Experimental analysis of neuronal conduction by neurogenerative treatment using PET neurorecepter imaging and optical imaging.

• Project/Area Number: 16390405
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: OHNO Kikuo Tokyo Medical and Dental University, Graduate School, Professor, 大学院・医歯学総合研究科, 教授 (50014238)
• Co-Investigator(Kenkyū-buntansha): NARIAI Tadashi Tokyo Medical and Dental University, Medical Hospital, Lecturer, 医学部附属病院, 講師 (00228090) ; SATO Katsushige Tokyo Medical and Dental University, Graduate School, Lecturer, 大学院・医歯学総合研究科, 講師 (80291342) ; SUHARA Tetsuya National Institute of Radiological Sciences, Molecular Imaging Center, Group leader, 分子イメージング研究センター・分子神経イメージング研究グループ, グループリーダー (90216490)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥14,300,000 (Direct Cost: ¥14,300,000); Fiscal Year 2005: ¥6,800,000 (Direct Cost: ¥6,800,000); Fiscal Year 2004: ¥7,500,000 (Direct Cost: ¥7,500,000)
• Keywords: neural transplantation / PET / dopaminergic neuron / neuroreceptor / optical imaging / neurogenerative therapy / Parkinson disease / substantia nigra / 再度医療

Research Abstract

Experimental use of neuro-receptor imaging with positron emission tomography (PET) is now accepted as an inevitable tool for the development of new therapeutic maneuver of incurable central nervous disease. Use of optical imaging on experimental animal is also considered as a key method to mediate between the well established electrophysiological method and newly developed imaging tool such as PET. We have conducted experimental research on animal model of cerebral disorders using both PET and optical imaging to apply them for the development of novel therapy for neural regeneration. Three major research themes were conducted.
1) PET neuroreceptor imaging to analyze neuronal damage by cerebral ischemia and neuro-trauma
PET adenosine receptor imaging using newly developed radioligand, ^<11>C-MPDX, on cats experimental mode of cerebral ischemia was completed. In our former experiment on acute phase of cerebral ischemia, there existed discrepancy between the binding of adenosine receptor an d benzodiazepine receptor. However, in the chronic condition, no discrepancy was detected between the binding of two receptor systems. We also conducted a clinical PET imaging of patients with cerebral ischemic disease in chronic condition and observed a coupled binding of two receptor systems. These results suggested that the binding of adenosine receptor in the acute ischemic phase reflection the change of intrinsic adenosine system counteracting against progressive ischemia, but the measurement in chronic phase reflected the component in the neuronal system.
We also performed an imaging of peripheral benzodiazepine receptor, which is considered as a marker of microglial activation, using newly developed ^<11>C-DAA1106 on rats fluid percussion injury model. The micro-PET system for rodent imaging was used for this experiment. We successfully imaged activation of microglia on the impact site, that was gradually increased and decreased on the follow-up of the same individual animal.
2) PET neuroreceptor imaging in the animal model of Parkinsonism
In the period of the present research grant, high resolution animal PET camera for rodent (micro-PET) was introduced into our research group. Using this high resolution PET system, imaging experiment of fetal nigral transplantation on OHDA lesioned rats' model of Parkinson disease was conducted. PET imaging clearly detected the recovery of pre- and post-synaptic dopaminergic function by neural implantation. This system was proved to be an inevitable research tool for the establishment of regeneration therapy by neural transplantation in the stage of pre-clinical condition.
3) Use of optical imaging in analyzing cortico-striatal neural conduction in the brain slice of post-natal rodent.
We have established an experimental system to monitor the neuronal activation of striatum after the stimulation of cortical neuron using optical imaging technique on post-natal rodent brain slice. Spread of signal from the stimulated site to the remote striatum was detected on high time and space resolution recording system. The conduction was attenuated or enhanced by the pharmacological manipulation of glutamatergic or GABAergic system, respectively. This system can be utilized to analyze the viability and connectivity of extrinsically implanted neuronal tissue for the treatment of Parkinson disease.

Research Products

• [Journal Article] Quantitative evaluation of cerebral hemodynamics in patients with moyamoya disease by dynamic susceptibility contrast magnetic resonance imaging-comparison with positron emission tomography. (2006)
  • Author(s): Tanaka Y, Nariai T, Nagaoka T, Akimoto H, Ishiwata K, Ishii K, et al.
