PET-Based Molecular Nuclear Neuro-Imaging

  • Kim, Jong-Ho (Department of Nuclear Medicine, Gachon Medical School, Gil Medical Center)
  • Published : 2004.04.30

Abstract

Molecular Nuclear Neuro-Imaging in "CNS" drug discovery and development tan be divided into four categories that are clearly inter-related.(1) Neuroreceptor mapping to examine the involvement of specific neurotransmitter system in CNS diseases, drug occupancy characteristics and perhaps examine mechanisms of action;(2) Structural and spectroscopic imaging to examine morphological changes and their consequences;(3) Metabolic mapping to provide evidence of central activity and "CNS fingerprinting" the neuroanatomy of drug effects;(4) Functional mapping to examing disease-drug interactions. In addition, targeted delivery of therapeutic agents could be achieved by modifying stem cells to release specific drugs at the site of transplantation('stem cell pharmacology'). Future exploitation of stem cell biology, including enhanced release of therapeutic factors through genetic stem cell engineering, might thus constitute promising pharmaceutical approaches to treating diseases of the nervous system. With continued improvements in instrumentation, identification of better imaging probes by innovative chemistry, molecular nuclear neuro-imaging promise to play increasingly important roles in disease diagnosis and therapy.

분자영상은 살아있는 개체의 몸 속에서 일어나는 생물학적 반응이나 특정한 표적분자를 비관혈적이며 반복적으로 영상화하는 기술이다. 이를 위해서는 두 가지 기본 요소가 요구되는 바 하나는 관심 생물현상에 의해 농도나 분광특성이 변하는 분자영상용 추적자이며 다른 하나는 이런 추적자를 모니터링하는 장비이다. 분자 핵의학 영상기술은 이제 신경과학분야에서도 활발히 적용되고 있으며 신경관련 기초연구나 뇌질환 관련 신약개발에 이미 중요한 역할을 하고 있다. 최근에는 살아있는 개체에서 약제 투여가 뇌에 미치는 약물학적, 생리적 영향을 조사하는 데에도 이용되고 있다. 다가오는 미래에는 각종 뇌질환에서 특이적 표적을 공략하는 새로운 분자치료가 개발되어 뇌질환 치료에 혁명적인 변화를 가져올 것으로 예상되고 있다. 그 예로, 파킨슨씨 병과 같은 퇴행성 신경질환에 줄기세포를 이용한 자가수선, 신경보호, 약물분비 치료, 성장인자와의 병행치료 등이 개발되고, 유전자 치료도 이용될 것으로 보인다. 신경 분자 핵의학 영상은 이와 같은 새로운 뇌질환 치료기술의 개발에 있어서 뇌 안에서 일어나는 분자수준의 변화를 실시간으로 모니터링함으로써 관련연구에 크게 기여할 것으로 기대된다.

Keywords

References

  1. Caceres M, Lachuer J, Zapala MA, Redmond JC, Kudo L, Geschwind DH, et al. Elevated gene expression levels distinguish human from non-human primate brains. Proc Natl Acad Sci USA 2003;100:13030-5 https://doi.org/10.1073/pnas.2135499100
  2. Geschwind DH. DNA microarrays: Translation of the genome from laboratory to clinic. Lancet Neurol 2003;2:275-82 https://doi.org/10.1016/S1474-4422(03)00379-X
  3. Dingman S, Hurlburt L, Branch C. Acute No-effect Dose for In Ova exposure to C3F7 tagged 5-Hydroxytriptophan, a novel probe for investigating neural development. Mol Imaging and Biol 2004;6:12-6 https://doi.org/10.1016/j.mibio.2003.11.001
  4. Singh RP, Smith DJ. Genome scale mapping of brain gene expression. Biol Psychiatry 2003;53:1069-74 https://doi.org/10.1016/S0006-3223(03)00238-5
  5. Liu D, Smith DJ. Voxelation and gene expression tomography for the acquisition of 3-D gene expression maps in the brain. Methods 2003;31:317-25 https://doi.org/10.1016/S1046-2023(03)00162-2
  6. Khan AH, Ossadtchi A, leahy RM, Smith DJ. Error-correcting design. Genomics 2003;81:157-65 https://doi.org/10.1016/S0888-7543(02)00032-0
  7. Fraser A. Rna interference: Human genes hit the big screen. Nature 2004;428:375-78 https://doi.org/10.1038/428375a
  8. Hargreaves R. Imaging substance p receptors(nk1) in the living human brain using positron emission tomography. J Clin Psychiatry 2002;63 Suppl 11:18-24
  9. Husky SW, Dean BJ, Bakhtiar R, Sanchez RI, Tattersall FD, Rycroft W, et al. Brain penetration of aprepitant, a substance P receptor anatgonist, in ferrets. Drug Metabolism and Disposition 2003;31:785-91 https://doi.org/10.1124/dmd.31.6.785
  10. Tai YT, Svendsen CN. Stem cells as a potential treatment of neurological disorders. Curr Opin Pharmacol 2004;4:98-104 https://doi.org/10.1016/j.coph.2003.09.006
