Curr Treat Options Neurol (2014) 16:314 DOI 10.1007/s11940-014-0314-5

Movement Disorders (O Suchowersky, Section Editor)

A Review of the Clinical Evidence for Complementary and Alternative Therapies in Parkinson’s Disease Danny Bega, MD* Paulina Gonzalez-Latapi, MD Cindy Zadikoff, MD Tanya Simuni, MD Address *Northwestern University Feinberg School of Medicine, 710 N Lake Shore Drive, 11th Floor, Chicago, IL 60611, USA Email: [email protected]

* Springer Science+Business Media New York 2014

This article is part of the Topical Collection on Movement Disorders The online version of this article (doi:10.1007/s11940-014-0314-5) contains supplementary material, which is available to authorized users. Keywords Parkinson’s disease I CAM I Complementary and alternative therapy I Mind-body I Tai chi I Dance I Music therapy I Yoga I Biofeedback I Guided imagery I Behavioral therapy I Acupuncture I Massage I Neutraceuticals I Vitamin E I Coenzyme q10 I Creatine I Glutathione I Uric acid I Mucuna pruriens I Cannabis I Herbals I Traditional Chinese medicine

Opinion statement No conventional treatment has been convincingly demonstrated to slow or stop the progression of Parkinson’s disease (PD). Dopaminergic therapy is the gold standard for managing the motor disability associated with PD, but it falls short of managing all of the aspects of the disease that contribute to quality of life. Perhaps for this reason, an increasing number of patients are searching for a more holistic approach to healthcare. This is not to say that they are abandoning the standard and effective symptomatic therapies for PD, but rather are complementing them with healthy living, mind-body practices, and natural products that empower patients to be active participants in their healthcare and widen the net under which disease modification might one day be achieved. Despite high rates of utilization of complementary and alternative medicine (CAM) practices, data on efficacy is generally limited, restricting physicians in providing guidance to interested patients. Exercise is now well-established as integral in the management of PD, but mind-body interventions such as Tai Chi that incorporate relaxation and mindfulness with physical activity should be routinely encouraged as well. While no comment can be made about

314, Page 2 of 19

Curr Treat Options Neurol (2014) 16:314

neuroplastic or disease-modifying effects of mind-body interventions, patients should be encouraged to be as active as possible and engage with others in enjoyable and challenging activities such as dance, music therapy, and yoga. Many PD patients also choose to try herbs, vitamins, and neutraceuticals as part of a healthy lifestyle, with the added expectation that these products may lower free radical damage and protect them against further cell death. Evidence for neuroprotection is limited, but patients can be encouraged to maintain a healthy diet rich in “high-power,” low-inflammatory foods, while at the same time receiving education that many promising natural products have produced disappointing results in clinical trials. It is vital that the science of holistic medicine reaches a point where all neutraceuticals are investigated with the same rigor as conventional drugs. A number of agents discussed here that have a proposed role in the treatment of neurodegenerative diseases (and PD in particular), including cannabis, mucuna pruriens, and Chinese herbals, deserve more attention from basic science researchers and clinical investigators before they can be either safely utilized or dismissed.

Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects about 1 % of the population over the age of 60, and is manifested by motor impairment as well as a constellation of non-motor symptoms which include depression, apathy, cognitive impairment, sleep disturbances, and autonomic dysfunction. The cause of PD remains unknown, but it is triggered by accumulation of alpha-synuclein aggregates and loss of dopamine-producing cells in the substantia nigra pars compacta. No treatment has yet been proven to slow or stop the disease progression in PD. In the absence of any disease-modifying therapy, the mainstay of treatment in PD is pharmacologic management aimed at dopamine replacement. While this is generally effective, it may become complicated by disabling motor fluctuations and dyskinesias. Furthermore, dopamine replacement may fail to treat – or may worsen – troublesome non-motor symptoms, which in some cases impact quality of life to a greater extent than motor symptoms [1, 2]. Chronic disease states and neurodegenerative diseases, like PD in particular, highlight the current limitations of conventional medicine. In the absence of neurorestorative therapies, the focus on symptom management in conventional practice may lead to frustration among patients and their caregivers, dissatisfaction with conventional healthcare, and a sense of loss of control over the future. It is perhaps not surprising, then, that a 2001 survey of outpatient PD clinics in the U.S. found that nearly 40 % of patients were using comple-

mentary and alternative medicine (CAM) practices [3], with rates perhaps as high as 76 % in Eastern countries like Korea [4]. CAM is awkwardly defined as a diverse group of medical therapies, interventions, treatments, practices, and products that share in common their exclusion from conventional Western medicine practices. CAM modalities are not routinely taught in U.S. medical schools, nor routinely underwritten by third-party payers within the existing U.S. healthcare system. Perhaps because of their diversity, CAM practices are often defined by these exclusionary criteria, but at the core, CAM therapies are tied together by a focus on individuality over typology, a holistic approach to wellness, and an emphasis on the importance of patient empowerment in the healing process. The National Center f or Co mp le men tary A lter native M ed icin e (NCCAM) classifies CAM interventions into the following groups: 1) natural products such as herbals, vitamins, minerals, and probiotics; 2) mind and body practices such as acupuncture, massage, meditation, movement therapies, relaxation techniques, Tai Chi, and yoga; 3) and alternative systems such as traditional Chinese medicine, Ayurvedic medicine, and homeopathy. Today, almost half of the U.S. population uses at least one of these modalities, usually in conjunction with conventional medicine, and often without discussing these practices with their physician. Furthermore, it is estimated that about $14 billion per year are spent on CAM practices in the U.S. Given the pub-

Curr Treat Options Neurol (2014) 16:314 lic demand for alternative solutions to chronic diseases like PD, conventional medicine cannot be practiced r esponsibly without an evidence-based acknowledgement of CAM practices. Furthermore, physicians have a duty to guide their patients in making safe and effective choices, even if those choices

Page 3 of 19, 314 strain the philosophical limits of conventional medical education. To this end, what follows is a review and summary of the current clinical evidence for various CAM practices in PD, with specific attention focused on 1) mind-body and manual interventions, and 2) natural products (neutraceuticals and herbals).

Methods Medline and Cochrane Library electronic databases were searched from inception to April 2014. The search was conducted separately by two independent reviewers (DB and PG). Several search terms were used to identify publications on CAM and PD, with specific interventions chosen based on surveys of the most commonly used CAM practices [3–5, 6•]. The search terms are provided in Appendix A. Resistance- or endurance-based exercise has intentionally been excluded from this review, as it is already considered an integral and conventional part of the management of PD. Articles were restricted to English language publications. Only those articles that reported a randomized controlled trial design in human subjects with PD were included in this review. All studies were classified for the level of evidence (class I, II, III, or IV) according to the American Academy of Neurology classification of level of evidence [7]. Both reviewers agreed on the level of classification for all studies.

Results A total of 40 RCTs were found using the above search terms, and all were included in this review. Table 1 below summarizes the breakdown of RCTs by CAM modality, and highlights those studies that meet criteria for higher (class I or II) level of evidence.

