2019
Stuart J. McCarter, MD | Levi M. Teigen, PhD, RD | Allison R. McCarter, BS | Eduardo E. Benarroch, MD | Erik K. St. Louis, MD, MS | Rodolfo Savica, MD, PhD
Potential Link to Reduced Cholinergic Transmission and Severity of Disease
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by prominent motor dysfunction including rest tremor, bradykinesia, and rigidity responsive to levodopa. However, postural instability, freezing of gait, and cognitive impairment are important non–levodopa-responsive symptoms of PD and are significant risk factors for falls, leading to hospitalization, disability, and death.1 Treatments for key nonmotor symptoms of PD that might improve cognitive decline and postural instability are currently a major gap in PD therapeutics.
Dysfunction of the cholinergic systems in PD is thought to possibly play a contributory role in postural instability and cognitive impairment. Therefore, modulation of cholinergic transmission could improve balance and cognition in these patients.1 Vitamin B12 is lower in patients with PD compared with controls, and low levels have been associated with peripheral neuropathy, cognitive impairment, and more rapid rate of disease progression in PD.2, 3, 4 Although this relationship does not necessarily mean causality, there are several hypothetical mechanisms by which reduced vitamin B12 may lead to reduced availability of choline as a substrate for cholinergic transmission.
Here we will review the proposed pathophysiology of nonmotor symptoms in PD and the potential relationship between vitamin B12 and acetylcholine metabolism. We propose that vitamin B12 supplementation could be considered as an adjuvant approach to improve cholinergic transmission and, potentially, motor and cognitive function in patients with PD.
The Role of Cholinergic Dysfunction in Nonmotor Symptoms of PD
There is evidence for major cholinergic dysfunction early in the course of PD.5 Acetylcholine is a primary neurotransmitter in many neuronal groups in the central nervous system (CNS). These include neurons of the basal forebrain innervating the cerebral cortex, which modulate attention and sensory processing; neurons in the pedunculopontine tegmental nucleus (PPN) that participate in both thalamocortical arousal and control of muscle tone during locomotion; and giant aspiny neurons in the striatum.
In addition to these direct effects, acetylcholine also contributes to control of dopaminergic activity both at the level of the midbrain and the striatum.6 Lower cholinergic terminal integrity as measured by [(11)C]methyl-4-piperidinyl propionate acetylcholinesterase positron emission tomography (PET) imaging and reduced cholinergic activity assessed with transmagnetic stimulation are associated with slower gait speed compared with patients with isolated striatal nigral degeneration in PD and lower in PD fallers compared with nonfallers.7, 8, 9
In vivo cerebral spinal fluid (CSF) studies have shown decreased acetylcholine levels in patients with PD who have postural instability gait disturbance (PIGD) phenotype compared with tremor predominant (TD) phenotypes; however, acetylcholine levels do not appear to be associated with severity of PIGD.10 Decreased PPN-thalamic cholinergic activity, independent of dopaminergic integrity, is associated with increased postural sway.11 This may be due to a decreased ability to integrate sensory cues for position monitoring and attention maintenance secondary to cholinergic dysfunction.
Supporting in vivo data, pathologic studies of patients with PD have shown that PD fallers have decreased numbers of cholinergic neurons in the PPN when compared with PD nonfallers.12
A significant contributing factor to falls in patients with PD is freezing of gait (FOG)—which is an unpredictable—and sudden inability to start or continue walking despite the desire to walk and is exacerbated with decreased attention or during directional change.13
The pathophysiology of FOG is not completely understood, but cholinergic dysfunction may play a role.8 Recent evidence indicated that it involves dysfunction in cerebellar circuits centered in the vermis.13 Although cholinergic input from the PPN to the medulla and spinal cord are, at present, not considered to be part of the central pattern generator for locomotion, they have an important role in regulating muscle tone during locomotion and possibly contribute to modulating attention during locomotion.8
Further, neocortical cholinergic innervation has shown to be decreased in patients with PD and FOG compared with those who do not have FOG.14 Overall, current data suggest a role for impaired cholinergic transmission as a contributory factor in FOG by impaired control of postural tone during gait, impaired attentional modulation during gait, or both.
Treatment of patients who have PD with anticholinesterase inhibitors may decrease falls compared with placebo.15, 16 In patients with PD dementia and mild cognitive impairment, cholinergic potentiation with anticholinesterase inhibitors has shown trends toward improved cognition.17, 18 The results of these trials provide evidence for the important role of acetylcholine in both postural stability as well as cognition, which are likely strongly interrelated, as recognition and correction of postural and gait errors are needed for postural stability.
Importantly, they highlight the need for additional methods to potentiate cholinergic transmission. However, it remains important to note that cognitive impairment in PD is multifactorial and likely also related to combined underlying microvascular disease, Lewy body deposition, as well as β-amyloid plaques and τ-neurofibrillary tangles in addition to dysfunction of multiple neurotransmitters including dopamine, acetylcholine, norepinephrine, and serotonin.19 As such, acetylcholine remains 1 part of complex neuronal dysfunction leading to cognitive impairment in PD.
