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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 disease.

The human brain selectively stores knowledge of the world to optimise future behaviour, automatically rehearsing, contextualising or discarding information to create a robust record of experiences. Storage or forgetting evolves over time, particularly during sleep. We have previously shown that dopamine given in the form of L-DOPA tablets improves long-term memory in Parkinson’s disease, but only when given overnight. L-DOPA is already prescribed widely with a good safety profile and could potentially be rapidly repurposed to improve cognitive performance and improve quality of life in, for example, early Alzheimer’s Disease, if we understood the best time of day to prescribe. Therefore, we sought to test how dopamine shaped long-term memory formation before and during sleep in a double-blind randomised placebo-controlled cross-over trial of healthy older adults (n = 35). We administered L-DOPA after word-list learning to be active during repeat exposure to a proportion of the words and during subsequent nocturnal sleep. Nocturnal dopamine accelerated forgetting for words presented once but it did not affect memory for words presented twice. During slow wave sleep, L-DOPA also increased spindle amplitude around slow oscillation peaks. Larger dopamine-induced difference in word memory was associated with a larger increase in spindle amplitude. Dopamine-dependent memory processing may therefore modulate spindles dependent on slow-oscillation phase. Further, overnight dopamine increased total slow wave sleep duration by approximately 11%. This pharmaceutical modification of slow wave sleep may have potential health-enhancing benefits in old age that could include cognitive enhancement and Alzheimer’s prevention.One Sentence SummaryDopamine before sleep promotes forgetting of weak memory traces associated with increased spindle amplitude around the peak of a slow oscillations.

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; pWe 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.

Dopamine has been implicated in learning from rewards and punishment, and in the expression of this learning. However, many studies do not fully separate retrieval and decision mechanisms from learning and consolidation. Here, we investigated the effects of levodopa (dopamine precursor) on choice performance (isolated from learning or consolidation). We gave 31 healthy older adults 150mg of levodopa or placebo (double-blinded, randomised) 1 hour before testing them on stimuli they had learned the value of the previous day. We found that levodopa did not affect the overall accuracy of choices, nor the relative expression of positively or negatively reinforced values. This contradicts several studies and suggests that dopamine may not play a role in the choice performance for values learned through reinforcement learning in humans.