Does tremor frequency generally increase as Parkinson's disease progresses?

Does tremor frequency generally increase as Parkinson's disease progresses?

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I've been trying to research this question, but most if not all the on-line journals require costly subscription, and the studies that are posted look at tremor frequency with regards to other factors.

My question has to do with the tremor frequency, starting at early onset to later stages of Parkinson's disease - over the course of the disease, and without drug treatment (such as L-dopa), does the tremor frequency generally increase?

Frequency of tremor typically remains constant for the person. Levadopa (sinemet) does not change the frequency.

Typically the tremor frequency will be in the range from 3Hz to 7Hz. There is a common phrase when dealing with PWP (Person With Parkinson's Disease). If you have seen one PWP, you have seen one PWP.

Currently I am part of a study by the Micheal J Fox Foundation using Pebble Watches and Smart phones to monitor PD. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55: 181-184.

Promising results from a recent pilot clinical trial showed that deep brain stimulation might be effective in treating early-stage disease.

Parkinson’s disease is a progressive neurodegenerative disease, meaning that brain cells will continuously die off as the illness persists. The brain cells that are mainly affected in Parkinson’s disease are ones that produce dopamine, a chemical in the brain that is known to be important in the control of the body’s movement. What this translates to in terms of symptoms is a disease progression in which the patient’s ability to control movement worsens over time . Patients start off feeling a slight resting tremor, which progresses to rigidity, and loss of balance. In the advanced stages of the disease, the patient loses the ability to walk or stand.

The current frontline treatment for Parkinson’s disease patients has remained much the same for the last 60 years . Levodopa, a chemical that is converted into dopamine in the brain, is used as a replacement therapy. It’s purpose is to replenish the dopamine that is continuously being lost for Parkinson’s disease patients. While levodopa treatment is effective in managing the symptoms seen in Parkinson’s disease, the benefits generally become less consistent over time. The drug is ultimately unable to slow down the disease progression. Commonly, as Parkinson’s disease progresses, patients will typically receive a combination of other medications in addition to levodopa. These include COMT, which mimics dopamine, or medications known as MAO-B inhibitors that slow the natural breakdown of dopamine.

For patients that either don’t respond, or stop responding to medication, there is a surgical procedure available. This treatment, called DBS or deep brain stimulation , is like inserting a “pacemaker” into the brain. The surgeon implants electrodes into the brain that will send electrical pulses to stimulate the firing of brain cells. Scientists have evidence that these electrical pulses serve to re-regulate the normal activation of brain cells that have been unregulated as a result of Parkinson’s disease, and that this ultimately helps to control disease symptoms. While this type of procedure is generally reserved for patients with advanced Parkinson’s disease, researchers have recently investigated whether DBS could be beneficial for early-stage Parkinson’s disease patients as well.

This is the location in the brain where the electrodes are placed for the DBS treatment. Andreashorn / CC BY-SA

At the Vanderbilt University Medical Center, scientists have completed a follow-up study to a pilot clinical trial in which early-stage Parkinson’s disease patients were given DBS in addition to their medication. These patients were compared to other early-stage patients that received only medication. The researchers looked at patient outcomes five years later, and found that the patients that received both medication and DBS fared much better on a variety of Parkinson’s disease outcome measures.

For example, the patients that received both DBS and medication were found to require much lower levodopa doses than early stage patients who did not undergo DBS. On average, patients that received both DBS and medication had an increase in their medication dose that was roughly half that of the patients that did not undergo DBS. They were also five times less likely to have a worsened resting tremor and were fifteen times less likely to need multiple types of Parkinson’s disease medications.

Taken together, the researchers concluded that early implementation of DBS may reduce the risk of Parkinson’s disease progression. If the results of future trials support these early results, the addition of DBS to early stage treatment of Parkinson’s disease may mean a better outcome and slower disease progression for patients. The researchers are now moving to a larger scale trial in order to more fully investigate the potential for DBS to slow Parkinson’s disease progression. If successful, this new treatment could be a landmark discovery for Parkinson’s disease care.

Related posts:

Dementia with Lewy Bodies

  • Dementia with Lewy bodies (DLB) is a progressive, neurodegenerative disorder in which abnormal deposits of a protein called alpha-synuclein build up in multiple areas of the brain.
  • DLB first causes progressive problems with memory and fluctuations in thinking, as well as hallucinations. These symptoms are joined later in the course of the disease by parkinsonism with slowness, stiffness and other symptoms similar to PD.
  • While the same abnormal protein (alpha synuclein) is found in the brains of those with PD, when individuals with PD develop memory and thinking problems it tends to occur later in the course of their disease.
  • There are no specific treatments for DLB. Treatment focuses on symptoms.

Understanding the Pathology

The nervous system is made up of individual units called nerve cells or neurons. Neurons serve as a "communication network" within the brain and throughout a person&rsquos body. Parkinson&rsquos disease develops when neurons in the brain and elsewhere in the nervous system fail to function normally or die. The hallmark symptoms of PD &mdash bradykinesia, tremor, postural instability, and rigidity &mdash result primarily from the death of neurons in the substantia nigra, a region in the midbrain critical for motor control.

In order to communicate, neurons use chemical messengers called neurotransmitters. Neurotransmitters send information between neurons by crossing the space between them, called the synapse. Normally, neurons in the substantia nigra produce a neurotransmitter known as dopamine. Dopamine is critical for movement and it helps transmit messages within the brain to make sure muscles produce smooth, purposeful movement. Loss of dopamine results in abnormal nerve firing patterns that impair movement. By the time Parkinson&rsquos is diagnosed, most people have lost an estimated 60 to 80 percent of their dopamine-producing cells in the substantia nigra.

While loss of dopamine accounts for the characteristic features of the disease, recent studies have revealed that a number of other brain systems are also damaged. These include the brain structures that regulate the chemical pathways that depend on norepinephrine, serotonin, and acetylcholine. The changes in these neurotransmitters and circuits may account for many of the non-motor features of PD.

A factor believed to play a fundamental role in the development of PD involves abnormalities of a protein called alpha-synuclein. In the normal brain, alpha-synuclein is located in nerve cells in specialized structures called presynaptic terminals. These terminals release neurotransmitters which carry signals between neurons. This signaling system is vital for normal brain function.

While normal alpha-synuclein functions are related to the storage and release of neurotransmitters, evidence suggests the buildup of excessive and abnormal alpha-synuclein plays a key role in the development of PD. There are rare examples of families in which certain genetic mutations in alpha-synuclein have been shown to cause the alpha-synuclein protein to misfold into an abnormal configuration. Most individuals with PD do not have a mutation in alpha-synuclein, but even when there is no mutation present, nearly every case of PD is associated with a buildup of abnormal and misfolded alpha-synuclein. As the misfolded protein accumulates, it clumps together into aggregates, or collections, that join together to form tiny protein threads called fibrils. Fibrils are the building blocks for Lewy bodies, abnormal structures that form inside nerve cells in the substantia nigra and elsewhere in the brain. Lewy bodies are a pathological hallmark of PD. Research suggests that the harmful buildup of alpha-synuclein may affect normal function and trigger nerve cell death.

Lewy bodies were discovered more than 100 years ago, and there are still unanswered questions about their role in disease. They are found in the brain of almost every patient affected by PD, but whether the Lewy bodies themselves contribute to the death of neurons is still unclear. Alternatively, the accumulation of protein in Lewy bodies may be part of an unsuccessful attempt to protect the cell from the toxicity of aggregates of alpha-synuclein.

