Parkinson's Disease

Parkinson's Disease

1 Overview

Summary and Quick Facts

  • Parkinson’s disease is a neurological disorder that causes movement problems and can progress into dementia. It’s caused by the loss of cells in the brain that produce dopamine, a neurotransmitter that controls movement and coordination. Several factors can contribute to the loss of dopamine-producing cells.
  • This protocol will help you understand the causes of Parkinson’s disease and what treatments are available. Learn about some emerging treatment strategies and how some supplements and dietary choices may help protect dopamine neurons.
  • Supplementation with coenzyme Q10 (CoQ10) and creatine has been shown to delay cognitive decline in people with Parkinson’s disease.

What is Parkinson's Disease?

Parkinson’s disease is a degenerative disease of the central nervous system resulting from depletion of dopamine-producing cells in the brain. While the underlying cause of the disease is not clearly understood, depletion of dopamine-producing cells may be exacerbated by oxidative stress, inflammation, and mitochondrial dysfunction. Parkinson’s patients generally experience decline in motor function and eventually cognitive decline and dementia.

Parkinson’s may manifest as a primary condition or secondary to another condition, such as a brain tumor, exposure to toxins, or after a viral infection.

Existing conventional treatments do not slow or reverse the course of the disease. However, natural interventions such as coenzyme Q10 and creatine may support neuronal health and promote mitochondrial function.

What are the Risk Factors for Parkinson’s Disease?

  • Family history/genetic predisposition
  • Exposure to pesticides or other toxins like carbon monoxide
  • Brain tumor
  • Viral encephalitis
  • AIDS
  • Chronic constipation
  • Repeated blows to the head (eg, professional fighters or football players)
  • Certain medications
  • Stroke

What are the Signs and Symptoms of Parkinson’s Disease?

Note: Symptoms of Parkinson’s generally progress slowly. Tremors are often the first sign.

  • Tremors, often in the hand
  • Muscle cramping or rigidity
  • Pain throughout the body
  • Slow movements
  • Incontinence or constipation
  • Difficulty swallowing and/or controlling saliva
  • Dizziness
  • Sleepiness
  • Depression and/or anxiety
  • Hallucinations or frightening dreams
  • Cognitive decline and/or dementia

What are Conventional Medical Treatments for Parkinson’s Disease?

  • Levodopa, or L-DOPA
  • Monoamine oxidase-B inhibitors (eg, selegiline and rasagiline)
  • Catechol-O-methyltransferase inhibitors
  • Dopamine agonists
  • In extreme cases, ablative surgery or deep-brain stimulation

What are Emerging Therapies for Parkinson’s Disease?

  • Amantadine, an antiviral drug, may help reduce the side effects of L-DOPA
  • Nicotine
  • Granulocyte colony-stimulating factor (G-CSF), a growth factor that promotes creation of new neurons, has shown promising results in animal models.
  • Stem cell replacement therapy
  • Cognitive-behavioral therapy

What Dietary and Lifestyle Changes Can Be Beneficial for Parkinson’s Disease?

  • Physical therapy and exercise
  • For patients on L-DOPA, protein meal distribution may be recommended (ie, eating dietary protein separate from dosing with L-DOPA)

What Natural Interventions May Be Beneficial for Parkinson’s Disease?

  • Coenzyme Q10 (CoQ10). Patients with Parkinson’s appear to be deficient in CoQ10. Supplementation may slow the progressive deterioration of function in Parkinson's disease (Shults 2002) and have a neuroprotective effect.
  • Creatine. Creatine deficiency is associated with neurological damage. Some studies indicate supplementation may slow disease progression.
  • Omega-3 fatty acids. Levels of omega-3 fatty acids in nerve cell membranes decrease with age, oxidative stress, and in neurodegenerative disorders such as Parkinson's disease. Supplementation may favorably modify brain function and protect brain health.
  • Coffee. Coffee consumption is linked to a reduced risk of developing Parkinson’s disease. Coffee extracts have been shown to act via mechanisms similar to some pharmaceutical Parkinson's therapies.
  • Nicotinamide riboside. Decline in NAD+, a cofactor critical for regulating cellular energy balance, is associated with Parkinson’s disease. Administering nicotinamide riboside, an NAD+ precursor, may offer benefits in Parkinson’s patients.
  • B vitamins. B vitamins (eg, folate, B12, B6, etc.) lower homocysteine levels. Many studies have shown B vitamins to have beneficial effects in Parkinson’s patients, and supplementation may be recommended in patients taking L-DOPA.
  • Vitamin D. Parkinson’s patients tend to have lower serum vitamin D levels than those without the disease. Several studies have shown that higher levels of vitamin D protect against the onset of Parkinson's disease symptoms.
  • Other natural interventions that may benefit Parkinson’s patients include carnitine, green tea, resveratrol, wild green oat extract, pyrroloquinoline quinone (PQQ), and others.

2 Introduction

Parkinson's disease is a degenerative disease of the central nervous system resulting from depletion of dopamine-producing cells in a region of the brain called the substantia nigra. A variety of genetic and environmental factors underlie this loss of brain cells. However, emergent research implicates oxidative stress, inflammation, and dysfunctional mitochondria as major contributors to neurodegeneration in Parkinson's disease.

Up to one million Americans live with Parkinson's disease, with 60,000 new cases being diagnosed each year. Men are more likely to be affected than women, and the risk increases substantially after age 50–60; however, one in 20 patients is diagnosed under the age of 40.1,2

Progression of the disease usually leads to characteristic symptoms such as tremors, muscle rigidity, bradykinesia (slowness and difficulty with movements), poor balance, sleep disturbances, and loss of coordination; eventually, cognitive decline occurs, and, in advanced disease, dementia arises.

Conventional medical approaches to treating Parkinson's disease aim to replace the lost dopamine, but fall short of addressing the ongoing destruction of dopaminergic neurons. Over time, the ability of medications to replenish dopamine levels becomes overwhelmed by further loss of dopaminergic cells. Moreover, the pharmaceutical drugs typically used to alleviate symptoms of Parkinson's disease are laden with debilitating side effects and often worsen affection over time. Thus, the prognosis for Parkinson's disease patients relying on conventional treatment remains limited.

The mainstream medical establishment has failed to recognize the urgent need to address the multiple, interrelated pathological features of Parkinson's disease in order to prevent further neuronal loss and slow disease progression.

Scientific innovation has led to the realization that natural compounds and some underappreciated pharmaceutical compounds can synergize to support mitochondrial function, suppress inflammation, ease oxidative stress and may improve outlook for Parkinson's disease patients.

Life Extension's approach encompasses a regimen combining conventional therapeutics to ease symptoms and innovative natural ingredients along with state-of-the-art pharmaceuticals to reduce the destruction of dopaminergic neurons. This approach offers Parkinson's disease patients a chance for symptomatic improvement and enhanced quality of life.

3 Brief History, Classifications, and Risk Factors

Dr. James Parkinson first described the motor system disorder known today as Parkinson's disease in an 1817 paper entitled "An Essay on the Shaking Palsy."3 In his report, Dr. Parkinson described several characteristic traits, including an abnormal posture and gait, and partial paralysis with muscle weakness; he also described the progression of the disease. The contribution of more clearly defining the condition, theretofore known as paralysis agitans, led to the adoption of Dr. Parkinson's last name as the moniker that remains with us today.

Since 1817, medical advancements have helped us establish a much greater understanding of Parkinson's disease. Today, clustered symptoms like tremor at rest, stiffness, slowed movement, and postural instability are classified, based upon their cause, into different categories.

Parkinson's Disease (Primary Parkinson's)

This is the most common form of the disease; what most of us think of when we hear the term "Parkinson's." Primary Parkinson's disease has no clear external cause, and is therefore classified as idiopathic or without cause (arising spontaneously). Recently, however, several genes directly tied with the development of Parkinson's disease have been identified. This has led to the classification of heritable Parkinson's disease of genetic origin as familial Parkinson's disease, while Parkinson's disease that arises independently of genetic predisposition is referred to as sporadic Parkinson's disease.

