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Microglial activation and amyloid deposition in mild cognitive impairment

A PET study

From the Division of Neuroscience and Mental Health (A.O., P.E., F.E.T., A.K., D.J.B.), Faculty of Medicine, Imperial College London; Dementia Research Centre, Department of Neurodegenerative Disease, Institute of Neurology (H.A.A., J.K., N.F., M.R.), and Department of Mental Health Sciences (Z.W.), University College London; Kingshill Research Centre (R.B.), Victoria Hospital, Swindon; and Hammersmith Imanet (D.J.B.), GE Healthcare, London, UK.

Address correspondence and reprint requests to Dr. Aren Okello, Cyclotron Building, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK aren.okello{at}imperial.ac.uk

Background: Activated microglia may play a role in the pathogenesis of Alzheimer disease (AD) as they cluster around beta-amyloid (Aβ) plaques. They are, therefore, a potential therapeutic target in both AD and its prodrome amnestic mild cognitive impairment (MCI).

Objective: To characterize in vivo with ¹¹C-(R)-PK11195 and ¹¹C-PIB PET the distribution of microglial activation and amyloid deposition in patients with amnestic MCI.

Methods: Fourteen subjects with MCI had ¹¹C-(R)-PK11195 and ¹¹C-PIB PET with psychometric tests.

Results: Seven out of 14 (50%) patients with MCI had increased cortical ¹¹C-PIB retention (p < 0.001) while 5 out of 13 (38%) subjects with MCI showed increased ¹¹C-(R)-PK11195 uptake. The MCI subgroup with increased ¹¹C-PIB retention also showed increased cortical ¹¹C-(R)-PK11195 binding (p < 0.036) though this increase only remained significant in frontal cortex after a correction for multiple comparisons. There was no correlation between regional levels of ¹¹C-(R)-PK11195 and ¹¹C-PIB binding in individual patients with MCI: only three of the five MCI cases with increased ¹¹C-(R)-PK11195 binding had increased levels of ¹¹C-PIB retention.

Conclusions: Our findings indicate that, while amyloid deposition and microglial activation can be detected in vivo in around 50% of patients with mild cognitive impairment (MCI), these pathologies can occur independently. The detection of microglial activation in patients with MCI suggests that anti-inflammatory therapies may be relevant to the prevention of AD.

Abbreviations: Aβ = beta-amyloid; AD = Alzheimer disease; BP = binding potential; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; PBBS = peripheral benzodiazepine binding site; ROI = region of interest; SD = standard deviation; SRTM = simplified reference tissue model.

Supplemental data at www.neurology.org

Disclosure: This work was conducted in collaboration with Imanet, GE Healthcare. The Dementia Research Centre is an Alzheimer's Research Trust Coordinating Centre. UCLH/UCL received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. A. Okello is an Alzheimer's Research Trust research associate; P. Edison is a Medical Research Council clinical research fellow; H. Archer received funding from the Alzheimer's Research Trust; J. Kennedy is supported by funding from the Alzheimer's Research Trust; Z. Walker has received consultancy fees from GE Healthcare; N. Fox is a Medical Research Council senior clinical fellow; David Brooks is Head of Neurology, Medical Diagnostics, GE Healthcare.

Received July 1, 2008. Accepted in final form September 25, 2008.

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				A. Okello, J. Koivunen, P. Edison, H. A. Archer, F. E. Turkheimer, K. Nagren, R. Bullock, Z. Walker, A. Kennedy, N. C. Fox, et al. Conversion of amyloid positive and negative MCI to AD over 3 years: An 11C-PIB PET study Neurology, September 8, 2009; 73(10): 754 - 760. [Abstract] [Full Text] [PDF]