Faculty Profiles - YAMASHITA Toru

Papers - YAMASHITA Toru

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Neurovascular protection by telmisartan via reducing neuroinflammation in stroke-resistant spontaneously hypertensive rat brain after ischemic stroke. Reviewed International journal

Syoichiro Kono, Tomoko Kurata, Kota Sato, Yoshio Omote, Nozomi Hishikawa, Toru Yamashita, Kentaro Deguchi, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 24 ( 3 ) 537 - 47 2015.3

Language：English Publishing type：Research paper (scientific journal)

Telmisartan is a highly lipid-soluble angiotensin receptor blocker (ARB), which improves insulin sensitivity and reduces triglyceride levels and, thus, is called metabo-sartan. We examined the effects of telmisartan on neurovascular unit (N-acetylglucosamine oligomer [NAGO], collagen IV, and glial fibrillary acidic protein [GFAP]) and neuroinflammation (matrix metalloproteinase-9 [MMP-9] and inflammasome) in brain of stroke-resistant spontaneously hypertensive rat (SHR-SR). At 12 weeks of age, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups, that is, vehicle group, low-dose telmisartan group (.3 mg/kg/d), and high-dose telmisartan group (3 mg/kg/d, postoral). Immunohistologic analysis at ages 6, 12, and 18 months showed progressive decreases of NAGO-positive endothelium and collagen IV-positive basement membrane and progressive increases of MMP-9-positive neurons, GFAP-positive astrocytes, and NLRP3-positive inflammasome in the cerebral cortex of vehicle group. Low-dose telmisartan reduced such changes without lowering blood pressure (BP), and high-dose telmisartan further improved such changes with lowering BP. The present findings suggest that a persistent hypertension caused a long-lasting inflammation after tMCAO in SHR-SR, which accelerated neurovascular disruption and emergent inflammasome, and that telmisartan greatly reduced such inflammation and protected the neurovascular unit via its pleiotropic effects in living hypertensive rat brain after ischemic stroke.

DOI： 10.1016/j.jstrokecerebrovasdis.2014.09.037

Tumefactive demyelinating disease mimicking malignant tumor in positron emission tomography with C-11-methionine

Kosuke Matsuzono, Kentaro Deguchi, Nozomi Hishikawa, Toru Yamashita, Tomotsugu Ichikawa, Isao Date, Koji Abe

NEUROLOGY AND CLINICAL NEUROSCIENCE 3 ( 2 ) 81 - 83 2015.3

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Tumefactive demyelination is sometimes difficult differentiate from malignant tumors. Positron emission tomography with C-11-methionine is useful for diagnosing cerebral malignant tumors, but there are previous reports for tumefactive demyelination. We experienced a 32-year-old man who suffered from subacute onset dysarthria and left hemiparesis with magnetic resonance image of a large lesion (5.3 x 4.2 cm) in the right frontal lobe. Positron emission tomography with F-18-fluorodeoxyglucose showed a high ring-shaped glucose uptake in the lesion and C-11-methionine showed a remarkable methionine uptake in the whole lesion. Although a malignant tumor was suspected, the patient was finally diagnosed with tumefactive demyelinating disease based on brain biopsy results, and was treated completely by methylpredonisolone therapy. Although C-11-methionine uptake with positron emission tomography commonly suggests a malignant tumor, there can still be a possibility of tumefactive demyelinating disease.

DOI： 10.1111/ncn3.150

Cognitive and affective functions in diabetic patients associated with diabetes-related factors, white matter abnormality and aging Reviewed

N. Hishikawa, T. Yamashita, K. Deguchi, J. Wada, K. Shikata, H. Makino, K. Abe

European Journal of Neurology 22 ( 2 ) 313 - 321 2015.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Ltd

Diabetes mellitus (DM) is associated with a decline in cognitive and affective functions. Methods: In all, 182 outpatients with DM were investigated for associations of cognitive and affective functions with diabetes-related factors and cerebral white matter abnormalities. In addition, the difference in cognitive decline of age-matched late elderly normal subjects and DM patients was investigated. Results: The present study revealed that cognitive and affective functions declined in some DM patients. Furthermore, the decline in these functions was unrelated to fasting blood sugar level but was related to glycosylated hemoglobin (HbA1c) and insulin resistance. Poor HbA1c control was associated with a significant decline in the 'calculation' subscale and insulin resistance for 'naming', 'read list of letters' and 'delayed recall' Montreal Cognitive Assessment (MoCA) subscale scores. Magnetic resonance imaging scans showed that both periventricular hyperintensity (PVH) and deep white matter hyperintensity were associated with Mini Mental State Examination (MMSE) and MoCA scores, but only PVH was related to homeostasis model assessment of insulin resistance scores. Compared with age-matched late elderly normal subjects, 'orientation to time' and 'registration' MMSE subscales declined in late elderly DM patients. Conclusions: These results suggest that cognitive and affective decline in DM patients was mostly related to glucose control and insulin resistance, whilst amongst late elderly subjects the impairment of 'attention' and 'orientation' were characteristic features of DM patients.

