Impairment in stimulus-response learning as a cognitive biomarker in a model of synucleinopathy

Translating findings from preclinical assessments of cognitive function relevant to synucleinopathies into successful clinical trials poses significant challenges. In this study, we examined the effectiveness of human-relevant touchscreen cognitive assessments in detecting the impact of α-synuclein pathology in a mouse model of synucleinopathy on the emergence of stimulus-response learning impairments as a potential cognitive biomarker. We generated two types of α-synuclein pre-formed fibrils, each displaying distinct biophysical characteristics in vitro and biochemical properties when stereotaxically injected in vivo. These two types of fibrils were capable of triggering impairments in stimulus-response learning in pre-motor, prodromal disease stages, akin to what is observed in humans with synucleinopathy. This work supports the use of touchscreen cognitive assessments in conjunction with robust preclinical rodent models for identifying targets and testing therapeutic strategies for synucleinopathic diseases.