Neuroscience Bulletin

, Volume 30, Issue 5, pp 713–732 | Cite as

PET imaging in ischemic cerebrovascular disease: current status and future directions

  • Wolf-Dieter HeissEmail author


Cerebrovascular diseases are caused by interruption or significant impairment of the blood supply to the brain, which leads to a cascade of metabolic and molecular alterations resulting in functional disturbance and morphological damage. These pathophysiological changes can be assessed by positron emission tomography (PET), which permits the regional measurement of physiological parameters and imaging of the distribution of molecular markers. PET has broadened our understanding of the flow and metabolic thresholds critical for the maintenance of brain function and morphology: in this application, PET has been essential in the transfer of the concept of the penumbra (tissue with perfusion below the functional threshold but above the threshold for the preservation of morphology) to clinical stroke and thereby has had great impact on developing treatment strategies. Radioligands for receptors can be used as early markers of irreversible neuronal damage and thereby can predict the size of the final infarcts; this is also important for decisions concerning invasive therapy in large (“malignant”) infarctions. With PET investigations, the reserve capacity of blood supply to the brain can be tested in obstructive arteriosclerosis of the supplying arteries, and this again is essential for planning interventions. The effect of a stroke on the surrounding and contralateral primarily unaffected tissue can be investigated, and these results help to understand the symptoms caused by disturbances in functional networks. Chronic cerebrovascular disease causes vascular cognitive disorders, including vascular dementia. PET permits the detection of the metabolic disturbances responsible for cognitive impairment and dementia, and can differentiate vascular dementia from degenerative diseases. It may also help to understand the importance of neuroinflammation after stroke and its interaction with amyloid deposition in the development of dementia. Although the clinical application of PET investigations is limited, this technology had and still has a great impact on research into cerebrovascular diseases.


stroke dementia PET brain metabolism brain ischemia 


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  1. [1]
    World Health Organisation 2008. Burden of Disease Statistics. Geneva: WHO Press.Google Scholar
  2. [2]
    Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006, 367: 1747–1757.PubMedGoogle Scholar
  3. [3]
    Johnston SC, Mendis S, Mathers CD. Global variation in stroke burden and mortality: estimates from monitoring, surveillance, and modelling. Lancet Neurol 2009, 8: 345–354.PubMedGoogle Scholar
  4. [4]
    Leary MC, Saver JL. Annual incidence of first silent stroke in the United States: a preliminary estimate. Cerebrovasc Dis 2003, 16: 280–285.PubMedGoogle Scholar
  5. [5]
    Pakkenberg B, Gundersen HJ. Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 1997, 384: 312–320.PubMedGoogle Scholar
  6. [6]
    Clarke DD, Sokoloff L. Circulation and energy metabolism of the brain. In: Siegel GJ, Agranoff BW, Albers RW, et al. (Eds.). Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, 6th ed. Philadelphia: Lippincott-Raven, 1999: 637–669.Google Scholar
  7. [7]
