Aberrant Hippocampal Functional Connectivity Is Associated with Fornix White Matter Integrity in Alzheimer’s Disease and Mild Cognitive Impairment

Article type: Research Article

Authors: Wang, Pan^{a; b} | Zhou, Bo^b | Yao, Hongxiang^c | Xie, Sangma^{d; e; i} | Feng, Feng^b | Zhang, Zengqiang^f | Guo, Yan’e^b | An, Ningyu^c | Zhou, Yuying^{a; *} | Zhang, Xi^{b; *} | Liu, Yong^{d; e; g; h; *}

Affiliations: [a] Department of Neurology, Tianjin Huanhu Hospital, Nankai University, Tianjin, China | [b] Department of Neurology, The Second Medical Centre, National Clinical Research Centre for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China | [c] Department of Radiology, The Second Medical Centre, National Clinical Research Centre for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China | [d] Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing, China | [e] National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China | [f] Hainan Hospital of Chinese PLA General Hospital, Sanya, China | [g] CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Automation, Chinese Academy of Sciences, Beijing, China | [h] School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China | [i] College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou, China

Correspondence: [*] Correspondence to: Dr. Yong Liu, Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China. E-mail: yliu@nlpr.ia.ac.cn.; Dr. Xi Zhang, The Second Medical Centre, National Clinical Research Centre for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China. E-mail: zhangxi@301hospital.com.cn.; Dr. Yuying Zhou, Department of Neurology, Tianjin Huanhu Hospital, Nankai University, Tianjin, 300350, China. E-mail: qiying789@sina.cn.

Abstract: Background:Alzheimer’s disease (AD) is the most common cause of dementia in older individuals, and amnestic mild cognitive impairment (aMCI) is currently considered the prodromal stage of AD. The hippocampus and fornix interact functionally and structurally, with the fornix being the major efferent white matter tract from the hippocampus. Objective:The main aim of this study was to examine the impairments present in subjects with AD or aMCI and the relationship of these impairments with the microstructure of the fornix and the functional connectivity (FC) and gray matter volume of the hippocampus. Methods:Forty-four AD, 34 aMCI, and 41 age- and gender-matched normal controls (NCs) underwent neuropsychological assessments and multimode MRI. We chose the bilateral hippocampi as the region of interest in which gray matter alterations and FC with the whole brain were assessed and the fornix body as the region of interest in which the microstructural integrity of the white matter was observed. We also evaluated the relationship among gray matter alterations, the abnormal FC of the hippocampus and the integrity of the fornix in AD/aMCI Results:Compared to the NC group, the AD and aMCI groups demonstrated decreased gray matter volume, reduced FC between the bilateral hippocampi and several brain regions in the default mode network and control network, and damaged integrity of the fornix body (decreased fractional anisotropy and increased diffusivity). We also found that left hippocampal FC with some regions, the integrity of the fornix body, and cognition ability were significantly correlated. Therefore, our findings suggest that damage to white matter integrity may partially explain the reduced resting-state FC of the hippocampus in AD and aMCI. Conclusion:AD and aMCI are diseases of disconnectivity including not only functional but also structural disconnectivity. Damage to white matter integrity may partially explain the reduced resting-state FC in AD and aMCI. These findings have significant implications for diagnostics and modeling and provide insights for understanding the disconnection syndrome in AD.

Keywords: Alzheimer’s disease, fornix, functional connectivity, hippocampus, mild cognitive impairment, white matter integrity

DOI: 10.3233/JAD-200066

Journal: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1153-1168, 2020