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Department of Neurology

Our research interests have focused on the radiological, ultrasonological and pathological changes that occur in stroke and dementia and how the alterations impact on brain health during old age. We target a wide range of stroke related diseases and conditions such as acute ischemic/hemorrhagic stroke, vascular dementia, poststroke epilepsy, and vascular parkinsonism. We are currently involved in translational research projects for stroke or mild cognitive impairment including clinical trials using new endovascular device for acute stroke and a vasoactive drug for mild cognitive impairment. We have also used brain autopsy materials and experimental rodent models to publish widely on these issues. Our department members have his/her own expertise to promote the following projects:

  1. Development of pre-hospital stroke scale to identify acute ischemic stroke caused by large vessel occlusion
  2. Development of a quantitative evaluation method for the cerebral collateral circulation
  3. A study to establish an algorithm for predicting recovery after stroke
  4. Research on etiology of stroke (especially cerebral hemorrhage)
  5. Association between juvenile stroke and the Moyamoya-related RNF213 p.R4810K polymorphism
  6. Ultrasound diagnosis for the vulnerability of carotid arteries plaques
  7. PROgnosis of Post Stroke Epilepsy (PROPOSE) Study
  8. Effects of genetic polymorphisms on the pharmacokinetics of anticoagulants study
  9. Research on the pathogenesis of hereditary vascular dementia CADASIL and CARASIL
  10. Vascular factors in Alzheimer's disease
  11. Cilostazol for Prevention of Conversion from MCI to Dementia (COMCID study)
  12. Development of rehabilitation program using virtual reality technology
  13. Finger tapping for evaluating early cognitive impairment
  14. The therapeutic potential of adrenomedulin (AM) in ischemic stroke
  15. Generation of animal models of sporadic vascular dementia

1. Development of pre-hospital stroke scale to identify acute ischemic stroke caused by large vessel occlusion

Patients with acute ischemic stroke caused by large vessel occlusion (LVO, occlusion of internal artery or proximal middle cerebral) present severe neurological symptoms. Furthermore, LVO is hardly recanalized by intravenous thrombolysis. Recently, efficacy of endovascular therapy in patients with acute ischemic stroke with LVO has been clarified. However, the efficacy of endovascular therapy depends on the time from symptom onset to initiation of this therapy. These patients should be transferred to comprehensive stroke center and treated with endovascular therapy immediately.

We have designed a simple prehospital stroke scale, FACE2-AD scale, by which emergency medical personnel can easily identify patients with acute ischemic stroke due to LVO. A validation study using this scale by paramedics is ongoing. We are planning to construct regional stroke care systems using the FACE2-AD scale.

Transfer and direct transport

Appropriate triage of LVO eligible patients and direct transport to the endovascular-capable stroke center can shorten the time from onset to treatment.

FACE2-AD (FACE to Acute Delivery score)

FACE2-AD

2. Development of a quantitative evaluation method for the cerebral collateral circulation

The aim of this collaborative work with radiology and bio-medical imaging department is to establish a new quantitative evaluation method for the cerebral collateral circulation after acute ischemic stroke by using non-invasive three-dimension arterial spin labeling perfusion MRI (3D-ASL). We have reported that 3D-ASL during intravenous thrombolysis can evaluate the leptomeningeal collateral flow and predict early reperfusion after thrombolysis (Figure 1; Okazaki et al, Stroke 2016). Our recent studies have also revealed that focal hyperperfusion after reperfusion therapy detected by 3D-ASL is well associated with hemorrhagic transformation.

According to these findings, we are now developing a new algorithm for selecting candidates for reperfusion therapy and a new quantitative evaluation method for the cerebral collateral circulation.

Figure 1. Repeated ASL perfusion images during intravenous thrombolysis.
Upper image: ASL shows arterial transit artifacts (ATA) in the hypoperfused area (white arrow heads). FLAIR shows hyperintense vessel sign in the corresponding site of ATA (black arrow heads).
Lower image: relative cerebral blood flow (CBF) changes during thrombolysis

Repeated ASL perfusion images during intravenous thrombolysis

3. A study to establish an algorithm for predicting recovery after stroke

The aim of this study is to establish a new algorithm for predicting recovery after stroke in combination of neurophysiological techniques and MRI in the acute phase. By insertion of this algorithm into the inclusion criteria of future clinical trials, we aim to establish effective neuroprotective drugs.

Proposed algorithm for prognosis prediction for stroke

Figure. Proposed algorithm for prognosis prediction for stroke.


