The Future of Freezing of Gait in Parkinson's: Exploring Potential Treatments and Preventive Strategies

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Freezing of gait becomes increasingly difficult to treat, especially when it becomes dopamine resistant in the advanced stages of the disease.
Freezing of gait becomes increasingly difficult to treat, especially when it becomes dopamine resistant in the advanced stages of the disease.

More than half of patients diagnosed with Parkinson disease (PD) experience freezing of gait (FOG).1,2 FOG symptoms vary, with some experiencing alternating trembling of the legs or a shortening of step length to a shuffle, whereas others describe their feet as "stuck to the floor" as their upper body continues to move.1,2

Episodic in nature, FOG can be triggered by various situational (eg, cognitive, emotional) and environmental factors, such as dual tasking, approaching or passing through a narrow passageway or doorway, turning, crowds, distractions, approaching one's destination (such as a couch), and simply being in a hurry.1 Ultimately, FOG increases risk of falling.3,4

The pathophysiology of FOG is not well understood. What is known is that comorbidities of PD, such as anxiety5 and cognitive decline,6 do aggravate FOG. Current pharmacologic and surgical treatments for FOG, such as conventional oral dopaminergic medication and deep brain stimulation (DBS), are only partially effective at best in many patients, according to the authors of a review published in Parkinsonism and Related Disorders.2

Neurology Advisor discussed current treatment challenges and potential new treatments for FOG with 2 of the contributing authors,2 Moran Gilat, PhD, a postdoctoral researcher in the Department of Rehabilitation, University of Leuven in Flanders, Belgium, and Simon J. G. Lewis, MBBCh, BSc, FRCP, FRACP, MD, a professor at the Parkinson's Disease Research Clinic, Brain and Mind Centre, The University of Sydney in Australia.

Neurology Advisor: Why are current treatments failing to adequately control FOG?

Dr Gilat: FOG has only recently come to light as 1 of the most debilitating features of PD. As such, only in the last decade has there been an influx of research studies investigating its underlying neural basis and the limited effectiveness of existing treatments (such as dopamine replacement therapies). Furthermore, FOG is more common in the advanced stages of PD, when both nigral and extranigral pathologies become widespread and affect a multitude of neuronal circuits that play a role in FOG. However, the spread of pathology and the resulting degeneration is different across patients and hard to delineate in vivo, making it difficult to tailor pharmacological interventions to each patient's neural requirements. In this advanced stage, a multidisciplinary approach of pharmacological and behavioral treatment options is, therefore, currently the best option, although future studies should aim to find better ways to also tailor nonpharmacologic interventions to each patient's characteristics affecting FOG severity.2

Neurology Advisor: Is FOG more difficult to treat in some patients vs others?

Professor Lewis: FOG becomes increasingly difficult to treat, especially when it becomes dopamine resistant in the advanced stages of the disease. As PD pathology spreads over time, more and more areas of the brain become affected that have been shown to play a role in the occurrence of FOG. For instance, with disease progression, patients notably develop cognitive deficits, especially in their executive functioning, implicating frontal cortical dysfunction. These cognitive deficits likely result from extranigral degeneration of cholinergic and noradrenergic neurons that project to these frontal regions of the brain. Given that executive dysfunctions have been implicated in the etiology of FOG, it becomes important to manage these deficits to counter cognitive decline and also to prevent FOG. However, as mentioned earlier, the spread of pathology and resulting degeneration is different across patients, making it difficult to tailor pharmacologic interventions and to test for the effects of newly developed pharmacological agents in future clinical trials, as these require large groups of patients clumped together for adequate statistical power. However, the heterogeneity of the neural substrates underlying FOG in each patient makes it more unlikely that on the group level, a positive effect of the intervention will be found, as not all patients will be sensitive to the intervention, based on their unique neural deficits.

Neurology Advisor: What makes treating FOG so difficult? How do disease heterogeneity/interindividual variability come into play?

Dr Gilat: FOG in PD is a highly heterogeneous symptom, as illustrated by the variety of situations that trigger FOG to a different degree for each patient. That is, some patients with PD often freeze when walking through doorways or when trying to turn on the spot, whereas others may freeze more commonly when performing a thinking task while walking or when feeling anxious. This indicates that each patient likely has a unique neural substrate that causes FOG. Any generic treatment is, therefore, prone to be helpful for some, but not others. Indeed, for the majority of patients with PD, dopamine replacement therapies help to prevent FOG, whereas in rare occasions, the same dopaminergic treatment can worsen FOG in others.

Neurology Advisor: What upcoming treatments for FOG do you think offer the most promise for patients?

Dr Gilat: The complex and heterogeneous nature of FOG likely requires a multidisciplinary approach to treatment, including pharmacologic (dopaminergic and nondopaminergic) and behavioral (eg, physiotherapy, occupational therapy, rehabilitation) interventions that can be tailored to each patient's clinical and environmental characteristics that affect FOG severity. For instance, intelligent cueing may prove more effective than commonly applied continuous cueing devices, as intelligent systems can offer the cues only during situations of imminent FOG, thereby prolonging the effectiveness of the cues and preventing distraction of the cues during successful walking. Similar on-demand strategies could be employed for other behavioral techniques, and even deep brain or noninvasive stimulation techniques. Indeed, high-frequency DBS is commonly used in eligible patients, as it often offers substantial relief of cardinal motor symptoms, such as rigidity and tremor. However, at present, these DBS devices continuously stimulate on a single high frequency that does not satisfactorily alleviate the paroxysmal symptom of FOG, which may also benefit from lowering the frequency of stimulation. Novel closed-loop DBS systems are, therefore, being developed that can modulate the stimulation frequency on the basis of some kind of external input, such as ongoing direct cell recording at the stimulation site or data from wearable sensors (eg, accelerometers) that can detect upcoming FOG episodes. Such closed-loop DBS systems could temporarily lower the stimulation frequency during periods of imminent FOG and switch back to the high-frequency setting that is more favorable to ameliorate other symptoms such as tremor during times when FOG does not pose a threat. Given that both cueing and DBS are current treatment options for PD, it is likely that improved versions of these may soon come on the market to ameliorate FOG as well.

