Advertisement

PET Imaging in Neuroinflammation

  • David J. Brooks
Chapter

Abstract

The presence of microglial activation in the brain provides a marker of disease activity. The function of activated microglia can be both detrimental and beneficial depending on the phenotype. Microglia with the M1 phenotype release cytokines, which may drive disease progression, while M2 microglia generate restorative growth factors, help clear cellular debris and abnormal protein aggregations, and remodel connections as an adaptive response to brain damage. Activated microglia express translocator protein and cannabinoid CB2 sites, which allows their presence to be imaged in vivo with positron emission tomography radioligands. In this chapter, the role of microglial imaging is discussed in Parkinsonian disorders and other neurodegenerative and inflammatory brain diseases.

Keywords

Mild Cognitive Impairment Microglial Activation Multiple System Atrophy Progressive Supranuclear Palsy Simple Reference Tissue Model 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19:312–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 2009;27:119–45.PubMedCrossRefGoogle Scholar
  3. 3.
    Varnum MM, Ikezu T. The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Arch Immunol Ther Exp (Warsz). 2012;60:251–66.CrossRefGoogle Scholar
  4. 4.
    Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006;27:402–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Banati RB. Visualising microglial activation in vivo. Glia. 2002;40:206–17.PubMedCrossRefGoogle Scholar
  6. 6.
    Doorduin J, de Vries EF, Dierckx RA, Klein HC. PET imaging of the peripheral benzodiazepine receptor: monitoring disease progression and therapy response in neurodegenerative disorders. Curr Pharm Des. 2008;14:3297–315.PubMedCrossRefGoogle Scholar
  7. 7.
    Dolle F, Luus C, Reynolds A, Kassiou M. Radiolabelled molecules for imaging the translocator protein (18 kDa) using positron emission tomography. Curr Med Chem. 2009;16:2899–923.PubMedCrossRefGoogle Scholar
  8. 8.
    Banati RB, Myers R, Kreutzberg GW. PK (‘peripheral benzodiazepine’)–binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK11195 binding to activated microglia. J Neurocytol. 1997;26:77–82.PubMedCrossRefGoogle Scholar
  9. 9.
    Banati RB. Brain plasticity and microglia: is transsynaptic glial activation in the thalamus after limb denervation linked to cortical plasticity and central sensitisation? J Physiol Paris. 2002;96:289–99.PubMedCrossRefGoogle Scholar
  10. 10.
    Anderson AN, Pavese N, Edison P, Tai YF, Hammers A, Gerhard A, et al. A systematic comparison of kinetic modelling methods generating parametric maps for [(11)C]-(R)-PK11195. Neuroimage. 2007;36:28–37.PubMedCrossRefGoogle Scholar
  11. 11.
    Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012;32:1–5.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 2004;318:121–34.PubMedCrossRefGoogle Scholar
  13. 13.
    McGeer P, Kawamata T, Walker DG, Akiyama H, Tooyama I, McGeer EG. Microglia in degenerative disease. Glia. 1993;7:84–92.PubMedCrossRefGoogle Scholar
  14. 14.
    Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y. Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains. Acta Neuropathol. 2003;106:518–26.PubMedCrossRefGoogle Scholar
  15. 15.
    Vingerhoets FJG, Snow BJ, Langston JW, Tetrud JM, Schulzer M, Calne DB. Positron emission tomographic evidence for progression of human MPTP-induced dopaminergic lesions. Ann Neurol. 1994;36:765–70.PubMedCrossRefGoogle Scholar
  16. 16.
    Langston JW, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D. Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol. 1999;46:598–605.PubMedCrossRefGoogle Scholar
  17. 17.
    Ouchi Y, Yoshikawa E, Sekine Y, Futatsubashi M, Kanno T, Ogusu T, et al. Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol. 2005;57:168–75.PubMedCrossRefGoogle Scholar
  18. 18.
    Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, et al. In vivo imaging of microglial activation with [(11)C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis. 2006;21:404–12.PubMedCrossRefGoogle Scholar
  19. 19.
    Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord. 2008;23:837–44.PubMedCrossRefGoogle Scholar
  20. 20.
    Edison P, Rowe CC, Rinne J, Ahmed I, Villemagne VL, Ng S, et al. Amyloid load in Lewy body dementia (LBD), Parkinson’s disease dementia (PDD) and Parkinson’s disease (PD) measured with C-11-PIB PET. Neurology. 2007;68:A98–A.Google Scholar
  21. 21.
    Simpson BS, Pavese N, Ramlackhansingh AF, Breen DP, Barker RA, Brooks DJ. Clinical correlates of brain inflammation in Parkinson’s disease: A PET study. Mov Disord. 2012;27 Suppl 1:775.Google Scholar
  22. 22.
    Ishizawa K, Komori T, Sasaki S, Arai N, Mizutani T, Hirose T. Microglial activation parallels system degeneration in multiple system atrophy. J Neuropathol Exp Neurol. 2004;63:43–52.PubMedGoogle Scholar