DOI： 10.1111/ene.12568

Comprehensive Clinical Evaluations of Frontotemporal Dementia Contrasting to Alzheimer's Disease (oFTD Study). Reviewed International journal

Kosuke Matsuzono, Nozomi Hishikawa, Toru Yamashita, Yasuyuki Ohta, Kota Sato, Shoichiro Kono, Kentaro Deguchi, Ryuta Morihara, Koji Abe

Journal of Alzheimer's disease : JAD 48 ( 1 ) 279 - 86 2015

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/OBJECTIVE: To examine comprehensive clinical evaluations of frontotemporal dementia (FTD) patients compared with Alzheimer's disease (AD) patients. METHODS: We used eight batteries and the touch panel test to retrospectively analyze 41 FTD patients compared with 121 AD patients. Furthermore, 34 FTD and all 121 AD patients were evaluated with a frontotemporal dementia-Alzheimer's disease index (FA index), which we developed for novel diagnosis with magnetic resonance imaging. RESULTS: Frontal assessment battery, geriatric depression scale, and Abe's behavioral and psychological symptom of dementia score were significantly worse in FTD patients than in AD patients ( **p < 0.01 in FAB, **p < 0.01 in the geriatric depression scale, and ***p < 0.001 in Abe's behavioral and psychological symptom of dementia score), although there was no significant difference in the other five scores. The finding mistakes game score of the touch panel test was worse in FTD than in AD ( *p < 0.05). The receiver operating characteristic curve of the FA index showed 91.4% sensitivity and 89.3% specificity with the FA index ≤0.6015 to discriminate FTD from AD. CONCLUSION: Combining clinical scores, a computerized touch panel test, and the FA index will help to provide a more accurate diagnosis of FTD in contrast to AD.

DOI： 10.3233/JAD-150416

Telmisartan promotes potential glucose homeostasis in stroke-resistant spontaneously hypertensive rats via peroxisome proliferator-activated receptor γ activation. Reviewed International journal

Yoshio Omote, Kentaro Deguchi, Tomoko Kurata, Toru Yamashita, Kota Sato, Nozomi Hishikawa, Koji Abe

Current neurovascular research 12 ( 1 ) 91 - 7 2015

Language：English Publishing type：Research paper (scientific journal)

An angiotensin 2 type 1 receptor blocker (ARB) telmisartan possesses not only an anti-hypertensive effect but also an anti-metabolic syndrome effect due to peroxisome proliferator-activated receptor γ (PPAR-γ) activation. In the present study, we examined the effects of telmisartan on the angiotensin 2 type 1 receptor (AT1R), PPAR-γ, and insulin receptor (IR) in stroke-resistant spontaneously hypertensive rats (SHR-SR), comparing them with Wistar rats. Three-months-old SHR-SR rats were divided into three treatment groups, i.e., vehicle (SHR/Ve), low-dose telmisartan (0.3 mg/kg/day, SHR/Low), and high-dose telmisartan (3 mg/kg/day, SHR/High). Compared with Wistar rats, SHR/Ve increased the staining of AT1R, PPAR-γ and IR in the cerebral cortical neurons. On the other hand, telmisartan dose-dependently suppressed the excessive expression of AT1R and IR, but enhanced PPAR-γ activation. Low-dose telmisartan showed these effects even without lowering blood pressure (BP), while high-dose telmisartan lowered BP and showed further effects. The present study suggests that even a low dose of telmisartan decreased AT1R and IR, and increased PPAR-γ in the cerebral cortex of SHR-SR without lowering BP, probably by improving glucose homeostasis. The high dose of telmisartan showed further decreases in AT1R and IR, and further PPAR-γ activation while lowering BP, suggesting an additive benefit to lowering BP, namely the improvement of glucose homeostasis.

