Background Direct translation of behavioural findings from animal models to human trials in Huntington’s disease (HD) can link cognitive assessment strategies more closely to the underlying pathophysiology. Spatial memory is one cognitive domain that has been shown to be impaired in animal models and in humans with HD, and can be easily tested in both species. Spatial memory deficits in HD are related to striatal and hippocampal pathology, and animal models of HD link reduced hippocampal brain-derived neurotrophic factor (BDNF), a key neuroplasticity protein that declines in HD, to spatial memory impairments. Several treatments in the pipeline for HD are specifically targeted at restoring BDNF. The specificity of spatial memory to the hippocampus and striatum in HD makes spatial memory an ideal cognitive outcome for testing BDNF-relevant treatments for HD.

Aim This paper aims to highlight evidence of spatial memory dysfunction HD, and to propose this domain as a cognitive outcome measure for the assessment of potential treatments for HD.

Method We systematically review existing data on spatial memory function in animal and human HD and analyse the literature in terms of paradigms, homologies, and neuroanatomical correlates.

Outcome We show comparative evidence in animals and humans that spatial memory deficits do occur in HD before onset of motor symptoms, and are present across a variety of spatial memory components. These deficits are related not only to striatal areas, the site of the most earliest and severe pathology in HD, but also to temporal and posterior brain regions. We propose to consider spatial memory as a translational link between animals and humans for the purpose of advancing clinical outcomes for people with HD.

Conclusion The use of spatial memory in the assessment of treatments for HD can maximise the potential for homologies across species in cognitive phenotyping, which will improve translational outcomes in HD research.