Neuroimaging findings in preclinical amyotrophic lateral sclerosis models-How well do they mimic the clinical phenotype? A systematic review.
3R
amyotrophic lateral sclerosis
external validity
magnetic resonance imaging (MRI)
motor neuron disease (MND)
neuroimaging
neuroscience
systematic review
Journal
Frontiers in veterinary science
ISSN: 2297-1769
Titre abrégé: Front Vet Sci
Pays: Switzerland
ID NLM: 101666658
Informations de publication
Date de publication:
2023
2023
Historique:
received:
31
12
2022
accepted:
10
04
2023
medline:
19
5
2023
pubmed:
19
5
2023
entrez:
19
5
2023
Statut:
epublish
Résumé
Animal models for motor neuron diseases (MND) such as amyotrophic lateral sclerosis (ALS) are commonly used in preclinical research. However, it is insufficiently understood how much findings from these model systems can be translated to humans. Thus, we aimed at systematically assessing the translational value of MND animal models to probe their external validity with regards to magnetic resonance imaging (MRI) features. In a comprehensive literature search in PubMed and Embase, we retrieved 201 unique publications of which 34 were deemed eligible for qualitative synthesis including risk of bias assessment. ALS animal models can indeed present with human ALS neuroimaging features: Similar to the human paradigm, (regional) brain and spinal cord atrophy as well as signal changes in motor systems are commonly observed in ALS animal models. Blood-brain barrier breakdown seems to be more specific to ALS models, at least in the imaging domain. It is noteworthy that the G93A-SOD1 model, mimicking a rare clinical genotype, was the most frequently used ALS proxy. Our systematic review provides high-grade evidence that preclinical ALS models indeed show imaging features highly reminiscent of human ALS assigning them a high external validity in this domain. This opposes the high attrition of drugs during bench-to-bedside translation and thus raises concerns that phenotypic reproducibility does not necessarily render an animal model appropriate for drug development. These findings emphasize a careful application of these model systems for ALS therapy development thereby benefiting refinement of animal experiments. https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022373146.
Sections du résumé
Background and objectives
UNASSIGNED
Animal models for motor neuron diseases (MND) such as amyotrophic lateral sclerosis (ALS) are commonly used in preclinical research. However, it is insufficiently understood how much findings from these model systems can be translated to humans. Thus, we aimed at systematically assessing the translational value of MND animal models to probe their external validity with regards to magnetic resonance imaging (MRI) features.
Methods
UNASSIGNED
In a comprehensive literature search in PubMed and Embase, we retrieved 201 unique publications of which 34 were deemed eligible for qualitative synthesis including risk of bias assessment.
Results
UNASSIGNED
ALS animal models can indeed present with human ALS neuroimaging features: Similar to the human paradigm, (regional) brain and spinal cord atrophy as well as signal changes in motor systems are commonly observed in ALS animal models. Blood-brain barrier breakdown seems to be more specific to ALS models, at least in the imaging domain. It is noteworthy that the G93A-SOD1 model, mimicking a rare clinical genotype, was the most frequently used ALS proxy.
Conclusions
UNASSIGNED
Our systematic review provides high-grade evidence that preclinical ALS models indeed show imaging features highly reminiscent of human ALS assigning them a high external validity in this domain. This opposes the high attrition of drugs during bench-to-bedside translation and thus raises concerns that phenotypic reproducibility does not necessarily render an animal model appropriate for drug development. These findings emphasize a careful application of these model systems for ALS therapy development thereby benefiting refinement of animal experiments.
Systematic review registration
UNASSIGNED
https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022373146.
Identifiants
pubmed: 37205225
doi: 10.3389/fvets.2023.1135282
pmc: PMC10185801
doi:
Types de publication
Systematic Review
Langues
eng
Pagination
1135282Informations de copyright
Copyright © 2023 Cannon, Zürrer, Zejlon, Kulcsar, Lewandowski, Piehl, Granberg and Ineichen.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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