Parkinson’s Disease
Table of contents:
DIAGNOSTIC SUMMARY
GENERAL CONSIDERATIONS
Etiology
Genetics
Apoptosis
Toxic Exposure
Oxidative Stress and Glutathione Deficiency
Detoxification Dysfunction
DIAGNOSTIC CONSIDERATIONS
Therapeutic considerations
Conventional Medicine
Diet
Food Source of Levodopa
Ketogenic Diets
Low-Protein Diet
Detoxification
Nutritional considerations
5-Hydroxy-l-Tryptophan
Antioxidants
Glutathione
B Vitamins, Folic Acid
Coenzyme Q10
Melatonin
Reduced Nicotinamide Adenine Dinucleotide
Phosphatidylserine
Creatine
Botanical Medicines
Camellia sinensis (Green Tea)
Ginkgo biloba
Mucuna pruriens
Piper methysticum (Kava Kava)
Therapeutic considerations
Conventional Medicine
● No conventional therapy can modify the pathologic progression of the PD neurologic degeneration. But PD is somewhat treatable.
● Levodopa (l-dopa) is a mainstay, synthesized by the enzyme tyrosine hydroxylase from food-derived aromatic amino acid tyrosine. Modern treatment combines levodopa with a peripheral decarboxylase enzyme inhibitor to minimize conversion of levodopa to dopamine outside the nervous system. l-dopa provides only symptomatic relief without altering disease progression, and it loses efficacy with time. l-dopa side effects: motor complications (fluctuations and dyskinesias), nausea and vomiting, orthostatic hypotension, sedation, hallucinations, delusions, propensity to gamble, and accelerated growth of malignant melanoma. l-dopa contributes to decreased slow-wave peristaltic activity and impaired digestion. See newer drugs on p. 604.
● Deep brain stimulation (DBS): involves implanting a brain stimulator in certain areas of the brain. Desired effect is to decrease overactivity of excitatory glutamatergic subthalamo-internal pallidum pathway caused by loss of dopaminergic neurons within the substantia nigra. Stimulation may modulate neuronal activity and thus avoid disease-related abnormal neuronal discharges. Candidates for DBS are selected with strict criteria. DBS may control symptoms so drugs can be reduced.
● Fetal nigral transplantation: to restore lost neuronal tissue. Results are mixed, with a high percentage of postsurgical dyskinesias. Stem cells may offer means to restore dopaminergic circuitry.
Diet
● Detoxification of heavy metals: high sulfur-containing foods such as garlic and onions and water-soluble fibers such as guar gum, oat bran, pectin, psyllium seed.
● Antioxidants: vegetables and fruits.
● PD patients consume fewer raw vegetables, more carbohydrates, less alcohol and coffee, more meat and equivalent protein and fat compared with control subjects. PD patients may have a higher intake of animal fats.
● Recommendation: higher intake of vegetables, low intake of fat.
Food Source of Levodopa
● Broad beans: give PD patients improved symptom control. Response to Vicia faba (fava beans) may be even greater than to levodopa medication. Fava beans contain levodopa: 100-g serving of V. faba pods contains 250 mg levodopa, equal to levodopa in one drug formulation. But unsupervised replacement or coadministration of l-dopa with fava beans is not recommended.
Ketogenic Diets
● Used for 70+ years to stabilize patients with epilepsy.
● D-beta-hydroxybutyrate (DbetaHB): ketone bodyproduced by hepatocytes and astrocytes during diets that are extremely low in carbohydrates and glucose.
● DbetaHB confers partial protection against dopaminergic neurodegeneration and motor deficits in animals. DbetaHB used for two 6-month-old infants with hyperinsulinemic hypoglycemia
at 32 g/day was well tolerated over several months. Long-term effectson cell metabolismand mitochondrial function are unknown.
Low-Protein Diet
● May be useful for patients taking levodopa.
● A diet of 50 g protein per day for men and 40 g protein per day for women, compared with a high-protein diet of 80 g/day for men and 70 g/day for women improved performance scores, tremor, hand agility, and mobility.
● Levodopa absorption is delayed or diminished by dietary
amino acids. Eating a majority of protein in the evening also im-
proved symptoms. Recommendation: take levodopa with a high-
carbohydrate meal and delay protein intake until final meal of the day to optimize efficacy of the drug.