    Sokoloff L. Energetics of functional activation in neural tissues. Neurochem Res 1999, 24: 321–329.PubMedGoogle Scholar
  8. [8]
    Laughlin SB, Attwell D. The metabolic cost of neural information: from fly eye to mammalian cortex. In: Frackowiak RSI, Magistretti PI, Shulman RG, et al. (Eds.). Neuroenergetics: Relevance for Functional Brain Imaging. Strasbourg: HFSP Workshop XI, 2001: 54–64.Google Scholar
  9. [9]
    Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999, 22: 391–397.PubMedGoogle Scholar
  10. [10]
    Hossmann KA. Pathophysiological basis of translational stroke research. Folia Neuropathol 2009, 47: 213–227.PubMedGoogle Scholar
  11. [11]
    Astrup J, Siesjö BK, Symon L. Thresholds in cerebral ischemia — the ischemic penumbra. Stroke 1981, 12: 723–725.PubMedGoogle Scholar
  12. [12]
    Heiss WD, Rosner G. Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol 1983, 14: 294–301.PubMedGoogle Scholar
  13. [13]
    Ackerman RH, Correia JA, Alpert NM, Baron JC, Gouliamos A, Grotta JC, et al. Positron imaging in ischemic stroke disease using compounds labeled with oxygen 15. Initial results of clinicophysiologic correlations. Arch Neurol 1981, 38: 537–543.PubMedGoogle Scholar
  14. [14]
    Baron JC, Bousser MG, Comar D, Soussaline F, Castaigne P. Noninvasive tomographic study of cerebral blood flow and oxygen metabolism in vivo. Potentials, limitations, and clinical applications in cerebral ischemic disorders. Eur Neurol 1981, 20: 273–284.PubMedGoogle Scholar
  15. [15]
    Lenzi GL, Frackowiak RSJ, Jones T. Cerebral oxygen metabolism and blood flow in human cerebral ischemic infarction. J Cereb Blood Flow Metab 1982, 2: 321–335.PubMedGoogle Scholar
  16. [16]
    Powers WJ, Grubb RL, Jr., Darriet D, Raichle ME. Cerebral blood flow and cerebral metabolic rate of oxygen requirements for cerebral function and viability in humans. J Cereb Blood Flow Metab 1985, 5: 600–608.PubMedGoogle Scholar
  17. [17]
    Heiss WD. Ischemic penumbra: evidence from functional imaging in man. J Cereb Blood Flow Metab 2000, 20: 1276–1293.PubMedGoogle Scholar
  18. [18]
    Powers WJ, Zazulia AR. PET in cerebrovascular disease. PET Clin 2010, 5: 83106.PubMedPubMedCentralGoogle Scholar
  19. [19]
    Heiss WD. David sherman lecture 2012: the role of positron emission tomography for translational research in stroke. Stroke 2012, 43: 2520–2525.PubMedGoogle Scholar
  20. [20]
    Heiss WD, Huber M, Fink GR, Herholz K, Pietrzyk U, Wagner R, et al. Progressive derangement of periinfarct viable tissue in ischemic stroke. J Cereb Blood Flow Metab 1992, 12: 193–203.PubMedGoogle Scholar
  21. [21]
    Baron JC. Mapping the ischaemic penumbra with PET: implications for acute stroke treatment. Cerebrovasc Dis 1999, 9: 193–201.PubMedGoogle Scholar
  22. [22]
    Graf R, Löttgen J, Ohta K, Wagner R, Rosner G, Pietrzyk U, et al. Dynamics of postischemic perfusion following transient MCA occlusion in cats determined by sequential PET. J Cereb Blood Flow Metab 1997, 17,Suppl. 1: S323.Google Scholar
  23. [23]
    Guadagno JV, Jones PS, Aigbirhio FI, Wang D, Fryer TD, Day DJ, et al. Selective neuronal loss in rescued penumbra relates to initial hypoperfusion. Brain 2008, 131: 2666–2678.PubMedGoogle Scholar
  24. [24]
    Barber PA, Darby DG, Desmond PM, Yang Q, Gerraty RP, Jolley D, et al. Prediction of stroke outcome with echoplanar perfusion-weighted and diffusion-weighted MRI. Neurology 1998, 51: 418–426.PubMedGoogle Scholar
