Published papers

White matter abnormalities in the CNS have been reported recently in various neurological and psychiatric disorders. Quantitation of non-Gaussianity for water diffusion by q-space diffusional MRI (QSI) renders biological diffusion barriers such as myelin sheaths; however, the time-consuming nature of this method hinders its clinical application. In the current study, we aimed to refine QSI protocols to enable their clinical application and to visualize myelin signals in a clinical setting. For this purpose, animal studies were first performed to optimize the acquisition protocol of a non-Gaussian QSI metric. The heat map of standardized kurtosis values derived from optimal QSI (myelin map) was then created. Histological validation of the myelin map was performed in myelin-deficient mice and in a nonhuman primate by monitoring its variation during demyelination and remyelination after chemical spinal cord injury. The results demonstrated that it was sensitive enough to depict dysmyelination, demyelination, and remyelination in animal models. Finally, its utility in clinical practice was assessed by a pilot clinical study in a selected group of patients with multiple sclerosis (MS). The human myelin map could be obtained within 10 min with a 3 T MR scanner. Use of the myelin map was practical for visualizing white matter and it sensitively detected reappearance of myelin signals after demyelination, possibly reflecting remyelination inMSpatients. Our results together suggest that the myelin map, a kurtosis-related heat map obtainable with time-saving QSI, may be a novel and clinically useful means of visualizing myelin in the human CNS.

BACKGROUND: Various sensory impairments have been reported in patients with lateral medullary syndrome, also known as Wallenberg syndrome. The typical sensory impairments experienced by patients with this condition are ipsilateral facial and contralateral trunk and limb thermal hypesthesia and hypoalgesia. Tactile (light touch) sensation is not generally diminished. Here we report the case of a 35-year-old man with lateral medullary infarction who had atypical sensory impairment. METHODS: We examined the results from the neurological examination of the patient as well as findings from computed tomography of the head and magnetic resonance imaging. RESULTS: Magnetic resonance imaging showed left lateral medullary infarction caused by left posterior inferior cerebellar artery dissection. Neurological examination revealed both tactile and thermal/pain hypesthesia on the left side of the patient's face, and thermal/pain hypesthesia on his right upper and lower limbs. CONCLUSION: There are two types of tactile sensation: epicritic and protopathic. Facial tactile sensation is usually thought to be associated with epicritic tactile sensation, which travels through principal sensory nuclei of the trigeminal nerve. The protopathic pathway travels down through the spinal tract via the trigeminal nerve and is not considered a primary pathway. However, in this case the protopathic tactile sensation pathway might be involved, and it caused facial tactile hypesthesia. Because most of previous case reports and literature reviews focused only on thermal/pain hypesthesia, we believe that this case provides critical information on the brainstem neuroanatomy, especially for the protopathic tactile sensation pathway in patients with stroke.

BACKGROUND: We undertook a multicenter cohort observational study to investigate the frequency and type of subsequent vascular events after an ischemic stroke and to compare the rates of vascular events between patients with and without hyperlipidemia. METHODS: This nationwide study was conducted in 19 hospitals participating in the Japan Standard Stroke Registry Study. We enrolled ischemic stroke patients, including those with a transient ischemic attack, who had not experienced any vascular events before enrollment after their ischemic stroke events. Each subject was observed prospectively from September 1, 2003, to October 1, 2005, or until a primary end point or death. Primary end points included subsequent fatal or nonfatal vascular events: stroke, angina pectoris, acute myocardial infarction, aortic aneurysm, or arteriosclerosis obliterans. RESULTS: A total of 449 patients (mean age, 67.6 years; 64.8% men) were enrolled in this study. Of the 41 vascular events observed during follow-up, 40 were stroke. The median observation period was 568 days. We found that patients with hyperlipidemia had a significantly higher rate of vascular events compared with those without hyperlipidemia according to the Kaplan-Meier method and the log-rank test (P = .013). Hyperlipidemia significantly increased the risk of vascular events (hazard ratio, 2.169 [1.125-4.312]; P = .021) according to the Cox proportional hazard model after adjusting for confounding factors (age, sex, days from ischemic stroke until enrollment, smoking habits, and daily drinking habits). CONCLUSIONS: This study demonstrated that stroke was the most common subsequent vascular event after ischemic stroke; the study also indicated that hyperlipidemia could be a risk factor for subsequent vascular events after ischemic stroke.