Despite the fact that conventional medical dogma holds tightly to the notion that primary Parkinson's disease truly lacks an identifiable cause (other than genetics in familial Parkinson's disease), metabolic phenomena, such as oxidative stress, mitochondrial fatigue, and other age-related abnormalities are linked with the death of dopamine-producing neurons.4

Exposure to pesticides may substantially increase risk for Parkinson's disease.5-10 In one study, higher pesticide exposure increased Parkinson's disease risk three-fold.10 Numerous epidemiological studies have confirmed the association.6,11 Toxin-induced Parkinson's symptoms may be classified as secondary, rather than primary Parkinson's.4,12

Interestingly, pesticides seem to accumulate in the dopaminergic tract, where they inhibit mitochondrial function and lead to neuronal death.7,13 Dopaminergic neurons are particularly susceptible to the pesticide dieldrin, which is no longer in use in the United States, but remains ubiquitous due to environmental contamination.14 In addition to acting as neuronal and mitochondrial toxins, some pesticides also impair the breakdown of protein aggregates, like Lewy bodies.15

Several lines of evidence suggest that a genetic inability to properly detoxify environmental toxicants may predispose some individuals to Parkinson's disease.16,17

In addition, those who experience constipation throughout their lives appear to be at increased risk.18 In one study, constipation documented in medical records as much as 20 years before disease onset was associated with a significantly increased risk.19 Some researchers believe that this may be related to intake of drinking water—lower water intake appears to be a risk factor as well.20 This may be linked to reduced elimination of water-soluble toxins.

Due to the strong association between pesticides, and other environmental toxins, with Parkinson's disease, readers are strongly encouraged to review Life Extension's “Metabolic Detoxification” protocol.

Parkinsonian Syndrome (Secondary Parkinson's)

Other forms of Parkinsonism can occur as a secondary effect of brain tumor, drugs, toxins (eg, carbon monoxide poisoning), post encephalitis (viral infectious disease, "sleeping sickness"). For example, another cause of Parkinsonism is brain damage sustained by repeated blows to the head such as suffered by professional prize fighters and athletes in high-impact sports like football. Traumatic events, infections, use of certain medications, etc. can all damage the dopaminergic cells within the midbrain and lead to the same symptoms as primary Parkinson's disease.

For example, the defining basis for Parkinsonism due to encephalitis (brain inflammation) was a worldwide influenza pandemic in 1917. After recovering from this illness, many patients developed Parkinson's disease years later.21 Acquired immunodeficiency syndrome (AIDS) may also lead to Parkinsonism.22 Resuscitation from cardiac arrest (due to temporary lack of oxygen supply to the brain), and stroke can lead to Parkinsonism as well.23

Several centrally acting drugs, especially those that exert an effect on the dopamine system within the brain, such as antipsychotics, frequently induce secondary Parkinsonism after sustained chronic use. In fact, drug-induced Parkinsonism is a well-documented phenomenon.24-26 Some antidepressants and calcium channel blockers, and the antiarrhythmic drug amiodarone, can lead to Parkinsonian tremors as well.26 Several illicit drugs can cause Parkinsonism as well.

Some diseases or disorders considered to cause Parkinsonian syndromes include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBGD), and Pick's disease.

4 Signs, Symptoms, and Diagnosis

Dopamine is a neurotransmitter that, among other functions, allows messages to be sent to regions of the brain responsible for coordinating movement. When dopamine levels decline, due to the death of dopaminergic cells, these messages no longer reach their destination, and so the regions of the brain that control movement no longer function properly. This results in loss of conscious control of movement, and, in advanced Parkinson's disease, loss of control over several other bodily functions.

The onset and course of Parkinson's disease may be different for each patient. For example, while tremor is evident in most patients, some may not experience movement complications until the disease has advanced considerably.

Initial symptoms of primary Parkinson's disease typically develop slowly and randomly as the supply of dopamine dwindles over time. In some cases, symptoms do not appear until approximately 70% of the dopaminergic cells in the substantia nigra are already destroyed.2

Motor Symptoms

The onset of a slight tremor, usually in the hand, which increases in intensity over time, is often the initial sign of Parkinson's. However, roughly 30% of patients do not develop a tremor. Parkinson's patients often experience muscle rigidity or cramping that can be painful—movements as simple as turning over in bed or buttoning a shirt can become arduous, and as the disease advances, nearly impossible. Progression of Parkinson's disease leads to slowness of movements, which can cause a great deal of frustration for patients who cannot move as quickly as they would like.

"Freezing" is a frequently reported motor symptom in advancing Parkinson's. This involves the sudden onset of the inability to move at all; patients sometimes describe freezing as feeling as if their feet are stuck to the floor. Freezing is temporary and usually lasts from a few seconds to a few minutes.

Non-Motor Symptoms

Dopamine is involved in a number of functions beyond control of movement, so loss of dopaminergic neurons (and other neurons in late-stage Parkinson's) can cause several non-motor symptoms as well. However, non-motor symptoms usually develop at later stages of disease progression; nonetheless, they can be equally as debilitating as motor symptoms for many patients.

Patients with advanced Parkinson's disease may experience a variety of non-motor symptoms. These can include incontinence, constipation, difficulty swallowing, inability to control saliva, dizziness, which can lead to falls, excessive daytime sleepiness, intense frightening dreams, depression and/or anxiety, and hallucinations.2 In addition, Parkinson's disease can cause perceptible pain throughout the body, which is sometimes severe.

Dementia

Dementia and related cognitive decline is a major concern among those with advanced Parkinson's disease; up to 75‒80% of those with Parkinson's develop dementia near the end of their life.27,28 In addition to loss of dopaminergic neurons, cholinergic neurons are also at risk. Cholinergic neurons produce a neurotransmitter called acetylcholine, which is important for cognitive function. The accumulation of protein aggregates (clumps of dysfunctional proteins) known as Lewy bodies within cholinergic neurons is a common characteristic of Parkinson's disease.

As Lewy bodies accumulate inside neurons, the cells can no longer function, and eventually die. Loss of acetylcholine leads to diminished attention span, blunted sensory perceptions, loss of arousal and structural changes in the synaptic junctions (the connections between neurons through which they communicate using chemical and electrical signals). Loss of acetylcholinergic signaling is thought to be associated with memory deficits in Alzheimer's disease as well, though the exact mechanisms are complex.29

Two subsets of dementia exist in the context of Parkinson's disease, Parkinson's disease dementia (PDD) and Dementia with Lewy bodies (DLB). The distinction of the two is quite subjective and largely based upon the time of dementia diagnosis in relation to onset of motor symptoms. Whether or not the two dementias are truly separate entities, or simply manifestations of different points along the "Lewy body spectrum," is a hotly debated topic.30

Diagnosis

Clinicians must rely on clinical experience, interpretation of symptoms, and evaluation of medical history in order to tentatively diagnose a patient as having Parkinson's disease. This is because there are no lab tests available that definitively diagnose Parkinson's disease. Parkinson's disease is a diagnosis of exclusion; in other words, the physician will first rule out other possible diagnoses before assuming Parkinson's.

If Parkinson's is suspected because the patient is exhibiting signs such as a tremor on one side of their body, or rigidity with loss of postural reflexes, oftentimes L-DOPA, a drug used to treat Parkinson's symptoms, is administered. If L-DOPA causes the symptoms to subside, the diagnosis of Parkinson's disease can be made more confidently, yet still not definitively.

Due to the elusive nature of a definitive Parkinson's disease diagnosis, patients should be reevaluated regularly to make sure that their symptoms are not due to another neurological disorder that causes similar symptoms.

5 Causes, Pathological Mechanisms, and Lessons from Biology

Genetics—Familial Parkinson's

Roughly 15% of Parkinson's disease patients have a first-degree relative who also has/had Parkinson's disease; this suggests that genetics play a consequential role in the development of familial Parkinson's disease.31 Roughly nine genetic mutations have been associated with Parkinson's disease; of these, six have been particularly well characterized.31,32 Mutations in these genes are generally associated with early onset Parkinson's disease, which is diagnosed before age 40; Parkinson's disease of genetic origin is sometimes diagnosed in childhood.

Mutations in the following genes are associated with an increased risk of Parkinson's disease:

  • SNCA33-36
  • LRRK237
  • PARK238
  • PINK139-42
  • PARK743-47
  • ATP13A248-51

Additional research is required to fully elucidate the role of genetics in Parkinson's etiology; it is likely that several additional genes involved in the pathology will be identified in the coming years. Treatments based upon genetic therapy are likely to become more widespread and therapeutic as scientific knowledge progresses.

