T2 heterogeneity as an in vivo marker of microstructural integrity in medial temporal lobe subfields in ageing and mild cognitive impairment

Alfie R Wearn*, Volkan Nurdal, Esther Saunders-Jennings, Michael J Knight, Christopher R Madan, Sean-James Fallon, Hanna Kristiina Isotalus, Risto A Kauppinen, Elizabeth J Coulthard

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

2 Citations (Scopus)
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A better understanding of early brain changes that precede loss of independence in diseases like Alzheimer’s disease (AD) is critical for development of disease-modifying therapies. Quantitative MRI, such as T2 relaxometry, can identify microstructural changes relevant to early stages of pathology. Recent evidence suggests heterogeneity of T2 may be a more informative measure of early pathology than absolute T2. Here we test whether T2 markers of brain integrity precede the volume changes we know are present in established AD and whether such changes are most marked in medial temporal lobe (MTL) subfields known to be most affected early in AD. We show that T2 heterogeneity was greater in people with mild cognitive impairment (MCI; n=49) compared to healthy older controls (n=99) in all MTL subfields, but this increase was greatest in MTL cortices, and smallest in dentate gyrus. This reflects the spatio-temporal progression of neurodegeneration in AD. T2 heterogeneity in the entorhinal cortex also predicted cognitive decline over a year in people with MCI, where measures of volume or T2 in any other subfield or whole hippocampus could not. Increases in T2 heterogeneity in MTL cortices may reflect localised pathological change and may present as one of the earliest detectible brain changes prior to atrophy. Finally, we describe a mechanism by which memory, as measured by accuracy and reaction time on a paired associate learning task, deteriorates with age. Age-related memory deficits were explained in part by lower subfield volumes, which in turn were directly associated with greater T2 heterogeneity. We propose that tissue with high T2 heterogeneity represents extant tissue at risk of permanent damage but with the potential for therapeutic rescue. This has implications for early detection of neurodegenerative diseases and the study of brain-behaviour relationships.
Original languageEnglish
Article number118214
Number of pages11
Early online date9 Jun 2021
Publication statusPublished - 1 Sept 2021

Bibliographical note

Funding Information:
The authors wish to thank Join Dementia Research and the Avon & Wiltshire Mental Health Partnership for their assistance with participant recruitment. We also wish to thank those who have helped collect data for the projects (Serena Dillon, Demitra Tsivos, Emma Hadley, Ellen Gaaikema, Lucy Adams, Candida Stainer, Ben Kershaw & Bryony McCann), Aileen Wilson for her help conducting MRI scans, and all the volunteers who gave up their time to take part in our studies.

Funding Information:
This research was funded in part by the Wellcome Trust [Grant number 109,067/Z/15/AI]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This study also was funded by Alzheimer's Research UK and BRACE.

Publisher Copyright:
© 2021


  • magnetic resonance imaging
  • Alzheimer's disease
  • early diagnosis
  • ageing
  • hippocampal subfields
  • medial temporal lobe
  • T2 relaxometry
  • T2 heterogeneity


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