol compounds may exert on amyloid deposition in vivo.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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)).
The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND PURPOSE:Dementia with Lewy bodies (DLB) needs to be distinguished from Alzheimer's disease (AD) because of important differences in patient management and outcome. Severe cardiac sympathetic degeneration occurs in DLB, but not in AD, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the diagnostic accuracy, in the ante-mortem differentiation of probable DLB from probable AD, of cardiac imaging with the ligand 123I-meta-iodobenzylguanidine (MIBG) which binds to the noradrenaline reuptake site, in the first multicenter study.
METHODS:We performed a multicenter study in which we used 123I-MIBG scans to assess 133 patients with clinical diagnoses of probable (n = 61) or possible (n = 26) DLB or probable AD (n = 46) established by a consensus panel. Three readers, unaware of the clinical diagnosis, classified the images as either normal or abnormal by visual inspection. The heart-to-mediastinum ratios of 123I-MIBG uptake were also calculated using an automated region-of-interest based system.
RESULTS:Using the heart-to-mediastinum ratio calculated with the automated system, the sensitivity was 68.9% and the specificity was 89.1% to differentiate probable DLB from probable AD in both early and delayed images. By visual assessment, the sensitivity and specificity were 68.9% and 87.0%, respectively. In a subpopulation of patients with mild dementia (MMSE ≥ 22, n = 47), the sensitivity and specificity were 77.4% and 93.8%, respectively, with the delayed heart-to-mediastinum ratio.
CONCLUSIONS:Our first multicenter study confirmed the high correlation between abnormal cardiac sympathetic activity evaluated with 123I-MIBG myocardial scintigraphy and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from AD, especially in patients with mild dementia.
PLoS ONE 03/2015; 10(3):e0120540. DOI:10.1371/journal.pone.0120540 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report the case of an 18-year-old Japanese woman with cobalamin (cbl) C disease. She was born between non- consanguineous parents, and had easy fatigability from a childhood. At 14 years old, she developed renal failure, and had repeated psychosis during 2 years. At 16 old, she developed her gait disturbance and her symptoms fluctuated, but the cause of gait disturbance was unclear. At 18 years old, she was admitted with worsening of gait disturbance. Physical examination revealed spastic paraparesis and bilateral peroneal nerve paralyses. Homocystinuria and methylmalonic aciduria were detected, although serum vitamin B12 was within normal range. Gene mutation analysis revealed Gly147Asp (440G>A) and Trp157Ser (470G>C) in the MMACHC gene as a compound heterozygous mutation. We diagnosed her as having late-onset cbl C disease, and her gait disturbance and renal failure improved after intramuscular hydroxocobalamin administration. Although late-onset cbl C disease is rare in Japan, it an important to consider this congenital disease because symptoms are expected to improve by medical intervention.
[Show abstract][Hide abstract] ABSTRACT: Background
To determine the relationships between regional white matter lesions (WMLs), lifestyle factors, and cognitive, motor function and mood.MethodsA comprehensive evaluation, including brain MRI, blood tests, the Unified Parkinson's Disease Rating Scale, the Mini Mental State Examination, and the Geriatric Depression Scale, was performed for people aged 65 years or older living in Ama-cho on October 1, 2009. Participants were classified by severity of periventricular hyperintensities (PVH) and deep white matter hyperintensities (DWMH) using the Fazekas score.ResultsOf 900 eligible participants, 688 (76.4%) were enrolled, including 303 men. Significant predictors of severe PVH were older age, lower low-density lipoprotein cholesterol (LDL-C) levels, elevated blood pressure (BP), cerebral infarction, and no current alcohol use. Significant predictors of severe DWMH were older age, lower 1,5-anhydroglucitol (1,5-AG) levels, elevated BP, cerebral infarction, and no current alcohol use. Higher cognitive function was associated with younger age, female sex, mild DWMH, more years of education, and higher high-density lipoprotein cholesterol levels. Depressive symptoms were associated with lower 1,5-AG levels, lower LDL-C levels, moderate to severe PVH, and no current alcohol use.Conclusions
White matter lesions in elderly people were related to hypertension and impaired glucose tolerance. The severity of WMLs was associated with cognitive function and mood.
Brain and Behavior 02/2015; 5(3). DOI:10.1002/brb3.315 · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AimIn order to evaluate the validity of the REM sleep behavior disorder (RBD) screening questionnaire (RBDSQ) as a screening tool for RBD in a general population setting, we conducted a validation study using residents of a rural community.Methods
We sent questionnaires that included the RBDSQ to 2,631 eligible adult residents in the town of Daisen, Japan.ResultsOf those residents, 1,572 participants (59.7%) gave complete answers to the RBDSQ. Among them, 179 participants (11.4%) scored 5 or more points on the questionnaire; an additional 149 participants scoring 4 or less points were randomly selected for further telephone interview. Based on obtained results, 9 participants (0.57%) were judged as having probable RBD. Receiver-operating characteristic curve analysis revealed that a total score of 6 points on the RBDSQ represented the best cut-off value for detecting probable RBD (sensitivity: 100%, specificity: 73.0%). Analysis based on the item response theory revealed that items 1, 4, 6-1, 7, and 8 had lower difficulty than the remaining items, suggesting that these items are more essential in the screening for probable RBD.Conclusion
The present study revealed that a score of 6 points on the RBDSQ could be used as a cut-off value for the screening of probable RBD in the general population. Evaluation of the distribution of positive items might be helpful for identifying the intensity of a person's RBD symptoms.
[Show abstract][Hide abstract] 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 09/2014; 4(5). DOI:10.1002/brb3.247 · 2.24 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: It is generally believed that cortical spreading depression (CSD) demonstrated by Leao underlie migraine aura and migraine headache depends on the activation of the trigeminovascular pain pathway proposed by Moskowitz. The onset of migraine attack and the association between CSD and the trigeminovascular pain pathway have remained largely unknown. Recent animal studies indicate that CSD can activate trigeminal nociception and thus trigger headache mechanism. Meanwhile, the nature and mechanism of migraine without aura is still an open question. It is considered that the pain in migraineur is affected by hereditary factors, internal factors such as female sex hormone, and external factors as medication, meal, weather, stress, etc. We review here the current understanding of the migraine pathophysiology, focusing on recent advance regarding cortical spreading depression and pain.