title: 18F-AV-1451 positron emission tomography in Alzheimer's disease and progressive supranuclear palsy.
abstract: The ability to assess the distribution and extent of tau pathology in Alzheimer's disease and progressive supranuclear palsy in vivo 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, F(2,41) = 17.5, P < 0.0001; region of interest × group interaction, F(2,68) = 7.5, P < 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, P'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, P < 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, P'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 in vivo. 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 in vivo, 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.
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.|Istituto di Bioimmagini e Fisiologia Molecolare, Consiglio Nazionale delle Ricerche, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Passamonti
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Vázquez Rodríguez
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.|Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK.
authors.forename: Young T
authors.initials: YT
authors.lastname: Hong
authors.affiliation: Department of Histopathology, Cambridge University Hospital, Cambridge, UK.
authors.forename: Kieren S J
authors.initials: KS
authors.lastname: Allinson
authors.affiliation: Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Williamson
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Borchert
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Saber
authors.initials: S
authors.lastname: Sami
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Cope
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: W Richard
authors.initials: WR
authors.lastname: Bevan-Jones
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: P Simon
authors.initials: PS
authors.lastname: Jones
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Arnold
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: Ajenthan
authors.initials: A
authors.lastname: Surendranathan
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: Elijah
authors.initials: E
authors.lastname: Mak
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.|Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Fryer
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.|Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK.
authors.forename: Franklin I
authors.initials: FI
authors.lastname: Aigbirhio
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: John T
authors.initials: JT
authors.lastname: O'Brien
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: James B
authors.initials: JB
authors.lastname: Rowe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000000981:diagnostic imaging*; D001344:Autopsy; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D002243:Carbolines / Q000493:pharmacokinetics*; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000000981:diagnostic imaging / Q000209:etiology; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D011569:Psychiatric Status Rating Scales; D013494:Supranuclear Palsy, Progressive / Q000150:complications / Q000000981:diagnostic imaging*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D002243:Carbolines; D016875:tau Proteins; D019788:Fluorodeoxyglucose F18; C000591008:7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole
keywords: Alzheimer’s disease; PET; neurodegeneration; progressive supranuclear palsy; tau