Insights

Report on Biomarkers I Session of 25th Symposium on ALS/MND


Courtesy of Dr Martin Turner, University of Oxford
Courtesy of Dr Martin Turner, University of Oxford

ALS is a very complicated disease. After years of study, diagnosis is still taking months. Lack of proper biomarkers also make the prognosis of the disease very difficult. Prediction of the progression of ALS is extremely important for patients and their caregivers. It is crucial for the researchers involved in clinical trials for new therapies.

This important issue is currently being investigated by several research groups. During Biomarker I session of 25th International Symposium on ALS/MND we had the occasion to familiarize ourself with several studies on biomarkers for this devastating disease. Story written in neurofilaments

Neurofilaments are core structures of the cytoskeleton of neurons. They give structural support, forming scaffolding for such complicated structures as axons. During neurodegeneration they are destroyed and their elements can be detected in bodily fluids, like blood and cerebrospinal fluid.

Dr Malaspina (Queen Mary University of London, UK) and Dr Turner (University of Oxford, UK) during their joint lecture presented results on the evaluation of the neurofilament light chain (NfL) as a prognostic biomarker for ALS. Levels of this molecule have been evaluated in plasma, serum and cerebrospinal fluid in a vast number of subjects. By using the ELISA assay they were able to discriminate between patients and controls with high sensitivity and selectivity. During two-year follow-up it has been proven that blood NfL levels were strongly correlated with disease progression rate and upper motor neuron score. Moreover by using magnetic resonance diffusion tensor imaging they were able to prove that elevated levels of NfL in the cerebrospinal fluid are related to the white matter micro-structure damage in the corticospinal tracts.

Study on exploitation of neurofilaments as an ALS biomarker was also proposed by Dr Bowser (Barrow Neurological Institute, USA). In his lecture he presented a validation of an assay based on phosphorylated neurofilament heavy chain (pNFH) and complement C3 (an element of complement pathway of the immune system). By analysing pNFH/C3 ratio in cerebrospinal fluid and pNFH in plasma of the patients, Dr Bowser and his colleagues were able to discriminate between ALS patients and the control group (93% and 70% of accuracy respectively). Those assays are giving a big hope to facilitate the diagnosis of ALS and are currently undergoing a prospective clinical qualification study in the United States and Europe.

Looking for a sign

Oxidative stress theory of ALS pathogenesis is well described in the literature. Contribution of this pathological process to the disease development has been proposed based on the numerous studies of patients and ALS model organisms. Overproduction of reactive oxygen species and malfunction of repair mechanisms can lead to severe damage of the affected cells. By-products of this pathological process in form of oxidated compounds, or changes in the molecules involved in processes related to oxidative stress, can be a very interesting candidate for an ALS biomarker.

Dr Mitsumoto (Columbia University Medical Center, USA) shared with us evaluation of several potential biomarkers for ALS, performed as a part of ALS COSMOS study. Among others, they have analysed a product of lipid peroxidation (isoprostane) and DNA oxidation (8-oxo-deoxyguanosine 8-oxo-dG) in the urine. Those two compounds are known oxidative stress biomarkers. Increase in their concentration in urine samples was correlated with a decrease in both ALSFRS-R (ALS functional rating scale revised) and %FVC (percentage forced vital capacity) values, which were used to assess the clinical status of over 300 subjects in the project. Moreover they have noticed that higher serum creatinine (a breakdown product of phosphocreatine in the muscles) was correlated with better ALSFRS-R and respiratory function.

In the last lecture of the Biomarker I session Dr Calvo (University of Torino, Italy) presented data in which increased levels of creatinine or albumin in the serum were positively correlated with better survival of patients. Data from over 600 patients had been analysed. The results indicated that creatinine and albumin could be a useful tool for establishing prognosis for newly diagnosed patients. Such information will be important not only for the clinicians, but will also facilitate clinical trial development for newly discovered therapies.

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