Combination Therapy of Cholinesterase Inhibitor (Donepezil or Galantamine) plus Memantine in the Okayama Memantine Study. Reviewed International journal

Kosuke Matsuzono, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Kentaro Deguchi, Yumiko Nakano, Koji Abe

Journal of Alzheimer's disease : JAD 45 ( 3 ) 771 - 80 2015

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/OBJECTIVE: To compare the effectiveness of combination therapy with cholinesterase inhibitors (ChEI) plus memantine in all AD patients and in older AD patients (age >75 years). METHODS: The Okayama Memantine Study was used to compare the clinical effects of combination therapy of donepezil plus memantine (n = 61) or galantamine plus memantine (n = 53) in all AD patients, and in older AD patients separately, with six batteries at baseline, at 6 months with ChEI only monotherapy, and at 3, 6, and 12 months after addition of memantine to the treatment schedule (18 months total). RESULTS: The addition of memantine resulted in stabilization of the Mini-Mental State Examination scores and Hasegawa dementia rating for 6 months, and then significantly declined at 12 months in both subgroups. Frontal assessment battery (FAB) declined significantly at 12 months after memantine addition in the donepezil subgroup, while the galantamine subgroup significantly improved at 6 months. Affective functions were well preserved after memantine addition until 12 months, except for the apathy scale at 12 months after memantine addition in the galantamine subgroup. The combination therapy of donepezil plus memantine was better for apathy in older AD patients, and galantamine plus memantine was better for cognitive functions. CONCLUSIONS: The addition of memantine stabilized cognitive scores for 6 months and affective scores for 12 months in the donepezil subgroup. Additionally, memantine significantly improved FAB at 6 months in the galantamine subgroup although apathy scale became significantly worse at 12 months.

DOI： 10.3233/JAD-143084

Computerized touch-panel screening tests for detecting mild cognitive impairment and Alzheimer's disease. Reviewed

Yusuke Fukui, Toru Yamashita, Nozomi Hishikawa, Tomoko Kurata, Kota Sato, Yoshio Omote, Syoichiro Kono, Taijun Yunoki, Yuko Kawahara, Noriko Hatanaka, Ryo Tokuchi, Kentaro Deguchi, Koji Abe

Internal medicine (Tokyo, Japan) 54 ( 8 ) 895 - 902 2015

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The increasing population of elderly people in Japan has accelerated the demand for a simple screening test to detect cognitive and affective declines in mild cognitive impairment (MCI) and the early stage of dementia. Methods We compared the cognitive and affective functions, activities of daily living (ADLs) and the results of four computerized touch-panel screening tests in 41 MCI subjects, 124 patients with Alzheimer's disease (AD) and 75 age- and gender-matched normal controls. RESULTS: All computerized touch-panel games were successfully used to discriminate the AD patients from the normal controls (** p<0.01). Although there were no differences in the findings of the conventional cognitive assessments, the results of the flipping cards game were significantly different (** p<0.01) between the normal controls (19.3 ± 9.5 sec) and MCI subjects (30.9 ± 18.4 sec). Three conventional affective assessments, the ADL score, Abe's behavioral and psychological symptoms of dementia (ABS) (** p<0.01) and the apathy scale (AS) (* p<0.05), could be used to discriminate the MCI subjects (ABS, 0.9 ± 1.5; AS, 12.8 ± 5.9) from the normal controls (ABS, 0.1 ± 0.4; AS, 8.9 ± 5.3). CONCLUSION: In the present study, all four touch-panel screening tests could be employed to discriminate AD patients from normal controls, whereas only the flipping cards game was effective for distinguishing MCI subjects from normal controls. Therefore, this novel touch-panel screening test may be a more sensitive tool for detecting MCI subjects among elderly patients.

DOI： 10.2169/internalmedicine.54.3931

[SCA6 presenting parkinsonism without ataxia--A case report]. Reviewed

Shinichi Takeshima, Ikuko Takeda, Keitaro Kobatake, Toru Yamashita, Koji Abe, Masaru Kuriyama

Rinsho shinkeigaku = Clinical neurology 55 ( 4 ) 243 - 7 2015

Language：Japanese Publishing type：Research paper (scientific journal)

A 57-year-old man was admitted to our hospital because of bradykinesia. He was diagnosed with Parkinson disease (Hoehn and Yahr grade 2) and administered levodopa at the maximum dose of 800 mg. However, his condition did not improve. While his symptoms were responsive to levodopa therapy, the sensitivity to the drug was poor. Brain MRI revealed atrophy of the upper vermis and cerebral hemispheres, and brain SPECT revealed low perfusion in both parietal lobes. I(123)-metaiodobenzylguanidine scintigraphy showed a decrease in the heart/mediastinum ratio. Striatal dopamine transporter (DAT) density was evaluated using I(123)-FP-CIT. The patient showed moderately reduced DAT density, which suggested nigrostriatal dopaminergic damage. His mother was found to have pure cerebellar ataxia without parkinsonism, and her two siblings also had celebellar type of multiple system atrophy (MSA-C) and progressive supranuclear palsy, respectively. Genetic testing revealed that the patient, his mother and the uncle with MSA-C had spinocerebellar ataxia type 6 (SCA6). SCA6 presenting parkinsonism without ataxia is very rare and important for the pathomechanism of disease.

