Entorhinal-based path integration selectively predicts midlife risk of Alzheimer's disease.

INTRODUCTION: Entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration (PI)-based spatial behaviors, we predicted that PI impairment would represent the first behavioral change in adults at risk of AD. METHODS: We compared immersive virtual reality (VR) PI ability to other cognitive domains in 100 asymptomatic midlife adults stratified by hereditary and physiological AD risk factors. In some participants, behavioral data were compared to 7T magnetic resonance imaging (MRI) measures of brain structure and function. RESULTS: Midlife PI impairments predicted both hereditary and physiological AD risk, with no corresponding multi-risk impairment in episodic memory or other spatial behaviors. Impairments associated with altered functional MRI signal in the posterior-medial EC. DISCUSSION: Altered PI may represent the transition point from at-risk state to disease manifestation in AD, prior to impairment in other cognitive domains.

Overestimation in angular path integration precedes Alzheimer's dementia.

Path integration (PI) is impaired early in Alzheimer's disease (AD) but reflects multiple sub-processes that may be differentially sensitive to AD. To characterize these sub-processes, we developed a novel generative linear-angular model of PI (GLAMPI) to fit the inbound paths of healthy elderly participants performing triangle completion, a popular PI task, in immersive virtual reality with real movement. The model fits seven parameters reflecting the encoding, calculation, and production errors associated with inaccuracies in PI. We compared these parameters across younger and older participants and patients with mild cognitive impairment (MCI), including those with (MCI+) and without (MCI-) cerebrospinal fluid biomarkers of AD neuropathology. MCI patients showed overestimation of the angular turn in the outbound path and more variable inbound distances and directions compared with healthy elderly. MCI+ were best distinguished from MCI- patients by overestimation of outbound turns and more variable inbound directions. Our results suggest that overestimation of turning underlies the PI errors seen in patients with early AD, indicating specific neural pathways and diagnostic behaviors for further research.

Path integration selectively predicts midlife risk of Alzheimer's disease.

The entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer's disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours. Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.

Assessing mild cognitive impairment using object-location memory in immersive virtual environments.

Pathological changes in the medial temporal lobe (MTL) are found in the early stages of Alzheimer's disease (AD) and aging. The earliest pathological accumulation of tau colocalizes with the areas of the MTL involved in object processing as part of a wider anterolateral network. Here, we sought to assess the diagnostic potential of memory for object locations in iVR environments in individuals at high risk of AD dementia (amnestic mild cognitive impairment [aMCI] n = 23) as compared to age-related cognitive decline. Consistent with our primary hypothesis that early AD would be associated with impaired object location, aMCI patients exhibited impaired spatial feature binding. Compared to both older (n = 24) and younger (n = 53) controls, aMCI patients, recalled object locations with significantly less accuracy (p < .001), with a trend toward an impaired identification of the object's correct context (p = .05). Importantly, these findings were not explained by deficits in object recognition (p = .6). These deficits differentiated aMCI from controls with greater accuracy (AUC = 0.89) than the standard neuropsychological tests. Within the aMCI group, 16 had CSF biomarkers indicative of their likely AD status (MCI+ n = 9 vs. MCI- n = 7). MCI+ showed lower accuracy in the object-context association than MCI- (p = .03) suggesting a selective deficit in object-context binding postulated to be associated with anterior-temporal areas. MRI volumetric analysis across healthy older participants and aMCI revealed that test performance positively correlates with lateral entorhinal cortex volumes (p < .05) and hippocampus volumes (p < .01), consistent with their hypothesized role in binding contextual and spatial information with object identity. Our results indicate that tests relying on the anterolateral object processing stream, and in particular requiring successful binding of an object with spatial information, may aid detection of pre-dementia AD due to the underlying early spread of tau pathology.

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

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-ß 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.