Freezing of Gait Levodopa Response Pattern in Parkinson's Disease Provides Clues to Pathophysiology

Freezing of gait (FOG) is a common and enigmatic feature of Parkinson's disease (PD) because of its episodic and unpredictable nature. It is now clear that FOG is not a monolithic phenomenon but instead exhibits substantial heterogeneity across patients, suggesting the existence of subtypes. Among the heterogeneous features are levodopa response patterns and nonmotor features, cognitive impairment and anxiety/depression. It remains an open question as to whether these phenotypes are the result of different pathophysiology. In this paper, we develop the hypothesis that levodopa response patterns may identify FOG subpopulations tied to nonmotor symptoms and alterations in different neurotransmitter systems. Here, we review the levodopa response patterns of FOG seen in PD based on a rigorous levodopa challenge paradigm using a 40% higher dose of levodopa and blood levodopa levels to demonstrate that the majority of patients are either levodopa responsive (OFF-FOG) or unresponsive (ONOFF-FOG). The literature demonstrates that executive and affective changes are not universal in FOG and actually relate closely to levodopa response patterns, OFF-FOG is associated with affective disorders, and ONOFF-FOG is related to cognitive decline. In turn, OFF-FOG and affective disorders appear to be associated with brain noradrenergic degeneration, whereas ONOFF-FOG and cognitive decline are associated with cholinergic loss. These observations suggest different therapeutic targets by subtype. We suggest that levodopa challenge testing may help stratify FOG patients in trials and mechanistic studies.