Disconnection Hypothesis Of Alzheimer’s Disease And Amnestic Mild Cognitive Impairment

Objective:Alzheimer’s disease (AD) is the most common cause of dementia in older individual. Because of insidious onset, high incidence and ineffective treatments, AD has become a public health problem. Amnestic mild cognitive impairment (aMCI) is currently considered as the prodromal stage of AD, and has the high-risk to convert to AD. The use of multi-modality imaging technology provides a mulitidisciplinary approach to investigate the pathophysiology mechanism of AD and aMCI. Functional connectivity (FC) and resting state networks, which mirrors the synchronism of neuronal activity between different brain regions, are important analytical methods of functional magnetic resonance imaging (fMRI). And diffusion tensor imaging (DTI) has been extensively applied to examine the integrity of white matter fiber bundles in the nervous system by evaluating the translational motion of water molecules. Now, some researchers proposed a disconnection hypothesis in AD and aMCI. To test this hypothesis, we combined fMRI and DTI to investigate the changes of resting state networks, hippocampal functional connectivity and fornix body microstructure, and furthermore to discuss the relationship between structural and functional connectivity.Methods:We recruited two cohort groups. We explored altered functional connectivities based on previously well-defined brain areas that comprised the five key functional systems (i.e., the default mode network, dorsal attention network, control network, salience network, and sensorimotor network) in a large sample of patients,35 with AD and 27 with MCI subjects, compared with 27 normal cognitive (NC) subjects. The other cohort study included 36 AD,33 aMCI, and 38 NC to study the changes of hippocampal functional connectivity with the whole brain and of fornix microstructure by combined fMRI and DTI. We also wished to examine the relationship between the structural and functional connectivity of hippocampus.Results:(1) We investigated the functional connectivity pattern both intra-and inter-networks in AD and MCI patients based on three levels. We found the control network showed a slight increase intranetwork FC and the interaction between dorsal attention network and sensorimotor network was first attacked in the MCI group. With the disease progression, we found that much of intra-and inter-network connectivity were impaired in AD. The aberrant FC pattern verified the disconnection hypothesis, which was not only included intranetwork disconnection, but also the internetwork disconnection.(2) We combined fMRI and DTI to investigate the functional and structural connectivity of hippocampus in AD and aMCI groups, which aimed to analysis the relationship between resting state FC and the integrity of white matter fiber bundles. We found decreased FC between the bilateral hippocampus and some brain regions in the default mode network and control network, as well as damaged integrity of fornix body (decreased fractional anisotropy and increased diffusivity) in AD and aMCI groups. We also found left hippocampal FC with some regions, the integrity of fornix body, and cognition were related. Therefore, our findings suggested that the damage of the integrity of white matter may partially explain the reduced resting-state FC of the hippocampus in AD and aMCI. So disconnection hypothesis not only included functional disconnection, but also anatomical disconnection.Conclusion:AD and aMCI were disconnectivity disease, whose disconnection not only included functional (intra- and inter-network disconnection), but also structural disconnection. The combined using of DTI and fMRI provide a multidisciplinary approach to investigate underlying pathophysiology mechanism in AD.