  11. Hwang WS, Ryu YJ, Park JH, Park ES, Lee EG, Koo JM, et al. Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Science 2004;303:1669-74 https://doi.org/10.1126/science.1094515
  12. Cowan CA, Klimanskaya I, McMahon J, Atienza J, Witmyer J, Zucker JP, et al. Morton CC, McMahon AP, Powers D, Melton DA. Derivation of embryonic stem-cell lines from human blastocysts. N Engl J Med 2004;350:1353-6 https://doi.org/10.1056/NEJMsr040330
  13. Phimister EG, Drazen JM. Two fillips for human embryonic stem cells. N Engl J Med 2004;350:1351-2 https://doi.org/10.1056/NEJMe048056
  14. Ying QL, Nichols J, Evans EP, Smith AG. Changing potency by spontaneous fusion. Nature 2002;416:545-8 https://doi.org/10.1038/nature729
  15. Clarke DL, Johansson CB, Wilbertz J, Veress B, Nilsson E, Karlstrom H, et al. Generalized potential of adult neural stem cells. Science 2000;288:1660-3 https://doi.org/10.1126/science.288.5471.1660
  16. Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002;416:542-5 https://doi.org/10.1038/nature730
  17. Khachaturian Z. The five-five, ten-ten plan for Alzheimer's disease. Neurobiol Aging 1992;13:197-8 https://doi.org/10.1016/0197-4580(92)90030-2
  18. Mega MS, Cummings JL, O'Connor SM, Dinov ID, Reback E, Felix J, et al. Cognitive and metabolic responses to metrifonate therapy in Alzheimer disease. Neuropsychiatry Neuropsychol Behav Neurol 2001;14:63-8
  19. Tune L, Tiseo PJ, Ieni J, Perdomo C, Pratt RD, Votaw JR, et al. Donepezil Hcl(e2020) maintains functional brain activity in patients with Alzheimer disease: Results of a 24-week, double-blind, placebo- controlled study. Am J Geriatr Psychiatry 2003;11:169-77 https://doi.org/10.1097/00019442-200303000-00007
  20. Potkin SG, Anand R, Fleming K, Alva G, Keator D, Carreon D, et al. Brain metabolic and clinical effects of rivastigmine in Alzheimer's disease. Int J Neuropsychopharmacol 2001;4:223-30
  21. Rogers SL, Cooper NM, Sukovaty R, Pederson JE, Lee JN, Frie dhoff LT. Pharmacokinetic and pharmacodynamic profile of donepezil Hcl following multiple oral doses. Br J Clin Pharmacol 1998;46 Suppl 1:7-12
  22. Namba H, Fukushi K, Nagatsuka S, Iyo M, Shinotoh H, Tanada S, et al. Positron emission tomography : quantitative measurement of brain acetylcholinesterase activity using radiolabeled substrate. Methods 2002;27:242-50 https://doi.org/10.1016/S1046-2023(02)00081-6
  23. Rinne JO, Kaasinen V, Jarvenpaa T, Naren K, Roivainen A, Yu M, et al, Brain acetylcholinesterase activity in mild cognitive inpairment and early Alzheimer's disease. J Neurol Neurosurg Psychiatry 2003;74:113-5
  24. Thomsen T, Kaden B, Fischer JP, Bickel U, Barz H, Gusztony G, et al. Inhibition of acetylcholinesterase activity in human brain tissue and erythrocytes by galantamine, physostigmine and tacrine. Eur J Clin Chem Clin Biochem 1991;29:487-92
  25. Albuquerque EX, Alkondon M, Pereira EF, Castro NG, Schrattenholz A, Barbosa CT, et al. Properties of neuronal nicotinic acetylcholine receptors: Pharmacological characterization and modulation of synaptic function. J Pharmacol Exp Ther 1997;280: 1117-36
  26. Maelicke A, Albuquerque EX. Allosteric modulation of nicotinic acetylcholine receptors as a treatment strategy for Alzheimer's disease. Eur J Pharmacol 2000;393:165-70 https://doi.org/10.1016/S0014-2999(00)00093-5
  27. Larrabee GJ, Crook TH, 3rd. Estimated prevalence of age-associated memory impairment derived from standardized tests of memory function. Int Psychogeriatr 1994;6:95-104 https://doi.org/10.1017/S1041610294001663
  28. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, et al. Current concepts in mild cognitive impairment. Arch Neurol 2001;58:1985-92 https://doi.org/10.1001/archneur.58.12.1985