4. Research on etiology of stroke (especially cerebral hemorrhage)

A collaborative work with Osaka University Graduate School of Dentistry (Prof. Nakano) showed that Streptococcus mutans is a strong risk factor of cerebral hemorrhage (Tonomura et al. Sci Rep 2016). Although reduced in incidence due to better control of hypertension, cerebral hemorrhage is still prevalent in Japan compared to western countries, and we hope this novel finding will lead to development of new treatment of cerebral hemorrhage.

Number of deep CMBs in stroke

Figure

Stroke patients with cnm-positive S. mutans showed a significantly higher number of deep microbleeds.


5. Association between juvenile stroke and the Moyamoya-related RNF213 p.R4810K polymorphism

Stroke in young adults accounts for about 10% of all stroke. Although some genetic predispositions have been previously reported, no susceptibility gene for juvenile stroke has been identified to date. We hypothesize that RNF213 p.R4810K polymorphism, the susceptibility gene for moyamoya disease, is also associated with the development of juvenile stroke in Asia (Figure 2). This is a collaborative study with the Department of Health and Environmental Sciences in Kyoto Univ. Graduate School of Medicine.

Figure 2. Hypothesis of the development of juvenile stroke.

Figure 2


6. Ultrasound diagnosis for the vulnerability of carotid arteries plaques

Atherosclerotic plaques contain necrotic core, which may result in plaque rupture and cause artery-to-artery embolism. We evaluate plaque vulnerability using contrast enhanced ultrasound (CEUS). CEUS can delineate intraplaque neovessels, and contrast effect of symptomatic plaques was significantly greater than that of asymptomatic plaques (Saito et al. Stroke 2014). CEUS can also detect small ulcers which could not be delineated using color Doppler mode.
We aim for a better qualitative evaluation of carotid plaques.

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7. PROgnosis of Post Stroke Epilepsy (PROPOSE) Study

Post stroke epilepsy (PSE) is a clinical problem for stroke survivors. The incidence rate of PSE was about 10 %. Previous reports showed that the occurrence of PSE led to poor prognosis and increased mortality.

Moreover, PSE has the high recurrence rate. Our previous study showed that PSE recurred in 30% patients within 360 days (Tanaka et al. PLoS One 2015). PSE patients are frightened by the recurrence in their daily lives; therefore, PSE may worsen the recovery and quality of life in stroke survivors.

Figure
Kaplan-Meier curve for proportion without recurrent PSE. After a median follow-up of 362 days, we identified recurrent PSE in 31 patients(29.8%). Dotted lines indicate the confidence interval.

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There are still many questions about PSE, we conducted multicentre prospective cohort study of PSE and ongoing. If is funded by AMED.
We hold hospital meeting of PSE every week and EEG reading conference once a month with Kyoto University. Moreover, we are developing the new diagnosis methods of PSE.

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8. Effects of genetic polymorphisms on the pharmacokinetics of anticoagulants study

In recent days, it became possible to use DOAC as anticoagulants without requiring dose adjustment. However, there are individual differences in the blood concentration of anticoagulants, which may affect the drug efficacy, due to genetic polymorphisms. In cooperation with our pharmaceutical and clinical laboratory examination departments, we are evaluating the concentration and genetic polymorphisms by using the triple quadrupole liquid chromatograph mass spectrometer (Shimadzu, LCMS-8030) and the gene analysis system (Shimadzu, GTS-7000).

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9. Research on the pathogenesis of hereditary vascular dementia CADASIL and CARASIL

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) are hereditary small vessel disease caused by mutations in NOTCH3 and HTRA1, respectively. Although the causative genes have been identified, their molecular pathogenesis is still unclear. We are investigating the pathogenesis of hereditary vascular dementia using animal models of CADASIL and CARASIL as well as induced pluripotent stem cells (iPSCs) from CADASIL patients. Currently we are also working on the establishment of CADASIL patient database. We aim to expand our research further to establish Japanese diagnostic criteria of CADASIL and develop new treatment in the future.

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10. Vascular factors in Alzheimer's disease

The elderly people often have multiple comorbidities. The most common cause of dementia, Alzheimer's disease, is no exception; it is accompanied by lifestyle-related disorders such as hypertension and diabetes mellitus. We therefore try to elucidate the underlying mechanism by which vascular disease accelerates neurodegenerative processes and to find treatment of Alzheimer's disease by targeting vascular diseases.

Studies of transgenic mice expressing tau gene mutations in a familial form of tauopathy (FTDP-17) implicate pathological tau in mechanisms of neurodegenerative dementia. In case of AD, however, the relationship between Aβ and tau has not been clearly elucidated. We are investigating the mechanism from both point of view; Aβ and tau.

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Figure "AD malignant cycle".
Abeta overproduction impairs Abeta elimination leading to vascular smooth muscle cells (vSMC) degeneration,cerebral ischemia, and microinfarcts. Ischemia also induces Abeta overproduction. Such vicious circle consists of core pathology in sporadic AD. Note that cessation of Abeta overproduction is not sufficient to sever the cycle.


