Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples. Fluorescence microscopy demonstrated intense labelling of non-ghost and ghost tangles with PBB3 and AV-1451, while dystrophic neurites were more clearly detected by PBB3 in brains of Alzheimer’s disease and diffuse neurofibrillary tangles with calcification, characterized by accumulation of all six tau isoforms. Correspondingly, partially distinct distributions of autoradiographic labelling of Alzheimer’s disease slices with ¹¹C-PBB3 and ¹⁸F-AV-1451 were noted. Neuronal and glial tau lesions comprised of 4-repeat isoforms in brains of progressive supranuclear palsy, corticobasal degeneration and familial tauopathy due to N279K tau mutation and 3-repeat isoforms in brains of Pick’s disease and familial tauopathy due to G272V tau mutation were sensitively detected by PBB3 fluorescence in contrast to very weak AV-1451 signals. This was in line with moderate ¹¹C-PBB3 versus faint ¹⁸F-AV-1451 autoradiographic labelling of these tissues. Radioligand binding to brain homogenates revealed multiple binding components with differential affinities for ¹¹C-PBB3 and ¹⁸F-AV-1451, and higher availability of binding sites on progressive supranuclear palsy tau deposits for ¹¹C-PBB3 than ¹⁸F-AV-1451. Our data indicate distinct selectivity of PBB3 compared to AV-1451 for diverse tau fibril strains. This highlights the more robust ability of PBB3 to capture wide-range tau pathologies.

Purpose Pathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (Aβ) levels in the brain early in Alzheimer’s disease (AD). The time course and relationships between astrocytosis and Aβ deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis. Methods PET imaging with the amyloid plaque tracer ¹¹C-AZD2184 and the astroglial tracer ¹¹C-deuterium-L-deprenyl (¹¹C-DED) was carried out in APPswe mice aged 6, 8–15 and 18–24 months (4–6 animals/group) and in wild-type (wt) mice aged 8–15 and 18–24 months (3–6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for Aβ deposition and astrocytosis by in vitro autoradiography using ³H-AZD2184, ³H-Pittsburgh compound B (PIB) and ³H-L-deprenyl and immunostaining performed with antibodies for Aβ₄₂ and glial fibrillary acidic protein (GFAP) in sagittal brain sections. Results ¹¹C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18–24 months than in age-matched wt mice. Cortical and hippocampal ¹¹C-DED PET binding was significantly higher at 6 months than at 8–15 months or 18–24 months in APPswe mice, and it was also higher than at 8–15 months in wt mice. In vitro autoradiography ³H-AZD2184 and ³H-PIB binding confirmed the in vivo findings with ¹¹C-AZD2184 and demonstrated age-dependent increases in Aβ deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in ³H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more Aβ₄₂ deposits in the cortex and hippocampus and more GFAP⁺ reactive astrocytes in the hippocampus at 18–24 months than at 6 months in APPswe mice. Conclusion The findings provide further in vivo evidence that astrocytosis occurs early in AD, preceding Aβ plaque deposition.

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.

Imaging fibrillar amyloid-β deposition in the human brain in vivo by positron emission tomography has improved our understanding of the time course of amyloid-β pathology in Alzheimer’s disease. The most widely used amyloid-β imaging tracer so far is ¹¹C-Pittsburgh compound B, a thioflavin derivative but other ¹¹C- and ¹⁸F-labelled amyloid-β tracers have been studied in patients with Alzheimer's disease and cognitively normal control subjects. However, it has not yet been established whether different amyloid tracers bind to identical sites on amyloid-β fibrils, offering the same ability to detect the regional amyloid-β burden in the brains. In this study, we characterized ³H-Pittsburgh compound B binding in autopsied brain regions from 23 patients with Alzheimer's disease and 20 control subjects (aged 50 to 88 years). The binding properties of the amyloid tracers FDDNP, AV-45, AV-1 and BF-227 were also compared with those of ³H-Pittsburgh compound B in the frontal cortices of patients with Alzheimer's disease. Saturation binding studies revealed the presence of high- and low-affinity ³H-Pittsburgh compound B binding sites in the frontal cortex (K_d1: 3.5 ± 1.6 nM; K_d2: 133 ± 30 nM) and hippocampus (K_d1:5.6 ± 2.2 nM; K_d2: 181 ± 132 nM) of Alzheimer's disease brains. The relative proportion of high-affinity to low-affinity sites was 6:1 in the frontal cortex and 3:1 in the hippocampus. One control showed both high- and low-affinity ³H-Pittsburgh compound B binding sites (K_d1: 1.6 nM; K_d2: 330 nM) in the cortex while the others only had a low-affinity site (K_d2: 191 ± 70 nM). ³H-Pittsburgh compound B binding in Alzheimer's disease brains was higher in the frontal and parietal cortices than in the caudate nucleus and hippocampus, and negligible in the cerebellum. Competitive binding studies with ³H-Pittsburgh compound B in the frontal cortices of Alzheimer's disease brains revealed high- and low-affinity binding sites for BTA-1 (K_i: 0.2 nM, 70 nM), florbetapir (1.8 nM, 53 nM) and florbetaben (1.0 nM, 65 nM). BF-227 displaced 83% of ³H-Pittsburgh compound B binding, mainly at a low-affinity site (311 nM), whereas FDDNP only partly displaced (40%). We propose a multiple binding site model for the amyloid tracers (binding sites 1, 2 and 3), where AV-45 (florbetapir), AV-1 (florbetaben), and Pittsburgh compound B, all show nanomolar affinity for the high-affinity site (binding site 1), as visualized by positron emission tomography. BF-227 shows mainly binding to site 3 and FDDNP shows only some binding to site 2. Different amyloid tracers may provide new insight into the pathophysiological mechanisms in the progression of Alzheimer’s disease.

The nicotinic receptors (nAChRs), which play a critical role in cognitive function, are impaired early in the course of Alzheimer's disease (AD). We have previously demonstrated that amyloid-β (Aβ) assemblies bind to α7 nAChRs and form complexes in AD brain, suggesting that this cooperative process may contribute to disruption of synaptic function in AD. In the current study, we further characterized the interaction between different nAChR subtypes and fibrillar Aβ by binding assays in postmortem brain from AD and control cases using a wide range of drugs with different molecular targets, including selective nAChR subtype agonists, and the amyloid ligand Pittsburgh compound B (PIB) that binds with high (nanomolar) affinity to fibrillar Aβ. The α7 nAChR agonists varenicline and JN403, but not the α4β2 nAChR agonist cytisine, increased the 3H-PIB binding in autopsy tissue homogenates from AD and control frontal cortex. This effect was blocked in the presence of the α7 nAChR antagonists methyllycaconitine, α-bungarotoxin, and mecamylamine, but not by the α4β2 nAChR antagonist dihydro-β-erythroidine. Increases in (3)H-PIB binding evoked by varenicline and JN403 were also prevented by pre-incubation with another amyloid ligand, BF-227. The acetylcholinesterase inhibitor and allosteric nAChR modulator galantamine as well as the N-methyl-d-aspartate receptor blocker memantine did not significantly alter (3)H-PIB binding levels in AD brain. The present findings further support a specific interaction between fibrillar Aβ and α7 nAChRs in the brain, suggesting that treatment with α7 nAChR stimulatory drugs can modulate Aβ/α7 nAChR pathogenic signaling mechanisms in AD brain.