  • Journal Title: J Cereb Blood Flow Metab 26 Pages: 291-300
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Quantitative evaluation of cerebral hemodynamics in patients with moyamoya disease by dynamic susceptibility contrast magnetic resonance imaging-comparison with positron emission tomography. (2006)
  • Author(s): Tanaka Y, Nariai T, Nagaoka T, Akimoto H, Ishiwata K, Ishii K, et al.
  • Journal Title: J Cereb Blood Flow Metab. 26(2) Pages: 291-300
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Imaging of somatotopic representation of sensory cortex with intrinsic optical signals as guides for brain tumor surgery (2005)
  • Author(s): Nariai T, Sato K, Hirakawa K, Ohta Y, Tanaka Y, Ishiwata K, Ishii K, Kamino K, Ohno K
  • Journal Title: Journal of Neurosurgery 103 Pages: 414-23
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional representation of the finger and face in the human somatosensory cortex : intraoperative intrinsic optical imaging (2005)
  • Author(s): K Sato, T Nariai, et al.
  • Journal Title: Neuroimage 25 Pages: 1292-301
  • NAID: 130007039125
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] in vivo PET measurement with [^<11>C]PE2I to evaluate fetal mesencephalic transplantation to the unilaterally 6-OHDA lesioned rats (2005)
  • Author(s): M Inaji, T Yoshizaki, T Okauchi, J Maeda, Y Nagai, H Okano, T Nariai
  • Journal Title: Cell Transplantation 14 Pages: 655-63
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Severe hemodynamic stress in selected subtypes of patients with moyamoya disease-A positron emission tomography study-. (2005)
  • Author(s): Nariai T, Matsushima Y, Imae S, Tanaka Y, Ishii K, Senda M, Ohno K
  • Journal Title: Journal of Neurology Neurosurgery Psychiatry 76 Pages: 663-6
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Correlation between quantitative imaging and behavior in unilaterally 6-OHDA-lesioned rats. (2005)
  • Author(s): Inaji M, Okauchi T, Ando K, Maeda J, Nagai Y, Yoshizaki T, Okano H, Nariai T, Ohno K, et al.
  • Journal Title: Brain Research 1064 Pages: 136-45
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Usefulness of L-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma (2005)
  • Author(s): Nariai T, Tanaka Y, Wakimoto H, Aoyagi M, Tamaki M, et al.
  • Journal Title: Journal of Neurosurgery 103 Pages: 498-507
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Preclinical and clinical evaluation of O-[(11)C]methyl-1-tyrosine for tumor imaging by positron emission tomography. (2005)
  • Author(s): Ishiwata K, Tsukada H, Kubota K, Nariai T, Harada N, Kawamura K, Kimura Y, Oda K, Iwata R, Ishii K
  • Journal Title: Nucl Med Biol 32 Pages: 253-62
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Omission of serial arterial blood sampling in neuroreceptor imaging with independent component analysis. (2005)
  • Author(s): Naganawa M, Kimura Y, Nariai T, Ishii K, Oda K, Manabe Y, Chihara K, Ishiwata K
  • Journal Title: Neuroimage 26 Pages: 885-90
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Plasma Concentrations of Brain Natriuretic Peptide in Patients with Acute Ischemic Stroke (2005)
  • Author(s): Nakagawa K, Yamaguchi T, Seida M, Yamada S, Imae S, Tanaka Y, Yamamoto K, Ohno K
  • Journal Title: Cerebrovasc Dis 19 Pages: 157-164
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Overexpressed Skp2 within 5p amplification detected by array-based comparative genomic hybridization is associated with poor prognosis of glioblastomas (2005)
  • Author(s): Saigusa K, Hashimoto N, Tsuda H, Yokoi S, Maruno M, Yoshimine T, Aoyagi M, Ohno K, et al.
