Interest and development of biomarkers in Amyotrophic Lateral Sclerosis

The Thierry Latran Foundation is pleased to make available scientific information written and selected by Committee of French neurologists that we strongly thank for their support to the Foundation.

NB: Translation done by the Foundation

This second contribution on the crucial topic of biomarkers was written by Caroline Moreau (Lille) in collaboration with D Devos (Lille), PF Pradat (Paris), JP Camdessanché (Saint-Etienne), P Corcia (Tours).

We will successively discuss biomarkers in blood, in cerebrospinal fluid, and biomarkers in imaging and neurophysiology. They are currently not used in current practice but are the main current topics of biomedical research in 2011.

1 / Why develop biomarkers?

The pathogenesis underlying amyotrophic lateral sclerosis (ALS) is not limited to the motor neurological system. We now know that patients may develop memory disorders  and behavioural changes related to frontal function  (Tsermentseli and al, 2011), extrapyramidal syndrome (hypertonia, akinesia or tremor) (Pradat and al, 2009) or pain. The hypothesis stating that ALS is restricted  to a selective impairment of the first and the second motor neuron should gradually be re-oriented in favor of the notion of “syndrome” (all clinical signs and symptoms that a patient is likely to develop for certain type of diseases) with different clinical expressions (called phenotypic): bulbar onset, limb onset limited for a long period to  upper limbs or pseudo polyneuropathy  form starting with lower limbs (mimicking an alteration of the legs nerves). The disease progression is also different from patient to another and the needs of patients must be anticipate accordingly.

The disease is in its most common form sporadic and therapeutic trials conducted on the only validated SOD1 murine model (SOD 1) remain insufficient, as they don’t reproduce the disease developed in humans (Bowling and al, 1993). Currently, the only therapeutic amending the duration of evolution is riluzole RILUTEK^® which brings an increase in ife expectancy of 7% in the treated group compared to placebo, meaning an average of additional  3 months in life expectancy. Clinical trials assess the efficacy on the following criteria: the date of death from the onset of the disease, functional vital capacity (respiratory parameter), the score of clinical disability on a scale specific to ALS (score ALS – FRS). These criteria are questionable because very strict (death) or insufficiently sensitive (ALS – FRS). Patients are evaluated in a single group which does not consider the various forms of the disease limiting the interest of some results. The discovery of biomarkers would certainly help refine analysis.

2 / Definition

The Council for research development in Great Britain define a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”.

There are :

• The “diagnostic” biomarkers that brings arguments for the diagnosis,
• The “phenotypic” biomarkers to distinguish the different clinical forms of disease,
• The “disease progression” biomarkers.
• The biomarkers to monitor a “therapeutic benefit”.

3 / Requirement for a perfect biomarker in ALS syndrome :

• Sensitive and specific for ALS syndrome, ideally detectable before the onset of severe clinical symptoms and/or at the pre-symptomatic stage for familial forms.

The specificity is in statistics and in epidemiology, the ability of a diagnostic test or examination to give negative results when the disease (or item) is not existing. The sensitivity demonstrates the probability to get a positive result only if the disease is there.

• Ability to differentiate different SLA clinical phenotypes.
• Able to describe in advance the evolution of major symptoms, including respiratory symptoms, in order to consider the earliest possible therapeutic interventions (non-invasive ventilation).
• Able to change quickly as a result of the administration of a therapeutic agent (shortening therapeutic trials, obtain a more relevant model than the murine’s one).
• Easy to use, easy to measure, reproducible, even in patients in advanced stage of the disease.

4 / Biomarkers in the blood or cerebrospinal : major publications.

	Blood	CSF
Amino acid (AA)	increase in tyrosine, glutamate, serine	increase lysine, leucine	Patten and al.
Fibronectin	decrease		Ono and al.
Hyaluronic acid	increase		Ono and al.
Interleukin 6	increase	increase	Ono and al, Moreau and al.
TGF β1 Plasma Transforming Growth Factor	increase		Houi and al.
MCP 1 Monocyte Chemoattractant Protein 1	increase		Simpson and al.
Angiogenine	increase		Cronin and al, Moreau and al.
VEGF	no difference	decrease in hypoxemic  patients	Devos and al, Moreau and al.
Erythropoietin	no difference	decrease	Brettschnieder and al, Just and al.
IGF, IGFBP Insulin Growth Factor	increase		Horsback and al.
Neurofilament (Tau)		increase	Rosengren and al.
Substance P		increase	Matsuiushi and al.
Anti oxydative Protein		decrease	Siciliano and al.

5 / Imaging Biomarkers:

Hypersignal T1	anterolateral cervical spinal		57% sensitivity100% specificity	Waragai and al.
Hypersignal  T2	spinal cords		76% sensitivity75% specificity	Waragai and al.
SPECTRO MRI	brain stem	decrease in the peak of N-acetyl-aspartate / Cr.		Pioro and al.
Diffusion tensor	cortico-spinal tractus	decrease of anisotropy		Ellis and al.
Morphometry	Pre motor cortexfrontal cortex	atrophy correlated with the degree of cognitive impairment		Abrahams and al.
Functional MRI	right lower frontal cortex	regional activation when motor function		Tessitore and al.

 

5 / Neurophysiological biomarkers :

A cortical hyperexcitability in Transcranial Magnetic stimulation by decrease in intra cortical inhibition interval is usually described in sporadic ALS (Ziemman and al,1997), this anomaly would be present at the early stage of the disease and in some healthy carriers of the SOD1 mutation (Bowling and al, 1993).

At a muscular level, the expression of Nogo A (protein associated with myelin, potential inhibitor of neuronal growth) on muscle biopsy would be an early positive predictive factor of evolution towards SLA with a sensitivity of 94% and a specificity of 91% (Pradat and al, 2007).

 

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