DOI： 10.5692/clinicalneurol.55.243

Time-dependent profiles of microRNA expression induced by ischemic preconditioning in the gerbil hippocampus. Reviewed International journal

Miao Sun, Toru Yamashita, Jingwei Shang, Ning Liu, Kentaro Deguchi, Juan Feng, Koji Abe

Cell transplantation 24 ( 3 ) 367 - 76 2015

Language：English Publishing type：Research paper (scientific journal)

MicroRNAs (miRNAs) are critically important in both normal neuronal development and neurological diseases. Although cerebral ischemia has been shown to alter the miRNA profiles of rats, the role of miRNA in the cornu ammonis 1 region of the gerbil hippocampus under ischemic tolerance has not been studied. In the present study, Mongolian gerbils were subjected to one or three times the nonlethal dose of 2-min transient common carotid artery occlusion (tCCAO). miRNA microarray technology detected 251 miRNAs and the expression of seven of these in terms of ischemic tolerance. They were compared at different time points: 1 day, 7 days, 1 month, and 6 months. mmu-miR-15a-5p, related to neurogenesis, showed increased expression after one dose of 2-min tCCAO and was much higher after three doses. An increase in sha-miR-24 and oan-let-7b-3p, related to transactivation response DNA-binding protein (TDP43), was observed after one dose of 2-min tCCAO, but the peak was accelerated to an earlier period of reperfusion after three doses. In contrast, mmu-miR-125b-5p and mmu-miR-132-5p, related to fused in sarcoma/translocated in liposarcoma (FUS/TLS), showed similar increases at both doses. mmu-miR-181c-5p and mmu-miR-378a-5p, related to heat shock protein 70 (HSP70), also showed accelerated expression after three doses. This data set provides new insight about miRNA expression during neurogenesis, and related to TDP43, FUS/TLS, and HSP70, which may be useful when pursuing further studies on the possible use of miRNAs as biomarkers in cerebral ischemic tolerance and neuroregeneration.

DOI： 10.3727/096368915X686869

Single photon emission computed tomography (SPECT) findings of a patient with a novel prion mutation. Reviewed

Kosuke Matsuzono, Ryuta Morihara, Kota Sato, Nozomi Hishikawa, Toru Yamashita, Kentaro Deguchi, Koji Abe

Internal medicine (Tokyo, Japan) 54 ( 1 ) 79 - 82 2015

Language：English Publishing type：Research paper (scientific journal)

We experienced a unique case of familial prion disease with a prion gene mutation that caused pan-autonomic failure, sensory neuropathy and mild cognitive impairment. No abnormal sites of intensity were observed on diffusion-weighted magnetic resonance image (MRI) over six to 11 years or fluid attenuated inversion recovery MRI at six or nine years. However, (99m)Tc-ethylcysteinate dimer single photon emission computed tomography (SPECT) showed a decreased cerebral blood flow in the bilateral parietal and occipital lobes at nine years, which then expanded at 11 years, corresponding to mild atrophy in these areas on MRI. In some cases of prion mutations, particularly the slowly progressive type, SPECT may show abnormalities, while MRI does not.

DOI： 10.2169/internalmedicine.54.3378

Clinical Benefits of Memantine Treatment for Alzheimer's Disease in the Okayama Memantine Study II (OMS II). Reviewed International journal

Kosuke Matsuzono, Toru Yamashita, Yasuyuki Ohta, Nozomi Hishikawa, Makoto Koike, Kota Sato, Syoichiro Kono, Kentaro Deguchi, Yumiko Nakano, Koji Abe

Journal of Alzheimer's disease : JAD 47 ( 2 ) 487 - 93 2015

Language：English Publishing type：Research paper (scientific journal)

