Blood biomarkers in ALS : challenges, applications and novel frontiers

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease among adults. With diagnosis reached relatively late into the disease process, extensive motor cell loss narrows the window for therapeutic opportunities. Clinical heterogeneity in ALS and the lack of disease‐specific biomarkers have so far led to large‐sized clinical trials with long follow‐up needed to define clinical outcomes. In advanced ALS patients, there is presently limited scope to use imaging or invasive cerebrospinal fluid (CSF) collection as a source of disease biomarkers. The development of more patient‐friendly and accessible blood biomarker assays is hampered by analytical hurdles like the matrix effect of blood components. However, blood also provides the opportunity to identify disease‐specific adaptive changes of the stoichiometry and conformation of target proteins and the endogenous immunological response to low‐abundance brain peptides, such as neurofilaments (Nf). Among those biomarkers under investigation in ALS, the change in concentration before or after diagnosis of Nf has been shown to aid prognostication and to allow the a priori stratification of ALS patients into smaller sized and clinically more homogeneous cohorts, supporting more affordable clinical trials. Here, we discuss the technical hurdles affecting reproducible and sensitive biomarker measurement in blood. We also summarize the state of the art of non‐CSF biomarkers in the study of prognosis, disease progression, and treatment response. We will then address the potential as disease‐specific biomarkers of the newly discovered cryptic peptides which are formed down‐stream of TDP‐43 loss of function, the hallmark of ALS pathobiology.

Mitochondrial Aconitase enzymatic activity: a potential long survival biomarker in the blood of ALS patients

“…We measured mitochondrial antioxidant activity in platelets obtained from peripheral blood since this was easily accessible and was a source of biomarkers for neuroaxonal and muscle degeneration. It may therefore be more representative of ALS pathobiology than samples extracted from other sources [40]. We also observed that this decrease in Aco2 activity was independent of our patients' respiratory, nutritional and functional status.…”

Elevated plasma p-tau181 levels unrelated to Alzheimer’s disease pathology in amyotrophic lateral sclerosis

“…Biomarkers of Alzheimer’s disease (AD) pathophysiology, namely amyloid-beta, phospho-tau (p-tau) and total tau (t-tau), and those detecting neuroaxonal degeneration, as neurofilament light chain (NfL), have provided the most substantial impact 5 6. Moreover, reliable assays that can detect p-tau and NfL in blood have become available, paving the way for more widespread use of these biomarkers in clinical practice 7 8. In particular, the measurement of blood p-tau is increasingly considered a realistic, cost-effective and non-invasive assay that will help the diagnostic process for patients with cognitive decline 7 9 10.…”

Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications

“…Factors that compromise the utility of blood include the presence of high abundance proteins (e.g., albumin) that interfere with the detection of low concentration proteins, sequestration in different aggregates and the formation of immunocomplexes or changes in molecular processes due to the pathophysiology of the disease (e.g., clearance of misfolded proteins by chaperones). A more detailed description of these features is beyond the scope of this review, but we recommend the work of Sturmey et al [ 13 ] for a more comprehensive discussion.…”