A multiple hits hypothesis for memory dysfunction in Parkinson disease

Cognitive disorders are increasingly recognized in Parkinson disease (PD), even in early disease stages, and memory is one of the most affected cognitive domains. Classically, hippocampal cholinergic system dysfunction was associated with memory disorders, whereas nigrostriatal dopaminergic system impairment was considered responsible for executive deficits. Evidence from PD studies now supports involvement of the amygdala, which modulates emotional attribution to experiences. Here, we propose a tripartite model including the hippocampus, striatum and amygdala as key structures for cognitive disorders in PD. First, the anatomo-functional relationships of these structures are explored and experimental evidence supporting their role in cognitive dysfunction in PD is summarized. We then discuss the potential role of alpha-synuclein, a pathological hallmark of PD, in the tripartite memory system as a key mechanism in the pathogenesis of memory disorders in the disease.This Perspective proposes a tripartite model involving the amygdala, hippocampus and striatum as key structures underlying cognitive dysfunction in Parkinson disease. The authors explore the anatomical and functional relationships of the structures and summarize evidence of their involvement in the cognitive aspects of the disease.