Faculty Profiles - YAMASHITA Toru

Papers - YAMASHITA Toru

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An autopsy case of intravascular large B-cell lymphoma with subcortical U-fiber sparing and unique lymphocyte markers. Reviewed International journal

Kota Sato, Emi Motokura, Kentaro Deguchi, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Junya Itakura, Koji Abe

Journal of the neurological sciences 369 273 - 275 2016.10

Differences between the behavioral and psychological symptoms of Alzheimer's disease and Parkinson's disease. Reviewed International journal

Ryo Tokuchi, Nozomi Hishikawa, Kota Sato, Noriko Hatanaka, Yusuke Fukui, Mami Takemoto, Yasuyuki Ohta, Toru Yamashita, Koji Abe

Journal of the neurological sciences 369 278 - 282 2016.10

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

AIM: We compared the behavioral and psychological symptoms of Alzheimer's disease (AD) and Parkinson's disease (PD) in order to determine the characteristic features of each disorder. METHODS: For this retrospective cohort study, we compared the behavioral and psychological symptoms of 288AD patients and 189 PD patients (mean age, 74.6±5.9 and 73.0±8.7years respectively). Symptoms were evaluated using the geriatric depression scale (GDS), apathy scale (AS), and Abe's behavioral and psychological symptoms of dementia score (ABS). RESULTS: AD patients had higher AS and ABS scores than PD patients. A gender-dependent comparison showed that ABS scores were worse in female AD patients than in female PD patients (p=0.001). A subscale analysis of ABS scores revealed that male AD patients were only significantly different from male PD patients in 1 item, whereas female AD patients were significantly different from female PD patients in 4 items. Among patients with mild cognitive decline, no differences in affective scores were observed. Alternatively, among patients with moderate cognitive decline, affective scores on all 3 scales were worse in PD patients than in AD patients. CONCLUSIONS: The present age- and gender-matched retrospective analysis identified greater behavioral and psychological disease severity in female AD patients relative to female PD patients, and greater affective severity in PD patients versus AD patients with a similar degree of cognitive decline.

DOI： 10.1016/j.jns.2016.08.053

Temporal Profiles of Stress Protein Inductions after Focal Transient Ischemia in Mice Brain. Reviewed International journal

Qian Li, Yumiko Nakano, Jingwei Shang, Yasuyuki Ohta, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 25 ( 10 ) 2344 - 51 2016.10

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

BACKGROUND: Stress proteins have been found to play important protective roles against ischemic brain injury under hypoxic, oxidative, heat shock, and proteasome stresses. METHODS: In the present study, we investigated the temporal profiles of the major stress proteins including hypoxia-inducible factor-1α (HIF-1α), glutathione (GSH), heat shock protein 72 (HSP72), constitutive heat shock cognate protein 73 (HSC73), and ubiquitin after 45 minutes of transient middle cerebral artery occlusion (tMCAO) in the mice brain up to 7 days after reperfusion. RESULTS: Immunohistochemical analyses of HIF-1α, GSH, HSP72, and ubiquitin showed little immunoreactivity of neural cells in sham control brain, whereas HSC73 showed a constitutive immunoreactivity. After tMCAO, HSC73 showed the fastest increase at 12 hours in the peri-ischemic area, followed by HIF-1α with a peak at 24 hours, GSH, HSP72, and ubiquitin with a peak at 72 hours. All these stress proteins returned toward the baseline levels until 7 days. In the ischemic core, these stress proteins showed a similar change with less reaction compared to the peri-ischemic area. CONCLUSIONS: These data showed temporal expressions of HIF-1α, GSH, HSP72, HSC73, and ubiquitin in the mice brain after tMCAO, which might provide a better understanding of neuroprotective mechanisms and novel targets for therapeutic intervention of brain ischemic disease.

