The Nervous System & Dopamine
To understand Parkinson’s, it is helpful to understand how neurons work and how PD affects the brain .
Nerve cells, or neurons, are responsible for sending and receiving nerve impulses or messages between the body and the brain. Try to picture electrical wiring in your home. An electrical circuit is made up of numerous wires connected in such a way that when a light switch is turned on, a light bulb will beam. Similarly, a neuron that is excited will transmit its energy to neurons that are next to it.
Neurons have a cell body with branching arms, called dendrites, which act like antennae and pick up messages. Axons carry messages away from the cell body. Impulses travel from neuron to neuron, from the axon of one cell to the dendrites of another, by crossing over a tiny gap between the two nerve cells called a synapse. Chemical messengers called neurotransmitters allow the electrical impulse to cross the gap.
Neurons talk to each other in the following manner :
Stage One Of Parkinsons Disease
In stage one, the earliest stage, the symptoms of PD are mild and only seen on one side of the body , and there is usually minimal or no functional impairment.
The symptoms of PD at stage one may be so mild that the person doesnt seek medical attention or the physician is unable to make a diagnosis. Symptoms at stage one may include tremor, such as intermittent tremor of one hand, rigidity, or one hand or leg may feel more clumsy than another, or one side of the face may be affected, impacting the expression.
This stage is very difficult to diagnose and a physician may wait to see if the symptoms get worse over time before making a formal diagnosis.
Stage Two Of Parkinsons Disease
Stage two is still considered early disease in PD, and it is characterized by symptoms on both sides of the body or at the midline without impairment to balance. Stage two may develop months or years after stage one.
Symptoms of PD in stage two may include the loss of facial expression on both sides of the face, decreased blinking, speech abnormalities, soft voice, monotone voice, fading volume after starting to speak loudly, slurring speech, stiffness or rigidity of the muscles in the trunk that may result in neck or back pain, stooped posture, and general slowness in all activities of daily living. However, at this stage the individual is still able to perform tasks of daily living.
Diagnosis may be easy at this stage if the patient has a tremor however, if stage one was missed and the only symptoms of stage two are slowness or lack of spontaneous movement, PD could be misinterpreted as only advancing age.
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Causes Of Motor Impairment In Pd
Role of dopamine. The principal brain area affected by PD is the substantia nigra, pars compacta , a vital part of the basal ganglia . This area is predominantly composed of neurons which secrete DA, an essential brain monoamine, which functions primarily as an inhibitory neurotransmitter. In healthy brain, DA regulates the excitability of striatal neurons, which are involved in controlling the balance of body movement. In PD, DA-neurons of SNpc degenerate, and DA levels are diminished . Inadequate DA levels cause less inhibition of the activity of striatal neurons, allowing them to fire excessively. This makes it difficult for PD patients to control their movements, leading to tremor, rigidity, and bradykinesia, the hallmarks of PD-associated motor symptoms .
Fig. 2
Neuronal circuits and neurotransmission mechanisms of control in the brains of normal individuals and those with Parkinsons disease. a: Neuronal circuit in basal ganglia in normal brain. b: Degeneration of substantia nigra pars compacta impairs cortico-striatal circuit in PD brain. Decrease in DA levels in the SNpc and striatum causes loss of control of striatal neuronal firing, leading to withdrawal of inhibitory effects on globus pallidus as well as thalamus, therefore, the thalamus becomes over-excitable, which activates the motor cortex excessively. This ultimately leads to impairment of motor coordination and causes Parkinsonism
What Treatments Are Available
Many Parkinson’s patients enjoy an active lifestyle and a normal life expectancy. Maintaining a healthy lifestyle by eating a balanced diet and staying physically active contributes to overall health and well-being. Parkinson’s disease can be managed with self-care, medication, and surgery.
Self careExercise is as important as medication in the treatment of PD. It helps maintain flexibility and improves balance and range of motion. Patients may want to join a support group and continue enjoyable activities to improve their quality of life. Equally important is the health and well being of the family and caregivers who are also coping with PD. For additional pointers, see Coping With Parkinsons Disease.
These are some practical tips patients can use:
Medications There are several types of medications used to manage Parkinson’s. These medications may be used alone or in combination with each other, depending if your symptoms are mild or advanced.
After a time on medication, patients may notice that each dose wears off before the next dose can be taken or erratic fluctuations in dose effect . Anti-Parkinsons drugs can cause dyskinesia, which are involuntary jerking or swaying movements that typically occur at peak dosage and are caused by an overload of dopamine medication. Sometimes dyskinesia can be more troublesome than the Parkinsons symptoms.
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Stage Three Of Parkinsons Disease
Stage three is considered mid-stage and is characterized by loss of balance and slowness of movement.
Balance is compromised by the inability to make the rapid, automatic and involuntary adjustments necessary to prevent falling, and falls are common at this stage. All other symptoms of PD are also present at this stage, and generally diagnosis is not in doubt at stage three.