  29. Chetelat G, Desgranges B, de la Sayette V, Viader F, Eustache F, Baron JC. Mild cognitive impairment: Can FDG-PET predict who is to rapidly convert to Alzheimer's disease? Neurology 2003;60: 1374-7 https://doi.org/10.1212/01.WNL.0000055847.17752.E6
  30. Silverman DH, Small GW, Chang CY, Lu CS, Kung De Aburto MA, et al. Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome. JAMA 2001; 286:2120-7 https://doi.org/10.1001/jama.286.17.2120
  31. Small GW, Ercoli LM, Silverman DH, Huang SC, Komo S, Bookheimer SY, et al. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc Natl Acad Sci USA 2000;97:6037-42 https://doi.org/10.1073/pnas.090106797
  32. Geschwind DH. Tau phosphorylation, tangles, and neurodegeneration: The chicken or the egg? Neuron 2003;40:457-60 https://doi.org/10.1016/S0896-6273(03)00681-0
  33. Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry 2002;10:24-35 https://doi.org/10.1097/00019442-200201000-00004
  34. Agdeppa ED, Kepe V, Liu J, Small GW, Huang SC, Petric A, Satyamurthy N, et al. 2-dialkylamino-6-acylmalononitrile substituted naphthalenes(DDND analogs): Novel diagnostic and therapeutic tools in Alzheimer's disease. Mol Imaging Biol 2003;5:404-17 https://doi.org/10.1016/j.mibio.2003.09.010
  35. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh compound-B. Ann Neurol 2004;55:306-19 https://doi.org/10.1002/ana.20009
  36. Kung MP, Hou C, Zhang B, CSkovronsky D, Trojanowski JQ, Lee VM, et al. IMPY: an improved thioflavin-T derivative for in vivo labelling of beta-amypoid plaques. Brain Res 2002:956(2);202-10
  37. Jacobs AH, Winkeler H, Hilker R, Knoess C, Ruger A, Galldiks N, et al. PET-based molecular imaging in neuroscience. Eur J Nucl Med Mol Imaging 2003;30:1051-65 https://doi.org/10.1007/s00259-003-1202-5
  38. Herschman HR, Talley JJ, DuBois R. Cyclooxygenase 2(cox-2) as a target for therapy and noninvasive imaging. Mol Imaging Biol 2003;5:286-303 https://doi.org/10.1016/j.mibio.2003.09.006
  39. Herschman HR. Molecular imaging: Looking at problems, seeing solutions. Science 2003;302:605-8 https://doi.org/10.1126/science.1090585
  40. McCarthy TJ, Sheriff AU, Graneto MJ, Talley JJ, Welch MJ. Radiosynthesis, in vitro validation, and in vivo evaluation of 18F-labeled cox-1 and cox-2 inhibitors. J Nucl Med 2002;43: 117-24
  41. Pasinetti GM, Aisen PS. Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer's disease brain. Neuroscience 1998;87:319-24 https://doi.org/10.1016/S0306-4522(98)00218-8
  42. Haslinger B, Boecker H, Buchel C, Vesper J, Tronnier VM, Pfister R, et al. Differential modulation of subcortical target and cortex during deep brain stimulation. Neuroimage 2003;18:517-24 https://doi.org/10.1016/S1053-8119(02)00043-5
  43. Hershey T, Black KJ, Carl JL, McGee-Minnich L, Snyder AZ, Perlmutter JS. Long term treatment and disease severity change brain responses to levodopa in Parkinson's disease. J Neurol Neurosurg Psychiatry 2003;74:844-51 https://doi.org/10.1136/jnnp.74.7.844
  44. Perlmutter JS, Mink JW, Bastian AJ, Zackowski K, Hershey T, Miyawaki E, et al. Blood flow responses to deep brain stimulation of thalamus. Neurology 2002;58:1388-94 https://doi.org/10.1212/WNL.58.9.1388
  45. Hershey T, Revilla FJ, Wernle AR, McGee-Minnich L, Antenor JV, Videen TO, et al. Cortical and subcortical blood flow effects of subthalamic nucleus stimulation in PD. Neurology 2003;61:816-21 https://doi.org/10.1212/01.WNL.0000083991.81859.73
  46. Trott CT, Fahn S, Greene P, Dillon S, Winfield H, Winfield L, et al. Cognition following bilateral implants of embryonic dopamine neurons in PD: A double blind study. Neurology 2003;60:1938-43 https://doi.org/10.1212/01.WNL.0000070181.28651.3B
  47. Nakamura T, Dhawan V, Chaly T, Fukuda M, Ma Y, Breeze R, et al. Blinded positron emission tomography study of dopamine cell implantation for Parkinson's disease. Ann Neurol 2001;50:181-7 https://doi.org/10.1002/ana.1075