Mind-body and manual practices Over the past few decades there has been increasing awareness of the importance of both motor and non-motor disability associated with PD, and how these symptoms may be intimately connected. Physicians who care for patients with PD are increasingly cognizant of the interplay of motor and non-motor dysfunction and impact on quality of life. In conventional practice, physicians tend to address and manage each problem separately. Typically, motor and non-motor issues are addressed separately. As an example a patient may leave the office with a medication for tremor, a medication for depression, and a separate medication for sleep dysfunction. An alternative approach subsumed by many CAM modalities is to direct treatment to individual wellness. Mind-body practices in particular may be apt to address the motor and non-motor dysfunction in PD simultaneously. The following is a summary of the review of mind-body interventions for PD.

314, Page 4 of 19

Curr Treat Options Neurol (2014) 16:314

Table 1. Breakdown of RCTs by CAM modality Modality/Intervention

No. of RCTs

Total No. of participants

Ref

No. of publications with level I/II evidence (AAN)

Tai Chi Qigong Dance Music Therapy Yoga Biofeedback Mindfulness/Behavioral Therapy Relaxation & Guided Imagery Massage & Manual Therapy Acupuncture Vitamin E Coenzyme Q10 Creatine Glutathione Uric Acid (inosine) Mucuna Pruriens Cannabis Art Therapy (theater) Homeopathy Chiropractic Hypnosis Reiki

7 2 6 2 1 1 2 2 2 3 1 4 2 1 1 1 2 1 0 0 0 0

415 82 254 54 13 20 71 70 129 100 800 1,024 1,941 21 75 8 26 24 0 0 0 0

[8•, 9–14] [15, 16] [17–22] [23, 24] [25] [26] [27, 28•] [29, 30] [31, 32] [33–35] [36] [37–39, 40•] [41, 42] [43] [44•] [45] [46, 47] [48]

5 [8•, 10, 11, 13, 14] 1 [16] 4 [19–22] 1 [24] 1 [25] 0 2 [27, 28•] 2 [29, 30] 1 [32] 2 [33, 34] 1 [36] [37–39, 40•] 2 [41, 42] 1 [43] 1 [44•] 0 0 0

Tai Chi & Qigong Tai Chi is a traditional Chinese martial art that combines deep breathing and relaxation with slow movements that maintain various postures. The benefits of Tai Chi have been described for stress reduction, improved agility and balance, postural control, and lower extremity strength. There have been seven RCTs of Tai Chi in the PD population, all of which have been published in the last decade [8•, 9–14]. These studies have consistently demonstrated that Tai Chi is both safe and feasible in the PD population. Only three of these studies [8•, 9, 12] used an active intervention comparator group to assess the relative effects of Tai Chi to conventional therapies; in the remaining four studies, the comparator group was given no intervention. The largest trial included 195 subjects with PD who were randomized to Tai Chi, conventional resistance training, or stretching exercises [8•]. Over six months, all groups in the study showed improved motor function, but the Tai Chi group performed significantly better on a measure of postural stability and recorded fewer falls over the period of observation. The studies in which Tai Chi was compared to no intervention showed similar results, with improvements in balance, motor outcomes, and quality of life scores in the active group. However, the remaining two studies [9, 12], which used active comparator groups, found that all subjects improved on specified motor outcomes without specific benefits unique to Tai Chi.

Curr Treat Options Neurol (2014) 16:314

Page 5 of 19, 314

Qigong is a predecessor of Tai Chi that focuses on the internal movement of energy through the practice of meditation and focused movement. The benefits of Qigong in PD have not been explored as extensively as those of Tai Chi. One non-blinded RCT demonstrated short-term motor benefits of Qigong in PD compared to a no-intervention control, but effects were not sustained [15]. The study also demonstrated benefits for various nonmotor symptoms in the treatment group. The one blinded study that did meet criteria for class I level of evidence did not demonstrate any significant benefits of Qigong over aerobic exercise [16]. There is sufficient evidence that Tai Chi is safe, feasible, and can improve postural stability in PD. The studies on Tai Chi were mostly of good quality, with five of the seven studies meeting criteria for class I or II level of evidence by AAN guidelines [7]. Since long-term outcome data is lacking, the duration of benefit from Tai Chi is unclear. Furthermore, while the largest study of Tai Chi demonstrated significant benefits compared to conventional physical activities, these benefits need to be replicated, as other studies have failed to demonstrate benefit beyond that of other active interventions. No recommendations with respect to Qigong can be made from the limited available data; in view of the mixed results from two studies, further investigations are needed to ascertain the effectiveness of Qigong for motor and non-motor symptoms in PD.

Dance Dance includes a variety of forms of individual or partnered exercise, which often incorporate elements of social engagement and musical cueing. In observational studies, different forms of dance have been associated with improved motor function and quality of life ratings in PD [49, 50]. Tango dancing has gained particular interest in PD because of the specific movements it incorporates, which involve deliberate steps such as backward walking. Tango is thought to offer physical and cognitive challenges, as it incorporates aerobic activity and movements that challenge gait and balance with progressive motor skill learning in the presence of external cues provided by the partner and the music. There have been five published RCTs of tango dancing in PD, all within the last decade [17–21]. Only one of these studies compared tango with conventional exercise, and found that while motor function improved in both groups over a three-month period, only the tango group demonstrated improved balance scores [17]. Similar improvements in motor function, balance, and measures of gait were demonstrated in studies where tango was compared to no intervention. Other forms of dance may show similar benefit to tango in PD. In a study by Hackney et al., tango was compared to waltz/foxtrot, and both groups demonstrated improved measures of gait and balance compared to a nointervention group [20]. Additionally, a recent six-month study of Irish set dance demonstrated improvements in motor ability, balance, and freezing of gait compared to conventional physiotherapy [22]. Based on these studies, there is sufficient evidence that dance therapy is safe, enjoyable, and effective for improving gait and balance in the PD population. The studies were largely of good quality, with four of six studies meeting criteria for class I or II level of evidence [7]. Once again, longterm outcome data is lacking. Furthermore, it is unclear whether dance has

314, Page 6 of 19

Curr Treat Options Neurol (2014) 16:314 benefits on motor function beyond that of conventional exercise, although at least one study did demonstrate relative improvement in balance measures. These studies also suggest that compliance with physical activity using dance may be improved, as the intervention is enjoyable compared to conventional exercise.

