Abstract
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Objectives Alzheimer’s disease (AD) is characterized by the aggregation of senile Aβ plaques, and neurofibrillary tau tangles. PET imaging has been used to detect in vivo pathological tau ([F-18]THK5351 & [F-18]THK5117) and Aβ ([C-11]PiB) aggregates. This study observes in vivo tau and Aβ aggregates in a presymptomatic and symptomatic AD cohort enriched for AD risk factors using T1w MRI, and [C-11]PiB, [F-18]THK5351, and/or [F-18]THK5117 PET to determine relationships between radiotracer binding and cognitive decline. Comparisons between THK5351 and THK5117 are also performed.
Methods N=17 subjects ranging from cognitively normal to Alzheimer’s dementia with various AD risk factors (e.g. APOE-ε4, familial history) underwent T1w MRI and dynamic [C-11]PiB (70 min), and [F-18]THK5351 (n=7, 90 min) and/or [F-18]THK5117 (n=14, 90 min) PET imaging. Twenty-one ROIs were selected a priori for analysis of PET binding estimates (Logan DVR cerebellar GM reference region) based on Thal and Braak AD pathological staging. Binding estimates were determined with and without correction for partial volume effects. Subjects were grouped and rank ordered based on longitudinal neuropsychological evaluation and clinical diagnosis. Spearman’s rank test was performed to test for correlations between radiotracer binding estimates (PiB and THK), and between radiotracer binding and cognitive rank both regionally (Bonferoni corrected for multiple comparisons) and globally. Standard uptake values (SUV) and target to reference ratios (cerebellum GM reference region) were determined for the PET time series to compare the in vivo dynamics of THK5351 and THK5117. One THK5117 subject was omitted from analysis due to suspected non-AD dementia based on PiB and THK5117 image results. Table 1 provides a summary of the study cohort.
Results Correlation Analyses: Subjects scanned with THK5117 (n=13) showed strong correlations between PiB and THK5117 DVR estimates in temporal, parietal, occipital, and frontal cortices, but generally not in mesial temporal lobe (MTL) or subcortical structures (see table 2A). Significant correlations between cognitive rank and THK5117 DVR were observed in temporal, parietal, and occipital cortices, but not in MTL. Subjects scanned with THK5351 (n=7) showed trend level correlations between PiB and THK5351 DVR values in temporal, parietal, occipital and frontal cortices, but not in MTL or subcortical structures (see table 2B). THK5351 DVR correlated with cognitive rank in inferior temporal, parietal, and lateral occipital cortices, but did not survive correction for multiple comparisons. For all subjects, regional PiB DVR was not significantly correlated with cognitive rank, though weak correlations were observed in neocortical structures. THK5351/THK5117 Comparison: THK5351 had a 52 ± 2% reduction in cerebellar GM SUV compared to THK5117. A significant reduction in cerebellar WM, and increased binding and more rapid kinetics in GM regions with elevated binding were observed in pre-MCI subjects for THK5351 compared to THK5117.
Conclusions Regional tau, but not Aβ, was observed to increase with cognitive decline in regions associated with Braak stages III-VI. Both [F-18]THK5351 and [F-18]THK5117 displayed dissimilar binding when compared to [C-11]PiB binding in MTL structures suggesting different in vivo molecular targets. [F-18]THK5351 displays decreased WM binding and more rapid kinetics in cortical GM compared to [F=18]-THK5117 and may be a viable PET radioligand for studying in vivo AD tau pathology. Continued paired [C-11]PiB and [F-18]THK5351 PET studies are ongoing.