  23. 23.
    Gerhard A, Banati RB, Goerres GB, Cagnin A, Myers R, Gunn RN, et al. [(11)C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy. Neurology. 2003;61:686–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Stefanova N, Reindl M, Neumann M, Kahle PJ, Poewe W, Wenning GK. Microglial activation mediates neurodegeneration related to oligodendroglial alpha-synucleinopathy: implications for multiple system atrophy. Mov Disord. 2007;22:2196–203.PubMedCrossRefGoogle Scholar
  25. 25.
    Dodel R, Spottke A, Gerhard A, Reuss A, Reinecker S, Schimke N, et al. Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial). Mov Disord. 2010;25:97–107.PubMedCrossRefGoogle Scholar
  26. 26.
    Ishizawa K, Dickson DW. Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J Neuropathol Exp Neurol. 2001;60:647–57.PubMedGoogle Scholar
  27. 27.
    Gerhard A, Trender-Gerhard I, Turkheimer F, Quinn NP, Bhatia KP, Brooks DJ. In vivo imaging of microglial activation with [(11)C](R)-PK11195 PET in progressive supranuclear palsy. Mov Disord. 2006;21:89–93.PubMedCrossRefGoogle Scholar
  28. 28.
    Dickson DW. The pathogenesis of senile plaques. J Neuropathol Exp Neurol. 1997;56:321–39.PubMedCrossRefGoogle Scholar
  29. 29.
    Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997;18:351–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al. In-vivo measurement of activated microglia in dementia. Lancet. 2001;358:461–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE, et al. Microglia, amyloid, and cognition in Alzheimer’s disease: An [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis. 2008;32:412–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Yasuno F, Ota M, Kosaka J, Ito H, Higuchi M, Doronbekov TK, et al. Increased binding of peripheral benzodiazepine receptor in Alzheimer’s disease measured by positron emission tomography with [11C]DAA1106. Biol Psychiatry. 2008;64:835–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE, Hammers A, et al. Microglia, amyloid, and cognition in Alzheimer’s disease: An [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis. 2008;32(3):412–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Yokokura M, Mori N, Yagi S, Yoshikawa E, Kikuchi M, Yoshihara Y, et al. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2011;38:343–51.PubMedCrossRefGoogle Scholar
  35. 35.
    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.PubMedCrossRefGoogle Scholar
  36. 36.
    Okello A, Edison P, Archer HA, Turkheimer FE, Kennedy J, Bullock R, et al. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology. 2009;72:56–62.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Yasuno F, Kosaka J, Ota M, Higuchi M, Ito H, Fujimura Y, et al. Increased binding of peripheral benzodiazepine receptor in mild cognitive impairment-dementia converters measured by positron emission tomography with [(11)C]DAA1106. Psychiatry Res. 2012;203:67–74.PubMedCrossRefGoogle Scholar
  38. 38.
    Cagnin A, Rossor M, Sampson EL, Mackinnon T, Banati RB. In vivo detection of microglial activation in frontotemporal dementia. Ann Neurol. 2004;56:894–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004;15:601–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Sapp E, Schwarz C, Chase K, Bhide PG, Young AB, Penney J, et al. Huntingtin localization in brains of normal and Huntington’s disease patients. Ann Neurol. 1997;42:604–12.PubMedCrossRefGoogle Scholar
  41. 41.
    Andrews TC, Weeks RA, Turjanski N, Gunn RN, Watkins LHA, Sahakian B, et al. Huntington’s disease progression PET and clinical observations. Brain. 1999;122:2353–63.PubMedCrossRefGoogle Scholar
  42. 42.
    Sapp E, Kegel KB, Aronin N, Hashikawa T, Uchiyama Y, Tohyama K, et al. Early and progressive accumulation of reactive microglia in the Huntington disease brain. J Neuropathol Exp Neurol. 2001;60:161–72.PubMedGoogle Scholar
  43. 43.
    Pavese N, Gerhard A, Tai YF, Ho AK, Turkheimer F, Barker RA, et al. Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Neurology. 2006;66:1638–43.PubMedCrossRefGoogle Scholar
  44. 44.
    Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, et al. Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain. 2007;130:1759–66.PubMedCrossRefGoogle Scholar
  45. 45.
    Politis M, Pavese N, Tai YF, Kiferle L, Mason SL, Brooks DJ, et al. Microglial activation in regions related to cognitive function predicts disease onset in Huntington’s disease: a multimodal imaging study. Hum Brain Mapp. 2011;32:258–70.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • David J. Brooks
    • 1
    • 2
    • 3
  1. 1.Imperial College LondonLondonUK
  2. 2.Aarhus UniversityAarhusDenmark
  3. 3.Medicine ICL, Nuclear Medicine AUHammersmith HospitalLondonUK

Personalised recommendations