Often a physician will diagnose impairments in reflexes at this stage by standing behind the patient and gently pulling the shoulders to determine if the patient has trouble maintaining balance and falls backward . An important clarifying factor of stage three is that the patient is still fully independent in their daily living activities, such as dressing, hygiene, and eating.
What Are The Surgical Treatments For Parkinsons Disease
Most patients with Parkinsons disease can maintain a good quality of life with medications. However, as the disease worsens, medications may no longer be effective in some patients. In these patients, the effectiveness of medications becomes unpredictable reducing symptoms during on periods and no longer controlling symptoms during off periods, which usually occur when the medication is wearing off and just before the next dose is to be taken. Sometimes these variations can be managed with changes in medications. However, sometimes they cant. Based on the type and severity of your symptoms, the failure of adjustments in your medications, the decline in your quality of life and your overall health, your doctor may discuss some of the available surgical options.
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What Is The Prognosis
The average life expectancy of a person with PD is generally the same as for people who do not have the disease. Fortunately, there are many treatment options available for people with PD. However, in the late stages, PD may no longer respond to medications and can become associated with serious complications such as choking, pneumonia, and falls.
PD is a slowly progressive disorder. It is not possible to predict what course the disease will take for an individual person.
One commonly used scale neurologists use for describing how the symptoms of PD have progressed in a patient is the Hoehn and Yahr scale.
What Is The Prognosis And Life Expectancy For Parkinson’s Disease
The severity of Parkinson’s disease symptoms and signs vary greatly from person to peson, and it is not possible to predict how quickly the disease will progress. Parkinson’s disease itself is not a fatal disease, and the average life expectancy is similar to that of people without the disease. Secondary complications, such as pneumonia, falling-related injuries, and choking can lead to death. Many treatment options can reduce some of the symptoms and prolong the quality of life.
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Role Of Mitochondrial Damage And Oxidative Stress In Pd
One of the most promising theories in PD research, as well as other age-related neurodegenerative diseases, is the oxidative stress theory . This theory posits that the mitochondria is the hot-spot for degenerative processes. In PD, the abnormal activity of complex-I in mitochondria has been observed, which directly interferes with cellular ATP production, leading to cell death . In addition, the brain monoamines, such as DA and 5-HT, generally act as antioxidants . However, breakdown of DA by monoamine oxidase-B , and combined with ground state O2, leads to the formation of ROS . Researchers have found increased oxidative stress markers and related changes in PD patients . In addition, increased levels of the apoptotic marker protein, Bax has been observed in DA-neurons of the SNpc in MPTP-treated mice . Recently, investigators have developed hybrid cells, called cybrid, to check the role of mitochondria in development of PD . They have placed mitochondrial DNA from PD patients into neuroblastoma cells and found these cybrids develop LB, just like those in the DA-neurons of PD patients. Similarly, certain gene mutations that are involved in cell-survival mechanisms may lead to impairment of mitochondrial activity and ATP production. These findings provide strong support for the idea that mitochondrial defects play a key role in the development of sporadic PD.
Fig. 10
Association Between Cognitive Impairment And Motor And Non
In the first regression model , with cognitive impairment as dependent variable, two variables were found to be significant. Hoehn and Yahr stage and the motor exploration subscale in SCOPA-Motor scale showed a positive association with cognitive dysfunction. This model explained 49.0% of the variance.
Table 4. Binary logistic regression model for normal cognition vs. cognitive impairment .
The second regression model , with dementia as dependent variable, showed that dementia was positively associated with higher age and disease duration , an increased score in HADS-D , and more hallucination symptoms . The motor complications SCOPA-Motor subscale was negatively associated with the presence of dementia. This model explained 63.5% of the variance.
Table 5. Binary logistic regression model for dementia vs. no dementia .
Finally, in the multinomial model , there was a positive association between the presence of PD-MCI and HY stage . On the other hand, age , HY stage , and the depression HADS subscale were positively associated with the PDD group, whereas years of education was negatively associated. This model explained 61.6% of the variance.
Table 6. Multinomial logistic regression model .
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Depression May Be An Early Symptom Of Parkinsons
Depression is one of the most common, and most disabling, non-motor symptoms of Parkinsons disease. As many as 50 per cent of people with Parkinsons experience the symptoms of clinical depression at some stage of the disease. Some people experience depression up to a decade or more before experiencing any motor symptoms of Parkinsons.
Clinical depression and anxiety are underdiagnosed symptoms of Parkinsons. Researchers believe that depression and anxiety in Parkinsons disease may be due to chemical and physical changes in the area of the brain that affect mood as well as movement. These changes are caused by the disease itself.
Here are some suggestions to help identify depression in Parkinsons:
- Mention changes in mood to your physician if they do not ask you about these conditions.
- Complete our Geriatric Depression Scale-15 to record your feelings so you can discuss symptoms with your doctor. Download the answer key and compare your responses.
- delusions and impulse control disorders
What Genes Are Linked To Parkinsons Disease
Several genes have been definitively linked to PD:
- SNCA. This gene, which makes the protein alpha-synuclein, was the first gene identified to be associated with Parkinsons. Research findings by the National Institutes of Health and other institutions prompted studies of the role of alpha-synuclein in PD, which led to the discovery that Lewy bodies seen in all cases of PD contain clumps of alpha-synuclein. This discovery revealed the link between hereditary and sporadic forms of the disease.
