Dataset Information

Structural connectivity centrality changes mark the path toward Alzheimer's disease.

ABSTRACT:

Introduction

The pathophysiological process of Alzheimer's disease is thought to begin years before clinical decline, with evidence suggesting prion-like spreading processes of neurofibrillary tangles and amyloid plaques.

Methods

Using diffusion magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative database, we first identified relevant features for dementia diagnosis. We then created dynamic models with the Nathan Kline Institute-Rockland Sample database to estimate the earliest detectable stage associated with dementia in the simulated disease progression.

Results

A classifier based on centrality measures provides informative predictions. Strength and closeness centralities are the most discriminative features, which are associated with the medial temporal lobe and subcortical regions, together with posterior and occipital brain regions. Our model simulations suggest that changes associated with dementia begin to manifest structurally at early stages.

Discussion

Our analyses suggest that diffusion magnetic resonance imaging-based centrality measures can offer a tool for early disease detection before clinical dementia onset.

SUBMITTER: Peraza LR

PROVIDER: S-EPMC6350419 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

Structural connectivity centrality changes mark the path toward Alzheimer's disease.

Peraza Luis R LR Díaz-Parra Antonio A Kennion Oliver O Moratal David D Taylor John-Paul JP Kaiser Marcus M Bauer Roman R

Alzheimer's & dementia (Amsterdam, Netherlands) 20190118

<h4>Introduction</h4>The pathophysiological process of Alzheimer's disease is thought to begin years before clinical decline, with evidence suggesting prion-like spreading processes of neurofibrillary tangles and amyloid plaques.<h4>Methods</h4>Using diffusion magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative database, we first identified relevant features for dementia diagnosis. We then created dynamic models with the Nathan Kline Institute-Rockland Sample dat ...[more]

PMID: 30723773

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Project description:Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants-TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1-potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish in vivo and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker-drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.

Dataset Information

Structural connectivity centrality changes mark the path toward Alzheimer's disease.

Introduction

Methods

Results

Discussion

Publications

Structural connectivity centrality changes mark the path toward Alzheimer's disease.

Similar Datasets

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