Imaging pathological tau in atypical parkinsonisms: A review

Abstract

Atypical parkinsonisms (APs) are a group of diseases linked to tau pathology. These include progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). In the initial stages, these APs may have similar clinical manifestations to Parkinson's disease (PD) and other parkinsonisms: bradykinesia, postural instability, tremor, and cognitive decline. Because of this, one major hurdle is the accurate early diagnosis of APs. Recent advances in positron emission tomography (PET) radiotracer development have allowed for targeting pathological tau in Alzheimer's disease (AD). Currently, work is still in progress for identifying a first-in-class radiotracer for imaging tau in APs. In this review, we evaluate the literature on in vitro and in vivo testing of current tau PET radiotracers in APs. The tau PET tracers assessed include both first-generation tracers ([18F]AV-1451, [18F]FDDNP, [18F]THK derivatives, and [11C]PBB3) and second-generation tracers ([18F]PM-PBB3, [18F]PI-2620, [18F]RO-948, [18F]JNJ-067, [18F]MK-6240, and [18F]CBD-2115). Concerns regarding off-target binding to cerebral white matter and the basal ganglia are still prominent with first-generation tracers, but this seems to have been mediated in a handful of second-generation tracers, including [18F]PI-2620 and [18F]PM-PBB3. Additionally, these two tracers and [18F]MK-6240 show promising results for imaging PSP- and CBD-tau. Overall, [18F]AV-1451 is the most widely studied tracer but the mixed results regarding its efficacy for use in imaging AP-tau is a cause for concern moving forward. Instead, future work may benefit from focusing on the second-generation radiotracers which seem to have a higher specificity for AP-tau than those originally developed for imaging AD-tau.

Keywords: CBD; CBD, corticobasal degeneration; Neuroimaging; PET; PET, positron emission tomography; PSP; PSP, progressive supranuclear palsy; Parkinsonism; Parkinson’s disease; SPECT; SPECT, single-photon emission computerized tomography.

Fig. 1

Representation of the human MAPT gene and the tau isoforms produced through alternative splicing. A. The MAPT gene is found on chromosome 17 and contains 16 exons, three of which are subjected to alternative splicing. E2, E3, AND E10 undergo alternative splicing which results in six isoforms in the adult human brain. B. The six tau isoforms that exist differ in terms of both N-terminal inserts and C-terminal repeats, the latter of which confers the designation of 3R or 4R tau. Figure is reproduced from Didonna A. Tau at the interface between neurodegeneration and neuroinflammation. Genes Immun 21: 288–300, 2020.

Fig. 2

Schematic of the process of neurofibrillary tangle (NFT) formation. Under normal conditions, tau acts as a microtubule-associated protein. Aggregation-prone pathological tau becomes hyper-phosphorylated, ultimately leading to microtubule destabilization through dissociation. Soluble phosphorylated tau proteins come together to form NFTs. Figure is reproduced from Balasa, Adrian & Chircov, Cristina & Grumezescu, Alexandru. (2020). Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview. Biomedicines. 8. 421. https://doi.org/10.3390/biomedicines8100421.

Fig. 3

Structural classification of tauopathies based on cryogenic electron microscopy (cryo-EM). Tau residues are depicted by colouration and listed from R1-R4. Tau filament composition is classified according to 1) composition by isoforms and 2) core layer structure. Among the 3R/4R tauopathies, the CTE tau fibril is distinct from AD, FBD, FDD, and PART fibrils. Similarly, the 4R tauopathies are divided into two classes with either three-layered core regions (PSP, GPT, and GGT) or four-layered core regions (CBD, ARTAG, and AGD). AD = Alzheimer’s disease, FBD = familial British dementia, FDD = familial Danish dementia, PART = primary age-related tauopathy, CTE = chronic traumatic encephalopathy, PiD = Pick’s disease, CBD = corticobasal degeneration, AGD = argyrophilic grain disease, ARTAG = ageing-related tau astrogliopathy, PSP = progressive supranuclear palsy, GGT = globular glial tauopathy, GPT = GGT-PSP-tau.  Figure is modified from Shi Y, Zhang W, Yang Y, Murzin AG, Falcon B, Kotecha A, van Beers M, Tarutani A, Kametani F, Garringer HJ, Vidal R, Hallinan GI, Lashley T, Saito Y, Murayama S, Yoshida M, Tanaka H, Kakita A, Ikeuchi T, Robinson AC, Mann DMA, Kovacs GG, Revesz T, Ghetti B, Hasegawa M, Goedert M, Scheres SHW. Structure-based classification of tauopathies. Nature. 2021 Oct;598(7880):359–363. https://doi.org/10.1038/s41586-021-03911-7. Epub 2021 Sep 29. PMID: 34588692; PMCID: PMC7611841.

Fig. 4

Representative [18F]-APN-1607 (or [18F]PM-PBB3) PET images superimposed on T1 MRI in PSP patients versus PD and controls. Compared to PD and HC, patients with PSP display heightened tracer binding in the midbrain, basal ganglia, subcortical nuclei, and brainstem. The colour scale represents standardized uptake value ratio (SUVR) with cerebellar cortex as the reference regions. PSP-RS = progressive supranuclear palsy-Richardson’s syndrome, PD = Parkinson’s disease, HC = healthy controls. Figure modified from Li L, Liu FT, Li M, Lu JY, Sun YM, Liang X, Bao W, Chen QS, Li XY, Zhou XY, Guan Y, Wu JJ, Yen TC, Jang MK, Luo JF, Wang J, Zuo C; Progressive Supranuclear Palsy Neuroimage Initiative (PSPNI). Clinical Utility of 18F-APN-1607 Tau PET Imaging in Patients with Progressive Supranuclear Palsy. Mov Disord. 2021 Oct;36(10):2314–2323. https://doi.org/10.1002/mds.28672. Epub 2021 Jun 5. PMID: 34089275.

Fig. 5

Representative [18F]PI-2620 distribution volume ratio (DVR) binding maps superimposed on standard MRI imaging templates for all disease cohorts. Differential tracer binding effectively distinguishes study groups. Binding is highest in the globus pallidus for PSP groups. PSP-RS = progressive supranuclear palsy-Richardson’s syndrome, PSP-non-RS = progressive supranuclear palsy-non-Richardson’s syndrome, a-syn = alpha-synucleinopathies, AD = Alzheimer’s disease, HC = healthy controls. Figure is reproduced from Brendel M, Barthel H, Van Eimeren T, Marek K, Beyer L, Song M, Palleis C, Gehmeyr M, Fietzek U, Respondek G, Sauerbeck J, Nitschmann A, Zach C, Hammes J, Barbe MT, Onur O, Jessen F, Saur D, Schroeter ML, Rumpf JJ, Rullmann M, Schildan A, Patt M, Neumaier B, Barret O, Madonia J, Russell DS, Stephens A, Roeber S, Herms J, Bötzel K, Classen J, Bartenstein P, Villemagne V, Levin J, Höglinger GU, Drzezga A, Seibyl J, Sabri O. Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy. JAMA Neurol 77: 1408–1419, 2020.