Papers - Takahashi, Shinichi

Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit

Takahashi S.

Cells 11 ( 5 )  2022.03

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The neurovascular unit (NVU) is a conceptual framework that has been proposed to bet-ter explain the relationships between the neural cells and blood vessels in the human brain, focused mainly on the brain gray matter. The major components of the NVU are the neurons, astrocytes (astroglia), microvessels, pericytes, and microglia. In addition, we believe that oligodendrocytes should also be included as an indispensable component of the NVU in the white matter. Of all these components, astrocytes in particular have attracted the interest of researchers because of their unique anatomical location; these cells are interposed between the neurons and the microvessels of the brain. Their location suggests that astrocytes might regulate the cerebral blood flow (CBF) in response to neuronal activity, so as to ensure an adequate supply of glucose and oxygen to meet the metabolic demands of the neurons. In fact, the adult human brain, which accounts for only 2% of the entire body weight, consumes approximately 20–25% of the total amount of glucose and oxygen consumed by the whole body. The brain needs a continuous supply of these essential energy sources through the CBF, because there are practically no stores of glucose or oxygen in the brain; both acute and chronic cessation of CBF can adversely affect brain functions. In addition, another important putative function of the NVU is the elimination of heat and waste materials produced by neuronal activity. Recent evidence suggests that astrocytes play pivotal roles not only in supplying glucose, but also fatty acids and amino acids to neurons. Loss of astrocytic support can be expected to lead to malfunction of the NVU as a whole, which underlies numerous neurological disorders. In this review, we shall focus on historical and recent findings with regard to the metabolic contributions of astrocytes in the NVU.

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Atrial Cardiopathy and Cryptogenic Stroke

Kato Y., Takahashi S.

Frontiers in Neurology 13 2022.02

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Recent advances in pathophysiology suggest that a pathological atrial substrate can cause embolic stroke even in patients without atrial fibrillation (AF). This pathological condition is called “atrial cardiopathy”, which indicates atrial structural and functional disorders that can precede AF. The objective of this narrative review was to provide a current overview of atrial cardiopathy and cryptogenic stroke. We searched the PubMed database and summarized the recent findings of the identified studies, including the pathogenesis of atrial cardiopathy, biomarkers of atrial cardiopathy, relationship between atrial cardiopathy and cryptogenic stroke, and therapeutic interventions for atrial cardiopathy. Abnormal atrial substrate (atrial cardiopathy) that leads to AF can result in embolic stroke before developing AF, and may explain the source of cryptogenic stroke in some patients. Although there are several potential biomarkers indicative of atrial cardiopathy, P-wave terminal force in lead V1 (>5,000 μV* ms), N-terminal pro-brain natriuretic peptide (>250 pg/ml), and left atrial enlargement are currently promising biomarkers for the diagnosis of atrial cardiopathy. Because the optimal combination and thresholds of biomarkers for diagnosing atrial cardiopathy remain uncertain, atrial cardiopathy represents a spectrum disorder. The concept of atrial cardiopathy appears to be most valuable as a starting point for therapeutic intervention to prevent stroke. Validation of the diagnosis of atrial cardiopathy and whether it can be used as a new therapeutic target for direct oral anticoagulants are currently being covered in the ARCADIA trial.

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Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease

Takahashi S., Mashima K.

Antioxidants 11 ( 1 )  2022.01

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Oxidative stress and neuroinflammation are common bases for disease onset and progression in many neurodegenerative diseases. In Parkinson disease, which is characterized by the degeneration of dopaminergic neurons resulting in dopamine depletion, the pathogenesis differs between hereditary and solitary disease forms and is often unclear. In addition to the pathogenicity of alpha-synuclein as a pathological disease marker, the involvement of dopamine itself and its interactions with glial cells (astrocyte or microglia) have attracted attention. Pacemaking activity, which is a hallmark of dopaminergic neurons, is essential for the homeostatic maintenance of adequate dopamine concentrations in the synaptic cleft, but it imposes a burden on mitochondrial oxidative glucose metabolism, leading to reactive oxygen species production. Astrocytes provide endogenous neuroprotection to the brain by producing and releasing antioxidants in response to oxidative stress. Additionally, the protective function of astrocytes can be modified by microglia. Some types of microglia themselves are thought to exacerbate Parkinson disease by releasing pro-inflammatory factors (M1 microglia). Although these inflammatory microglia may further trigger the inflammatory conversion of astrocytes, microglia may induce astrocytic neuroprotective effects (A2 astrocytes) simultaneously. Interestingly, both astrocytes and microglia express dopamine receptors, which are upregulated in the presence of neuroinflammation. The anti-inflammatory effects of dopamine receptor stimulation are also attracting attention because the functions of astrocytes and microglia are greatly affected by both dopamine depletion and therapeutic dopamine replacement in Parkinson disease. In this review article, we will focus on the antioxidative and anti-inflammatory effects of astrocytes and their synergism with microglia and dopamine.