Music therapy Music therapy is the use of music or any of its elements (sound, rhythm, melody, or harmony) to facilitate and promote mobilization and expression in order to meet physical, emotional, mental, social, or cognitive needs. Over the last decade, data has emerged to suggest that music may have the potential to affect social function, cognition, psychological function (such as anxiety, apathy, and depression), and mobility (including gait and dexterity) by inducing unique chemical, physiological, and anatomic changes that may have particular relevance to neurodegenerative diseases like PD. Both animal and human studies have shown that music is associated with the release of certain neurochemicals and hormones [51–53]. In a study using functional magnetic resonance imaging (fMRI), music was associated with increased limbic activity in the orbitofrontal cortex and increased mesolimbic dopamine release [54]. Pleasurable music in particular has been shown in positron emission tomography (PET) and fMRI studies to activate the nucleus accumbens as well as midbrain nuclei responsible for inhibiting pain signals [51, 54]. It has been theorized that the repetitive practice of movements when playing an instrument may promote the reorganization of neural networks through neuroplasticity that is ongoing even in degenerative disorders [55]. Because it provides immediate auditory feedback on how each movement was performed, music may be particularly suited to induce cortical plasticity. Musical training in healthy adults has been associated with increases in gray matter volume in motor and auditory cortices as well as unique changes in patterns of brain activation on fMRI imaging, but this has not yet been described specifically in the PD population [56, 57]. Finally, a number of studies have shown that musical rhythm, or cueing, can entrain gait and other movements, and that reaction time for auditory cues is actually faster than for visual cues. Trials of rhythmic auditory stimulation (RAS) using simple metronome beats to encourage rhythmic entrainment have shown improvement in gait velocity, cadence, and stride length, and shorter freezing episodes in patients with PD. Similarly, entrainment of movements through playing of instruments has been shown to improve measures of fine motor coordination [58–60]. While the extent to which the established effects of auditory cueing differ from the effects of music is unclear, these studies underscore the elemental dysfunction of rhythm that characterizes PD and which can be targeted with specific interventions. Pacchetti et al. [23] studied the effects of music therapy compared to physical therapy in 32 patients with PD who were observed over a threemonth period, and found that the patients in the music therapy group demonstrated significant improvement in certain motor and quality-of-life measures. De Bruin et al. [24] demonstrated improvements in stride length, gait velocity, and cadence among PD patients walking to an individualized playlist compared to controls. The remainder of the published data on music and

Curr Treat Options Neurol (2014) 16:314

Page 7 of 19, 314

PD is largely observational, and includes descriptions of improved freezing of gait associated with rhythmic cues, as well as improved vocal quality associated with singing. Based on the existing data, there is sufficient evidence to support music therapy as a safe, non-invasive, inexpensive, and enjoyable intervention for patients with PD. Since there are only two RCTs, and only one of them meets AAN criteria for class I or II level of evidence, there is insufficient data to assess efficacy. Further data with larger populations and longer follow-up are needed to replicate and confirm these positive findings. The understanding of the physiology of music is still growing, but current explanations for the mechanism by which music and rhythm may affect function in PD is intriguing and worthy of further investigation using structural-functional correlations with imaging.

Art/expressive therapy (theater) Expressive therapies are commonly used as complementary to conventional treatment of PD, although there is little objective data assessing the benefits of these interventions. Active theater combines movements with stimulation of different sensory pathways and emotions, enforcing socialization through the continuous interaction between performers. In one RCT, the effect of long-term theater therapy was found to delay the need to increase dopaminergic therapy compared with conventional physiotherapy. Theater patients showed significant improvement from baseline on all clinical motor and non-motor scales measured [48]. Further investigation, including studies providing class I/II evidence, are needed to clearly assess the role of theater and other expressive therapies in PD.

Yoga Yoga is a unique form of exercise that has been shown to significantly improve measures of gait, flexibility, muscle force, fatigue, and quality of life in healthy elderly individuals and people with medical disorders including back pain, arthritis, hypertension, anxiety, and depression [61, 63]. This discipline dates back to India, circa 2000 BC, but is only recently gaining popularity throughout the Western world. Yoga encompasses a holistic mindbody approach to exercise, which may better address the combined motor and non-motor needs of patients with PD through specific impact on the body’s stress response. In healthy patients, yoga breathing alone has been shown to decrease cortisol levels, increase GABAergic activity, and in turn, improve mood and reduce anxiety [63]. Yoga can be adapted to suit participants with different abilities, as well as to meet different goals including flexibility, strength, postural alignment, and relaxation. As such, it may be uniquely adapted to address the specific risk factors that contribute to falling in PD, which include posture, freezing gait, poor balance, and lower extremity weakness. Finally, yoga may engage patients socially and mentally in a way that may provide motivation to patients and improve cognitive function through the proposed mechanism of enhanced neuroplasticity.

314, Page 8 of 19

Curr Treat Options Neurol (2014) 16:314 There is a single pilot study demonstrating the feasibility of a yoga treatment program in patients with PD. In the 13-subject 12-week RCT by Colgrove et al., yoga practice resulted in improved UPDRS motor scores and balance scores compared to a non-intervention control group. Nonmotor outcomes were not assessed [25]. There are no published RCTs comparing yoga to other interventions in PD. Based on this limited data from one small study, no clear recommendations can be made at this time regarding the safety, efficacy, or feasibility of yoga in the PD population. Although the study does meet AAN criteria for class II level of evidence, larger samples are clearly needed [7]. Given the rising popularity and availability of yoga classes, further studies are warranted, with additional attention paid to non-motor outcomes and structuralfunctional imaging correlates.

Biofeedback and cognitive-behavioral interventions The severity of symptoms in PD will often change with certain psychological and task-specific factors. Certain emotional states will be associated with enhanced tremor or freezing of gait, and it has been repeatedly described in the literature that these exacerbations can be transiently overcome using visual, auditory, or behavioral cues. The mechanism behind the effects of cueing is not well understood, but some have proposed that movements are improved by simply capturing the attention of the patient, thereby invoking alternate, more conscious motor control pathways and bypassing the “automatic” faulty basal ganglia connections. The notion that faulty pathways can be bypassed and new motor pathways learned is at the core of not just cueing, but also physical therapy, motor imagery (mental practice of movements), and biofeedback training. Biofeedback using vibrotactile information has been used to provide patients with information regarding body sway and posture, and in one study it was shown to improve sway compared to no-feedback control [26]. In an observational study of 20 subjects with PD, relaxation-guided imagery resulted in improvement in tremor for up to 14 hours in some subjects [64]. Tamir et al. [29] demonstrated that physical therapy with motor imagery resulted in faster movement and better motor scores compared to PT alone in 23 patients with PD studied over 12 weeks. In a similar study by Braun et al. [30], PT with motor imagery was compared to PT with relaxation, and no significant difference in walking performance was seen between the groups. Relaxation training in the context of behavioral treatment may be particularly useful where psychological factors lead to impaired function. In one RCT, behavioral treatment focused on control of motor activity was compared to non-specific psychological treatment in 41 subjects with PD, and the investigators found that only the behavioral intervention was effective in reducing tremor and dexterity over a 10-week period [27]. Mindfulness-based therapy involves the development of awareness of present-moment experiences. Extensive evidence has established the efficacy of mindfulness-based interventions (MBI) on anxiety, depression, and chronic pain in non-PD groups [65]. Among PD patients, eight weeks of MBI has been associated with a significant increase in gray matter density in the right amygdala, bilateral hippocampus, thalamus, and caudate nucleus when

Curr Treat Options Neurol (2014) 16:314

Page 9 of 19, 314

compared to usual care [28•]. A prospective mixed-method randomized clinical trial is currently underway to determine whether participation in a mindfulness and lifestyle program could improve PD-related function [66]. While the literature on cueing in PD is extensive, the three studies discussed here are the only RCTs on other behavioral interventions meeting criteria for class I or II level of evidence by AAN guidelines [7]. The literature does provide proof of concept that behavioral interventions can impact motor function in PD, and highlights the power of the mind-body connection. However, the extent to which the impact of these different interventions is clinically relevant and maintainable in daily practice is unclear. Cueing, for instance, only seems to work while the cue is present. Whether any of these interventions result in imprinted behavioral changes, and whether interventions like mindfulness-based cognitive therapy can really affect the underlying disease process by forming new motor networks, remains to be determined.