The clinical benefits of memantine, depending on the baseline cognitive and affective conditions in real world dementia clinics, have not been completely examined. We performed the "Okayama Memantine Study II (OMS II)" to retrospectively evaluate the clinical effects of memantine monotherapy (n = 38) in Alzheimer's disease (AD) patients using seven batteries to assess dementia at the baseline, at 3, 6, and 12 months. Additionally, we divided 163 AD patients treated with memantine into two subgroups depending on the baseline cognitive score of the Mini-Mental State Examination (MMSE): the MMSE <15 group (n = 36) and the baseline MMSE ≥15 group (n = 127). We also analyzed 71 AD patients based on the baseline behavioral and psychological symptoms of dementia (BPSD) severity using Abe's BPSD score (ABS). Memantine monotherapy maintained cognitive functions until 6 months of treatment, but showed a decrease at 12 months ( *p < 0.05 versus baseline). However, memantine monotherapy greatly improved BPSD symptoms until 12 months ( *p < 0.05, **p < 0.01) and maintained other affective functions as well as the activity of daily living. Memantine treatment showed similar effects, regardless of the baseline cognitive functions, but showed better effects on ABS for higher baseline cognitive functions. Memantine treatment greatly improved ABS depending on baseline BPSD severity. Our present OMS II showed that memantine monotherapy improved BPSD until 12 months. The higher baseline cognitive subgroup (MMSE ≥15) and the worse baseline BPSD subgroup were expected to show better effects with memantine.

DOI： 10.3233/JAD-150094

Long-Term Efficacy of Galantamine in Alzheimer's Disease: The Okayama Galantamine Study (OGS). Reviewed International journal

Yumiko Nakano, Kosuke Matsuzono, Toru Yamashita, Yasuyuki Ohta, Nozomi Hishikawa, Kota Sato, Kentaro Deguchi, Koji Abe

Journal of Alzheimer's disease : JAD 47 ( 3 ) 609 - 17 2015

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Alzheimer's disease (AD) is one of the most significant diseases affecting an increasingly aging society. OBJECTIVE: To determine the long-term efficacy of galantamine treatment in a Japanese population. METHODS: We performed "Okayama Galantamine Study (OGS)" to retrospectively analyze the clinical effects of galantamine in 279 AD patients using 7 batteries for assessing dementia at baseline, 3, 6, 12, and 24 months. We further analyzed the effects of galantamine based on gender and the severity of their baseline cognitive, affective, and activity of daily living (ADL) functions. RESULTS: In all 279 AD patients (80.6 ± 7.2 years old, MMSE 20.0 ± 4.5), cognitive functions were well preserved until 12 months and even frontal assessment battery improved after 12 months although Hasegawa dementia scale-revised finally worsened at 24 months ( *p < 0.05) with galantamine treatment. Affective and ADL functions were also well maintained after galantamine treatment with significant improvement of Geriatric Depression Scale scores at 3 months ( *p < 0.05). Subanalyses showed the better response to galantamine for male and lower baseline function subgroups. CONCLUSIONS: Our present study (OGS) revealed a long-term efficacy of galantamine in very elderly AD patients, and suggested a better efficacy for male and baseline lower cognitive, affective, and ADL functions.

DOI： 10.3233/JAD-150308

Selective disappearance of medial back muscles in a case of myotonic dystrophy type 1. Reviewed International journal

Ryuta Morihara, Nozomi Hishikawa, Toru Yamashita, Kentaro Deguchi, Tomoko Kurata, Koji Abe

Journal of the neurological sciences 353 ( 1-2 ) 185 - 6 2015

Language：English

Here, we report a unique case of late-onset myotonic dystrophy type 1 in a 64-year-old woman, with selective disappearance of the medial lower back muscles. We compared the clinical features of this patient with those of a cohort of 29 patients with myotonic dystrophy type 1 to clarify the correlation between clinical features and lower back muscle atrophy. After classification into three subgroups according to muscle atrophy pattern, medial muscle atrophy was present in 17.2% of the patients. Affected patients were older at onset than non-affected patients, and limb muscle power and respiratory function decreased with atrophy progression.

DOI： 10.1016/j.jns.2015.04.020

Dynamic Cerebrospinal Fluid Flow on MRI in Cortical Cerebellar Atrophy and Multiple System Atrophy-cerebellar Type. Reviewed

Yusuke Fukui, Nozomi Hishikawa, Kota Sato, Syoichiro Kono, Kosuke Matsuzono, Yumiko Nakano, Yasuyuki Ohta, Toru Yamashita, Kentaro Deguchi, Koji Abe

