Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of toxic misfolded proteins, which are believed to have propagated from disease-specific epicenters through their corresponding large-scale structural networks in the brain. Although previous cross-sectional studies have identified potential AD-associated epicenters and corresponding brain networks, it is unclear whether these networks are associated with disease progression. Hence, this study aims to identify the most vulnerable epicenters and corresponding large-scale structural networks involved in the early stages of AD and to evaluate its associations with multiple cognitive domains using longitudinal study design. Annual neuropsychological and MRI assessments were obtained from 23 patients with AD, 37 patients with amnestic mild cognitive impairment (MCI), and 33 healthy controls (HC) for 3 years. Candidate epicenters were identified as regions with faster decline rate in the gray matter volume (GMV) in patients with MCI who progressed to AD as compared to those regions in patients without progression. These epicenters were then further used as pre-defined regions of interest to map the synchronized degeneration network (SDN) in HCs. Spatial similarity, network preference and clinical association analyses were used to evaluate the specific roles of the identified SDNs. Our results demonstrated that the hippocampus and posterior cingulate cortex (PCC) were the most vulnerable AD-associated epicenters. The corresponding PCC-SDN showed significant spatial association with the patterns of GMV atrophy rate in each patient group and the overlap of these patterns was more evident in the advanced stages of the disease. Furthermore, individuals with a higher GMV atrophy rate of the PCC-SDN also showed faster decline in multiple cognitive domains. In conclusion, our findings suggest the PCC and hippocampus are two vulnerable regions involved early in AD pathophysiology. However, the PCC-SDN, but not hippocampus-SDN, was more closely associated with AD progression. These results may provide insight into the pathophysiology of AD from large-scale network perspective.
Highlights
The human brain is traditionally considered to be a patchwork composed of neurons with specific functions and has been thoroughly dissected into histologically distinct regions based on functional organization or cellular cytoarchitecture
AD, Alzheimer’s disease; BNT, Boston Naming Test; CFT, Complex Figure Test; CSFV, Cerebrospinal fluid volume; CVVLT, Chinese version of the Verbal Learning Test; GMV, gray matter volume; HC, healthy controls; MCI progressed to AD (MCIp), mild cognitive impairment-progression; MCIs, mild cognitive impairment-stable; Mini-Mental State Examination (MMSE), Mini-Mental Screening Examination; TIV, total intracranial volume; TMT-B lines, Trail-making Test Part B lines completed in 120 s; VFT, Verbal Fluency Test; WMV, white matter volume
Our results indicated that the posterior cingulate cortex (PCC) and hippocampus were the two most vulnerable regions involved in the early-stage of AD
Summary
The human brain is traditionally considered to be a patchwork composed of neurons with specific functions and has been thoroughly dissected into histologically distinct regions based on functional organization or cellular cytoarchitecture. Recent studies further suggested that these misfolded proteins may be deposited in certain vulnerable anatomical regions early on, and spread along their corresponding largescale networks in the brain as the disease progresses (Pievani et al, 2014; Franzmeier et al, 2020). Misfolded proteins spread along corresponding brain networks rather than by geographical proximity (Iba et al, 2013) Based on this hypothesis, several cross-sectional studies have identified AD epicenters as brain areas with maximal atrophy in patients with AD compared to healthy controls (HCs). Several cross-sectional studies have identified AD epicenters as brain areas with maximal atrophy in patients with AD compared to healthy controls (HCs) These epicenters were used as seeds to determine their corresponding structural and functional brain networks in HCs (Seeley et al, 2009; Dickerson et al, 2017). It is unclear whether these identified brain networks are associated with disease progression
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