Abstract
BackgroundBiomarkers 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 (sAPPα and sAPPß) correlated with clinical subtypes of ALS and were of prognostic value.Methodology/Principal FindingsIn 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 sAPPα a, sAPPß and neurofilaments (NfHSMI35) were measured by multiplex assay, Progranulin by ELISA. CSF sAPPα 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 NfHSMI35 was elevated in ALS compared to PD and controls, with highest concentrations found in patients with rapid disease progression (p<0.01). High CSF NfHSMI3 was linked to low CSF sAPPα and sAPPß (p = 0.001, and p = 0.007, respectively). The ratios CSF NfHSMI35/CSF sAPPα,-ß were elevated in patients with fast progression of disease (p = 0.002 each). CSF Progranulin decreased with ongoing disease (p = 0.04).ConclusionsThis 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-axonal damage (increase of NfHSMI35) and to progression of disease.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease characterized by progressive degeneration of spinal and bulbar innervating motor neurons as well as the pyramidal motor neurons [1]
This study provides new Cerebrospinal fluid (CSF) candidate markers associated with progression of disease in amyotrophic lateral sclerosis (ALS)
The data suggest that a deficiency of cellular neuroprotective mechanisms is linked to progressive neuro-axonal damage and to progression of disease
Summary
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease characterized by progressive degeneration of spinal and bulbar innervating motor neurons as well as the pyramidal motor neurons [1]. It is expected that the discovery of sensitive biomarkers of disease progression could be useful for the rapid identification of beneficial drugs in clinical trials, as well as for the prompt exclusion of ineffective ones [4]. They could help to shorten clinical trials and limit the need for large placebo-controlled groups [5]. In a previous study on frontotemporal lobar degeneration (FTLD) including a limited number of patients with ALS [9], we analyzed soluble non-amyloidogenic fragments of beta-amyloid precursor protein (APP), sAPPa and sAPPß which were suggested to protect neurons from proteasomal stress [10]. 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
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