18 F-AV-1451 positron emission tomography in Alzheimer’s disease and progressive supranuclear palsy

<span class="paragraphSection"><div class="boxTitle">Abstract</div>The ability to assess the distribution and extent of tau pathology in Alzheimer’s disease and progressive supranuclear palsy <span style="font-style:italic;">in vivo</span> would help to develop biomarkers for these tauopathies and clinical trials of disease-modifying therapies. New radioligands for positron emission tomography have generated considerable interest, and controversy, in their potential as tau biomarkers. We assessed the radiotracer ¹⁸F-AV-1451 with positron emission tomography imaging to compare the distribution and intensity of tau pathology in 15 patients with Alzheimer’s pathology (including amyloid-positive mild cognitive impairment), 19 patients with progressive supranuclear palsy, and 13 age- and sex-matched controls. Regional analysis of variance and a support vector machine were used to compare and discriminate the clinical groups, respectively. We also examined the ¹⁸F-AV-1451 autoradiographic binding in post-mortem tissue from patients with Alzheimer’s disease, progressive supranuclear palsy, and a control case to assess the ¹⁸F-AV-1451 binding specificity to Alzheimer’s and non-Alzheimer’s tau pathology. There was increased ¹⁸F-AV-1451 binding in multiple regions in living patients with Alzheimer’s disease and progressive supranuclear palsy relative to controls [main effect of group, <span style="font-style:italic;">F</span>(2,41) = 17.5, <span style="font-style:italic;">P</span> < 0.0001; region of interest × group interaction, <span style="font-style:italic;">F</span>(2,68) = 7.5, <span style="font-style:italic;">P</span> < 0.00001]. More specifically, ¹⁸F-AV-1451 binding was significantly increased in patients with Alzheimer’s disease, relative to patients with progressive supranuclear palsy and with control subjects, in the hippocampus and in occipital, parietal, temporal, and frontal cortices (t’s > 2.2, <span style="font-style:italic;">P</span>’s < 0.04). Conversely, in patients with progressive supranuclear palsy, relative to patients with Alzheimer’s disease, ¹⁸F-AV-1451 binding was elevated in the midbrain (t = 2.1, <span style="font-style:italic;">P</span> < 0.04); while patients with progressive supranuclear palsy showed, relative to controls, increased ¹⁸F-AV-1451 uptake in the putamen, pallidum, thalamus, midbrain, and in the dentate nucleus of the cerebellum (t’s > 2.7, <span style="font-style:italic;">P</span>’s < 0.02). The support vector machine assigned patients’ diagnoses with 94% accuracy. The post-mortem autoradiographic data showed that ¹⁸F-AV-1451 strongly bound to Alzheimer-related tau pathology, but less specifically in progressive supranuclear palsy. ¹⁸F-AV-1451 binding to the basal ganglia was strong in all groups <span style="font-style:italic;">in vivo.</span> Postmortem histochemical staining showed absence of neuromelanin-containing cells in the basal ganglia, indicating that off-target binding to neuromelanin is an insufficient explanation of ¹⁸F-AV-1451 positron emission tomography data <span style="font-style:italic;">in vivo</span>, at least in the basal ganglia. Overall, we confirm the potential of ¹⁸F-AV-1451 as a heuristic biomarker, but caution is indicated in the neuropathological interpretation of its binding. Off-target binding may contribute to disease profiles of ¹⁸F-AV-1451 positron emission tomography, especially in primary tauopathies such as progressive supranuclear palsy. We suggest that ¹⁸F-AV-1451 positron emission tomography is a useful biomarker to assess tau pathology in Alzheimer’s disease and to distinguish it from other tauopathies with distinct clinical and pathological characteristics such as progressive supranuclear palsy.</span>

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