The ability to assess the distribution and extent of tau pathology and neuroinflammation in Progressive Supranuclear Palsy (PSP) and Alzheimer’s disease (AD) ‘in vivo’ and to validate it using post mortem data is critical to develop reliable biomarkers for these disorders, and for tracking the effects of clinical trials using disease-modifying therapies. The main aim of my PhD was therefore to assess the utility of the PET radiotracers [18F]AV1451 and 11C-PK11195 to compare the distribution and intensity of tau pathology and neuroinflammation respectively, in PSP and AD. I use both in vivo scanning and post mortem tissue from archival cases in the Cambridge Brain Bank. For the in vivo studies, I investigated whether tau accumulation and neuroinflammation relate to clinical measures of disease severity and cognitive impairment.

My PhD was undertaken as part of the Neuroimaging of Inflammation in MemoRy and Other Disorders (NIMROD). Nineteen people with PSP-Richardson’s syndrome, 15 patients with amnestic Alzheimer’s disease and biomarker-positive mild cognitive impairment (MCI+) and 13 age- and sex-matched controls participated. Post mortem brain tissue from three subjects (one PSP case, one AD patient, and one control with similar age) were included. Autoradiographic and immunohistochemical analyses were conducted in different cases from those included in the [18F]AV1451 and 11C-PK11195 PET in vivo studies.

[18F]AV1451 PET imaging revealed distinct patterns of tau binding in AD and its prodromal state of MCI+, in comparison to PSP. The clinical syndromes of AD and MCI+ were associated with increased [18F]AV1451 BPND in widely distributed subcortical and cortical areas that have been consistently implicated in the pathogenesis and progression of AD (e.g. hippocampus, amygdala as well as frontal, parietal, temporal, and occipital cortices). Conversely, PSP was associated with a pattern of increased [18F]AV1451 uptake in the basal ganglia, midbrain, and dentate nucleus of the cerebellum, consistent with the pathophysiology of the disease. Despite this potential of [18F]AV1451 as a tau biomarker, caution in the interpretation of its binding targets is indicated by the neuropathological and autoradiographic data. In particular, while [18F]AV1451 strongly bound to AD-related tau pathology, non-specific binding of the same tracer can be found in PSP patients and controls. Furthermore, [18F]AV1451 uptake was not correlated with disease severity in the clinical groups.

11C-PK11195 PET imaging revealed distinct patterns of inflammation in AD and PSP, and mirrored the pathological distribution for each disease seen by 11C-PK11195 post mortem phosphor screen autoradiography and immunohistochemistry. In AD, microglial activation was observed in prefrontal cortex, and medial temporal lobe. In PSP microglial activation was observed in midbrain and basal ganglia. In both clinical cohorts, disease severity correlated with neuroinflammation in the regions most closely associated with principal neuropathological markers including tau aggregates.