  25. [25]
    Kidwell CS, Alger JR, Saver JL. Beyond mismatch: evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging. Stroke 2003, 34: 2729–2735.PubMedGoogle Scholar
  26. [26]
    Heiss WD, Sobesky J, Smekal U, Kracht LW, Lehnhardt FG, Thiel A, et al. Probability of cortical infarction predicted by flumazenil binding and diffusion-weighted imaging signal intensity: a comparative positron emission tomography/magnetic resonance imaging study in early ischemic stroke. Stroke 2004, 35: 1892–1898.PubMedGoogle Scholar
  27. [27]
    Kane I, Carpenter T, Chappell F, Rivers C, Armitage P, Sandercock P, et al. Comparison of 10 different magnetic resonance perfusion imaging processing methods in acute ischemic stroke: effect on lesion size, proportion of patients with diffusion/perfusion mismatch, clinical scores, and radiologic outcomes. Stroke 2007, 38: 3158–3164.PubMedGoogle Scholar
  28. [28]
    Sobesky J, Weber OZ, Lehnhardt FG, Hesselmann V, Neveling M, Jacobs A, et al. Does the mismatch match the penumbra? Magnetic resonance imaging and positron emission tomography in early ischemic stroke. Stroke 2005, 36: 980–985.PubMedGoogle Scholar
  29. [29]
    Takasawa M, Jones PS, Guadagno JV, Christensen S, Fryer TD, Harding S, et al. How reliable is perfusion MR in acute stroke? Validation and determination of the penumbra threshold against quantitative PET. Stroke 2008, 39: 870–877.PubMedGoogle Scholar
  30. [30]
    Zaro-Weber O, Moeller-Hartmann W, Heiss WD, Sobesky J. The performance of MRI-based cerebral blood flow measurements in acute and subacute stroke compared with 15O-water positron emission tomography: identification of penumbral flow. Stroke 2009, 40: 2413–2421.PubMedGoogle Scholar
  31. [31]
    Olivot JM, Albers GW. Diffusion-perfusion MRI for triaging transient ischemic attack and acute cerebrovascular syndromes. Curr Opin Neurol 2011, 24: 44–49.PubMedGoogle Scholar
  32. [32]
    Hernandez DA, Bokkers RP, Mirasol RV, Luby M, Henning EC, Merino JG, et al. Pseudocontinuous arterial spin labeling quantifies relative cerebral blood flow in acute stroke. Stroke 2012, 43: 753–758.PubMedPubMedCentralGoogle Scholar
  33. [33]
    Campbell BC, Christensen S, Levi CR, Desmond PM, Donnan GA, Davis SM, et al. Cerebral blood flow is the optimal CT perfusion parameter for assessing infarct core. Stroke 2011, 42: 3435–3440.PubMedGoogle Scholar
  34. [34]
    Mathias CJ, Welch MJ, Kilbourn MR, Jerabek PA, Patrick TB, Raichle ME, et al. Radiolabeled hypoxic cell sensitizers: Tracers for assessment of ischemia. Life Sci 1987, 41: 199–206.PubMedGoogle Scholar
  35. [35]
    Hoffman JM, Rasey JS, Spence AM, Shaw DW, Krohn KA. Binding of the hypoxia tracer [3H]misonidazole in cerebral ischemia. Stroke 1987, 18: 168–176.PubMedGoogle Scholar
  36. [36]
    Yeh SH, Liu RS, Hu HH, et al. Ischemic penumbra in acute stroke: demonstration by PET with fluorine-18 fluoromisonidazole. J Nucl Med 1994, 35: 205P.Google Scholar
  37. [37]
    Read SJ, Hirano T, Abbott DF, Sachinidis JI, Tochon-Danguy HJ, Chan JG, et al. Identifying hypoxic tissue after acute ischemic stroke using PET and 18F-fluoromisonidazole. Neurology 1998, 51: 1617–1621.PubMedGoogle Scholar
  38. [38]
    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: 2646–2652.PubMedGoogle Scholar
  39. [39]
    Read SJ, Hirano T, Abbott DF, Markus R, Sachinidis JI, Tochon-Danguy HJ, et al. The fate of hypoxic tissue on 18F-fluoromisonidazole PET after ischemic stroke. Ann Neurol 2000, 48: 228–235.PubMedGoogle Scholar
