IntroductionRecent studies have implicated changes in the blood-central nervous system barriers (BCNSB) in amyotrophic lateral sclerosis (ALS). The objective of this scoping review is to synthesize the current evidence for BCNSB structure and functional abnormalities in ALS studies and propose how BCNSB pathology may impact therapeutic development.MethodsA literature search was conducted using Ovid Medline, EMBASE, and Web of Science, from inception to November 2021 and limited to entries in English language. Simplified search strategy included the terms ALS/motor neuron disease and [BCNSB or blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB)]. Henceforth, BCNSB is used as a term that is inclusive of the BBB and BSCB. Four independent reviewers conducted a title and abstract screening, hand-searched the reference lists of review papers, and performed a full text review of eligible studies. Included studies were original peer-reviewed full text publications, evaluating the structure and function of the BCNSB in preclinical models of ALS, clinical ALS, or postmortem human ALS tissue. There was no restriction on study design. The four reviewers independently extracted the data.ResultsThe search retrieved 2,221 non-duplicated articles and 48 original studies were included in the synthesis. There was evidence that the integrity of the BCNSB is disrupted throughout the course of the disease in rodent models, beginning prior to symptom onset and detectable neurodegeneration. Increased permeability, pharmacoresistance with upregulated efflux transporters, and morphological changes in the supporting cells of the BCNSB, including pericytes, astrocytes, and endothelial cells were observed in animal models. BCNSB abnormalities were also demonstrated in postmortem studies of ALS patients. Therapeutic interventions targeting BCNSB dysfunction were associated with improved motor neuron survival in animal models of ALS.ConclusionBCNSB structural and functional abnormalities are likely implicated in ALS pathophysiology and may occur upstream to neurodegeneration. Promising therapeutic strategies targeting BCNSB dysfunction have been tested in animals and can be translated into ALS clinical trials.
Health administrative databases can be used to quantify prevalence and incidence of neurodegenerative diseases and their impact on health service utilization outcomes at the population level. Algorithms based on diagnosis codes and health service patterns can be used to identify persons suspected to have a neurodegenerative disease. Previous studies have developed and validated algorithms to identify persons with Alzheimer’s and related dementias using primary care medical records as the reference standard, however, little previous work has focused on developing algorithms for rare neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). This session will discuss challenges in developing algorithms to identify persons with neurodegenerative diseases accurately and opportunities to improve existing definitions using novel data sources including electronic medical record databases. Preliminary findings regarding the development of an ALS algorithm will be presented.
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