Soluble Beta-Amyloid Precursor Protein Is Related to Disease Progression in Amyotrophic Lateral Sclerosis

Background: Biomarkers of disease progression in amyotrophic lateral sclerosis (ALS) could support the identification of beneficial drugs in clinical trials. We aimed to test whether soluble fragments of beta-amyloid precursor protein (sAPPa and sAPPß) correlated with clinical subtypes of ALS and were of prognostic value. Methodology/Principal Findings: In a cross-sectional study including patients with ALS (N = 68) with clinical follow-up data over 6 months, Parkinson’s disease (PD, N = 20), and age-matched controls (N = 40), cerebrospinal fluid (CSF) levels of sAPPa a, sAPPß and neurofilaments (NfH SMI35) were measured by multiplex assay, Progranulin by ELISA. CSF sAPPa and sAPPß levels were lower in ALS with a rapidly-progressive disease course (p = 0.03, and p = 0.02) and with longer disease duration (p = 0.01 and p = 0.01, respectively). CSF NfH SMI35 was elevated in ALS compared to PD and controls, with highest concentrations found in patients with rapid disease progression (p,0.01). High CSF NfH SMI3 was linked to low CSF sAPPa and sAPPß (p = 0.001, and p = 0.007, respectively). The ratios CSF NfH SMI35 /CSF sAPPa,-ß were elevated in patients with fast progression of disease (p = 0.002 each). CSF Progranulin decreased with ongoing disease (p = 0.04). Conclusions: This study provides new CSF candidate markers associated with progression of disease in ALS. The data suggest that a deficiency of cellular neuroprotective mechanisms (decrease of sAPP) is linked to progressive neuro-axona

1H-NMR-Based Metabolomic Profiling of CSF in Early Amyotrophic Lateral Sclerosis

Background: Pathophysiological mechanisms involved in amyotrophic lateral sclerosis (ALS) are complex and none has identified reliable markers useful in routine patient evaluation. The aim of this study was to analyze the CSF of patients with ALS by 1 H NMR (Nuclear Magnetic Resonance) spectroscopy in order to identify biomarkers in the early stages of the disease, and to evaluate the biochemical factors involved in ALS. Methodology: CSF samples were collected from patients with ALS at the time of diagnosis and from patients without neurodegenerative diseases. One and two-dimensional 1 H NMR analyses were performed and metabolites were quantified by the ERETIC method. We compared the concentrations of CSF metabolites between both groups. Finally, we performed principal component (PCA) and discriminant analyses. Principal Findings: Fifty CSF samples from ALS patients and 44 from controls were analyzed. We quantified 17 metabolites including amino-acids, organic acids, and ketone bodies. Quantitative analysis revealed significantly lower acetate concentrations (p = 0.0002) in ALS patients compared to controls. Concentration of acetone trended higher (p = 0.015), and those of pyruvate (p = 0.002) and ascorbate (p = 0.003) were higher in the ALS group. PCA demonstrated that the pattern of analyzed metabolites discriminated between groups. Discriminant analysis using an algorithm of 17 metabolites reveale

Platelet Serotonin Level Predicts Survival in Amyotrophic Lateral Sclerosis

International audienceBACKGROUND: Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease involving upper and lower motor neurons loss. Clinical features are highly variable among patients and there are currently few known disease-modifying factors underlying this heterogeneity. Serotonin is involved in a range of functions altered in ALS, including motor neuron excitability and energy metabolism. However, whether serotoninergic activity represents a disease modifier of ALS natural history remains unknown. METHODOLOGY: Platelet and plasma unconjugated concentrations of serotonin and plasma 5-HIAA, the major serotonin metabolite, levels were measured using HPLC with coulometric detection in a cohort of 85 patients with ALS all followed-up until death and compared to a control group of 29 subjects. PRINCIPAL FINDINGS: Platelet serotonin levels were significantly decreased in ALS patients. Platelet serotonin levels did not correlate with disease duration but were positively correlated with survival of the patients. Univariate Cox model analysis showed a 57% decreased risk of death for patients with platelet serotonin levels in the normal range relative to patients with abnormally low platelet serotonin (p = 0.0195). This protective effect remained significant after adjustment with age, gender or site of onset in multivariate analysis. Plasma unconjugated serotonin and 5-HIAA levels were unchanged in ALS patients compared to controls and did not correlate with clinical parameters. CONCLUSIONS/SIGNIFICANCE: The positive correlation between platelet serotonin levels and survival strongly suggests that serotonin influences the course of ALS disease

Transcriptional Regulator PerA Influences Biofilm-Associated, Platelet Binding, and Metabolic Gene Expression in Enterococcus faecalis

Enterococcus faecalis is an opportunistic pathogen and a leading cause of nosocomial infections, traits facilitated by the ability to quickly acquire and transfer virulence determinants. A 150 kb pathogenicity island (PAI) comprised of genes contributing to virulence is found in many enterococcal isolates and is known to undergo horizontal transfer. We have shown that the PAI-encoded transcriptional regulator PerA contributes to pathogenicity in the mouse peritonitis infection model. In this study, we used whole-genome microarrays to determine the PerA regulon. The PerA regulon is extensive, as transcriptional analysis showed 151 differentially regulated genes. Our findings reveal that PerA coordinately regulates genes important for metabolism, amino acid degradation, and pathogenicity. Further transcriptional analysis revealed that PerA is influenced by bicarbonate. Additionally, PerA influences the ability of E. faecalis to bind to human platelets. Our results suggest that PerA is a global transcriptional regulator that coordinately regulates genes responsible for enterococcal pathogenicity

Plasma Neurofilament Heavy Chain Levels Correlate to Markers of Late Stage Disease Progression and Treatment Response in SOD1(G93A) Mice that Model ALS

Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder characterised by progressive degeneration of motor neurons leading to death, typically within 3–5 years of symptom onset. The diagnosis of ALS is largely reliant on clinical assessment and electrophysiological findings. Neither specific investigative tools nor reliable biomarkers are currently available to enable an early diagnosis or monitoring of disease progression, hindering the design of treatment trials. Methodology/Principal Findings: In this study, using the well-established SOD1G93A mouse model of ALS and a new in-house ELISA method, we have validated that plasma neurofilament heavy chain protein (NfH) levels correlate with both functional markers of late stage disease progression and treatment response. We detected a significant increase in plasma levels of phosphorylated NfH during disease progression in SOD1G93A mice from 105 days onwards. Moreover, increased plasma NfH levels correlated with the decline in muscle force, motor unit survival and, more significantly, with the loss of spinal motor neurons in SOD1 mice during this critical period of decline. Importantly, mice treated with the disease modifying compound arimoclomol had lower plasma NfH levels, suggesting plasma NfH levels could be validated as an outcome measure for treatment trials. Conclusions/Significance: These results show that plasma NfH levels closely reflect later stages of disease progression and therapeutic response in the SOD1G93A mouse model of ALS and may potentially be a valuable biomarker of later disease progression in ALS