  40. [40]
    Markus R, Donnan G, Kazui S, Read S, Reutens D. Penumbral topography in human stroke: methodology and validation of the ‘Penumbragram’. Neuroimage 2004, 21: 1252–1259.PubMedGoogle Scholar
  41. [41]
    Saita K, Chen M, Spratt NJ, Porritt MJ, Liberatore GT, Read SJ, et al. Imaging the ischemic penumbra with 18F-fluoromisonidazole in a rat model of ischemic stroke. Stroke 2004, 35: 975–980.PubMedGoogle Scholar
  42. [42]
    Spratt NJ, Donnan GA, Howells DW. Characterisation of the timing of binding of the hypoxia tracer FMISO after stroke. Brain Res 2009, 1288: 135–142.PubMedGoogle Scholar
  43. [43]
    Takasawa M, Beech JS, Fryer TD, Jones PS, Ahmed T, Smith R, et al. Single-subject statistical mapping of acute brain hypoxia in the rat following middle cerebral artery occlusion: a microPET study. Exp Neurol 2011, 229: 251–258.PubMedGoogle Scholar
  44. [44]
    Alawneh JA, Moustafa RR, Marrapu ST, Jensen-Kondering U, Morris RS, Jones PS, et al. Diffusion and perfusion correlates of the F-MISO PET lesion in acute stroke: pilot study. Eur J Nucl Med Mol Imaging 2014, 41(4): 736–744.PubMedGoogle Scholar
  45. [45]
    Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010, 375: 1695–1703.PubMedGoogle Scholar
  46. [46]
    Grotta JC, Alexandrov AV. tPA-associated reperfusion after acute stroke demonstrated by SPECT. Stroke 1998, 29: 429–432.PubMedGoogle Scholar
  47. [47]
    Heiss WD, Grond M, Thiel A, von Stockhausen HM, Rudolf J, Ghaemi M, et al. Tissue at risk of infarction rescued by early reperfusion: a positron emission tomography study in systemic recombinant tissue plasminogen activator thrombolysis of acute stroke. J Cereb Blood Flow Metab 1998, 18: 1298–1307.PubMedGoogle Scholar
  48. [48]
    Heiss WD, Kracht L, Grond M, Rudolf J, Bauer B, Wienhard K, et al. Early [11C]Flumazenil/H2O positron emission tomography predicts irreversible ischemic cortical damage in stroke patients receiving acute thrombolytic therapy. Stroke 2000, 31: 366–369.PubMedGoogle Scholar
  49. [49]
    Hossmann KA. Pathophysiology and therapy of experimental stroke. Cell Mol Neurobiol 2006, 26: 1057–1083.PubMedGoogle Scholar
  50. [50]
    Nakamura H, Strong AJ, Dohmen C, Sakowitz OW, Vollmar S, Sue M, et al. Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions. Brain 2010, 133: 1994–2006.PubMedPubMedCentralGoogle Scholar
  51. [51]
    Dohmen C, Sakowitz OW, Fabricius M, Bosche B, Reithmeier T, Ernestus RI, et al. Spreading depolarizations occur in human ischemic stroke with high incidence. Ann Neurol 2008, 63: 720–728.PubMedGoogle Scholar
  52. [52]
    Juttler E, Bosel J, Amiri H, Schiller P, Limprecht R, Hacke W, et al. DESTINY II: DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY II. Int J Stroke 2011, 6: 79–86.PubMedGoogle Scholar
  53. [53]
    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: 2152–2158.PubMedGoogle Scholar
  54. [54]
    Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007, 10: 1387–1394.PubMedGoogle Scholar
  55. [55]
    Weinstein JR, Koerner IP, Moller T. Microglia in ischemic brain injury. Future Neurol 2010, 5: 227–246.PubMedPubMedCentralGoogle Scholar
  56. [56]
    Thiel A, Heiss WD. Imaging of microglia activation in stroke. Stroke 2011, 42: 507–512.PubMedGoogle Scholar
  57. [57]
