A possible pathway to freezing of gait in Parkinson's disease

Freezing of gait (FOG), a common, perplexing gait disorder observed in Parkinson's disease (PD), is a leading cause of injurious falls and contributes significantly to social isolation. Unlike other PD cardinal features, FOG appears to develop independently, and its heterogeneity presents challenges for both definition and measurement. The pathophysiological mechanisms underlying FOG remain poorly understood, limiting the development of effective treatments. Although the roles of specific, targetable biomarkers in FOG development remain unidentified, evidence suggests that it is likely multimodal, potentially involving extranigral transmitter circuits. The diversity of FOG phenotypes may also reflect underlying differences in pathophysiology. In this paper, we first present evidence that FOG may occur independently of dopaminergic influence. We then review an expanding body of research supporting the hypothesis that FOG arises from a dysfunctional pathophysiological feedback loop, involving norepinephrine (NE) depletion, neuroinflammation, and amyloid-beta (A beta) accumulation. This biological disruption occurs concurrently with, but distinct from, the primary dopaminergic pathology of PD. When they occur on the background of dopamine loss, the interactions between NE, A beta, and inflammation, as observed in Alzheimer's disease models, may similarly play a critical role in the development of FOG in PD and could serve as pathobiological markers. The proposed changes in the pathophysiological loop might even precede its onset, highlighting the need for further investigation. A deeper understanding of the involvement of A beta, NE, and inflammatory markers in FOG could pave the way for rapid clinical trials to test existing amyloid-clearing therapies and noradrenergic drugs in appropriate patient populations.