DOI： 10.1016/j.jstrokecerebrovasdis.2016.05.031

Different clinical features in siblings with identical mutations of the Parkin gene (PARK2). Reviewed International journal

Kota Sato, Toru Yamashita, Noriko Hatanaka, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

Journal of the neurological sciences 368 147 - 9 2016.9

Autophagic down-regulation in motor neurons remarkably prolongs the survival of ALS mice. Reviewed International journal

Kuo-Wei Hsueh, Tzyy-Wen Chiou, Shu-Fen Chiang, Toru Yamashita, Koji Abe, Cesar V Borlongan, Paul R Sanberg, Angela Yu Hsuan Huang, Shinn-Zong Lin, Horng-Jyh Harn

Neuropharmacology 108 152 - 60 2016.9

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

Amyotrophic lateral sclerosis (ALS) is a lethal degenerating disease, characterized by progressive muscular atrophy without any effective treatment. Here, we demonstrated the efficacy of abrograting autophagy in motor neurons (MN) by treatment with n-butylidenephthalide (n-BP) in ALS transgenic mice (SOD1(G93A)). Pre-symptomatic oral administration of 250 mg/kg/bid n-BP significantly prolonged the survival period (203.9 ± 18.3 days), improved motor function, and attenuated MN loss compared to vehicle control (126.4 ± 7.2 days). This prolonged survival of ALS mice is much more robust than that reported with riluzole (140 days), which is an approved clinical therapy for ALS. The therapeutic mechanism targeted by n-BP involved the autophagic pathway as evidenced by decreased LC3-II expression (a biomarker of autophagy), enhanced mTOR levels, and attenuated autophagic activity, altogether increasing MN survival in a dose-dependent manner. This result was also confirmed by double transgenic mice (SOD1(G93A):LC3-GFP) which showed that oral administration of n-BP reduced GFP density and decreased caspase-3 expression. In addition, electron microscopy revealed that n-BP administration not only decreased autophagosome number but also reduced morphological dysfunction of mitochondria. In summary, these results indicate that down-regulation of autophagy activation via n-BP may pose as a therapeutic regimen for ALS and relevant neurodegenerative diseases.

DOI： 10.1016/j.neuropharm.2016.03.035

Effects of Pretreatment with Warfarin or Rivaroxaban on Neurovascular Unit Dissociation after Tissue Plasminogen Activator Thrombolysis in Ischemic Rat Brain. Reviewed International journal

Jingwei Shang, Toru Yamashita, Syoichiro Kono, Ryuta Morihara, Yumiko Nakano, Yusuke Fukui, Xianghong Li, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 25 ( 8 ) 1997 - 2003 2016.8

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

BACKGROUND: Warfarin and rivaroxaban are highly effective in reducing stroke risk in patients with atrial fibrillation (AF). However, their effects on anticoagulation and neurovascular unit (NVU) change remain elusive. In this study, we assessed the risks and benefits of pre-treatment with warfarin or rivaroxaban after tissue-type plasminogen activator (tPA) thrombolysis in ischemic rat brain. METHODS: Pre-treatment with warfarin (.2 mg/kg/day), low dose rivaroxaban (60 mg/kg/day), high dose rivaroxaban (120 mg/kg/day) or vehicle was performed for 2 weeks, transient middle cerebral artery occlusion (tMCAO) was induced for 90 min, then followed by reperfusion with tPA. At 24 hours (h) after reperfusion, we observed the changes of matrix metalloproteinase-9 (MMP-9), tissue factor, caspase 3 and NVU dissociation. RESULTS: Prothrombin time (PT) was significantly prolonged in the warfarin and rivaroxaban pretreated groups. MMP-9 expression greatly increased in the warfarin group, and this was reduced in the rivaroxaban groups compared with the vehicle group. Tissue factor expression remarkably decreased in the warfarin and rivaroxaban groups. The number of caspase 3-positive cells had no difference among all the groups. Marked dissociations between astrocyte foot processes and the basal lamina or pericytes were observed in the warfarin pretreated group, but such dissociations were improved in the rivaroxaban groups. CONCLUSIONS: Our present study shows that pre-treatment with rivaroxaban was noninferior to warfarin in the anticoagulation, but a lower risk of NVU dysfunction and dissociation after tPA treatment in rivaroxaban. This finding could partly explain the mechanism of reducing hemorrhagic complications by rivaroxaban in clinical studies.

