The Need for Biomarkers in the ALS–FTD Spectrum: A Clinical Point of View on the Role of Proteomics

Mele, Angelica; Tondo, Giacomo; Giorgis, Veronica; Manfredi, Marcello; Comi, Cristoforo; Mazzini, Letizia; Marchi, Fabiola De

doi:10.3390/proteomes11010001

Cited by 10 publications

(12 citation statements)

References 131 publications

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“…The last two decades of research have pushed the identification and monitoring of fluid and imaging biomarkers, aiming at revealing pathogenic mechanisms and potential therapeutic targets [ 4 ]. Since ALS and other NDDs share the deposition of misfolded proteins as a common pathogenic mechanism, a promising field of research is represented by the investigation of protein complexes and their interactions, but large-scale confirmation is still needed [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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

De Marchi,

Tondo,

Corrado

et al. 2023

Genes

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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.

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Section: Introductionmentioning

confidence: 99%

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

De Marchi,

Tondo,

Corrado

et al. 2023

Genes

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“…In contrast, proteomics gives a lower identification rate (<10% of total proteins) but provides direct information on possible drug targets. Thus, proteomics is a good choice for biomarker research [ 141 ]. One study from Xu et al demonstrated that the plasma proteomic profile of ALS correlates with some clinical features [ 43 ].…”

Section: Molecular Heterogeneitymentioning

confidence: 99%

Unraveling the Heterogeneity of ALS—A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials

Tzeplaeff,

Jürs,

Wohnrade

et al. 2024

Cells

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Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular.

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“…Given that synaptic dysfunction often precedes neuronal loss, the presence of altered synaptic biomarkers could signal disease onset before the appearance of clinical symptoms. Additionally, biomarkers like NfL that correlate with disease progression could provide valuable prognostic information, guiding patient care and management (Swift et al, 2021;Vignaroli et al, 2023).…”

Section: Opportunities For Synaptic Biomarkers In Als and Ftdmentioning

confidence: 99%

Emerging perspectives of synaptic biomarkers in ALS and FTD

Krishnamurthy,

Pradhan

2024

Front. Mol. Neurosci.

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Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are debilitating neurodegenerative diseases with shared pathological features like transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions and genetic mutations. Both diseases involve synaptic dysfunction, contributing to their clinical features. Synaptic biomarkers, representing proteins associated with synaptic function or structure, offer insights into disease mechanisms, progression, and treatment responses. These biomarkers can detect disease early, track its progression, and evaluate therapeutic efficacy. ALS is characterized by elevated neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) and blood, correlating with disease progression. TDP-43 is another key ALS biomarker, its mislocalization linked to synaptic dysfunction. In FTD, TDP-43 and tau proteins are studied as biomarkers. Synaptic biomarkers like neuronal pentraxins (NPs), including neuronal pentraxin 2 (NPTX2), and neuronal pentraxin receptor (NPTXR), offer insights into FTD pathology and cognitive decline. Advanced technologies, like machine learning (ML) and artificial intelligence (AI), aid biomarker discovery and drug development. Challenges in this research include technological limitations in detection, variability across patients, and translating findings from animal models. ML/AI can accelerate discovery by analyzing complex data and predicting disease outcomes. Synaptic biomarkers offer early disease detection, personalized treatment strategies, and insights into disease mechanisms. While challenges persist, technological advancements and interdisciplinary efforts promise to revolutionize the understanding and management of ALS and FTD. This review will explore the present comprehension of synaptic biomarkers in ALS and FTD and discuss their significance and emphasize the prospects and obstacles.

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The Need for Biomarkers in the ALS–FTD Spectrum: A Clinical Point of View on the Role of Proteomics

Cited by 10 publications

References 131 publications

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

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

Unraveling the Heterogeneity of ALS—A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials

Emerging perspectives of synaptic biomarkers in ALS and FTD

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