- LRRK2. Mutations in LRRK2 were originally identified in several English and Basque families as a cause of a late-onset PD. Subsequent studies have identified mutations of this gene in other families with PD as well as in a small percentage of people with apparently sporadic PD. LRRK2 mutations are a major cause of PD in North Africa and the Middle East.
- DJ-1. This gene normally helps regulate gene activity and protect cells from oxidative stress and can cause rare, early forms of PD.
- PRKN . The parkin gene is translated into a protein that normally helps cells break down and recycle proteins.
- PINK1. PINK1 codes for a protein active in mitochondria. Mutations in this gene appear to increase susceptibility to cellular stress. PINK1 has been linked to early forms of PD.
- GBA . Mutations in GBA cause Gaucher disease , but different changes in this gene are associated with an increased risk for Parkinsons disease as well.
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Neuroinflammation Involved In Pd
A cascade of events are involved in neuroinflammation processes in PD, including activation of microglia and an increase secretion of cytokines . For example, researchers have found strong links between pro-inflammatory cytokines and degeneration of DA neurons, following sub-chronic administration of MPTP in animals . Several clinical studies have shown that the level of inflammatory enzymes, such as cyclo-oxygenase-2 , is increased several times in DA-neurons of the postmortem PD brain and in a mouse models of PD .
Fig. 11
Mechanism of neuroinflammation in PD. T-lymphocytes and complementary systems can activate microglia to secrete several cytokines, which causes DA-neuronal injury. Similarly, aggregated SNCA can also activate astrocytes, which causes oxidative stress, leading to neuronal injury
Prion hypothesis
Pd Caused By Impairment Of Protein Degradation Pathways
Molecular chaperones . The molecular chaperone, is one of the most efficient, highly conserved cellular defense mechanisms involved in protein folding, refolding of partially misfolded proteins, and protein degradation . Major HSPs involved in PD are HSP 26, 40, 60, 70, 90 and 100. Some of the HSPs are localized in synapses and axons, and their levels are down-regulated in PD as well as other neurodegenerative diseases . Importantly, HSPs can bind to aggregated SNCA or tau oligomers or pre-fibrillar structures, and interfere by forming low MW soluble oligomers or higher order insoluble structures which reduce their toxicity . HSPs also play pivotal roles in the regulation and precise functioning of ubiquitin proteasome and the autophagy-lysosomal pathways .
In drosophila and yeast models of PD, HSP70 co-expression prevents DA cell death by decreasing the SNCA toxicity , whereas mutations of ATPase domain in HSP70 increase toxicity . Similarly, over-expression of HSP70 decreases MPTP- or rotenone-induced neurotoxicity in rat brain slices and also in cultured SK-N-SH or PC12 cells . Furthermore, a reduction of total and detergent-insoluble fractions of misfolded SNCA aggregates were observed in an in vitro model of PD, which co-express different yeast HSPs , suggesting molecular chaperones become dysregulated in PD.
Fig. 5Fig. 6
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Environmental Factors And Exposures
Exposure to pesticides and a history of head injury have each been linked with PD, but the risks are modest. Never having smoked cigarettes, and never drinking caffeinated beverages, are also associated with small increases in risk of developing PD.
Low concentrations of urate in the blood is associated with an increased risk of PD.
Drug-induced parkinsonism
Different medical drugs have been implicated in cases of parkinsonism. Drug-induced parkinsonism is normally reversible by stopping the offending agent. Drugs include:
The Facts About Parkinsons Disease
Parkinson’s disease is a progressive neurogenerative disease that causes nerve cells in the area of the brain that controls movement to weaken and/or die. While healthy neurons produce a chemical called dopamine, which the brain needs a certain amount of in order to regulate movement, weakened neurons produce lower levels of dopamine. What causes these neurons to weaken is currently unknown.
Some patients with Parkinson’s disease also suffer from a decline in norepinephrine, a chemical that transmits signals across nerve endings and controls various functions, such as blood pressure and heart rate.
More than 10 million people worldwide are currently living with Parkinson’s disease and nearly one million will be living with the disease in the United States this year, according to the Parkinson’s Foundation.
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What Is Parkinson’s Gait
Parkinsons gait is a symptom of Parkinsons disease that usually develops as the condition becomes more severe. Effect of the disease such as a lack of balance and strength contribute to an unsteady, stooped gait. Often, Parkinsons gait is mistaken for a walking style thats consistent with old age, until the condition gets worse. Other common signs of Parkinsons gait include short steps, difficulty in turning or stopping and the patient feeling as if he or she is constantly leaning forward.
Parkinsons disease affects the human brain and slows the speed of signals traveling through the nervous system. This reduced speed of transmission can have a major effect on everyday activities, including walking, showering and getting dressed. Other problems include a lack of balance and fatigue. As the condition gets worse, the symptoms become more apparent, including Parkinsons gait.