Patterns of tau pathology identified with 18 F-MK-6240 PET imaging

William Charles Kreisl, Patrick J Lao, Aubrey Johnson, Zeljko Tomljanovic, Julia Klein, Krista Polly, Benjamin Maas, Krystal K Laing, Anthony G Chesebro, Kay Igwe, Qolamreza R Razlighi, Lawrence S Honig, Xinyu Yan, Seonjoo Lee, Akiva Mintz, José A Luchsinger, Yaakov Stern, D P Devanand, Adam M Brickman, William Charles Kreisl, Patrick J Lao, Aubrey Johnson, Zeljko Tomljanovic, Julia Klein, Krista Polly, Benjamin Maas, Krystal K Laing, Anthony G Chesebro, Kay Igwe, Qolamreza R Razlighi, Lawrence S Honig, Xinyu Yan, Seonjoo Lee, Akiva Mintz, José A Luchsinger, Yaakov Stern, D P Devanand, Adam M Brickman

Abstract

Introduction: Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of 18 F-MK-6240 in a clinical sample and determined the relationships among 18 F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers.

Methods: Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aβ)42 , tau, and phosphorylated tau (p-tau).

Results: 18 F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aβ42 . 18 F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of 18 F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants.

Discussion: 18 F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.

Keywords: Alzheimer's disease; MK-6240; amyloid positivity; cerebrospinal fluid; cognition; tau positivity; tau positron emission tomography.

Conflict of interest statement

COMPETING INTERESTS

Dr. Kreisl has a consulting agreement with Cerveau Technologies. However, Cerveau was not involved in the study design or interpretation of the results.

© 2021 the Alzheimer's Association.

Figures

Fig 1.. Scatterplot of 18 F-MK-6240 binding…
Fig 1.. Scatterplot of 18F-MK-6240 binding for Braak stages across amyloid and cognitive status.
The solid line represents 2 standard deviations above the mean 18F-MK-6240 binding in an independent, healthy sample. The dotted lines represent 1 and 3 standard deviations above the mean.
Fig 2.. Voxelwise differences in 18 F-MK-6240…
Fig 2.. Voxelwise differences in 18F-MK-6240 binding across amyloid and cognitive status.
(A) Average 18F-MK-6240 SUVR images. (B) Voxelwise differences in 18F-MK-6240 SUVR images, highlighting the early differences in medial temporal cortex followed by progressively larger and more spatially diffuse differences in lateral temporal, parietal, and frontal cortex with sparing of motor and occipital cortices. * denotes uncorrected p < 0.001. ** denotes family-wise error corrected p<0.05.
Fig 3.. Dissociative relationships between 18 F-MK-6240…
Fig 3.. Dissociative relationships between 18F-MK-6240 binding and age based on amyloid status.
Amyloid-negative participants show positive correlations between 18F-MK-6240 binding and age in early Braak regions, while amyloid-positive participants show negative correlations between 18F-MK-6240 binding and age in late Braak regions. Scatterplots are unadjusted associations between SUVR and age, while Pearson’s correlation coefficients and p-values are MMSE and sex adjusted. An asterisk (*) indicates the association survived correction for multiple comparisons using false detection rate.
Fig 4.. Voxelwise associations of 18 F-MK-6240…
Fig 4.. Voxelwise associations of 18F-MK-6240 binding and cognition.
Amyloid-positive participants demonstrate region-specific associations with 3 cognitive domains. Note that there were no associations in amyloid-negative participants or amyloid-negative controls alone.
Fig 5.. Correlation plots showing associations between…
Fig 5.. Correlation plots showing associations between 18F-MK-6240 binding and CSF-based measures of total tau and phospho-tau, without and without correction for CSF Aβ42.
An asterisk (*) indicates the association survived correction for multiple comparisons using false detection rate.

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