Genetic Testing

Genetic testing for mutations known to be associated with Parkinson's disease is available through genetics health care professionals. Specifically, tests are available that check for mutations in PINK1, PARK7, SNCA, and LRRK2. Although the testing is expensive, and accuracy is a potential concern, those individuals with a family history of Parkinson's disease are encouraged to discuss genetic testing with their healthcare provider.

The National Human Genome Research Institute, a division of the National Institutes of Health, has compiled further information about the role of genetics and genetic testing in Parkinson's disease. This resource can also assist with the location of a genetic counselor near you. Their website is: http://www.genome.gov/10001217#4.

Individuals found to have a mutation in one or more of the genes linked to Parkinson's, as well as those with a family history of Parkinson's, should consult a Parkinson's disease specialist, and initiate nutritional and lifestyle strategies to combat neurodegeneration.

Mitochondrial Dysfunction

A flurry of emergent research has linked mitochondrial dysfunction to the pathogenesis of Parkinson's disease. Mitochondrial dysfunction results in impaired ATP generation, loss of cellular repair mechanisms, and cellular inefficiency.

As mitochondria become dysfunctional they generate large quantities of free radicals, which contribute to oxidative stress that, in turn, causes further mitochondrial dysfunction. Concurrently, loss of mitochondria to oxidative damage means fewer mitochondria are available to meet the energy demands of the cell to repair damaged components. The cascade of mitochondrial dysfunction, oxidative stress, and loss of mitochondria form a continuity that ultimately leads to cell death.52,53

Numerous studies have clearly identified mitochondrial dysfunction as a central pathological feature of both genetic and sporadic Parkinson's disease.54,55 Moreover, many of the genes that confer predisposition to familial Parkinson's are intimately related to mitochondrial function; much of the neuronal death in Parkinson's of genetic origin is due to mitochondrial dysfunction, and impaired mitophagy.56-58 While several factors, including exposure to environmental toxins,56,59,60 also contribute to mitochondrial dysfunction in the substantia nigra, age-related mutations in mitochondrial DNA are thought to be a primary culprit.60,61 Alarmingly, dopamine itself, and L-DOPA, may contribute to mitochondrial toxicity in dopaminergic neurons.62-64

Mitophagy, Lewy Bodies, and alpha-Synuclein

Damaged mitochondria are continually being cleared from within the cell through a process calledmitophagy. Mitophagy, a type of autophagy, is a kind of cellular recycling system that clears damaged mitochondria before they can accumulate and cause cellular dysfunction. However, age-related mutations in mitochondrial DNA, which cause mitophagy to become less efficient, coupled with an ever-intensifying propensity for endogenous and environmentally mediated mitochondrial damage cause the neuronal mitophagic system to become overwhelmed.57,65 Over time, damaged mitochondria build up inside the neuron, leading to cell death. Not surprisingly, several of the genetic mutations linked to familial Parkinson's disease cause disturbances in mitophagy.57,58

Another toxic byproduct of mitochondrial dysfunction and impaired mitophagy is the formation of Lewy bodies. Lewy bodies form as reactive oxygen species derived from dysfunctional mitochondria damage structural components of the cell called microtubules. As microtubules are damaged, they release a protein called alpha-synuclein. The loose alpha-synuclein proteins then group together, or aggregate, and form a toxic mass (a Lewy body) that further damages the cell. Moreover, alpha-synuclein has been shown to directly interfere with mitochondrial function and inhibit ATP synthesis, furthering the spread of mitochondrial dysfunction in the brains of Parkinson's disease patients.66-68 Over time, Lewy bodies spread to neighboring cells, damaging neurons within the vicinity of a dead or dying neuron.69

Lewy bodies share some characteristics with toxic proteins that develop in the brains of patients with Alzheimer's disease and other neurodegenerative diseases, primarily in that they cannot be broken down and cleared from the cell by normal autophagic (cellular house cleaning) actions.

The Role of Inflammation in Parkinson's Disease

Inflammatory responses contribute to the perpetuation of neurodegeneration in Parkinson's disease. The brain contains immune cells called microglia, which are known to be activated in Parkinson's disease.70,71 Upon activation, microglia release inflammatory cytokines that can spread to nearby healthy neurons and cause degeneration. Dopaminergic neurons in the substantia nigra, the brain region most affected by Parkinson's disease, express receptors for an inflammatory cytokine called tumor necrosis factor-alpha (TNF-α), which suggests that excess TNF-α released by nearby activated microglia may damage nigral dopaminergic cells.

Elevated cytokines in the brain of those with Parkinson's disease is a consequence of neurodegeneration.72 In experimental models, exposure to the neurotoxin MPTP (a chemical used to induce Parkinson's disease in experiments) leads to death of dopaminergic neurons. Interestingly, in monkeys, inflammation is increased even years after initial exposure to MPTP.71 This suggests inflammation, once initiated, has long-term consequences in Parkinson's disease.

As dopaminergic cells succumb to either environmentally or genetically induced mitochondrial dysfunction, they release free radicals. These free radicals then activate nearby microglial cells, which in turn, excrete inflammatory cytokines that bind to and damage nearby dopaminergic neurons. This positive feedback loop may continue over years or even decades and slowly contribute to the loss of dopaminergic neurons that leads to Parkinson symptoms.72,73

Epidemiological studies on the use of anti-inflammatory drugs and the risk of Parkinson's onset are conflicting. Some studies suggest a protective role of ibuprofen, but not other anti-inflammatory drugs.74 However, a large study published in the British Medical Journal involving over 22,000 subjects found no association between use of any NSAID reduced risk.75 These findings reinforce the notion that, rather than initiating dopaminergic cell death, inflammation may perpetuate it, thus contributing to Parkinson's disease progression. Life Extension believes that suppressing inflammation may slow disease progression in Parkinson's disease patients.

Simvastatin as an Anti-Inflammatory and Neuroprotective Agent in Parkinson's Disease

Groundbreaking research suggests that the cholesterol lowering drug simvastatin may provide powerful neuroprotection in Parkinson's disease. A little-known fact among the public is that statin drugs do more than simply lower cholesterol, they are also anti-inflammatory agents. In fact, many researchers believe that some of the cardiovascular benefits are due to their anti-inflammatory properties.76

Simvastatin is efficient at crossing the blood-brain barrier, and it has been shown to exert potent anti-inflammatory and neuroprotective action in the dopaminergic tract.77,78

In animal models, simvastatin was shown to attenuate the neurotoxicity of MPTP. In fact, simvastatin accumulated in the nigra and suppressed microglial activation, leading to reduced expression of inflammatory cytokines and increased dopaminergic neuroprotection.79 Another animal experiment found that simvastatin was able to completely reverse the decline in dopamine receptors associate with exposure to the neurotoxin 6-hydroxydopamine.80

In a large human clinical study involving over 700,000 subjects, use of simvastatin was associated with a 49% reduction in the likelihood of onset of Parkinson's symptoms, as well as a 54% reduction in the risk of dementia, suggesting a substantial neuroprotective effect.81

Due to the emergence of strong evidence that simvastatin may have anti-inflammatory and neuroprotective actions, Life Extension encourages those Parkinson's disease patients taking a cholesterol-lowering medication to talk with their doctor about switching to simvastatin. Even those whose cholesterol is not significantly elevated may benefit from low-dose simvastatin—those not taking cholesterol-lowering medication should discuss this with their doctor.

Importantly, those taking any statin drug should be aware that statins deplete coenzyme Q10 (CoQ10) levels. If taking statins, supplement with CoQ10 and ensure maintenance of healthy CoQ10 blood levels by periodically having a CoQ10 blood test.

6 Conventional Medical Treatment

For decades, the conventional standard of care for Parkinson's disease has focused on symptomatic relief. Pharmaceutical treatments for Parkinson's accomplish this by either increasing dopamine levels or mimicking its action. While conventional therapeutics are indispensable for improving quality of life in Parkinson's patients, they do not provide fundamental neuroprotection or support for neuronal mitochondria. Thus, mainstream pharmaceutical treatments cannot be expected to address the underlying cause of disease progression—neurodegeneration.

Treatment with L-DOPA causes patients to be less responsive to the medication over time and can evoke a number of adverse side effects. However, careful dosing strategies, and utilization of ancillary medications may help limit side effects and maintain the effectiveness of conventional pharmaceutical therapies.

