The principal result of this study is a widespread reduction in synaptic density in PSP-Richardson’s syndrome and amyloid-negative Corticobasal Syndrome (CBS) (which we define as Corticobasal Degeneration (CBD). This accords with post mortem estimates of synaptic loss in PSP and CBD, using synaptophysin immunohistochemistry (6), imaging of neurite density in PSP (41) and morphological studies of cortical dendrites in the closely related condition of frontotemporal lobe dementia (42). Indirect evidence of synaptic loss, from consequential reduction in metabolism, comes from [₁₈F]FDG PET changes in frontal, temporal and parietal lobes (43-46). However, PET imaging with the ligand [₁₁C]UCB-J provides direct evidence in vivo of severe and extensive loss of cortical and subcortical synapses, including areas of the brain that are minimally atrophic (47).

Progressive supranuclear palsy and corticobasal degeneration are progressive, with an average disease duration of five to eight years from symptom onset (48). In our clinically diagnosed CBD and PSP groups, the mean symptom duration at the time of PET was three and a half years, and our patients were likely to be approximately mid-way through their symptomatic disease course (not including a potentially long pre-symptomatic period). The median reduction of 20% (and maximal 50%) in [₁₁C]UCB-J binding observed in vivo compared to controls, is therefore in keeping with the predictions from post mortem data.

The synaptic loss observed in our study is widespread, extending beyond the regions that are arguably most associated with the diseases. In PSP, from post mortem studies, these include basal ganglia, thalamus, substantia nigra, premotor cortex, as well as the dentate nucleus and cerebellar white matter. In CBD, areas associated with the disease include cortex, thalamus, basal ganglia and brainstem, without cerebellar involvement (48-50). However, in our study the loss of synapses in PSP is global across the cortex, and not confined to the premotor and motor areas, and extends beyond the substantia nigra in the brainstem with pontine and medullary involvement. The loss of synapses in the cerebellum in PSP echoes pathological studies of tau distribution in this disease (49). Interestingly, the cerebellum was also markedly abnormal in CBD; although cerebellar atrophy and tau accumulation are not typical associations of CBD (49). Cerebellar synaptic loss in CBD may therefore represent cerebellar diaschisis in response to widespread cortical pathology and loss of cortico-cerebellar projections; a small minority of individuals in an amyloid-negative CBS cohort may have PSP as the underlying cause for their corticobasal syndrome, although this is unlikely to be sufficient to drive the group-wise effect.

Preclinical models of tauopathy suggest early synaptotoxicity with reduced plasticity and density (ii), in response to soluble oligomeric tau aggregates (12) and inflammation (51). The toxicity associated with tau pathology leading to synapse loss is complex and involves direct and indirect pathways (reviewed in Spires-Jones et al. 2014 (52)). Naturally occurring tau plays a role in synaptic function through modulating microtubule and axonal stability; disruptions to this machinery leads to prevention of the trafficking of essential components to synapses such as synaptic receptors (53) and mitochondria. Indeed, over-expression of tau interferes with mitochondria transport (54), and contributes to hyperexcitability of neurons and impaired calcium influx in transgenic mouse models (rTg4510) (55). The global nature of synaptic reduction suggests a more widespread pathology in the primary tauopathies of PSP and CBD beyond the areas that are histologically reported as harbouring a high tau burden such as the basal ganglia, thalamus, and brain stem (56). This may in part be explained by the global damage caused by oligomers of tau which are not easily visible on tau PET imaging or histology. In support of this are biochemical studies that report tau accumulation in both grey and white matter by western blot in PSP but not necessarily by immunohistochemistry (57).

We observed a significant correlation between synaptic loss and disease severity in PSP and amyloid-negative CBS. Synaptic loss correlates with cognitive impairment in another clinical tauopathy, Alzheimer’s disease (13,58), and preclinical models of this (59,60). Our in vivo PET results support the potential use of synaptic PET as a marker of disease and progression, but longitudinal data are required. Synaptic PET may support early stage clinical trials in PSP and CBS/CBD; it is encouraging in this latter respect that [₁₁C]UCB-J PET is sensitive to changes in synaptic density, for example in response to treatment with the synaptic modulator Saracatinib (61).

Our study has several limitations. Although the sample size is small, it is adequately powered in view of the large effect sizes predicted. However, subtler relationships with mild disease, progression or individual clinical features, or phenotypic variants of PSP and CBS, require larger studies. We acknowledge the potential for off-target binding, but preclinical data indicate very high correlations between UCB-J and synaptophysin, a marker of pre-synaptic vesicular density (25). Our diagnoses were clinical, without neuropathology, although the clinicopathological correlations of PSP-Richardson syndrome are very high, and in the absence of Alzheimer’s disease, the clinicopathological correlation of CBS with a 4R-tauopathy (CBD or PSP) is also high (18). Binding potentials for SV2A radioligands such as [₁₁C]UCB-J can be confounded by the use of concurrent medication that may bind to SV2A. We did not enrol any individuals taking levetiracetam or any member of this family of drugs that are SV2A-specific ligands (62). Previously reported studies using [₁₁C]UCB-J in disease have usually not commented on medications used by participants, however one study using this ligand in major depressive disorders reports exclusion of participants on psychotropic medications in the 2 months preceding PET scanning (63); whilst many of our PSP and CBD patients are on medications falling under the psychotropic umbrella, to our knowledge, none of these bind to SV2A.

Arterial blood sampling was not carried out in this study; we used reference tissue modelling to reduce the demand on our patient cohort. Reference tissue modelling of [₁₁C]UCB-J with the centrum semiovale as the reference tissue has been verified against arterial input function compartmental modelling in healthy controls (39,40) and in Alzheimer’s disease (64). To assess the validity of the centrum semiovale in our cohort, we determined the mean total distribution volume (V_T) for each of our subject groups using standard arterial input function data from the literature (26,65); this approach assumed that the standard input function was equally valid for all groups. This analysis indicated a small positive bias in centrum semiovale V_T for CBD (5%) and less so PSP (2%) relative to that in controls, which would lead to a commensurate reduction in BP_ND under the assumption that the non-displaceable distribution volume (Vnd) in the target ROIs remains invariant. These biases cannot, however, explain the much greater BP_ND reductions seen for CBD and PSP, which is especially true for PSP. Indeed, scaling BP_ND in the CBD and PSP cohorts to account for the above biases in centrum semiovale V_T, produced a similar pattern of significant global reduction in BP_ND for patients compared to controls, except that the significant differences in the midbrain, pons, substantia nigra, pallidum, and occipital lobe were primarily driven by the PSP cohort in the post-hoc analysis.

The therapeutic challenge in tauopathies is partly due to the complex nature of the underlying pathology. Early stage trials will require early accurate diagnosis, although diagnosis is typically made 3 years after symptom onset (66,67). It is unlikely that synaptic PET could provide pre-symptomatic diagnosis in rare conditions, but it is a promising tool to characterise pathogenetic mechanisms, monitor progression and assess response to experimental medicines (68).