ケトン体(KB),すなわちアセト酢酸(ACA)とβヒドロキシ酪酸(BHB)は,飢餓状態やインスリン抵抗性など,グルコース利用制限がある成体脳のエネルギー基質となる.KBは肝臓において脂肪酸から合成され,授乳期の脳ではKBが主要な脳のエネルギー基質となる.またACAはミエリンの構成成分であるコレステロール合成にも利用される.エネルギー基質としてのKBは,グルコースとは異なりピルビン酸を経由せずacetyl-CoAに変換されるため,ピルビン酸脱水素酵素複合体(PDHC)を必要としない.すなわちKBは,虚血障害を受けやすいPDHCに依存せずニューロンのATP産生を可能とする.脳では内因性のKB産生も可能であり,アストログリアがその役割を担う.KBの抗てんかん作用は古くから難治性てんかんに対するケトン食療法として利用されてきたが,KBの多彩なメカニズムによる神経保護作用から,脳卒中や神経変性疾患への治療応用が期待される.BHBは好中球,マクロファージ,単球,ミクログリアに発現するナイアシン受容体(HCA2)の内因性リガンドであり,プロスタグランジンD2産生を介して神経炎症反応を抑制することで,多発性硬化症に対しても治療効果をもつ可能性がある.(著者抄録)

BACKGROUND: A previous history of myocardial infarction (MI), stroke, and the presence of atrial fibrillation (AF) are known risk factors for the onset of arterial thromboembolic events such as MI and ischemic stroke. To clarify the rate of incidence of such events for these high-risk patients in Japan, a nation-wide cohort study was conducted that was named the 'Japan Thrombosis Registry of Atrial Fibrillation, Coronary and Cerebrovascular Events' (ie, J-TRACE) [UMIN Registered ID C000000189]. METHODS AND RESULTS: In the J-TRACE registry, a total of 8,093 Japanese patients with either a history of stroke and/or MI or patients with non-valvular AF were registered. This registry was developed by specialists in cardiology and neurology, physicians working at general hospitals, as well as general practice physicians, from whole regions of Japan, possibly reflecting the real-world medical practice. Recruited patients will be followed up for 2-3 years. Medical history, accompanying risk factors, demographic characteristics, and information regarding the use of medications were collected for these patients at baseline. Cardiovascular ischemic events and serious adverse experiences, including cerebral bleedings, which occur during the follow-up period will be recorded over a maximum of 3 years. CONCLUSION: The J-TRACE offers an opportunity to provide fundamental information regarding the incidence of cardiovascular ischemic events by a stratum of the risk factor profile and current medical treatment for Japanese patients at high risk for thromboembolic diseases.

脳実質内細動脈の血管口径がアストロサイトを介して調節されていることを示す証左が集積しつつある.興奮性ニューロンの機能活動亢進に伴って放出されるグルタミン酸が,シナプスを包むアストロサイトに発現する代謝型グルタミン酸受容体に作用し,IP3を介して細胞内Ca2+濃度上昇を惹起する.続いて起こるアストロサイトの細胞内アラキドン酸代謝経路の活性化は,PGE2,EET等の産生を介してアストロサイトの足突起に接した脳動脈平滑筋の弛緩を起こす.またアストロサイトを通じてシナプスから血管壁近傍に運搬されるK+も動脈拡張反応に関与する可能性がある.総じてアストロサイトの介在するメカニズムはfunctional hyperemiaとして生じるCBF増加の約50%を担うと推定される.一方,ノルアドレナリン作動性ニューロンの神経終末はアストロサイトに存在し,その興奮がアストロサイトから搬送されたアラキドン酸を直接血管平滑筋内で20-HETEに変換することで血管収縮作用を惹起している可能性もある.(著者抄録)

脳の機能再生には、ニューロンによる神経回路網の再構築のみならず、ニューロン(シナプス)-アストロサイト-微小循環の3者間ネットワークの再構築が必要である。エネルギー需要と連動する脳循環調節と、ニューロンのエネルギー代謝を円滑に行うためのエネルギー基質の受け渡しの2点において、アストロサイト(アストログリア)の役割が注目されている。神経再生医療においても、移植や内在性神経幹細胞性の賦活化による「機能的ニューロン」への再生とともに、「機能的アストロサイト」への再生が必須と考えられるが、これまで後者について機能評価は十分に行われていない。本研究結果は、ラット胎児脳由来neurosphereから分化させた培養アストログリアのin vitroグルコース代謝機能は、対照アストログリアと差異を認めず、再生脳におけるニューロン-アストロサイトのエネルギー代謝連関の再構築に十分寄与し得る可能性を示した。(著者抄録)