  48. Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol 2003;54:403-4 https://doi.org/10.1002/ana.10720
  49. Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, et al. Ubiquitination of a new form of alpha-Synuclein by Parkin from human brain: Implications for Parkinson's disease. Science 2001;293:263-9 https://doi.org/10.1126/science.1060627
  50. Burton EA, Glorioso JC, Fink DJ. Gene therapy progress and prospects: Parkinson's disease. Gene Ther 2003;10:1721-7 https://doi.org/10.1038/sj.gt.3302116
  51. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkinsonism. Science 2003;299:256-9 https://doi.org/10.1126/science.1077209
  52. Le WD, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG, et al. Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 2003;33:85-9 https://doi.org/10.1038/ng1066
  53. Crocker SJ, Wigle N, Liston P, Thompson CS, Lee CJ, Xu D, et al. NAIP protects the nigrostriatal dopamine pathway in an intrastriatal 6-ohda rat model of Parkinson's disease. Eur J Neurosci 2001;14:391-400 https://doi.org/10.1046/j.0953-816x.2001.01653.x
  54. Mochizuki H, Hayakawa H, Migita M, Shibata M, Tanaka R, Suzuki A, et al. An AAV-derived apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease. Proc Natl Acad Sci USA 2001;98:10918-23 https://doi.org/10.1073/pnas.191107398
  55. Grondin R, Zhang Z, Yi A, Cass WA, Maswood N, Andersen AH, et al. Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced Parkinsonian monkeys. Brain 2002; 125:2191-201 https://doi.org/10.1093/brain/awf234
  56. Eberhardt O, Coelln RV, Kugler S, Lindenau J, Rathke-Hartlieb S, Gerhardt E, et al. Protection by synergistic effects of adenovirus- mediated x-chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. J Neurosci 2000;20:9126-34 https://doi.org/10.1523/JNEUROSCI.20-24-09126.2000
  57. Luo J, Kaplitt MG, Fitzsimons HL, Zuzga DS, Liu Y, Oshinsky ML, et al. Subthalamic GAD gene therapy in a Parkinson's disease rat model. Science 2002;298:425-9 https://doi.org/10.1126/science.1074549
  58. Azzouz M, Martin-Rendon E, Barber RD, Mitrophanous KA, Carter EE, Rohll JB, et al. Multicistronic lentiviral vector-mediated striatal gene transfer of aromatic l-amino acid decarboxylase, tyrosine hydroxylase, and GTP cyclohydrolase i induces sustained transgene expression, dopamine production, and functional improvement in a rat model of Parkinson's disease. J Neurosci 2002;22:10302-12 https://doi.org/10.1523/JNEUROSCI.22-23-10302.2002
  59. Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol 2000;18:675-9 https://doi.org/10.1038/76536
  60. Kim JH, Auerbach JM, Rodriguez-Gomez JA, Velasco I, Gavin D, Lumelsky N, et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 2002;418:50-6 https://doi.org/10.1038/nature00900
  61. Bjorklund LM, Isacson O. Regulation of dopamine cell type and transmitter function in fetal and stem cell transplantation for Parkinson's disease. Prog Brain Res 2002;138:411-20 https://doi.org/10.1016/S0079-6123(02)38090-7
  62. Windisch M, Hutter-Paier B, Rockenstein E, Hashimoto M, Mallory M, Masliah E. Development of a new treatment for Alzheimer's disease and Parkinson's disease using anti-aggregatory beta-Synuclein- derived peptides. J Mol Neurosci 2002;19:63-9 https://doi.org/10.1007/s12031-002-0012-8
  63. Petrucelli L, O'Farrell C, Lockhart PJ, Baptista M, Kehoe K, Vink L, et al. Parkin protects against the toxicity associated with mutant alpha-synuclein: Proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 2002;36:1007-19 https://doi.org/10.1016/S0896-6273(02)01125-X
  64. During MJ, Kaplitt MG, Stern MB, Eidelberg D. Subthalamic GAD gene transfer in Parkinson disease patients who are candidates for deep brain stimulation. Hum Gene Ther 2001;12:1589-91