A key objective for researchers moving forward is to better understand the normal and abnormal functions of alpha-synuclein and its relationship to genetic mutations that impact PD.

In the past decade, NINDS-funded researchers have discovered much about the genetic factors that contribute to PD. In most instances the cause of PD is unknown, however, a small proportion of cases can be attributed to genetic factors. An estimated 15 to 25 percent of people with Parkinson&rsquos disease have a family history of the disorder. It is relatively rare for PD to be caused by a single mutation of one of several specific genes. This only accounts for about 30 percent of cases in which there is a family history of PD and only 3 to 5 percent of sporadic cases &mdash instances with no known family history.

Researchers increasingly believe that most, if not all, cases of PD probably involve both a genetic and environmental component. Early-onset Parkinson's disease is relatively rare and is more likely to be influenced by genetic factors than the forms of the disease that develop later in life.

Multiple NIH projects helped build an infrastructure for PD genetics research. The Human Genome Project and the International HapMap Project laid the groundwork for this research, producing tools to help researchers find genetic contributions to common diseases. Using these tools, researchers supported the Parkinson&rsquos Disease Genome Wide Association Study (PD-GWAS). Funded by both the NINDS and the National Institute on Aging ( NIA ), this effort aims to detect genetic risk factors for PD from groups around the world. Included in PD-GWAS are data from nearly 14,000 people with PD and more than 95,000 people without PD. By comparing these two groups, researchers can identify patterns in certain regions, or loci, of the human genome where genes that cause or increase the risk of PD are likely to reside. Much like a zip code, genetic loci describe the general neighborhood of a gene.

Based on an analysis of PD-GWAS data and other sources, NIH-funded scientists have identified 28 loci believed to be independently associated with PD risk and many more loci have been tentatively linked to the disorder.

Next generation genetic technologies have led to a number of new discoveries and allowed scientists learn more about what genetic factors contribute to the risk of developing PD. The first successes were a result of high-content genotyping, a method of identifying common variants in the human genome. Currently, there is a great deal of excitement regarding next generation sequencing &mdash methods of genetic sequencing that allow for rapid sequencing of DNA base pairs in particular loci of the genome. These methods have significantly cut the time and costs required to identify genes involved with PD and will continue to facilitate the identification of PD-related genes in the future.

Another breakthrough in genetic sequencing is NeuroX, the first DNA chip able to identify genetic variants in a person&rsquos genome to determine any risk for developing a number of late-onset neurodegenerative diseases, including PD. A joint venture between the NINDS and investigators at the NIA , the NeuroX chip was developed as a result of a 2011 NINDS workshop. The workshop led to an analysis of data from worldwide PD-GWAS investigations. Those studies helped correlate genetic variants and common traits among people with PD, which made the NeuroX chip possible.

Despite these innovations, significantly more research is needed to identify PD-related genes and the cellular processes they support in order to understand how these functions contribute to the onset and progression of PD. Common genetic variations alone cannot fully explain how genetics contributes to the risk of developing PD. Instead, researchers hypothesize there must be additional genetic contributions from variants that are not common enough to be detected by PD-GWAS investigations.

Known Genetic Mutations

Inherited PD has been found to be associated with mutations in a number of genes including SNCA, LRRK2, PARK2,PARK7, and PINK1. Many more genes may yet be identified. Genome-wide association studies have shown that common variants in these genes also play a role in changing the risk for sporadic cases.

Mutations in other types of genes, including GBA, the gene in which a mutation causes Gaucher&rsquos disease, do not cause PD, but appear to modify the risk of developing the condition in some families. There may also be variations in other genes that have not been identified that contribute to the risk of the disease.

In 1997, scientists identified the first genetic mutation (SNCA) associated with PD among three unrelated families with several members affected with PD. The SNCA gene provides instructions for making the protein alpha-synuclein, which is normally found in the brain as well as other tissues in the body. Finding this mutation led to the discovery that alpha-synuclein aggregates were the primary component of the Lewy body. This is an example of how a disease-causing rare mutation can shed light on the entire disease process.

PD related to SNCA gene mutations is autosomal dominant, meaning that just one mutated copy of the gene in each cell is sufficient for a person to be affected. People with this mutation usually have a parent with the disease.

Though more than a dozen mutations in the SNCA gene have been linked to PD, these mutations are considered a relatively rare cause of the disease. In some cases, SNCA gene mutations are believed to cause the alpha-synuclein protein to misfold. Other SNCA mutations create extra copies of the gene, leading to excessive production of the alpha-synuclein protein. Even when no mutation is present, buildup of abnormal synuclein is a hallmark of PD. The NINDS is funding multiple studies aimed at determining how misfolded and excessive levels of alpha-synuclein might contribute to developing PD.

Mutations of the LRRK2 gene are the most common genetic cause of autosomal dominant PD. These mutations play a role in about 10 percent of inherited forms of PD and about 4 percent of people who have no family history of the disease. Studies show that one particular LRRK2 mutation, G2019S, accounts for up to 20 percent of PD in specific groups, such as the Ashkenazi Jewish population.

Researchers are still studying exactly how LRRK2 gene mutations lead to PD, but it appears these mutations influence both the manufacturing and disposal of unwanted proteins in multiple ways. PD associated with LRRK2 mutations involves both early- and late-onset forms of the disease. The LRRK2 gene is a kinase enzyme, a type of protein that tags molecules within cells with chemicals called phosphate groups. This process of tagging, called phosphorylation, regulates protein enzymes by turning them &ldquoon&rdquo or &ldquooff&rdquo and it is fundamental to basic nerve cell function and health.

NINDS-supported investigators at the Udall Center at Johns Hopkins University (JHU) have found that LRRK2 mutations increase the rate at which the gene&rsquos protein tags ribosomal proteins, a key component of the protein-making machinery inside cells. This can cause the machinery to manufacture too many proteins, leading to cell death.

LRRK2 gene mutations also are believed to inhibit a waste disposal method called autophagy, the process by which cells breakdown nutrients, recycle cellular components, and get rid of unusable waste. Autophagy is a critical means for quality control by enabling the cell to eliminate damaged organelles and abnormal proteins.

LRRK2 gene mutations inhibit a type of autophagy called chaperone-mediated autophagy. During this type of autophagy a &ldquochaperone&rdquo protein escorts a damaged protein to the lysosome, spherical vesicles within cells that contain acid that help breakdown unwanted molecules. As a result, the LRRK2 gene mutations may lead to the buildup of alpha-synuclein into toxic aggregates within the cells. Researchers are exploring whether certain compounds might be capable of overriding LRRK2 gene mutation effects by rebooting the chaperone-mediated disposal system.

  • Gene for parkin (PARK2)/ Gene for PTEN induced putative kinase 1, or PINK1 (PARK6)

PARK2 mutations are the most common genetic mutations associated with early-onset PD, which first appear at age 50 or younger. PARK6 gene mutations also are associated with early-onset PD, but they are far more rare. Both types of mutations are associated with autosomal recessive PD, meaning that two mutated copies of the gene are present in each cell and that anyone affected may have unaffected parents who each carried a single copy of the mutated gene.

Findings from a NINDS-funded study suggest that people with PARK2 mutations tend to have slower disease progression compared with those who do not carry PARK2 mutations.

