MMP-2 and MMP-9 are elevated in spinal cord and skin in a mouse model of ALS.

We aimed to clarify the role of matrix metalloproteinases (MMP) as a possible link between neurodegeneration and skin pathology in ALS by determination of gelatinase MMP-2 and MMP-9 in spinal cord and skin of transgenic SOD1((G93A)) mice. To elucidate mechanisms influencing MMPs, markers of oxidative damage (malondialdehyde (MDA), 3-nitrotyrosine (3-NT) and 8-hydroxy-2'-deoxyguanosine (8OH2'dG)) as well as cytokines (tumor necrosis factor alpha (TNF-alpha) and interleukin 1ss (IL-1ss)) were determined. We measured MMP-9, MMP-2, 3-NT, TNF-alpha, and IL-1ss using ELISA, MDA using High Performance Liquid Chromatography (HPLC) and 8OH2'dG using HPLC with electrochemical detection (HPLC-ECD) in SOD1 and WT. MMP-9 was elevated in spinal cord and skin of SOD1 at 90 days (p=0.009, p<0.001) and 120 days (p<0.01, p=0.04). MMP-2 was elevated in the spinal cord at 90 days (p=0.01) and in the skin at 120 days (p=0.039). We observed a correlation of MMP-9 in spinal cord and skin of SOD1 (p=0.04). MDA was elevated in the spinal cord of SOD1 at 90 and 120 days (p=0.00006, p=0.01) and 8OH2'dG at 90 days (p=0.048). IL-1ss was elevated in the spinal cord of SOD1 at 120 days (p=0.02). Our data confirms that gelatinase MMPs are a common factor linking neurodegeneration and skin changes in ALS. It suggests that oxidative stress and microglial-derived cytokines contribute to the elevation of gelatinase MMPs especially in later stages of disease. Our data raises the question whether the skin may function as a biomarker for specific aspects of disease pathology in ALS.

Linking neuron and skin: matrix metalloproteinases in amyotrophic lateral sclerosis (ALS).

Amyotrophic lateral sclerosis (ALS) mainly affects the motor neurons but may also include other organs such as the skin. We aimed to determine whether matrix metalloproteinases could provide a link between neuronal degeneration and skin alterations in ALS. We measured CSF, serum and skin tissue MMP-2 and MMP-9 using ELISA and malondialdehyde (MDA), a marker of lipid peroxidation, using High Performance Liquid Chromatography (HPLC) in 54 ALS patients and 36 controls. We found CSF and skin MMP-9 to be elevated in ALS as compared to controls (p<0.001, p=0.03, respectively). We observed CSF MMP-9 to be highest in patients with a rapid progressive course of disease (p=0.008). In contrast, we found no significant differences of CSF, serum or skin concentrations of MMP-2 as compared to controls. CSF MMP-2 concentrations decreased with duration of disease (p=0.04, R=-0.31). MDA was elevated in serum of ALS (p<0.001), though no correlation with MMP-2 or MMP-9 was observed. Our findings indicate a general upregulation of MMP-9 in ALS. MMP-9 seems to play a role in both neurodegeneration and skin changes in ALS and could thus be a common factor linking otherwise distant aspects of disease pathology.

Erythropoietin in cerebrospinal fluid: age-related reference values and relevance in neurological disease.

We aimed to establish age-related reference values for Erythropoietin (EPO) in cerebrospinal fluid (CSF) and to evaluate concentrations in neurological diseases. CSF and serum EPO was measured in controls with tension-type headache (CTTH), in patients with ALS, dementia and depression using ELISA technique. Stability experiments showed CSF EPO to be stable for two and a half months and over two thaw/freeze cycles. A positive correlation of CSF EPO with age was found (P<0.01). We found a CSF/serum EPO concentration ratio of 0.126, pointing towards an intrathecal synthesis of EPO. The ALS group showed significantly lowered CSF EPO compared to age-matched CTTH (P<0.012), whereas the dementia and depression group showed no significant differences compared to CTTH.The establishment of age-related reference values in a large cohort of controls will improve the interpretation of future CSF EPO evaluations in neurological diseases.

Cerebrospinal fluid erythropoietin (EPO) in amyotrophic lateral sclerosis.

A candidate neuroprotective agent for neurodegenerative disorders is erythropoietin (EPO). We measured EPO in cerebrospinal fluid (CSF) and serum of patients with amyotrophic lateral sclerosis (ALS). Patients with ALS (N=60), Alzheimer's disease (AD, N=20) and age-matched controls (N=33) were included. Patients with ALS included 30 patients who showed a rapid progression of disease, and 30 patients that showed a slower progression. EPO was measured using ELISA technique. We found CSF EPO levels to be lower in ALS as compared to AD and controls (p<0.05), while no differences were found with regard to serum levels. Patients with ALS who showed a rapid disease progression had lower CSF EPO levels compared to those who progressed more slowly (p=0.03). Low CSF EPO in ALS may imply that the EPO-associated capacity to protect neurons from degeneration is impaired in ALS. Low concentrations of CSF EPO seem to point towards a rapid progression of disease that may be associated with a poorer prognosis.