    Rojas S, Martin A, Arranz MJ, Pareto D, Purroy J, Verdaguer E, et al. Imaging brain inflammation with [(11)C]PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats. J Cereb Blood Flow Metab 2007, 27: 1975–1986.PubMedGoogle Scholar
  58. [58]
    Demerle-Pallardy C, Duverger D, Spinnewyn B, Pirotzky E, Braquet P. Peripheral type benzodiazepine binding sites following transient forebrain ischemia in the rat: effect of neuroprotective drugs. Brain Res 1991, 565: 312–320.PubMedGoogle Scholar
  59. [59]
    Schroeter M, Dennin MA, Walberer M, Backes H, Neumaier B, Fink GR, et al. Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer [11C]PK11195- and [18F]FDG-PET study. J Cereb Blood Flow Metab 2009, 29: 1216–1225.PubMedGoogle Scholar
  60. [60]
    Hughes JL, Jones PS, Beech JS, Wang D, Menon DK, Aigbirhio FI, et al. A microPET study of the regional distribution of [11C]-PK11195 binding following temporary focal cerebral ischemia in the rat. Correlation with post mortem mapping of microglia activation. Neuroimage 2012, 59: 2007–2016.PubMedGoogle Scholar
  61. [61]
    Tsukada H, Ohba H, Nishiyama S, Kanazawa M, Kakiuchi T, Harada N. PET imaging of ischemia-induced impairment of mitochondrial complex I function in monkey brain. J Cereb Blood Flow Metab 2014, 34(4): 708–714PubMedGoogle Scholar
  62. [62]
    Gerhard A, Schwarz J, Myers R, Wise R, Banati RB. Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. Neuroimage 2005, 24: 591–595.PubMedGoogle Scholar
  63. [63]
    Radlinska BA, Ghinani SA, Lyon P, Jolly D, Soucy JP, Minuk J, et al. Multimodal microglia imaging of fiber tracts in acute subcortical stroke. Ann Neurol 2009, 66: 825–832.PubMedGoogle Scholar
  64. [64]
    Thiel A, Radlinska BA, Paquette C, Sidel M, Soucy JP, Schirrmacher R, et al. The temporal dynamics of poststroke neuroinflammation: a longitudinal diffusion tensor imaging-guided PET study with 11C-PK11195 in acute subcortical stroke. J Nucl Med 2010, 51: 1404–1412.PubMedGoogle Scholar
  65. [65]
    Thiel A, Heiss W-D. Imaging of microglia activation in stroke. Stroke 2011, 42: 507–512.PubMedGoogle Scholar
  66. [66]
    Gibbs JM, Wise RJ, Leenders KL, Jones T. Evaluation of cerebral perfusion reserve in patients with carotid-artery occlusion. Lancet 1984, 1: 310–314.PubMedGoogle Scholar
  67. [67]
    Powers WJ, Press GA, Grubb RL, Jr., Gado M, Raichle ME. The effect of hemodynamically significant carotid artery disease on the hemodynamic status of the cerebral circulation. Ann Intern Med 1987, 106: 27–35.PubMedGoogle Scholar
  68. [68]
    Sette G, Baron JC, Mazoyer B, Levasseur M, Pappata S, Crouzel C. Local brain haemodynamics and oxygen metabolism in cerebrovascular disease. Positron emission tomography. Brain 1989, 112(Pt 4): 931–951.PubMedGoogle Scholar
  69. [69]
    Grubb RL, Jr., Derdeyn CP, Fritsch SM, Carpenter DA, Yundt KD, Videen TO, et al. Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion. JAMA 1998, 280: 1055–1060.PubMedGoogle Scholar
  70. [70]
    Yamauchi H, Fukuyama H, Nagahama Y, Nabatame H, Ueno M, Nishizawa S, et al. Significance of increased oxygen extraction fraction in five-year prognosis of major cerebral arterial occlusive diseases. J Nucl Med 1999, 40: 1992–1998.PubMedGoogle Scholar
  71. [71]
    Hokari M, Kuroda S, Shiga T, Nakayama N, Tamaki N, Iwasaki Y. Impact of oxygen extraction fraction on long-term prognosis in patients with reduced blood flow and vasoreactivity because of occlusive carotid artery disease. Surg Neurol 2009, 71: 532–538; discussion 538, 538–539.PubMedGoogle Scholar
