Skip to main content
SpringerLink
Log in

Extrastriatal spreading of microglial activation in Parkinson’s disease: a positron emission tomography study

  • Original Article
  • Published:
Annals of Nuclear Medicine Aims and scope Submit manuscript

Abstract

Background

The neuroinflammatory glial response contributes to the degenerative process in Parkinson’s disease (PD). However, the pattern of microglial progression remains unclear.

Methods

We evaluated microglial activation in early stage PD patients by quantifying changes in neuroinflammation using PET with [11C]DPA713, a selective PET tracer for microglial activation. Eleven PD patients (Hoehn and Yahr stages 1–2) without dementia underwent the [11C]DPA713 PET scan two times with 1 year apart. The binding potential (BPND) was estimated with the simplified reference tissue model. Voxelwise and regions of interest analyses were used to compare the regional BPND among groups.

Results

Significant increase in [11C]DPA713 BPND was found extrastriatally in the occipital, temporal and parietal cortex in PD patients, and the degree of BPND became much higher over the brain regions predominantly in the temporal and occipital cortex 1 year later.

Conclusion

The current results indicated that an extrastriatal spreading of microglial activation reflects one of PD pathophysiology occurring at an early stage.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Muller CM, de Vos RA, Maurage CA, Thal DR, Tolnay M, Braak H. Staging of sporadic Parkinson disease-related alpha-synuclein pathology: inter- and intra-rater reliability. J Neuropathol Exp Neurol. 2005;64:623–8.

    Article  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  Google Scholar 

  3. Banati RB, Daniel SE, Blunt SB. Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson’s disease. Mov Disord. 1998;13:221–7.

    Article  CAS  PubMed  Google Scholar 

  4. McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology. 1988;38:1285–91.

    Article  CAS  PubMed  Google Scholar 

  5. Ouchi Y, Yagi S, Yokokura M, Sakamoto M. Neuroinflammation in the living brain of Parkinson’s disease. Parkinsonism Relat Disord. 2009;15(Suppl 3):S200–4.

    Article  PubMed  Google Scholar 

  6. Mrak RE, Griffin WS. Common inflammatory mechanisms in Lewy body disease and Alzheimer disease. J Neuropathol Exp Neurol. 2007;66:683–6.

    Article  CAS  PubMed  Google Scholar 

  7. Iannaccone S, Cerami C, Alessio M, Garibotto V, Panzacchi A, Olivieri S, et al. In vivo microglia activation in very early dementia with Lewy bodies, comparison with Parkinson’s disease. Parkinsonism Relat Disord. 2013;19:47–52.

    Article  CAS  PubMed  Google Scholar 

  8. Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis. 2006;21:404–12.

    Article  CAS  PubMed  Google Scholar 

  9. Edison P, Ahmed I, Fan Z, Hinz R, Gelosa G, Ray Chaudhuri K, et al. Microglia, amyloid, and glucose metabolism in Parkinson’s disease with and without dementia. Neuropsychopharmacology. 2013;38:938–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bartels AL, Willemsen AT, Doorduin J, de Vries EF, Dierckx RA, Leenders KL. [11C]-PK11195 PET: quantification of neuroinflammation and a monitor of anti-inflammatory treatment in Parkinson’s disease? Parkinsonism Relat Disord. 2010;16:57–9.

    Article  CAS  PubMed  Google Scholar 

  11. Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, et al. Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006;27:402–9.

    Article  CAS  PubMed  Google Scholar 

  12. Yokokura M. Depiction of microglial activation in the living human brain by different TSPO tracers. Abstr Soc Neurosci; 2013; San Diego, USA.

  13. Hagell P, Nilsson MH. The 39-item Parkinson’s Disease Questionnaire (PDQ-39): is it a unidimensional construct? Ther Adv Neurol Disord. 2009;2:205–14.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Tombaugh TN, McIntyre NJ. The mini-mental state examination: a comprehensive review. J Am Geriatr Soc. 1992;40:922–35.

    Article  CAS  PubMed  Google Scholar 

  15. Holmes CB, Fouty HE, Wurtz PJ, Burdick BM. Zung Self-Rating Depression Scale scores of psychiatric outpatients by age and sex. Psychol Rep. 1988;62:259–62.

