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Parkinson's disease

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 twenty patients is diagnosed under the age of 40 (Parkinson's Disease Foundation 2011; Heisters 2011).

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 lead 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.

Parkinson's Disease – Brief History, Classifications, and Risk Factors

Dr. James Parkinson first described the motor system disorder known today as Parkinson's diseases in an 1817 paper entitled "An Essay on the Shaking Palsy" (Parkinson 1817). 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, lead 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 instabilityare 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 lead 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 Prakinson'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 (Martinez 2011).

Exposure to pesticides may substantially increase risk for Parkinson's disease (Astiz 2009; Fleming 1994; Betarbet 2000; Brooks 1999; Kenborg 2011; Wang 2011). In one study, higher pesticide exposure increased Parkinson's disease risk three-fold (Wang 2011). Numerous epidemiological studies have confirmed the association (Flemming 1994; Priyadarshi 2000). Toxin-induced Parkinson's symptoms may be classified as secondary (see below), rather than primary Parkinson's (Martinez 2011; Moretto 2011).

Interestingly, pesticides seem to accumulate in the dopaminergic tract, where they inhibit mitochondrial function and lead to neuronal death (Betarbet 2000; Corrigan 2000). 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 (Kanthasamy 2005). In addition to acting as neuronal and mitochondrial toxins, some pesticides also impair the breakdown of protein aggregates, like Lewy bodies (Sun 2005).

Several lines of evidence suggest that a genetic inability to properly detoxify environmental toxicants may predispose some individuals to Parkinson's disease (Steventon 2001; Williams 1991).

In addition, those who experience constipation throughout their lives appear to be at increased risk (Petrovitch 2009). In one study, constipation documented in medical records as much as 20-years before disease onset was associated with a significantly increased risk (Savica 2009). Some researchers believe that this may be related to intake of drinking water – lower water intake appears to be a risk factor as well (Ueki 2004). 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 (secondaryParkinson's) – Other forms of Parkinsonism can occur as a secondary effect of brain tumor, drugs, toxins (e.g. 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, the 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 (Dickman 2001). Acquired immunodeficiency syndrome (AIDS) may also lead to Parkinsonism (Sardar 1996). Resuscitation from cardiac arrest (due to temporary lack of oxygen supply to the brain), and stroke can lead to Parkinsonism as well (PubMed Health 2011).

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 (Mamo 1999; Schouten 2011; Bondon-Guitton 2011). Some antidepressants and calcium channel blockers, and the antiarrhythmic drug amiodarone, can lead to Parkinsonian tremors as well (Bondon-Guitton 2011). 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.

Parkinson's Disease – 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 is 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 (Heisters 2011).

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 (Heisters 2011). In addition, Parkinson's disease can cause perceptible pain throughout the body, which is sometimes severe.


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 (Francis 2009; Aarsland 2010). 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 (Francis 1999).

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 (McKeith 2009).


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.

Parkinson's Disease – 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 (Samii 2004). Roughly, nine genetic mutations have been associated with Parkinson's disease; of these, six have been particularly well characterized (Lesage 2009; Samii 2004). 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:

  • SNCA (Mata 2010; Pihlstrom 2011; Lewis 2010; Singleton 2003).
  • LRRK2 (Papapetropoulos 2006).
  • PARK2 (Poorkaj 2004).
  • PINK1 (Yu 2011; Whitworth 2009; Khan 2002; Zhang 2011).
  • PARK7 (Xu 2010; van Duijn 2001; Bonifati 2002; Hering 2004; Inden 2006).
  • ATP13A2 (Hampshire 2001; Hampshire 2001; Ugolino 2011; Park 2011; Fong 2011).

Additional research is required to fully elucidate the role of genetics in Parkinson's aetiology; 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:

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 & 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 (Kempster 2010; Lee 2011).

Numerous studies have clearly identified mitochondrial dysfunction as a central pathological feature of both genetic and sporadic Parkinson's disease (Schapira 2008; Zhu 2010). 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 (Lin 2009; Van Humbeeck 2011; Geisler 2010). While several factors, including exposure to environmental toxins (Song 2004; Kraytsberg 2006; Lin 2009), also contribute to mitochondrial dysfunction in the substantia nigra, age-related mutations in mitochondrial DNA are thought to be a primary culprit (Kraytsberg 2006; de Castro 2011). Alarmingly, dopamine itself, and L-DOPA, may contribute to mitochondrial toxicity in dopaminergic neurons (Gautam 2011; Khan 2005; Mosharov 2009).

Mitophagy, Lewy Bodies, and alpha-Synuclein

Damaged mitochondria are continually being cleared from within the cell through a process called mitophagy. 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 (Van Humbeeck 2011; Chu 2011). 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 (Van Humbeeck 2011; Geisler 2010).

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 (Li 2007; Liu 2009; Devi 2008). Over time, Lewy bodies spread to neighboring cells, damaging neurons within the vicinity of a dead or dying neuron (Iseki 2000).

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 Parkinsons's disease. The brain contains immune cells called microglia, which are known to be activated in Parkinson's disease (McGrer 1988; McGeer 2004). 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- αreleased 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 (Barcia 2009). In experimental models, exposure to the neurotoxin MPTP (a chemical used to induce Parkisnon's disease in experiments) leads to death of dopaminergic neurons. Interestingly, in monkeys, inflammation is increased even years after initial exposure to MPTP (McGeer 2004). This suggests that 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 (Barcia 2009; Glass 2010).

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-inflammaotry drugs (Chen 2005). 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 (Driver 2011). 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 (Quist-Paulsen 2010).

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 (Roy 2011; Yan 2011).

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 (Ghosh 2009). Another animal experiment found that simvastatin was able to completely reverse the decline in dopamine receptors associate with exposure to the neurotoxin 6-hydroxydopamine (Wang 2005).

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 Parkinon's symptoms, as well as a 54% reduction in the risk of dementia, suggesting a substantial neuroprotective effect (Wolozin 2007).

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.