Neuroinflammatory Pathways in the ALS-FTD Continuum: A Focus on Genetic Variants

Abstract

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FDT) are progressive neurodegenerative disorders that, in several cases, overlap in clinical presentation, and genetic and pathological disease mechanisms. About 10-15% of ALS cases and up to 40% of FTD are familial, usually with dominant traits. ALS and FTD, in several cases, share common gene mutations, such as in C9ORF72, TARDBP, SQSTM-1, FUS, VCP, CHCHD10, and TBK-1. Also, several mechanisms are involved in ALS and FTD pathogenesis, such as protein misfolding, oxidative stress, and impaired axonal transport. In addition, neuroinflammation and neuroinflammatory cells, such as astrocytes, oligodendrocytes, microglia, and lymphocytes and, overall, the cellular microenvironment, have been proposed as pivotal players in the pathogenesis the ALS-FTD spectrum disorders. This review overviews the current evidence regarding neuroinflammatory markers in the ALS/FTD continuum, focusing on the neuroinflammatory pathways involved in the genetic cases, moving from post-mortem reports to in vivo biofluid and neuroimaging data. We further discuss the potential link between genetic and autoimmune disorders and potential therapeutic implications.

Keywords: amyotrophic lateral sclerosis; autoimmune; frontotemporal dementia; genetic; immune system; neuroinflammation; therapy.

Figure 1

Genes with genetic mutations that cause ALS, ALS-FTD, and FTD. The figure shows the main causative genes associated with the ALS-FTD continuum and the main related clinical features. ALS: amyotrophic lateral sclerosis; FTD: frontotemporal dementia.

Figure 2

Biomarkers in genetic ALS-FTD. The figure shows the main biomarkers in the ALS-FTD continuum, divided into post-mortem, neurofilament, neuroinflammatory fluid biomarkers, and imaging. ALS: amyotrophic lateral sclerosis; FTD: frontotemporal dementia.