Internal medicine (Tokyo, Japan) 54 ( 14 ) 1717 - 23 2015

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The purpose of this study was to examine a new MRI technology, dynamic cerebrospinal fluid (CSF) flow, to examine sporadic cerebellar ataxia patients with cortical cerebellar atrophy (CCA) and multiple system atrophy-cerebellar type (MSA-C). METHODS: Nine CCA patients (3 men and 6 women; mean age: 64.2±6.9 years) and 31 MSA-C patients (13 men and 18 women; mean age: 62.7±6.8 years) were examined by a dynamic CSF flow analysis. All CSF flow data were evaluated by phase contrast-MRI using a 1.5T MRI scanner. The CSF flow was calculated by 15 images in the equidistant MRI sequence which was taken through a cardiac cycle. RESULTS: Compared with the CCA patients, the absolute values of the mean velocity of the MSA-C patients were significantly reduced at time points 5 (CCA, 0.24±0.14 cm/s; MSA-C, 0.13±0.11 cm/s; (*) p<0.05) and 13 (CCA, -0.60±0.37 cm/s; MSA-C, -0.31±0.17 cm/s; (**) p<0.01). Significant correlations in Spearman's rank correlation coefficient were also found in MSA-C patients between the disease duration and the difference between the maximum and minimum velocities (Vheight) (r=-0.429, (*) p<0.05), the minimum velocity of the CSF (Vmin) (r=0.486, (**) p<0.01) or the length of the minor axis of the pons (r=-0.529, (**) p<0.01). The linear regressions between the disease duration and Vheight or Vmin revealed a significant strong correlation only in the MSA-C patients. CONCLUSION: The present CSF flow study showed for the first time that Vheight and Vmin revealed good correlations with the disease duration in the MSA-C patients. Furthermore, the velocity of the prepontine CSF flow tended to decrease in the MSA-C patients compared with the CCA patients, suggesting that this particular CSF flow analysis may be a new surrogate marker for differentiating both types of cerebellar ataxia.

DOI： 10.2169/internalmedicine.54.4747

Clinical Benefits of Rivastigmine in the Real World Dementia Clinics of the Okayama Rivastigmine Study (ORS). Reviewed International journal

Kosuke Matsuzono, Kota Sato, Syoichiro Kono, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Kentaro Deguchi, Yumiko Nakano, Koji Abe

Journal of Alzheimer's disease : JAD 48 ( 3 ) 757 - 63 2015

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) is one of the most important diseases in an aging society, but the clinical effects of rivastigmine have not been fully examined in real world domestic clinics. METHODS: We performed the "Okayama Rivastigmine Study (ORS)" to retrospectively analyze the clinical effects of rivastigmine (n = 75) or donepezil (n = 71) on AD patients with seven dementia assessment batteries at the baseline, 3, 6, and 12 months. In addition, we divided the rivastigmine group into two subgroups at the baseline: the mild behavioral and psychological symptoms of dementia (BPSD) group (Abe's BPSD score (ABS) <6) and the severe BPSD group (6≤ABS). In these two subgroups, baseline scores and changes were also retrospectively analyzed until 12 months. RESULTS: Rivastigmine significantly improved the Mini-Mental State Examination score at 3 months (*p < 0.05 versus baseline) and at 6 months (*p < 0.05), the Frontal Assessment Battery (FAB) at 6 months (*p < 0.05), and ABS at 3 months (**p < 0.01) while donepezil only stabilized the three cognitive scores. On the other hand, the Geriatric Depression Scale and the Apathy Scale were stable until 12 months in both groups. Baseline BPSD severity-dependent analysis showed a small improvement of FAB at 6 months in the mild BPSD subgroup (*p < 0.05) and a great improvement of ABS at 3 months in the severe BPSD subgroup (**p < 0.01) in the rivastigmine group. CONCLUSIONS: Our present study showed that rivastigmine improved both cognitive and affective functions at 3 and 6 months, and suggested an advantage at 3 and 6 months compared to donepezil in real world dementia clinics.

DOI： 10.3233/JAD-150518

Clinical Benefits for Older Alzheimer's Disease Patients: Okayama Late Dementia Study (OLDS). Reviewed International journal

Kosuke Matsuzono, Toru Yamashita, Yasuyuki Ohta, Nozomi Hishikawa, Kota Sato, Syoichiro Kono, Kentaro Deguchi, Yumiko Nakano, Koji Abe

