Amyloid and Tau Positron Emission Tomography Imaging in Alzheimer's Disease and Other Tauopathies

Abstract

The detection and staging of Alzheimer's disease (AD) using non-invasive imaging biomarkers is of substantial clinical importance. Positron emission tomography (PET) provides readouts to uncover molecular alterations in the brains of AD patients with high sensitivity and specificity. A variety of amyloid-β (Aβ) and tau PET tracers are already available for the clinical diagnosis of AD, but there is still a lack of imaging biomarkers with high affinity and selectivity for tau inclusions in primary tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease (PiD). This review aims to provide an overview of the existing Aβ and tau PET imaging biomarkers and their binding properties from in silico, in vitro, and in vivo assessment. Imaging biomarkers for pathologic proteins are vital for clinical diagnosis, disease staging and monitoring of the potential therapeutic approaches of AD. Off-target binding of radiolabeled tracers to white matter or other neural structures is one confounding factor when interpreting images. To improve binding properties such as binding affinity and to eliminate off-target binding, second generation of tau PET tracers have been developed. To conclude, we further provide an outlook for imaging tauopathies and other pathological features of AD and primary tauopathies.

Keywords: Alzheimer’s disease; Amyloid-beta; affinities; binding sites; biomarker; positron emission tomography; tau.

FIGURE 1

Structural and binding properties of the tau protein. (A) Side view of [¹⁸F]PM-PBB3 binding to straight filaments in AD. (B) Images from cryo-EM showing paired helical filaments and straight filaments in AD with bound [¹⁸F]PM-PBB3 (+APN-1607) and without [¹⁸F]PM-PBB3 (–APN-1607). Reproduced from Shi et al. (2021b) with permission from Springer Nature. (C) Chemical structure of a tau protofibril, representing the four high-affinity binding sites for tau tracers. S1, S3, and S4 show the core sites, and S2 shows the surface site. Reproduced from Murugan et al. (2018) with permission from American Chemical Society.

FIGURE 2

Disease staging with the tau PET tracer [¹⁸F]AV1451 and autoradiography with [³H]PI-2620, [³H]MK6240, [³H]RO948, and [³H]JNJ067. (A) Representation of tau PET images labeled with flortaucipir ([¹⁸F]AV1451) for staging tau pathology. An increase in SUVR is visible in the cortex and subcortex from stage 0 to 4. Stage 0 represents tau levels of healthy controls. In stage 1, tau levels are elevated in medial temporal areas. [¹⁸F]AV1451 accumulates in extramedial temporal regions in stage 2, followed by higher SUVRs in the inferior and lateral temporal lobes in stage 3. Significantly increased uptake finally occurred in the neocortex in stage 4. Reproduced from Chen et al. (2021) with permission from Springer Nature. (B) Characteristics of the binding properties of the tau tracers [³H]PI-2620, [³H]MK6240, [³H]RO948, and [³H]JNJ067 in the medial temporal lobe of patients with AD, primary tauopathies and healthy controls. (R406W = FTD), here a MAPT R406W missense mutation leads to the formation of NTFs in the case of FTD with parkinsonism linked to chromosome 17 (FTDP-17), PCA, posterior cortical atrophy; PSP, progressive supranuclear palsy. Reproduced from Yap et al. (2021) with permission from Oxford press.