DOI： 10.1016/j.jstrokecerebrovasdis.2016.04.002

Peripheral arterial endothelial dysfunction of neurodegenerative diseases. Reviewed International journal

Yusuke Fukui, Nozomi Hishikawa, Jingwei Shang, Kota Sato, Yumiko Nakano, Ryuta Morihara, Yasuyuki Ohta, Toru Yamashita, Koji Abe

Journal of the neurological sciences 366 94 - 99 2016.7

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

This study evaluates endothelial functions of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and spinocerebellar ataxia (SCA). The reactive hyperemia index (RHI) of peripheral arterial tonometry and serological data were compared between age- and gender-matched normal controls (n=302) and five disease groups (ALS; n=75, PD; n=180, PSP; n=30, MSA; n=35, SCA; n=53). Correlation analyses were performed in ALS with functional rating scale-revised (FRS-R), and in PD with the Hehn-Yahr scale (H-Y) and a heart to mediastinum ratio using (123)I-MIBG scintigraphy (MIBG). The RHI of ALS and PD, but not of PSP, MSA or SCA, were significantly lower than normal controls (p<0.01). ALS showed a negative correlation of RHI with serum triglycerides (TG) and immunoreactive insulin (IRI) levels, but not with disease severity (FRS-R) or rates of disease progression (∆FRS-R). On the other hand, PD showed a negative correlation of RHI with a progressive disease severity (H-Y) and a positive correlation of RHI with early/delayed MIBG scintigraphy, but not with serological data. The present study demonstrated significant declines of peripheral arterial endothelial functions in ALS and PD. The RHI of ALS was more correlated with disease duration and serum parameters while the RHI of PD was more correlated with disease severity and MIBG, suggesting different mechanisms of endothelial dysfunction.

DOI： 10.1016/j.jns.2016.04.042

Age-dependent cognitive and affective differences in Alzheimer's and Parkinson's diseases in relation to MRI findings. Reviewed International journal

Ryo Tokuchi, Nozomi Hishikawa, Kota Sato, Noriko Hatanaka, Yusuke Fukui, Mami Takemoto, Yasuyuki Ohta, Toru Yamashita, Koji Abe

Journal of the neurological sciences 365 3 - 8 2016.6

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

OBJECTIVE: To compare age-dependent changes in cognitive and affective functions related to white matter changes between patients with Alzheimer's disease (AD) and Parkinson's disease (PD). METHODS: We retrospectively compared age-dependent cognitive and affective functions in 216 AD patients, 153 PD patients, and 103 healthy controls with cerebral white matter lesions (WMLs), periventricular hyperintensity (PVH), deep white matter hyperintensity (DWMH), micro-bleeds (MBs), and lacunar infarcts (LIs). RESULTS: The average mini-mental state examination (MMSE) scores were 19.6±6.1 and 26.8±3.6 in AD and PD patients, respectively. Significant decreases were found in the MMSE score, Hasegawa's dementia scale-revised (HDS-R) score, frontal assessment battery score, and Abe's BPSD score (ABS) among the age-dependent AD subgroups and in the MMSE, HDS-R, Montreal cognitive assessment, geriatric depression scale, and ABS scores among the age-dependent PD subgroups; they were worse in AD patients. White matter changes were observed in >88% and >72% of patients with AD and PD, respectively. An age-dependent direct comparison of AD and PD showed significant differences in the PVH and DWMH grades, and numbers of MBs and LIs. CONCLUSION: WML-related cognitive and affective functions worsen with age in AD and PD patients; however, the abnormalities were more frequent and stronger in AD patients.

