Chapter 31 Parkinson’s disease
With contribution from Dr Lily Tomas
Introduction
Parkinson’s disease (PD) is a degenerative neurological disorder that becomes more prevalent with age and is of unknown aetiology. It is characterised by a progressive degeneration of the nigrostriatal dopaminergic pathway subsequently leading to progressive tremor, bradykinesis, rigidity and postural instability. As such, the primary features of PD relate to a deficiency of dopamine, with the development of traditional pharmaceutical therapies being based around the replacement of this particular neurotransmitter. However, effective as these are, they do not address all features of the disease that may not be secondary to low dopamine.1 This appears to be 1 of the prime reasons that complementary and alternative medicine (CAM) therapies are widely used by patients afflicted with this disease. Surveys throughout the world demonstrate that 40–76% patients with PD have used at least 1 CAM therapy since their original diagnosis.2–5
Incidence/prevalence in Australia
Patients using CAM are seeking to improve their motor symptoms (57.6%), for fatigue (19.6%), for pain relief (4.3%), for constipation (5.4%) or for no specific reason (13%).2 The most common therapies used by Westerners include vitamins, herbs, massage and acupuncture. Users of CAM tend to be younger and have a younger age of onset of PD, and have a higher income and education level than non-users.5 Patients with more severe motor dysfunction symptoms at onset are also more likely to use CAM.4
In 1998, the Parkinson’s Disease Society (PDS) set up a working group to look at complementary therapies and PD. Their first initiative was to survey PDS members about their experiences of complementary therapies. Over 2000 people replied and the results are presented in Table 31.1.6, 7
Table 31.1 Complementary therapies utilised and reported effective, together with the percent benefits
| CAM modality | Benefit described by those who reported a positive effect |
|---|---|
| Acupuncture/acupressure |
(Source: adapted and modified from Paccetti C, Mancini F, Agliera R et. al. Active music therapy in PD: an integrative method for motor and emotional rehabilitation. Psychosom Med 2000:62(3):386–93)
Lifestyle
It has been suggested that there are several environmental, lifestyle, and physical attributes that appear to be precursors of PD.8 In summary these include:
Factors that showed an inverse association with PD included:
Mind–body medicine
Cognitive behavioural therapy (CBT)
There have been several studies demonstrating a benefit of CBT for those individuals suffering with PD. There is a strong comorbidity between PD and depression and for these patients there is a faster progression of physical symptoms, greater cognitive decline and poorer quality of life. It is important to note that depressed PD patients often differ from depressed non-PD patients and therefore CBT may need to be adapted to their individual needs.10, 11
One such study of individually tailored CBT demonstrated that PD patients with depression experienced a significant reduction in depressive symptoms and negative cognitions with a greater perception of social support over the course of treatment. These gains were maintained at 1 month follow-up. Larger randomised control trials (RCTs) are needed to further evaluate the efficacy of this intervention.12 CBT has also been shown to be efficacious for carers of those with PD.13
Alexander technique (AT)
Alexander technique is a process of psycho–physical re-education. A systematic review of controlled clinical trials has shown that AT is effective in reducing disability of patients suffering with PD.14 Earlier studies have also shown that AT may be effective for reducing depression for PD patients on drug therapy.15, 16
Imagery
One recent study has shown that the combination of motor imagery and real exercise practice was effective in the treatment of PD, particularly for reducing bradykinesia.7, 17
Music therapy
Available data shows that music therapy is effective on motor, affective and behavioural functioning in PD and ideally should be included in rehabilitation programmes.18
Repetitive transcranial magnetic stimulation (rTMS)
rTMS is a non-invasive brain stimulation technique that can produce lasting changes in excitability and activity in cortical regions underneath the stimulation coil (designated as a local effect), but also within functionally connected cortical or sub-cortical regions (designated as remote effects).19 Moreover, although the results from a small efficacy study support the beneficial effects of rTMS on Parkinsonian symptoms, long-term studies with large numbers of participants should be conducted to assess the efficacy of the rTMS on PD.20 A recent study has demonstrated that rTMS is significantly safe for use in PD patients.21 However, a comprehensive screening schedule should include electroencephalogram (EEG) before higher-frequency rTMS is applied.