Massage, manual therapies, and Alexander technique Anecdotally, PD patients have described transient improvement in stiffness and posture after massage therapy. In observational studies of massage for PD, improvement in gait speed as well as subjective self-confidence and well-being have been described [67, 68]. The Alexander technique uses hand contact to assess and manipulate changes in muscle activity by addressing the relationship between thought and the resultant muscle activity. Stallibrass et al. [31] published the only RCT of massage and Alexander technique in 93 subjects with PD, followed with biweekly sessions for three months. Compared with a non-intervention group, only the Alexander technique participants improved on self-assessment disability scores and depression ratings. More objective motor assessments were not performed. On the other hand, in a study by Craig et al. that did look at objective motor outcomes [32], the authors demonstrated that neuromuscular therapy (NMT), a technique similar to massage but which relies on direct compression of trigger points, was more effective than relaxation at improving motor UPDRS scores in 36 PD patients over a four-week intervention period. Only the latter study meets criteria for class II level of evidence, and thus no clear recommendations can be made regarding the efficacy of massage or Alexander technique in the PD population. While manual interventions appear to be safe, data is too limited to make any firm conclusions, particularly with regard to effects on motor function. Based on the limited data, there is reason to believe that these techniques may positively impact mood and subjective assessments of quality of life, and may have a short-term impact on motor function, but these outcomes need to be reproduced with more carefully designed studies. With regard to other commonly used manual therapies, there are no RCTs investigating the effects of chiropractic manipulation in subjects with PD, and so no comment can be made with regard to its safety or efficacy, and caution should be exercised.

Acupuncture Acupuncture has been a part of traditional Chinese medicine for thousands of years. It is based on the premise that disease states are characterized by im-

314, Page 10 of 19

Curr Treat Options Neurol (2014) 16:314 balances in flow of energy, or “Qi,” and that insertion of needles along various points within energy channels can restore balance and health. As an adaptation of this technique, bee venom acupuncture (BVA) has gained some popularity, particularly for the treatment of pain, arthritis, and cancer. This treatment involves the injections of dilute bee venom into acupuncture points, which is thought to convey anti-inflammatory effects. Ten published trials in English on the effects of acupuncture in PD were available. Among these, only three were RCTs [33–35], and only one had a sham intervention-controlled design [34]. Two of these studies met AAN criteria for class I or II level of evidence. Among the studies comparing acupuncture to non-intervention, some improvements in measures of mobility were seen in the studies by Cho et al. [33] and Wang et al. [35]. A functional MRI study [69] recently demonstrated increased activity in the substantia nigra, caudate, thalamus, and putamen after acupuncture in PD patients. Even among observational studies, however, there were inconsistencies in outcomes [70–72]. The same was true when adjuvant acupuncture was compared to drug treatment alone. Cho et al. [33] found that acupuncture and bee venom acupuncture were both more effective than non-intervention on measures of mobility (the UPDRS) as well as non-motor measures such as the Beck Depression Inventory (BDI). However, Cristian et al. [34] examined the effects of acupuncture compared to an intervention with sham points in 14 PD patients, and found no difference in outcomes measured. In a review article, Lee et al. [73] describe two additional sham procedurecontrolled trials in Chinese publications, which also failed to demonstrate a significant effect of true acupuncture over sham points. This raises concern about the possibility of placebo response in the more positive studies that were not designed accordingly. Therefore, while acupuncture appears to be safe, and many patients anecdotally describe benefit, there is not sufficient evidence to recommend it for patients with PD at this time, given inconsistencies in the data.

Natural products (neutraceuticals and herbals) While the etiology of PD remains unknown, multiple lines of evidence support oxidative stress and mitochondrial dysfunction as part of the pathogenic cascade, with the substantia nigra pars compacta (SNc) particularly susceptible to injury. To this end, CAM practices often focus on nutrition, neutraceuticals, and antioxidants as part of a healthy lifestyle, with the expectation that lowering inflammation and free radical damage may protect against further cell death and thus delay or halt disease progression. Questions are frequently raised regarding foods such as blueberries, which are high in antioxidants, but there is no data to guide dosing and no trials to define clinical effects. Since there are no safety concerns surrounding “highpower foods,” patients should be encouraged to maintain a healthy diet incorporating these foods as much as possible. On the other hand, the idea that “natural” products are safer and more beneficial than pharmaceutical products is also pervasive throughout much of the PD community, and requires closer examination. Some of these commonly encountered products are reviewed below.

Curr Treat Options Neurol (2014) 16:314

Page 11 of 19, 314

Vitamin E Alpha-tocopherol, a biologically active component of vitamin E, attenuates the effects of lipid peroxidation by trapping free radicals. Nearly three decades ago, this was one of the first potential neuroprotective agents to be tested in PD. In the seminal DATATOP study [36], a multicenter placebocontrolled RCT of 800 de novo PD patients randomized to tocopherol (2,000 IU per day), selegiline, a combination of both, or placebo, tocopherol demonstrated no benefit over placebo in delaying disability or the need to initiate conventional treatment with levodopa. This study provides class I evidence against the use of vitamin E at the tested dose of 2,000 IU per day as a neuroprotective agent in PD.

Coenzyme Q10 Coenzyme Q10 (CoQ10) is an essential cofactor in the electron transport chain and a potent antioxidant. In PD, reduced levels of CoQ10 and mitochondrial complex I activity have been described compared to agematched controls [37]. In 2002, a placebo-controlled trial of 80 PD subjects raised hope that CoQ10 might have protective benefits in PD in a dosedependent manner [39]. The definitive study published by the Parkinson Study Group (PSG) in 2014 examined the effects of CoQ10 at 1,200 mg and 2,400 mg compared to placebo in 600 PD patients over a 16-month period. The study was terminated early for futility, as subjects in all groups worsened and required conventional treatment at similar rates. There were no safety concerns [40•]. This study provides class I evidence against the use of CoQ10 as a neuroprotective agent. Despite this data, many patients choose to remain on this expensive supplement. Given the convincing data from the PSG study, patients particularly for whom this expense is detrimental to quality of life should be counseled to discontinue the supplement.

Creatine Creatine is a nutritional supplement that enhances cellular energy function and has antioxidant properties. Creatine demonstrated neuroprotective effect in preclinical models of parkinsonism and was shown to be non-futile in a phase II study [41]. The National Institute of Neurological Disorders and Stroke NIH Exploratory Trials in Parkinson’s Disease (NINDS NET-PD) investigators conducted the definitive human trial of creatine in PD in a five-year placebo-controlled RCT in over 1,500 patients. Unfortunately, the study was terminated for futility in 2013, as no clinical evidence of a protective effect was demonstrated [42]. This data, which has not yet been published, provides class I evidence against the use of creatine as a neuroprotective agent in PD.