Detoxification
● Nutritional factors that combat heavy metal poisoning: high-potency multiple vitamin/mineral, minerals (calcium, magnesium, chromium), vitamin C, vitamin B complex, sulfur-containing amino acids (methionine, cysteine, taurine) (Textbook, “Metal
Toxicity: Assessment of Exposure and Retention” and “Urinary Porphyrins for the Detection of Heavy Metal and Toxic Chemical Exposure”).
Nutritional considerations
5-Hydroxy-l-Tryptophan
● 5-Hydroxy-l-tryptophan (5-HTP) is beneficial only if used in combination with the drug Sinemet (a combination of l-dopa and decarboxylase inhibitor carbidopa). Brain serotonin is decreased in PD, but reduction in dopamine receptors is more severe. In PD, 5-HTP helps counteract negative effects that l-dopa in Sinemet has on sleep and mood. 5-HTP also improves physical symptoms of PD.
● Nine of 10 people with PD have depression as a reflection of serotonin levels. The lower the level of serotonin, the more severe the depression. Starting 5-HTP at 75 mg and increasing by 25 mg every 3 days until depression was relieved, or up to a maximum of 500 mg/day for 4 months gave impressive results in PD patients on Sinemet. Dosage range for response was only 75 to 125 mg.
● CAUTION: increasing serotonin with 5-HTP in patients not taking Sinemet can worsen symptoms of rigidity.
Antioxidants
● Prevent damage from oxidation and may reduce risk of PD. They slow progression of PD in patients not yet taking drugs.High dosages are required; increasing antioxidant levels in brain tissue is more difficult.
● Pilot study: 3000 mg/day vitamin C and 3200 IU/day of vitamin E over a 7-year period delayed the need for medication for up to 2-3 years longer than in patients not taking antioxidants.
● Prospective study: health care professionals—76,890 women during 14 years and 47,331 men during 12 years—completed dietary and supplement surveys every 2 to 4 years. Results:
vitamin C and carotenoids did not lower PD risk; vitamin E supplements also were not helpful. Yet vitamin E–rich foods in the diet was protective. Dosages or quality of supplements may have been low, whereas quality of antioxidants in foods may have been higher. Furthermore, alpha-tocopherol is the main form in supplements, but beta-, gamma-, and delta-tocopherol are present in food. Gamma-tocopherol is more effective than alpha-tocopherol at inhibiting peroxynitrite-induced oxidation. Furthermore, supplementing only alpha-tocopherol decreases levels of other forms of vitamin E. Food may be best source, but supplements containing mixed tocopherols would be a better choice than cheaper alpha-tocopherol.
Glutathione
● Combined intravenous and oral GSH replacement is safe and well tolerated and provides ongoing benefit.
● Precursors N-acetylcysteine and alpha-lipoic acid may also be
of use.
● GSH is a systemic antioxidant; repletion may help ameliorate PD-related damage in the heart, liver, muscles.
● High-dose vitamin C provides antioxidant-reducing equivalents that conserve GSH.
B Vitamins, Folic Acid
● Elevated serum homocysteine is linked to increased risk of
coronary heart disease, stroke, and dementia. Increased hom-
ocysteine has been linked to PD. Cause: therapy with levo-
dopa. Breakdown of levodopa by catechol-O-methyltransferase increases homocysteine formation. Management of PD may increase risk of stroke, heart disease, dementia, and accelerated nigral degeneration.
● Pyridoxine (vitamin B6) helps lower homocysteine. But effects of levodopa may be enhanced by low intake of B6; daily doses of 5+ mg of B6 can reverse drug effect. Patients on levodopa are warned to avoid foods containing high amounts of B6. Lowered B6 should be encouraged in those unresponsive to levodopa. But PD patients with high homocysteine and high risk for cardiac disease who are responding well to medicines may consider increasing B vitamins, with careful monitoring for exacerbated PD symptoms.
Coenzyme Q10
● Ubiquinone (coenzyme Q10 [CoQ10]) is a cofactor in the
electron-transport chain of redox reactions that synthesize
adenosine triphosphate (ATP). Used in cardiovascular diseases, AIDS, and cancer, it may also be helpful in neurodegenerative conditions.
