Tau Imaging in Neurodegenerative Diseases Using Positron Emission Tomography

Abstract

Purpose of review: Abnormal accumulation of tau protein is the main hallmark of tauopathies and is closely associated with neurodegeneration and cognitive impairment, whereas the advance in PET imaging provides a non-invasive detection of tau inclusions in the brain. In this review, we discuss the potential of PET imaging as a biomarker in tauopathies, the latest development of novel tau tracers with new clinical information that has been disclosed, and the opportunities for improving diagnosis and designing clinical trials in the future.

Recent findings: In recent years, several first-generation tau PET tracers including [¹¹C]PBB3, [¹⁸F]THK-5117, [¹⁸F]THK-5351 and [¹⁸F]AV-1451 have been developed and succeeded in imaging neurofibrillary pathology in vivo. Due to the common off-target binding and subcortical white matter uptake seen in the first-generation tracers, several research institutes and pharmaceutical companies have been working on developing second-generation tau PET tracers which exhibit higher binding affinity and selectivity. Tau PET imaging is promising to serve as a biomarker to support differential diagnosis and monitor disease progression in many neurodegenerative diseases.

Keywords: Dementia; Neurodegeneration; Neurodegenerative diseases; Neurofibrillary tangles; Positron emission tomography; Tau.

Fig. 1

Tau protein isoforms in the human CNS. Six tau isoforms are present in the brain. N1 (green) and N2 (blue) are produced through the alternative splicing of exons 2 and 3 respectively. Exon 10 encodes the second aspect of the microtubule-binding repeat domain, R2 (red). Depending on the presence of the R2 domain, tau proteins are termed either 3R-tau or 4R-tau. (Figure used with permission from BMB Rep. Park SA, Ahn SI, Gallo J-M. Tau mis-splicing in the pathogenesis of neurodegenerative disorders. BMB Rep. 2016;49:405–413)

Fig. 2

[¹⁸F]FDDNP-PET images. Co-registered FDDNP-PET, PIB-PET and MRI scans of a patient with Alzheimer’s disease. Images in the left column: parietal lobe; images in the right column: temporal lobe. [16]. (Reprinted from J. Alzheimers Dis;26. Shin J, Kepe V, Barrio JR, Small GW. The merits of FDDNP-PET imaging in Alzheimer’s disease., Suppl 3:135–145. Copyright (2011), with permission from IOS Press”.) The publication is available at IOS Press through 10.3233/JAD-2011-0008

Fig. 3

[¹¹C]PBB3 PET images. [¹¹C]PBB3 parametric standardised uptake value ratio (SUVR) images compared with [¹¹C]PiB. [¹¹C]PBB3 shows tracer uptake in cortical areas in advanced AD patient. This research was originally published in JNM. Shah M, Catafau AM. Molecular Imaging Insights into Neurodegeneration: Focus on Tau PET Radiotracers. J. Nucl. Med. 2014;55:871–874. © SNMMI [21]

Fig. 4

PET images of THK compounds. [¹⁸F]AV-1451 (T807). [¹⁸F]AV-1451 (flortaucipir, T807) exhibited strong and selective binding affinity to PHF-tau on AD brain [13, 30]. With favourable pharmacokinetics and a binding pattern consistent with the Braak staging, [¹⁸F]AV-1451 is considered as the most promising PET candidates for tau imaging [21]. Clinical [¹⁸F]AV-1451 PET scans are demonstrated in Fig. 5. (THK-523 This research was originally published in Alzheimers Res. Ther) [29] (THK-5105 and THK-5351 Images courtesy of Prof. Nobuyuki Okamura, Tohoku University) (THK-5117 Reprinted by permission from Copyright Clearance Center. This research was originally published in Springer Nature, Eur. J. Nucl. Med. Mol. Imaging [28] Copyright (2015)

Fig. 5

[¹⁸F]AV-1451 PET images. [¹⁸F]AV-1451 showed an increased parieto-temporal uptake in an AD subject. Other figures presented the tracer retention in CBD, PSP and a cognitively healthy elderly subject. [Image courtesy of Prof. Oskar Hansson, The Swedish BIOFINDER Study. http://biofinder.se]

Fig. 6

PET images of second-generation Tau tracers. (APN-1607 Image courtesy of Kunju Lin, Chang Gung Memorial Hospital and Ming-Kuei Jang, APRINOIA Therapeutics.) (GTP1 Image courtesy of Sandra Sanabria Bohorquez, Genentech) (MK-6240 Image courtesy of Cyrille Sur, Merck.) (PI-2620 Reproduced from Leuzy, Antoine et al., Molecular Psychiatry, January 2019; https://www.nature.com/articles/s41380-018-0342-8; Creative Commons user licence http://creativecommons.org/licenses/by/4.0/) (RO-948 Image courtesy of Prof. Oskar Hansson)