Glutathione Glutathione is a potent free radical scavenger in the central nervous system, and levels of glutathione are reduced in PD. Glutathione does not cross the bloodbrain barrier, and as such, alternative modes of delivery are explored. There is widespread practice of intravenous (IV) infusion of glutathione for a putative

314, Page 12 of 19

Curr Treat Options Neurol (2014) 16:314 neuroprotective benefit. In an observational study, Sechi et al. described a reduction in motor disability lasting up to four months in nine subjects with PD who received IV glutathione twice a day for one month [74]. A single small RCT compared glutathione to placebo in 21 patients with PD [43], in which subjects received IV glutathione or placebo three times a week. At one month, no difference in UPDRS was seen between groups. Such study design precludes any conclusions regarding neuroprotective effects of the agent, but prior to embarking on any larger studies, the ability of CNS penetration of glutathione must be convincingly demonstrated. Based on this initial data, there is no evidence at this time to recommend glutathione for neuroprotection in PD. Future studies may also assess the efficacy of N-acetylcysteine (NAC), which is the ratelimiting substrate for glutathione synthesis. In a small observational study that included three subjects with PD, administration of a single dose of NAC was able to increase brain glutathione concentrations [75].

Uric acid (inosine) Urate is the breakdown product of purine metabolism, and possesses potent antioxidant properties. The neuroprotective benefits of urate have been demonstrated in rodent models of PD [76, 77], and higher serum and CSF urate levels have been associated with reduced risk of developing PD and slower clinical disease progression [78]. The Safety of Urate Elevation in PD (SURE-PD) investigators demonstrated the safety and feasibility of urate administration in a phase II study over 24 months, in which 75 de novo patients with PD were randomized to receive placebo or inosine (uric acid precursor) [44•]. The study provided class I level of evidence that oral inosine treatment (over the time course and doses studied) was safe and tolerable, and that it can produce an increase in serum and CSF urate levels. While a relationship between higher uric acid and lower risk of disease has been demonstrated repeatedly, causality has not been established, and no recommendation can be made regarding neuroprotective properties. A phase III efficacy study is currently planned.

Mucuna pruriens Mucuna pruriens is a legume endemic to India that has been used in Ayurvedic remedies for centuries. In the early 20th century, it was discovered that levodopa could be isolated from the M. pruriens seeds, and effects on parkinsonian symptoms were anecdotally described as similar to standard levodopa preparations. Antioxidant substances such as CoQ10 and NADH have also been isolated from the herb. In 1995, the HP-200 Study Group reported results of a three-month observational study of the effects of M. pruriens on 60 subjects with PD, noting reduced disability ratings and motor function scores. Only one RCT has compared the effects of M. pruriens with that of standard therapy (levodopa). In this study [45], which did not meet level I or II evidence criteria, eight patients with PD participated in a single-dose crossover design study where pharmacokinetics and motor function were assessed. There was no difference in the impact on motor function or motor complications between the groups, but M. pruriens seemed to be associated with faster time to onset of action. These data would suggest that M. pruriens

Curr Treat Options Neurol (2014) 16:314

Page 13 of 19, 314

is likely effective for the treatment of motor symptoms in PD, but further studies are needed in the form of double-blinded placebo-controlled trials with long-term outcome assessments before comparisons to standard levodopa preparations can be made. Furthermore, at this time there is no evidence that M. pruriens has neuroprotective benefits, but the possible presence of antioxidant substances in the herb is worthy of further investigation. In the absence of data regarding purity, potency, dosing, and drug–drug interactions, the use of M. pruriens cannot be recommended over standard therapy at this time, but deserves further evaluation.

Cannabis Cannabis is a plant substance that has been used for centuries for recreational and medicinal purposes. Cannabis extract contains over 400 chemical compounds, some of which have activity on central and peripheral nervous system receptors. These receptors exist for endogenous cannabinoids, which likely impact various functions ranging from immunity and inflammation to appetite, pain, and neuro-excitability. Cannabinoid receptors have their highest concentrations in the basal ganglia, cerebellum, and hippocampus. The fact that cannabis may exert direct effects on basal ganglia neurotransmission has made it a valid area of research for the symptomatic treatment of tremors and dyskinesias in PD. Further descriptions of potential antioxidant and anti-inflammatory effects of the substance have also raised questions about potential neuroprotective benefits. There have been no RCTs of the effects of smoked cannabis compared to placebo in the PD population. A small study in 2001 demonstrated decreased dyskinesias compared to placebo in seven subjects with PD who received the cannabinoid agonist nabilone [46], but the 2004 study Carroll et al. of oral cannabis extract did not find any notable improvement in dyskinesias or motor function compared to placebo [47]. In a recent observational assessment of the effects of smoked cannabis among 22 subjects with PD who were identified as cannabis users, improvements in motor and nonmotor outcome measures were described after cannabis was smoked [79]; unfortunately, the open-label design of this study limits the generalizability of the conclusions. At this time, there is not sufficient evidence to recommend the use of cannabis for motor symptoms in PD, and even less evidence with regard to safety in this population. There are currently no RCTs of cannabis in the PD population that meet the criteria for class I or II level of evidence. Future well-designed studies are needed to assess the short-term and long-term effects of smoked cannabis in patients with PD. The widespread distribution of cannabinoid receptors throughout the nervous system are both enticing and concerning with regard to potential efficacy and adverse effects in this population. While cannabinoids binding to basal ganglia receptors may exert control over excitatory and inhibitory neurotransmitters involved in the motor complications of PD (and thus improve tremor and dyskinesias), non-targeted binding to cerebellar, hippocampal, and other widespread receptors may lead to adverse effects that these patients may be particularly susceptible to, including balance

314, Page 14 of 19

Curr Treat Options Neurol (2014) 16:314 dysfunction, impaired reaction time and decision-making, cognitive impairment, amotivation, and a host of psychiatric manifestations including anxiety, panic, and psychosis. Whether these complications related to the use of cannabis are more likely to occur in the PD population needs to be clarified, particularly if the substance is to be administered for non-palliative purposes. Furthermore, if benefits can be consistently demonstrated, future research should be aimed at developing cannabinoid receptor agonists and antagonists with more targeted effects at specific receptors. Finally, there is no evidence that cannabis is neuroprotective in PD; future studies should be dedicated to providing a more definitive answer to this question, especially considering that PD may be related in part to glutamine-induced excitotoxicity and damage from oxygen free radicals, both of which may be inhibited to some extent by cannabinoid receptors.