● High-dose CoQ10 may slow symptom progression in early PD. At dosages of 300, 600, and 1200 mg/day over a 6-month period, patients on CoQ10 faired significantly better than did a placebo group, with 1200 mg showing greatest results. At 360 mg for
4 weeks, CoQ10, in treated and stable PD patients, gave mild symptomatic benefit and much better improvement of visual defects compared with placebo.
● High doses (1200, 1800, 2400, and 3000 mg/day) of CoQ10 are safe in the short term (2 weeks). Ubiquinone reaches a blood plateau at 2400 mg/day dosage. Although serum levels of CoQ10 are not necessarily lower in PD patients versus healthy control subjects, doses up to 2400mg may have an added benefit for symptomatic patients. Because of the expense of CoQ10, start at 1200 mg dose and ramp it up if benefits are not seen in the first few months.
Melatonin
● Hormone manufactured from serotonin and secreted by the pineal gland.
● Powerful antioxidant and treatment option for jet lag, sleep problems, and cancer.
● May be protector of neuronal cells by supporting mitochondrial function and preventing apoptosis.
● Directly scavenges oxidants produced during the normal metabolism and indirectly promotes activity of antioxidant enzymes superoxide dismutase and catalase.
● Increases activities and expression of electron transport chain complexes. Melatonin increases ATP production and promotes GSH homeostasis. It may interact with the mitochondrial genome to enhance production of proteins. Melatonin may help prevent neuronal apoptosis.
● Theoretically, melatonin may actually exacerbate symptoms because of its putative interference with dopamine release. But most studies agree that PD is caused by multiple issues of compromised mitochondrial activity in substantia nigra and loss of GSH, oxidative damage, and increased apoptosis. Clinical studies are needed to evaluate efficacy in PD. If melatonin is used, start with low dose (1-5 mg); gradually increase while carefully monitoring symptoms.
Reduced Nicotinamide Adenine Dinucleotide
● Coenzyme reduced nicotinamide adenine dinucleotide (NADH) enhances endogenous dopamine production by supplying reducing equivalents to rate-limiting, tyrosine hydroxylase–catalyzed step of dopamine synthesis.
● Both intravenous and intramuscular dosed NADH gave a moderate to very good improvement of disability. Effect of NADH depends on dosage and severity of the case. Optimal dosage: 25-50 mg/day.
● Intravenous dosing seems to work better than intramuscular.
● Homovanillic acid in urine increases; this metabolite indicates stimulation of endogenous l-dopamine biosynthesis.
● One 10-mg treatment over a 30-minute period every day for 7 days, in patients also taking levodopa, improved UPDRS scores and significantly increased plasma levodopa.
● More rigorous studies are needed to confirm benefit and elucidate any side effects.
Phosphatidylserine
● Major phospholipid in the brain, determining integrity and fluidity of cell membranes.
● Low levels of brain phosphatidylserine (PS) are linked to impaired mental function and depression in the elderly.
● Clinically effective in senile dementia; promising treatment for early Alzheimer’s disease. It has greater treatment effects in patients with less-severe cognitive deficits.
● PS accelerates slowed electroencephalography in PD patients with senile dementia of Alzheimer’s type. It positively affects anxiety, motivation, and affect.
● Deficient phospholipid metabolism may be caused by toxic insult or oxidative stress. Deficiency of methyl donors—S-adenosylmethionine, folic acid, and vitamin B12—or essential fatty acids, the brain may not be able to make sufficient PS. Cosupplementation with docosahexanoic acid is advised when using PS from soy sources.
● PS is well absorbed orally.
Creatine
● Body-building supplement that acts as a temporal and spatial buffer for cytosolic or mitochondrial pools of cellular energy currency ATP and its regulator, adenosine diphosphate.
● Oral creatine monohydrate enhances memory. It is being studied to treat neurologic and neuromuscular disorders and athero-
sclerosis.
● Oral intake of creatine significantly increases brain creatine levels but has failed to provide consistent improvement in patients with a variety of neurologic disorders.
● Whether creatine intake will prove beneficial to PD patients in the future is doubtful.