Journal of Alzheimer's disease : JAD 46 ( 3 ) 687 - 93 2015

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/OBJECTIVE: There are few reports on the effects of anti-Alzheimer's disease (AD) drugs on older AD patients, and possible differences based on gender in a real world setting. METHODS: "Okayama Late Dementia Study (OLDS)" is a retrospective clinical cohort study focusing on older AD patients (n = 373; age≥75 years) treated with monotherapy donepezil (n = 55), galantamine (n = 222), rivastigmine (n = 63), or memantine (n = 33). The patients were evaluated as an entire group and separated by gender, using seven batteries for dementia assessment at baseline and at 3, 6, and 12 months of drug therapy. RESULTS: All four drugs preserved cognitive and affective functions until 12 months, except for Frontal Assessment Battery (FAB) with memantine ( *p < 0.05 versus baseline). Donepezil monotherapy significantly improved Hasegawa Dementia Rating Scale-Revised (HDS-R) at 3 months ( *p < 0.05), and memantine (3 and 6 months, *p < 0.05) and rivastigmine (3 months, **p < 0.01) improved Abe's Behavior and Psychological Symptom of Dementia Score (ABS), respectively. Activities of daily living (ADL) became significantly worse with galantamine at 12 months ( *p < 0.05). Male Mini-Mental State Examination scores became worse at 12 months with donepezil ( *p < 0.05), as did female Geriatric Depression Scale scores at 6 months ( *p < 0.05). Male HDS-R and ABS scores were preserved in the galantamine group until 12 months. Female ABS scores with memantine improved at 6 months ( *p < 0.05), while male ADL scores became worse with rivastigmine at 12 months ( *p < 0.05). CONCLUSION: OLDS revealed that anti-AD drugs were effective even for older AD patients, and the clinical benefits of each drug showed a small difference with regard to gender.

DOI： 10.3233/JAD-150175

A new simple score (ABS) for assessing behavioral and psychological symptoms of dementia Reviewed

K. Abe, T. Yamashita, N. Hishikawa, Y. Ohta, K. Deguchi, K. Sato, K. Matsuzono, Y. Nakano, Y. Ikeda, Y. Wakutani, Y. Takao

Journal of the Neurological Sciences 350 ( 1-2 ) 14 - 17 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier B.V.

In addition to cognitive impairment, behavioral and psychological symptoms of dementia (BPSD) are another important aspect of most dementia patients. This studywas designed for a newsimple assessment of BPSD. Wefirst employed a clinical survey for the local community with sending an inquiry letter to all members (n= 129) of dementia caregiver society, and then attempted to create a new BPSD score for dementia with 10 BPSD items. This new simple BPSD score was compared to a standard-detailed BPSD score neuropsychiatric inventory (NPI) for a possible correlation (n=792) and a time to complete (n=136). Inter-rater reliabilitywas examined comparing scores between main and second caregivers (n = 70) for AD. Based on the clinical survey for local caregivers, a new BPSD score for dementia (ABS, Abe's BPSD score) was newly created, in which each BPSD item was allotted by an already-weighted score (maximum 1-9) based on the frequency and severity, and was finalized with taking temporal occurrences into account. ABS was filled by the main caregiver with a full score of 44, was well correlated with NPI (r = 0.716,p &lt
0.01) in 792 AD patients (age 78.6 ± 7.0 years, MMSE 19.0 ± 5.9), and took a shorter time as only 56.8 ± 38.8 s (p &lt
0.01) than NPI score (132.7 ± 94.0 s) with 136 AD patients. A high inter-rater reliability was obtained (r = 0.964,p &lt
0.01) with a little smaller score (0.877 time) of ABS in secondary than the main caregivers. ABS provides a new simple and quick test for BPSD assessment, with a good correlation to NPI but a shorter time, and with a high inter-rater reliability. Thus ABS is useful for evaluating BPSD for mild to moderate dementia patients.

DOI： 10.1016/j.jns.2015.01.029

Clinical and demographic predictors of mild cognitive impairment for converting to Alzheimer's disease and reverting to normal cognition. Reviewed International journal

Ryo Tokuchi, Nozomi Hishikawa, Tomoko Kurata, Kota Sato, Syoichiro Kono, Toru Yamashita, Kentaro Deguchi, Koji Abe

