Dataset Information

Disrupted structural and functional brain connectomes in mild cognitive impairment and Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is the most common type of dementia, comprising an estimated 60-80% of all dementia cases. It is clinically characterized by impairments of memory and other cognitive functions. Previous studies have demonstrated that these impairments are associated with abnormal structural and functional connections among brain regions, leading to a disconnection concept of AD. With the advent of a combination of non-invasive neuroimaging (structural magnetic resonance imaging (MRI), diffusion MRI, and functional MRI) and neurophysiological techniques (electroencephalography and magnetoencephalography) with graph theoretical analysis, recent studies have shown that patients with AD and mild cognitive impairment (MCI), the prodromal stage of AD, exhibit disrupted topological organization in large-scale brain networks (i.e., connectomics) and that this disruption is significantly correlated with the decline of cognitive functions. In this review, we summarize the recent progress of brain connectomics in AD and MCI, focusing on the changes in the topological organization of large-scale structural and functional brain networks using graph theoretical approaches. Based on the two different perspectives of information segregation and integration, the literature reviewed here suggests that AD and MCI are associated with disrupted segregation and integration in brain networks. Thus, these connectomics studies open up a new window for understanding the pathophysiological mechanisms of AD and demonstrate the potential to uncover imaging biomarkers for clinical diagnosis and treatment evaluation for this disease.

SUBMITTER: Dai Z

PROVIDER: S-EPMC5562665 | biostudies-other | 2014 Apr

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:Patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) show functional and structural connectivity alterations in the default mode network (DMN) while cerebrovascular disease (CeVD) shows functional and structural connectivity changes in the executive control network (ECN). Such disruptions are associated with memory and executive function impairment, respectively. Concurrent AD and CeVD pathology is associated with a higher rate of cognitive decline and differential neurodegenerative patterns. Together, such findings are likely reflective of different underlying pathology in AD with and without CeVD. However, few studies have examined the effect of CeVD on network functional connectivity (task-free functional magnetic resonance imaging (fMRI)) and structural connectivity (diffusion MRI) of the DMN and ECN in aMCI and AD using a hypothesis-driven multiple seed-based approach.We examined functional and structural connectivity network changes in 39 aMCI, 50 aMCI+CeVD, 47 AD, 47 AD+CeVD, and 65 healthy controls (HCs) and their associations with cognitive impairment in the executive/attention and memory domains.We demonstrate divergent DMN and ECN functional connectivity changes in CeVD and non-CeVD subjects. Compared with controls, intra-DMN hippocampal functional connectivity reductions were observed in both AD and AD+CeVD, while intra-DMN parietal and medial prefrontal-parietal functional connectivity was higher in AD+CeVD and aMCI+CeVD, but lower in AD. Intra-ECN frontal functional connectivity increases and fronto-parietal functional connectivity decreases occurred in CeVD but not non-CeVD subjects. Such functional connectivity alterations were related with cognitive impairment in a dissociative manner: intra-DMN functional connectivity changes were associated with worse cognition primarily in non-CeVD groups, while intra-ECN functional connectivity changes were associated with worse cognition primarily in CeVD groups. Additionally, CeVD and non-CeVD groups showed overlapping and distinct alterations in inter-network DMN-ECN functional connectivity depending on disease severity. In contrast to functional connectivity, CeVD groups had greater network structural connectivity damage compared with non-CeVD groups in both aMCI and AD patients. Network structural connectivity damage was associated with worse cognition.We demonstrate differential functional and structural network changes between aMCI and AD patients with and without CeVD through diverging and deleterious network-based degeneration underlying domain-specific cognitive impairment.

Project description:BackgroundAll cells accumulate insoluble protein aggregates throughout their lifespan. While many studies have characterized the canonical disease-associated protein aggregates, such as those associated with amyloid plaques, additional, undefined proteins aggregate in the brain and may be directly associated with disease and lifespan.MethodsA proteomics approach was used to identify a large subset of insoluble proteins in the mild cognitively impaired (MCI) and Alzheimer's disease (AD) human brain. Cortical samples from control, MCI, and AD patients were separated into detergent-soluble and detergent-insoluble fractions, and high-resolution LC/MS/MS technology was used to determine which proteins became more insoluble in the disease state. Bioinformatics analyses were used to determine if the alteration of protein aggregation between AD and control patients was associated with any specific biological process. Western blots were used to validate the proteomics data and to assess the levels of secondary protein modifications in MCI and AD.ResultsThere was a stage-dependent increase in detergent-insoluble proteins, with more extreme changes occurring in the AD cohort. Glycolysis was the most significantly overrepresented gene ontology biological process associated with the alteration of protein aggregation between AD and control patients. It was further shown that many low molecular weight proteins that were enriched in the AD brain were also highly aggregated, migrating on SDS-PAGE far above their predicted molecular masses. Glucose-6-phosphate isomerase, ubiquitin carboxyl-terminal hydrolase isoenzyme L1 (UCHL1/PARK5), and the DNA damage repair enzyme KU70 were among the top insoluble proteins identified by proteomics and validated by Western blot to be increased in the insoluble fractions of both MCI and AD brain samples.ConclusionsDiverse proteins became more detergent-insoluble in the brains of both MCI and AD patients compared to age-matched controls, suggesting that multiple proteins aggregate in these diseases, likely posing a direct toxic insult to neurons. Furthermore, detergent-insoluble proteins included those with important biological activities for critical cellular processes such as energetics, proteolysis, and DNA damage repair. Thus, reduced protein solubility likely promotes aggregation and limits functionality, reducing the efficiency of multiple aspects of cell physiology. Pharmaceutical interventions that increase autophagy may provide a useful therapeutic treatment to combat protein aggregation.

Dataset Information

Disrupted structural and functional brain connectomes in mild cognitive impairment and Alzheimer's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets