The function and structure of the entorhinal cortex in mild cognitive impairment

Background: The entorhinal cortex (EC) is the first brain region to exhibit neurodegeneration in Alzheimer’s disease (AD). As such, tests of EC function may help aid detection of the disease in its earliest stages. Animal and human studies indicate that the posteromedial (pmEC) and anterolateral (alEC) subdivisions of the EC are involved respectively in navigation and object-location memory. The advent of immersive VR (iVR) technology provides an opportunity to determine whether tests of pmEC and alEC function has value in the detection of AD prior to dementia onset. Aim: To test the hypotheses that measures of pmEC and alEC function and structure differentiate i) patients with mild cognitive impairment (MCI) from age-matched healthy controls and ii) MCI patients at high and low risk of developing AD dementia. Methodology: Participants underwent testing of EC function using novel iVR paradigms of path integration and object-location memory. Total EC, pm-EC and al-EC volumes were segmented from high resolution MRI. A proportion of MCI patients underwent CSF testing for AD biomarkers to separate into biomarker-positive and negative groups (MCI+ and MCI-). The ability of the VR tests to classify pre-dementia AD (i.e. MCI+ patients) was compared with that of a battery of comparator cognitive tests used in current clinical and research practice. 8 Results: Performance on the path integration task was not only impaired in MCI but importantly differentiated MCI+ from MCI- with greater classification accuracy than comparator cognitive tasks. Task performance correlated with pm-EC volume. For the object-location task MCI patients demonstrated larger distance errors than controls, with performance associated with both anterolateral EC volume and total hippocampal volume. However, no difference between MCI+ and MCI- was observed. Conclusion This work demonstrates that iVR-based testing of EC function may improve diagnosis of early AD above and beyond current cognitive tests. The basis of such tests on single cell physiology and their comparability with behavioural tasks used in animal models of disease, confers additional advantages for translational research aimed at understanding the mechanisms linking pathological spread, disruption of cell physiology and behavioural alterations in early AD.