  • Journal Title: Cancer Sci 96 Pages: 676-83
  • NAID: 10017091131
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Aortic Wall Inflammation Due to Takayasu Arteritis Imaged with 18F-FDG PET Coregistered with Enhanced CT. (2005)
  • Author(s): Kobayashi Y, Ishii K, Oda K, Nariai T, Tanaka Y, Ishiwata K, Numano F
  • Journal Title: J Nucl Med 46 Pages: 917-22
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Comparative overview of brain perfusion imaging techniques. (2005)
  • Author(s): Wintermark M, Sesay M, Barbier E, Borbely K, Dillon WP, Eastwood JD, Glenn TC, Grandin CB, Pedraza S, Soustiel JF, Nariai T, Zaharchuk G, Caille JM, Dousset V, Yonac
  • Journal Title: Stroke 36
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Comparative overview of brain perfusion imaging techniques. (2005)
  • Author(s): Wintermark M, Sesay M, Barbier E, Borbely K, Dillon WP, Eastwood JD, Glenn TC, Grandin CB, Pedraza S, Soustiel JF, Nariai T, Zaharchuk G, Caille JM, Dousset V, Yonac
  • Journal Title: J Neuroradiol 32 Pages: 294-314
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Correlation between quantitative imaging and behavior in unilaterally 6-OHDA-lesioned rats. (2005)
  • Author(s): Inaji M, Okauchi T, Ando K, Maeda J, Nagai Y, Yoshizaki T, Okano H, Nariai T, Ohno K, Obayashi S, Higuchi M, Suhara T.
  • Journal Title: Brain Res. 1064(1-2) Pages: 136-145
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] In vivo PET measurements with [11C]PE2I to evaluate fetal mesencephalic transplantations to unilateral 6-OHDA-lesioned rats. (2005)
  • Author(s): Inaji M, Yoshizaki T, Okauchi T, Maeda J, Nagai Y, Nariai T, Ohno K, Ando K, Okano H, Obayashi S, Suhara T.
  • Journal Title: Cell Transplant. 14(9) Pages: 655-663
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Severe haemodynamic stress in selected subtypes of patients with moyamoya disease : a positron emission tomography study. (2005)
  • Author(s): Nariai T, Matsushima Y, Imae S, Tanaka Y, Ishii K, Senda M, Ohno K.
  • Journal Title: J Neurol Neurosurg Psychiatry. 76(5) Pages: 663-666
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Imaging of somatotopic representation of sensory cortex with intrinsic optical signals as guides for brain tumor surgery. (2005)
  • Author(s): Nariai T, Sato K, Hirakawa K, Ohta Y, Tanaka Y, Ishiwata K, Ishii K, Kamino K, Ohno K.
  • Journal Title: J Neurosurg. 103(3) Pages: 414-423
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Usefulness of L-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma. (2005)
  • Author(s): Nariai T, Tanaka Y, Wakimoto H, Aoyagi M, Tamaki M, Ishiwata K, Senda M, Ishii K, Hirakawa K, Ohno K.
  • Journal Title: J Neurosurg. 103(3) Pages: 498-507
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional representation of the finger and face in the human somatosensory cortex : intraoperative intrinsic optical imaging. (2005)
  • Author(s): Sato K, Nariai T, Tanaka Y, Maehara T, Miyakawa N, Sasaki S, Momose-Sato Y, Ohno K.
  • Journal Title: Neuroimage. 25(4) Pages: 1292-1301
  • NAID: 130007039125
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Preclinical and clinical evaluation of O-[(11)C]methyl-l-tyrosine for tumor imaging by positron emission tomography. (2005)
  • Author(s): Ishiwata K, Tsukada H, Kubota K, Nariai T, Harada N, Kawamura K, Kimura Y, Oda K, Iwata R, Ishii K.
  • Journal Title: Nucl Med Biol. 32(3) Pages: 253-262
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Omission of serial arterial blood sampling in neuroreceptor imaging with independent component analysis. (2005)
  • Author(s): Naganawa M, Kimura Y, Nariai T, Ishii K, Oda K, Manabe Y, Chihara K, Ishiwata K.