DOI： 10.1016/j.jns.2016.03.031

Recurrent cervical internal carotid artery vasospasm relating to menstruation with endothelial dysfunction. Reviewed International journal

Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Koji Abe

Journal of the neurological sciences 365 72 - 3 2016.6

Chronic Cerebral Hypoperfusion Accelerates Alzheimer's Disease Pathology with Cerebrovascular Remodeling in a Novel Mouse Model. Reviewed International journal

Yun Zhai, Toru Yamashita, Yumiko Nakano, Zhuoran Sun, Jingwei Shang, Tian Feng, Ryuta Morihara, Yusuke Fukui, Yasuyuki Ohta, Nozomi Hishikawa, Koji Abe

Journal of Alzheimer's disease : JAD 53 ( 3 ) 893 - 905 2016.6

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

Recently, aging societies have been showing an increasingly strong relationship between Alzheimer's disease (AD) and chronic cerebral hypoperfusion (HP). In the present study, we created a new mouse model for AD with HP, and investigated its clinical and pathological characteristics. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral HP. In contrast to simple APP23 mice, cerebral HP exacerbated motor and cognitive dysfunctions with white matter lesions and meningo-parenchymal amyloid-β (Aβ) burdens. Strong cerebrovascular inflammation and severe amyloid angiopathy with cerebrovascular remodeling were also observed in APP23 + HP mouse brains. An acetylcholinesterase inhibitor galantamine improved such clinical dysfunctions, retrieved above neuropathological characteristics, and enhanced nicotinic acetylcholine receptor (nAChR)-binding activity. The present study demonstrates that chronic cerebral HP enhanced cognitive/motor dysfunctions with parenchymal/cerebrovascular Aβ accumulation and cerebrovascular remodeling. These neuropathological abnormalities were greatly ameliorated by galantamine treatment associated with nAChR-mediated neuroprotection by allosterically potentiating ligand action.

DOI： 10.3233/JAD-160345

Phase II Trial of Intravenous Low-Dose Granulocyte Colony-Stimulating Factor in Acute Ischemic Stroke. Reviewed International journal

Atsushi Mizuma, Toru Yamashita, Syoichiro Kono, Taira Nakayama, Yasuhiko Baba, Shinji Itoh, Kunihiko Asakura, Yoshiki Niimi, Takashi Asahi, Kazuya Kanemaru, Tatsuro Mutoh, Satoshi Kuroda, Hiroyuki Kinouchi, Koji Abe, Shunya Takizawa

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 25 ( 6 ) 1451 - 7 2016.6

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

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) has shown neuroprotective and neurogenerative activities in experimental studies, and our previous phase I clinical study suggested the safety and potential efficacy of low-dose G-CSF in acute ischemic stroke patients. The present phase II trial is aimed to evaluate the effect of G-CSF administration on neurological function and infarct volume, compared with a placebo group. METHODS: Forty-nine acute ischemic stroke patients (29 males, 20 females; 71 ± 10 years) within 24 hours after onset were recruited. Eligible patients were randomized 2:2:1 to receive G-CSF 150 µg/body/day, G-CSF 300 µg/body/day, and placebo, respectively. We evaluated clinical outcome in terms of the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index at 90 days after onset, together with changes in infarct volume on magnetic resonance imaging. RESULTS: We found no serious adverse event, including change in leukocyte levels, which remained below 31,000/µL, at 150 and 300 µg G-CSF/body/day. Clinical outcome scores did not show any significant difference among the 3 groups. Chronological changes in infarct volume also showed no significant difference. CONCLUSIONS: G-CSF was well-tolerated at 150 and 300 µg/body/day in patients with acute ischemic stroke. However, administration of G-CSF at both 150 and 300 µg/body/day neither contributed to functional recovery nor reduced infarct volume at 3 months after onset, compared with the control group. The apparent lack of effectiveness may have been due to the small sample size. A trial of combination therapy with recombinant tissue plasminogen activator and G-CSF is planned.

