The methodology for this study was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) guidelines. ¹²

Study Selection

Using an internet‐based software called Covidence (www.covidence.org), we conducted study screening and data extraction (Fig. 1). Initial screening included abstract and title reviews. Following this, eligible studies underwent full‐text reviews against our inclusion and exclusion criteria. Finally, unanimously approved studies were moved into data extraction.

The included studies meet the following criteria: (1) published in English; (2) involve human tau PET imaging; (3) assess tau PET tracer binding; (4) compare PD, PSP, CBD, or MSA patients to HC or APs to PD; and (5) report tau PET tracer binding as mean ± SD in at least one ROI.

Our first main finding of this meta‐analysis was that all tau PET tracers assessed demonstrate trends towards higher binding in AP patients (i.e., PSP, and CBD) when compared to HC and PD. This is a trend that we would expect to see because pathological tau accumulates in patients with these diseases. ⁴⁰ , ⁴¹ , ⁴² Consistent with the literature, we found that the second‐generation tracer [¹⁸F]PI‐2620 outperforms first‐generation tracers for both PSP and CBD. ³³ , ³⁴ , ³⁵ , ³⁷ , ⁴³ The larger effect sizes and reduced heterogeneity (i.e. lower I² values) in the analyses when using this tracer demonstrates increased reliability for this data and supports the use of [¹⁸F]PI‐2620 as a potential imaging biomarker for these tauopathies. Interestingly, when comparing PD patients to HC, we found opposing trends for the first‐generation tracer [¹⁸F]AV‐1451 and the second‐generation tracer [¹⁸F]PM‐PBB3. The trend towards higher binding to HC with [¹⁸F]AV‐1451 seems to be predominantly driven by binding to the SN. This tracer is reported to observe extensive off‐target binding to the SN, neuromelanin, and MAO‐B. ¹³ This off‐target binding could be the main reason for the trend observed with this tracer but there is also the issue of extensive SN degeneration in late‐stage PD patients. ⁴⁴ , ⁴⁵ Data for [¹⁸F]PM‐PBB3 tracer binding to the SN was insufficient for the present model, but recent literature states that this tracer has mediated many of the off‐target binding issues observed with first‐generation tracers, including off‐target binding to the SN. ⁴⁶ , ⁴⁷

Our second finding was that when comparing parkinsonisms head‐to‐head, there was significantly higher binding to PSP patients over PD when using the first‐generation tracer [¹⁸F]AV‐1451. There was only sufficient data to conduct this group comparison with one tracer but these results show that despite the limitations of using [¹⁸F]AV‐1451, this tracer is still able to differentiate PSP from PD patients using tau binding values. In particular, the GP is the ROI that presents with the largest SMD in tracer binding and this has been one of the regions cited in the literature as the most severely affected in PSP patients. ⁴⁸ Although there was insufficient data to conduct this group comparisons with the other tracers, recent studies have provided evidence that some second‐generation tracers can effectively distinguish PD from APs. In their large‐scale, multi‐site study, Brendel et al ³⁷ provided evidence for the use of [¹⁸F]PI‐2620 in differential diagnosis of PSP from other neurodegenerative diseases, including PD. Here, the researchers cited the GP internus (GPi) as the region with the strongest differences between PSP and other neurodegenerative diseases.

Our third finding was that the ROIs that consistently presented with the largest effect sizes in the pathological groups were the subcortical structures. Reviews of AP neuropathology have cited the basal ganglia as the most severely affected region for both PSP and CBD. This part of the brain observes extensive neurodegeneration and tau accumulation throughout disease progression. In our analysis, we observe large effect size values particularly for the GP. The main function of the GP is the control of voluntary movement; that is, it facilitates the control of conscious and voluntary movements. ⁴⁹ , ⁵⁰ , ⁵¹ Hence, the extensive accumulation of tau in this region, particularly for PSP and CBD patients explains the complex motor symptoms observed in these patients. The symptomology for APs is quite heterogenous and this is thought to be a direct link to differential patterns of tau accumulation. Although the patterns of tau deposits may vary, the GP seems to be one of the most consistently affected regions and could be a good ROI to serve as a means for differential diagnosis of PSP and CBD from other parkinsonisms.