  • Journal Title: Neuroimage. 26(3) Pages: 885-890
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Plasma Concentrations of Brain Natriuretic Peptide in Patients with Acute Ischemic Stroke (2005)
  • Author(s): Nakagawa K, Yamaguchi T, Seida M, Yamada S, Imae S, Tanaka Y, Yamamoto K, Ohno K
  • Journal Title: Cerebrovasc Dis. 19 Pages: 157-164
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpressed Skp2 within 5p amplification detected by array-based comparative genomic hybridization is associated with poor prognosis of glioblastomas (2005)
  • Author(s): Saigusa K, Hashimoto N, Tsuda H, Yokoi S, Maruno M, Yoshimine T, Aoyagi M, Ohno K, Imoto I, Inazawa J
  • Journal Title: Cancer Sci. 96 Pages: 676-683
  • NAID: 10017091131
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Aortic Wall Inflammation Due to Takayasu Arteritis Imaged with 18F-FDG PET Coregistered with Enhanced CT. (2005)
  • Author(s): Kobayashi Y, Ishii K, Oda K, Nariai T, Tanaka Y, Ishiwata K, Numano F.
  • Journal Title: J Nucl Med. 46(6) Pages: 917-922
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparative overview of brain perfusion imaging techniques. (2005)
  • Author(s): Wintermark M, Sesay M, Barbier E, Borbely K, Dillon WP, Eastwood JD, Glenn TC, Grandin CB, Pedraza S, Soustiel JF, Nariai T, Zaharchuk G, Caille JM, Dousset V, Yonas H.
  • Journal Title: Stroke. 36(9)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparative overview of brain perfusion imaging techniques (2005)
  • Author(s): Wintermark M, Sesay M, Barbier E, Borbely K, Dillon WP, Eastwood JD, Glenn TC, Grandin CB, Pedraza S, Soustiel JF, Nariai T, Zaharchuk G, Caille JM, Dousset V, Yonas H.
  • Journal Title: J Neuroradiol. 32(5) Pages: 294-314
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Imaging of somatotopic representation of sensory cortex with intrinsic optical signals as guides for brain tumor surgery. (2005)
  • Author(s): Nariai T, Sato K, Hirakawa K, Ohta Y, Tanaka Y, Ishiwata K, Ishii K, Kamino K, Ohno K
  • Journal Title: Journal of Neurosurgery 103 Pages: 414-423
• [Journal Article] Functional representation of the finger and face in the human somatosensory cortex : intraoperative intrinsic optical imaging (2005)
  • Author(s): K Sato, T Nariai, Y Tanaka, T Maehara, N Miyakawa, S Sasaki, Y Momo
  • Journal Title: Neuroimage 25 Pages: 1292-1301
  • NAID: 130007039125
• [Journal Article] Severe hemodynamic stress in selected subtypes of patients with moyamoya disease - A position emission tomography study-. (2005)
  • Author(s): Nariai T, Matsushima Y, Imae S, Tanaka Y, Ishii K, Senda M, Ohno K
  • Journal Title: Journal of Neurology Neurosurgery Psychiatry 76 Pages: 663-666
• [Journal Article] Correlation between quantitative imaging and behavior in unilaterally 6-OHD A-lesioned rats. (2005)
  • Author(s): Inaji M, Okauchi T, Ando K, Maeda J, Nagai Y, Yoshizaki T, Okano H, Nariai T, Ohno K, Obayashi S, Higuchi M, Suhara T.
  • Journal Title: Brain Research 1064 Pages: 136-145
• [Journal Article] Usefulness of L-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma. (2005)
  • Author(s): Nariai T, Tanaka Y, Wakimoto H, Aoyagi M, Tamaki M, Ishiwata K, Senda M, Ishii K, Hirakawa K, Ohno K.
  • Journal Title: Journal of Neurosurgery 103 Pages: 498-507
• [Journal Article] Functional representation of the finger and face in the human somatosensory cortex : intraoperative intrinsic optical imaging (2005)
  • Author(s): K Sato, T Nariai, Y Tanaka, T Maehara, N Miyakawa, S Sasaki, Y Momo
  • Journal Title: Neuroimage (In press)
  • NAID: 130007039125
• [Journal Article] in vivo PET measurement with [^<11>C]PE2I to evaluate fetal mesencephalic transplantation to the unilaterally 6-OHDA lesioned rats (2005)
  • Author(s): M Inaji, T Yoshizaki, T Okauchi, J Maeda, Y Nagai, H Okano, T Nariai
  • Journal Title: Cell Transplantation (In press)
• [Journal Article] Severe hemodynamic stress in selected subtypes of patients with moyamoya disease - A positron emission tomography study-. (2005)
  • Author(s): Nariai T, Matsushima Y, Imae S, Tanaka Y, Ishii K, Senda M, Ohno K
  • Journal Title: J Neurol Neurosurg Psychiatry (In press)
• [Journal Article] Omission of serial arterial blood sampling for neuroreceptor imaging with in dependent component analysis (2005)
  • Author(s): M Naganawa, Y Kimura, T Nariai, et al.