DOI： 10.1016/j.jstrokecerebrovasdis.2016.01.022

超実践!脳卒中に用いる薬の基礎知識エダラボン

森原隆太, 山下徹, 阿部康二

脳神経外科速報 26 ( 6 ) 621 - 625 2016.6

Language：Japanese Publisher：(株)メディカ出版

(1)エダラボンは急性期脳梗塞患者の神経症候を改善する効果がある。(2)エダラボンはt-PA療法との併用において、出血性合併症軽減や再開通率向上に寄与する可能性がある。(3)エダラボンはALSの治療薬としても認可され、その効果が期待されている。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J03120&link_issn=&doc_id=20160609170008&doc_link_id=issn%3D0917-1495%26volume%3D26%26issue%3D6%26spage%3D621&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0917-1495%26volume%3D26%26issue%3D6%26spage%3D621&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

ADとPDにおける認知機能、情動機能ならびにMRI画像の加齢性変化に関する検討

徳地亮, 菱川望, 佐藤恒太, 太田康之, 山下徹, 阿部康二

日本老年医学会雑誌 53 ( Suppl. ) 166 - 166 2016.5

Disruption of White Matter Integrity by Chronic Cerebral Hypoperfusion in Alzheimer's Disease Mouse Model. Reviewed International journal

Yun Zhai, Toru Yamashita, Yumiko Nakano, Zhuoran Sun, Ryuta Morihara, Yusuke Fukui, Yasuyuki Ohta, Nozomi Hishikawa, Koji Abe

Journal of Alzheimer's disease : JAD 52 ( 4 ) 1311 - 9 2016.4

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

A rapidly progressing aging society has raised attention to white matter lesions in Alzheimer's disease. In the present study, we applied an AD plus cerebral hypoperfusion (HP) mouse model and investigated the alternation of key protein molecules in the nodal, paranodal, and intermodal sites in the white matter as well as the efficacy of galantamine. Cerebral HP was induced in APP23 mice by bilateral common carotid arteries stenosis with ameroid constrictors. Compared with the wild type and simple APP23 mice, APP23 + HP mice showed a progressive loss of MAG and NF186 from 6 to 12 months, broken misdistribution of MBP, and extended relocation of Nav1.6 and AnkG beyond the primary nodal region in the corpus callosum. Such abnormal neuropathological processes were retrieved with galantamine treatment. The present study demonstrated that cerebral HP strongly disrupted white matter integrity (WMI) at intermodal, paranodal, and Ranvier's nodal sites which may be associated with cognitive decline. Galantamine treatment significantly protected such WMI probably by allosterically potentiating ligand action.

DOI： 10.3233/JAD-160120

Characteristic features of cognitive, affective and daily living functions of late-elderly dementia. Reviewed

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

Geriatrics & gerontology international 16 ( 4 ) 458 - 65 2016.4

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

AIMS: The world is rapidly aging, and is facing an increase of late-elderly dementia patients. It is important to investigate the characteristic features of late-elderly dementia in a super-aged country. METHODS: We examined 1554 patients with cognitive decline in Department of Neurology, Okayama University Hospital, Okayama, Japan, divided into three subgroups according to the age: young-elderly (age ≤64 years), middle-elderly (age 65-74 years) and late-elderly (age 75 years), and investigated the cognitive, affective and activities of daily living functions (ADL), especially in late-elderly patients compared with young-elderly and middle-elderly patients. RESULTS: Among 1554 patients, Alzheimer's disease dominated at 62%, and age-dependently increased up to 69% in the late-elderly group. The total scores of four cognitive tests were significantly worse with aging for specific subscales of orientation, recall, visual retention, word fluency and so on. In contrast, total scores of the affective tests showed only an increase in the apathy scale in the late-elderly group. Each subgroup showed depressive/depression in 63.2-55.2%, and apathy in 44.2-54.8%. Furthermore, instrumental ADL items significantly deteriorated in the late-elderly group, which statistically correlated with Mini-Mental State Examination score. CONCLUSIONS: These results show that the late-elderly group is characterized by significant cognitive declines, increasing apathy, and instrumental ADL decrease. The cognitive decline may be related to such affective and ADL declines.

