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Differentiation of mild cognitive impairment using an entorhinal cortex-based test of virtual reality navigation.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Howett, David 
Castegnaro, Andrea 
Krzywicka, Katarzyna 
Hagman, Johanna 
Marchment, Deepti 

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.

Description

Keywords

Alzheimer’s disease, entorhinal cortex, mild cognitive impairment, path integration, virtual reality, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Biomarkers, Cognitive Dysfunction, Diagnosis, Differential, Early Diagnosis, Entorhinal Cortex, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Sensitivity and Specificity, Virtual Reality

Journal Title

Brain

Conference Name

Journal ISSN

0006-8950
1460-2156

Volume Title

142

Publisher

Oxford University Press (OUP)
Sponsorship
Alzheimer's Research UK (ARUK-NC2017-CAM)
MRC (Unknown)
Medical Research Council (MC_UU_00005/8)