Pharmaceutical treatment of Parkinson's disease symptoms is usually initiated when the patient has already developed some disability for which he/she needs to be treated. This is typically referred to as the initial stage of therapy. The primary goal of treatment during the initial stage is to limit symptoms arising from progression of the disease. However, with time, adverse side effects of the medications arise, which leads into the secondary treatment stage. The aim of the secondary treatment stage is to reduce Parkinson's symptoms, as well as counterbalance the adverse side effects of levodopa.

Levodopa (L-DOPA)/Carbidopa

Since its FDA approval in 1970, Levodopa (L-DOPA) has been a staple for the management of Parkinson's disease symptoms.

L-DOPA (the precursor to dopamine) is metabolized into dopamine in the body by an enzyme called aromatic L-amino acid decarboxylase (AADC). Dopamine itself cannot pass through the protective blood-brain barrier, but L-DOPA can. When L-DOPA is administered orally, a small percentage passes into the brain and is converted into dopamine. This temporary increase in dopamine levels within the brain offers relief of Parkinson's disease symptoms for a short period.

However, the body presents many obstacles that limit the efficiency of oral L-DOPA therapy. First, AADC exists outside the brain as well, which means that the majority of orally administered L-DOPA will be converted into dopamine peripherally (not in the central nervous system). Therefore, L-DOPA is typically administered with an inhibitor of peripheral AADC, called carbidopa. Carbidopa (or another AADC inhibitor) helps preserve orally administered L-DOPA for conversion to dopamine in the brain.

Regrettably, the use of orally administered L-DOPA over time results in diminished production of endogenous (naturally occurring within the body) L-DOPA. L-DOPA therapy is further complicated by the development of movement disorders called dyskinesias after 5–10 years of use in most cases.

Dyskinesias are movement disorders in which neurological discoordination results in uncontrollable, involuntary movements. This discoordination can also affect the autonomic nervous system, resulting in, for example, respiratory irregularities.82 Dyskinesia is the result of L-DOPA-induced synaptic dysfunction and inappropriate signaling between areas of the brain that normally coordinate movement, namely the motor cortex and the striatum.83

With long-term L-DOPA use (usually after about five years), responsiveness declines and dose adjustment is often necessary. This phenomenon leads to fluctuations in the effectiveness of L-DOPA therapy that cause the patient to experience dyskinesia as the post-dose concentration of L-DOPA peaks, and rapid reversion to severe Parkinsonism towards the end of the dosing period.

Several strategies exist for enhancing L-DOPA effectiveness. Some of these include varying combinations of L-DOPA and other medications discussed in this section as well as altering dose timing and amount. Other strategies can involve "rest periods" or "drug holidays" during which the patient abstains from L-DOPA for a short time; as little as skipping a single dose each day may help lessen the damage caused by oxidation products of L-DOPA metabolism and maintain dopamine receptor sensitivity. A patient should never adjust their L-DOPA dose without close supervision by their physician.

Other strategies for stabilizing dopamine levels include combining L-DOPA with inhibitors of enzymes that breakdown dopamine. Medications of this type include monoamine oxidase-B (MAO-B) inhibitors, and catechol-O-methyltransferase (COMT) inhibitors. By combining L-DOPA with COMT and/or MAO-B inhibitors, a physician may be able to reduce the dose of L-DOPA required to relieve symptoms, and widen dose intervals, which is more convenient for the patient.

There are a variety of ways that pharmaceuticals can be combined to deliver optimal effects in each Parkinson's case, but the needs of each patient may vary widely. Therefore, patients should always consult an experienced physician to discuss medication combinations that may be ideal for their unique situation.

L-DOPA can produce several adverse side effects, including:

  • Arrhythmia
  • Gastrointestinal discomfort (taking L-DOPA with low protein snacks may help avoid stomach upset)
  • Breathing disturbances
  • Hair loss
  • Confusion
  • Extreme emotional variability with prevalent anxiety
  • Vivid dreams
  • Hallucinations
  • Impaired social behavior
  • Sleepiness
  • Excessive libido
  • Compulsive behavior (ie, reckless gambling)

L-DOPA-induced elevations in homocysteine, a potentially harmful amino-acid derivative, are another major concern for Parkinson's patients. High levels of homocysteine have been implicated in various cardiovascular diseases, including cerebral small vessel disease, as well as brain atrophy.84,85 A comprehensive review of 16 studies found that elevated homocysteine was associated with dementia and markers of neurodegeneration in patients with Parkinson's patients.86

Parkinson's disease patients taking L-DOPA should read Life Extension's “Homocysteine Reduction” protocol and strive to maintain homocysteine levels of less than 7–8 µmol/L.

L-DOPA Drug Holidays

Regular, chronic use of L-DOPA causes dopamine receptors within the brain to become less sensitive, leading to the eventual need for increased dosages of L-DOPA. Research suggests taking a "drug holiday" from L-DOPA may re-sensitize dopaminergic receptors and lower the patient’s L-DOPA requirements, or at least prevent the need for increasing L-DOPA in the near future. In a three-year study, 15 Parkinson's patients were submitted to a seven-day L-DOPA drug holiday. Within the first six-months following the drug holiday, symptoms improved dramatically, and all of the study subjects were able to maintain a L-DOPA dose regimen of 50–70% of their pre-holiday dose for the entire three-year period.87

Despite these promising results, there are serious risks associated with stopping L-DOPA therapy, one of which is neuroleptic malignant syndrome, a potentially life-threatening situation. Therefore, a drug holiday should only be initiated under the close supervision of a physician. However, at least one study suggests use of amantadine, another drug used to alleviate Parkinson's symptoms, during an L-DOPA drug holiday may limit the severity of side effects associated with stopping L-DOPA therapy. In this study, 12 Parkinson's patients were submitted to a three-day L-DOPA drug holiday, and during that time they were given I.V. infusions of amantadine. The subjects were then started back on the pre-holiday L-DOPA dose and symptomatic improvements lasting up to four months were noted.88

Dopamine Agonists

Another method used to restore dopaminergic signaling in Parkinson's disease is medicating with a dopamine agonist. A dopamine agonist is a drug containing a molecule that binds to and activates dopamine receptors, similar to dopamine itself, thus compensating for low dopamine levels. Dopamine agonists are often used in younger patients, or in very early Parkinson's disease.

Research comparing the results of initial therapy with a dopamine agonists or L-DOPA is conflicting. Some studies suggest that initiating therapy with a dopamine agonist may delay the onset of dyskinesias as the disease progresses, while some seem to indicate that this may not be the case. Other studies suggest initial dopamine agonist therapy delivers results similar to those seen in L-DOPA plus COMT inhibitor therapy.89 Results from a 14-year follow up study found that initial therapy with a dopamine agonist offered no greater benefit over standard L-DOPA therapy in the long term.90

Dopamine agonists pose a greater risk of serious side effects than L-DOPA and are therefore not as tolerable for some patients. Some side effects of dopamine agonists include:

  • Euphoria
  • Hallucinations
  • Psychosis
  • Orthostatic hypotension (low blood pressure upon standing)
  • Increased orgasmic intensity
  • Weight loss
  • Nausea
  • Insomnia
  • Unusual tiredness or weakness
  • Dizziness or fainting
  • Twitching, twisting, or other unusual body movements
  • Pathological addiction and compulsive behavior (ie, hyper-sexuality, gambling)

Selegiline and Rasagiline

Selegiline is a MAO-B inhibitor that, due to its unique chemical structure, also exerts other neuropharmacological actions via its metabolites. By blocking the breakdown of dopamine, selegiline helps compensate for the diminished production of dopamine in Parkinson's disease. This can lead to symptomatic improvement, especially in early-stage Parkinson's.

Numerous clinical trials have confirmed the efficacy of selegiline alone and in combination with L-DOPA in early Parkinson's disease.91-93 One study showed that selegiline was highly effective if initiated within five years of Parkinson's disease diagnosis, but less effective if initiated 10 years or more after diagnosis.91

Selegiline exerts a number of other benefits as well, including maintenance of whole-brain blood flow in depressed Parkinson's disease patients.94 Moreover, selegiline may reduce the formation and toxicity of alpha-synuclein aggregates.95

Rasagiline is a newer generation medication based upon selegiline. Laboratory studies suggest that, in addition to functioning very similarly to selegiline, rasagiline may exert a greater neuroprotective effect.96

Rasagiline was superior to placebo in slowing progression of Parkinson's disease in a cohort of 1,176 early-stage patients. In this study, subjects receiving rasagiline were less likely than those taking placebo to need additional anti-Parkinson drugs to manage symptoms.97 More trials need to be conducted to determine if rasagiline is significantly more effective than selegiline for treating Parkinson's disease.

