Inflammation in Amyotrophic Lateral Sclerosis - a Study of Soluble Cluster of Differentiation 163 in the Cerebrospinal Fluid

Introduction Amyotrophic lateral sclerosis (ALS) is a fatal disease with progressive muscle weakness leading to severe disability and eventually death. It is the most common form of motor neuron diseases and involves both the upper and lower motor neurons. The median survival from debut of symptoms to dead is approximately 3 years.

Since the diagnosis relies on clinical features and electromyographic abnormalities, which may occur rather late in the disease course, there is a need to identify diagnostic tests that can confirm or exclude the diagnosis of ALS in the earlier phase of the disease.

ALS is a neurodegenerative disease, however the pathogenesis is not well established. The causes are probably multifactorial and a complex interaction between genetic factors and dysfunction of vital molecular pathways concerning the dominantly inherited c9orf72 gene and impaired glutamate uptake in astrocytes (EAAT2-receptor) from the synaptic cleft and thereby glutamate excitotoxicity. This glutamate excitotoxicity may cause oxidative stress, voltage-gated persistent sodium channels and activation of microglia resulting in secretion of proinflammatory cytokines.

More recently, there are studies suggesting neuroinflammation to play a role for the development of ALS. A study from 2012 (a mouse model of ALS, that overexpress mutant superoxide dismutase (mSOD1)), has documented that microglia can both protect and injure the motor neurones depending on which phenotype of the microglia is activated. It seems like it is a continuum between the protective M2 phenotypic state (disease onset) and the neurotoxic M1 phenotypic state (disease end-stage). Furthermore, at disease onset the mice expressed higher levels of Ym1, CD163 and brain-derived neurotrophic factor (markers of M2).

Of other molecular mechanisms, it is worth to mention the structural and functional abnormalities of mitochondria, impairment of axonal transport systems and endosomal trafficking and induction of the endoplasmic reticulum stress response although they appear to be secondary events in ALS. The net result is degeneration of motor neurones in cerebral cortex, the cranial nerve nuclei, the anterior horn of the spinal cord and the corticospinal tracts. The only present treatment available is Riluzole that has proven to extend life or time to onset of serious respiratory problems in patients with ALS. The mode of action for Riluzole still has to be determined, possibly the dynamic is an inhibition of glutamate release from the presynaptic neuron. (1,2,3,4,5,6) Though it seems that the inflammatory process is a secondary event, it seems to be critical for neuronal degeneration. In a study, ALS pathology was sought to be reduced through central nervous system targeted glucocorticoid and succeeded by reducing brainstem pathology in mouse models of ALS. Of different biomarkers, inflammatory markers have also been tested: the interleukin-1 family cytokines. Among them only total interleukin-18, its endogenous inhibitor interleukin-18BP, and the active form of the cytokine (free interleukin-18) were significantly higher in the ALS patients than in controls. The cytokine showed no correlation to the different clinical forms of ALS or the clinical setting of the disease. Cytokines have also been tried as neuroprotective agents. Erythropoietin (EPO) is known as the growth factor that maintains the number of circulating erythrocytes. However, the biological role of EPO has been expanded to other cells, such as neurons, microglia, and astrocytes in the brain. EPO seems to suppress the proinflammatory cytokines during disease progression, maintain the anti-inflammatory cytokines until the late symptomatic stage and finally seems to delay symptom onset and preserve number of motor neurons. (7,8,9,10) Cluster of differentiation 163 (CD-163) - a new way to monitor inflammation in ALS? CD-163 is a scavenger receptor (recognizes and uptakes macromolecules) which marks the monocyte-macrophage activation. CD163 works for macrophages as a receptor for hemoglobin-haptoglobin complexes. The soluble form of the receptor is called sCD163 and is found in plasma and cerebrospinal fluid, where it is found to be up regulated in a large range of inflammatory diseases.