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 K Isotalus,Risto A Kauppinen,Elizabeth J Coulthard

doi:10.1016/j.neuroimage.2021.118214

Abstract

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 MRI 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 CA1-3 and entorhinal cortex and volume of entorhinal cortex showed some ability to predict cognitive decline, where absolute T2 could not, however further studies are required to verify this result. 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.

Highlights

Accurate early diagnosis of Alzheimer’s disease (AD) is likely a necessity for development of disease-modifying therapies (Cummings et al, 2014; Alzheimer’s Association, 2015)
We describe a mechanism by which cognitive ability deteriorates with age through direct effects on T2 heterogeneity, which lead to the changes in volume which in turn lead to cognitive decline
The analyses presented in this paper comprise the first detailed exploration of quantitative T2 across subfields of the medial temporal lobe in older people with and without cognitive impairment

Summary

Introduction

Accurate early diagnosis of Alzheimer’s disease (AD) is likely a necessity for development of disease-modifying therapies (Cummings et al, 2014; Alzheimer’s Association, 2015). Identifying which people with mild cognitive impairment (MCI) will progress to AD dementia has been shown to be possible by measuring the volume of subfields within the medial temporal lobe (MTL) (Chételat et al, 2008; de Flores et al, 2015a, 2015b; deToledo-Morrell et al, 2004; Apostolova et al, 2006, 2010). In these groups, large changes in volume tend to indicate significant, and likely irreversible, atrophy. Smaller scale microstructural changes that occur prior to volume loss could help to identify patients in which such a treatment can still rescue damaged brain tissue

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