  72. [72]
    Baron JC, Yamauchi H, Fujioka M, Endres M. Selective neuronal loss in ischemic stroke and cerebrovascular disease. J Cereb Blood Flow Metab 2014, 34: 2–18.PubMedGoogle Scholar
  73. [73]
    Matsubara S, Moroi J, Suzuki A, Sasaki M, Nagata K, Kanno I, et al. Analysis of cerebral perfusion and metabolism assessed with positron emission tomography before and after carotid artery stenting. Clinical article. J Neurosurg 2009, 111: 28–36.PubMedGoogle Scholar
  74. [74]
    Kuhl DE, Phelps ME, Kowell AP, Metter EJ, Selin C, Winter J. Effects of stroke on local cerebral metabolism and perfusion: Mapping by emission computed tomography of 18FDG and 13NH3. Ann Neurol 1980, 8: 47–60.PubMedGoogle Scholar
  75. [75]
    Baron JC, Bousser MG, Comar D, Castaigne P. “Crossed cerebellar diaschisis” in human supratentorial brain infarction. Trans Am Neurol Assoc 1980, 105: 459–461.Google Scholar
  76. [76]
    Sobesky J, Thiel A, Ghaemi M, Hilker RH, Rudolf J, Jacobs AH, et al. Crossed cerebellar diaschisis in acute human stroke: a PET study of serial changes and response to supratentorial reperfusion. J Cereb Blood Flow Metab 2005, 25: 1685–1691.PubMedGoogle Scholar
  77. [77]
    Feeney DM, Baron JC. Diaschisis. Stroke 1986, 17: 817–830.PubMedGoogle Scholar
  78. [78]
    Szelies B, Herholz K, Pawlik G, Karbe H, Hebold I, Heiss WD. Widespread functional effects of discrete thalamic infarction. Arch Neurol 1991, 48: 178–182.PubMedGoogle Scholar
  79. [79]
    Madai VI, Altaner A, Stengl KL, Zaro-Weber O, Heiss WD, von Samson-Himmelstjerna FC, et al. Crossed cerebellar diaschisis after stroke: can perfusion-weighted MRI show functional inactivation? J Cereb Blood Flow Metab 2011, 31: 1493–1500.PubMedPubMedCentralGoogle Scholar
  80. [80]
    Kushner M, Reivich M, Fieschi C, Silver F, Chawluk J, Rosen M, et al. Metabolic and clinical correlates of acute ischemic infarction. Neurology 1987, 37: 1103–1110.PubMedGoogle Scholar
  81. [81]
    Karbe H, Herholz K, Szelies B, Pawlik G, Wienhard K, Heiss WD. Regional metabolic correlates of Token test results in cortical and subcortical left hemispheric infarction. Neurology 1989, 39: 1083–1088.PubMedGoogle Scholar
  82. [82]
    Nudo RJ. Mechanisms for recovery of motor function following cortical damage. Curr Opin Neurobiol 2006, 16: 638–644.PubMedGoogle Scholar
  83. [83]
    Mountz JM. Nuclear medicine in the rehabilitative treatment evaluation in stroke recovery. Role of diaschisis resolution and cerebral reorganization. Eura Medicophys 2007, 43: 221–239.PubMedGoogle Scholar
  84. [84]
    Heiss W-D. WSO Leadership in Stroke Medicine Award Lecture Vienna, September 26, 2008: Functional imaging correlates to disturbance and recovery of language function. Int J Stroke 2009, 4: 129–136.PubMedGoogle Scholar
  85. [85]
    Cramer SC, Nudo RJ (Eds). Brain Repair after Stroke. Cambridge: Cambridge University Press, 2010.Google Scholar
  86. [86]
    Roman GC, Sachdev P, Royall DR, Bullock RA, Orgogozo JM, Lopez-Pousa S, et al. Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci 2004, 226: 81–87.PubMedGoogle Scholar
  87. [87]
    Rockwood K, Wentzel C, Hachinski V, Hogan DB, MacKnight C, McDowell I. Prevalence and outcomes of vascular cognitive impairment. Vascular Cognitive Impairment Investigators of the Canadian Study of Health and Aging. Neurology 2000, 54: 447–451.PubMedGoogle Scholar