Botanical Medicines
Camellia sinensis (Green Tea)
● Polyphenols penetrate the blood-brain barrier with antioxidant actions, free radical scavenging, iron-chelating properties, (3)H-dopamine and (3)H-methyl-4-phenylpyridine uptake inhibition, catechol-O-methyltransferase activity reduction, protein kinase C or extracellular signal-regulated kinases signal pathway activation, and cell survival/cell cycle gene modulation.
● Green tea polyphenols such as (-)-epigallocatechin-3-gallate (EGCG) are being considered as therapeutic agents to alter brain aging processes and serve as neuroprotective agents.
● Clinical data are limited, but several recent studies suggest green tea polyphenols may protect against PD and other neurodegenerative diseases.
● In animal models of PD, both green tea and oral EGCG prevented loss of tyrosine hydroxylase–positive cells in the substantia nigra and tyrosine hydroxylase activity in striatum and prevented neurotoxin-induced elevations in antioxidant enzymes superoxide dismutase and catalase. These treatments also retained striatal levels of dopamine and its metabolite homovanillic acid and inhibited nitric oxide synthetase in the substantia nigra.
Ginkgo biloba
● Ginkgo biloba extract (GBE) effects: stabilizes membranes, is an antioxidant, scavenges free radicals, enhances utilization of oxygen and glucose, is an extremely effective inhibitor of lipid peroxidation of cellular membranes.
● No clinical studies in PD exist, but it is proven beneficial in Alzheimer’s disease and useful in animal models of PD, where it is protective in vivo and in vitro.
● Mechanism of action: antioxidation and antiapoptosis. It may also help decrease toxicity of levodopa. Levodopa has a neuro
toxic effect that GBE may inhibit. Researchers have concluded that combined use of GBE with levodopa is advisable to treat PD and may be better than using levodopa alone.
● Dose-response relation is not yet established for human beings, but 240 mg q.d. GBE shows higher rate of treatment response than does 120 mg q.d.
● Safety: adverse event profile of GBE was not different from placebo. Give GBE consistently for 12+ weeks to determine efficacy.
Mucuna pruriens
● In Ayurveda PD, or “kampavata,” is seen as an imbalance of vata dosha.
● Mucuna puriens: a legume; rich source of antioxidant vitamin E.
● Rat studies: has an antiparkinson effect, perhaps from components other than levodopa or levodopa-enhancing effect.
● Clinical trial: powdered preparation of this legume is called HP-200; a 7.5-g sachet mixed with water and given orally three to six times per day was given to 26 patients taking synthetic levodopa/carbidopa before treatment and 34 not using medications. Results: statistically significant reductions in Hoehn and Yahr stage and UPDRS scores from baseline to end of 12-week treatment. Adverse effects: mild gastrointestinal upset.
Piper methysticum (Kava Kava)
● No side effects reported with standardized kava extracts at recommended levels in clinical studies.
● CAUTION: isolated reports of kava causing onset of parkinsonian symptoms; case reports that kava may interfere with do-
pamine and worsen PD. Avoid kava in PD patients or those genetically susceptible.
Other therapeutic considerations
Smoking
● Smoking is linked to lower incidence and delayed onset of PD. Nicotine may enhance striatal stimulation of dopaminergic neurons selectively damaged in PD. Inverse association between smoking and PD has been solidly grounded in multicentered, longstanding research.
● Other nonnicotine chemicals in cigarettes may be neuroprotective by decreasing monoamine oxidase B activity and lowering hydrogen peroxide, a byproduct of dopamine metabolism.
● Other explanations: neuroprotective effect of carbon monoxide in cigarette smoke; carbon monoxide is a free radical scavenger. Or it may reduce dietary intake, conferring an advantage.
● Risk/benefit ratio is quite high with smoking; smoking is not a reasonable prevention for PD.
Estrogen
● Estrogens may modulate activity of dopamine, act as an antiapoptotic agent, and affect neuronal pathways affected in PD.
● Animal studies: estrogens influence synthesis, release, and metabolism of dopamine and may modulate dopamine receptor expression and function.
● Clinical studies: conflicting findings whether PD symptoms may worsen after menopause and whether hormone replacement therapy can be protective. Several variables—age, dose and formulation, timing and length of dosing period—may determine effect. Monitor menstrual pattern correlations to symptoms to make best patient-specific choices for hormone replacement therapy.