Chinese herbals Various combinations of herbs have been used in traditional Chinese medicine for centuries, and recent research has suggested that some of these herbs may have neuroprotective effects in rat models of PD [80]. Anecdotal evidence, primarily in Asian countries, shows that some of the herbs may offer beneficial effects in PD, although RCTs are needed to assess safety and efficacy. In a review of over 30 publications in the Chinese literature, Li et al. [81] described reports of many different preparations and ingredients improving motor symptoms and quality of life in patients with PD. However, these studies almost uniformly lack standardized ratings and randomized blinded assessments. They also tend to be vague about dosing and other aspects of methodology. A new multicenter open-label randomized active-control study is currently underway in China to investigate the efficacy of the Chinese herbal medication Xifeng Dingchan (XFDCP), which is proposed to act by both reducing striatal dopamine metabolism and protecting against cell death [82]. The study will enroll 320 subjects with early- and mid-stage PD over a three-month treatment and six-month follow-up period. There is insufficient evidence at this time to recommend the use of any specific Chinese herbal remedies for the treatment of PD. However, they are worthy of further well-designed studies to demonstrate safety and efficacy.

Conclusions According to several surveys of patients with PD, the most commonly used nonconventional therapies include vitamins, herbs, massage, and acupuncture [3, 6•]. The epidemiologic studies have demonstrated that patients with PD who use CAM modalities are often younger and have higher levels of income and education, longer disease duration, and more severe symptoms or poorer health status [3–5, 6•]. We have highlighted the limited body of literature that fails to demonstrate convincing safety or efficacy for many CAM treatments, but patients still turn to these modalities either because of a desire for a holistic approach to healthcare, desire for control over their illness, or dissatisfaction with conventional healthcare, which in the case of most neurodegenerative dis-

Curr Treat Options Neurol (2014) 16:314

Page 15 of 19, 314

eases fails to provide protective therapy and focuses on symptomatic care. Some CAM practices claim to offer the hope of impacting neurogenesis, providing anti-inflammatory effects, improving mitochondrial dysfunction and oxidative stress, and increasing brain connectivity through neuroplasticity and the release of neurotrophic factors. Unfortunately, both the clinical and molecular effects of many of these modalities are largely unexamined. CAM modalities must be tested in the same rigorous manner as conventional therapies in order to provide an evidence-based rationale for their use and to avoid ineffective and possibly harmful or costly treatments. While the benefits of conventional exercise have been demonstrated repeatedly, more than half of American seniors fail to engage in the recommended amount of exercise, and those with PD engage in 15 % less than their peers [83]. There is a need, therefore, to identify alternative but effective forms of activity that may foster better adherence, and ideally slow the disease process or the disability associated with the disease. Based on the current data, there is evidence that physical activity through modalities like Tai Chi and dance are safe and beneficial in PD. However, further studies are needed to determine whether these effects are different from conventional exercise, and whether other interventions emphasizing the mind-body connection are particularly useful in PD. Enjoyable interventions like music and dance may be associated with an additional increase in pleasure sensations related to reward and, perhaps more importantly in PD, the potential for improved compliance with therapy, as well as less apathy, depression, and fatigue due to an arousing and motivating stimulus. No manual therapy has been definitively shown to be helpful in the treatment of PD, although studies are limited in this regard. Acupuncture is perhaps the most commonly used manual therapy; in this regard, safety has been demonstrated and observational descriptions of benefit can be found, but study designs have failed to demonstrate a clear and consistent benefit over placebo in the PD population. Despite substantial preclinical data on the beneficial effects of nutritional antioxidants as neuroprotective agents in PD, there is no clinical evidence that any vitamin, food additive, or supplement can improve motor function or delay disease progression in PD. Vitamin E, creatine, and coenzyme Q10 have been among the promising neutraceuticals investigated for potential disease-modifying properties in PD. Unfortunately, in each of these cases, there has been convincing evidence against their use for neuroprotective purposes in humans. Questions are frequently raised regarding foods such as blueberries that are high in antioxidants, but there is no data to guide dosing and no trials to define clinical effects. Since there are no safety concerns surrounding “high-power foods,” patients should be encouraged to maintain a healthy diet and incorporate them as much as possible. Other neutraceuticals and herbs may deserve additional attention from basic scientists and clinicians. The widespread use of CAM practices among patients with PD worldwide mandates that physicians educate themselves about evidence-based CAM practices in order to better guide patients to make safe and appropriate decisions. Patients should be informed that all CAM therapies must be evaluated based on the same principals of evidence-based medicine that guide the use of traditional therapies, and funding should be made available for welldesigned studies.

314, Page 16 of 19

Curr Treat Options Neurol (2014) 16:314

Compliance with Ethics Guidelines Conflict of Interest Danny Bega has received a junior investigator award from the Northwestern University Parkinson’s Disease Advisory Council to study the efficacy of yoga in Parkinson’s disease. Paulina Gonzalez-Latapi declares no conflict of interest. Cindy Zadikoff has served as a paid consultant for UCB Pharma, AbbVie, and Merz. She has also served as a paid speaker for Teva and GSK. Tanya Simuni has served as a paid consultant and has received honoraria from Novartis, Ibsen, General Electric, UCB Pharma, TEVA, IMPAX, Merz, Boehringer Ingelheim, National Parkinson Foundation, and GSK (terminated April 2009). She has also received research support from NIH, MJ Fox Foundation, TEVA, IMPAX, National Parkinson Foundation, and Northwestern Memorial Foundation. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance 1.

Global Parkinson’s Disease Survey Steering Committee. Factors impacting on quality of life in Parkinson’s disease: results from an international survey. Mov Disord. 2002;17(1):60–7. 2. Hely MA, Morris JG, Reid WG, et al. Sydney Multicenter Study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord. 2005;20(2):190–9. 3. Rajendran PR, Thompson RE, Reich SG. The use of alternative therapies by patients with Parkinson’s disease. Neurology. 2001;57(5):790–4. 4. Kim JY, Jeon BS. Complementary and alternative medicine in Parkinson’s disease patients in Korea. Curr Neurol Neurosci Rep. 2012;12(6):631–2. 5. Lökk J, Nilsson M. Frequency, type and factors associated with the use of complementary and alternative medicine in patients with Parkinson’s disease at a neurological outpatient clinic. Parkinsonism Relat Disord. 2010;16(8):540–4. 6.• Wang Y, Xie CL, Wang WW, et al. Epidemiology of complementary and alternative medicine use in patients with Parkinson’s disease. J Clin Neurosci. 2013;20(8):1062–7. This review describes the worldwide use of CAM practices and identifies important issues with regard to CAM use which require more attention.

7.

