PET Imaging of Neuroinflammation in Alzheimer's Disease

Abstract

Neuroinflammation play an important role in Alzheimer's disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with Alzheimer's disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer's disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer's disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable in vivo brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.

Keywords: Alzheimer’s disease; TSPO (18 kDa translocator protein); amyloid (A) 42; astrocyte; microglia; neuroinflammation; positron emission tomography (PET); tau.

Figure 1

Cellular location of emerging neuroinflammation imaging targets. (A, B) The RNA expression of TSPO, CSF1R, P2RX7, and P2RY12 in mouse (A) and human (B) brain [based on RNA-Seq data (189, 190)]. FPKM, fragments per kilobase of transcript per million mapped reads. Reproduced from https://www.brainrnaseq.org and (189, 190) with permission. (C) Representative transverse planes of [¹¹C]GW2580 and [¹¹C]CPPC SUV 60-120min images of a monkey brain superimposed on the monkey’s own MR images at baseline and with a homologous blocker treatment. (D, E) Time–radioactivity curves of [¹¹C]GW2580 and [¹¹C]CPPC in various brain regions obtained from corresponding PET images. FCTX, frontal cortex; CS, centrium semi-ovale. Reproduced from (64) with permission from Sage Publication. (F, G) Tau lesion-associated microglial TSPO was more sensitively captured by in vivo positron emission tomography (PET) imaging with [¹⁸F]FEBMP than [¹¹C]PK11195. T2 magnetic resonance imaging (MRI) images and PET images with [¹⁸F]FEBMP and [¹¹C]PK11195 in non-transgenic, and PS19 mice with less and severe brain atrophy at 9 months of age (F). Time course of hippocampus (Hip)-to-striatum (ST) ratios of radioactivity and binding potential (BPnd) calculated by simplified reference tissue model with striatum as reference tissue showing significantly increased [¹⁸F]FEBMP but not [¹¹C]PK11195 signal in PS19 compared with non-transgenic mice (G). Reproduced from (57) with permission from Sage Publication.

Figure 2

Biological parametric mapping (BPM) correlation between [¹¹C]BU99008 and [¹⁸F]florbetaben binding in (A) all cognitively impaired (CI) subjects and in (B) Aβ-positive cognitively impaired subjects at a cluster threshold of p < 0.05 with an extent threshold of 50 voxels. These BPM are T maps describing the strength of the voxel-wise correlations between binding of the two radioligands represented in a common brain space. (C) Dot plot demonstrating the regional [¹¹C]BU99008 total volumes of distribution (Vt) using two-tissue compartmental models in Aβ-positive cognitively impaired subjects (purple filled circle), Aβ-negative CI subjects (purple open circle), and healthy controls (HC, green triangle). “Brain” refers to the composite cortex, combining all the major cortical regions. *p < 0.05, uncorrected. Reproduced from (176) with permission from Springer Nature. (D, E) Voxel-level correlation between [¹⁸C]PBR28, [¹⁸F]florbetapir, and [¹⁸F]flutemetamol in the patients with mild cognitive impairment and Alzheimer’s disease who were positive for all three tracers. (D) Voxel-level correlations between microglial activation assessed by using [¹⁸C]PBR28 and tau aggregation assessed by using [¹⁸F]florbetapir. (E) Voxel-level correlations between microglial activation assessed by using [¹⁸C]PBR28 and amyloid deposition assessed by using [¹⁸F]flutemetamol. Reproduced from (69) with permission from Oxford University Press.