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The overall workflow of the present study. A To identify the causal associations between inflammation and neurodegenerative disorders via MR analysis. B To identify the causal associations between inflammation and brain structures via MR analysis. C Mapping of the genes coding inflammatory cytokines and differential analysis in the occipitotemporal cortex between AD and controls. D Enrichment analysis of AD-DEGs and protein–protein interactions among AD-DEGs plus inflammatory cytokines. AD: Alzheimer’s disease; CTR: control; DEGs: differentially expressed genes; SNP: single nucleotide polymorphism
Source publication
Previous in vitro and post-mortem studies have reported the role of inflammation in neurodegenerative disorders. However, the association between inflammation and brain structure in vivo and the transcriptome-driven functional basis with relevance to neurodegenerative disorders remains elusive. The aim of the present study is to identify the associ...
Citations
... Moreover, the morphological modifications occurring in distinct areas of the caudal middle frontal, inferior parietal, superior temporal, and bankssts regions could potentially correlate with a multitude of intricate molecular mechanisms underlying the progressive neurodegeneration observed in ALS. These mechanisms encompass aberrant aggregation of TDP-43, inflammatory responses and astroglial activation, synaptic dysfunction and tissue integrity impairment (Illán-Gala et al., 2020;Liu et al., 2023), etc. More longitudinal studies are warranted to elucidate the extent of cortical alterations in individuals diagnosed with ALS. ...
Background
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord with a poor prognosis. Previous studies have observed cognitive decline and changes in brain morphometry in ALS patients. However, it remains unclear whether the brain structural alterations contribute to the risk of ALS. In this study, we conducted a bidirectional two-sample Mendelian randomization (MR) and colocalization analysis to investigate this causal relationship.
Methods
Summary data of genome-wide association study were obtained for ALS and the brain structures, including surface area (SA), thickness and volume of subcortical structures. Inverse-variance weighted (IVW) method was used as the main estimate approach. Sensitivity analysis was conducted detect heterogeneity and pleiotropy. Colocalization analysis was performed to calculate the posterior probability of causal variation and identify the common genes.
Results
In the forward MR analysis, we found positive associations between the SA in four cortical regions (lingual, parahippocampal, pericalcarine, and middle temporal) and the risk of ALS. Additionally, decreased thickness in nine cortical regions (caudal anterior cingulate, frontal pole, fusiform, inferior temporal, lateral occipital, lateral orbitofrontal, pars orbitalis, pars triangularis, and pericalcarine) was significantly associated with a higher risk of ALS. In the reverse MR analysis, genetically predicted ALS was associated with reduced thickness in the bankssts and increased thickness in the caudal middle frontal, inferior parietal, medial orbitofrontal, and superior temporal regions. Colocalization analysis revealed the presence of shared causal variants between the two traits.
Conclusion
Our results suggest that altered brain morphometry in individuals with high ALS risk may be genetically mediated. The causal associations of widespread multifocal extra-motor atrophy in frontal and temporal lobes with ALS risk support the notion of a continuum between ALS and frontotemporal dementia. These findings enhance our understanding of the cortical structural patterns in ALS and shed light on potentially viable therapeutic targets.
Introduction
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with poorly understood pathophysiology. Recent studies have highlighted systemic inflammation, especially the role of circulating inflammatory proteins, in ALS.
Methods
This study investigates the potential causal link between these proteins and ALS. We employed a two-sample Mendelian Randomization(MR) approach, analyzing data from large-scale genome-wide association studies to explore the relationship between 91 circulating inflammatory proteins and ALS. This included various MR methods like MR Egger, weighted median, and inverse-variance weighted, complemented by sensitivity analyses for robust results.
Results
Significant associations were observed between levels of inflammatory proteins, including Adenosine Deaminase, Interleukin-17C, Oncostatin-M, Leukemia Inhibitory Factor Receptor, and Osteoprotegerin, and ALS risk. Consistencies were noted across different P-value thresholds. Bidirectional MR suggested that ALS risk might influence levels of certain inflammatory proteins.
Discussion
Our findings, via MR analysis, indicate a potential causal relationship between circulating inflammatory proteins and ALS. This sheds new light on ALS pathophysiology and suggests possible therapeutic targets. Further research is required to confirm these results and understand the specific roles of these proteins in ALS.
