Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain

Abstract

PurposeSeveral tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (11C-THK5351 and 11C-PBB3) in a head-to-head, in vivo, multimodal design.MethodsNine patients with a diagnosis of mild cognitive impairment or probable Alzheimer’s disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer’s disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers 11C-THK5351 and 11C-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer 11C-AZD2184, a T1-MRI sequence, and neuropsychological assessment.ResultsThe load and regional distribution of binding differed between 11C-THK5351 and 11C-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of 11C-PBB3, but not that of 11C-THK5351, in the temporal lobe resembled that of 11C-AZD2184, with strong correlations detected between 11C-PBB3 and 11C-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with 11C-THK5351 than with 11C-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with 11C-THK5351 than with 11C-PBB3 binding.ConclusionThis research suggests different molecular targets for these tracers; while 11C-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of 11C-THK5351 fitted the expected distribution of tau pathology in Alzheimer’s disease better and was more closely related to downstream disease markers.Electronic supplementary materialThe online version of this article (10.1007/s00259-018-4012-5) contains supplementary material, which is available to authorized users.

Apolipoprotein E ε4 Specifically Modulates the Hippocampus Functional Connectivity Network in Patients With Amnestic Mild Cognitive Impairment

“…Although the occipital cortex is a central visual processing area in the brain (Wandell et al, 2007 ), this area was also demonstrated to be significantly related to cognitive performance in neurodegenerative disease (Johnson et al, 2015 ) and emotion recognition (Scahill et al, 2013 ). Both overload tau and Aβ accumulation were found in the occipital cortex by PET imaging (Cho et al, 2017 ; Chiotis et al, 2018 ). Different amplitudes of the occipital sources of low-frequency alpha rhythms (8–10.5 Hz) were shown in aMCI and AD in a resting-state electroencephalographic study (Babiloni et al, 2015 ).…”

Applications of amyloid, tau, and neuroinflammation PET imaging to Alzheimer's disease and mild cognitive impairment

“…The latter may be more selective to tau aggregations that have a spatial relationship with amyloid deposits, while the former may show preference for tau closely linked to brain atrophy, CSF tau, and neuropsychological functioning (Chiotis et al, 2018). The latter may be more selective to tau aggregations that have a spatial relationship with amyloid deposits, while the former may show preference for tau closely linked to brain atrophy, CSF tau, and neuropsychological functioning (Chiotis et al, 2018).…”

“…Research suggests that radiotracers from the THK family bind to a different site than that of [ 11 C]PBB3 . The latter may be more selective to tau aggregations that have a spatial relationship with amyloid deposits, while the former may show preference for tau closely linked to brain atrophy, CSF tau, and neuropsychological functioning (Chiotis et al, 2018 THK5317 shows a good ability to differentiate between AD and MCI patients and healthy controls with a pattern of regional uptake that includes selected areas in the temporal, frontal, occipital, and parietal cortex, in addition to the precuneus . Similar results are shown with [ 18 F]THK5351 with particularly high retention in temporal brain areas (Harada et al, 2016;Lockhart et al, 2016).…”

The imaging features and clinical associations of a novel tau PET tracer - 18F-APN1607(18F-PM-PBB3) in Alzheimer’s disease

“…The advantages of the secondgeneration compounds include a lack of off-target binding in the basal ganglia and thalamus and a relatively low affinity for the enzyme MAO-B [46][47][48]. A directly head-to-head comparison between the first-generation and second-generation tau tracers also revealed that different molecular binding targets existed in these tracers [49]. In the current study, we showed that there is no significant uptake of the PET tracer 18 F-APN1607 in the midbrain or the basal ganglia.…”