The genes PARK2, PARK6, PINK1, along with the protein parkin, are all involved at different points along a pathway that controls the integrity of mitochondria, the powerhouses inside cells that produce energy by regulating quality control processes. Brain cells are especially energetic and dependent upon mitochondrial energy supply. Specifically, parkin andPINK1 regulate mitochondrial autophagy &mdash a process known as mitophagy. These processes are critical for maintaining a healthy pool of mitochondria by providing a means to eliminate those that no longer function properly.

Much work remains to be done to understand the association of PARK2 and PARK6 mutations and mitochondrial dysfunction, as well as to investigate if and how mitochondrial dysfunction leads to PD. Evidence suggests that parkin and PINK1 function together. When PINK1 (which is located on mitochondria) senses mitochondrial damage, it recruits parkin to get the process of mitophagy underway.

NINDS researchers are exploring ways to stimulate the PINK1/parkin pathway to encourage mitophagy. Scientists hope this will help them develop treatments for people with mitochondrial diseases, including certain forms of PD. Additionally, NINDS researchers are screening chemicals to identify agents that may be able to stimulate the expression of PINK1, and looking for other genes that may affect the functions of PINK1 and parkin.

Evidence suggests that parkin is a factor in several additional pathways leading to PD, including sporadic forms of the disease associated with alpha-synuclein toxicity.

The PARK7 gene encodes for the protein DJ-1. Several mutations in the gene for DJ-1 are associated with some rare, early-onset forms of PD. The function of the DJ-1 gene remains a mystery. However, one theory is it can help protect cells from oxidative stress. Oxidative stress occurs when unstable molecules called free radicals accumulate to levels that can damage or kill cells. Some studies suggest that the DJ-1 gene strengthens the cells&rsquo ability to protect against metal toxicity and that this protective function is lost in some DJ-1 mutations. Animal studies suggest DJ-1 plays a role in motor function and helps protect cells against oxidative stress.

Mutations in the gene encoding the lysosomal enzyme beta-glucocerebrosidase (GBA) are associated with a lysosomal storage disorder, Gaucher&rsquos disease. People with Gaucher&rsquos disease are also more likely to have parkinsonism, a group of nervous disorders with symptoms similar to Parkinson's disease. This has spurred investigators to look for a possible link between the two diseases. NIH-funded researchers have conducted studies of individuals with both disorders to assess their brain changes, family histories, and to screen tissues and DNA samples, which have helped confirm this link.

An NIH-led, multicenter study involving more than 10,000 people with and without PD showed that people with PD were more than 5 times more likely to carry a GBA mutation than those without the disease. Mutation carriers also were more likely to be diagnosed with PD earlier in their lives and to have a family history of the disease. Scientists have observed that depletion of beta-glucocerebrosidase results in alpha-synuclein accumulation and neurodegeneration.

Further research is needed to understand the association between GBA gene mutations and PD. The NINDS supports many lines of research investigating the role of GBA gene mutations. Projects are aimed at estimating the risk of PD associated with being a GBA carrier and identifying the phenotypic traits.

Studying the genes responsible for inherited cases of PD can help shed light on both inherited and sporadic cases of PD. The same genes and proteins that are altered in inherited cases of PD may play a role in sporadic cases of the disease. In some cases genetic mutations may not directly cause PD but may increase the susceptibility of developing the disease, especially when environmental toxins or other factors are present.

Cellular and Molecular Pathways to PD

What happens in a person&rsquos brain that causes him or her to develop PD? To answer this question scientists are working to understand the cellular and molecular pathways that lead to PD.

Mitochondrial Dysfunction

Research suggests that damage to mitochondria plays a major role in the development of PD. Mitochondria are unique parts of the cell that have their own DNA entirely separate from the genes found in the nucleus of every cell.

Mitochondrial dysfunction is a leading source of free radicals &mdash molecules that damage membranes, proteins, DNA, and other parts of the cell. Oxidative stress is the main cause of damage by free radicals. Oxidative stress-related changes, including free radical damage to DNA, proteins, mitochondria, and fats has been detected in the brains of individuals with PD. A number of the genes found to cause PD disturb the process by which damaged mitochondria are disposed of in the neuron (mitophagy).

To learn more about how the process of mitophagy relates to PD, scientists have turned to RNA interference (RNAi), a natural process occurring in cells that helps regulate genes. Scientists are able to use RNAi as a tool to turn off genes of interest to investigate their function in cultured cells or animal models of PD. A technique known as high-throughput RNAi technology enabled NIH scientists to turn off nearly 22,000 genes one at a time. This process helped scientists identify dozens of genes that may regulate the clearance of damaged mitochondria. Researchers continue to study how these genes regulate the removal of damaged mitochondria from cells and the genes identified in this study may represent new therapeutic targets for PD.

One mechanism that helps regulate the health of mitochondria is autophagy, which allows for the breakdown and recycling of cellular components. Scientists have long observed that disruptions in the autophagy processes are associated with cell death in the substantia nigra and the accumulation of proteins in the brains of people with PD as well as other neurodegenerative diseases.

Ubiquitin-proteasome System

Another area of PD research focuses on the ubiquitin-proteasome system (UPS), which helps cells stay healthy by getting rid of abnormal proteins. A chemical called ubiquitin acts as a &ldquotag&rdquo that marks certain proteins in the cell for degradation by proteasomes, structures inside cells that launch chemical reactions that break peptide bonds. Researchers believe that if this disposal symptom fails to work correctly, toxins and other substances may accumulate to harmful levels, leading to cell death. Impairment of the UPS is believed to play a key role in several neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's diseases.

The contribution of UPS to the development of PD appears to be multifactorial, meaning UPS influences the interactions of several genes. NINDS-funded researchers have found that UPS is critical for the degradation of misfolded alpha-synuclein in cells. Conversely, evidence suggests that abnormal or misfolded alpha-synuclein may also inhibit the proper functioning of UPS. A feedback loop may exist whereby abnormal alpha-synuclein inhibits the functions of UPS, causing more abnormal alpha-synuclein to accumulate and additional suppression of UPS activity. NINDS-funded researchers have also identified proteins that accumulate in the absence of parkin that contribute to the loss of dopaminergic neurons.

Several NINDS-funded investigators are exploring ways of enhancing UPS function as a potential therapeutic strategy.

Cell-to-cell Transmission of Abnormally-folded Proteins

Researchers have learned more about how PD-related damage spreads to various parts of the brain and nervous system. A characteristic pattern has emerged by which Lewy bodies are distributed in various regions of the brain. The earliest brain changes appear to involve Lewy bodies in the brain stem region (medulla oblongata and pontine tegmentum, as well as the olfactory bulb).

Braak staging is a six-tier classification method used to identify the degree of postmortem pathology resulting from PD. According to this classification, people in Braak stages 1 and 2 are generally thought to be presymptomatic. As the disease advances to Braak stages 3 and 4, Lewy bodies spread to the substantia nigra, areas of the midbrain, the basal forebrain, and the neocortex.

More recent evidence suggests that even before such brain changes have occurred, alpha-synuclein aggregates and Lewy bodies can be found in the nervous system of the gastrointestinal tract and in the salivary glands, a finding that supports the theory that PD many originate not in the brain but in the autonomic nervous system. Non-motor symptoms such as constipation may in fact be a sign of the disease affecting nerves outside the brain before the disease moves into the brain where it later affects regions that control movement.

Researchers at the Udall Center at the Perelman School of Medicine of the University of Pennsylvania injected mice with a synthetic form of abnormal alpha-synuclein and found that misfolded alpha-synuclein appeared to spread throughout the brain. The researchers hypothesize that the injected abnormal alpha-synuclein may act like a seed that triggers the mouse&rsquos own alpha-synuclein to misfold, leading to a cell-to-cell transmission of PD-like brain changes, especially in regions of the brain important for motor function. The mice also exhibited PD-like motor symptoms.

