Gait Dysfunction in Parkinson Disease: The Role of the Cholinergic System

PARKINSON DISEASE (PD) IS THE most common neurodegenerative movement disorder, affecting approximately 0.1% to 0.2% of the population and approximately 1% of individuals 60 years or older.¹ PD manifests through a multitude of symptoms, including the classic quartet of bradykinesia, cogwheel rigidity, resting tremor, and impairment of gait and balance. Other nonmotor symptoms include cognitive dysfunction, psychosis, hallucinations, and constipation. Although there are a handful of definitive genetic causes of PD,² most patients with PD have an idiopathic form of the disease. As a chronic, progressive, and degenerative condition, PD leads to a significant burden on health care resources and society as a whole, one that is expected to increase in the future as the nation’s percentage of elderly patients increases.³

By the early 1960s, PD pathophysiology was determined to be due to dopamine deficiency in the striatum, which was a direct result of neuronal loss in the substantia nigra.⁴ Combination carbidopa-levodopa, in various formulations, remains the gold standard treatment of many of the motor features of PD to this day, and it is especially effective in treating bradykinesia, rigidity, and tremor.⁵ Gait dysfunction, on the other hand, remains more difficult to treat.

More Than Just Dopamine

Although dopaminergic deficiency is seen as the primary driver of most of the motor symptoms of PD, gait dysfunction often responds poorly to dopaminergic therapies.⁶ This prompted investigators to look for other potential underlying mechanisms of symptom development in PD, including investigations of cholinergic degeneration. In 2003, Bohnen et al used positron emission tomography (PET) to show that there is actually greater in vivo cortical cholinergic dysfunction in PD dementia than in Alzheimer dementia.⁷ Subsequent studies revealed that cholinergic degeneration is also closely associated with gait dysfunction, balance impairment, and falls.^8-12 Dopaminergic degeneration in PD seems to lead to a loss of gait automaticity, thus requiring more sustained attention from individuals and placing a greater burden on the neocortical cholinergic system.¹³ When there is concurrent cholinergic degeneration, significant gait dysfunction occurs.

There are 3 main sources of acetylcholine within the brain. The first is the basal forebrain, including the nucleus basalis of Meynert, which has widespread projections to the neocortex, thalamus, and striatum. The second is the pedunculopontine nucleus (PPN) within the brainstem, which projects mainly to the cerebellum, thalamus, and basal forebrain. Third, cholinergic interneurons are present within the striatum and help to regulate dopaminergic pathways. In general, degeneration of the basal forebrain leads to cortical cholinergic denervation, whereas degeneration of the brainstem (especially the PPN) leads to thalamic cholinergic denervation.^8,14-17

Why Gait Matters

PATIENTS WITH PD OFTEN experience postural instability, reduced gait speed, reduced stride length, slower turns, freezing of gait, and falls.^6,22 These various forms of gait dysfunction are often quite disabling, and can be a primary driver of accumulation of disability for many patients. Results of a 2008 study showed that axial impairment, defined as the combination of postural instability and gait dysfunction, was the primary contributor to disability as measured through 3 different scales. Gait dysfunction and postural instability accounted for 31% to 37% of the variance in these metrics. Additionally, gait dysfunction and postural instability were major drivers of decreased quality of life, accounting for 44% of the variance in measures of social functioning, and 55% of the variance in overall quality of life.²³ Falls, which often arise as a consequence of postural instability and gait dysfunction, are a major contributor to injury and comorbidity as well as to caregiver burden.²⁴ Results of a separate study indicated that decline in gait function was closely associated with worsening quality of life,²⁵ whereas results of another study revealed that gait dysfunction was a predictor of cognitive decline in early PD.²⁶

Results of a recent review showed that up to 25% of patients will experience a hip fracture within 10 years of receiving a diagnosis of PD due to gait dysfunction. In addition, the results showed that minor injuries such as bruises, joint dislocations, and skin lacerations are common. Fear of future falls often restricts daily activities, leading to a loss of independence and worsened social isolation. Falls and immobility are closely associated with admission to nursing homes, thus increasing the socioeconomic burden of disease. Most worrisome is that patients with significant gait and balance impairment have increased mortality risk. Average survival is reduced to 7 years once recurrent falls are present.²⁷

Current treatments for gait dysfunction are few and far between. Levodopa, dopamine agonists, catechol-O-methyl transferase inhibitors, monoamine oxidase type B inhibitors, and adenosine antagonists do not have data supporting their use for gait.²⁸ Amantadine may be associated with improvement in freezing of gait,²⁸ but more evidence is needed. Anticholinergic agents, although useful for tremor, can actually worsen freezing of gait.²⁹ Deep brain stimulation (regardless of target) has shown mild benefit in some gait metrics, mainly related to improvement in bradykinesia, but has not shown efficacy in improving freezing of gait,³⁰ and in some instances can worsen gait dysfunction.³¹ A dedicated physical therapy regimen seems to be the current treatment with the best evidence in improving gait and reducing falls.⁵

Unfortunately, it can be difficult to quantify cholinergic degeneration because the major nuclei (basal forebrain, PPN) lack clear borders on standard imaging techniques. Until recently, most studies investigating cholinergic degeneration in PD have relied on PET or short latency afferent inhibition (SAI; a transcranial magnetic stimulation-based measure of motor cortex function dependent on thalamocortical cholinergic input) to quantify the degree of degeneration of the cholinergic nuclei. Results of a 2009 study showed that patients with PD who fall frequently had similar rates of striatal dopaminergic degeneration compared with nonfallers, but that they had significantly worsened thalamic cholinergic degeneration compared with nonfallers.⁹ Thalamic acetylcholine, as mentioned above, largely arises from the PPN in the brainstem, thus it was surmised that this finding represents degeneration of the PPN in patients with PD and frequent falls. These results were replicated in a similar study in 2010.⁸

