Abstract
BackgroundEarly Alzheimer’s disease (AD) diagnosis is vital for development of disease-modifying therapies. Prior to significant brain tissue atrophy, 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. We propose that different microstructural changes affect T2 in opposing ways, such that average ‘midpoint’ measures of T2 are less sensitive than measuring distribution width (heterogeneity). T2 heterogeneity in the brain may present a sensitive early marker of AD pathology.MethodsIn this cohort study, we tested 97 healthy older controls, 49 people with mild cognitive impairment (MCI) and 10 with a clinical diagnosis of AD. All participants underwent structural MRI including a multi-echo sequence for quantitative T2 assessment. Cognitive change over 1 year was assessed in 20 participants with MCI. T2 distributions were modelled in the hippocampus and thalamus using log-logistic distribution giving measures of log-median value (midpoint; T2μ) and distribution width (heterogeneity; T2σ).ResultsWe show an increase in T2 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 1 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.ConclusionsWe show that T2 heterogeneity can identify subtle changes in microstructural integrity of brain tissue in MCI and predict cognitive decline over a year. We describe a new model that considers the competing effects of factors that both increase and decrease T2. These two opposing forces suggest that previous conclusions based on T2 midpoint may have obscured the true potential of T2 as a marker of subtle neuropathology. We propose that T2 heterogeneity reflects microstructural integrity with potential to be a widely used early biomarker of conditions such as AD.
Highlights
Alzheimer’s disease treatments and therapies that stop or slow down neuropathology will be most effective if administered as early as possible; before significant neurodegeneration has occurred
T2 heterogeneity, but not midpoint, differentiates healthy older adults from those with mild cognitive impairment (MCI) T2 midpoint (μ) There was no significant difference between HC, MCI and Alzheimer’s disease (AD) groups (F(2, 152) = 1.61, p = .204; Fig. 2a) on T2 midpoint in the hippocampus
T2 midpoint was higher in the AD group than other groups, this effect was not statistically significant compared to either healthy controls or the MCI group
Summary
Alzheimer’s disease treatments and therapies that stop or slow down neuropathology will be most effective if administered as early as possible; before significant neurodegeneration has occurred. Structural and quantitative MRI show promise in their ability to identify changes in the brain that indicate early Alzheimer’s pathology. As treatment with disease-modifying therapies would be optimal before such significant macrostructural change, we ask whether MRI could be used to identify microstructural changes that occur earlier in the disease-course, before significant volume loss. Prior to significant brain tissue atrophy, 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. T2 heterogeneity in the brain may present a sensitive early marker of AD pathology
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