Understanding more about how abnormal proteins spread through the nervous system may provide a potential window for a therapeutic strategy that interrupts the process of protein transmission and slows or halts disease progression. For example, NINDS-funded investigators are looking at immune therapy and antibodies or immunization against alpha-synuclein, to block PD transmission in the brains of mice.

Environmental Influences
Environmental circumstances are thought to impact the development of PD. Exposure to certain toxins may have a direct link to the development of PD. This was the case among people exposed to MPTP, a by-product accidentally produced in the manufacture of a synthetic opioid with effects similar to morphine. During the 1980s, street drugs contaminated with this substance caused a syndrome similar to PD. MPTP is also structurally similar to some pesticides. The brain converts MPTP into MPP+, which is toxic to substantia nigra neurons. MPP+ exposure produces severe, permanent parkinsonism and has been used to create animal models of PD.

In other cases, exposure to the metal manganese among those with working in the mining, welding, and steel industries has been associated with an increased risk of developing parkinsonism. Some evidence suggests that exposure to certain herbicides such as paraquat and maneb increase the risk of PD. Scientists believe that there are other yet-to-be identified environmental factors that play a role in PD among people who are already genetically susceptible to developing the disease.

The National Institute of Environmental Health Sciences ( NIEHS ) is the lead institute at the NIH investigating the association between PD and environmental influences such as pesticides and solvents as well as other factors like traumatic brain injury. For example, NIEHS is funding a project at the University of Washington aimed at developing and validating biomarkers to identify early-stage neurological disease processes associated with toxic agents such as chemicals, metals, and pesticides. Animal models are being developed to study the impact of pesticides on farmworkers and metals on professional welders.

The NIEHS also funds the Parkinson&rsquos, Genes & Environment study. The study is designed to determine the role genes as well dietary, lifestyle, and environmental factors play on the risk for developing PD and their potential to cause the illness. The more than 500,000 study participants were originally recruited in 1995 as part of the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study. Researchers will continue to follow participants over time to address some of the most interesting theories about the causes of PD. Already they have found, for example, that people who consume low levels of healthy dietary fats, such as those from fish, or high levels of saturated fats are more vulnerable to developing PD after being exposed to neurotoxins such as pesticides. The findings need to be confirmed, however, they suggest the possibility that diets rich in healthy fats and low in saturated fats may reduce the risk of PD.

The development of PD is a complex interplay between environmental, genetic, and lifestyle factors. Scientists are increasingly aware that in any given individual, there may be multiple factors that cause the disease.

In some cases, environmental factors may also have a protective effect. Population-based studies have suggested, for example, that people with high levels of vitamin D in their blood have a much lower risk of developing PD compared with people with very low concentrations of vitamin D. Further research is need to determine if vitamin D deficiency puts people at higher risk for PD, but such findings suggest the possibility that vitamin D supplements may have a beneficial effect. However, there may be genetic factors that cause people with low vitamin D levels to have higher rates of PD in which case vitamin D supplements would not be helpful.

To answer to this question, researchers at the Udall Center at the University of Miami are examining the pharmacogenetics of vitamin D. The investigators are studying a large dataset to confirm the finding that low levels of vitamin D is a risk factor for PD. At the same time, they are trying to identify any potential genetic modifiers of vitamin D&rsquos effect on PD risk.

Certain drugs and chemicals available as a supplement or in a person&rsquos diet also have been shown to have a neuroprotective effect for PD and other disorders. For example, regular use of caffeine (coffee, tea) was found to reduce the loss of dopamine-producing neurons. Studies hope to define the optimal caffeine dose in treating movement disorders like PD while gaining a better understanding of the mechanisms involving caffeine&rsquos benefit. Uric acid, because of its antioxidative effect, may lower the risk for multiple neurodegenerative disorders, in particular, PD. A preliminary clinical trial funded by the Michael J. Fox Foundation examined the effectiveness of the drug inosine to safely raise uric acid levels and possibly slow the progression of Parkinson&rsquos disease.

Neuroinflammation is a protective biological response designed to eliminate damaged cells and other harmful agents in nervous system tissue. Mounting evidence suggests that neuroinflammation plays a role in PD. Several lines of research funded by the NINDS are investigating this connection.

Compared to people without PD, those with PD tend to have higher levels of pro-inflammatory substances known as cytokines in their cerebrospinal fluid. Immune cells in the brain called microglia also are more likely to be activated in the brains of individuals with PD. Epidemiological studies suggest that rates of PD among people who frequently use non-steroidal anti-inflammatory drugs (NSAIDS) are lower than in those who do not use NSAIDS.

Evidence from animal studies also suggests that elevated levels of the protein alpha-synuclein may trigger microglia to become activated in the brains of people with PD.

Currently, scientists are investigating whether inflammation itself is a cause of brain cell death or if it is a response to an already occurring process that contributes to the development of a disease. If researchers can interrupt the neuroinflammatory processes, they may be able to develop neuroprotective treatments for people with PD that prevent or slow the progression of the disease by halting, or at least reducing, the loss of neurons.

Models for Studying PD
Much of the research advancing our understanding and treatment of PD would not be possible without research models &mdash yeast, fruit flies, worms, fish, rodents, and non-human primates &mdash that have specific characteristics that mimic PD biology in humans. Scientists depend on these models to investigate questions about what goes wrong in PD, how cellular processes fit into the context of neuronal circuits, and how potential new treatments affect these disease processes.

The NINDS supports ongoing studies at the Udall Centers and elsewhere to refine existing research models and develop new ones. Better models are needed to more accurately mimic human disease in animals and to study PD&rsquos mechanisms and potential treatments. Currently, none of the models express all the key pathologic features of PD or reflect the complement of clinical motor and non-motor features of the disease in humans.

In addition to creating new animal models, NINDS-funded researchers also look for ways of combining different types of models (i.e., genetic and toxin-induced) to better understand the interplay between genetic and environmental factors that contribute to the development of PD.

Genetic Models
The identification of genetic mutations among some families with hereditary forms of PD led to the development of animal models (rodent, non-human primate, worm, and fly) engineered to have mutations or deletions of PD genes. Each model has its strengths and shortcomings in helping researchers study the disease.

For example, mice with SNCA mutations develop an adult-onset degenerative disease characterized by movement dysfunction and aggregation of alpha-synuclein, but these mice have no loss of dopaminergic neurons. Other mice have been engineered to express LRRK2 mutations, but show little evidence of PD symptoms. Fruit flies and worms engineered to overexpress LRRK2 exhibit reductions in motor abilities and loss of dopamine neurons, but they do not adequately reflect the disease as it occurs in humans.

Scientists have developed numerous models aimed at interrupting key cellular functions known to play a role in PD. For example, the MitoPark mouse model disrupts the functioning of the mitochondria, leading to some PD-like motor symptoms that respond to levodopa treatment.

Toxin-induced Models
For decades, the most widely used models for studying PD involved those in which toxins were used to induce PD-like motor symptoms. Such models were used to evaluate potential therapies. The first toxin-induced models relied on MPTP or the neurotoxin 6-hydroxydopamine to kill dopamine-producing neurons in the substantia nigra, causing PD-like motor symptoms. Later, researchers developed another type of model that examined how toxins interfered with the activities of mitochondria. Toxins for this purpose included the pesticide rotenone and the herbicides paraquat and maneb. Rats exposed to such toxins develop large inclusions in substantia nigra neurons that resemble Lewy bodies and contain alpha-synuclein and ubiquitin. The animals also developed bradykinesia, rigidity, and gait problems. Such toxin models are helpful for studying the consequences of dopamine depletion. However, they are limited in their ability to model the all the factors that cause PD in humans.