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Preprocedural Prediction of Underlying Atherosclerotic Lesions in Cerebral Large-Vessel Occlusions: Clinical Backgrounds, Radiological Findings, and Treatment Outcomes

Kuribara T., Sato H., Iihoshi S., Tsukagoshi E., Teranishi A., Kinoshita Y., Sugasawa S., Kohyama S., Takahashi S., Kurita H.

Journal of Atherosclerosis and Thrombosis 29 ( 11 ) 1613 - 1624 2022

ISSN  13403478

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Aims: Mechanical thrombectomy using a standard device has been effective for acute cerebral large-vessel occlusions, particularly those due to cardiogenic embolism. However, evidence for those with underlying atherosclerotic lesions is lacking. In this study, we evaluated the predictive factors, treatment details, and outcomes of acute cerebral large-vessel occlusions with underlying atherosclerotic lesions in patients who underwent mechanical thrombectomy. Methods: We retrospectively analyzed consecutive patients with acute large-vessel occlusions who underwent mechanical thrombectomy at our institution between August 2014 and May 2021. Predictive factors of underlying atherosclerotic lesions were evaluated using univariate and multivariate analyses. In addition, treatment details and outcomes were evaluated and compared with those of other etiologies. Results: Among 322 included patients, 202 (62.7%) were males and 65 (20.2%) had underlying atherosclerotic lesions. Multivariate analysis identified dyslipidemia, lack of arterial fibrillation documented on admission, smoking, internal carotid artery lesions, and stenosis ≥ 25% in non-occluded large vessels as predictive factors of underlying atherosclerotic lesions. Regarding treatment for underlying atherosclerotic lesions, the need for percutaneous transluminal angioplasty, stent placement, medical therapy, and longer procedure time were observed, while successful reperfusion rates, favorable outcomes, and mortality rates showed no significant differences with those of other etiologies. Conclusion: Coexisting diseases and radiological findings were useful for predicting underlying atherosclerotic lesions. Further understanding these characteristics may lead to the early detection of underlying atherosclerotic lesions, optimal treatment strategies, and better outcomes.

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Neuroprotective function of high glycolytic activity in astrocytes: Common roles in stroke and neurodegenerative diseases

Takahashi S.

International Journal of Molecular Sciences 22 ( 12 )  2021.06

ISSN  16616596

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Astrocytes (also, astroglia) consume huge amounts of glucose and produce lactate regard-less of sufficient oxygen availability, indicating a high capacity for aerobic glycolysis. Glycolysis in astrocytes is activated in accordance with neuronal excitation and leads to increases in the release of lactate from astrocytes. Although the fate of this lactate remains somewhat controversial, it is believed to fuel neurons as an energy substrate. Besides providing lactate, astrocytic glycolysis plays an important role in neuroprotection. Among the minor pathways of glucose metabolism, glucose flux to the pentose-phosphate pathway (PPP), a major shunt pathway of glycolysis, is attracting research interest. In fact, PPP activity in astrocytes is five to seven times higher than that in neurons. The astrocytic PPP plays a key role in protecting neurons against oxidative stress by providing neurons with a reduced form of glutathione, which is necessary to eliminate reactive oxygen species. Therefore, enhancing astrocytic glycolysis might promote neuronal protection during acute is-chemic stroke. Contrariwise, the dysfunction of astrocytic glycolysis and the PPP have been impli-cated in the pathogenesis of various neurodegenerative diseases such as Parkinson’s disease, Alz-heimer’s disease, and amyotrophic lateral sclerosis, since mitochondrial dysfunction and oxidative stress trigger and accelerate disease progression.

