Elsevier

The Lancet Neurology

Volume 8, Issue 1, January 2009, Pages 94-109
The Lancet Neurology

Review
Biomarkers in amyotrophic lateral sclerosis

https://doi.org/10.1016/S1474-4422(08)70293-XGet rights and content

Summary

Amyotrophic lateral sclerosis (ALS; motor neuron disease) is a relentlessly progressive disorder. After half a century of trials, only one drug with modest disease-modifying potency—riluzole—has been developed. The diagnosis of this disorder is still clinical and there is a pronounced delay between the onset of symptoms and diagnosis, possibly beyond the therapeutic window. Bedside quantification of the involvement of the corticospinal tract and extramotor areas is inadequate and functional rating scales, forced vital capacity, and patient survival have been the measures of therapeutic response so far. Potential biomarkers that are sensitive to the progression of disease, which might enhance the diagnostic algorithm and provide new drug targets, are now being identified from analysis of the blood and cerebrospinal fluid, as well as from neuroimaging and neurophysiology studies. In combination, these biomarkers might be sensitive to early therapeutic effects and would reduce our reliance on animal models, which have uncertain relevance to sporadic ALS in human beings. Such biomarkers might also resolve complexities of phenotypic heterogeneity in clinical trials. In this Review, we discuss the development of biomarkers in ALS and consider potential future directions for research.

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 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

References (131)

  • G Kolde et al.

    Skin involvement in amyotrophic lateral sclerosis

    Lancet

    (1996)
  • J Brettschneider et al.

    Cerebrospinal fluid erythropoietin (EPO) in amyotrophic lateral sclerosis

    Neurosci Lett

    (2007)
  • MM Dietl et al.

    Substance P receptors in the human spinal cord: decrease in amyotrophic lateral sclerosis

    Brain Res

    (1989)
  • YH Hong et al.

    Diffusion tensor MRI as a diagnostic tool of upper motor neuron involvement in amyotrophic lateral sclerosis

    J Neurol Sci

    (2004)
  • C Bartels et al.

    Callosal dysfunction in amyotrophic lateral sclerosis correlates with diffusion tensor imaging of the central motor system

    Neuromuscul Disord

    (2008)
  • CA Sage et al.

    Quantitative diffusion tensor imaging in amyotrophic lateral sclerosis

    Neuroimage

    (2007)
  • A Tessitore et al.

    Subcortical motor plasticity in patients with sporadic ALS: an fMRI study

    Brain Res Bull

    (2006)
  • O Ciccarelli et al.

    Diffusion-based tractography in neurological disorders: concepts, applications, and future developments

    Lancet Neurol

    (2008)
  • J Ashburner et al.

    Voxel-based morphometry—the methods

    Neuroimage

    (2000)
  • RM Liscic et al.

    ALS and FTLD: two faces of TDP-43 proteinopathy

    Eur J Neurol

    (2008)
  • KJ De Vos et al.

    Role of axonal transport in neurodegenerative diseases

    Ann Rev Neurosci

    (2008)
  • PJ Shaw

    Molecular and cellular pathways of neurodegeneration in motor neurone disease

    J Neurol Neurosurg Psychiatry

    (2005)
  • JC Schymick et al.

    Genetics of sporadic amyotrophic lateral sclerosis

    Hum Mol Genet

    (2007)
  • BR Brooks et al.

    El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis

    Amyotroph Lateral Scler Other Motor Neuron Disord

    (2000)
  • J Ravits et al.

    Focality of upper and lower motor neuron degeneration at the clinical onset of ALS

    Neurology

    (2007)
  • J Ravits et al.

    Implications of ALS focality: rostral–caudal distribution of lower motor neuron loss postmortem

    Neurology

    (2007)
  • M Swash et al.

    Preclinical and subclinical events in motor neuron disease

    J Neurol Neurosurg Psychiatry

    (1988)
  • MR Turner et al.

    Clinical phenotypes

  • MR Turner et al.

    Prolonged survival in motor neuron disease: a descriptive study of the King's database 1990–2002

    J Neurol Neurosurg Psychiatry

    (2003)
  • MT Hu et al.

    Flail arm syndrome: a distinctive variant of amyotrophic lateral sclerosis

    J Neurol Neurosurg Psychiatry

    (1998)
  • S Vucic et al.

    Abnormalities in cortical and peripheral excitability in flail arm variant amyotrophic lateral sclerosis

    J Neurol Neurosurg Psychiatry

    (2007)
  • CL Shoesmith et al.

    Prognosis of amyotrophic lateral sclerosis with respiratory onset

    J Neurol Neurosurg Psychiatry

    (2007)
  • PN Leigh et al.

    The management of motor neurone disease

    J Neurol Neurosurg Psychiatry

    (2003)
  • L Lacomblez et al.

    Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II

    Lancet

    (1996)
  • S Scott et al.

    Design, power, and interpretation of studies in the standard murine model of ALS

    Amyotroph Lateral Scler

    (2008)
  • AC Ludolph et al.

    Guidelines for the preclinical in vivo evaluation of pharmacological active drugs for ALS/MND: report on the 142nd ENMC international workshop

    Amyotroph Lateral Scler

    (2007)
  • H Ryberg et al.

    Protein biomarkers for amyotrophic lateral sclerosis

    Expert Rev Proteomics

    (2008)
  • BM Patten et al.

    Free amino acid levels in amyotrophic lateral sclerosis

    Ann Neurol

    (1978)
  • W Camu et al.

    Fasting plasma and CSF amino acid levels in amyotrophic lateral sclerosis: a subtype analysis

    Acta Neurol Scand

    (1993)
  • J Ilzecka et al.

    Plasma amino acids percentages in amyotrophic lateral sclerosis patients

    Neurol Sci

    (2003)
  • S Ono et al.

    Decreased plasma levels of fibronectin in amyotrophic lateral sclerosis

    Acta Neurol Scand

    (2000)
  • S Ono et al.

    Increased serum hyaluronic acid in amyotrophic lateral sclerosis: relation to its skin content

    Amyotroph Lateral Scler Other Motor Neuron Disord

    (2000)
  • K Houi et al.

    Increased plasma TGF-beta1 in patients with amyotrophic lateral sclerosis

    Acta Neurol Scand

    (2002)
  • EP Simpson et al.

    Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden

    Neurology

    (2004)
  • S Cronin et al.

    Elevated serum angiogenin levels in ALS

    Neurology

    (2006)
  • L Dupuis et al.

    Dyslipidemia is a protective factor in amyotrophic lateral sclerosis

    Neurology

    (2008)
  • M Neumann et al.

    Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

    Science

    (2006)
  • P Foulds et al.

    TDP-43 protein in plasma may index TDP-43 brain pathology in Alzheimer's disease and frontotemporal lobar degeneration

    Acta Neuropathol

    (2008)
  • PG Ince et al.

    Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS

    Neurology

    (2003)
  • ER Peskind et al.

    Safety and acceptability of the research lumbar puncture

    Alzheimer Dis Assoc Disord

    (2005)
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