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Molecular imaging of neuroinflammation in Alzheimer’s disease

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Abstract

Neuroinflammatory changes are observed in the brain of patients with Alzheimer’s disease (AD). Studies have shown the presence of activated microglia and astrocytes surrounding the amyloid plaques, along with the presence of cytokines and other mediators of inflammation. The role of inflammation in AD is not yet completely understood. More specifically, some inflammatory processes, such as the activation of microglia, may have detrimental or beneficial effects on the underlining neuropathology, by promoting inflammation and tissue damage or rather phagocytic activity and tissue repair. Imaging of neuroinflammation with positron emission tomography (PET) is the only technology that enables the visualization of microglia and astrocyte activation in the living human brain. PET studies with first- or second-generation radioligands binding to the 18-kDa translocator protein (TSPO) ([11C]-R-PK11195, [11C]DAA1106, [11C]PBR28, [18F]FEMPA, [18F]FEPPA) have shown some conflicting results, demonstrating on average a ~30 % higher TSPO availability in AD patients compared with controls, with a few studies showing no statistically significant difference between the two groups. Similar conflicting evidences have been shown when comparing subjects with mild cognitive impairment (MCI) and control subjects. Therefore, whether TSPO is a good marker for detecting in vivo microglia activation in AD is still a matter of debate. Imaging of MAO-B as a marker for astrocyte activation in AD is a valid alternative to TSPO imaging in the context of neuroinflammation. Only limited MAO-B imaging studies with [11C]l-deprenyl-D2 are available so far in AD and MCI, showing increased MAO-B binding in MCI patients compared with controls with a degree higher than that observed in AD. There are two unmet questions that are still under discussion. The first question is which neuroinflammatory process, microglia or astrocyte activation, occurs earlier in the natural course of AD from prodromal to dementia stage? Comparative studies using these two markers in MCI and AD could be important to clarify which marker can be used for earliest detection of neuroinflammatory changes in vivo. The second question is whether imaging of microglia or astrocytes per se is a useful marker of neuroinflammation associated with neurodegeneration. The development of new radioligands for other targets that are more directly associated with the pro- or anti-inflammatory activity of microglia could help in understanding the relevance of neuroinflammation in the pathological processes leading to neurodegeneration in AD. Molecular imaging with PET can be a useful tool to determine the nature and temporal evolution of inflammation in early stages of AD in relation to other pathological markers, such as deposition of amyloid plaques and tau as well as clinical presentation of the disease.

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Acknowledgments

The work has been supported by funds from the Swedish Research Council (Project 05817), Karolinska Institutet Strategic Neuroscience program, the Stockholm County Council-Karolinska Institutet regional agreement on medical training and clinical research (ALF Grant), Swedish Brain Power, the Swedish Brain Foundation, the Alzheimer Foundation in Sweden, Karolinska Institutet’s Foundation for Aging Research, Swedish Foundation for Strategic Research (SFF), and by the EU project INMiND, FP7/2007-2013-no HEALTH-F2-2011-278850 (http://www.uni-muenster.de/InMind). Part of the work has been also supported by Bayer Healthcare, Berlin, Germany.

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Andrea Varrone is responsible for literature search and review, content planning, manuscript writing and editing. Agneta Nordberg contributed to literature search and review, content planning, manuscript writing and editing.

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  1. Department of Clinical Neuroscience, Karolinska Institutet, Centre for Psychiatry Research, Stockholm, Sweden

    Andrea Varrone

  2. Department of Neurobiology, Karolinska Institutet, Care Sciences and Society, Stockholm, Sweden

    Agneta Nordberg

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Andrea Varrone and Agneta Nordberg declare no conflicts of interest. The work performed using [18F]FEMPA has been supported by Bayer Healthcare, Berlin, Germany.

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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study. In cases of animal studies, all institutional and national guidelines for the care and use of laboratory animals were followed.

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Varrone, A., Nordberg, A. Molecular imaging of neuroinflammation in Alzheimer’s disease. Clin Transl Imaging 3, 437–447 (2015). https://doi.org/10.1007/s40336-015-0137-8

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