Interhemispheric Functional and Structural Disconnection in Alzheimer’s Disease: A Combined Resting-State fMRI and DTI Study

May Interhemispheric Functional and Structural Disconnection in Alzheimer's Disease: A Combined Resting-State fMRI and DTI Study Zhiqun Wang 0 1 Jianli Wang 0 1 Han Zhang 0 1 Robert Mchugh 0 1 Xiaoyu Sun 0 1 Kuncheng Li 0 1 Qing X. Yang 0 1 0 1 Department of Radiology, Xuanwu Hospital of Capital Medical University , Beijing , China , 2 Center for NMR Research, Department of Radiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America, 3 Center for Cognition and Brain Disorders and the Affiliated Hospital, Hangzhou Normal University , Hangzhou, Zhejiang , China , 4 Key Laboratory for Neurodegenerative Diseases (Capital Medical University), Ministry of Education , Beijing , China , 5 Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics , Beijing , China , 6 Department of Neurosurgery (George M. Leader Foundation Alzheimer's Laboratory), The Pennsylvania State University College of Medicine , Hershey, Pennsylvania , United States of America 1 Academic Editor: Yong Liu, & National Laboratory of Pattern Recognition , CHINA Neuroimaging studies have demonstrated that patients with Alzheimer's disease presented disconnection syndrome. However, little is known about the alterations of interhemispheric functional interactions and underlying structural connectivity in the AD patients. In this study, we combined resting-state functional MRI and diffusion tensor imaging (DTI) to investigate interhemispheric functional and structural connectivity in 16 AD, 16 mild cognitive impairment (MCI), as well as 16 cognitive normal healthy subjects (CN). The pattern of the resting state interhemispheric functional connectivity was measured with a voxel-mirrored - Funding: This work was supported by the NSF of China (Grant Nos. 81030028, 81000606, 81370037, 81225012, and 81471649), Beijing Natural Science Foundation (Grant No 7153166), and a NIH RO1 AG027771. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. homotopic connectivity (VMHC) method. Decreased VMHC was observed in AD and MCI subjects in anterior brain regions including the prefrontal cortices and subcortical regions with a pattern of AD<MCI<CN. Increased VMHC was observed in MCI subjects in posterior brain regions with patterns of AD/CN < MCI (sensorimotor cortex) and AD < CN/MCI (occipital gyrus). DTI analysis showed the most significant difference among the three cohorts was the fractional anisotropy in the genu of corpus callosum, which was positively associated with the VMHC of prefrontal and subcortical regions. Across all the three cohorts, the diffusion parameters in the genu of corpus callosum and VMHC in the above brain regions had significant correlation with the cognitive performance. These results demonstrate that there are specific patterns of interhemispheric functional connectivity changes in the AD and MCI, which can be significantly correlated with the integrity changes in the midline white matter structures. These results suggest that VMHC can be used as a biomarker for the degeneration of the interhemispheric connectivity in AD. Competing Interests: The authors have declared that no competing interests exist. Alzheimer's disease (AD), the most common form of dementia, presents with memory and cognitive decline. Mild cognitive impairment (MCI) is considered a precursor of AD; people with MCI are diagnosed with AD at a rate of 1015% per year [1] compared to 23% per year for the general population of the same age range. It is unclear, however, how the AD pathological lesions initiated in the medial temporal lobes lead to prominent functional deficits in memory and ultimately to dementia. Deciphering such structural-functional relationships could shed light into the trajectory of the functional pathogenesis of AD and MCI from normal aging. It has been shown that AD patients can perform normally for some tasks that relied on intrahemispheric processing but perform poorly for the tasks that required interhemispheric communication [2], which suggests a plausible hypothesis that AD patients may present a deficit in the interhemispheric integration of information. This hypothesis is supported by morphologic MRI findings that the corpus callosum, the most important fiber tract for interhemispheric connectivity, has consistently exhibited marked atrophy in AD and MCI [3, 4]. Diffusion tensor imaging (DTI) studies of the corpus callosum have demonstrated significant changes in fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity () as well as axial diffusivity (k) in early AD and MCI [57]. Yet, the relationship between these structural changes and the functional deficits remains to be determined [8]. To begin to address this issue, one must have a quantitative measure for inter-hemispheric functional connectivity. Recently, resting-state functional connectivity (RSFC) has been applied to investigate AD and MCI [915]. Using regions-of-interest-based functional connectivity approach, reduced functional connectivity related to the hippocampus [9, 10] and posterior cingulate cortex (PCC) [1113] has been observed in AD and MCI patients. By employing the independent component analysis (ICA) method, researchers have reported widespread disruptions of selective brain networks such as the default mode network (DMN) and attention network in AD and MCI [14,15]. Furthermore, functional connectivity is consistently found across homotopic sites in the two hemispheres [16, 17]. Strong interhemispheric RSFC is a common characteristic of the brains intrinsic functional networks such as the DMN, memory and sensorimotor networks [9,18,19]. Thus, the interhemispheric RSFC can be potentially used for assessing the integration of information from the two hemispheres. At present, interhemispheric functional connectivity in AD and MCI remains barely explored. Recently, a novel voxel-wise image analysis method called voxel-mirrored homotopic connectivity (VMHC) was proposed to assess RSFC between the two hemispheres. VMHC quantifies the RSFC between each voxel in one hemisphere and its mirrored counterpart in the other. Using this method, interhemispheric RSFC was found to increase in the sensorimotor regions and decrease in higher-order cognitive regions during normal aging [20]. Clinically, characteristic patterns of significant VMHC disruptions have been found in autism [21], cocaine addiction [22], schizophrenia [23], multiple sclerosis [24], and depression [25]. These findings suggested that specific patterns of interhemispheric disconnection could reflect the functional consequences of pathologic damages in the associated diseases. Thus, a specific pattern of interhemispheric connectivity change is anticipated in MCI and AD when cognitive impairments are significantly progressed. We hypothesize that there are measureable differences in interhemispheric connectivity in AD an (...truncated)