DOI： 10.1111/ggi.12492

Cognitive and affective benefits of combination therapy with galantamine plus cognitive rehabilitation for Alzheimer's disease. Reviewed

Ryo Tokuchi, Nozomi Hishikawa, Kosuke Matsuzono, Yoshiki Takao, Yosuke Wakutani, Kota Sato, Syoichiro Kono, Yasuyuki Ohta, Kentaro Deguchi, Toru Yamashita, Koji Abe

Geriatrics & gerontology international 16 ( 4 ) 440 - 5 2016.4

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

AIM: The aim of the present study was to compare the effects of a galantamine only therapy and a combination therapy with galantamine plus ambulatory cognitive rehabilitation for Alzheimer's disease patients. METHODS: For this retrospective cohort study, we enrolled 86 patients with Alzheimer's disease, dividing them into two groups - a galantamine only group (group G, n = 45) and a combination with galantamine plus ambulatory rehabilitation group (group G + R, n = 41). The present cognitive rehabilitation included a set of physical therapy, occupational therapy and speech therapy for 1-2 h once or twice a week. We compared the Mini-Mental State Examination and Frontal Assessment Battery for cognitive assessment, and Geriatric Depression Scale, Apathy Scale, and Abe's Behavioral and Psychological Symptoms of Dementia score for affective assessment in two groups over 6 months. RESULTS: The baseline Mini-Mental State Examination score was 20.2 and 18.7 in groups G and G + R, respectively. Other baseline data (Frontal Assessment Battery, Geriatric Depression Scale, Apathy Scale, and Abe's Behavioral and Psychological Symptoms of Dementia) were not different between the two groups. Although group G kept all the scores stable until 6 months of the treatment, the Apathy Scale score showed a significant improvement in group G + R as early as 3 months, followed by the Mini-Mental State Examination and Frontal Assessment Battery improvements at 6 months (*P = 0.04 and *P = 0.02, respectively). The Geriatric Depression Scale and Abe's Behavioral and Psychological Symptoms of Dementia did not show any changes. CONCLUSION: The combination therapy of galantamine plus ambulatory cognitive rehabilitation showed a superior benefit both on cognitive and affective functions than galantamine only therapy in Alzheimer's disease patients.

DOI： 10.1111/ggi.12488

Thrombolysis with Low-Dose Tissue Plasminogen Activator 3-4.5 h After Acute Ischemic Stroke in Five Hospital Groups in Japan. Reviewed International journal

Ryuta Morihara, Syoichiro Kono, Kota Sato, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Kentaro Deguchi, Yasuhiro Manabe, Yoshiki Takao, Kenichi Kashihara, Satoshi Inoue, Hideki Kiriyama, Koji Abe

Translational stroke research 7 ( 2 ) 111 - 9 2016.4

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

Clinical data from Japan on the safety and real-world outcomes of alteplase (tPA) thrombolysis in the extended therapeutic window are lacking. The aim of this study was to assess the safety and real-world outcomes of tPA administered within 3-4.5 h of stroke onset. The study comprised consecutive acute ischemic stroke patients (n = 177) admitted across five hospitals between September 2012 and August 2014. Patients received intravenous tPA within <3 or 3-4.5 h of stroke onset. Endovascular therapy was used for tPA-refractory patients. In the 3-4.5 h subgroup (31.6 % of patients), tPA was started 85 min later than the <3 h group (220 vs. 135 min, respectively). However, outcome measures were not significantly different between the <3 and 3-4.5 h subgroups for recanalization rate (67.8 vs. 57.1 %), symptomatic intracerebral hemorrhage (2.5 vs. 3.6 %), modified Rankin Scale score of 0-1 at 3 months (36.0 vs. 23.4 %), and mortality (6.9 vs. 8.3 %). We present data from 2005 to 2012 using a therapeutic window <3 h showing comparable results. tPA following endovascular therapy with recanalization might be superior to tPA only with recanalization (81.0 vs. 59.1 %). Compared with administration within 3 h of ischemic stroke onset, tPA administration within 3-4.5 h of ischemic stroke onset in real-world stroke emergency settings at multiple sites in Japan is as safe and has the same outcomes.

