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

• Published in: Journal of Parkinson's disease Vol. 15; no. 2; pp. 282 - 290
• Main Authors: Factor, Stewart A, Weinshenker, David, McKay, J Lucas
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.03.2025; Sage Publications Ltd
• Subjects: Alzheimer's disease; Amyloid beta-Peptides - metabolism; Clinical trials; Dopamine; Dopamine - metabolism; Dopamine receptors; Drug development; Gait; Gait Disorders, Neurologic - etiology; Gait Disorders, Neurologic - metabolism; Gait Disorders, Neurologic - physiopathology; Humans; Hypotheses; Inflammation; Movement disorders; Neurodegenerative diseases; Neuroinflammatory Diseases - metabolism; Neuroinflammatory Diseases - physiopathology; Neurological diseases; Norepinephrine; Norepinephrine - metabolism; Parkinson Disease - complications; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; Parkinson's disease; Patients; Phenotypes; Social interactions; Social isolation; β-Amyloid; norepinephrine; Parkinson's disease; amyloid; freezing of gait; inflammation
• ISSN: 1877-7171; 1877-718X
• DOI: 10.1177/1877718X241308487

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-β (Aβ) 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, Aβ, 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 Aβ, 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. Plain language summary Parkinson's disease (PD) is a progressive neurological disease associated with the loss of dopamine in the brain. Freezing of gait (FOG) is a complex abnormality of walking seen in people with PD where they feel like their feet are glued to the floor. It is common (affecting up to 60% of patients), a leading cause of injurious falls and contributes significantly to social isolation. It appears to develop and progress separately from other clinical symptoms of PD. Cognitive impairment is frequently associated with FOG. The cause is unknown, and treatment is limited. It is well known that there are several types of FOG suggesting that there might be more than one cause. There is also information suggesting that FOG, in some cases, may occur independent of the loss of dopamine that typically occurs in PD. In this paper we review information supporting that notion. Then, we develop our hypothesis of a different chemical pathway as a possible cause of FOG. This pathway involves the protein amyloid (too much in the brain) and the chemical norepinephrine (too little in the brain), both have been previously related to the development of Alzheimer's disease. We review the literature (including some of our work) that supports the possible role of this chemical pathway in the development of FOG. A deeper understanding of this chemical pathway in FOG could pave the way for the development of new effective drugs in appropriate patient populations.