11. Cilostazol for Prevention of Conversion from MCI to Dementia (COMCID study)

COMCID

Epidemiological, clinicopathological and animal studies show that vascular disease in various forms contributes to cognitive decline. Increasing age is the strongest risk for dementia irrespective of whether it results from a vascular etiology or neurodegenerative disease processes such as in Alzheimer's disease (AD). AD and vascular cognitive impairment, the two most common causes of dementia, represent two extremes of a spectrum of disorders; however, a number of entities, which possess varying degrees of neurodegenerative and vascular pathologies, occur in between. The pure forms of the disorders are preferred for convenience to label, treat or manage but conditions within the spectrum are the norm rather than the exception as dementia advances. Therefore, combinatorial therapy directed at both vascular and neurodegenerative aspects of dementia is a promising approach for the treatment of dementia in the elderly.


12. Development of rehabilitation program using virtual reality technology

It is clear that rehabilitation will lead to improvement of motor function, but it is difficult to continue monotonous rehabilitation. Due to progress of virtual reality technology, applications of three dimensional space images have been studied in various fields; however, there are few studies in the stroke rehabilitation field. We cooperate with Osaka University and Medi VR Inc. to create novel virtual reality program for rehabilitation after stroke.

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13. Finger tapping for evaluating early cognitive impairment

With continuous increase of elderly people in Japan, dementia has become a major social issue. It is important to detect cognitive impairment at early stage because relevant medication and life support may somewhat prevent the disease progression. At present, however, Minimental State Examination (MMSE), a well-known screening test for simplicity and utility, is insufficient for evaluating executive function including motor skill function. Thus, we are conducting a finger tapping study (Fig 2) using "UB-1" magnetic detection system produced by HITACHI Ltd (Fig 1).

Fig 3 and 4 show right finger-tapping data while subjects tap both fingers at the same time. Both examinees achieved normal score in MMSE but Frontal Assessment Battery (FAB, which is known to be related with executive function) was normal in Fig 3 but low in Fig 4.

Further study is being planned to establish early diagnosis of dementia, especially focusing on stroke-related condition.

Fig 1
Fig 2
Fig 3(MMSE: 29/30, FAB:16/18)

Fig 4(MMSE: 28/30, FAB: 9/18)


14. The therapeutic potential of adrenomedulin in ischemic stroke

Although the mortality rate of stroke has decreased due to the progress of acute therapies of infarction such as recombinant tissue plasminogen activator and endovascular thrombectomy, the next stage of therapy is being desired for further improvement in stroke mortality and morbidity.

Adrenomedullin (AM) has a variety of effects on the vasculature that include vasodilation, regulation of permeability, inhibition of endothelial cell apoptosis and oxidative stress, regulation of smooth muscle cell proliferation, and promotion of angiogenesis. We previously reported that after bilateral common carotid artery stenosis (BCAS), mice overexpressing circulating AM showed significantly faster cerebral perfusion recovery due to substantial growth of the capillaries, the circle of Willis, and the leptomeningeal anastomoses and reduced oxidative damage in vascular endothelial cells compared with wild-type mice (Maki T, et al. Stroke 2011). A translational study is being planned.

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Figure
Images showing temporal changes of CBF in wild-type (WT) and AM-Tg mice after BCAS. On Days 1 and 3 post-BCAS, there was a slight, but not significant, increase in CBF in mice overexpressing circulating AM BCAS compared with WT BCAS. On Day 7 post-BCAS, AM BCAS showed significantly faster cerebral perfusion recovery: cerebral perfusion was significantly higher in AM BCAS compared with WT BCAS.


15. Generation of animal models of sporadic vascular dementia

We are developing animal models of sporadic vascular dementia using mice and rats which can be applied to drug development for human vascular dementia. Recently, we have established a mouse model of vascular dementia named ACAS (asymmetric common carotid artery surgery) model (Hattori Y, et al. J Neurosci 2015). For this publication, our post-doc Dr. Yorito Hattori won the Kusano prize in 2016. Our review paper about cerebral small vessel disease was published in Stroke and one of the figures was printed in cover page (Ihara M and Yamamoto Y. Stroke 2016) (see figure below).

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Figure
Mechanism of cerebral small vessel disease. In addition to the old pathway consisting of arteriolosclerosis -> thrombosis formation -> cerebral infarction -> dementia, a lot of 'unknown' factors such as salt toxicity, inflammation/infection, large and small artery crosstalk, and disrupted cell-cell interaction in the blood-brain barrier seem to contribute to the pathogenesis of cerebral small artery disease.

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