DOI： 10.1007/s12975-016-0448-8

New susceptible variant of COQ2 gene in Japanese patients with sporadic multiple system atrophy Reviewed International journal

Zhuoran Sun, Yasuyuki Ohta, Toru Yamashita, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Koji Abe

NEUROLOGY-GENETICS 2 ( 2 ) e54 2016.4

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

OBJECTIVE: The aim of this study was to analyze the association between the variations of coenzyme Q2 4-hydroxybenzoate polyprenyltransferase gene (COQ2) and Japanese patients with multiple system atrophy (MSA). METHODS: We investigated the genetic variations in exons 1, 2, 6, and 7 of the COQ2 gene in 133 Japanese patients with MSA and 200 controls and analyzed the association between the variations and MSA. RESULTS: Six DNA variations (G21S, L25V, V66L, P157S, V393A, and X422K) were found in the 133 patients with MSA, and G21S and X422K were new variations that had never been reported. V66L was a common variation that was found in all 133 patients with MSA. G21S, P157S, V393A, and X422K did not show gene frequency differences between patients with MSA and controls. On the other hand, L25V was newly proven to be the only risk factor of sporadic MSA with predominant olivopontocerebellar ataxia. CONCLUSIONS: The present study suggests L25V variant of COQ2 gene as a genetic risk factor in Japanese patients with MSA with cerebellar ataxia.

DOI： 10.1212/NXG.0000000000000054

[Regenerative therapy for post-stroke patients]. Reviewed

Toru Yamashita, Koji Abe

Nihon rinsho. Japanese journal of clinical medicine 74 ( 4 ) 661 - 5 2016.4

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

Cell replacement therapy is attractive as a novel strategy for stroke patients. To realize this therapy, safer and more effective cell resources are now required. Since both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can retain high replication competence and pluripotency when they differentiate into various kinds of cells, they are regarded as a promising cell source for cell replacement therapy. Recent progress includes the combination of novel transcriptional factors that can convert somatic cells to various kinds of mature neuronal cells and neural stem cells without requiring embryonic stem fate. In this paper, we would like to discuss the advantage, issues, and possibility of clinical application of these cells for cell replacement therapy for post-stroke patient.

Strong Impact of Chronic Cerebral Hypoperfusion on Neurovascular Unit, Cerebrovascular Remodeling, and Neurovascular Trophic Coupling in Alzheimer's Disease Model Mouse. Reviewed International journal

Jingwei Shang, Toru Yamashita, Yun Zhai, Yumiko Nakano, Ryuta Morihara, Yusuke Fukui, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

Journal of Alzheimer's disease : JAD 52 ( 1 ) 113 - 26 2016.3

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

Although chronic cerebral hypoperfusion (CCH) may affect Alzheimer's disease (AD) pathogenesis, the mechanism remains elusive. In the present study, we investigated the role of CCH on an AD mouse model in neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of galantamine. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral hypoperfusion. CCH exacerbated neuronal loss and decrease of α7 subunit of nicotinic acetylcholine receptors (α7-nAChRs) expression in hippocampus and thalamus at 12 months. Meanwhile, CCH greatly induced advanced glycation end products expression, and blood-brain barrier leakage through observing IgG and MMP9 expressions. Furthermore, a significant number of dramatic enlarged cerebral vessels with remodeling, BDNF/TrkB decreased in neurovascular trophic coupling. The present study demonstrated that CCH strongly enhanced primary AD pathology including neurodegeneration, neurovascular unit disruption, cerebrovascular remodeling and neurovascular trophic coupling damage in AD mice, and that galantamine treatment greatly ameliorated such neuropathologic abnormalities.

DOI： 10.3233/JAD-151126

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