  65. Ourednik J, Ourednik V, Lynch WP, Schachner M, Snyder EY. Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat Biotechnol 2002;20:1103-10 https://doi.org/10.1038/nbt750
  66. Pfeifer A, Ikawa M, Dayn Y, Verma IM. Transgenesis by lentiviral vectors: Lack of gene silencing in mammalian embryonic stem cells and preimplantation embryos. Proc Natl Acad Sci USA 2002; 99:2140-5 https://doi.org/10.1073/pnas.251682798
  67. Gorelick PB. New horizons for stroke prevention: Progress and hope. Lancet Neurol 2002;1:149-56 https://doi.org/10.1016/S1474-4422(02)00070-4
  68. Gorelick PB. Stroke prevention therapy beyond antithrombotics: Unifying mechanisms in ischemic stroke pathogenesis and implications for therapy: An invited review. Stroke 2002;33:862-75
  69. Kidwell CS, Warach S. Acute ischemic cerebrovascular syndrome: Diagnostic criteria. Stroke 2003;34:2995-8 https://doi.org/10.1161/01.STR.0000098902.69855.A9
  70. Saver JL, Kidwell C, Eckstein M, Starkman S. Prehospital neuroprotective therapy for acute stroke: Results of the field administration of stroke therapy-magnesium(FAST-MAG) pilot trial. Stroke 2004;35:e106-8 https://doi.org/10.1161/01.STR.0000124458.98123.52
  71. Heiss WD, Thiel A, Grond M, Graf R. Which targets are relevant for therapy of acute ischemic stroke? Stroke 1999;30:1486-9
  72. Kidwell CS, Alger JR, Saver JL. Beyond mismatch: Evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging. Stroke 2003;34:2729-35 https://doi.org/10.1161/01.STR.0000097608.38779.CC
  73. Kidwell CS, Saver JL, Starkman S, Duckwiler G, Jahan R, Vespa P, et al. Late secondary ischemic injury in patients receiving intraarterial thrombolysis. Ann Neurol 2002;52:698-703 https://doi.org/10.1002/ana.10380
  74. Leary MC, Saver JL, Gobin YP, Jahan R, Duckwiler GR, Vinuela F, et al. Beyond tissue plasminogen activator: Mechanical intervention in acute stroke. Ann Emerg Med 2003;41:838-46 https://doi.org/10.1067/mem.2003.194
  75. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. Proact: A phase Ⅱ randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT investigators. Prolyse in acute cerebral thromboembolism. Stroke 1998;29:4-11
  76. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT Ⅱ study: A randomized controlled trial. Prolyse in acute cerebral thromboembolism. JAMA 1999;282:2003-11 https://doi.org/10.1001/jama.282.21.2003
  77. Kidwell CS, Saver JL, Mattiello J, Starkman S, Vinuela F, Duckwiler G, et al. Thrombolytic reversal of acute human cerebral ischemic injury shown by diffusion/perfusion magnetic resonance imaging. Ann Neurol 2000;47:462-69 https://doi.org/10.1002/1531-8249(200004)47:4<462::AID-ANA9>3.0.CO;2-Y
  78. Markus R, Reutens DC, Kazui S, Read S, Wright P, Chambers BR, et al. Topography and temporal evolution of hypoxic viable tissue identified by 18F-fluoromisonidazole positron emission tomography in humans after ischemic stroke. Stroke 2003;34:2646-52 https://doi.org/10.1161/01.STR.0000094422.74023.FF
  79. Dohmen C, Bosche B, Graf R, Staub F, Kracht L, Sobesky J, et al. Prediction of malignant course in MCA infarction by PET and microdialysis. Stroke 2003;34:2152-58 https://doi.org/10.1161/01.STR.0000083624.74929.32
  80. Bosche B, Dohmen C, Graf R, Neveling M, Staub F, Kracht L, et al. Extracellular concentrations of non-transmitter amino acids in peri-infarct tissue of patients predict malignant middle cerebral artery infarction. Stroke 2003;34:2908-13 https://doi.org/10.1161/01.STR.0000100158.51986.EB
  81. Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, et al. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation 2002;105:2708-11 https://doi.org/10.1161/01.CIR.0000020548.60110.76
  82. Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002;110:429-41 https://doi.org/10.1016/S0092-8674(02)00862-0
  83. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 2002;8:963-70 https://doi.org/10.1038/nm747