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The entorhinal-hippocampal circuit is one of the earliest sites of cortical pathology in Alzheimer's disease (AD). Visuospatial memory paradigms that are mediated by the entorhinal-hippocampal circuit may offer a means to detect memory impairment during the early stages of AD. In this study, we developed a 4-min visuospatial memory paradigm called VisMET (Visuospatial Memory Eye-Tracking Task) that passively assesses memory using eye movements rather than explicit memory judgements. We had 296 control or memory-impaired participants view a set of images followed by a modified version of the images with either an object removed, or a new object added. Healthy controls spent significantly more time viewing these manipulations compared to subjects with mild cognitive impairment and AD. Using a logistic regression model, the amount of time that individuals viewed these manipulations could predict cognitive impairment and disease status with an out of sample area under the receiver-operator characteristic curve of 0.85. Based on these results, VisMET offers a passive, sensitive, and efficient memory paradigm capable of detecting objective memory impairment and predicting cognitive and disease status.

Introduction: We and collaborators discovered that flickering lights and sound at gamma frequency (40 Hz) reduce Alzheimer’s disease (AD) pathology and alter immune cells and signaling in mice. To determine the feasibility of this intervention in humans we tested the safety, tolerability, and daily adherence to extended audiovisual gamma flicker stimulation. Methods: Ten patients with mild cognitive impairment due to underlying AD received 1-hour daily gamma flicker using audiovisual stimulation for 4 or 8 weeks at home with a delayed start design. Results: Gamma flicker was safe, tolerable, and adherable. Participants’ neural activity entrained to stimulation. Magnetic resonance imaging and cerebral spinal fluid proteomics show preliminary evidence that prolonged flicker affects neural networks and immune factors in the nervous system. Discussion: These findings show that prolonged gamma sensory flicker is safe, tolerable, and feasible with preliminary indications of immune and network effects, supporting further study of gamma stimulation in AD. [ABSTRACT FROM AUTHOR]

Objective: Compared to individuals without cognitive impairment (CI), those with CI exhibit differences in both basic oculomotor functions and complex viewing behaviors. However, the characteristics of the differences and how those differences relate to various cognitive functions have not been widely explored. In this work we aimed to quantify those differences and assess general cognitive impairment and specific cognitive functions., Methods: A validated passive viewing memory test with eyetracking was administered to 348 healthy controls and CI individuals. Spatial, temporal, semantic, and other composite features were extracted from the estimated eye-gaze locations on the corresponding pictures displayed during the test. These features were then used to characterize viewing patterns, classify cognitive impairment, and estimate scores in various neuropsychological tests using machine learning., Results: Statistically significant differences in spatial, spatiotemporal, and semantic features were found between healthy controls and individuals with CI. CI group spent more time gazing at the center of the image, looked at more regions of interest (ROI), transitioned less often between ROI yet in a more unpredictable manner, and had different semantic preferences. A combination of these features achieved an area under the receiver-operator curve of 0.78 in differentiating CI individuals from controls. Statistically significant correlations were identified between actual and estimated MoCA scores and other neuropsychological tests., Conclusion: Evaluating visual exploration behaviors provided quantitative and systematic evidence of differences in CI individuals, leading to an improved approach for passive cognitive impairment screening., Significance: The proposed passive, accessible, and scalable approach could help with earlier detection and a better understanding of cognitive impairment.

Introduction: We and collaborators discovered that flickering lights and sound at gamma frequency (40 Hz) reduce Alzheimer's disease (AD) pathology and alter immune cells and signaling in mice. To determine the feasibility of this intervention in humans we tested the safety, tolerability, and daily adherence to extended audiovisual gamma flicker stimulation., Methods: Ten patients with mild cognitive impairment due to underlying AD received 1-hour daily gamma flicker using audiovisual stimulation for 4 or 8 weeks at home with a delayed start design., Results: Gamma flicker was safe, tolerable, and adherable. Participants' neural activity entrained to stimulation. Magnetic resonance imaging and cerebral spinal fluid proteomics show preliminary evidence that prolonged flicker affects neural networks and immune factors in the nervous system., Discussion: These findings show that prolonged gamma sensory flicker is safe, tolerable, and feasible with preliminary indications of immune and network effects, supporting further study of gamma stimulation in AD., Competing Interests: Annabelle C. Singer owns shares in Cognito Therapeutics, which aims to develop gamma stimulation‐related products; these conflicts of interest have been disclosed to and are managed by the Georgia Institute of Technology Office of Research Integrity Assurance. Since the completion of this study, Dr. Levey serves as a consultant to Cognito Therapeutics, who provides funding support for this study and manufactures products used in this study. Dr. Levey receives compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. The authors declare no other competing financial interests., (© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)