Shingo Mitaki

Validation of a new mass screening tool for cognitive impairment: Cognitive Assessment for Dementia, iPad version

Background We have developed a new screening test for dementia that runs on an iPad and can be used for mass screening, known as the Cognitive Assessment for Dementia, iPad version (CADi). The CADi consists of items involving immediate recognition memory for three words, semantic memory, categorization of six objects, subtraction, backward repetition of digits, cube rotation, pyramid rotation, trail making A, trail making B, and delayed recognition memory for three words. The present study examined the reliability and validity of the CADi. Methods CADi evaluations were conducted for patients with dementia, healthy subjects selected from a brain checkup system, and community-dwelling elderly people participating in health checkups. Results CADi scores were lower for dementia patients than for healthy elderly individuals and correlated significantly with Mini-Mental State Examination scores. Cronbach’s alpha values for the CADi were acceptable (over 0.7), and test–retest reliability was confirmed via a significant correlation between scores separated by a one-year interval. Conclusion These results suggest that the CADi is a useful tool for mass screening of dementia in Japanese populations.

Gastroesophageal Reflux during Enteral Feeding in Stroke Patients: A 24-hour Esophageal pH-monitoring Study

BACKGROUND Patients who are unable to eat or drink after stroke may receive percutaneous endoscopic gastrostomy (PEG) or nasogastric tube feeding. Although the most common serious complication is well known to be aspiration pneumonia, the role of gastroesophageal reflux (GER) has not been fully assessed. The aim of this study was to examine, by means of 24-hour esophageal pH monitoring, whether GER is related to aspiration pneumonia and whether the size and laterality of brain lesions influence GER. METHODS Sixteen stroke patients were examined using a Degitrapper pH400 (Medtronic Japan Co., Tokyo, Japan) and Zinetics 24ME multiuse pH catheter (Medtronic). All patients had stroke lesions in the territory of the left or right middle cerebral artery that were confirmed by magnetic resonance imaging (MRI) and were receiving PEG or nasogastric feeding. Stroke volume was measured with MRIcron software. RESULTS Nine patients (56%) were diagnosed with GER, and 10 (63%) developed aspiration pneumonia after enteral feeding. The rate of aspiration pneumonia was significantly higher in patients with GER (88.9%) than in those without GER (42.9%; P = .04). Patients with left hemispheric lesions had a significantly higher incidence of acid reflex than those with right lesions (116 ± 105 vs 13 ± 17; P = .04). There were no significant differences in total time of acid reflux or mean pH value between patients with left and right hemispheric lesions. The lesion volume had no significant effect on any of 3 indices of GER. CONCLUSIONS GER is associated with aspiration pneumonia and occurs more often in patients with stroke lesions in the left hemisphere.

Human mesenchymal stem cell transplantation changes proinflammatory gene expression through a nuclear factor‐κB‐dependent pathway in a rat focal cerebral ischemic model

Previous studies have demonstrated the immunomodulatory functions of mesenchymal stem cells (MSCs) in cerebral ischemic rats. However, the underlying mechanisms are unclear. The purpose of this study is to investigate the effects of MSC transplantation on transcriptional regulations of proinflammatory genes in cerebral ischemia. Transient ischemia was induced by middle cerebral artery occlusion (MCAO) in adult male Sprague‐Dawley rats. After 24 hr, vehicle (PBS) or a human MSC line (B10) was transplanted intravenously. The neurological deficits, infarct volume, cellular accumulations, and gene expression changes were monitored by means of behavior tests, MRI, immunohistochemistry, Western blotting, laser capture microdissection, and real‐time PCR. In the core area of the B10 transplantation group, the number of ED1‐positive macrophage/microglia was decreased compared with the PBS group. In the core, nuclear factor‐κB (NF‐κB) was decreased, although CCAAT/enhancer‐binding protein β was not changed; both were expressed mainly in ED1‐positive macrophage/microglia. Likewise, mRNAs of NF‐κB‐dependent genes including interleukin‐1β, MCP‐1, and inducible nitric oxide synthase were decreased in ED1‐positive and Iba‐1‐positive macrophage/microglia in the B10 transplantation group. Moreover, upstream receptors of the NF‐κB pathway, including CD40 and Toll‐like receptor 2 (TLR2), were decreased. Immunofluorescence results showed that, in the B10 transplantation group, the percentages of NF‐κB‐positive, CD40‐positive, and TLR2‐positive cells were decreased in ED1‐positive macrophage/microglia. Furthermore, NF‐κB‐positive cells in the CD40‐ or TLR2‐expressing cell population were decreased in the B10 transplantation group. This study demonstrates that B10 transplantation inhibits NF‐κB activation, possibly through inhibition of CD40 and TLR2, which might be responsible for the inhibition of proinflammatory gene expression in macrophage/microglia in the infarct lesion.