Physical activity/exercise
A systematic review has stated that regardless of the strength of the evidence, the published literature that was reviewed reported that exercise resulted in improvements in postural stability and balance task performance in patients with PD.22 It was also recognised that despite these improvements, the number and quality of the studies and the outcomes used were limited. The authors concluded that there is a need for longer term follow-up so as to establish the trajectory of change in PD patients and to determine if any gains are retained long term. The optimal delivery and content of physical activity interventions (i.e. dosing, component exercises) at different stages of the disease are not clear and require further study.
A recent RCT investigating changes in walking activity and endurance following rehabilitation for people with PD demonstrated that an interdisciplinary rehabilitation program can improve walking activity and endurance depending on baseline walking levels in people diagnosed with PD.23
Despite treatment with drugs or neurosurgery, people with PD are faced with progressively increasing mobility problems.24 Recent meta-analyses have confirmed evidence to support exercise being beneficial with regard to physical functioning, health-related quality of life, strength, balance and gait speed for people with PD.25, 26, 27 Tango dancing, in fact, has been shown to ameliorate some functional mobility deficits in those that are frail and elderly when compared to a general exercise programme.28 A systematic review has also indicated that the effect of a physical treatment declines after the treatment has ended, suggesting the need for permanent treatment for patients with PD.29
A further study has demonstrated that the effects of aerobic exercise are more beneficial than qigong for people with advanced PD.30
There is currently insufficient evidence to support or refute the value of exercise in reducing falls or depression.25 Those with PD are twice as likely to fall compared with the non-PD elderly. An Australian RCT is currently under way to investigate whether exercises focusing on balance, leg muscle strength and gait will benefit those with PD.31
Tai chi
The objective of a critical review was to assess the effectiveness of tai chi as a treatment option for PD.32 The review concluded that the evidence was insufficient to suggest tai chi was an effective intervention for PD. Further research is hence required to investigate whether there are specific benefits of tai chi for people with PD, such as its potential effect on balance and on the frequency of falls.
Recently a pilot study has examined the effects of tai chi on balance, gait and mobility in people with PD.33 This study reported that all tai chi participants reported satisfaction with the program and improvements in wellbeing. Furthermore, the tai chi program appeared to be an appropriate, a safe and effective form of exercise for some individuals with mild–moderately severe PD.33
Environment
Toxins
Health and disease are shaped for all individuals by interactions between their genes and environment, such is the phenomenon now known as epigenetics.34, 35 In recent years, an increased emphasis has been placed on an integrating role of medicine in the prevention, early diagnosis and treatment of diseases that have been linked to environmental factors.36
A lack of heritability in idiopathic PD has implicated adulthood environmental factors in the aetiology of the disease. However, there is increasing evidence that exposure in the womb to a variety of environmental factors (such as exposure to pesticides, heavy metals and an iron-enriched diet) can either directly cause a reduction in the number of dopaminergic neurons, or cause an increased susceptibility to degeneration of these neurons with subsequent environmental insults or with aging alone.37
It should be noted that previous work in an electronics plant, use of chlorpyrifos products and exposure to fluorides are also associated with a significantly increased risk of developing PD. The association exists but is not as strong for previous work in a paper/lumber mill and exposure to cadmium.38
Repeated traumatic loss of consciousness is associated with increased risk of PD. Hypnotic, anxiolytic or anti-depressant drug use for more than 1 year and a family history of PD show significantly increased odds ratios for developing PD. Tobacco use is protective against developing PD.39
Recent evidence has demonstrated that cigarette smoking, alcohol use, fish intake and carbon monoxide intoxication are associated with reduced risk of PD.36, 38 Consuming well-water and living/working on a farm are not associated with PD.40
Heavy metals
There have been a multitude of studies regarding the neurotoxic effects of certain heavy metals and their relationship to PD.28 Several of these reports concern a village in Italy, Valcamonica, that was previously exposed to heavy metals, especially manganese. A high prevalence of PD was observed within the close vicinity (407/100 000) and it was determined that such Parkinsonian patients who had exposure to heavy metals developed a more severe neuropsychological phenotype, without detectable contribution from genetic factors.41