Selegiline is available via prescription in a clinically studied transdermal patch called Emsam. Selegiline and rasagiline may cause dizziness, dry mouth, sleeplessness, and an overall stimulating effect.

7 Alternative and Emerging Therapies

In addition to the conventional standard of care, which relies heavily on L-DOPA therapy, physicians may sometimes implement other pharmaceutical agents that complement the effects of L-DOPA therapy, or limit its side effects.

Amantadine

Amantadine is an antiviral drug that exerts a number of actions in the brain. Amantadine has been shown in some studies to benefit Parkinson's patients, primarily by reducing the side effects of L-DOPA, or as an adjuvant during L-DOPA drug holidays as mentioned above, though the mechanisms are largely unclear.

In clinical studies, amantadine has been shown to temporarily reduce L-DOPA induced dyskinesia; an effect which dissipates after about eight months.98,99 However, in some patients, discontinuation of amantadine appears to cause a rebound worsening of dyskinesias to an even higher intensity than before its introduction.99

As mentioned earlier in this protocol, at least one study suggests amantadine may suppress side effects of L-DOPA abstinence during a drug holiday.88

Amantadine may ease Parkinson's symptoms in some patients, but should only be initiated under physician supervision.

Nicotine

Within the brain, there exists a grand diversity of neurotransmitter interaction and overlap. One such relationship, very symbiotic in many ways, is that existing between the dopaminergic and cholinergic systems. For example, acetylcholine modulates dopaminergic signaling in the striatum, an area considerably impacted in Parkinson's disease.

Nicotine interacts with the cholinergic system by to binding sites known as nicotinic acetylcholinergic receptors (nAChRs), which influence several functions relevant in Parkinson's disease, including dopamine signaling.100 Moreover, loss of nAChRs accompanies many neurodegenerative disease, including Parkinson's disease, suggesting that declining cholinergic signaling be a key etiological feature.101 Several studies indicate that nicotine exerts powerful neuroprotective effects via activation of nAChRs.102 Recent data indicates that among the neuroprotective effects of nicotine is the ability to reduce alpha-synuclein aggregation, which may suppress the formation of Lewy bodies.103

Many epidemiological studies have confirmed that smoking tobacco confers a substantial reduction in risk for developing Parkinson's disease.104,105 Moreover, transdermal nicotine patches have been shown to improve cognitive functioning in patients with Parkinson's disease.106 Other evidence suggests a therapeutic effect of nicotine in reducing L-DOPA-induced dyskinesias.107

Nicotine appears to have potential to deliver significant and clinically meaningful benefits in Parkinson's disease. If you have Parkinson's disease, you are encouraged to speak with your physician about potentially complementing your anti-Parkinsonian therapy with transdermal nicotine. Your doctor should help you determine an appropriate dose; however, the Holms study cited above used 7mg/24hrs delivered via a transdermal nicotine patch. Newer studies aim to evaluate higher doses (eg, 90 mg/week) via transdermal patch.

Granulocyte Colony-Stimulating Factor (G-CSF)

G-CSF is a signaling glycoprotein (produced in several tissues) that stimulates the production and differentiation of white blood cells, thereby playing a significant role in immune system function. Recombinant G-CSF is frequently given to chemotherapy patients to restore levels of white blood cells that have been suppressed by treatment.

The interaction of G-CSF with the immune system is very complex. However, current evidence suggests that besides stimulating white blood cell generation, it pushes the immune system towards a less autoreactive, anti-inflammatory TH2 phenotype rich in T-regulatory cells.108 Due to this unique action, G-CSF may be of benefit in diseases in which inflammation contributes to the pathology.

Interestingly, receptors for G-CSF are expressed in neurons throughout the central nervous system and activation of those receptors (by G-CSF) stimulates neurogenesis and protects neurons from damage.108,109

In animal models of both Alzheimer 's disease and Parkinson 's disease, subcutaneous injections of recombinant human G-CSF suppressed inflammation in brain regions centrally involved in the pathology of each disease and stimulated the formation of new synapses.110-112 In these studies, mice treated with G-CSF performed much better on cognitive tests than those not treated with G-CSF. These findings are very exciting and hold promise for future research.

Stem Cells and Cell Replacement Therapy

The hallmark of Parkinson's disease is loss of dopaminergic neurons in the substantia nigra. Therefore, many therapeutic approaches have aimed at replacing lost neurons in this region using cell replacement therapy, or stem cell therapy. These therapies are largely experimental as of the current time and no large-scale clinical trials have been conducted as of yet. In fact, small-scale clinical trials have shown that benefit of replacing dopamine neurons may be questionable, and that the therapy caused severe dyskinesias in some subjects.113

Another major challenge associated with cell replacement therapy is ensuring survival of transplanted neurons. So far, this has proven extremely difficult.114 However, further studies are underway, and advancements in research may allow for widespread use of these therapies in the not-too-distant future.

Ablative Surgery and Deep-Brain Stimulation

A conventional therapy of last resort involves ablative surgery, or deep-brain stimulation, in which areas of the brain that are normally under control of dopamine are destroyed. This helps alleviate symptoms in some cases because when the regulatory actions of dopamine are absent, as in advanced Parkinson's disease, those regions of the brain can become dysregulated and dysfunctional.

Only a small percentage of Parkinson's patients are good candidates for ablative surgery or deep-brain stimulation, and there are many risks. Surgical options may be considered in advanced Parkinson's disease when other treatments are no longer able to control symptoms effectively.

However, researchers in the Netherlands have recently developed a method of dramatically improving the accuracy and reliability of deep-brain stimulation.115 This may make it a more viable option in the near future.

Cognitive-Behavioral Therapy

Parkinson's disease is often accompanied by comorbid psychological disturbances such as depression and/or anxiety, and psychosis (a potential side effect of anti-Parkinson medications). Treatment of psychological disturbances is limited, to some degree, due to potential interactions between pharmaceuticals used to treat Parkinson's and those used to treat other psychological conditions.

Cognitive-behavioral therapy offers a highly effective drug free alternative for relieving psychological disturbances in Parkinson's disease patients. In one study, depressed Parkinson's patients were either clinically monitored or engaged in cognitive-behavioral therapy for just over three years. While a mere 8% of patients undergoing clinical monitoring experienced improvements in their depressive symptoms, significant improvement was noted in 56% of those engaged in cognitive-behavioral therapy.116

In addition to the psychological benefits, cognitive-behavioral therapy may be effective for the treatment of some physical symptoms of Parkinson's disease. A 2011 study found that in patients older than 50 years, cognitive-behavioral therapy led to a significant reduction in the incidence of urinary incontinence.117

Several different types of cognitive-behavioral therapy are available and different styles may be appropriate in some cases while inappropriate in others. Patients with Parkinson's disease may benefit from cognitive-behavioral therapy and therefore, should discuss this option with their physicians.

Physical Therapy and Exercise

Parkinson's patients are prone to motor disturbances, such as poor balance and a greater chance of falling, which can lead to decreased mobility. As the disease progresses, engaging in structured physical therapy or exercise may be an effective way of maintaining balance and avoiding falls.118

Moreover, an array of studies has shown that exercise and physical activity in general exert substantial supportive effects upon brain structure and function. In fact, physical activity is associated with a decreased propensity for aging adults to develop dementia, a common problem in Parkinson's disease.119 Experimental Parkinson's disease models demonstrate that physical activity provides neuroprotection and promotes mitochondrial integrity.120

Staying active is very important for Parkinson's disease patients. Those not engaged in regular physical activity are encouraged to speak with their healthcare provider about initiating a structured exercise or physical therapy regimen. A target goal of 75% maximum age adjusted heart rate for a minimum of 20 minutes at least three times per week is ideal. However, this may not be possible for advanced Parkinson's disease patients.

8 Diet

Low-Protein Diet/Protein Meal Redistribution

L-DOPA therapy is hindered by many obstacles, one of which is excess protein (specifically, aromatic amino acids) competing with L-DOPA for transport into the brain. Therefore, some studies have evaluated the effects of engaging in protein meal redistribution, involving eating dietary protein separate from dosing with L-DOPA.

