Rates of regional tau accumulation in ageing and across the Alzheimer's disease continuum: an AIBL 18F-MK6240 PET study

Natasha Krishnadas; Vincent Doré; Joanne S Robertson; Larry Ward; Christopher Fowler; Colin L Masters; Pierrick Bourgeat; Jurgen Fripp; Victor L Villemagne; Christopher C Rowe

doi:10.1016/j.ebiom.2023.104450

Rates of regional tau accumulation in ageing and across the Alzheimer's disease continuum: an AIBL ¹⁸F-MK6240 PET study

EBioMedicine. 2023 Feb:88:104450. doi: 10.1016/j.ebiom.2023.104450. Epub 2023 Jan 27.

Affiliations

¹ Florey Department of Neurosciences & Mental Health, The University of Melbourne, Parkville, Victoria, 3052, Australia; Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Victoria, 3084, Australia. Electronic address: natasha.krishnadas@florey.edu.au.
² Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Victoria, 3084, Australia; Health and Biosecurity Flagship, The Australian eHealth Research Centre, Melbourne, Victoria, Australia.
³ Florey Institute of Neurosciences & Mental Health, Parkville, Victoria, 3010, Australia.
⁴ Health and Biosecurity Flagship, The Australian eHealth Research Centre, Brisbane, Queensland, Australia.
⁵ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Florey Department of Neurosciences & Mental Health, The University of Melbourne, Parkville, Victoria, 3052, Australia; Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Victoria, 3084, Australia; Florey Institute of Neurosciences & Mental Health, Parkville, Victoria, 3010, Australia.

Abstract

Background: Tau positron emission tomography (PET) imaging enables longitudinal observation of tau accumulation in Alzheimer's disease (AD). ¹⁸F-MK6240 is a high affinity tracer for the paired helical filaments of tau in AD, widely used in clinical trials, despite sparse longitudinal natural history data. We aimed to evaluate the natural history of tau accumulation, and the impact of disease stage and reference region on the magnitude and effect size of regional change.

Methods: One hundred and eighty-four participants: 89 cognitively unimpaired (CU) beta-amyloid negative (Aβ-), 44 CU Aβ+, 51 cognitively impaired Aβ+ (26 with mild cognitive impairment [MCI] and 25 with dementia) had follow-up ¹⁸F-MK6240 PET for one to four years (median 1.48). Regional standardised uptake value ratios (SUVR) were generated. Two reference regions were examined: cerebellar cortex and eroded subcortical white matter.

Findings: CU Aβ- participants had very low rates of tau accumulation in the mesial temporal lobe (MTL). In CU Aβ+, significantly higher rate of accumulation was seen in the MTL (particularly the amygdala), extending into the inferior temporal lobes. In MCI Aβ+, the rate of accumulation was greatest in the lateral temporal, parietal and lateral occipital cortex, and plateaued in the MTL. Accumulation was global in AD Aβ+, except for a plateau in the MTL. The eroded subcortical white matter reference region showed no significant advantage over the cerebellar cortex and appeared prone to spill-over in AD participants. Data fitting suggested approximately 15-20 years to accumulate tau to typical AD levels.

Interpretation: Tau accumulation occurs slowly. Rates vary according to brain region, disease stage and tend to plateau at high levels. Rates of tau accumulation are best measured in the MTL and inferior temporal cortex in preclinical AD and in large neocortical areas, in MCI and AD.

Funding: NHMRC; Cerveau Technologies.

Keywords: (18)F-MK6240; Alzheimer's disease; Longitudinal; Positron emission tomography (PET); Tau.

MeSH terms

Aging
Alzheimer Disease* / diagnostic imaging
Amyloid beta-Peptides
Cognitive Dysfunction* / diagnostic imaging
Humans
Positron-Emission Tomography / methods
tau Proteins

Substances

tau Proteins
Amyloid beta-Peptides