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

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.

Figure 1

PET biological targets for measuring neuroinflammation in AD. Amyloid-beta (Aβ)_1–42 and neurofibrillary tangles (NFTs) - the classic hallmarks of Alzheimer’s disease (AD) - can trigger neuroinflammatory changes, which induces the release of complement factors, cytokines and others inflammatory factors. Positron emission tomography (PET) uses biological surrogates for measuring neuroinflammation. Microglial activation is estimated by the expression of the 18-kDa translocator protein (TSPO), which is mainly found on the outer mitochondrial membrane of the microglial cells under inflammatory conditions. Monoamine oxidase-B (MAO-B), an enzyme usually located on the outer mitochondrial membrane of astrocytes, is proposed as an index of reactive astrocytosis. Radiolabeled arachidonic acid (AA), a phospholipid present in the cell membrane and cleaved by phospholipase A2 (PLA₂), can estimate the AA metabolism. AA is the precursor of eicosanoids - prostaglandins and leukotrienes - which are potent mediators of the inflammatory response.

Figure 2

Illustrative [¹¹C](R)PK11195 PET imaging. Representative [¹¹C](R)PK11195 images in a healthy control (age 65 years) and in a patient with Alzheimer’s disease (AD) dementia (age 68 years). The brain axial view shows increased [¹¹C](R)PK11195 binding in the AD subject (yellow-red spots) in comparison to the healthy control subject. Standardized uptake value (SUV) defined by the ratio of brain to reference region (supervised reference tissue extraction) radioactivity was used for estimating [¹¹C](R)PK11195 binding. Image provided by Dr Paul Edison of the Division of Brain Sciences, Department of Medicine, Imperial College London, UK.

Figure 3

Illustrative [¹¹C]PBR28 PET imaging. Representative [¹¹C]PBR28 images in a healthy control (age 61 years) and in a patient with Alzheimer’s disease (AD) dementia (age 57 years). The brain axial view show increased [¹¹C]PBR28 binding in the AD subject (yellow-red spots) in comparison to the healthy control subject. Of note, both subjects are high-affinity binders. Distribution volume corrected for free fraction of the radioligand in plasma (V_T/f_P) was used for estimating [¹¹C]PBR28 binding values. Image provided by Drs William Kreisl and Robert Innis of the Molecular Imaging Branch, National Institute of Mental Health-NIMH, USA.