Journal of the neurological sciences 346 ( 1-2 ) 288 - 92 2014.11

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: To identify clinical and demographic predictors for mild cognitive impairment (MCI) conversion to Alzheimer's disease (AD) or reversion to normal cognition, and sustained MCI. METHODS: In total, 74 baseline MCI subjects were retrospectively investigated and categorized into three subgroups: conversion to AD, sustained MCI, or reversion to normal cognition during one year. The clinical and demographic characteristics assessed were age, gender, educational attainment, vascular risk factors, white matter lesions (WMLs), and parahippocampal gyrus atrophy (PGA), analyzed by magnetic resonance imaging (MRI) using the voxel-based specific regional analysis system for AD (VSRAD). RESULTS: Of the 74 MCI subjects, 29 (39.2%) were classified as "converters", 39 (52.7%) as "sustained MCI", and 6 (8.1%) as "reverters". Among the three subgroups, there were significant differences in educational attainment (years) (*p = 0.03), baseline mini-mental state examination (MMSE) scores (***p<0.001), and periventricular and deep white matter hyperintensity grades (*p = 0.02 and *p = 0.03, respectively). Baseline PGA showed a significant increasing trend among the three subgroups (reverters<sustained MCI<converters, (###)p<0.001). MCI subjects with higher educational attainment and low VSRAD Z-scores without WMLs were associated with reversion to normal cognitive function. CONCLUSIONS: Risk factors for MCI conversion to AD were low educational attainment, low baseline MMSE scores, high grade WMLs, and high VSRAD Z-scores. High educational attainment, low VSRAD Z-scores, and no WMLs characterized reversion to normal cognition.

DOI： 10.1016/j.jns.2014.09.012

Characteristic RNA foci of the abnormal hexanucleotide GGCCUG repeat expansion in spinocerebellar ataxia type 36 (Asidan) Reviewed

W. Liu, Y. Ikeda, N. Hishikawa, T. Yamashita, K. Deguchi, K. Abe

European Journal of Neurology 21 ( 11 ) 1377 - 1386 2014.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Ltd

Background and purpose: Spinocerebellar ataxia type 36 (SCA36), also called Asidan, is an autosomal-dominant neurodegenerative disorder identified as a hexanucleotide GGCCTG repeat expansion in the first intron 1 of the NOP56 gene. In the present study, for the first time an autopsy sample from an Asidan patient was examined and cytoplasmic inclusions and (GGCCUG)n repeat RNA foci were detected. Methods: Hematoxylin and eosin staining, immunohistochemical staining, as well as fluorescence in situ hybridization were used to investigate the cytoplasmic inclusions of ubiquitin and p62 and the (GGCCUG)n repeat RNA foci. Results: The present study showed both ubiquitin- and p62-positive inclusions in the cytoplasm of the inferior olivary nucleus of the Asidan patient, (GGCCUG)n RNA foci in neuronal nuclei of the cerebrum, cerebellum, inferior olive, spinal cord and temporal muscle, and three types of RNA foci, i.e. single small, multiple small and giant. Of interest is that the giant RNA foci, nearly 10 μm in diameter, that were detected in Purkinje cells, spinal motor neurons and most frequently in the inferior olivary nucleus, may be responsible for pivotal clinical symptoms of Asidan. Conclusions: The present study is the first report to show neuronal cytoplasmic inclusion bodies and giant RNA foci in an Asidan patient. The relationships between the giant RNA foci and neurodegeneration have yet to be studied.

DOI： 10.1111/ene.12491

Pericyte protection by edaravone after tissue plasminogen activator treatment in rat cerebral ischemia. Reviewed International journal

Kentaro Deguchi, Ning Liu, Wentao Liu, Yoshio Omote, Syoichiro Kono, Taijun Yunoki, Shoko Deguchi, Toru Yamashita, Yoshio Ikeda, Koji Abe

Journal of neuroscience research 92 ( 11 ) 1509 - 19 2014.11

Language：English Publishing type：Research paper (scientific journal)

Pericytes play a pivotal role in contraction, mediating inflammation and regulation of blood flow in the brain. In this study, changes of pericytes in the neurovascular unit (NVU) were examined in relation to the effects of exogenous tissue plasminogen activator (tPA) and a free radical scavenger, edaravone. Immunohistochemistry and Western blot analyses showed that the overlap between platelet-derived growth factor receptor β-positive pericytes and N-acetylglucosamine oligomers (NAGO)-positive endothelial cells increased significantly at 4 days after 90 min of transient middle cerebral artery occlusion (tMCAO). The number of pericytes and the overlap with NAGO decreased with tPA but recovered with edaravone 4 days after tMCAO with proliferation. Thus, tPA treatment damaged pericytes, resulting in the detachment from astrocytes and a decrease in glial cell line-derived neurotrophic factor secretion. However, treatment with edaravone greatly improved tPA-induced damage to pericytes. The present study demonstrates that exogenous tPA strongly damages pericytes and destroys the integrity of the NVU, but edaravone treatment can greatly ameliorate such damage after acute cerebral ischemia in rats.

DOI： 10.1002/jnr.23420

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