Abstract
The entorhinal cortex is one of the first regions to exhibit neurodegeneration in Alzheimer's disease, and as such identification of entorhinal cortex dysfunction may aid detection of the disease in its earliest stages. Extensive evidence demonstrates that the entorhinal cortex is critically implicated in navigation underpinned by the firing of spatially modulated neurons. This study tested the hypothesis that entorhinal-based navigation is impaired in pre-dementia Alzheimer's disease. Forty-five patients with mild cognitive impairment (26 with CSF Alzheimer's disease biomarker data: 12 biomarker-positive and 14 biomarker-negative) and 41 healthy control participants undertook an immersive virtual reality path integration test, as a measure of entorhinal-based navigation. Behavioural performance was correlated with MRI measures of entorhinal cortex volume, and the classification accuracy of the path integration task was compared with a battery of cognitive tests considered sensitive and specific for early Alzheimer's disease. Biomarker-positive patients exhibited larger errors in the navigation task than biomarker-negative patients, whose performance did not significantly differ from controls participants. Path-integration performance correlated with Alzheimer's disease molecular pathology, with levels of CSF amyloid-β and total tau contributing independently to distance error. Path integration errors were negatively correlated with the volumes of the total entorhinal cortex and of its posteromedial subdivision. The path integration task demonstrated higher diagnostic sensitivity and specificity for differentiating biomarker positive versus negative patients (area under the curve = 0.90) than was achieved by the best of the cognitive tests (area under the curve = 0.57). This study demonstrates that an entorhinal cortex-based virtual reality navigation task can differentiate patients with mild cognitive impairment at low and high risk of developing dementia, with classification accuracy superior to reference cognitive tests considered to be highly sensitive to early Alzheimer's disease. This study provides evidence that navigation tasks may aid early diagnosis of Alzheimer's disease, and the basis of this in animal cellular and behavioural studies provides the opportunity to answer the unmet need for translatable outcome measures for comparing treatment effect across preclinical and clinical trial phases of future anti-Alzheimer's drugs.
Highlights
To date, all interventional trials aimed at slowing the progression of Alzheimer’s disease have failed
Addenbrooke’s Cognitive Examination-Revised (ACE-R) score correlated with absolute distance errors across healthy control subjects and total mild cognitive impairment (MCI) patients [t(1,85) = 2.89, P 5 0.01] and across MCI + and MCIÀ groups [t(1,26) = 4.01, P 5 0.01], with lower ACER scores being associated with greater distance errors
This study demonstrated that performance on a novel immersive virtual reality path integration paradigm, based on the central role of the entorhinal cortex in navigation, was impaired in MCI patients compared to healthy controls
Summary
All interventional trials aimed at slowing the progression of Alzheimer’s disease have failed. Detection of Alzheimer’s disease-related changes in entorhinal cortex (EC) function provides a potential solution to both of these problems. There is emerging evidence that the initial stages of Alzheimer’s disease may be associated with the trans-neuronal spread of pathological tau within the EC-hippocampal circuit (de Calignon et al, 2012; Ahmed et al, 2014), prior to neocortical infiltration. Tests sensitive to EC function might have added value in identifying the very earliest stages of Alzheimer’s disease, prior to hippocampal involvement
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