Neurology Advisor: A recent study demonstrated significant improvement in walking after 6 weeks of 1-hour computer-assisted cognitive rehabilitation sessions (specifically, training of attention ability and information processing tasks) twice weekly in people with moderate to severe PD who were experiencing FOG.7 How might future cognitive interventions improve the treatment of FOG?

Professor Lewis: There is growing evidence of a link between cognitive deficits and FOG. In particular, patients with FOG have been shown to have executive deficits in their attention, set-shifting, and motor inhibition.8-11 It is thus theoretically attractive to investigate whether improving patient's executive functioning would also ameliorate FOG. Cognitive training (CT) is a nonpharmacologic intervention that has been shown to improve executive functioning in PD12 and may prove beneficial to reduce FOG.11

Our group recently conducted a randomized, placebo-controlled clinical trial to test whether CT targeting these executive deficits in patients with FOG would reduce the severity of objective FOG compared with an active control group that received memory- and language-related CT.13 In short, 65 patients with FOG were randomly assigned into this study, of whom patients 20 in the CT group and 18 in the control group experienced FOG at baseline testing and were included in the analysis of interest. The primary outcome was the difference in the percentage of time spent with FOG during standardized timed up-and-go tests before and after the CT intervention. Interestingly, the findings revealed that targeted CT reduced the severity of FOG when patients were on their regular dopaminergic medication, but not when they were off their medication, as compared with the control group. This finding has strong clinical implications, given that patients are mainly in their on state at home. The finding that CT did not improve FOG when patients were off their dopaminergic medications further indicates that CT alone is not sufficient to overcome the severe striatal deficits associated with FOG.13

Neurology Advisor: Are there any additional areas of research on FOG that are of particular interest?

Professor Lewis: By the time FOG has become troublesome to the patient, the management of FOG is already very difficult. Another line of research is, therefore, aimed at finding the best predictors of developing FOG to allow for earlier interventions that may prevent the actual development of FOG. One could envision that providing targeted CT in the early stages of PD, when FOG has not yet developed, may prevent, or at least postpone, the onset of FOG.

References

  1. Nutt JG, Bloem BR, Giladi N, Hallett M, Horak FB, Nieuwboer A. Freezing of gait: moving forward on a mysterious clinical phenomenon. Lancet Neurol. 2011;10:734-744.
  2. Gilat M, Lígia Silva de Lima A, Bloem BR, Shine JM, Nonnekes J, Lewis SJG. Freezing of gait: promising avenues for future treatment. Parkinsonism Relat Disord. 2018; Mar 12.
  3. Latt MD, Lord SR, Morris JG, Fung VS. Clinical and physiological assessments for elucidating falls risk in Parkinson's disease. Mov Disord. 2009;24:1280-1289.
  4. Kerr GK, Worringham CJ, Cole MH, Lacherez PF, Wood JM, Silburn PA. Predictors of future falls in Parkinson disease. Neurology. 2010;75:116-124.
  5. Ehgoetz Martens KA, Ellard CG, Almeida QJ. Does anxiety cause freezing of gait in Parkinson's disease?PLoS One. 2014;9(9):e106561.
  6. Walton CC, Shine JM, Mowszowski L, Gilat M, et al. Impaired cognitive control in Parkinson's disease patients with freezing of gait in response to cognitive load. J Neural Transm (Vienna). 2015;122(5):653-660.
  7. Dibilio V, Nicoletti A, Mostile G, Portaro G, Luca A, Patti F, Zappia M. Computer-assisted cognitive rehabilitation on freezing of gait in Parkinson's disease: A pilot study. Neurosci Lett. 2017;654:38-41.
  8. Amboni M, Cozzolino A, Longo K, Picillo M, Barone P. Freezing of gait and executive functions in patients with Parkinson's disease. Mov Disord. 2008;23:395-400.
  9. Cohen RG, Klein KA, Nomura M, Fleming M, Mancini M, Giladi N, et al. Inhibition, executive function, and freezing of gait. J Parkinsons Dis. 2014;4:111-122.
  10. Naismith SL, Shine JM, Lewis SJG. The specific contributions of set-shifting to freezing of gait in Parkinson's disease. Mov Disord. 2010;25:1000-1004.
  11. Walton CC, Shine JM, Mowszowski L, Naismith SL, Lewis SJG. Freezing of gait in Parkinson's disease: current treatments and the potential role for cognitive training. Restor Neurol Neurosci. 2014;32:411-422.
  12. Leung IHK, Walton CC, Hallock H, Lewis SJG, Valenzuela M, Lampit A. Cognitive training in Parkinson disease: a systematic review and meta-analysis. Neurology. 2015;85:1843-1851.
  13. Walton CC, Mowszowski L, Gilat M, Hall JM, O'Callaghan C, Muller AJ, Georgiades MJ, Szeto YY, Ehgoetz Martens KA, Shine JM, Naismith SL, Lewis SJG. Cognitive training for freezing of gait in parkinson's disease: a randomized controlled trial. NPJ Parkinsons Dis. 2018;4:15.
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