Impaired Parahippocampal Gyrus–Orbitofrontal Cortex Circuit Associated with Visuospatial Memory Deficit as a Potential Biomarker and Interventional Approach for Alzheimer Disease
1 Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing 210009, China
2 Shenzhen Key Laboratory of Neuropsychiatric Modulation, Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, Chinese Academy of Science (CAS) Key Laboratory of Brain Connectome and Manipulation, the Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China
3 Laboratory Animal Center, Southeast University, Nanjing 210009, China
4 Department of Neurology, Xuan Wu Hospital of Capital Medical University, Beijing 100053, China
5 Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
6 University of the Chinese Academy of Sciences, Beijing 100049, China
7 Beijing Institute of Geriatrics, Beijing, China
8 National Clinical Research Center for Geriatric Disorders, Beijing, China
9 Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Beijing, China
Abstract
The parahippocampal gyrus–orbitofrontal cortex (PHG–OFC) circuit in humans is homologous to the postrhinal cortex (POR)–ventral lateral orbitofrontal cortex (vlOFC) circuit in rodents. Both are associated with visuospatial malfunctions in Alzheimer’s disease (AD). However, the underlying mechanisms remain to be elucidated. In this study, we explored the relationship between an impaired POR–vlOFC circuit and visuospatial memory deficits through retrograde tracing and in vivo local field potential recordings in 5XFAD mice, and investigated alterations of the PHG–OFC circuit by multi-domain magnetic resonance imaging (MRI) in patients on the AD spectrum. We demonstrated that an impaired glutamatergic POR–vlOFC circuit resulted in deficient visuospatial memory in 5XFAD mice. Moreover, MRI measurements of the PHG–OFC circuit had an accuracy of 77.33% for the classification of amnestic mild cognitive impairment converters versus non-converters. Thus, the PHG–OFC circuit explains the neuroanatomical basis of visuospatial memory deficits in AD, thereby providing a potential predictor for AD progression and a promising interventional approach for AD.
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