Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease

Abstract

Although brain neuroinflammation may play an instrumental role in the pathophysiology of Alzheimer's disease, its actual impact on disease progression remains controversial, being reported as either detrimental or protective. This work aimed at investigating the temporal relationship between microglial activation and clinical progression of Alzheimer's disease. First, in a large cohort of patients with Alzheimer's disease we analysed the predictive value of microglial activation assessed by 18F-DPA-714 PET imaging on functional, cognitive and MRI biomarkers outcomes after a 2-year follow-up. Second, we analysed the longitudinal progression of 18F-DPA-714 binding in patients with Alzheimer's disease by comparison with controls, and assessed its influence on clinical progression. At baseline, all participants underwent a clinical assessment, brain MRI, 11C-PiB, 18F-DPA-714 PET imaging and TSPO genotyping. Participants were followed-up annually for 2 years. At the end of the study, subjects were asked to repeat a second 18F-DPA-714-PET imaging. Initial 18F-DPA-714 binding was higher in prodromal (n = 33) and in demented patients with Alzheimer's disease (n = 19) compared to controls (n = 17). After classifying patients into slow and fast decliners according to functional (Clinical Dementia Rating change) or cognitive (Mini-Mental State Examination score decline) outcomes, we found a higher initial 18F-DPA-714 binding in slow than fast decliners. Negative correlations were observed between initial 18F-DPA-714 binding and the Clinical Dementia Rating Sum of Boxes score increase, the MMSE score loss and the progression of hippocampal atrophy. This suggests that higher initial 18F-DPA-714 binding is associated with better clinical prognosis. Twenty-four patients with Alzheimer's disease and 15 control subjects performed a second DPA-PET. We observed an increase of 18F-DPA-714 in patients with Alzheimer's disease as compared with controls (mean 13.2% per year versus 4.2%) both at the prodromal (15.8%) and at the demented stages (8.3%). The positive correlations between change in 18F-DPA-714 binding over time and the three clinical outcome measures (Clinical Dementia Rating, Mini-Mental State Examination, hippocampal atrophy) suggested a detrimental effect on clinical Alzheimer's disease progression of increased neuroinflammation after the initial PET examination, without correlation with PiB-PET uptake at baseline. High initial 18F-DPA-714 binding was correlated with a low subsequent increase of microglial activation and favourable clinical evolution, whereas the opposite profile was observed when initial 18F-DPA-714 binding was low, independently of disease severity at baseline. Taken together, our results support a pathophysiological model involving two distinct profiles of microglial activation signatures with different dynamics, which differentially impact on disease progression and may vary depending on patients rather than disease stages.

Applications of amyloid, tau, and neuroinflammation PET imaging to Alzheimer's disease and mild cognitive impairment

“…Similar to [ 11 C]PK11195, in vivo increases in TSPO binding are associated with impairments in global cognition and memory (Hamelin et al, 2018;Kreisl et al, 2013), but also extend to domains that include visuospatial and language ability, and executive functioning, in addition to dementia severity and brain atrophy (Hamelin et al, 2018;Kreisl et al, 2013;Kreisl et al, 2016;Suridjan et al, 2015). However, some studies demonstrate no such correlations with the ADAS-Cog or MMSE (Yasuno et al, 2008;Yasuno et al, 2012) upregulated cortical tracer retention when compared to healthy controls, especially in the temporal lobe Yasuno et al, 2012), and others showing no such significant differences (Knezevic et al, 2017;Kreisl et al, 2013).…”

“…While many second-generation TSPO tracers have been discovered, we will cover only those that have been most widely used in humans and specifically in AD or MCI. In AD patients, yearly average increases in TSPO binding that ranged from 2.5 to 7.7% were shown using [ 11 C]PBR28 (Kreisl et al, 2016), whilst for [ 18 F]DPA-714 an elevated annual change of 13.2% in tracer binding was displayed (Hamelin et al, 2018). The temporal pattern of neuroinflammation over the course of the AD has also been well-characterised through longitudinal investigations.…”

“…The temporal pattern of neuroinflammation over the course of the AD has also been well-characterised through longitudinal investigations. In AD patients, yearly average increases in TSPO binding that ranged from 2.5 to 7.7% were shown using [ 11 C]PBR28 (Kreisl et al, 2016), whilst for [ 18 F]DPA-714 an elevated annual change of 13.2% in tracer binding was displayed (Hamelin et al, 2018).…”

NG2 glia are required for maintaining microglia homeostatic state

“…Microglia play vital roles in brain health and diseases. Depending on their cellular state, microglia exert distinct functions in different disease contexts (Sousa et al, ) and even in different stages of the same disease (Hamelin et al, ; Keren‐Shaul et al, ). Understanding the mechanisms of the transition between different microglia cellular states is essential for developing therapeutic approaches against neurodegenerative diseases.…”

“…Microglia play vital roles in brain health and diseases. Depending on their cellular state, microglia exert distinct functions in different disease contexts (Sousa et al, 2018) and even in different stages of the same disease (Hamelin et al, 2018;Keren-Shaul et al, 2017).…”