Current research indicates that protein meal redistribution may be favorable with a low protein diet. It appears that protein meal redistribution reduces fluctuations, or "on-off periods" in response to L-DOPA therapy.121 Taking L-DOPA at least 30 minutes before consuming protein and/or having your highest protein meal at a time when L-DOPA is not needed may be an effective strategy. However, patients should speak with their physician to determine which dieting approach is appropriate for them.

Coffee Consumption

Coffee contains a multitude of pharmacologically active compounds, some of which have been shown to suppress oxidative stress and protect against diabetes, cancer, cognitive decline, and so on.122 Additionally, several epidemiological studies have found that those who consume large amounts of coffee are much less likely to develop Parkinson's disease.105,123,124

Coffee constituents (compounds) protect brain cells which can be extremely beneficial for Parkinson's disease patients. Coffee extracts have been shown to inhibit MAO-A and -B enzymes, a mechanism similar to that of some pharmaceutical Parkinson's therapies.125 Experimental models suggest that coffee constituents promote neuronal development and increase antioxidant defense systems in the brain.126,127

Green coffee extract contains more of the active antioxidant compounds than brewed coffee, and may be a promising option for Parkinson's disease patients.128 However, clinical trials have yet to confirm this potential benefit.

Intriguing research suggests that caffeine itself may be a potent anti-Parkinson agent. Upon ingestion, caffeine readily crosses the blood-brain barrier and blocks adenosine receptors, an effect responsible for many of its pharmacologic actions. The adenosine receptor system interacts with the dopaminergic system in several ways.129 Experimental studies have shown that caffeine binds to presynaptic adenosine receptors causing an increase in dopamine release, thereby temporarily ameliorating some symptoms of Parkinson's disease.130 In fact, some data from non-human primate studies indicate that adenosine receptor antagonists, like caffeine, may allow for a reduced dosage of L-DOPA. Data in mice also supports this notion, but more studies need to be done.131,132

In a clinical trial, a daily caffeine dose of 100 mg was shown to reduce "freezing." However, it appeared the subjects developed a tolerance after a few months. The researchers went on to suggest that caffeine might have therapeutic potential, but a periodic 2-week abstinence period may be required to maintain long term effectiveness.133

Current evidence suggests that coffee consumption may provide some neuroprotection and pharmacologic support, with very little potential downside for Parkinson's patients.

9 Natural Ingredients to Support Neuronal and Mitochondrial Health

Conventional treatment of Parkinson's disease relies heavily on targeting amelioration of symptoms, without providing neuroprotection against continual cell death in the substantia nigra. On the other hand, a variety of natural ingredients have been shown to support neuronal health and promote mitochondrial function in a variety of ways, including suppressing oxidative stress and limiting inflammation. Many natural ingredients may have a complementary effect in combination with conventional therapies.

Coenzyme Q10 (CoQ10)

The strong connection between defects in mitochondrial energy management and oxidative stress has led neuroscientists to explore a number of supplemental compounds with energy enhancing, antioxidant capabilities. Excellent laboratory and clinical evidence suggests that coenzyme Q10 (CoQ10), also known as ubiquinone or ubiquinol because of its omnipresence in living cells, is an outstanding contender in this field.134,135 CoQ10 is used in a myriad of enzymatic reactions involving the transport of electrons from energy supplying nutrients and their safe disposal within cells. CoQ10 deficiencies disrupt these reactions, contributing to many age-related neurodegenerative conditions. Plasma and platelet levels of CoQ10 are known to be low in patients with Parkinson's disease, suggesting a systemic deficiency state. A late 2008 study from England demonstrated for the first time that reduced CoQ10 levels are found in cortical regions of the brain of Parkinson's disease patients.136

In a multicenter clinical trial, 80 treatment naïve patients with early Parkinson's disease were randomly assigned to receive either placebo or CoQ10 at daily doses of 300, 600, or 1,200 mg for 16 months or until disability required drug treatment. All subjects were scored using the standard Unified Parkinson Disease Rating Scale (UPDRS), for which higher scores indicate a progressively worsening disease state. The results were compelling with a mean change of 11.99 with placebo, 8.81 with the 300 mg dose, 10.82 with the 600 mg dose, and 6.69 with the 1,200 mg dose—a significant difference. All doses were well tolerated. The authors concluded that "coenzyme Q10 appears to slow the progressive deterioration of function in Parkinson's disease."137 Two years later the same researchers showed that dosages up to 3,000 mg/day of ubiquinone were safe and well tolerated, though plasma levels reached a plateau at 2,400 mg/day.138

German researchers were intrigued by the aforementioned laboratory observations which suggested that CoQ10 might not only prevent the loss of dopaminergic neurons, but could also improve functioning of the remaining cells. Their own randomized trial results were somewhat discouraging, showing no change in UPDRS scores. However, their subjects received a lower dose of CoQ10 (100 mg three times daily) over just three months. Unlike the previous trial, they also studied patients with "mid-range" Parkinson's disease, already requiring L-DOPA. Therefore, they would have been by definition unable to detect significant neuroprotective effects. They did conclude however that the CoQ10 was safe and well tolerated.139

While exploring the relationship between mitochondrial dysfunction and Parkinson's disease, a group of pharmacologists in Egypt came across strong laboratory evidence supporting the need for high doses of CoQ10 either alone or in combination with L-DOPA therapy. They induced Parkinson's disease in rats by injecting them with a toxin known to create an accurate model of the disease. They found that the animals developed slower movements and rigidity within 20 days. Their brains also showed marked decreases in levels of dopamine and energy transfer molecules such as ATP, with increased levels of a cell death signaling protein called Bcl-2—identical to the brain of a human Parkinson's disease patient. Remarkably, after so much damage had already been done, treatment with CoQ10 prevented cell death, restored ATP levels, and decreased movement disorder scores. Another group of rats treated with L-DOPA alone showed symptomatic improvement, but it had no effect on cell survival or energy function. The researchers concluded that "addition of coenzyme Q10 in a high dose in early Parkinson's disease could be recommended based on its proved disease-modifying role on several levels of the proposed mechanisms, including improvement of respiratory chain activity."140

An animal study conducted at Cornell University demonstrated CoQ10's protective qualities as it prevented dopaminergic neurons from destruction, prevented loss of enzymes that make dopamine, and prevented the development of toxic alpha-synuclein complexes that predict severe Parkinson's disease. The researchers noted that their results "provide further evidence that administration of CoQ10 is a promising therapeutic strategy for the treatment of Parkinson's disease."141

Creatine

Creatine, an important amino acid-like compound, is vital to cellular energy management. Creatine deficiency is associated with neurological damage.142 Several animal studies have shown creatine, because of its "pro-mitochondrial" effect, to be effective in preventing or slowing the progression of Parkinson's disease.54,143,144 Influential Harvard neurologists noted that "creatine is a critical component in maintaining cellular energy homeostasis, and its administration has been reported to be neuroprotective in a wide number of both acute and chronic experimental models of neurological disease."145 Studies have shown that creatine is safe and well tolerated by patients with Parkinson's disease.146

In 2006, the Neuroprotective Exploratory Trials in Parkinson’s Disease (NET-PD) group at the National Institute of Neurological Disorders and Stroke (NINDS) studied 200 treatment-naïve subjects who had been diagnosed with Parkinson’s disease within the past five years. Subjects were randomly assigned to receive creatine 10 grams/day, the antibiotic drug minocycline (a proposed neuroprotectant) 200 mg/day, or placebo for 12 months while their scores on a standard Parkinson's disease rating scale were monitored. Both creatine and minocycline performed well, yet creatine showed a substantial edge in performance over minocycline. Tolerability of the treatment was 91% in the creatine group and 77% in the minocycline group.147 However, a follow-up study published by this same research group in 2015 failed to show a benefit associated with creatine supplementation (10 grams daily) for a minimum of five years.148

While it is unclear why the latter study did not identify a benefit with creatine supplementation, small differences in inclusion criteria and patient characteristics between the two studies may have contributed. Also, some evidence suggests that perhaps creatine in combination with other neuroprotective nutrients (as opposed to alone, as in the NET-PD studies) might be of benefit: a recent animal study found that creatine, in combination with CoQ10, conferred significant neuroprotection by reducing the accumulation of alpha-synuclein and suppressing lipid oxidation. In addition, animals being treated with the nutrient combination survived longer than those not being treated.149 Clinical trials are needed to assess the effects of creatine in combination with other neuroprotective nutrients in Parkinson’s patients.