Induced Pluripotent Stem Cells
Genetic engineering is another mechanism for modeling some of the processes that go wrong in PD. Recently scientists developed a breakthrough modeling mechanism using induced pluripotent stem cells (iPSCs), which are cells that can become any type of cell in the body. Researchers take samples of skin, blood, hair follicles, or other types of tissue from a person with PD and then manipulate those cells to become iPSCs. These cells are then programmed to become dopaminergic neurons, making it possible for scientists to study the molecular and cellular mechanisms that lead to PD as well as potential treatments. NIH-funded researchers have also coaxed iPSCs to become tissue from other parts of the body such as the gastrointestinal tract and the heart, allowing them to study the mechanisms of PD in other regions of the body.

NINDS-funded researchers at the Udall Center at Johns Hopkins University have used iPSCs from people with PD as well as presymptomatic people who carry PARK6 or LRRK2 genetic mutations to develop brain cells to study specific aspects of mitochondrial functioning. They also are testing potential ways of intervening to reverse mitochondrial dysfunction.

The ability to create neurons or other cell types from an individual with PD presents the possibility of providing a personalized treatment approach. iPSC-derived neurons may prove useful for testing the effectiveness of a drug before giving it to people with PD.

The NINDS created and supports an open-access repository of iPSCs from people who have genetic mutations associated with PD. Specimens in the repository are collected and characterized by a team of collaborating researchers at seven major institutions participating in the Parkinson&rsquos iPSC Consortium. The iPSCs are available through the NINDS Repository for researchers to study the causes of PD, as well as to screen potential drug therapies.


Cohort demographics

Table 1 describes the demographics of the EMR and Claims based cohorts, stratified by the PD case status. The EMR dataset contained records from 22,102 individuals, while the Claims dataset contained records from 28,216 individuals. Age of first diagnosis was slightly higher in the Claims cohort but was over 70 in both datasets. Our cohorts align with accepted estimates of PD incidence in the population [26]. Population statistics between cases and matched controls largely align between the EMR and Claims data though the latter population is slightly younger (owing to the transfer of individuals above 65 to Medicare) and has more extended terms of coverage due to the nature of the data sources. EMR records only capture an individual’s interactions with that particular hospital system, while claims records capture all of an individual’s paid interactions while they were insured.

Parkinson’s disease trajectory is characterized by a prodromal period

We began by constructing two prediction algorithms, one linear and one non-linear, for future PD diagnosis utilizing 2 years of observations prior to the PD diagnosis in cases and matched controls. In contrast to prior models, we sequentially compared different time periods before the PD diagnosis date. We found a significant spike in prediction accuracy as the size of this window was reduced, which reached a maximum immediately prior to the PD diagnosis (Fig. 1a, b). We found that the accuracy of the deep neural network and a logistic regression model trained on identical claims data converged as the diagnosis date approached, implying that the most relevant signal for that time period was additive, with linear relationships between clinical events (diagnoses and procedures) driving predictions of PD status. In contrast, prediction accuracy at earlier time points appeared to be driven by non-linear, complex relationships between factors that only neural networks could resolve. The increase in performance closer to PD diagnosis date by both prediction models indicated the existence of a pre-diagnostic window during which motor symptoms were present but the diagnosis had not yet been made. Clinicians have described a time period immediately prior to diagnosis ranging between 3 months to 1 year [19] where PD is suspected and the patient is referred to neurologists or subjected to more rigorous clinical evaluation before a formal PD diagnosis is rendered. Consequently, the strong performance of classifiers that include this period may be illusory: the models draw signal from the actions of clinicians who already suspect PD. We find that the dominant features of this window include diagnoses of abnormality of gait, as well as diagnoses corresponding to tremor disorders (abnormal involuntary movements, essential tremor) (Table 2), which likely represent proxy diagnoses for PD prior to a neurologist or specialist confirming the diagnosis. Other features represent traditional, well-known, prodromal features of PD such as depression and constipation while others are less traditional such as malaise and fatigue, pain, and type 2 diabetes. To take advantage of these observations, we sought to construct models using diagnoses represented in Table 2 as new engagement points for deploying prediction models to then enable accelerated diagnosis of PD. We specifically selected gait and tremor disorders for the first set of engagement or index points for future analysis due to their comparatively extreme odds ratios. However, the remaining diagnoses, either alone or in combination, represent alternative points that could have been chosen.

Area under the ROC Curve predicting PD onset at various points prior to PD diagnosis. a Logistic Regression vs. Neural Network in Claims b EMR vs. Claims Logistic Regression

Gait and tremor disorders highlight PD differential diagnostic window

In order to better characterize the predictive implications and utility of this pre-diagnostic window, we examined the rates of different diagnoses relative to the PD diagnosis date corresponding to select phenotypes (Fig. 2): gait disorders, tremor disorders, constipation (a known prodromal symptom of PD), as well as a clinical event with little if any known physiological connection to PD: breast cancer screening (Supplementary Table 2). It was hypothesized that, after controlling for gender, the frequency of this clinical event among PD and non-PD patients would be roughly equivalent. Gait and tremor diagnoses were chosen based on their strength of association and the presence of sufficient patients to create PD classifiers indexed to their first diagnosis point. In the case of constipation, we found elevated rates of diagnosis prior to the PD diagnosis date, that steadily rise prior to and post PD diagnosis. A small spike at PD diagnosis is likely due to increased documentation at this critical inflection point in care. In contrast, constipation among PD controls increases more gradually over the whole window but is agnostic to the baseline date itself. This behavior is consistent with constipation’s role as a symptom of PD. Breast cancer testing, a test performed as a part of the standard of care, showed little variance between PD cases and controls throughout the entire window, consistent with the lack of evidence for a physiological association to PD. We find that gait and tremor disorders among PD cases slowly diverge from controls until a large spike approximately 1 year prior to the PD diagnosis and fall off in the years post diagnosis, likely due to their replacement with a PD code. This suggests that gait and tremor diagnoses are being used as proxy diagnoses in the runup to the PD diagnosis, consistent with the presence of a pre-diagnostic window.