  • Journal Title: Neuroimage (In press)
• [Journal Article] Preclinical and clinical evaluation of O-[^<11>C]methyl-L-tyrosine for tumor imaging by positron emission tomography (2005)
  • Author(s): K.Ishiwata, H Tsukada, K Kubota, T Nariai, et al.
  • Journal Title: Nucl Med Biol (In press)
• [Journal Article] Usefulness of [11C]methionine PET in the diagnosis of dysembryoplastic neuroepithelial tumor with temporal lobe epilepsy. (2004)
  • Author(s): Maehara T, Nariai T, et al.
  • Journal Title: Epilepsia 45 Pages: 41-45
  • NAID: 10013099166
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Impairment of both apoptotic and cytoprotective signalings in glioma cells resistant to the combined use of cisplatin and tumor necrosis factor alpha. (2004)
  • Author(s): Duan L, Aoyagi M, Tamaki M, Yoshino Y, Morimoto T, Wakimoto H, Nagasaka Y, Hirakawa K, Ohno K, Yamamoto K
  • Journal Title: Clin Cancer Res 10 Pages: 234-43
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Novel peripheral benzodiazepine receptor ligand [^<11>C]DAA1106 for PET : An imaging tool for glial cells in the brain. (2004)
  • Author(s): Maeda J, Suhara T, Zhang MR, Okauchi T, Yasuno F, Ikoma Y, Inaji M, Nagai Y, Takano A, Obayashi S, Suzuki K.
  • Journal Title: Synapse 52 Pages: 283-291
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Isolation and transplantation of dopaminergic neurons generated from mouse embryonic stem cells. (2004)
  • Author(s): Yoshizaki T, Inaji M, Kouike H, Shimazaki T, Sawamoto K, Ando K, Date I, Kobayashi K, Suhara T, Uchiyama Y, Okano H
  • Journal Title: Neuroscience Letters 363 Pages: 33-7
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Usefulness of [11C]methionine PET in the diagnosis of dysembryoplastic neuroepithelial tumor with temporal lobe epilepsy. (2004)
  • Author(s): Maehara T, Nariai T, Arai N, Kawai K, Shimizu H, Ishii K, Ishiwata K, Ohno K
  • Journal Title: Epilepsia 45 Pages: 41-45
  • NAID: 10013099166
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Isolation and transplantation of dopaminergic neurons generated from mouse embryonic stem cells. (2004)
  • Author(s): Yoshizaki T, Inaji M, Kouike H, Shimazaki T, Sawamoto K, Ando K, Date I, Kobayashi K, Suhara T, Uchiyama Y, Okano H.
  • Journal Title: Neuroscience Letters 363 Pages: 33-37
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Usefulness of [11C]Methionine PET in the Diagnosis of Dysembryoplastic Neuroepithelial Tumor with Temporal Lobe Epilepsy. (2004)
  • Author(s): Maehara T, Nariai T, Arai N, Kawai K, Shimizu H, Ishii K, Ishiwata K, Ohno K
  • Journal Title: Epilepsia 45 Pages: 41-45
  • NAID: 10013099166
• [Book] PET Multitracer Studyの脳神経疾患の臨床と研究への応用 Annual Review 神経2006 (柳澤信夫, 篠原幸人, 岩田誠, 清水輝夫, 寺本明 編) (2006)
  • Author(s): 成相直
  • Publisher: 中外医学社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] PET Multitracer Studyの脳神経疾患の臨床と研究への応用:Annual Review 神経2006(柳澤信夫,篠原幸人,岩田誠,清水輝夫,寺本明 編) (2006)
  • Author(s): 成相直
  • Publisher: 中外医学社