Omega-3 Fatty Acids

These natural components of omega-3 fats, obtained chiefly from fish and some plant sources, exert significant anti-inflammatory action. Their concentration in nerve cell membranes decrease with age, oxidant stress, and in neurodegenerative disorders such as Parkinson's disease.150,151 In fact, researchers in Norway have presented convincing evidence of a systematic omega-3 deficit in Parkinson's disease, Alzheimer's disease, and autism, suggesting a fundamental neurological role for these vital fat molecules.152,153 Supplementation with the omega-3 DHA can favorably modify brain functions and has been proposed as a nutraceutical tool in Parkinson's and Alzheimer's disease.154

A study from Japan found that treatment of nerve cells with omega-3 prevents apoptosis, the programmed cell death that occurs in part as the result of inflammatory stimuli in the brain. Interestingly, results were a lot better when treatment was introduced before the chemical stresses that induced apoptosis were imposed, leading them to conclude that "dietary supplementation with [omega-3s] may be beneficial as a potential means to delay the onset of the diseases and/or their rate of progression."155

Canadian researchers took this study to the next level when they supplemented mice with omega-3 before injecting them with a Parkinson's inducing chemical.156 The mice were fed either a control or a high omega-3 diet for 10 months prior to injection. Control mice demonstrated a rapid loss of the dopamine producing cells in their substantia nigra accompanied by profound drops of dopamine levels in brain tissue. These effects were prevented in the mice receiving the high omega-3 diet.

A study of primates at the same institution demonstrated actual changes in Parkinson's symptoms, providing further compelling evidence for omega-3's protective and therapeutic effects. In this study, one group of animals was first treated for several months with L-DOPA before being given omega-3 DHA, while a second group was pre-treated with omega-3 DHA before starting on L-DOPA. The study was designed this way because L-DOPA, though effective in treating Parkinson's symptoms, as stated earlier in the protocol is also known to damage dopamine producing cells and induce dyskinesias. Omega-3 DHA reduced the occurrence of dyskinesias in both groups of monkeys, without altering the beneficial effects of L-DOPA. The researchers concluded that "DHA may represent a new approach to improve the quality of life of Parkinson's disease patients."157

B Vitamins

B vitamin deficiencies have long been implicated in many neurological disorders, including Parkinson's disease. Studies as early as the 1970's directed at demonstrating the effects of supplementation yielded discouraging results158-160 However, as our understanding of the close link between the toxic amino acid homocysteine and B vitamins grew, more targeted and mechanism-based studies became possible. Homocysteine levels are closely linked to folate, vitamins B6 and B12 status. Elevated homocysteine levels are found in cardiovascular disease as well as a variety of neurological and psychiatric disturbances.161-163 Also, L-DOPA treatment can itself lead to elevated homocysteine levels. As a result, more recent studies have led researchers to recommend B complex supplementation in those utilizing L-DOPA therapy.164

Definitive evidence supporting the benefit of this approach came from Singapore where Parkinson's disease patients, already on a stable dose of L-DOPA, were supplemented with pyridoxine (a common form of vitamin B6).165 Mean motor and activities of daily living scores improved significantly following supplementation, and worsened again when the supplements were stopped. Low serum folate is also found in Parkinson's disease patients, especially those taking L-DOPA.163 Canadian researchers demonstrated that a supplement containing folate and B12 could decrease plasma homocysteine levels in patients taking L-DOPA.166

A systematic review paper concluded that B vitamin supplementation may be of value for neurocognitive function.167 A similar review points to recent work with the active form of vitamin B6, pyridoxal-5' phosphate (P5P), noting that a number of neurological disorders including Parkinson's disease offer attractive therapeutic targets for this substance.168 The consensus among experts is that due to the deleterious effect that elevated homocysteine levels has on both Parkinson's itself and L-DOPA therapy, supplementation with folate, B6, and B12 is warranted.169-172

Thiamine, also known as vitamin B1, may benefit Parkinson’s patients. In 1999, low levels of free thiamine were detected in the cerebrospinal fluid of Parkinson’s disease patients.173 In 2013, researchers treated three newly diagnosed Parkinson’s patients with high-dose thiamine injections. Remarkably, the injections considerably improved the patients’ motor symptom deficits.174 Although only three subjects participated in this uncontrolled, informal clinical trial, the results corroborated very similar findings from another small trial in 2012.175

More recently, in 2015, an open-label clinical trial on 50 Parkinson’s disease patients showed that intramuscular injections of 100 mg of thiamine twice weekly led to significant and lasting improvements on a standardized Parkinson’s disease rating scale. Some participants—those with mild symptoms—had a complete clinical recovery. The benefits persisted throughout the follow-up period of up to about 2.2 years.176 In another open-label study, published in 2016, researchers treated 10 consecutive Parkinson’s patients with intramuscular 100 mg thiamine injections twice weekly without changing their medication regimens. Several measures of Parkinson’s disease symptoms improved significantly, and when the investigators increased the dosage of thiamine into the second month of treatment, the benefits became even more pronounced. Researchers speculated that the benefits of thiamine may arise from improvements in energy metabolism in surviving dopaminergic neurons in the substantia nigra.177 Additional clinical trials are needed to test whether oral thiamine, or thiamine derivatives such as benfotiamine, may have similarly beneficial effects.

Vitamin D

Vitamin D functions more like a hormone than a vitamin. Vitamin D receptors are expressed ubiquitously throughout the body, including on microglial cells.178 Upon activation by vitamin D, vitamin D receptors signal for increased or decreased expression of numerous genes, many of which are immunomodulatory.179

Several studies have shown that higher levels of vitamin D protect against the onset of Parkinson's disease symptoms. Also, that patients diagnosed with Parkinson's have lower serum vitamin D levels than those without the disease.180,181

Since many of the actions of vitamin D are anti-inflammatory, Life Extension believes that maintaining optimal vitamin D blood levels (50–80 ng/mL) may quell some of the inflammatory aspects of Parkinson's disease neurodegeneration. It is likely that having optimal vitamin D levels might decrease the activation of microglial cells and reduce the release of inflammatory cytokines.

Carnitine

Carnitine is a vital nutrient that serves as a co-factor in fatty acid metabolism. It helps to "ferry" large fat molecules into the mitochondrial "furnaces" where they are burned for energy, making it an important component of brain energy management and mitochondrial function.182 There is a growing body of literature suggesting that carnitine supplementation, through its support of brain energy management, protects against Parkinson's disease.

Mount Sinai researchers were able to prevent chemically induced Parkinson's disease in monkeys by pre-treating them with acetyl-l-carnitine, a readily absorbed form of the nutrient.183 Moreover, Italian researchers have studied carnitine as a neuroprotectant in the brains of methamphetamine users. Methamphetamines cause the same basic mitochondrial destruction and free radical brain damage as that seen in Parkinson's patients.182,184 This work has been extended in similar studies at the U.S. National Center for Toxicological Research.185

In an intriguing study, Chinese nutritional scientists in Shanghai explored in culture both acetyl-L-carnitine and lipoic acid (each alone and in combination with the other) in preventing Parkinson's disease-like changes in human neural cells. They found that both nutrients either alone or in combination, applied for four weeks prior to a Parkinson's disease-inducing chemical, protected the cells from mitochondrial dysfunction, oxidative damage, and an accumulation of the dangerous alpha-synuclein proteins. Notably, the combination of supplements was effective at 100- to 1000-fold lower concentrations than were required for either acting alone—powerful evidence that led the researchers to state that "this study provides important evidence that combining mitochondrial antioxidant/nutrients at optimal doses might be an effective and safe prevention strategy for Parkinson's disease."186

Green Tea

Increased tea consumption is correlated with reduced incidence of dementia, Alzheimer's and Parkinson's disease.187 Green tea contains valuable antioxidant polyphenols known to be protective against a host of chronic age-related conditions. There is tremendous scientific interest in green tea and its active compound epigallocatechin gallate (EGCG) as a neuroprotectant in Parkinson's disease; especially since when compared to many drugs, EGCG is extremely effective at penetrating brain tissue.188,189

Israeli researchers showed that they could prevent the cellular changes associated with Parkinson's by pre-treating mice with either green tea extracts or EGCG ahead of inducing the disease by chemical injection.188,190 This research has subsequently been repeated and extended in laboratories around the world.191-195 Utilizing the brain cell cultures pretreated to develop Parkinson's-like changes, the Israeli group also showed that green tea extracts prevented activation of the inflammation producing NF-kappaB system.190 EGCG's specific anti-inflammatory properties have been demonstrated to protect cultured brain tissue from the loss of dopaminergic cells as well.196 L-theanine, a component of green and black tea, was shown by Korean scientists to prevent dopaminergic cell death such as that seen in Parkinson's disease.197

Another potential benefit of green tea extract is its ability to inhibit the dopamine degrading enzyme COMT.74 This may help to sustain dopamine levels in ailing brain tissue thereby reducing the severity of symptoms.

