Biomarker discovery and development for frontotemporal dementia and amyotrophic lateral sclerosis

Abstract

Frontotemporal dementia refers to a group of neurodegenerative disorders characterized by behaviour and language alterations and focal brain atrophy. Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized 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 summarized.

Keywords: amyotrophic lateral sclerosis; biomarkers; frontotemporal dementia; neurofilament; proteomics.

Figure 1

An overview of current biomarker development in frontotemporal dementia and amyotrophic lateral sclerosis. The main genetic biomarkers evaluated are TDP-43, MAPT, C9ORF72 and SOD1. Neurofilament biomarkers evaluated are NfL and NfH. The main immune-related biomarkers evaluated are YKL-40, GFAP and CST3. All of these markers have limitations in the diagnosis of frontotemporal dementia and amyotrophic lateral sclerosis, and therefore there is an urgent need for new biomarker development for the two diseases.

Figure 2

Mass spectrometry-based proteomics biomarker development in frontotemporal dementia and amyotrophic lateral sclerosis. Patient plasma/serum and CSF samples are processed and analysed by liquid chromatography and mass spectrometry. Proteins identified as potential biomarkers for frontotemporal dementia and amyotrophic lateral sclerosis are listed with their references.