From Reproducibility to Translation in Neurodegenerative Disease

Despite tremendous investment and preclinical success in neurodegenerative disease, effective disease-altering treatments for patients have remained elusive. One highly cited reason for this discrepancy is flawed animal study design and reporting. If this can be broadly remedied, reproducibility of preclinical studies will improve. However, without concurrent efforts to improve generalizability, these improvements may not translate effectively from animal experiments to more complex human neurodegenerative diseases. Mechanistic and phenotypic variability of neurodegenerative disease is such that most models are only able to interrogate individual aspects of complex phenomena. One approach is to consider animals as models of individual targets rather than as models of individual diseases and to migrate the concept of predictive validity from the individual model to the body of experiments that demonstrate translatability of a target. Both exploratory and therapeutic preclinical studies are dependent upon study design methods that promote rigor and reproducibility. However, the body of evidence that is needed to demonstrate efficacy in therapeutic studies is substantially broader than that needed for exploratory studies. In addition to requiring rigor within individual experiments, convincing evidence for therapeutic potential must assess the relationships between model choice, intended goal of the intervention, pharmacologic criteria, and integration of biomarker data with outcome measures that are clinically relevant to humans. It is conceivable that proof-of-concept studies will migrate to cell-based systems and that animal systems will be increasingly reserved for more distal translational purposes. If this occurs, it is likely to prompt reexamination of what the term "translational" truly means.