Measuring brain integrity using MRI: a novel biomarker for Alzheimer’s disease using T2 relaxometry

Early Alzheimer’s disease diagnosis is vital for development of disease-modifying therapies. Prior to significant loss of brain tissue, several microstructural changes take place as a result of Alzheimer’s pathology. These include deposition of amyloid, tau and iron, as well as altered water homeostasis in tissue and some cell death. T2 relaxation time, a quantitative MRI measure, is sensitive to these changes and may be a useful non-invasive, early marker of tissue integrity which could predict conversion to dementia. The different factors that affect T2 may cause it to increase, as in the case of free water, or decrease, as in the case of iron, amyloid and tau. Thus, tissue affected by early Alzheimer’s disease could become more heterogeneous yet show no change in average T2. We hypothesise that T2 heterogeneity in regions affected early in Alzheimer’s disease (hippocampus and thalamus) may present a sensitive early marker of microstructural changes in Alzheimer’s disease. In this cohort study, we tested 97 healthy older controls, 49 people with mild cognitive impairment (MCI) and 10 with a diagnosis of Alzheimer’s disease. All participants underwent structural MRI including multi-echo sequence for assessing quantitative T2. Cognitive change over one year was assessed in participants with MCI. Hippocampus and thalamus were automatically masked using ASHS and Freesurfer, respectively. T2 distributions were modelled using log-logistic distribution giving measures of log-median value (midpoint; T2μ) and distribution width (heterogeneity; T2σ). We show an increase in heterogeneity (T2σ; p<.0001) in MCI compared to healthy controls, which was not seen with midpoint (T2μ; p=.149) in the hippocampus and thalamus. Hippocampal T2 heterogeneity predicted cognitive decline over one year in MCI participants (p=.018), but midpoint (p=.132) and volume (p=.315) did not. Age affects T2, but the effects described here are significant even after correcting for age. We show that T2 heterogeneity can identify subtle changes in microstructural integrity of brain tissue in prodromal Alzheimer’s disease. We describe a new model that takes into account the competing effects of factors that both increase and decrease T2. These two opposing forces act in opposition and mean that previous human literature focusing on midpoint T2 has obscured the true potential of T2 as an early marker of Alzheimer’s disease. In fact, T2 heterogeneity outperforms midpoint and volumetry in predicting cognitive decline in those with MCI. We propose that T2 heterogeneity reflects microstructural integrity with potential to be a widely used early biomarker of Alzheimer’s disease. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by Alzheimer's Research UK, BRACE and Wellcome (109067/Z/15/AI). ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data that support the findings of this study are available from corresponding authors upon request. * Ap : Beta-amyloid ACE-III : Addenbrooke’s cognitive examination version 3 AD : Alzheimer’s disease AIC : Akaike Information Criteria HC : Healthy control MCI : Mild cognitive impairment MoCA : Montreal cognitive assessment MPRAGE : Magnetization-prepared rapid gradient echo T2μ : T2 midpoint model parameter T2σ : T2 distribution width model parameter (heterogeneity) TSE : Turbo spin-echo YOE : Years of education