French J, Gronseth G. Lost in a jungle of evidence: we need a compass. Neurology. 2008;71(20):1634–8. 8.• Li F, Harmer P, Fitzgerald K, et al. Tai chi and postural stability in patients with Parkinson’s disease. N Engl J Med. 2012;366(6):511–9. This study provided strong evidence that Tai Chi reduced balance impairments, improved functional capacity, and reduced falls in patients with PD compared to other active interventions. 9. Amano S, Nocera JR, Vallabhajosula S, et al. The effect of Tai Chi exercise on gait initiation and gait performance in persons with Parkinson’s disease. Parkinsonism Relat Disord. 2013;19(11):955–60. 10. Gao Q, Leung A, Yang Y, et al. Effects of Tai Chi on balance and fall prevention in Parkinson’s disease: a randomized controlled trial. Clin Rehabil. 2014;28(8):748–53. 11. Choi HJ, Garber CE, Jun TW, et al. Therapeutic effects of Tai Chi in patients with Parkinson’s disease. ISRN Neurol. 2013;2013:548240. 12. Cheon SM, Chae BK, Sung HR, et al. The efficacy of exercise programs for Parkinson’s disease: Tai Chi versus combined exercise. J Clin Neurol. 2013;9:237–43. 13. Nocera JR, Amano S, Vallabhajosula S, et al. Tai Chi exercise to improve non-motor symptoms of

Curr Treat Options Neurol (2014) 16:314

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

Parkinson’s disease. J Yoga Phys Ther. 2013. doi:10.4172/2157-7595.1000137. Hackney ME, Earhart GM. Tai Chi improves balance and mobility in people with Parkinson disease. Gait Posture. 2008;456–60. Schmitz-Hübsch T, Pyfer D, Kielwein K, et al. Qigong exercise for the symptoms of Parkinson’s disease: a randomized, controlled pilot study. Mov Disord. 2006;21(4):543–8. Burini D, Farabollini B, Iacucci S, et al. A randomised controlled cross-over trial of aerobic training versus Qigong in advanced Parkinson’s disease. Eura Medicophys. 2006;42(3):231–8. Hackney ME, Kantorovich S, Levin R, et al. Effects of tango on functional mobility in Parkinson’s disease: a preliminary study. J Neurol Phys Ther. 2007;31(4):173–9. Foster ER, Golden L, Duncan RP, et al. Communitybased Argentine tango dance program is associated with increased activity participation among individuals with Parkinson’s disease. Arch Phys Med Rehabil. 2013;94(2):240–9. Duncan RP, Earhart GM. Randomized controlled trial of community-based dancing to modify disease progression in Parkinson disease. Neurorehabil Neural Repair. 2012;26(2):132–43. Hackney ME, Earhart GM. Effects of dance on movement control in Parkinson’s disease: a comparison of Argentine tango and American ballroom. J Rehabil Med. 2009;41(6):475–81. Hackney ME, Earhart GM. Effects of dance on gait and balance in Parkinson’s disease: a comparison of partnered and nonpartnered dance movement. Neurorehabil Neural Repair. 2010;24(4):384–92. Volpe D, Signorini M, Marchetto A, et al. A comparison of Irish set dancing and exercises for people with Parkinson’s disease: a phase II feasibility study. BMC Geriatr. 2013;13:54. Pacchetti C, Mancini F, Aglieri R, et al. Active music therapy in Parkinson’s disease: an integrative method for motor and emotional rehabilitation. Psychosom Med. 2000;62(3):386–93. de Bruin N, Doan JB, Turnbull G, et al. Walking with music is a safe and viable tool for gait training in Parkinson’s disease: the effect of a 13-week feasibility study on single and dual task walking. Park Dis. 2010:483530. Colgrove YS, Sharma N, Kluding P, et al. Effect of yoga on motor function in people with Parkinson’s disease: a randomized, controlled pilot study. J Yoga Phys Ther. 2012;2(112). Nanhoe-Mahabier W, Allum JH, Pasman EP, et al. The effects of vibrotactile biofeedback training on trunk sway in Parkinson’s disease patients. Parkinsonism Relat Disord. 2012;18(9):1017–21. Mohr B, Müller V, Mattes R, et al. Behavioral treatment of Parkinson’s Disease leads to improvement of

Page 17 of 19, 314 motor skills and to tremor reduction. Behav Ther. 1996;27(2):235–55. 28.• Pickut BA, Van Hecke W, Kerckhofs E, et al. Mindfulness based intervention in Parkinson’s disease leads to structural brain changes on MRI: a randomized controlled longitudinal trial. Clin Neurol Neurosurg. 2013;115(12):2419–25. This study used brain MRI voxel-based morphometry to make a quantitative analysis of the neurobiological effects of mindfulness based intervention in PD. 29. Tamir R, Dickstein R, Huberman M. Integration of motor imagery and physical practice in group treatment applied to subjects with Parkinson’s disease. Neurorehabil Neural Repair. 2007:68–75. 30. Braun S, Beurskens A, Kleynen M, et al. Rehabilitation with mental practice has similar effects on mobility as rehabilitation with relaxation in people with Parkinson’s disease: a multicentre randomised trial. J Physiother. 2011;57(1):27–34. 31. Stallibrass C, Sissons P, Chalmers C. Randomized controlled trial of the Alexander technique for idiopathic Parkinson’s disease. Clin Rehabil. 2002;16(7):695–708. 32. Craig LH, Svircev A, Haber M, et al. Controlled pilot study of the effects of neuromuscular therapy in patients with Parkinson’s disease. Mov Disord. 2006;21(12):2127–33. 33. Cho SY, Shim SR, Rhee HY, et al. Effectiveness of acupuncture and bee venom acupuncture in idiopathic Parkinson’s disease. Parkinsonism Relat Disord. 2012;18(8):948–52. 34. Cristian A, Katz M, Cutrone E, et al. Evaluation of acupuncture in the treatment of Parkinson’s disease: a double-blind pilot study. Mov Disord. 2005;20(9):1185–8. 35. Wang L, He C, Liu Y, et al. Effect of acupuncture on the auditory evoked brain stem potential in Parkinson’s disease. J Tradit Chin Med. 2002;22(1):15–7. 36. Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med. 1993;328(3):176–83. 37. NINDS NET-PD Investigators. A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease. Neurology. 2007;68(1):20–8. 38. Storch A, Jost WH, Vieregge P, et al. Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease. 2007;64(7):938–44. 39. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002;59(10):1541–50. 40.• Investigators Parkinson Study Group QE3. A randomized clinical trial of high-dosage coenzyme q10 in early Parkinson disease: no evi-

314, Page 18 of 19 dence of benefit. JAMA Neurol. 2014;71(5):543–52. This was a large phase III randomized controlled trial demonstrating the lack of efficacy of coenzyme q10 in slowing disease progression in PD. 41. Investigators NINDS NET-PD. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology. 2006;66(5):664–71. 42. ClinicalTrials.gov. [Online]. Available from: HYPERLINK “http://clinicaltrials.gov/ct2/show/ NCT00449865”. 43. Hauser RA, Lyons KE, McClain T, et al. Randomized, double-blind, pilot evaluation of intravenous glutathione in Parkinson’s disease. Mov Disord. 2009;24(7):979–83. 44.• Investigators Parkinson Study Group SURE-PD. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol. 2014;71(2):141–50. This was a phase II trial demonstrating the safety, tolerability, and urate-elevating capability of inosine in PD. A phase III efficacy trial to determine whether inosine can slow disease progression in PD is expected. 45. Katzenschlager R, Evans A, Manson A, et al. Mucuna pruriens in Parkinson’s disease: a double blind clinical and pharmacological study. J Neurol Neurosurg Psychiatry. 2004;75(12):1672–7. 46. Sieradzan KA, Fox SH, Hill M, et al. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson’s disease: a pilot study. Neurology. 2001;57(11):2108–11. 47. Carroll CB, Bain PG, Teare L, et al. Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study. Neurology. 2004;63(7):1245–50. 48. Modugno N, Iaconelli S, Fiorlli M, et al. Active theater as a complementary therapy for Parkinson’s disease rehabilitation: a pilot study. Sci World J. 2010:2301–13. 49. Heiberger L, Maurer C, Amtage F, et al. Impact of a weekly dance class on the functional mobility and on the quality of life of individuals with Parkinson’s disease. Front Aging Neurosci. 2011;eCollection 2011:3–14. 50. Marchant D, Sylvester JL, Earhart GM. Effects of a short duration, high dose contact improvisation dance workshop on Parkinson disease: a pilot study. Complement Ther Med. 2010;18(5):184–90. 51. Chanda ML, Levitin DJ. The neurochemistry of music. Trends Cogn Sci. 2013;17(4):179–93. 52. Knight WE, Rickard PhD NS. Relaxing music prevents stress-induced increases in subjective anxiety, systolic blood pressure, and heart rate in healthy males and females. J Music Ther. 2001;38(4):254–72. 53. Möckel M, Röcker L, Störk T, et al. Immediate physiological responses of healthy volunteers to different types of music: cardiovascular, hormonal and mental