It is important to note, however, that manganese exposure can cause neuro-behavioural and neurological symptoms at concentrations much less than is currently considered to be the minimum acceptable level. The relationship appears to be dose-dependent, with adults presenting primarily with motor symptoms and children with dysfunctions in cognition and behaviour.42 Preliminary studies show that manganese may be transported into the brain by either transferrin or non-transferrin-dependent mechanisms which may include calcium channels.43
Chronic occupational exposure to manganese or copper, individually, or dual combinations of lead, iron and copper have also been associated with PD.44, 45
Recently, PD has been characterised by elevated tissue iron (not currently connected with hemochromatosis) and mis-compartmentalisation of copper and zinc.46 Zinc levels appear to be greater in PD independently from metal exposure whereas the perturbation of copper metabolism seem to be associated with exposure to environmental toxins or metals and could, indeed, be involved in the progression of the disease itself.47
Although brain uptake mechanisms for some metals have been identified, the efflux of metals from the brain has received little attention, preventing the integration of all processes that contribute to brain metal concentrations.43
As such new information comes to light, however, there has been steadily growing interest in how particular metal ions (especially zinc, copper and iron) are involved in neurobiological processes such as the regulation of synaptic transmission. Increasingly sophisticated medicinal chemistry approaches (that are correcting these metal imbalances without resulting in systemic disturbances of these essential minerals) are being investigated. Furthermore, this process shows great promise of being disease-modifying.46
Pesticides
There has been considerable research in the last decade as to the association between the neurotoxic effects of pesticides and the development of PD. Epidemiological evidence certainly suggests that exposure to pesticides may play a significant role in the aetiology of idiopathic PD.35, 38, 40, 48 Indeed, most studies reveal that moderate pesticide exposure is linked to neurological symptoms and altered neuro-behavioural performance, reflecting cognitive and psychomotor dysfunction. There is less evidence that exposure is related to sensory/motor deficits or peripheral nerve conduction, but fewer studies have considered these outcomes. It is also possible that general malaise and mild cognitive dysfunction may be the most sensitive manifestation of symptoms of pesticide neurotoxicity.49
Many pesticides (organophosphates, carbamates, pyrethroids, organochlorines) target the nervous system of insect pests and, because of the similarity in brain biochemistry, such chemicals may also be neurotoxic to humans. Indeed, adverse effects on brain development can be severe and irreversible.50 This may be of more concern in the case of developing brains that are particularly vulnerable to the adverse effects of neurotoxins.50, 51
There is strong human epidemiological evidence for persistent nervous system damage following acute intoxication with several pesticide groups such as organophosphates and certain fumigants.52 Investigations are now concentrating on whether chronic low-level exposure to pesticides in adults, children or in-utero may also result in persistent nervous system damage.51 There is evidence that exposure to the common agricultural pesticides such as maneb, paraquat and rotenone increases the risk of PD, particularly when exposure occurs at a younger age.35, 53 Such an association suggests a causative role.39 However, despite definitive evidence from animal and cell models that pesticides cause a neurodegenerative process leading to PD, human data are insufficient to support this claim for any specific pesticide primarily because of ethical challenges in exposure assessment.53
It is recommended that the residues of pesticides in food and other types of human exposures should be prevented with regards to those pesticide groups that are known to be neurotoxic. ‘Whilst awaiting more definitive evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development.’50
Nutritional influences
Diets
There has been much research attempting to elucidate the most beneficial diet in order to prevent and/or treat PD. Caloric restriction has been proposed to counteract neuronal loss and be associated with extended lifespan. Although there are mixed results, recent animal models with PD have not confirmed this association.54, 55
The dietary patterns of approximately 50 000 men and 80 000 women were followed for 16 years. During this time, 508 new cases of PD were diagnosed. It was found that a high intake of vegetables, fruit, legumes, whole grains, nuts, fish and poultry with a low intake of saturated fat and a moderate intake of alcohol was protective against PD. In comparison, a typical Western diet high in saturated/animal fats was directly associated with PD risk. Indeed, the benefits of a whole-food, plant-based diet with fish warrants further investigation.56, 57
