18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers

Ruben Smith, Andreas Puschmann, Michael Schöll, Tomas Ohlsson, John van Swieten, Michael Honer, Elisabet Englund, Oskar Hansson, Ruben Smith, Andreas Puschmann, Michael Schöll, Tomas Ohlsson, John van Swieten, Michael Honer, Elisabet Englund, Oskar Hansson

Abstract

Tau positron emission tomography ligands provide the novel possibility to image tau pathology in vivo However, little is known about how in vivo brain uptake of tau positron emission tomography ligands relates to tau aggregates observed post-mortem. We performed tau positron emission tomography imaging with (18)F-AV-1451 in three patients harbouring a p.R406W mutation in the MAPT gene, encoding tau. This mutation results in 3- and 4-repeat tau aggregates similar to those in Alzheimer's disease, and many of the mutation carriers initially suffer from memory impairment and temporal lobe atrophy. Two patients with short disease duration and isolated memory impairment exhibited (18)F-AV-1451 uptake mainly in the hippocampus and adjacent temporal lobe regions, correlating with glucose hypometabolism in corresponding regions. One patient died after 26 years of disease duration with dementia and behavioural deficits. Pre-mortem, there was (18)F-AV-1451 uptake in the temporal and frontal lobes, as well as in the basal ganglia, which strongly correlated with the regional extent and amount of tau pathology in post-mortem brain sections. Amyloid-β ((18)F-flutemetamol) positron emission tomography scans were negative in all cases, as were stainings of brain sections for amyloid. This provides strong evidence that (18)F-AV-1451 positron emission tomography can be used to accurately quantify in vivo the regional distribution of hyperphosphorylated tau protein.

Keywords: Alzheimer’s disease; MAPT R406W mutation; frontotemporal dementia; positron emission tomography; tau.

© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4995360/bin/aww163fig1g.jpg
Little is known about how the in vivo tau PET signal relates to post-mortem tau neuropathology. Smith et al. provide the first evidence that the two are highly correlated by showing that the tau PET tracer 18F-AV-1451 accurately detects tau pathology in subjects with mutations in the tau (MAPT) gene.
Figure 1
Figure 1
18F-AV-1451 and 18F-flutemetamol PET. (A–D) 18F-AV-1451 scans of tau mutation carriers A–C in panels A–C, respectively. A representative control subject is shown in D. (E–H) 18F-flutemetamol PET. Patients A–C in panels E–G, respectively. (H) A positive scan typical for a patient with Alzheimer’s disease. The signal in A–C represents non-specific white matter binding. Numbers below images indicate the composite score for global cortical mean uptake. (I) SUVRs, expressed as per cent of control values for (from left to right for each region) Patients A (red), B (green), C (orange), and Alzheimer’s disease (AD) (blue). Patients with Alzheimer’s disease are presented ± standard error of the mean.
Figure 2
Figure 2
Correlation of 18F-FDG with 18F-AV-1451. (A–D) Images of Patient A. (A and C) Transverse and sagittal images of 18F-FDG, scale showing range of SUVR values. (B and D) Transverse and sagittal images of 18F-AV-1451, scale showing range of SUVR values. (E and F) Correlation between FDG and AV-1451 in Patients A (E) and B (F). Patient FDG-SUVRs have been normalized to control FDG-SUVR values for each region. Line represents a linear regression.
Figure 3
Figure 3
18F-AV-1451 correlation with neuropathology. (A and B) Tau inclusions, grade +, at ×4 (A) and ×20 magnification (B). (C and D) Grade ++, at ×4 (C) and ×20 magnification (D). Grade +++, at ×4 (E) and ×20 magnification (F). (G) Cerebellar white matter and cortex (grade 0) at ×4 magnification. Inset at ×20 magnification. (H) Positive control, cortex from a patient with Alzheimer’s disease at ×20 magnification. Scale bars = 500 µm at ×4 and 100 µm at ×20 magnifications. (I) Correlation between 18F-AV-1451 and neuropathological grade. Line represents a linear regression. Spearman correlation: rs = 0.93, P < 0.01. (J) Neuropathological grades in the brain regions analysed. (K) Correlation of tau-positive neurite density and 18F-AV-1451 SUVR in the cortical regions analysed and the putamen. Line represents a linear regression. Spearman correlation: rs = 0.92, P < 0.01.

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Source: PubMed

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