Biomarker discovery and development for frontotemporal dementia and amyotrophic lateral sclerosis

Abstract

Frontotemporal dementia refers to a group of neurodegenerative disorders characterised by behaviour and language alterations and focal brain atrophy. Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterised by loss of motor neurons resulting in muscle wasting and paralysis. Frontotemporal dementia and amyotrophic lateral sclerosis are considered to exist on a disease spectrum given substantial overlap of genetic and molecular signatures. The predominant genetic abnormality in both frontotemporal dementia and amyotrophic lateral sclerosis is an expanded hexanucleotide repeat sequence in the C9ORF72 gene. In terms of brain pathology, abnormal aggregates of TAR-DNA binding protein-43 are predominantly present in frontotemporal dementia and amyotrophic lateral sclerosis patients. Currently, sensitive and specific diagnostic and disease surveillance biomarkers are lacking for both diseases. This has impeded the capacity to monitor disease progression during life and the development of targeted drug therapies for the two diseases. The purpose of this review is to examine the status of current biofluid biomarker discovery and development in frontotemporal dementia and amyotrophic lateral sclerosis. The major pathogenic proteins implicated in different frontotemporal dementia and amyotrophic lateral sclerosis molecular subtypes and proteins associated with neurodegeneration and the immune system will be discussed. Furthermore, the use of mass spectrometry-based proteomics as an emerging tool to identify new biomarkers in frontotemporal dementia and amyotrophic lateral sclerosis will be summarised.

Protein Biomarkers Shared by Multiple Neurodegenerative Diseases Are Calmodulin-Binding Proteins Offering Novel and Potentially Universal Therapeutic Targets

“…The third most common progressive neurodegenerative disease (~20% of dementia cases), FTD is a heterogeneous disease, originating in the frontal and/or temporal lobes, that affects behavior, language, and executive function, beginning prior to age 65 [94,95]. Since FTD symptoms are common to several primary psychiatric disorders including autism spectrum disorders, bipolar disorder, and schizophrenia, family history, neurologic testing, neuroimaging, and genetic testing can be used to rule other diseases out.…”

“…The presence of CaMBP biomarkers for other diseases (e.g., AD: Aβ, pTau; PD: αSyn) can differentiate some, but other disease variants are less easy to determine. For example, not only do FTD and ALS share overlapping biomarkers, including the presumptive CaMBP TDP-43, but approximately 15% of FTD cases also share ALS-like motor symptoms, while ALS sufferers share a similar percentage of FTD symptomology [94]. Mutations in the putative CaMBP TREM2 increase the risk for familial FTD but not LBD [60].…”

“…Because the diagnosis of ALS typically comes late in the disease, finding rapid and inexpensive biomarkers for its early detection is critical to finding a cure or ways to slow disease progression [111]. In the meantime, the utility of certain CaMBP biomarkers common to other neurodegenerative diseases has been studied as an evaluator of ALS status and progression including ABCA1, APOE, C9Orf72, FUS, and pTau/Tau [3,55,94,[111][112][113] A recent study presents evidence that the CaMBP αSyn is a biomarker that could be used in the diagnosis and prediction of MS [114].…”

Abnormal brain protein abundance and mRNA expression of SARM1 in amyotrophic lateral sclerosis

“…Furthermore, dysfunctional proteins and the loss of motor neurons in the brain of ALS patients [11] can result in the typical clinical manifestations of ALS like muscle paralysis and muscle wasting [12].Therefore, studying the abnormalities of protein abundance in the brain is essential to reveal ALS pathogenesis and to identify reliable biomarkers.…”

Multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis

“…Our primary aim was to identify lipid pathways that were altered in ALS, to understand lipid dysregulation that may contribute to ALS pathogenesis. 28 Our secondary aim was to identify lipids for the purpose of developing biomarkers for ALS diagnosis and for monitoring disease progression.…”