Evaluation of [18F]PI-2620, a second-generation selective tau tracer, for assessing four-repeat tauopathies

Abstract

Tau aggregates represent a key pathologic feature of Alzheimer’s disease and other neurodegenerative diseases. Recently, PET probes have been developed for in vivo detection of tau accumulation; however, they are limited because of off-target binding and a reduced ability to detect tau in non-Alzheimer’s disease tauopathies. The novel tau PET tracer, [18F]PI-2620, has a high binding affinity and specificity for aggregated tau; therefore, it was hypothesized to have desirable properties for the visualization of tau accumulation in Alzheimer’s disease and non-Alzheimer’s disease tauopathies. To assess the ability of [18F]PI-2620 to detect regional tau burden in non-Alzheimer’s disease tauopathies compared with Alzheimer’s disease, patients with progressive supranuclear palsy (n = 3), corticobasal syndrome (n = 2), corticobasal degeneration (n = 1), or Alzheimer’s disease (n = 8), and healthy controls (n = 7) were recruited. All participants underwent MRI, amyloid β assessment, and [18F]PI-2620 PET (Image acquisition at 60–90 minutes post-injection). Cortical and subcortical tau accumulations were assessed by calculating standardized uptake value ratios using [18F]PI-2620 PET. For pathologic validation, tau pathology was assessed using tau immunohistochemistry and compared with [18F]PI-2620 retention in an autopsied case of corticobasal degeneration. In Alzheimer’s disease, focal retention of [18F]PI-2620 was evident in the temporal and parietal lobes, precuneus, and cingulate cortex. Standardized uptake value ratio analyses revealed that patients with non-Alzheimer’s disease tauopathies had elevated [18F]PI-2620 uptake only in the globus pallidus, as compared to patients with Alzheimer’s disease, but not healthy controls. A head-to-head comparison of [18F]PI-2620 and [18F]PM-PBB3, another tau PET probe for possibly visualizing the 4-repeat tau pathogenesis in non-Alzheimer’s disease, revealed different retention patterns in one subject with progressive supranuclear palsy. Imaging-pathology correlation analysis of the autopsied patient with corticobasal degeneration revealed no significant correlation between [18F]PI-2620 retention in vivo. High [18F]PI-2620 uptake at 60–90 minutes post-injection in the globus pallidus may be a sign of neurodegeneration in four-repeat tauopathy, but not necessarily practical for diagnosis of non- Alzheimer’s disease tauopathies. Collectively, this tracer is a promising tool to detect Alzheimer’s disease-tau aggregation. However, late acquisition PET images of [18F]PI-2620 may have limited utility for reliable detection of four-repeat tauopathy because of lack of correlation between postmortem tau pathology and different retention pattern than the non-Alzheimer’s disease-detectable tau radiotracer, [18F]PM-PBB3. A recent study reported that [18F]PI-2620 tracer kinetics curves in four-repeat tauopathies peak earlier (within 30 minutes) than Alzheimer’s disease; therefore, further studies are needed to determine appropriate PET acquisition times that depend on the respective interest regions and diseases.

Clinical Spectrum of Tauopathies

“…Clinical studies, however, were not able to find a consistent binding to non-AD tau. Moreover, there was no postmortem correlation to tau pathology in a CBD case (244). However, in another study using a dynamic technique, [18F]-PI-2620 was able to differentiate PSP-RS from healthy controls, PD, MSA, and non-RS PSP (245) and in a follow-up study, an improved imaging technique was proposed (246).…”

Neuropathology and emerging biomarkers in corticobasal syndrome

“…150 A recent study using autopsy-confirmed AD and non-AD tauopathies, however, revealed that [18F]PI-2620 retention was not correlated with tau burden at postmortem pathological assessment. 151 [18F]PM-PBB3 is another second-generation tau PET tracer, which has great promise to visualise pathological tau aggregates in AD and non-AD tauopathies. 139 The retention of [18F] PM-PBB3 was increased in the primary motor cortex, basal ganglia, brainstem and middle frontal gyrus in a patient with CBD confirmed by brain biopsy.…”

Imaging pathological tau in atypical parkinsonisms: A review

“…Furthermore, non-invasive static [18F]PI-2620 PET scans during this period provides comparable quantification accuracy to dynamic scans with arterial sampling in this cohort [74] . Although these are the optimal conditions for [18F]PI-2620 PET in AD, recent work has found that [18F]PI-2620 tracer kinetics differ in 4R-tauopathies, presenting with earlier peaks than in AD [80] .…”

“…Another area of investigation in tau PET imaging is the appropriate acquisition time and measurement parameters for these tracers. As evidenced by the work with [18F]PI-2620, the optimal time windows in AD versus non-AD tauopathies may differ [80] , [85] , [99] . Overall, standardized uptake value ratio (SUVR) and DVR are the most common parameters for describing the binding patterns of these tau PET tracers in the brain.…”