The lack of effective therapies for gait and balance abnormalities in advancing PD stems in large part from a limited understanding of the role of non-dopaminergic systems in the pathophysiology of these symptoms. It is increasingly clear that normal gait depends upon a complex interplay of motor, sensory and cognitive functions, indicating that the full spectrum of PD neuropathology must be considered to identify the responsible neural substrates. The PET work of Udall Center investigators demonstrated that PD patients with a history of falls have significantly reduced cholinergic function compared to non-falling patients, whereas these groups do not differ in the degree of dopaminergic denervation. This was the first in vivo study to link cholinergic deficits explicitly to gait dysfunction in PD patients, and is consistent with a considerable and growing body of work supporting a critical role for cholinergic function in locomotion. This work includes several reports indicating that enhancing cholinergic neurotransmission improves gait, while anti-cholinergic drugs may have deleterious effects.

Despite these intriguing observations, the relationship between cholinergic lesions and gait dysfunction in PD is poorly understood, and it is not clear whether or how these lesions synergize with striatal dopamine deficiency. Two cholinergic projections in the brain degenerate in PD and are implicated in the control of locomotion. The basal forebrain (BF) complex, including the nucleus basalis of Meynert, provides the principal cholinergic input to the entire cortical mantle. The pedunculopontine nucleus (PPN) provides cholinergic inputs to the thalamus, cerebellum, several brainstem nuclei, the basal ganglia, and the spinal cord. The extent to which gait dysfunction in PD is caused by independent or combined BF or PPN cholinergic lesions is not well understood.