Peripheral inflammation in neurodegenerative diseases
This thesis constitutes an exhaustive analysis of peripheral blood gene expression across a diverse set of neurodegenerative disease. The first manuscript included in the thesis focuses on the analysis of peripheral blood gene expression in Friedreich’s ataxia, a rare pediatric onset neurodegenerative disease caused by an autosomal recessive repeat expansion in the FXN gene, where the genetic basis of the disease is fully understood. The second manuscript takes a similar approach but instead focuses on neurodegenerative disorders with complex genetics and later onset, in particular Alzheimer’s disease (AD), mild cognitive impairment (MCI), and five disorders in the frontotemporal dementia (FTD) spectrum: behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and non-fluent variant primary progressive aphasia (nfvPPA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The initial focus of the project was to find specific gene expression biomarker candidates to build a biomarker panel, and to develop predictive models for disease status or severity from gene expression in blood. It became clear as the thesis progressed that both of these goals were not feasible, because expression changes in individual genes were too subtle and noisy to make viable biomarkers, and machine learning models had no predictive power for disease status or severity. However, systems level of analysis of the peripheral blood transcriptome with weighted gene co-expression network analysis (WGCNA) revealed evidence of an increased innate immune inflammatory response in monocytes and neutrophils. This inflammatory response was found to overlap strongly with microglia-expressed genes, particularly those genes found to be affected in post-mortem AD brains. Because of this overlap with microglial genes, the genes in the inflammatory response in blood are also enriched for genetic risk for AD as determined by genome wide association studies (GWAS). The remarkable similarity of this inflammatory response across a wide array of neurodegenerative diseases warrants further investigation, particularly to determine how and why inflammatory signals enter peripheral blood from the central and peripheral nervous system in the diseases and whether this inflammation is pathological or protective and should be a target for future therapeutic interventions.