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Status of Acute Stroke Practice in Patients with a Cardiac Implantable Electronic Device

Kato Y., Hayashi T., Kato R., Uchino A., Takao M., Takahashi S.

Acta Medica Okayama 75 ( 6 ) 691 - 697 2021

ISSN  0386300X

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Although diagnostic and therapeutic strategies for acute stroke patients in Japan depend largely on magnetic resonance imaging (MRI), patients with cardiac implantable electronic devices (CIED) must still rely on computedtomography (CT). We retrospectively analyzed clinical and neuroimaging data of ischemic strokepatients with CIED treated at our hospital. Forty-five patients were enrolled in the study. Patients were dividedinto two groups according to whether corresponding lesions were detected (group A, n=21) or not detected(group B, n=24) by the first brain CT. We also evaluated in detail the clinical courses of patients who arrived athospital within therapeutic time windows for recanalization therapy. Negative fresh infarct in the first CT wasassociated, though not significantly, with early onset-to-arrival time and subcortical white matter infarction.Five patients did not undergo recanalization therapy because their families did not agree to the procedure. Thereasons for their lack of consent included inadequate information about the safety and efficacy of recanalizationtherapy because MRI could not be performed. Our study confirmed delayed detection of the correspondinglesion and undertreatment for acute stroke in patients with CIED

Coagulation Assay and Stroke Severity upon Admission of Patients with Cardioembolic Cerebral Infarction during Direct Oral Anticoagulant Use

Deguchi I., Osada T., Takao M., Takahashi S.

Keio Journal of Medicine 70 ( 4 ) 93 - 99 2021

ISSN  00229717

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Although the severity of acute cerebral infarction varies in patients receiving direct oral anticoagulants (DOACs), no practical method to predict the severity has been established. We analyzed retrospectively the relationship between cardioembolic cerebral infarction severity and coagulation indicators in patients treated with DOACs. We assessed the anticoagulation effect of DOACs using the activated partial thromboplastin time (APTT), prothrombin time (PT), and prothrombin time international standardized ratio (PT-INR) in 71 patients with cardioembolic cerebral infarction admitted to our hospital between January 2015 and December 2019. The participants were divided into a prolongation group (prolonged APTT for oral thrombin inhibitors or prolonged PT for oral factor Xa inhibitors, n =37) and a normal group (no prolongation of coagulation markers, n =34). Of the 71 patients, 21 (30%) and 50 (70%) were using oral thrombin and oral factor Xa inhibitors, respectively. PT, PT-INR, and APTT were significantly higher in the prolongation group (PT: 17.4 ± 5.1 vs. 12.8 ± 1.4 s, P < 0.001; PT-INR: 1.5 ± 0.5 vs. 1.1 ± 0.1, P < 0.001; APTT: 44.8 ± 26.4 vs. 30.4 ± 4.1 s, P = 0.003). The median National In-stitutes of Health Stroke Scale (NIHSS) score on admission and the prevalence of large vessel occlusion were significantly lower in the prolongation group (NIHSS: 2.0 vs. 9.5, P = 0.007; large vessel occlusion: 27% vs. 53%, P = 0.031). The prevalence of large vessel occlusion was low and stroke severity was mild in patients undergoing DOAC therapy with prolongation of coagulation assay markers upon onset of cardioembolic cerebral infarction.

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Diameter of fluorescent microspheres determines their distribution throughout the cortical watershed area in mice.

Naoki Tsukada, Masahiro Katsumata, Koichi Oki, Kazushi Minami, Takato Abe, Yoshiaki Itoh, Shinichi Takahashi, Norihiro Suzuki

Bain Research 1679   109 - 115 2018

Research paper (scientific journal), Joint Work, Accepted

Neuro-protective role of astroglia in Parkinson disease by reducing oxidative stress through dopamine-induced activation of pentose-phosphate pathway.

Kyoko Mahima, Shinichi Takahashi, Kazushi Minami, Yoshikane Izawa, Takato Abe, Naoki Tsukada, Takako Hishiki, Makoto Suematsu, Mayumi Kajimura, Norihiro Suzuki

ASN Neuro 10   1 - 12 2018

Research paper (scientific journal), Joint Work, Accepted

Trends of Antiplatelet Therapy for the Management of Moyamoya Disease in Japan: Results of a Nationwide Survey.