Frequency of phenotypes relative to PD diagnosis date (cases)/matched baseline date (controls). Each point represents the frequency of the phenotype among the population in the year defined at the point: a tremor frequency of 0.08 at day 730 implies that 8.0% of PD cases had a tremor diagnosis between 730 and 365 days prior to their PD diagnosis. The data in subfigures represent the population diagnosed with a (a) gait disorder, b tremor disorders, c constipation, or d breast cancer testing. Details of the ICD/CPT codes associated with each subfigure are presented in Supplementary Table 2

Predicting Parkinson’s disease progression from first gait/tremor diagnosis

Based on the importance of gait and tremor diagnoses in the prediagnostic models and the above finding that they are widely used as proxies for a PD diagnosis, we constructed three new cohorts where baseline classification dates were defined as i) the diagnosis of first gait or tremor disorder, ii) the first diagnosis of gait disorder only, and iii) the first diagnosis of tremor disorder only. In all three cases, all subjects were gait/tremor naive prior to their baseline. Two years of features for each subject prior to the baseline were collected. The shift from a predictor based on a case-control study to a cohort study is useful in several ways. Not only are cohort studies considered a higher level of evidence [21], but the presence of a well-defined entry date allows for deployment of a predictor in clinical workflow. We used identical model architectures/parameters (both neural network and penalized logistic regression) for gait and tremor indexed models as for prediagnostic models (Fig. 1). The primary difference was the selection of the baseline point: a point in the future for the prediagnostic models, compared to a point at present for the gait/tremor models. We find that as the models are directed to focus on more specific cohorts, accuracy declines, in both claims and EMR, as well as between both logistic regression and deep neural network-based models (Table 4). The feature importance of both models trained on both data sources showed strong correlation (Pearson correlation of 0.71) between individual feature odds ratios. Furthermore, the logistic regression model trained over EMR generalized to the external Claims population with an AUC of 0.701 (95% CI: 0.698–0.704). The strongest predictor for future PD diagnosis for all three (gait or tremor, gait only, tremor only) cohorts was bipolar disorder (Table 4A, Supplementary Tables 3–4), an association that has been highlighted by other epidemiologic studies [27]. It is important to note that many Bipolar treatments (antipsychotic medications, valproic acid) are known to cause secondary Parkinsonism, which may be a reason underlying the high observed odds ratio. However, overall, the impact of bipolar on the accuracy of the model is low given the small affected population, with 2.6% of those eventually being diagnosed with PD. Other identified features align with what has previously been documented as potential risk factors for PD including major depressive disorder [28] and voice disturbance [29]. Progression into PD from gait disorders only was uniquely defined by a history of features such as urinary tract infection and chronic laryngitis, while progression from tremor disorders only was uniquely defined by parasomnia. While both gait and tremor are known to be early symptoms of PD, the distinction that the presence of these additional diagnoses may contribute towards risk in these cohorts and may indicate differences between two subsets of disease.

We examined the strongest performing model (Table 3A), the neural network predicting PD progression from either first gait or tremor in more depth (Tables 3B and 4). For this model, we examined the average days-in-advance that the model predicted PD for individuals who truly went on to experience a PD diagnosis on record at various false positive rate (FPR) thresholds. While the mean days saved declined slightly as the FPR threshold was increased, the average was still in excess of 300 days with an FPR rate of 0.01. This indicates that model performance is not dominated by individuals who immediately go on to develop PD after a gait or tremor diagnosis, and that among this selective cohort, early diagnosis is feasible.

Upon review of the results, we highlighted sets of diagnoses that were significantly different between the first prediagnostic model and the gait and tremor cohort model (Table 4B). In particular, the odds ratio directionality of anemia and hypotension reversed when evaluated in the presence of first gait/tremor, meaning that these diagnoses were no longer predictive of future PD. Similarly, while constipation is a known symptom of prediagnostic PD [26], it is less useful at predicting who will progress to PD from gait/tremor than in the original cohorts. These results suggest that distinct trajectories into PD may be present, including trajectories characterized by gait or tremor disorders. Further analysis motivated by these findings, outside the scope of this article, may be warranted to evaluate differential subtypes prior to a PD diagnosis. These findings also suggest that the controls defined in gait/tremor indexed cohorts represent a distinct population from traditionally defined PD controls, and that the true real-world PD progression prediction task is sensitive to the particular comparisons that a clinician is making.


PD is a multifactorial disease, with both genetic and environmental factors playing a role. Age is the biggest risk factor for PD, with the median age of onset being 60 years of age (15). The incidence of the disease rises with age to 93.1 (per 100,000 person-years) in age groups between 70 and 79 years (16, 17). Additionally, there are cross-cultural variations, with higher prevalence reported in Europe, North America, and South America compared with African, Asian and Arabic countries (1).

Cigarette smoking

Cigarette smoking has been extensively studied with respect to PD, with mostly consistent results. Most of the epidemiological reports are case-control studies showing a reduced risk of developing PD, with larger cohort studies also in agreement (18�). A large meta-analysis including 44 case-control studies and 8 cohort studies from 20 countries showed an inverse correlation between smoking and PD, with a pooled relative risk of 0.39 for current smokers (21). Two other meta-analyses also reported an inverse correlation between smoking and PD, with a pooled odds ratio ranging from 0.23 to 0.70, indicating a protective mechanism against PD (22, 23). They also reported an inverse correlation between the number of pack years, the number of years smoking and the risk of PD, with the risk of developing PD being significantly reduced in heavy or long-term smokers compared with nonsmokers (23).

The reasons underlying this associated reduced risk are not fully understood. Activation of nicotinic acetylcholine receptors on dopaminergic neurons by nicotine or selective agonists has been shown to be neuroprotective in experimental models of PD (24, 25). Nevertheless, nicotine can also stimulate the release of dopamine, which is involved in the reward mechanisms it is therefore difficult to confirm whether smoking prevents PD or whether PD helps prevent the habitual use of cigarettes. As a result of a reduction in dopamine in patients with PD, patients may be less prone to addictive behaviours, and thus less likely to smoke. This hypothesis is supported by the fact that patients with prodromal PD and PD were able to give up smoking much easier than controls, suggesting this association could be due to the decreased responsiveness to nicotine (26).


Several studies have investigated the effect of caffeine on the development of PD and reported a reduced risk of developing PD among coffee drinkers. Caffeine is an adenosine A2A receptor antagonist, which is believed to be protective in PD (27) and has been shown to be neuroprotective in a mouse model of PD (28). It has been previously reported that there is a 25% risk reduction in developing PD among coffee drinkers (14). Two large prospective epidemiological studies (27, 29), as well as multiple retrospective studies (30), have also shown a reduced risk of developing PD with a relative risk ranging from 0.45 to 0.80 in coffee drinkers versus non-coffee drinkers. A meta-analysis including eight case-control studies and five cohort studies also showed a significantly reduced risk of developing PD in coffee drinkers (RR 0.69) (21). Regular tea drinkers also have been reported to have a lower risk of developing PD (29).

As with smoking, the causative role of caffeine in preventing PD remains to be established. Furthermore, there were differences noted between studies with respect to gender. In two cohort studies (27, 29), there was a strong inverse correlation between coffee and the development of PD in men, whereas in women this association was weaker. Additionally, in post-menopausal women, the effect of caffeine depended on whether the females were taking hormone replacement therapy including estrogens. As estrogen competitively inhibits caffeine metabolism, interactions between estrogen and caffeine may explain in part why PD risk is dependent on hormone replacement therapy in post-menopausal women (31, 32).

Pesticides, herbicides, and heavy metals

In 1983, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was first discovered to be associated with nigrostriatal degeneration when several people developed typical PD signs after injecting themselves with a drug contaminated with MPTP. MPTP is metabolized into the neurotoxin, MPP+ (1-methyl-4-phenylpyridinium), which is a mitochondrial complex-I inhibitor that selectively damages dopaminergic cells in the substantia nigra (32, 33). The identification of MPTP as a cause of nigral degeneration led to the idea that PD could be caused by an environmental toxin. Since then, several studies have shown an association between pesticides and PD, with one case-control study showing an increased association with professional pesticide exposure in men and late-onset PD (odds ratio [OR] 2.2) (34). Paraquat (a herbicide which is structurally very similar to MPP+) (35) and rotenone (a pesticide) are also selective complex-I inhibitors and induce dopaminergic depletion in animal models of PD (36). The relationship between exposure to these chemicals and the risk of developing PD has been investigated in other epidemiological studies (37). It has also led to the study of surrogate markers, including the association of farming, drinking well water, and living in rural areas with PD risk. Welding and heavy metal exposure (e.g., iron, copper, lead, aluminum, and zinc) have also been investigated, but the relationship between these and PD remains inconclusive.