Finally, our meta‐regression analyses revealed interesting points of consideration for future in vivo studies with these tau PET tracers. The effect moderator patterns for second‐generation tracers were in line with what we expected to see. For example, with longer PD disease durations, we expected to see a stronger correlation with increased binding to PD over HC and this was indeed the case with [¹⁸F]PM‐PBB3. Similarly, with more experience applying second‐generation tracers to this patient population it is expected that a trend in the data arises. Thus, the association between more recent publications and higher binding to CBD patients over HC with the [¹⁸F]PI‐2620 tracer is in line with our expectations. With regard to the first‐generation tracers' meta‐regression analyses, the [¹⁸F]AV‐1451 PSP‐PD group comparison revealed a significant association between PSP duration and binding to PSP over PD. Tau accumulates with advanced age under normal physiological conditions and especially with late‐stage parkinsonism patients, but this build‐up is evidently heightened in patients with late‐stage PSP.

Interestingly, we saw an unexpected trend for the [¹⁸F]THK‐5351 PSP‐HC and [¹⁸F]AV‐1451 CBD‐HC group comparisons. Here, we observed misleading positive correlation coefficients associated with disease duration, suggesting that with increased disease duration there was a trend towards decreased binding to the pathological groups. To our knowledge, there are no longitudinal studies with [¹⁸F]THK‐5351 PET in APs, but there is at least one conducted with [¹⁸F]AV‐1451 PET. ¹⁷ In this study, researchers reported [¹⁸F]AV‐1451 measures to increase over time, in line with disease duration, although these changes did not correlate with changes on the PSPRS. Therefore, we suggest that these unexpected correlations are potential artifacts and may be explained by the inconsistencies and off‐target binding issues observed with first‐generation tracers when applied to patients with APs.

As stated, tau accumulation tends to build up with advanced age which is referred to as primary age‐related tauopathy (or PART). For this reason, we included age as a moderator in our meta‐regression analysis. Typically, we would expect studies with older participants to have higher tau PET binding values and this is what we found with the [¹⁸F]AV‐1451 CBD‐HC and [¹⁸F]PM‐PBB3 PD‐HC group comparisons. For [¹⁸F]AV‐1451, advanced CBD age was associated with higher binding to CBD participants over HC. Similarly, the [¹⁸F]PM‐PBB3 tracer demonstrated that advanced PD age was associated with higher binding to PD patients over HC. Although [¹⁸F]AV‐1451's binding patterns in relation to patient age are consistent for the CBD‐HC comparison, we observed an opposite pattern arise for the PSP‐PD comparison. Here, contrary to what we expected, advanced PSP age was associated with decreased binding to PSP relative to PD. Typically, we would expect the opposite pattern due to the neuropathologic nature of PSP and the increased accumulation of tau in older PSP patients. As already noted above, these unexpected correlations seemed to be present solely for the first‐generation tracers which may, in part, be explained by their instability and reduced capacity for application with 4R‐tauopathies like PSP and CBD.

Overall, the percentage of female participants was a significant effect moderator for the [¹⁸F]AV‐1451 PD‐HC group comparison. The percentage of PD females in the [¹⁸F]AV‐1451 PD‐HC comparison correlated with decreased binding to PD relative to HC. The correlation coefficient for this effect was quite low (estimate = 0.021, 95% CI: 0.006 to 0.037, P = 0.008), indicating a weak correlation. Additionally, it has been reported that there are sex differences in off‐target binding with [¹⁸F]AV‐1451, where women demonstrate higher off‐target binding particularly to the skull/meninges. ⁵² No such study has been conducted using the other tracers but since there are some inconsistencies here, it would be interesting to explore this phenomenon further in future work.