Previous epidemiological studies have shown that consumption of diets rich in antioxidant and anti-inflammatory agents, such as those found in fruits and vegetables, may lower the risk of PD and other age-related neurodegenerative diseases. Further research suggests that the polyphenolic compounds found in fruits such as blueberries exert their positive effects through signal conduction and neuronal communication.58
Uric acid is a natural antioxidant and recent studies demonstrate that it may play a neuroprotective role in the pathogenesis of PD. Dietary manipulation of uric acid through increased consumption of purines (meat/crustaceans) may slow progression of the disease.59 This finding was supported by several earlier studies which show that uric acid levels are lower in individuals with PD than controls. It should also be noted that plasma uric acid correlated strongly with serum ferritin in both patients and control groups.60, 61
As can be easily seen, correct levels of protein intake are currently debatable, with mixed results of studies showing positive benefits for both ketogenic and low-protein dietary regimes.55, 62, 63 A further recent investigation demonstrated that low saturated fat/cholesterol, especially in the presence of high iron intake, may be associated with an increased risk of PD.64
The dietary patterns of approximately 58 000 men and 73 000 women from the American Cancer Society’s Cancer Prevention Study II Nutrition Cohort were also followed for 9 years. It was found that dairy product consumption was positively associated with risk of PD, particularly in men. This is once again controversial and more studies are required to confirm these findings and explore possible underlying mechanisms.65
There have been multiple studies demonstrating the association between caffeine intake and PD. Results are mixed, with some studies showing a protective effect of caffeine and others with no effect.66, 67, 68 A recent study showed that consumption of green tea was unrelated to risk of PD, however, black tea, a caffeine-containing beverage, showed an inverse association with risk of PD. Therefore, it was concluded that the ingredients of black tea other than caffeine appear to be responsible for this inverse association.69
Previous dietary exposure to food contaminants such as polychlorinated biphenyls (PCBs) and methyl mercury (MeHg) have also been positively associated with PD.70
Nutritional supplements
Vitamins and minerals
The nutraceutical treatment for PD is still in its infancy. For example, it has been postulated that imbalances in body metal levels could be a significant risk factor as the homeostasis of trace metals in the brain is important for brain function and also for the prevention of brain diseases.71 Hair mineral analyses indicate significantly lower levels of iron in the hair of patients with PD compared with controls. Calcium and magnesium were slightly lower while zinc was higher in PD, but these differences were not significant.72
Atomic absorption spectrophotometer studies have correspondingly revealed a significant zinc deficiency combined with elevated iron and selenium in the CSF of patients with PD on L-dopa. This provided clear evidence of increased iron and selenium in the brain which could be correlated with decreased dopamine levels and increased oxidative stress in PD patients.73
B group vitamins
Vitamin B6
Adequate dietary vitamin B6 has also been shown to decrease the risk of PD, probably through its antioxidant effects rather than mechanisms related to homocysteine metabolism.75
Folate and vitamin B12
L-dopa treated PD patients have significantly lower serum folate and vitamin B12 than controls.76 In fact, L-dopa treatment may represent an acquired cause of hyperhomocysteinaemia, as evidenced by studies in animals as well as PD patients.77 PD patients with depression have significantly lower folate levels compared with non-depressed PD, and cognitively impaired PD patients have significantly lower vitamin B12 levels compared with non-cognitively impaired PD. Supplementation with cobalamin and folate is effective in reducing homocysteine, and this may have important implications in the management of PD patients who are at risk for vascular diseases, cognitive impairment or dementia. The effects of vitamin supplementation certainly warrant further attention and investigation given that elevated concentrations of total homocysteine in plasma (>12 micromol/l) is epidemiologically associated as a risk factor for several diseases of the central nervous system (CNS).76
A recent review has concluded that treatment with folate, B12, and B6 can improve cerebral function. Hence, preventive vitamin B supplementation and sufficient intake seem very important for secondary and primary prevention of neuropsychiatric disorders, especially in those individuals with a low intake or status of these vitamins.78