Association of Mild Kidney Dysfunction with Silent Brain Lesions in Neurologically Normal Subjects

Background: Chronic kidney disease (CKD) has been closely associated with stroke. Although a large number of studies reported the relationship between CKD and different types of asymptomatic brain lesions, few comprehensive analyses have been performed for all types of silent brain lesions. Methods: We performed a cross-sectional study involving 1,937 neurologically normal subjects (mean age 59.4 years). Mild CKD was defined as an estimated glomerular filtration rate between 30 and 60 ml/min/1.73 m2 or positive proteinuria. Results: The prevalence of mild CKD was 8.7%. Univariate analysis revealed an association between CKD and all silent brain lesions, including silent brain infarction, periventricular hyperintensity, subcortical white matter lesion, and microbleeds, in addition to hypertension and diabetes mellitus after adjusting for age and sex. In binary logistic regression analysis, the presence of CKD was a significant risk factor for all types of silent brain lesions, independent of other risk factors. Conclusions: These results suggest that mild CKD is independently associated with all types of silent brain lesions, even in neurologically normal subjects.

Cystatin C induces apoptosis and tyrosine hydroxylase gene expression through JNK-dependent pathway in neuronal cells

Cystatin C (CysC), an endogenous cysteine protease inhibitor, has been implicated in the apoptosis and differentiation processes of neuronal cells. In this study, we have investigated the pathway involved in the process. A human neuronal hybridoma cell line (A1 cell) was treated with CysC in both undifferentiated and retinoic acid (RA)-induced differentiated conditions, which decreased overall process length in both conditions. Also, CysC increased apoptotic cell number time-dependently, as revealed by TUNEL assay. Western blot analysis demonstrated that in differentiated A1 cells, CysC treatment decreased Bcl-2 and increased active caspase-9 protein level time-dependently. Immunocytochemistry results revealed that, CysC treatment significantly increased active form of Bax expressing cell number, which co-localized with mitochondria. Mitogen activated protein (MAP) kinase inhibition experiments showed that Bax mRNA induction and Bcl-2 mRNA inhibition by CysC treatment were c-Jun N-terminal kinase (JNK)-dependent. After RA-induced differentiation, choline acetyltransferase (ChAT) and neurofilament (NF) mRNA levels were increased in A1 cells. CysC treatment inhibited NF mRNA level in both undifferentiated and RA-differentiated, and increased TH mRNA in differentiated A1 neurons. Analysis of signal transduction pathway demonstrated that TH gene induction was also JNK-dependent. Thus, our results demonstrated the significance of JNK-dependent pathways on CysC-induced apoptosis and TH gene expression in neuronal cells, which might be an important target in the management of CysC dependent neurodegenerative processes.

A human neural stem cell line provides neuroprotection and improves neurological performance by early intervention of neuroinflammatory system

A human neural stem cell line, HB1.F3, demonstrated neuroprotective properties in cerebral ischemia animal models. In this study, we have investigated about the mechanisms of such neuroprotection, mainly focusing on the neuroinflammatory system at an earlier time point of the pathology. Cerebral ischemia model was generated by middle cerebral artery occlusion (MCAO) in adult male Wister rats. HB1.F3 cells were transplanted through jugular vein 6h after MCAO. Forty eight hours after MCAO, transplanted rats showed better neurological performance and decreased TUNEL positive apoptotic cell number in the penumbra. However, haematoxylin and eosin staining and immunostaining showed that, HB1.F3 cells did not affect the necrotic cell death. Twenty four hours after MCAO (18h after HB1.F3 transplantation), infiltrated granulocytes and macrophage/microglia number in the core regions were decreased compared to PBS-treated controls. Immunohistochemical analysis further demonstrated that the transplantation decreased inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expressing cell number in the core and penumbra, respectively. Double immunofluorescence results revealed that iNOS was mainly expressed in granulocytes and macrophage/microglia in the core region, and COX-2 mainly expressed in neurons, endothelial cells and granulocytes in penumbra. Further analysis showed that although the percentage of iNOS expressing granulocytes and macrophage/microglia was not decreased, COX-2 expressing neurons and vessel number was decreased by the transplantation. In vitro mRNA analysis showed that brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor (βFGF) and bone morphogenic protein (BMP)-4 expression was high in cultured HB1.F3 cells. Thus, our results demonstrated that HB1.F3 cell transplantation provide neuroprotection possibly through the regulation of early inflammatory events in the cerebral ischemia condition.

