Tauopathies are a class of neurodegenerative diseases associated with the pathological aggregation of the tau protein in the brain. Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer’s disease (AD) are common tauopathies. Typical pathological characteristics of PSP include tufted astrocytes, coiled bodies, and globose tangles. Conversely, CBD is pathologically characterized by astrocytic plaques and achromatic and ballooned neurons. Both PSP and CBD are four-repeat tauopathies and show overlapping pathological characteristics. Ultrastructurally, tau proteins in PSP and CBD form straight filaments, while those in AD form paired helical filaments. The clinical characteristics of corticobasal syndrome (CBS) include asymmetric motor symptoms (i.e., Parkinsonism, dystonia, and myoclonus) and cortical dysfunction. The CBS phenotypes include CBD, PSP, and AD. Because of the overlapping clinical symptoms of these diseases, their differential diagnosis is often difficult (Litvan et al., 2003 Osaki et al., 2004; Day et al., 2017).

Positron emission tomography (PET) has been used for the visualization of abnormal protein deposits such as amyloid-β (Klunk et al., 2004), tau, and α-synuclein (Kikuchi et al., 2010). The first generation of tau probes include ¹¹C-PBB3 (Maruyama et al., 2013), ¹⁸F-AV-1451 (¹⁸F-T807) (Chien et al., 2013; Johnson et al., 2016; Smith et al., 2017a,b), and ¹⁸F-THK5351 (Harada et al., 2016; Kikuchi et al., 2016; Brendel et al., 2017; Ishiki et al., 2017; Okamura et al., 2018; Ezura et al., 2019). ¹⁸F-THK5351 (Harada et al., 2016 Brendel et al., 2017; Ishiki et al., 2017) was originally developed to visualize tau deposits in the AD brain. However, ¹⁸F-THK5351 shows high binding affinity to monoamine oxidase B (MAO-B), which enables astrocytosis visualization in the human brain (Harada et al., 2018; Ishiki et al., 2018; Tago et al., 2019). MAO-B inhibitor prescription has reduced ¹⁸F-THK5351 retention on average by 36.7–51.8% (Ng et al., 2017). In several neurodegenerative diseases, one of the prominent changes is reactive astrogliosis associated with the accumulation of misfolded proteins (Leyns and Holtzman, 2017). Therefore, the spatial information of ¹⁸F-THK5351 binding is expected to be useful for the early and differential diagnosis of tauopathies and disease progression monitoring. Tau PET studies have been performed in patients with CBS, PSP, and AD (Dani et al., 2016; Coakeley and Strafella, 2017). However, comparative study of these three tauopathies have never been performed at a single center. In the present study, we aim to evaluate the clinical utility of tau deposits and MAO-B PET imaging using ¹⁸F-THK5351 for the differential diagnosis and clinical assessment of tauopathies.

Clinical and pathological overlaps between CBS and PSP (Armstrong et al., 2013) make the differential diagnosis of CBS and PSP difficult. Thus, several studies have been conducted to explore novel neuroimaging markers (Niethammer et al., 2014; Fujioka et al., 2021). ¹⁸F-THK5351 PET showed the characteristic spatial pattern of tracer distribution in CBS, PSP, and AD. High ¹⁸F-THK5351 uptake was observed in the precentral and postcentral gyri; midbrain; and inferior temporal, fusiform, and parahippocampal gyri of the patients with CBS, PSP, and AD, respectively (Figure 1). These spatial patterns of ¹⁸F-THK5351 retention were consistent with the distribution of gliosis in the postmortem analysis of the brains of the patients with CBD, PSP, and AD (Yoshida, 2014; Harada et al., 2018). The precentral gyrus, where patients with CBS showed the highest retention of ¹⁸F-THK5351, was the best region for the differentiation between CBS and PSP or AD (Figure 2A). Furthermore, the inferior temporal gyrus, where a high density of paired helical filament-tau and associated gliosis have been observed in AD (Harada et al., 2018), was a good region to differentiate AD from PSP and CBS, because patients with AD showed higher retention of ¹⁸F-THK5351 in the region compared to those with CBS and PSP (Figure 2B). Thus, the bivariate ¹⁸F-THK5351 SUVR values in these two regions clearly distinguished the patients among three groups (Figure 2C). Our results suggest that tau deposits and MAO-B imaging by ¹⁸F-THK5351 PET is a valuable method for the differential diagnosis of tauopathies. Moreover, one of the advantages of this study is the consistent acquisition of PET images in CBS, PSP, and AD patients in a single center, which minimizes data variability.

In this study, we additionally evaluated the relationship between the clinical parameters and SUVR values of ¹⁸F-THK5351. ¹⁸F-THK5351 retention was associated with cognitive parameters in the patients with CBS and PSP (Figure 3), while no significant association was observed between ¹⁸F-THK5351 retention and motor parameters. These results differed from the previous results in PSP (Brendel et al., 2017) and in CBS (Kikuchi et al., 2016). In the prior study, significant relation between the clinical motor severity and ¹⁸F-THK5351 retention in midbrain was demonstrated in the patients with PSP (Brendel et al., 2017). Contrarily, all of patients with PSP in the present study met the criteria for the Richardson syndrome type and were administrated with L-dopa (500 ± 249 mg). Supposedly, dopamine-replenishing therapy may somehow alleviate motor dysfunction in PSP and obscure the relationship between the clinical motor and imaging parameters. Further research is needed to clarify the correlations between clinical motor severities and ¹⁸F-THK5351 retention in more patients with PSP with various subtypes and stages. On the other hand, our previous report failed to elucidate a meaningful relationship between clinical severities including cognitive dysfunction and ¹⁸F-THK5351 retention in patients with CBS because of the very limited small sample size (Kikuchi et al., 2016). ¹⁸F-THK5351 PET may be useful to evaluate disease stages in CBS.

Several limitations are noted in this study. Firstly, our sample size was relatively small. Secondly, there was the absence of neuropathological confirmation of clinical diagnosis for all the cases. Thirdly, the current PET data are difficult to interpret due to the non-selective binding properties of ¹⁸F-THK5351 to MAO-B and tau. However, because of the substantial reduction of ¹⁸F-THK5351 retention after the treatment with the MAO-B inhibitor (Ng et al., 2017), we consider that a majority of the tracer signals in ¹⁸F-THK5351 PET are derived from the binding to MAO-B (Ishiki et al., 2018). The elevation of MAO-B level is thought to reflect reactive astrogliosis caused by tau burden in the affected brain regions. Thus, ¹⁸F-THK5351 signals reflect a sequence of pathogenic process in tauopathies. In the future, selective PET tracers for MAO-B or four-repeat tau will clarify the association of tau protein accumulation and reactive astrocytosis in the PSP and CBD pathogenesis.

In conclusion, the spatial pattern of ¹⁸F-THK5351 PET signals adequately coincided with the disease-related regions and was a good diagnostic marker in neurodegenerative tauopathies. Considering the high binding affinity of THK5351 to tau deposits and MAO-B, ¹⁸F-THK5351 PET imaging is a potentially useful technique in the differential diagnosis of tauopathies.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of Tohoku University Hospital (approval number, 2016-2-266). The patients/participants provided their written informed consent to participate in this study.

AK and NO designed the experiments. ME, AK, and NO analyzed and interpreted the data. ME, AK, NO, and TH wrote the manuscript. All authors contributed to the data collection and analysis and reviewed the manuscript.

NO, SF, and YK declare that this study received funding from GE Healthcare, Clino Ltd. and Sumitomo Electric Industries. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

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