[¹⁸F]Flortaucipir PET to autopsy pathology comparisons in Alzheimer’s disease and other neurodegenerative diseases

Abstract

Background Few studies have evaluated the relationship between in vivo [18F]Flortaucipir (FTP) PET and post‐mortem pathology. Method We sought to compare antemortem FTP‐PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative diseases. 80‐100 min FTP‐PET standardized uptake value ratio (SUVR) images were created using an inferior cerebellar gray matter reference. W‐score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. Mean SUVRs were calculated for Braak stage regions of interest (ROIs), and these values were compared to SUVRs derived from young, non‐autopsy, cognitively normal controls used as a standard for tau negativity. Result Nineteen patients were included (mean age at PET 61 [range 34‐76]; 8 female; mean PET‐to‐autopsy time of 30 months [range 4‐59 months]; Table 1). Eight patients had primary Alzheimer’s disease (AD) pathology, 9 had non‐AD tauopathies (progressive supranuclear palsy [PSP], corticobasal degeneration [CBD], argyrophilic grain disease [AGD], and frontotemporal lobar degeneration [FTLD] with tau inclusions), 2 patients had non‐tau related FTLD. There was excellent correspondence between areas of FTP retention and neurofibrillary tangle (NFT) distribution in patients with primary AD neuropathology. Patients with non‐AD tauopathies showed a range of tracer retention that was less than AD and more than age‐matched, cognitively normal controls, with CBD and FTLD due to MAPT mutations showing the most extensive and distinct binding patterns (Figure 1). Patients with non‐tau related FTLD also showed small areas of tracer retention (Figure 1). Overall, binding across both tau‐positive and tau‐negative non‐AD disorders did not reliably correspond with post‐mortem tau pathology. Quantification of FTP‐PET SUVR images at Braak stage ROIs reliably detected high Alzheimer’s Disease Neuropathologic Change (Braak VI) pathology. However, patients with earlier Braak stages did not show elevated tracer uptake in these regions compared to young, tau‐negative controls (Figure 2). Conclusion In summary, PET‐to‐autopsy correlations confirm that FTP‐PET is a reliable biomarker of advanced tau pathology in AD. The tracer cannot reliably differentiate non‐AD tauopathies and may not detect early Braak stages of NFT pathology.

Tau Beats Amyloid in Predicting Brain Atrophy in Alzheimer Disease: Implications for Prognosis and Clinical Trials

“…18 F-flortaucipir is, to date, the only tau PET tracer to receive Food and Drug Administration approval for clinical use in the United States. 18 F-flortaucipir PET distinguishes AD from other underlying neuropathologies, including non-AD tauopathies to which the tracer shows a low binding affinity (5)(6)(7)(8). In contrast to the early widespread distribution of amyloid PET binding, tau PET signal originates in the entorhinal cortex and other medial temporal regions.…”

Tau PET Imaging in Neurodegenerative Disorders

“…Tracer retention is observed mostly in the basal ganglia and substantia nigra, complicating the interpretation because these regions also show off-target binding for several tau PET tracers ("Methodologic Considerations" section). The number of autopsy-confirmed cases is low (24,37,38) and demonstrated no correlation between cortical 18 F-flortaucipir PET signal and neuropathologic 4R tau (38), with little binding outside the off-target regions (24). The binding profile of 18 F-PI2620 in progressive supranuclear palsy seems more promising, potentially because of lower off-target binding in the basal ganglia.…”

“…2). There is strong evidence, provided by a relatively large end-of-life study (23) and extended case series (24,25), that 18 F-flortaucipir accurately detects AD-like tau neuropathology in individuals in more advanced Braak stages (i.e., Braak . IV; the accuracy for detecting tau load corresponding to Braak stages V and VI was 87.5% [95% CI, 77.2%-93.5%] (23)).…”

“…Some in vivo signal has been detected in individuals clinically diagnosed with a corticobasal syndrome (29)(30)(31). However, so far only 5 autopsyconfirmed cases have been published showing either moderateto-high correlations (R 2 range, 0.59-0.79) of 18 F-flortaucipir PET signal with tau pathology (32,33) or only minor increases in tracer uptake compared with controls with a limited correlation between the tau PET signal and neuropathology (24). There are multiple reports of group-level differences in vivo between controls and clinically diagnosed progressive supranuclear palsy patients using both 18 F-flortaucipir (29,(34)(35)(36) and 18 F-PI2620 (21).…”