C‐reactive protein levels are associated with cerebral small vessel‐related lesions

Inflammation has received increasing attention as a cause of stroke. Although several lines of evidence suggest that inflammatory processes have a role in arteriosclerotic vascular events, their involvement remains to be determined. The purpose of this study was to examine the associations between serum high‐sensitive C‐reactive protein (hs‐CRP) levels and cerebral small vessel (CSV)‐related lesions as a manifestation of arteriosclerosis.

Randomized Trial of Repetitive Transcranial Magnetic Stimulation for Apathyand Depression in ParkinsonâÂÂs Disease

Objective: Repetitive transcranial magnetic stimulation (rTMS) has been reported to improve motor function and depression in Parkinson’s disease (PD) patients, but there has been only one randomized controlled trial for apathy. We evaluated the efficacy of rTMS for apathy and depression in Parkinson’s disease. Methods: Fifteen PD patients received real rTMS (5 Hz, 500 pulses/day) and placebo stimulation over the supplementary motor area (SMA) for each 5 days with total amount of 2500 real pulses and 2500 placebo pulses, using a randomized real-first or placebo-first protocol. The modified apathy scale, the Zung Self-rating Depression Scale (SDS) and Unified Parkinson’s Disease Rating Scale (UPDRS) were used to assess apathy, depression and clinical status before and after each stimulative treatment. Results: Real rTMS improved the apathy score by 3 points (P<0.05) compared to the baseline, while placebo stimulation produced no improvement, irrespective of the order of treatment. Real rTMS also improved the depression scale, SDS by 5 points (P<0.05) compared to the baseline, while placebo stimulation was ineffective. Combined analysis confirmed that real rTMS was significantly superior to placebo stimulation in apathy and depression (p<0.05). Real rTMS also improved UPDRS by 10 points (P=0.001), while placebo stimulation was ineffective. No side effects were observed in either real rTMS or placebo stimulation. Clinical factors including age, gender, disease duration, UPDRS score pre-rTMS, and daily dose of L-DOPA did not influence the improvement of UPDRS and apathy scores by real rTMS. Conclusions: rTMS over the SMA appears to be effective for treatment of apathy and depression in PD patients in addition to UPDRS.

Apathy is associated with a single-nucleotide polymorphism in a dopamine-related gene.

Dopaminergic neurotransmission is an important factor in the pathogenesis of apathy. In addition, the contribution of genetic factors to the regulation of brain dopaminergic activity is widely acknowledged. Therefore, we hypothesized that genes associated with brain dopaminergic activity may have some effects on apathy. In the current study, we evaluated the association between four functional single-nucleotide polymorphisms (SNPs) in specific genes related to dopaminergic neurotransmission and apathy in a general population. Participants in the health examination at the Shimane Institute of Health Science were recruited for this study (n=963). Apathy was assessed using the Japanese version of the apathy scale. SNPs were genotyped using the TaqMan method. In our population, 22.1% had apathy. We confirmed that apathy was associated with decreased cognitive function and depressive state. A significant association was found between an SNP in the catechol-O-methyltransferase (COMT) gene (rs4680) encoding the low-activity Met allele and apathy. This relationship was still significant after adjustment for confounding factors. Our study indicates an association between rs4680, an SNP in the COMT gene, and lower risk of apathy. Considering the function of rs4680, the current study suggests the importance of dopaminergic neurotransmission in the pathogenesis of apathy in a general population.

The Effectiveness of Repetitive Transcranial Magnetic Stimulation for Poststroke Apathy Is Associated with Improved Interhemispheric Functional Connectivity

Poststroke apathy is relatively common and has negative effects on the functional recovery of the patient; however, few reports have demonstrated the existence of effective treatments for poststroke apathy. Here, we describe a case of poststroke apathy that was successfully treated with repetitive transcranial magnetic stimulation (rTMS). Using resting-state functional magnetic resonance imaging, we detected improved interhemispheric functional connectivity that was correlated with the patients recovery from poststroke apathy. Our case suggests that rTMS can improve the transfer of information through the corpus callosum, which is crucial for helping patients recover from poststroke apathy.