Early and protective microglial activation in Alzheimer’s disease: a prospective study using¹⁸F-DPA-714 PET imaging

Abstract

While emerging evidence suggests that neuroinflammation plays a crucial role in Alzheimer's disease, the impact of the microglia response in Alzheimer's disease remains a matter of debate. We aimed to study microglial activation in early Alzheimer's disease and its impact on clinical progression using a second-generation 18-kDa translocator protein positron emission tomography radiotracer together with amyloid imaging using Pittsburgh compound B positron emission tomography. We enrolled 96 subjects, 64 patients with Alzheimer's disease and 32 controls, from the IMABio3 study, who had both (11)C-Pittsburgh compound B and (18)F-DPA-714 positron emission tomography imaging. Patients with Alzheimer's disease were classified as prodromal Alzheimer's disease (n = 38) and Alzheimer's disease dementia (n = 26). Translocator protein-binding was measured using a simple ratio method with cerebellar grey matter as reference tissue, taking into account regional atrophy. Images were analysed at the regional (volume of interest) and at the voxel level. Translocator protein genotyping allowed the classification of all subjects in high, mixed and low affinity binders. Thirty high+mixed affinity binders patients with Alzheimer's disease were dichotomized into slow decliners (n = 10) or fast decliners (n = 20) after 2 years of follow-up. All patients with Alzheimer's disease had an amyloid positive Pittsburgh compound B positron emission tomography. Among controls, eight had positive amyloid scans (n = 6 high+mixed affinity binders), defined as amyloidosis controls, and were analysed separately. By both volumes of interest and voxel-wise comparison, 18-kDa translocator protein-binding was higher in high affinity binders, mixed affinity binders and high+mixed affinity binders Alzheimer's disease groups compared to controls, especially at the prodromal stage, involving the temporo-parietal cortex. Translocator protein-binding was positively correlated with Mini-Mental State Examination scores and grey matter volume, as well as with Pittsburgh compound B binding. Amyloidosis controls displayed higher translocator protein-binding than controls, especially in the frontal cortex. We found higher translocator protein-binding in slow decliners than fast decliners, with no difference in Pittsburgh compound B binding. Microglial activation appears at the prodromal and possibly at the preclinical stage of Alzheimer's disease, and seems to play a protective role in the clinical progression of the disease at these early stages. The extent of microglial activation appears to differ between patients, and could explain the overlap in translocator protein binding values between patients with Alzheimer's disease and amyloidosis controls.

TREM2, Microglia, and Neurodegenerative Diseases

“…By using tracers that specifically bind to the translocator protein TSPO -expressed by microglia -it was suggested that microglial activation in AD brain could track temporally and spatially with the spread of amyloid as well as tau [ 5 4 4 _ T D $ D I F F ] pathology [32,33]. Interestingly, higher binding of TSPO ligand has been documented in AD patients with a slower rate of disease progression, raising the possibility that microglial activation can exert a protective effect [34]. Microglia play [ 5 4 5 _ T D $ D I F F ] a myriad of functions in the healthy and diseased brain; however, emerging data from the field suggests that microglia become impaired during neurodegenerative disorders.…”

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology

“…A large number of second generation tracers with higher specificity has been developed but their binding is subject to a genetic polymorphisms that blurs the advantage of these tracers [454]. Nonetheless, beyond these limitations, the development of these tracers could provide relevant biomarkers and offer new insights in the variability of evolution of AD [455]. There are also tracers for imaging of astrogliosis, and markers for cytokines and inflammatory endothelial changes are being developed.…”

Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia

“…In another study measuring 11 C-( R )-PK-11195 binding, Okello and colleagues found that only 5 of 13 MCI patients had elevated 11 C-( R )PK-11195 binding and that this was not related to amyloid binding (Okello et al, 2009). Hamelin and colleagues found that amyloid-positive MCI patients had greater 18 F-DPA-714 binding than controls (Hamelin et al, 2016). However, in contrast to the findings of Kreisl et al (2013) and Lyoo et al (2015)—where AD patients had greater TSPO binding than MCI patients—and those of Yasuno and colleagues, which found that MCI and AD patients both had increased binding compared to controls, Hamelin and colleagues found that binding was greater in MCI than in AD patients (Hamelin et al, 2016); that study further found that 18 F-DPA-714 binding was inversely correlated with cognitive measures, with more affected patients having lower TSPO binding.…”

“…Hamelin and colleagues found that amyloid-positive MCI patients had greater 18 F-DPA-714 binding than controls (Hamelin et al, 2016). However, in contrast to the findings of Kreisl et al (2013) and Lyoo et al (2015)—where AD patients had greater TSPO binding than MCI patients—and those of Yasuno and colleagues, which found that MCI and AD patients both had increased binding compared to controls, Hamelin and colleagues found that binding was greater in MCI than in AD patients (Hamelin et al, 2016); that study further found that 18 F-DPA-714 binding was inversely correlated with cognitive measures, with more affected patients having lower TSPO binding. The study by Hamelin and colleagues was the first to present results demonstrating that amyloid-positive control subjects (preclinical AD) had greater TSPO binding than amyloid-negative controls.…”

“…This conclusion was predicated on the assumption that decreases in TSPO in the more severely affected patients reflected a loss of protective function of microglia—such as amyloid phagocytosis—and that the loss of this protective microglial function allows AD to progress. While the study by Hamelin and colleagues included an unusually large sample size for a clinical PET study (n¼96), it was a cross-sectional study, and it has not yet been determined if individual subjects demonstrate increased 18 F-DPA-714 binding over time (Hamelin et al, 2016). The study also used a simplified tissue-ratio method to quantify 18 F-DPA-714 binding that has not yet been validated against the “gold standard” for reversible radioligands without a true reference region (i.e., kinetic modeling using the metabolite-corrected arterial input function).…”