References for this Review were identified through searches of PubMed by use of the search terms “motor neuron disease” or “amyotrophic lateral sclerosis” and other appropriate targets, such as “biomarker”, “cerebrospinal fluid”, “blood”, “serum”, “plasma”, “neuroimaging”, “MRI”, “neurophysiology”, “electromyography”, and “transcranial magnetic stimulation”, up to September, 2008. Articles were also identified from the authors' own files. Only papers published in English that were limited
ReviewBiomarkers in amyotrophic lateral sclerosis
Introduction
The “syndrome” of amyotrophic lateral sclerosis (ALS; also known as motor neuron disease) consists of progressive—although variable—degeneration of the corticospinal tract, brainstem, and spinal anterior horn neurons, with a markedly heterogeneous clinical presentation and course. One manifestation of this disease, despite a uniformly fatal outcome, is a wide range of survival times from a few months to several decades, with a consistent median of 2–4 years from onset of symptoms in population-based studies.1
The pathological process in ALS is now recognised to extend beyond the motor system, although only a few patients develop pronounced cognitive impairment. The idea that ALS is a typical example of a disease in which certain populations of neurons are “selectively vulnerable” to degeneration is becoming less tenable. ALS is a syndrome—probably another “multiple system” neurodegenerative disorder—that has clinical and pathological overlap with frontotemporal dementia that is yet to be fully defined.2
ALS has a similar occurrence globally, with no obvious geographical boundaries or associated environmental toxins. A comprehensive model for the degeneration of motor neurons in ALS is needed, but contemporary hypotheses include aberrant axonal transport,3 protein aggregation, excitotoxicity, oxidative stress, apoptosis, mitochondrial dysfunction, and microglial activation (figure 1).4 Although linkage studies in a subset of familial cases have identified mutations in SOD1 (the gene that encodes copper–zinc superoxide dismutase-1), genetic association and genome-wide association studies in patients with sporadic ALS have not established a simple genetic model for ALS,5 and the disorder is best understood as a predominantly sporadic disease.6
Section snippets
The need for biomarkers in ALS
The UK Medical Research Council has defined a biomarker as “an objective measurement that acts as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to therapeutic intervention.” The characteristics of the ideal biomarker(s) in ALS are summarised in the panel.
Blood biomarkers
Plasma (whole blood with the red cells removed) or serum (plasma without the clotting factors) would be the most convenient source of biomarkers. However, this approach makes the assumption that a CNS-based pathological process will be indicated in systemic compartments, and the precedents for such biomarkers in neurological practice remain largely limited to diseases that have an autoimmune or metabolic basis. We have identified 52 studies of candidate biomarkers in the blood for ALS, of which
CSF biomarkers
ALS is both a cerebral and a spinal disease with a range of phenotypes (including those with clinically LMN-only signs41); hence, the surrounding milieu (ie, the CSF) might be expected to indicate the underlying activity of the pathological processes in ALS. CSF biomarkers could indicate neuronal damage at an early and potentially reversible stage or might even indicate changes in molecular pathways that occur before neuronal damage in at-risk individuals. Lumbar puncture is less convenient and
MRI biomarkers
The greatest contribution of MRI to ALS research so far has been its use in reliably excluding other diagnoses. Owing to the widespread availability of MRI, it is now also the most promising neuroimaging tool for biomarker discovery in ALS. Magnetic resonance spectroscopy, diffusion tensor imaging (DTI), and the assessment of regional atrophy by use of voxel-based morphometry are the techniques that have had the largest effect on biomarker discovery. We have identified 78 MRI studies that have
Neurophysiological biomarkers
An important focus in the development of a neurophysiological biomarker of ALS is the identification of central hyperexcitability and the quantification of dysfunction of UMNs. However, ALS also has peripheral features of hyperexcitability (eg, cramps and fasciculations), in part through motor unit loss, and these features might also be quantifiable in vivo.
Future developments
The search for biomarkers in ALS is now underway and makes use of advances in molecular biology and non-invasive imaging. A successful discovery could be a key advance towards an effective therapy. Multiprotein profiling in the CSF, DTI, and motor unit number estimation are so far the most promising techniques in a multimodal strategy. An increasingly bioinformatic approach to the analysis of the CSF and blood is needed, with higher throughput by way of raised automation. This strategy is being
Search strategy and selection criteria
References (131)
- et al.
The epidemiology of ALS and the role of population-based registries
Biochim Biophys Acta
(2006) - et al.
Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data
Lancet Neurol
(2007) - et al.
Electrodiagnostic criteria for diagnosis of ALS
Clin Neurophysiol
(2008) - et al.
Predictors of delay in the diagnosis and clinical trial entry of amyotrophic lateral sclerosis patients: a population-based study
J Neurol Sci
(2006) - et al.
Motor neuron disease presenting with respiratory failure
J Neurol Sci
(1996) - et al.
Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS
Prog Neurobiol
(2008) - et al.
Assessment of disease progression in motor neuron disease
Lancet Neurol
(2005) - et al.
Increased interleukin-6 of skin and serum in amyotrophic lateral sclerosis
J Neurol Sci
(2001) - et al.
Increased IL-13-producing T cells in ALS: positive correlations with disease severity and progression rate
J Neuroimmunol
(2007) - et al.
Circulating insulin-like growth factors and related binding proteins are selectively altered in amyotrophic lateral sclerosis and multiple sclerosis
Growth Horm IGF Res
(2007)
Skin involvement in amyotrophic lateral sclerosis
Lancet
Cerebrospinal fluid erythropoietin (EPO) in amyotrophic lateral sclerosis
Neurosci Lett
Substance P receptors in the human spinal cord: decrease in amyotrophic lateral sclerosis
Brain Res
Diffusion tensor MRI as a diagnostic tool of upper motor neuron involvement in amyotrophic lateral sclerosis
J Neurol Sci
Callosal dysfunction in amyotrophic lateral sclerosis correlates with diffusion tensor imaging of the central motor system
Neuromuscul Disord
Quantitative diffusion tensor imaging in amyotrophic lateral sclerosis
Neuroimage
Subcortical motor plasticity in patients with sporadic ALS: an fMRI study
Brain Res Bull
Diffusion-based tractography in neurological disorders: concepts, applications, and future developments
Lancet Neurol
Voxel-based morphometry—the methods
Neuroimage
ALS and FTLD: two faces of TDP-43 proteinopathy
Eur J Neurol
Role of axonal transport in neurodegenerative diseases
Ann Rev Neurosci
Molecular and cellular pathways of neurodegeneration in motor neurone disease
J Neurol Neurosurg Psychiatry
Genetics of sporadic amyotrophic lateral sclerosis
Hum Mol Genet
El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis
Amyotroph Lateral Scler Other Motor Neuron Disord
Focality of upper and lower motor neuron degeneration at the clinical onset of ALS
Neurology
Implications of ALS focality: rostral–caudal distribution of lower motor neuron loss postmortem
Neurology
Preclinical and subclinical events in motor neuron disease
J Neurol Neurosurg Psychiatry
Clinical phenotypes
Prolonged survival in motor neuron disease: a descriptive study of the King's database 1990–2002
J Neurol Neurosurg Psychiatry
Flail arm syndrome: a distinctive variant of amyotrophic lateral sclerosis
J Neurol Neurosurg Psychiatry
Abnormalities in cortical and peripheral excitability in flail arm variant amyotrophic lateral sclerosis
J Neurol Neurosurg Psychiatry
Prognosis of amyotrophic lateral sclerosis with respiratory onset
J Neurol Neurosurg Psychiatry
The management of motor neurone disease
J Neurol Neurosurg Psychiatry
Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II
Lancet
Design, power, and interpretation of studies in the standard murine model of ALS
Amyotroph Lateral Scler
Guidelines for the preclinical in vivo evaluation of pharmacological active drugs for ALS/MND: report on the 142nd ENMC international workshop
Amyotroph Lateral Scler
Protein biomarkers for amyotrophic lateral sclerosis
Expert Rev Proteomics
Free amino acid levels in amyotrophic lateral sclerosis
Ann Neurol
Fasting plasma and CSF amino acid levels in amyotrophic lateral sclerosis: a subtype analysis
Acta Neurol Scand
Plasma amino acids percentages in amyotrophic lateral sclerosis patients
Neurol Sci
Decreased plasma levels of fibronectin in amyotrophic lateral sclerosis
Acta Neurol Scand
Increased serum hyaluronic acid in amyotrophic lateral sclerosis: relation to its skin content
Amyotroph Lateral Scler Other Motor Neuron Disord
Increased plasma TGF-beta1 in patients with amyotrophic lateral sclerosis
Acta Neurol Scand
Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden
Neurology
Elevated serum angiogenin levels in ALS
Neurology
Dyslipidemia is a protective factor in amyotrophic lateral sclerosis
Neurology
Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Science
TDP-43 protein in plasma may index TDP-43 brain pathology in Alzheimer's disease and frontotemporal lobar degeneration
Acta Neuropathol
Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS
Neurology
Safety and acceptability of the research lumbar puncture
Alzheimer Dis Assoc Disord
Cited by (361)
Novel therapeutic approaches for motor neuron disease
2023, Handbook of Clinical NeurologyIdentification of dysregulated canonical pathways associated with pathogenesis and progression of Amyotrophic Lateral Sclerosis—An integrated bioinformatics approach
2023, Advances in Protein Chemistry and Structural BiologyNerve excitability measured with the TROND protocol in amyotrophic lateral sclerosis: a systematic review and meta-analysis
2023, Journal of Neurophysiology