Just as we use multiple combinations of prescription drugs to capitalize on their synergistic effects, we can capitalize on green tea's neuroprotective effects in Parkinson's and other neurodegenerative diseases.198 While more human studies are yet to be completed, green tea polyphenols have proven to exert powerful protection for dopaminergic neurons making them a key component in the prevention and treatment of Parkinson's disease.195,199-202

Resveratrol

Resveratrol is a polyphenolic antioxidant compound that has shown stunning potential in preventing cardiovascular disease and prolonging life.203-205 Not surprisingly, scientists interested in protecting brain tissue and enhancing the quality of life in aging individuals have directed their attention towards this remarkable compound.

Since dopamine itself is an oxidant compound which can contribute to the early destruction of neurons, Korean scientists studied the impact of resveratrol at preventing this paradoxical effect.206 They found that through the loss of mitochondrial function, human neural tissue treated with dopamine underwent rapid cell death. However, exposing the cells to resveratrol for one hour prior to dopamine treatment prevented cell loss and preserved mitochondrial function. In addition, Canadian scientists used resveratrol to prevent neuronal cell death caused by inflammation.207

Resveratrol's anti-inflammatory action was further explored by Chinese researchers who at first administered a Parkinson's disease-inducing chemical to rats, then gave them oral daily doses of resveratrol for 10 weeks. They found that after only two weeks of supplementation, the rats demonstrated significant improvement in their movement. Also, examination of their brains showed marked reduction in mitochondrial damage and loss of dopaminergic cells. Remarkably, they also found a reduction in the levels of COX-2 and TNF-alpha (inflammatory markers). They concluded with justifiable excitement that "resveratrol exerts a neuroprotective effect on [a chemically-] induced Parkinson's disease rat model, and this protection is related to the reduced inflammatory reaction."208

As with green tea extracts, it appears that resveratrol's potential for preventing Parkinson's disease may reside in its multi-modal mechanism of action targeting oxidant stress, inflammation, and systems such as sirtuins that are fundamental in regulating mitochondrial function and ultimately affecting longevity.204

Mucuna pruriensis a vine whose seeds contain a high concentration of naturally occurring L-DOPA and a variety of other psychoactive compounds.209 Compounds in Mucuna seeds act as AADC inhibitors, mimicking the action of carbidopa, and complementing the action L-DOPA in the central nervous system. In an animal experiment, Mucuna seed extract was shown to alleviate symptoms of chemically-induced Parkinson's with similar efficacy to traditional L-DOPA treatment, but without inducing dyskinesia.210 These results were repeated in another, similar trial.209

In a double-blind, randomized, placebo-controlled trial, Mucuna extract proved superior over standard L-DOPA/carbidopa therapy. Compared to traditional therapy, Mucuna led to a faster onset of symptom relief, longer duration of relief, and significantly fewer dyskinesias. The scientists conducting this study concluded that "The rapid onset of action and longer on time without concomitant increase in dyskinesias on mucuna seed powder formulation suggest that this natural source of L-dopa might possess advantages over conventional L-dopa preparations in the long term management of [Parkinson's disease]."211

Wild Green Oat Extract

Oats (Avena sativa L.) have been a foodstuff for many centuries and are an important cereal crop in North America, Europe, and Russia.212,213 Oats are the only known natural source of avenanthramides, which are bioavailable compounds with anti-inflammatory, anti-atherogenic, and antioxidant properties.214-216

Monoamine oxidase B (MAO-B) is responsible for the breakdown of dopamine in neurons217; however, excess MAO-B activity increases with age and depletes dopamine levels through excessive dopamine metabolism.218,219 Indeed, the loss of dopaminergic neurons is considered the hallmark of Parkinson’s disease, and restoration of dopaminergic signaling is the focus of most treatments.220-222 Drugs that inhibit MAO-B, such as deprenyl (Selegeline) and rasagiline (Azilect), are used in the treatment of early Parkinson’s disease.223-225 Blocking MAO-B with medications such as deprenyl not only raises dopamine levels in brain tissue, but also appears to be neuroprotective. MAO-B inhibitors block free radical formation that occurs during dopamine metabolism and blocks apoptosis (programmed cell death) of neurons.226

Wild green oat extract has shown the ability to inhibit MAO-B activity227,228 and demonstrated in numerous clinical trials to be a neuroprotective agent capable of improving cognitive function with as little as a single dose, while also increasing blood flow both systemically and to the brain by as much as 40%.229-232 Research demonstrates wild green oat extract is a neuroactive compound that shares a critical mechanism of action, MAO-B inhibition, with important Parkinson’s disease medications. This body of evidence suggests wild green oat extract is a promising natural therapy for those concerned with Parkinson’s disease.

Pyrroloquinoline Quinone (PQQ)

Pyrroloquinoline quinone, or PQQ, is a highly bioactive compound present in a vast range of cell types, and research suggests boosting PQQ levels may improve mitochondrial function, inhibit oxidative stress, and support neurological health.233-238 Since oxidative stress and mitochondrial dysfunction are believed to be key factors in Parkinson’s disease,239 PQQ is being actively studied as an agent to prevent and treat this condition.240

One mechanism by which PQQ may benefit those with Parkinson’s disease is by stimulating cerebral blood flow and oxygen use. Two studies using near-infrared spectrometry in healthy older adults have found supplementing with 20 mg PQQ daily for 12 weeks resulted in increased brain blood flow as well as increased oxygen utilization.237,241 In one of the studies, cognitive testing revealed PQQ was also associated with better preservation of cognitive function than placebo.237 These studies confirm earlier studies where PQQ prevented neurodegeneration and maintained memory function in a rodent experiment.242

A number of laboratory and animal studies have indicated PQQ can protect nerve cells from toxic and inflammatory damage by reducing oxidative stress and protecting mitochondria.240,243-245 Several preclinical studies have shown PQQ may prevent the accumulation of damaging amyloid proteins such as beta-amyloid,246-249 and might in this way protect against conditions such as Parkinson’s disease and Alzheimer’s disease.

Other Promising Nutrients

Curcumin. Curcumin, a derivative of the spice turmeric, through its potent modulation of the NF-kappa B system is a natural inhibitor of inflammation. It prevents chemically-induced changes in lab models of Parkinson's disease and exerts significant neuroprotection.250-257

Melatonin. The antioxidant hormone melatonin (synthesized and secreted by the pineal gland) may help to reduce the accumulation of alpha-synuclein proteins while preserving the cell's ability to make dopamine. It is also an invaluable sleep aid for Parkinson's patients, who often suffer from distressing problems with sleep.258-267

N-acetyl cysteine (NAC). NAC is a precursor to the potent cellular antioxidant glutathione. In animal models, NAC prevented dopamine induced neurotoxicity and protected against some of the damaging effects of alpha-synuclein proteins.268,269

Lipoic acid. Lipoic acid, a potent reducing agent, is considered a universal antioxidant due to its amphipathic nature (both fat- and water-soluble). Lipoic acid is produced naturally within the body and contributes to xenobiotic detoxification and antioxidant protection. It also contributes to cellular energy production.270 In addition to its ability to directly neutralize toxins and free radicals, lipoic acid bolsters levels of other cellular protectants such as glutathione and vitamin E.271

The low molecular weight of lipoic acid allows it to easily cross the blood-brain barrier, delivering neuroprotection within the central nervous system. Lipoic acid also combats inflammatory reactions.271 Large scale clinical trials have yet to be conducted in Parkinson's patients. However, given its potential for efficacy and excellent safety profile, lipoic acid should be considered as a therapeutic agent for Parkinson's disease.

Probiotics. Because dopaminergic signaling exerts considerable influence over intestinal function, constipation is a common problem in Parkinson's disease.

In a recent clinical trial, 40 Parkinson's patients complaining of constipation were treated with probiotics for five weeks. Probiotic therapy significantly increased the number of normal stools as well as reduced the incidence of bloating and abdominal pain.272

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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