Curr Treat Options Neurol (2014) 16:314

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

changes. Eur J Appl Physiol Occup Physiol. 1994;68(6):451–9. Menon V, Levitin DJ. The rewards of music listening: response and physiological connectivity of the mesolimbic system. Neuroimage. 2005;28(1):175–84. Advocat J, Russell G, Enticott J, et al. The effects of a mindfulness-based lifestyle programme for adults with Parkinson’s disease: protocol for a mixed methods, randomised two-group control study. BMJ Open. 2013;3(10):e003326. Gaser C, Schlaug G. Brain structures differ between musicians and non-musicians. J Neurosci. 2003;23(27):9240–5. Berkowitz AL, Ansari D. Generation of novel motor sequences: the neural correlates of musical improvisation. Neuroimage. 2008;41(2):535–43. Arias P, Cudeiro J. Effect of rhythmic auditory stimulation on gait in Parkinsonian patients with and without freezing of gait. PLoS One. 2010;5(3):e9675. Thaut MH, McIntosh GC, Rice RR, et al. Rhythmic auditory stimulation in gait training for Parkinson’s disease patients. Mov Disord. 1996;11(2):193–200. Bernatzky G, Bernatzky P, Hesse HP, et al. Stimulating music increases motor coordination in patients afflicted with Morbus Parkinson. Neurosci Lett. 2004;361(1–3):4–8. Hagins M, States R, Selfe T, et al. Effectiveness of yoga for hypertension: systematic review and meta-analysis. Evid Based Complement Alternat Med. 2013:649836. Cramer H, Lauche R, Haller H, et al. A systematic review and meta-analysis of yoga for low back pain. Clin J Pain. 2013;29(5):450–60. Streeter CC, Gerbarg PL, Saper RB, et al. Effects of yoga on the autonomic nervous system, gammaaminobutyric acid, and allostasis in epilepsy, depression, and post-traumatic stress disorder. Med Hypotheses. 2012;78(5):571–9. Schlesinger I, Benyakov O, Erikh I, et al. Parkinson’s disease tremor is diminished with relaxation guided imagery. Mov Disord. 2009;24(14):2059–62. Hofmann SG, Sawyer AT, Witt AA, et al. The effect of mindfulness-based therapy on anxiety and depression: a meta-analytic review. J Consult Clin Psychol. 2010;78(2):169–83. Advocat J, Russell G, Enticott J, et al. The effects of a mindfulness-based lifestyle programme for adults with Parkinson’s disease: protocol for a mixed methods, randomised two-group control study. BMJ Open. 2013;3(10):e003326. Donoyama N, Ohkoshi N. Effects of traditional Japanese massage therapy on various symptoms in patients with Parkinson’s disease: a case-series study. J Altern Complement Med. 2012;18(3):294–9.

Curr Treat Options Neurol (2014) 16:314 68.

69.

70.

71.

72.

73.

74.

75.

Paterson C, Allen JA, Browning M, et al. A pilot study of therapeutic massage for people with Parkinson’s disease: the added value of user involvement. Complement Ther Clin Pract. 2005;11(3):161–71. Yeo S, Lim S, Choe IH, et al. Acupuncture stimulation on GB34 activates neural responses associated with Parkinson’s disease. CNS Neurosci Ther. 2012;18(9):781–90. Eng ML, Lyons KE, Greene MS, et al. Open-label trial regarding the use of acupuncture and yin tui na in Parkinson’s disease outpatients: a pilot study on efficacy, tolerability, and quality of life. J Altern Complement Med. 2006;12(4):395–9. Shulman LM, Wen X, Weiner WJ, et al. Acupuncture therapy for the symptoms of Parkinson’s disease. Mov Disord. 2002;17(4):799–802. Ren XM. Fifty cases of Parkinson’s disease treated by acupuncture combined with madopar. J Tradit Chin Med. 2008;28(4):255–7. Lee HS, Park HL, Lee SJ, et al. Scalp acupuncture for Parkinson’s disease: a systematic review of randomized controlled trials. Chin J Integr Med. 2013;19(4):297–306. Sechi G, Deledda MG, Bua G. Reduced intravenous glutathione in the treatment of early Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 1996;20(7):1159–70. Holmay MJ, Terpstra M, Coles LD, et al. NAcetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin Neuropharmacol. 2013;36(4):103–6.

Page 19 of 19, 314 76.

77.

78.

79.

80.

81.

82.

83.

Cipriani S, Desjardins CA, Burdett TC, et al. Urate and its transgenic depletion modulate neuronal vulnerability in a cellular model of Parkinson’s disease. PLoS One. 2012;7(5):e37331. Gong L, Zhang QL, Zhang N, et al. Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson’s disease: linking to Akt/GSK3β signaling pathway. J Neurochem. 2012;123(5):876–85. Ascherio A, LeWitt PA, Xu K, Eberly S, et al. Urate as a predictor of the rate of clinical decline in Parkinson disease. Arch Neurol. 2009;66(12):1460–8. Lotan I, Treves TA, Roditi Y, et al. Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study. Clin Neuropharmacol. 2014:41–4. Lo YC, Shih YT, Tseng YT. Neuroprotective effects of San-Huang-Xie-Xin-Tang in the MPP(+)/MPTP models of Parkinson’s disease in vitro and in vivo. Evid Based Complement Alternat Med. 2012;2012:501032. Li Q, Zhao D, Bezard E. Traditional Chinese medicine for Parkinson’s disease: a review of Chinese literature. Behav Pharmacol. 2006;17(5):403–10. Zhang J, Ma YZ, Shen XM. Evaluation on the efficacy and safety of Chinese herbal medication Xifeng Dingchan Pill in treating Parkinson’s disease: study protocol of a multicenter, open-label, randomized active-controlled trial. J Integr Med. 2013;11(4):285–90. Chen H, Zhang SM, Schwarzschild MA, et al. Physical activity and the risk of Parkinson disease. Neurology. 2005;64(4):664–9.