  88. [88]
    Ferrer I. Cognitive impairment of vascular origin: Neuropathology of cognitive impairment of vascular origin. J Neurol Sci 2010, 299(1–2): 139–149PubMedGoogle Scholar
  89. [89]
    Jellinger KA. The pathology of “vascular dementia”: a critical update. J Alzheimers Dis 2008, 14: 107–123.PubMedGoogle Scholar
  90. [90]
    Hachinski VC, Lassen NA, Marshall J. Multi-infarct dementia. A cause of mental deterioration in the elderly. Lancet 1974, 2: 207–210.PubMedGoogle Scholar
  91. [91]
    Moorhouse P, Rockwood K. Vascular cognitive impairment: current concepts and clinical developments. Lancet Neurol 2008, 7: 246–255.PubMedGoogle Scholar
  92. [92]
    Heiss WD, Zimmermann-Meinzingen S. PET imaging in the differential diagnosis of vascular dementia. J Neurol Sci 2012, 322: 268–273.PubMedGoogle Scholar
  93. [93]
    Frackowiak RSJ, Pozzilli C, Legg NJ, Du Boulay GH, Marshall J, Lenzi GL, et al. Regional cerebral oxygen supply and utilization in dementia. A clinical and physiological study with oxygen-15 and positron tomograhy. Brain 1981, 104: 753–778.PubMedGoogle Scholar
  94. [94]
    Meguro K, Hatazawa J, Yamaguchi T, Itoh M, Matsuzawa T, Ono S, et al. Cerebral circulation and oxygen metabolism associated with subclinical periventricular hyperintensity as shown by magnetic resonance imaging. Ann Neurol 1990, 28: 378–383.PubMedGoogle Scholar
  95. [95]
    Benson DF, Kuhl DE, Hawkins RA, Phelps ME, Cummings JL, Tsai SY. The fluorodeoxyglucose 18F scan in Alzheimer’s disease and multi-infarct dementia. Arch Neurol 1983, 40: 711–714.PubMedGoogle Scholar
  96. [96]
    Leys D, Henon H, Mackowiak-Cordoliani MA, Pasquier F. Poststroke dementia. Lancet Neurol 2005, 4: 752–759.PubMedGoogle Scholar
  97. [97]
    Cechetto DF, Hachinski V, Whitehead SN. Vascular risk factors and Alzheimer’s disease. Expert Rev Neurother 2008, 8: 743–750.PubMedGoogle Scholar
  98. [98]
    Whitehead SN, Cheng G, Hachinski VC, Cechetto DF. Progressive increase in infarct size, neuroinflammation, and cognitive deficits in the presence of high levels of amyloid. Stroke 2007, 38: 3245–3250.PubMedGoogle Scholar
  99. [99]
    Sokoloff L, Ingvar DH, Lassen NA. Influence of functional activity on local cerebral glucose utilization. Brain Work 1975: 385–388.Google Scholar
  100. [100]
    Heiss WD, Turnheim M, Vollmer R, Rappelsberger P. Coupling between neuronal activity and focal blood flow in experimental seizures. Electroenceph Clin Neurophysiol 1979, 47: 396–403.PubMedGoogle Scholar
  101. [101]
    Ingvar DH. Functional landscapes of the dominant hemisphere. Brain Res 1976, 107: 181–197.PubMedGoogle Scholar
  102. [102]
    Phelps ME, Mazziotta JC. Positron emission tomography: Human brain function and biochemistry. Science 1985, 228: 799–809.PubMedGoogle Scholar
  103. [103]
    Raichle ME. Behind the scenes of functional brain imaging: a historical and physiological perspective. Proc Natl Acad Sci U S A 1998, 95: 765–772.PubMedPubMedCentralGoogle Scholar
  104. [104]
    Thiel A, Schumacher B, Wienhard K, Gairing S, Kracht LW, Wagner R, et al. Direct demonstration of transcallosal disinhibition in language networks. J Cereb Blood Flow Metab 2006, 26: 1122–1127.PubMedGoogle Scholar
  105. [105]
    Thiel A, Habedank B, Herholz K, Kessler J, Winhuisen L, Haupt WF, et al. From the left to the right: How the brain compensates progressive loss of language function. Brain Lang 2006, 98: 57–65.PubMedGoogle Scholar
