Tracking neuroinflammation in Alzheimer's disease: the role of positron emission tomography imaging.

Eduardo Rigon Zimmer,Andréa Lessa Benedet,John Breitner,Antoine Leuzy,Pedro Rosa-Neto,Serge Gauthier

doi:10.1186/1742-2094-11-120

Abstract

Alzheimer’s disease (AD) has been reconceptualized as a dynamic pathophysiological process, where the accumulation of amyloid-beta (Aβ) is thought to trigger a cascade of neurodegenerative events resulting in cognitive impairment and, eventually, dementia. In addition to Aβ pathology, various lines of research have implicated neuroinflammation as an important participant in AD pathophysiology. Currently, neuroinflammation can be measured in vivo using positron emission tomography (PET) with ligands targeting diverse biological processes such as microglial activation, reactive astrocytes and phospholipase A2 activity. In terms of therapeutic strategies, despite a strong rationale and epidemiological studies suggesting that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the prevalence of AD, clinical trials conducted to date have proven inconclusive. In this respect, it has been hypothesized that NSAIDs may only prove protective if administered early on in the disease course, prior to the accumulation of significant AD pathology. In order to test various hypotheses pertaining to the exact role of neuroinflammation in AD, studies in asymptomatic carriers of mutations deterministic for early-onset familial AD may prove of use. In this respect, PET ligands for neuroinflammation may act as surrogate markers of disease progression, allowing for the development of more integrative models of AD, as well as for the measuring of target engagement in the context of clinical trials using NSAIDs. In this review, we address the biological basis of neuroinflammatory changes in AD, underscore therapeutic strategies using anti-inflammatory compounds, and shed light on the possibility of tracking neuroinflammation in vivo using PET imaging ligands.

Highlights

We describe some of the most important insights provided by positron emission tomography (PET) imaging agents targeting neuroinflammation in Alzheimer’s disease (AD), revise the evidence provided by preclinical and clinical trials using non-steroidal anti-inflammatory drug (NSAID), and underscore the role that PET biomarkers may play in terms of the development of novel therapeutic strategies, monitoring of disease progression, as well as biomarkers of target engagement
Though the failure of clinical trials using NSAIDs has been ascribed to timing of intervention, duration of treatment, dosage, and drug class, the underlying problem remains the lack of consensus surrounding whether neuroinflammation causes neurodegeneration in AD, or is a protective response to primary pathological processes. These findings offer only limited data making it difficult to evaluate the therapeutic utility of NSAIDs in AD
Potential role of PET in monitoring responsivity to anti-inflammatory therapies in AD The literature suggests that neuroinflammation occurs early in the course of AD, likely as a response to Aβ and pathologically phosphorylated forms of tau, and that early use of NSAIDs may prove effective in individuals with minimal AD pathology and/or carriers of the apolipoprotein E (APOE) ε4 allele

Summary

Introduction

Research advances over the past decade have led to the reconceptualization of Alzheimer’s disease (AD) as a progressive pathophysiological process in which the accumulation of amyloid-beta (Aβ) is thought to trigger a cascade of neurodegenerative events, including the intracellular accumulation of hyperphosphorylated tau [1,2].From a clinical standpoint, AD is viewed as a continuum, comprising a clinically silent phase [3] (characterized by cognitive normality in the presence of AD pathology), a prodromal mild cognitive impairment (MCI) phase [4]— during which individuals exhibit cognitive dysfunction, but of insufficient severity to meet criteria for dementia— and, a dementia phase [5].In addition to the pathological hallmarks of AD, Aβ and hyperphosphorylated tau, a growing body of literature points to neuroinflammation as an important player in the pathogenesis of AD. In keeping with the biphasic hypothesis of neuroinflammation, additional studies have shown activated microglia to release neuroprotective cytokines such as transforming growth factor-β1, and there may be worsening of AD pathology following microglial inhibition [59].

Results

Conclusion