    Article  CAS  PubMed  Google Scholar 

  16. McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65:1863–72.

    Article  CAS  PubMed  Google Scholar 

  17. Maeda T, Takano D, Yamazaki T, Satoh Y, Nagata K. Zonisamide in the early stage of Parkinson’s disease. Neurol Clin Neurosci. 2015;3:127–30.

    Article  CAS  Google Scholar 

  18. Okada H, Ouchi Y, Ogawa M, Futatsubashi M, Saito Y, Yoshikawa E, et al. Alterations in alpha4beta2 nicotinic receptors in cognitive decline in Alzheimer’s aetiopathology. Brain. 2013;136:3004–17.

    Article  PubMed  Google Scholar 

  19. Yokokura M, Terada T, Bunai T, Nakaizumi K, Takebayashi K, Iwata Y, et al. Depiction of microglial activation in aging and dementia: Positron emission tomography 11CDPA713 versus 11C PK11195. J Cereb Blood Flow Metab. 2016;. doi:10.1177/0271678X16646788.

    PubMed  Google Scholar 

  20. Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage. 1996;4:153–8.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. Yagi S, Yoshikawa E, Futatsubashi M, Yokokura M, Yoshihara Y, Torizuka T, et al. Progression from unilateral to bilateral parkinsonism in early Parkinson disease: implication of mesocortical dopamine dysfunction by PET. J Nucl Med. 2010;51:1250–7.

    Article  PubMed  Google Scholar 

  23. Grover ND, Limaye RP, Gokhale DV, Patil TR. Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson’s disease. Indian J Pharmacol. 2013;45:547–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Asanuma M, Miyazaki I, Diaz-Corrales FJ, Kimoto N, Kikkawa Y, Takeshima M, et al. Neuroprotective effects of zonisamide target astrocyte. Ann Neurol. 2010;67:239–49.

    Article  CAS  PubMed  Google Scholar 

  25. Choudhury ME, Moritoyo T, Kubo M, Kyaw WT, Yabe H, Nishikawa N, et al. Zonisamide-induced long-lasting recovery of dopaminergic neurons from MPTP-toxicity. Brain Res. 2011;1384:170–8.

    Article  CAS  PubMed  Google Scholar 

  26. Yokoyama H, Yano R, Kuroiwa H, Tsukada T, Uchida H, Kato H, et al. Therapeutic effect of a novel anti-parkinsonian agent zonisamide against MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine) neurotoxicity in mice. Metab Brain Dis. 2010;25:305–13.

    Article  CAS  PubMed  Google Scholar 

  27. Murata M, Horiuchi E, Kanazawa I. Zonisamide has beneficial effects on Parkinson’s disease patients. Neurosci Res. 2001;41:397–9.

    Article  CAS  PubMed  Google Scholar 

  28. Ji B, Maeda J, Sawada M, Ono M, Okauchi T, Inaji M, et al. Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer’s and other CNS pathologies. J Neurosci. 2008;28:12255–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dickens AM, Vainio S, Marjamaki P, Johansson J, Lehtiniemi P, Rokka J, et al. Detection of microglial activation in an acute model of neuroinflammation using PET and radiotracers 11C-(R)-PK11195 and 18F-GE-180. J Nucl Med. 2014;55:466–72.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Mr. Toshihiko Kanno (Hamamatsu Medical Center) for his valuable technical assistance.

Author information

Authors and Affiliations

  1. Department of Biofunctional Imaging, Medical Photonics Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan

    Tatsuhiro Terada & Yasuomi Ouchi

  2. Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Masamichi Yokokura

  3. Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan

    Etsuji Yoshikawa & Masami Futatsubashi

  4. First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Satoshi Kono, Takashi Konishi & Hiroaki Miyajima

  5. Osaka Ohtani University, Tondabayashi, Japan

    Takanori Hashizume

Authors
  1. Tatsuhiro Terada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masamichi Yokokura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Etsuji Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masami Futatsubashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Satoshi Kono
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takashi Konishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroaki Miyajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takanori Hashizume
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yasuomi Ouchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuomi Ouchi.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Terada, T., Yokokura, M., Yoshikawa, E. et al. Extrastriatal spreading of microglial activation in Parkinson’s disease: a positron emission tomography study. Ann Nucl Med 30, 579–587 (2016). https://doi.org/10.1007/s12149-016-1099-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12149-016-1099-2

Keywords

Search

Navigation