  106. [106]
    Saur D, Lange R, Baumgaertner A, Schraknepper V, Willmes K, Rijntjes M, et al. Dynamics of language reorganization after stroke. Brain 2006, 129: 1371–1384.PubMedGoogle Scholar
  107. [107]
    Heiss WD, Kessler J, Thiel A, Ghaemi M, Karbe H. Differential capacity of left and right hemispheric areas for compensation of poststroke aphasia. Ann Neurol 1999, 45: 430–438.PubMedGoogle Scholar
  108. [108]
    Richter M, Miltner WH, Straube T. Association between therapy outcome and right-hemispheric activation in chronic aphasia. Brain 2008, 131: 1391–1401.PubMedGoogle Scholar
  109. [109]
    Thiel A, Hartmann A, Rubi-Fessen I, Anglade C, Kracht L, Weiduschat N, et al. Effects of noninvasive brain stimulation on language networks and recovery in early poststroke aphasia. Stroke 2013, 44: 2240–2246.PubMedGoogle Scholar
  110. [110]
    Thiel A, Schumacher B, Wienhard K, Gairing S, Kracht LW, Wagner R, et al. Direct demonstration of transcallosal disinhibition in language networks. J Cereb Blood Flow Metab 2006, 26: 1122–1127.PubMedGoogle Scholar
  111. [111]
    Wehrl HF, Judenhofer MS, Wiehr S, Pichler BJ. Pre-clinical PET/MR: technological advances and new perspectives in biomedical research. Eur J Nucl Med Mol Imaging 2009, 36Suppl 1: S56–68.PubMedGoogle Scholar
  112. [112]
    Heiss W-D. The potential of PET/MR for brain imaging. Eur J Nucl MEd Mol Imaging 2009, 36.Suppl 1: 105–112.Google Scholar
  113. [113]
    Sauter AW, Wehrl HF, Kolb A, Judenhofer MS, Pichler BJ. Combined PET/MRI: one step further in multimodality imaging. Trends Mol Med 2010, 16: 508–515.PubMedGoogle Scholar
  114. [114]
    Catana C, Drzezga A, Heiss WD, Rosen BR. PET/MRI for neurologic applications. J Nucl Med 2012, 53(12): 1916–1925.PubMedGoogle Scholar
  115. [115]
    Schlemmer HP, Pichler BJ, Schmand M, Burbar Z, Michel C, Ladebeck R, et al. Simultaneous MR/PET imaging of the human brain: Feasibility study. Radiology 2008, 248: 1028–1035.PubMedGoogle Scholar
  116. [116]
    Lanfermann H, Kugel H, Heindel W, Herholz K, Heiss WD, Lackner K. Metabolic changes in acute and subacute cerebral infarctions: findings at proton MR spectroscopic imaging. Radiology 1995, 196: 203–210.PubMedGoogle Scholar
  117. [117]
    Hsu AR, Chen X. Advances in anatomic, functional, and molecular imaging of angiogenesis. J Nucl Med 2008, 49: 511–514.PubMedGoogle Scholar
  118. [118]
    Hoehn M, Himmelreich U, Kruttwig K, Wiedermann D. Molecular and cellular MR imaging: potentials and challenges for neurological applications. J Magn Reson Imaging 2008, 27: 941–954.PubMedGoogle Scholar
  119. [119]
    Bliss T, Guzman R, Daadi M, Steinberg GK. Cell transplantation therapy for stroke. Stroke 2007, 38: 817–826.PubMedGoogle Scholar
  120. [120]
    Wang J, Chao F, Han F, Zhang G, Xi Q, Li J, et al. PET demonstrates functional recovery after transplantation of induced pluripotent stem cells in a rat model of cerebral ischemic injury. J Nucl Med 2013, 54: 785–792.PubMedGoogle Scholar
  121. [121]
    Heiss WD, Grond M, Thiel A, Ghaemi M, Sobesky J, Rudolf J, Bauer B, Wienhard K. Permanent cortical damage detected by flumazenil positron emission tomography in acute stroke. Stroke 1998, 29(2): 454–461.PubMedGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Max Planck Institute for Neurological ResearchCologneGermany

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