Table 3.

Strengths and limitations of preclinical models used within the VCI field.

Model	Strengths	Limitations
iPSC	•Human model system •Genetic diversity •Ease of genetic manipulation •High throughput drug screening and toxicity studies	•Constrained artificial environment •Lack complex tissue organisation and physiological context •Quality, purity and maturity of differentiated cells •Significant variability in differentiation potential and genetic stability between iPSC line •Absence of vascularization •Lack cognitive outcome measures
Organoid	•Human model system •Spatial organization of tissues, cell-cell and cell-matrix connections •Model complex interaction and connection amongst brain regions and structures •More mature phenotype of iPSC-derived cells •Can be maintained for extended periods •Drug screening and toxicity studies	•Lack complex organisation of the in vivo brain •Significant variability in differentiation potential and genetic stability between iPSC line •Absence of vascularization •Absence of microglia •Lack of cognitive outcome measures
Zebrafish model	•Ease of genetic manipulation •Transparent during development allowing for non-invasive in vivo imaging •Prolific reproduction rates •Basic functional outcome measures •Drug screening and toxicity studies	•Simpler nervous systems •Genomic differences between zebrafish and human greater than mammalian models •Lack higher cognitive outcome measures
Rodent models	•Study of non–cell-autonomous effects •Rapid assessment of neuronal and circuit function •Cognitive outcome measures •Availability of powerful genetic toolkits •Greater acceptability in terms of ethics compared to large mammalian model	•Small white matter volume •Different brain structure relative to human •Domain specific genomic differences between rodent and human •Species differences when evaluating cognitive deficits and their relevance to human SVD progression •Inbred animals do not reflect the genetic diversity of a population •Short lifespan of rodents means that it is difficult to reproduce the symptoms of dementia
Large mammalian model	•Gyrencephalic brain anatomy •More white matter •More human-like vasculature •Longer lifespan than rodents •Non-human primate models allow for sophisticated cognitive tests and have a very close evolutionary relationship to humans	•Relative lack of behavioural assays currently available compared to rodent models •Scarcity of species-specific reagents •Costly and therefore constrained by the number of centres which have the infrastructure and resources to house this model •Longer duration of studies •Ethical constraints