Real-space path integration is impaired in Alzheimer’s disease and mild cognitive impairment

Mokrišová, Ivana; Laczó, Jan; Andel, Ross; Gažová, Ivana; Vyhnálek, Martin; Nedelská, Zuzana; Levčík, David; Cerman, Jiří; Vlček, Kamil; Hort, Jakub

doi:10.1016/j.bbr.2016.03.052

Cited by 51 publications

(42 citation statements)

References 43 publications

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“…The navigational impairments observed in MCI patients is in line with previous navigation research (Hort et al, 2007;Laczó et al, 2014;Peter et al, 2018) and with the sparse literature on real-space PI in MCI and AD (Mokrisova et al, 2016). Significantly larger absolute distance errors were observed in MCI+ than in MCI-, with near-total separation of these two groups on this primary outcome measure, with the latter group exhibiting comparable performance to HCs.…”

Section: !supporting

confidence: 88%

“…Absolute distance error, the primary outcome measure, was defined as the Euclidean distance between estimated and actual location of cone one, in line with previous research (Fig. 2, Chrastil et al, 2015;Mokrisova et al, 2016). Two secondary outcome measures were included to deconstruct absolute distance errors into its proportional angular and linear components.…”

Section: !mentioning

confidence: 99%

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Differentiation of mild cognitive impairment using an entorhinal cortex-based test of VR navigation

Howett

Castegnaro

Krzywicka

et al. 2018

Preprint

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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-dependent navigation is impaired in predementia 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-dependent 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 biomarkernegative patients, whose performance did not significantly differ from controls participants.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 ! 3! 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.

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Section: !supporting

confidence: 88%

Section: !mentioning

confidence: 99%

Differentiation of mild cognitive impairment using an entorhinal cortex-based test of VR navigation

Howett

Castegnaro

Krzywicka

et al. 2018

Preprint

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“…Moreover, deficits in route learning performance in early AD have been associated with hypometabolism in the retrosplenial cortex, thalamus and parietal cortex (Pengas et al, 2012). Mokrisova et al (2016) showed that deficits in path integration in AD and MCI were mediated in part by changes in hippocampal, entorhinal and parietal cortex volumes. Cumulatively, these findings suggest that changes in the ‘navigation circuit’ may be a predominant and early consequence of AD and manifest as behavioral deficiencies in spatial navigation.…”

Section: Clinical Potential Of Spatial Navigationmentioning

confidence: 99%

The Aging Navigational System

Lester

Moffat

Wiener

et al. 2017

Neuron

298

280

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“…AD patients show severe difficulty storing and retrieving a cognitive map of virtual environments (DeIpolyi et al, 2007;Jheng and Pai, 2009;Serino et al, 2015), consistent with significant cell loss in the hippocampus which is home to the place cells, the cellular building blocks of the human and rodent 'cognitive map' (Bird and Burgess, 2008;O'Keefe & Nadel, 1978). Navigation tests also show egocentric self-reference strategies are also lost in AD patients, due to various metabolic and volumetric changes that occur in the retrosplenial cortex, posterior cingulate cortex (PCC) and parietal cortex where head direction and border cells reside (Mokrisova et al, 2016;Pai and Yang, 2013;Pengas et al, 2010;Serino et al, 2015).…”

Section: Introductionmentioning

confidence: 76%

“…Gold standard episodic memory tests fail to capture the first symptomatic manifestation of AD (Coughlan et al, 2018b;Jessen et al, 2014;Zimermann et al, 2019) and therefore, alternative diagnostic tools are urgently required. Spatial navigation has emerged as a critical diagnostic tool in the clinical AD and mild cognitively impaired cohorts due to its sensitivity and specificity for AD pathophysiology (Hort et al, 2014(Hort et al, , 2007Howett et al, 2019;Laczó et al, 2009;Lester et al, 2017;Mokrisova et al, 2016;Pai and Jacobs, 2004;Serino and Riva, 2013;Tu et al, 2015;Vlček, K., & Laczó, 2014). For example, spatial navigation tasks, such as the Virtual Supermarket Test (VST) can distinguish AD from other dementias and have been implemented in many high-profile clinical trials as treatment outcome measures.…”

Section: Introductionmentioning

confidence: 99%

Functional connectivity between the entorhinal and posterior cingulate cortices associated with navigation impairment following path integration in at-genetic-risk Alzheimer’s disease

Coughlan

Zhukovsky²,

Puthusseryppady

et al. 2019

Preprint

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count: Main text count: Tables: Figures: Abbreviations: AD = Alzheimer's disease; VST = Virtual Supermarket task, APOE = Apolipoprotein Epsilon; EC = Entorhinal Cortex; MCI = Mild Cognitive Impairment; PCC = Posterior Cingulate CortexABSTRACT Navigation processes mediated selectively by the entorhinal cortex (EC) may be impaired in individuals with suspected preclinical Alzheimer's disease (AD), but the clinical utility of navigation tests to detect such impairments remains to be established. In a sample of 64 individuals (32 e3e3 and 32 e3e4), we tested whether an existing paradigm, the Virtual Supermarket Test (VST), can reliably detect the presence or absence of the APOE e4 allele which accelerates amyloid plaque deposition in the brain. The present study assessed four major navigational processes that are subserved by functionally specialised cell groups located in AD vulnerable regions including the EC and examined the relationship between navigation process and regional functional connectivity (FC) given FC is a marker early ADrelated tau seeding. While heading direction and spatial memory were unaffected by at-risk AD, clear altered navigational strategies following path integration were found on the VST in the e3e4 group. The APOE-sensitive VST measure correctly classified 77% of the APOE cohort. Including resting-state FC between the EC and the posterior cingulate cortex, a correlate of the path integration deficit in the APOE e4 group, the classification model increased the accuracy to 85%. Our findings show that at-genetic-risk AD selectively impairs path integration and biases self-reported spatial locations away from the centre and towards the boundary of a virtual environment. Importantly, this impairment is associated with reduced FC between the EC and the posterior cingulate cortex, which in turn informs the neurobiological mechanisms of at-genetic-risk of AD.

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Real-space path integration is impaired in Alzheimer’s disease and mild cognitive impairment

Cited by 51 publications

References 43 publications

Differentiation of mild cognitive impairment using an entorhinal cortex-based test of VR navigation

Differentiation of mild cognitive impairment using an entorhinal cortex-based test of VR navigation

The Aging Navigational System

Functional connectivity between the entorhinal and posterior cingulate cortices associated with navigation impairment following path integration in at-genetic-risk Alzheimer’s disease

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