Although degeneration of the PPN and subsequent thalamic cholinergic denervation have been implicated in increased fall risk in PD, degeneration of the basal forebrain and subsequent cholinergic denervation of the neocortex have been implicated in reduced gait speed in PD.^10-12 Investigators in a study in 2013 used PET imaging to show that patients with PD and reduced cortical cholinergic innervation had slower gait speeds compared with those with PD without evidence of cholinergic degeneration and compared with healthy controls.¹⁰ Of note, there was no difference in nigrostriatal dopaminergic degeneration between the 2 PD groups, thus clarifying that cortical cholinergic degeneration is a large driver of the difference. In another study, SAI was used as a surrogate marker of cholinergic activity. The results showed that loss of SAI is associated with reduced gait speed, stride length, and stride time deviation in patients with PD.¹¹ Recently, an MRI-based method has been described to quantify degeneration of cholinergic nucleus 4, one of the major cholinergic nuclei within the basal forebrain.¹² This method also confirmed an association between cholinergic degeneration and reduced gait speed in a retrospective cohort of patients with PD undergoing work-up for deep brain stimulation.

Given this evidence, the cholinergic system becomes an obvious therapeutic target for improving gait dysfunction in PD.

Treatment Implications

Three studies have investigated the effect of cholinesterase inhibitors on falls in PD.^18-20 All 3 were phase 2, randomized, double-blind, and placebo controlled. The first, published by Chung et al in 2010, enrolled 23 patients with PD who were falling at least 2 times per week. Utilizing a crossover design, the participants received either donepezil or placebo for 6 weeks, followed by a 3-week washout and then a crossover. The primary outcomes of the study were self-reported falls and near-falls. Fall frequency was 0.25 (± 0.08) per day on placebo versus 0.13 (± 0.03) on donepezil (P = .049), whereas the frequency of near-falls did not significantly differ across the treatment and placebo phases. That said, the statistical significance of this study was driven in large part by those participants who fell most often at baseline having rather dramatic improvements in their number of falls, whereas the majority of participants did not show a significant improvement.¹⁸

The second, published by Li et al in 2015, enrolled 176 patients with PD (with and without cognitive dysfunction) and randomized the patients with evidence of cognitive dysfunction to either receive rivastigmine or placebo for 1 year. At baseline, the number and incidence of falls increased with worsening cognition. After 1 year of either rivastigmine or placebo treatments, patients in the rivastigmine group had both higher Montreal Cognitive Assessment scores (P = .002) and fewer falls (P < .01) compared with the placebo group. The authors concluded that the degree of cognitive impairment is closely associated with the incidence of falls and that rivastigmine could potentially be a treatment for both.¹⁹

The third study, published by Henderson et al in 2016, enrolled 130 total patients and treated them with rivastigmine or placebo for a total of 32 weeks.²⁰ The primary end point of this study was adjusted difference in step time variability (a component of gait variability) between the 2 groups at week 32. The patients in the rivastigmine group showed improved step time variability compared with those in the control group for both normal walking (ratio of means 0.72; P = .002) and in simple dual task (0.79; P = .045). Given that gait variability has been shown to be a marker for fall risk in patients with PD,²¹ the authors surmised that rivastigmine may be an effective treatment for reducing falls in PD.

Unfortunately, given the small sample sizes as well as the heterogeneous outcome measures used in these trials, many questions remain regarding the use of cholinesterase inhibitors for the treatment of gait dysfunction in PD.¹⁷

Next Steps

Determining evidence-based treatments to help gait and balance and to reduce falls in PD is of utmost importance. If the above results can be replicated on a larger scale in phase 3 trials, then cholinesterase inhibitors would likely be adopted as standard of care for the treatment of gait dysfunction in PD. Determining consistent, validated, and clinically relevant outcome measures will be necessary for the adoption of cholinesterase inhibitors in standard practice.¹⁷ Many studies investigating falls have relied on the retrospective reporting of patients and family members. Perhaps as wearable devices become more mainstream, it will be easier to gather objective data on falls and near-falls in this patient population.

It is also possible that patient selection has been imperfect. In the study by Chung et al in 2010, the statistically significant results were largely driven by only a handful of super-responders, which begs the question of exactly why those particular patients responded so robustly and others not at all.¹⁸ None of the above studies used quantified measures of cholinergic degeneration at baseline, which could potentially serve as a biomarker of sorts to determine if cholinesterase inhibition would be useful in any given patient.

Alternatively, it is conceivable that cholinesterase inhibition is not adequate. In treating the other motor symptoms of PD, true dopaminergic supplementation (levodopa, dopamine agonists) provides a much more robust symptom response than medications that inhibit metabolizing enzymes (catechol-O-methyl transferase inhibitors, monoamine oxidase type B inhibitors).⁵ Similarly, perhaps the degree of cholinergic degeneration needed to significantly impair gait would itself hinder the effect of cholinesterase inhibitors, as there simply could be little to no acetylcholine produced in the brains of affected patients. Since acetylcholine is a ubiquitous neurotransmitter throughout the body, it may be a challenge to develop targeted therapies that act solely on the brain.

Finally, future studies should seek to better understand the underlying mechanism of cholinergic degeneration and its relationship with dopaminergic degeneration in PD. It is likely that cholinergic degeneration, although clearly associated with gait dysfunction and falls, is but another piece of the complex pathophysiological puzzle that is PD.