Plasma biomarkers associated with ALS and their relationship to iron homeostasis

George M. Leader Family Laboratory, Department of Neurosurgery, Pennsylvania State University College of Medicine, 500 University Drive (H110), Hershey, PA 17033-0850, USA.
Muscle & Nerve (Impact Factor: 2.28). 07/2010; 42(1):95-103. DOI: 10.1002/mus.21625
Source: PubMed


Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with complicated pathogenesis with variable presentation and disease progression. There is a critical need for a panel of biomarkers to provide clinicians and researchers with additional information. In this study, multiplex immunoassays were used to screen a number of cytokines, growth factors, and iron-related proteins. ALS patients had significantly higher plasma levels of L-ferritin and lower concentrations of transferrin when compared to healthy controls and together classified a test group of subjects with 82% accuracy. Duration of ALS symptoms correlated positively with levels of monocyte chemoattractant protein 1 (MCP-1) and negatively with levels of granulocyte-macrophage colony stimulating factor (GM-CSF). The biomarker profile suggests iron homeostasis is disrupted in ALS patients, and changes in ferritin and transferrin (Tf) appear to be indicators of ongoing inflammatory processes. The data demonstrate a plasma biomarker profile in ALS patients that may differ from published reports of cerebrospinal fluid biomarkers.

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    • "High levels of high mobility group box 1 (HMGB1) autoantibody (Hwang et al., 2013), increased granzyme B (Ilzecka, 2011), higher CSF IL-8 levels (Mitchell et al., 2009) and wide-range C-reactive protein (wrCRP) (Keizman et al., 2009) correlated with disease severity as measured by ALSFRS-R. In addition, increased levels of blood MCP-1, TNF-α and GM-CSF correlated with disease duration (Kuhle et al., 2009; Mitchell et al., 2010). Two glial-derived proteins, sCD14 (a soluble monocyte receptor involved in inflammation in neurodegenerative diseases) and S100B (an astrocyte-derived neurotrophic protein) show decreased levels in CSF of patients with ALS (Sussmuth et al., 2003, 2010). "
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    ABSTRACT: The past decade has seen a dramatic increase in the discovery of candidate biomarkers for ALS. These biomarkers typically can either differentiate ALS from control subjects or predict disease course (slow versus fast progression). At the same time, late-stage clinical trials for ALS have failed to generate improved drug treatments for ALS patients. Incorporation of biomarkers into the ALS drug development pipeline and the use of biologic and/or imaging biomarkers in early- and late-stage ALS clinical trials have been absent and only recently pursued in early-phase clinical trials. Further clinical research studies are needed to validate biomarkers for disease progression and develop biomarkers that can help determine that a drug has reached its target within the central nervous system. In this review we summarize recent progress in biomarkers across ALS model systems and patient population, and highlight continued research directions for biomarkers that stratify the patient population to enrich for patients that may best respond to a drug candidate, monitor disease progression and track drug responses in clinical trials. It is crucial that we further develop and validate ALS biomarkers and incorporate these biomarkers into the ALS drug development process.
    Full-text · Article · Oct 2014 · Brain Research
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    • "Previously, Ikeda et al. (2012), assessing a range of serum biomarkers in 92 Japanese ALS patients and 92 age-matched healthy controls, also found that increased serum ferritin correlated with clinical deterioration. Increased ferritin was also reported (Goodall et al., 2008; Qureshi et al., 2008) together with lower serum Tf (Mitchell et al., 2010) in ALS patients. The latter study found that, as biomarkers, higher serum ferritin and lower Tf discriminated between ALS patients and controls with 82% accuracy. "
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    ABSTRACT: Modulations of the potentially toxic transition metals iron (Fe) and copper (Cu) are implicated in the neurodegenerative process in a variety of human disease states including amyotrophic lateral sclerosis (ALS). However, the precise role played by these metals is still very much unclear, despite considerable clinical and experimental data suggestive of a role for these elements in the neurodegenerative process. The discovery of mutations in the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD-1) in ALS patients established the first known cause of ALS. Recent data suggest that various mutations in SOD-1 affect metal-binding of Cu and Zn, in turn promoting toxic protein aggregation. Copper homeostasis is also disturbed in ALS, and may be relevant to ALS pathogenesis. Another set of interesting observations in ALS patients involves the key nutrient Fe. In ALS patients, Fe loading can be inferred by studies showing increased expression of serum ferritin, an Fe-storage protein, with high serum ferritin levels correlating to poor prognosis. Magnetic resonance imaging of ALS patients shows a characteristic T2 shortening that is attributed to the presence of Fe in the motor cortex. In mutant SOD-1 mouse models, increased Fe is also detected in the spinal cord and treatment with Fe-chelating drugs lowers spinal cord Fe, preserves motor neurons, and extends lifespan. Inflammation may play a key causative role in Fe accumulation, but this is not yet conclusive. Excess transition metals may enhance induction of endoplasmic reticulum (ER) stress, a system that is already under strain in ALS. Taken together, the evidence suggests a role for transition metals in ALS progression and the potential use of metal-chelating drugs as a component of future ALS therapy.
    Full-text · Article · Jul 2014 · Frontiers in Aging Neuroscience
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    • "Therefore, the circulating levels of eosinophil-derived neurotoxin, eotaxin, granzyme A and granzyme B, high mobility group box 1 (HMGB1) autoantibody, interleukin-6, interferon-γ, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), tumor necrosis factor receptor, and wide-range C-reactive protein (wrCRP) were found to be increased in ALS patients [48–51, 57–63, 67]. In contrast, levels of granulocyte-macrophage colony stimulating factor (GM-CSF), OX40, soluble receptor for advanced glycation end products, and soluble tumor necrosis factor-related apoptosis-inducing ligand were shown to be decreased [50, 64, 66, 68]. In some cases, these changes were associated with clinical parameters. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal condition primarily characterized by the selective loss of upper and lower motor neurons. At present, the diagnosis and monitoring of ALS is based on clinical examination, electrophysiological findings, medical history, and exclusion of confounding disorders. There is therefore an undeniable need for molecular biomarkers that could give reliable information on the onset and progression of ALS in clinical practice and therapeutic trials. From a practical point of view, blood offers a series of advantages, including easy handling and multiple testing at a low cost, that make it an ideal source of biomarkers. In this review, we revisited the findings of many studies that investigated the presence of systemic changes at the molecular and cellular level in patients with ALS. The results of these studies reflect the diversity in the pathological mechanisms contributing to disease (e.g., excitotoxicity, oxidative stress, neuroinflammation, metabolic dysfunction, and neurodegeneration, among others) and provide relatively successful evidence of the usefulness of a wide-ranging panel of molecules as potential biomarkers. More studies, hopefully internationally coordinated, would be needed, however, to translate the application of these biomarkers into benefit for patients.
    Full-text · Article · Jun 2014 · BioMed Research International
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