18F-flortaucipir PET to autopsy comparisons in Alzheimer’s disease and other neurodegenerative diseases

Abstract

Few studies have evaluated the relationship between in vivo 18F-flortaucipir PET and post-mortem pathology. We sought to compare antemortem 18F-flortaucipir PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative conditions. Twenty patients were included [mean age at PET 61 years (range 34–76); eight female; median PET-to-autopsy interval of 30 months (range 4–59 months)]. Eight patients had primary Alzheimer’s disease pathology, nine had non-Alzheimer tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutations), and three had non-tau frontotemporal lobar degeneration. Using an inferior cerebellar grey matter reference, 80–100-min 18F-flortaucipir PET standardized uptake value ratio (SUVR) images were created. Mean SUVRs were calculated for progressive supranuclear palsy, corticobasal degeneration, and neurofibrillary tangle Braak stage regions of interest, and these values were compared to SUVRs derived from young, non-autopsy, cognitively normal controls used as a standard for tau negativity. 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. There was excellent correspondence between areas of 18F-flortaucipir retention, on both SUVR images and W-score maps, and neurofibrillary tangle distribution in patients with primary Alzheimer’s disease neuropathology. Patients with non-Alzheimer tauopathies and non-tau frontotemporal lobar degeneration showed a range of tracer retention that was less than Alzheimer’s disease, though higher than age-matched, cognitively normal controls. Overall, binding across both tau-positive and tau-negative non-Alzheimer disorders did not reliably correspond with post-mortem tau pathology. 18F-flortaucipir SUVRs in subcortical regions were higher in autopsy-confirmed progressive supranuclear palsy and corticobasal degeneration than in controls, but were similar to values measured in Alzheimer’s disease and tau-negative neurodegenerative pathologies. Quantification of 18F-flortaucipir SUVR images at Braak stage regions of interest reliably detected advanced Alzheimer’s (Braak VI) pathology. However, patients with earlier Braak stages (Braak I–IV) did not show elevated tracer uptake in these regions compared to young, tau-negative controls. In summary, PET-to-autopsy comparisons confirm that 18F-flortaucipir PET is a reliable biomarker of advanced Braak tau pathology in Alzheimer’s disease. The tracer cannot reliably differentiate non-Alzheimer tauopathies and may not detect early Braak stages of neurofibrillary tangle pathology.

Identifying degenerative effects of repetitive head trauma with neuroimaging: a clinically-oriented review

“…Some patients exhibited FTP binding in a non-contiguous “dot-like” pattern, similar to data reported in a small group of veterans with history of multiple low-level blast exposures [ 74 ]. This pattern is also observed in some healthy controls [ 43 ] and may simply represent noise or imaging artifact [ 43 , 127 ].…”

“…FTP was developed to detect paired helical filament tau in neurofibrillary tangles characteristic of AD (now FDA approved). Multiple investigations consistently support FTP use for differentiation of AD from controls and non-AD tauopathies [ 127 – 129 ], but there is limited comparison to CTE. There were high hopes that the science of CTE and repetitive head trauma biomarker development could ride the wave of extremely promising research demonstrating strong affinity of the FTP tracer to AD tau [ 127 ].…”

“…Multiple investigations consistently support FTP use for differentiation of AD from controls and non-AD tauopathies [ 127 – 129 ], but there is limited comparison to CTE. There were high hopes that the science of CTE and repetitive head trauma biomarker development could ride the wave of extremely promising research demonstrating strong affinity of the FTP tracer to AD tau [ 127 ]. Excitement over potential CTE diagnosis stemmed from known similarities in phosphorylated tau isoforms between AD and CTE – mixed 3-repeat/4-repeat tau tangles with paired helical filament structures.…”

“…FTP exhibits “off-target” (i.e., non-tau related) binding to choroid plexus (often complicating medial temporal signal interpretation) [ 132 , 133 ], caudate, putamen, pallidum, thalamus, and white matter [ 133 – 135 ], and cortically in some cases of tau-negative neurodegenerative disease [ 127 ]. An early case report speculating that FTP binding in the basal ganglia reflected a “novel variant” of CTE likely represented off-target tracer binding [ 133 , 134 , 136 ].…”

Developing methods to detect and diagnose chronic traumatic encephalopathy during life: rationale, design, and methodology for the DIAGNOSE CTE Research Project

“…For instance, the PET radiotracer flortaucipir (AV1451; T807) demonstrates high affinity binding to the mixed 3R/4R tau isoforms in AD [ 92 ]. Flortaucipir’s binding to other tauopathies with primarily 4R isoforms has not been as promising [ 93 , 94 ]. Although CTE and AD have similar (3R/4R) tau isoforms, there are differences at the molecular level [ 19 ], and, as mentioned earlier, in CTE the ratio of 3R:4R differs across disease stage and between neuronal and glial tau [ 22 ].…”