Overview of the cholinergic contribution to gait, balance and falls in Parkinson's disease

Abstract

Mobility deficits, including gait disturbance, balance impairments and falls, are common features of Parkinson's disease (PD) that negatively impact quality of life. Mobility deficits respond poorly to dopaminergic medications, indicating a role for additional neurotransmitters. Due to the critical role of cortical input to gait and balance, acetylcholine-an essential neurotransmitter system for attention-has become an area of interest for mobility. This review aimed to identify the role of cholinergic function on gait, balance, and falls in PD using three techniques; pharmacological, imaging, and electrophysiological. Studies supported the role of the cholinergic system for mobility in PD, with the most promising evidence indicating a role in falls. Imaging studies demonstrated involvement of anterior cholinergic (basal forebrain) systems in gait, and posterior (brainstem) systems in balance. However, this review identified a small number of studies which used varying protocols, making comparisons difficult. Further studies are warranted, measuring comprehensive gait and balance characteristics as well as gold standard falls detection to further quantify the relationship between ACh and mobility in PD.

Keywords: Acetylcholine; Balance; Falls; Gait; Parkinson's disease.

Figure 1:

Cholinergic projections of the central nervous system. Blue: basal forebrain cholinergic system which contains the medial septal nucleus (MS), the diagonal band of Broca (DB), nucleus basalis of meynert (NBM) and the substantia innominate (SI). The basal forebrain nuclei project to the prefrontal cortex, thalamus and striatum. Green: the brainstem cholinergic system contains the pedunculopontine nucleus (PPN) and the laterodorsal tegmental nucleus (LDT) which project to the thalamus, brainstem and cerebellum. IN= cholinergic striatal interneurons.

Figure 2:

PRISMA diagram of search yield used for structured review.

Figure 3:

Single and double hit hypothesis of dopaminergic and cholinergic loss for falls risk in Parkinson’s disease. Single hit hypothesis; mainly loss of dopamine with minimal, age-related loss of acetylcholine. Double hit hypothesis; loss of both dopamine and acetylcholine. Dotted red line indicates the decreased fall threshold with both dopaminergic and cholinergic loss causing falls to occur earlier in disease

Figure 4:

Reduced cholinergic activity in PD causes deficit in attention (direct relationship) and gait and balance (direct relationship). Impaired attention, gait and balance then lead to an increased falls risk (direct relationship). It is proposed that reduced cholinergic activity leads to poorer attention which indirectly affects gait and balance leading to increased falls risk (dashed line).