Although PD is generally an idiopathic disorder, there is a minority of cases (10�%) that report a family history, and about 5% have Mendelian inheritance (38). Furthermore, an individual’s risk of PD is partially the product of as-yet poorly defined polygenic risk factors. The genes that have been found to potentially cause PD are assigned a “PARK” name in the order they were identified. To date, 23 PARK genes have been linked to PD. Mutations in the PARK genes demonstrate either autosomal dominant (e.g., SCNA, LRRK2, and VPS32) or autosomal recessive inheritance (e.g., PRKN, PINK1, and DJ-1) and are summarized in Table 1. The involvement of some of these genes has not been conclusively confirmed (PARK5, PARK11, PARK13, PARK18, PARK21, and PARK23), while others are considered risk factors (PARK3, PARK10, PARK12, PARK16, and PARK22) (39).

Table 1

PARK-designated genes involved in familial Parkinson’s disease.

The numerically most important genetic risk factors predisposing to PD are mutations in GBA1, a gene encoding β-glucocerebrosidase𠅊 lysosomal enzyme responsible for the hydrolysis of glucocerebrosides (see Chapter 3) (40). GBA1 mutations are known to cause Gaucher disease, which is the most common lysosomal storage disorder (41). Other genetic risk factors include the major histocompatibility complex, class II (HLA-DQB1) (42) and the gene encoding the protein tau, MAPT (43), among others.

Autosomal dominant PD

The first type of familial PD caused by a point mutation in the α-synuclein gene (SNCA) was discovered in 1997 (44). Four additional point mutations, as well as gene duplication or triplication, have now been linked to autosomal dominant PD (45�). However, these mutations are relatively rare. The most frequent autosomal dominant monogenic PD is caused by mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2). Six LRRK2 mutations have been confirmed as pathogenic (51), the most common of which is p.G2019S, estimated to account for 1% of sporadic and 4% of familial PD worldwide (51). More recent genetic studies have led to the discovery of additional mutations in other genes responsible for autosomal dominant PD, including VPS35 (Table 1).

Autosomal recessive PD

Autosomal recessive forms of PD typically present with an earlier onset than classical PD. Three of the PARK-designated genes causing autosomal recessive PD have been linked to mitochondrial homeostasis (PRKN, PINK1, and DJ-1). Specifically, the proteins PINK1 and parkin (encoded by the PRKN gene) are both involved in the same mitochondrial quality control pathway, with PINK1 recruiting parkin to dysfunctional mitochondria and thus initiating mitophagy (52). Mutations in PRKN are the most common cause of autosomal recessive familial PD, occurring in up to 50% of all early-onset cases (39). Finally, several of the autosomal recessive genes have been linked to atypical parkinsonism with variable features (Table 1), including ATP13A2 (PARK9), PLA2G6 (PARK14), FBX07 (PARK17), and SYNJ1 (PARK20) (53�).


Tremors are classified as either resting or action (Table 1) .8 A rest tremor occurs in a body part that is relaxed and completely supported against gravity (e.g., when resting an arm on a chair). It is typically enhanced by mental stress (e.g., counting backward) or movement of another body part (e.g., walking), and diminished by voluntary movement of the affected body part.3 , 9 , 10 Most tremors are action tremors, which occur with voluntary contraction of a muscle. Action tremors can be further subdivided into postural, isometric, and kinetic tremors.8 , 9 A postural tremor is present while maintaining a position against gravity. An isometric tremor occurs with muscle contraction against a rigid stationary object (e.g., when making a fist). A kinetic tremor is associated with any voluntary movement and includes intention tremor, which is produced with target-directed movement.2

Broad Classification of Tremor

Occurs with voluntary contraction of muscle

Includes postural, isometric, and kinetic tremors

Occurs when the body part is voluntarily maintained against gravity

Includes essential, physiologic, cerebellar, dystonic, and drug-induced tremors

Occurs with any form of voluntary movement

Includes classic essential, cerebellar, dystonic, and drug-induced tremors

Subtype of kinetic tremor amplified as the target is reached

Presence of this type of tremor implies that there is a disturbance of the cerebellum or its pathways

Occurs in a body part that is relaxed and completely supported against gravity

Most commonly caused by parkinsonism, but may also occur in severe essential tremor

Adapted with permission from Leehey MA. Tremor: diagnosis and treatment . Primary Care Case Rev . 20014:34 .

Broad Classification of Tremor

Occurs with voluntary contraction of muscle

Includes postural, isometric, and kinetic tremors

Occurs when the body part is voluntarily maintained against gravity

Includes essential, physiologic, cerebellar, dystonic, and drug-induced tremors

Occurs with any form of voluntary movement

Includes classic essential, cerebellar, dystonic, and drug-induced tremors

Subtype of kinetic tremor amplified as the target is reached

Presence of this type of tremor implies that there is a disturbance of the cerebellum or its pathways

Occurs in a body part that is relaxed and completely supported against gravity

Most commonly caused by parkinsonism, but may also occur in severe essential tremor

Adapted with permission from Leehey MA. Tremor: diagnosis and treatment . Primary Care Case Rev . 20014:34 .


The most common pathologic tremor is essential tremor. In one-half of cases, it is transmitted in an autosomal dominant fashion, and it affects 0.4 to 6 percent of the population.4 , 8 Careful history reveals that patients with essential tremor have it in early adulthood (or sooner), but most patients do not seek help for it until 70 years of age because of its progressive nature. Despite being sometimes called �nign essential tremor,” essential tremor often causes severe social embarrassment, and up to 25 percent of those afflicted retire early or modify their career path.8

Essential tremor is an action tremor, usually postural, but kinetic and even sporadic rest tremors have also been described.3 , 11 It is most obvious in the wrists and hands when patients hold their arms in front of themselves (resisting gravity) however, essential tremor can also affect the head, lower extremities, and voice.12 It is generally bilateral, is present with a variety of tasks, and interferes with activities of daily living.1 , 5 In a series of 200 Italian patients referred to a neurologist for evaluation of tremor, 15 percent had uncommon clinical features that included postural, action, rest, orthostatic, and writing tremors, and 10 percent had tongue or facial dyskinesia.13

Diagnostic criteria have been proposed, but none have been accepted universally. Persons with essential tremor typically have no other neurologic findings therefore, it is often considered a diagnosis of exclusion.12 If the tremor responds to a therapeutic trial of alcohol consumption (two drinks per day), the diagnosis of essential tremor is assured.


Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia, rigidity, and postural instability. Many patients will also have micrographia, shuffling gait, masked facies, and an abnormal heel-to-toe test.10 , 14 – 16 Causes of parkinsonism include brainstem infarction, multiple system atrophy, and medications that block or deplete dopamine, such as methyldopa, metoclopramide (Reglan), haloperidol, and risperidone (Risperdal).9 , 10 Idiopathic Parkinson disease is a chronic neurodegenerative disorder its prevalence increases with age. It is the most common cause of parkinsonism.17

More than 70 percent of patients with Parkinson disease have tremor as the presenting feature. The classic parkinsonian tremor begins as a low-frequency, pill-rolling motion of the fingers, progressing to forearm pronation/supination and elbow flexion/extension. It is typically asymmetric, occurs at rest, and becomes less prominent with voluntary movement. Although rest tremor is one of the diagnostic criteria for Parkinson disease, most patients exhibit a combination of action and rest tremors.3 , 11


A physiologic tremor is present in all persons. It is a low-amplitude, high-frequency tremor at rest and during action that is not reported as symptomatic. This tremor can be enhanced by anxiety, stress, and certain medications and metabolic conditions. Patients with a tremor that comes and goes with anxiety, medication use, caffeine intake, or fatigue do not need further testing.1 , 8

Drug Treatment of Tremor


Treatment of Parkinson's disease includes both medical and surgical intervention. Dopamine replacement therapy by means of levodopa clearly revolutionized the treatment of Parkinson's disease. Levodopa is almost exclusively given in combination with the peripheral decarboxylase inhibitor carbidopa (Sinemet). Carbidopa blocks the peripheral metabolism of levodopa to dopamine, decreasing the peripheral adverse effects of levodopa, such as nausea and vomiting, while increasing levodopa's availability in the brain.15 , 16 In addition to modulating the tremor associated with Parkinson's disease, levodopa improves bradykinesia, rigidity and other commonly associated symptoms. Carbidopa–levodopa is available in formulations of 10/100 mg, 25/100 mg and 25/250 mg. It is advantageous to begin treatment of mild disease with the 25/100-mg dosage, one tablet three times a day, and then increase the dosage as symptoms become less manageable.

When tremor is the predominant presenting symptom of Parkinson's disease or when tremor persists despite adequate control of other parkinsonian symptoms with low dosages of levodopa, an anticholinergic agent such as trihexyphenidyl (Artane) or benztropine (Cogentin) may be the treatment of choice. In most patients, however, anticholinergics do not significantly improve bradykinesia and rigidity. Trihexyphenidyl dosages necessary to improve tremor are between 4 and 10 mg per day (maximum: 32 mg), and useful benztropine dosages range from 1 to 4 mg per day. The side effects of these agents are their limiting factor, particularly in the elderly. Side effects include memory impairment, hallucinations, dry mouth, urinary difficulties and blurred vision.15

Other antiparkinsonian drugs𠅏or example, amantadine (Symmetrel), tolcapone (Tasmar) and dopamine agonists such as pergolide (Permax), bromocriptine (Parlodel), ropinirole (Requip) and pramipexole (Mirapex)𠅊re most helpful in patients whose tremor responds poorly to levodopa alone.


As with other tremors, effective treatment of essential tremor is not found in a single, universal agent. Some therapies may be satisfactory in some patients and ineffective in others. The most widely used drugs for essential tremor are the beta-adrenergic blocker propranolol (Inderal) and the anticonvulsant primidone (Mysoline). The typical dosage range for propranolol is 80 to 320 mg per day and for primidone, 25 to 750 mg per day.3 Other beta-adrenergic receptor antagonists used in the treatment of essential tremor include metoprolol (Lopressor) and nadolol (Corgard).2 Alcohol is also effective in relieving essential tremor, but abuse may be an adverse consequence.3

In our experience, propranolol and primidone are equally effective in the treatment of essential tremor. Patients who do not respond to one medication after a few weeks of therapy should be tried on the other one. Primidone may be preferred, because of the exercise intolerance associated with high-dose beta blockade. Patients who have a very-low-amplitude rapid tremor are generally more responsive to these agents than those who have a slower tremor with greater amplitude. Patients who have tremor of the head and voice may also be more resistant to treatment than patients with essential tremor of the hands.


There is no established treatment for cerebellar tremor.2 In patients with multiple sclerosis, severe cerebellar tremor may be improved with isoniazid, in a dosage of 600 to 1,200 mg per day, given together with pyridoxine.4

Propranolol in a dosage of 160 mg per day is very effective in reducing the tremor associated with alcohol withdrawal.10

Treatment of orthostatic tremor should first be attempted with clonazepam (Klonopin). In one small study,14 eight of nine patients responded to clonazepam in dosages ranging from 0.5 to 2.0 mg per day. The patient who did not respond to clonazepam responded to chlordiazepoxide (Librium), in a dosage of 30 mg twice a day. In another study,12 10 of 18 patients had sustained improvement with clonazepam, and valproic acid was effective in the remaining eight patients. However, propranolol in daily dosages of up to 320 mg had no effect on controlling orthostatic tremor.

Tremor due to peripheral neuropathy may be ameliorated with propranolol, primidone, benzodiazepines or baclofen (Lioresal), but the underlying cause of the neuropathy itself should be treated as well.2

Other medications have been shown to be helpful in the management of tremor but should probably only be tried in consultation with a neurologist, when the previously mentioned drugs have failed to control the tremor.

Motor symptoms in Parkinson's disease

This chapter reviews the pathophysiological mechanisms and the clinical features of motor manifestations of Parkinson's disease (PD). The most typical and easily recognized symptom of PD is unilateral, 4–6 Hz, rest tremor. This is differentiated from the typical 5–8 Hz postural tremor of essential tremor (ET), enhanced physiologic tremor (8–12 Hz), and cerebellar outflow tremor (2–5 Hz). The rest tremor characteristically disappears with action (a feature differentiating it from ET) and during sleep. Stimulation of the subthalamic nucleus (STN), which is typically hyperactive in PD, can also normalize the amplitude and frequency of PD tremor towards physiologic ranges. In PD, the rigidity is usually accompanied by a “cogwheel” phenomenon, probably a manifestation of underlying tremor. Rigidity often increases with reinforcing maneuvers such as voluntary movements of the contralateral limb. This examination technique can greatly assist in the diagnosis of early PD, as the rigidity is ipsilateral to the rest tremor, if present.


Parkinson's disease is a recognisable clinical syndrome with a range of causes and clinical presentations. Parkinson's disease represents a fast-growing neurodegenerative condition the rising prevalence worldwide resembles the many characteristics typically observed during a pandemic, except for an infectious cause. In most populations, 3–5% of Parkinson's disease is explained by genetic causes linked to known Parkinson's disease genes, thus representing monogenic Parkinson's disease, whereas 90 genetic risk variants collectively explain 16–36% of the heritable risk of non-monogenic Parkinson's disease. Additional causal associations include having a relative with Parkinson's disease or tremor, constipation, and being a non-smoker, each at least doubling the risk of Parkinson's disease. The diagnosis is clinically based ancillary testing is reserved for people with an atypical presentation. Current criteria define Parkinson's disease as the presence of bradykinesia combined with either rest tremor, rigidity, or both. However, the clinical presentation is multifaceted and includes many non-motor symptoms. Prognostic counselling is guided by awareness of disease subtypes. Clinically manifest Parkinson's disease is preceded by a potentially long prodromal period. Presently, establishment of prodromal symptoms has no clinical implications other than symptom suppression, although recognition of prodromal parkinsonism will probably have consequences when disease-modifying treatments become available. Treatment goals vary from person to person, emphasising the need for personalised management. There is no reason to postpone symptomatic treatment in people developing disability due to Parkinson's disease. Levodopa is the most common medication used as first-line therapy. Optimal management should start at diagnosis and requires a multidisciplinary team approach, including a growing repertoire of non-pharmacological interventions. At present, no therapy can slow down or arrest the progression of Parkinson's disease, but informed by new insights in genetic causes and mechanisms of neuronal death, several promising strategies are being tested for disease-modifying potential. With the perspective of people with Parkinson's disease as a so-called red thread throughout this Seminar, we will show how personalised management of Parkinson's disease can be optimised.