Weak Electromagnetic Fields
● Extracranial treatment with low frequency pico-Tesla magnetic fields may be an effective, safe, and revolutionary modality to manage symptoms.
● Theory: intermittent-pulsed pico-Tesla electromagnetic fields (EMFs) may induce in PD reactivation of reticular-limbic-pineal systems; nondopaminergic systems might be positively affected by weak EMFs.
● Case studies: decreased need for medicines, decreased micrographic symptoms, and return of absent dream recall, all associated with right hemispheric dysfunction.
● Drawback: only one researcher is involved and no follow-up during decade since original work.
Hypnosis
● Mindset affects severity of most movement disorders, including PD. Symptoms improve with relaxation and are exacerbated by anxiety.
● Case study: hypnosis while monitoring patient with polygraphic electroencephalogram-electromyogram revealed direct correlation between degree of trance and tremor cessation. Effect only lasted a few hours after each session, but clinical gains manifested over 6 months with repeated practice of guided imagery.
● Techniques used during trance: role-play time distortion was most effective in halting tremors.
Therapeutic approach
Diagnosis: besides standard neurologic rating scales and imaging, serum iron, ferritin, and total iron binding identify iron overload. Rule out blood homocysteine. Careful history and testing for heavy metal and pesticide toxicities.
Dietary Recommendations
● Eat a low-fat, low-animal, and high-fiber vegetable diet.
● Eat vitamin E–rich foods: sunflower seeds, almonds, chard, mustard greens, broccoli, olives, kale, turnip greens, and papaya.
● Avoid foods high in pesticides and attempt to eat organic foods exclusively.
● To detoxify heavy metals, eat high sulfur–containing foods—garlic, onions, and eggs—plus water-soluble fibers: guar gum, oat bran, pectin, and psyllium seed.
● Patients taking levodopa: lower protein intake (50 g q.d. for men and 40 g q.d. for women); take medication with a high-carbohydrate meal and delay protein intake until the final meal of the day to optimize therapeutic efficacy of medication.
● Because of constant movement, weight loss may be an issue; adjust caloric intake to specific patient needs.
Lifestyle Recommendations
● Avoid cooking in aluminum pots.
● Banisters along walls and chairs with higher arms ease the ability to walk through halls and sit.
● Thick carpeting may be helpful to avoid falls.
Nutritional Supplementation
● Avoid iron and maganese supplements.
● 5-HTP: 75 to 125 mg q.d. in patients taking Sinemet (levodopa plus carbidopa). Those not on this drug should avoid 5-HTP.
● Vitamin C: 3000 mg q.d.
● Vitamin E: 1000 IU q.d. mixed tocopherols. Avoid supplements that are solely alpha-tocopherol.
● Glutathione: orally and/or intravenously.
● Restrict B vitamins in patients who are levodopa unresponsive to see if drug treatment efficacy improves. B vitamins and folic acid may be increased in patients with high homocysteine levels and those at greater cardiac risk along with careful monitoring of PD symptoms.
● CoQ10: 1200-2400 mg q.d.
● Phosphatidylserine: 100 mg t.i.d.
Botanical Medicines
● Green tea: 3 cups q.d. or 3 g of soluble components providing 240-320 mg polyphenols. For green tea extract standardized for 80% total polyphenol and 55% epigallocatechin gallate content: 300-400 mg q.d.
● Ginkgo biloba extract: 240 mg q.d. for 12+ weeks.
● Mucuna pruriens: 7.5 g mixed with water and given orally three to six times per day.
Conventional Medications
● Sinemet: is a combination of l-dopa and carbidopa.
● Amantadine (Symmetrel): modulates motor fluctuations; is a dopamine receptor agonist.
—Other dopamine receptor agonists: bromocriptine, pergolide, pramipexole, ropinirole.
● Tolcapone (Tasmar) or entacapone (Comtan): inhibit dopamine breakdown.
● Anticholinergic drugs: for resting tremor.
● Clozapine: for levadopa-induced dyskinesias.
(Note: All these medications can produce hallucinations and daytime somnolence.)
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