Koichi Oki, Masahiro Katsumata, Yoshikane Izawa, Shinichi Takahashi, Norihiro Susuki, Kiyohiro Houkin; Research Committee on Spontaneous Occlusion of Circle of Willis (moyamoya disease)

J Stroke Cerebrovasc Dis (in press)  2018

Research paper (scientific journal), Joint Work, Accepted

Rivaroxaban induces reduction of embolus size within intracranial arteries in a mouse model of embolic stroke.

Masahiro Katsumata, Koichi Oki, Naoki Tsukada, Takato Abe, Yoshiaki Itoh, Shinichi Takahashi, Norihiro Suzuki

Keio J Med (in press)  2018

Research paper (scientific journal), Joint Work, Accepted

De novo design of RNA-binding proteins with a prion-like domain related to ALS/FTD proteinopathies.

Kana Mitsuhashi, Daisuke Ito, Munenori Oyama, Kyoko Mashima, Shinichi Takahashi, Norihiro Suzuki

Scientific Reports Dec 4;7(1):16871. 2017.12

Research paper (scientific journal), Joint Work, Accepted

Serial changes of corticospinal tract hyperintensity on MRI from the pre-clinical stage in ALS.

Tsubasa Takizawa, Gen Shiihashi, Junki Maehara, Koichi Oki, Mayuko Osaka, David Y Chung, Hirokazu Fujiwara, Hidenori Ojima, Yuichi Ichinose, Mamoru Shibata, Shinichi Takahashi, Norihiro Suzuki

Neurology and Clinical Neuroscience  2017.10

Research paper (scientific journal), Joint Work, Accepted

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q-Space Myelin Map imaging for longitudinal analysis of demyelination and remyelination in multiple sclerosis patients treated with fingolimod: A preliminary study.

Tanikawa M, Nakahara J, Hata J, Suzuki S, Fujiyoshi K, Fujiwara H, Momoshima S, Jinzaki M, Nakamura M, Okano H, Takahashi S, Suzuki N

J Neurol Sci.  2017.01

Research paper (scientific journal), Joint Work

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Possible Involvement of Hypotension in Postprandial Headache: A Case Series.

akizawa T, Shibata M, Hiraide T, Seki M, Takahashi S, Suzuki N

Headache  2017

Research paper (scientific journal), Joint Work, Accepted

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Blood pressure reduction and noncontrast CT markers of intracerebral hemorrhage expansion.

Morotti A, Boulouis G, Romero JM, Brouwers HB, Jessel MJ, Vashkevich A, Schwab K, Afzal MR, Cassarly C, Greenberg SM, Martin RH, Qureshi AI, Rosand J, Goldstein JN; ATACH-II and NETT investigators.

Neurology  2017

Research paper (scientific journal), Joint Work, Accepted

ステロイド治療に抵抗して急速に進行し、脳生検にて診断しえた中枢神経限局性血管炎の28歳男性の1例．

'Takahashi,' Shinichi

臨床神経学 57   509 - 514 2017

Research paper (scientific journal), Joint Work, Accepted

The first report of Japanese case of seipinopathy with BSCL2 N88S mutation.

Kazushi Minami, Shinichi Takahashi*, Yoshihiro Nihei,Koichi Oki, Shigeaki Suzuki, Daisuke Ito, Hiroshi Takashima, Norihiro Suzuki

Internal Medicine  2017

Research paper (scientific journal), Joint Work, Accepted

New onset of myasthenia gravis after intravesical Bacillus Calmette-Guerin: A case report and literature review.

Tsubasa Takizawa. Marenori Kojima, Shigeaki Suzuki, Takashi Osada, Satoshi Kitagawa; Jin Nakahara, Shinichi Takahashi,Norihiro Suzuki

Medicine (Baltimore) 96 ( 46 ) e8757. 2017

Research paper (scientific journal), Joint Work

A possible role of microglia-derived nitric oxide by lipopolysaccharide in activation of astroglial pentose-phosphate pathway via the Keap1/Nrf2 system

Iizumi, Takuya, Takahashi, Shinichi, Mashima, Kyoko, Minami, Kazushi, Izawa, Yoshikane, Abe, Takato, Hishiki, Takako, Suematsu, Makoto, Kajimura, Mayumi, Suzuki, Norihiro

JOURNAL OF NEUROINFLAMMATION 13 2016.05

Research paper (scientific journal),  ISSN  1742-2094

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