Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is a highly progressive and debilitating neurodegenerative disease, which usually leads to the death of affected individuals within a few years after the onset of symptoms. ALS is currently incurable and very little is known about its pathophysiology. Finding validated biomarkers will help us to advance our understanding of ALS etiology and find better strategies for early diagnosis and management of the disease. The main aim of the present systematic review is to evaluate the concentration of 11 frequently reported biomarkers for ALS in peripheral blood and CSF of patients diagnosed with ALS compared with controls.MethodsThis systematic review protocol has been established according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) 2015 guideline. We will include all types of observational studies with human subjects that investigated the concentrations of intended biomarkers (amyloid beta (Aβ-42), tau and phosphorylated tau (p-Tau), neurofilaments, S100β, cystatin C, progranulin (PGRN), glial fibrillary acidic protein (GFAP), monocyte chemoattractant protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), TAR DNA-binding protein-43 (TDP43), YKL-40, and CHIT1 in CSF or peripheral blood of ALS patients for initial assessment. Also, we will include case series with a minimum of 10 cases and clinical trials which have measured baseline biomarker levels. Case studies, case reports, reviews, letters, and animal and in vitro studies will be excluded. Multiple electronic databases including Cochrane Library, MEDLINE (PubMed), ISI Web of Science, and EMBASE will be searched to find all eligible articles published since 1980. No language restriction will be applied. All titles and abstracts retrieved by searching information sources will be evaluated independently by two authors against the eligibility criteria. The following information will be extracted from each included study by two independent authors: bibliographic details (first author, study title, year of publication, country), demographics and clinical information (number of patients and controls, type of ALS and controls, study design, age, gender, specimen, biomarkers levels, ALS functional rating scale Revised (ALSFRS-R), duration of disease), and measurements (method, value type, biomarkers levels). We will use the extracted mean and standard deviation (SD) of biomarkers concentrations to calculate the standardized mean difference (SMD) and 95% confidence intervals (CI). The primary outcome measures are the mean difference of biomarker levels between ALS patients and controls, different types of ALS, and ALS patients with genetic mutations.DiscussionWe will systematically review the literature and analyze studies of biomarker level in CSF and peripheral blood of patients with ALS and controls. The results will help us to identify biomarkers with possible diagnostic and prognostic value.Systematic review registrationPROSPERO CRD42017078127
Highlights
Amyotrophic lateral sclerosis (ALS) is a highly progressive and debilitating neurodegenerative disease, which usually leads to the death of affected individuals within a few years after the onset of symptoms
Amyotrophic lateral sclerosis (ALS) is a highly progressive neurodegenerative disease, which usually leads to severe disability, respiratory dysfunction, and death in the affected patients within 3 to 5 years after the onset of symptoms [1]
The aim of the present systematic review is to evaluate the concentration of 11 frequently reported biomarkers for ALS in peripheral blood and cerebrospinal fluid (CSF) of patients diagnosed with ALS compared with controls
Summary
This systematic review protocol has been established according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) 2015 guideline (Additional file 1). Data collection process The following information will be extracted from each included study by two independent authors: bibliographic details: first author, study title, year of publication, and country; demographics and clinical information: number of patients and controls, type of ALS and controls, study design, age, gender, specimen, ALSFRS-R, and duration of disease; measurements: method, value type, and biomarker levels; STROBE-ME checklist [17]. Investigation of heterogeneity To find the possible sources of heterogeneity and to investigate their influence on biomarkers levels, we will undertake subgroup analyses based on the following factors if sufficient data are available: Discussion In this systematic review and meta-analysis, first, we will assess the concentration of commonly reported biomarkers in patients with ALS, and we will clarify how these biomarkers can be related to clinical characteristics of the patients and their disease outcome by subgroup analyses. Intervention-related factors: type of recruitment (population-based or referral-based settings), measurements method (ELISA, Luminex, others)
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