Parkinson's Disease Research Paper
!
Pathophysiology
Research Paper - Parkinson’s Disease
7/20/13
!
Parkinson’s disease (PD) is a common neurodegenerative disorder second to Alzheimer’s disease in prevalence (1). PD is marked by rigidity, a tremor at rest, unstable posture, and bradykinesia. Incident rates of PD increase with age the earliest occurring around 40 years with a significant increase after 60 years (7). Approximately 1 in 272 people have PD in the United States though it is believed that there are many undiagnosed, or improperly diagnosed individuals who have PD (7). The population with PD and increasing efficiency in diagnosis coupled with longer lifespans pose a potential burden on the individuals and health care system for their cumulative costs. …show more content…
!
There are four hallmark motor symptoms of PD: 1) resting tremor, 2) bradykinesia, 3) rigidity with “cogwheel” properties, and 4) unstable posture (8). These symptoms may not be found in all individuals, though most do occur at some point throughout their life with postural instability typically occurring last. All symptoms are bilateral though they first exhibit themselves on one side of the body and become apparent in the other as PD further develops. The side where symptoms were first pronounced continue to be more affected than the other side (5).
! symptoms are paramount to the diagnosis of PD. A resting tremor is the most frequently
These
occurring early presentation of PD (5), typically found in the patients thumb or wrist. Resting tremors can also be seen in the legs or oral region (chin, lips, jaw) and infrequently involve the neck or head (7).
Supination-pronation “Pill-rolling” is a feature of this tremor causing a circular motion between the index finger and thumb approximately 4-6 times per second (3). This tremor is usually apparent during times of rest and absent with voluntary movement or sleep. Individuals may have a long history of tremors before the parkinsonian tremor manifests. Postural tremors also occur in PD patients which present like an essential tremor. These tremors can also be the first indications of PD which are severely disabling (3).
These tremors are the easiest recognizable trait of PD.
! to these tremors PD patients incur increased muscle tone causing rigidity. Continued and
Due
excessive contractions of muscle cells because of their tremor or otherwise cause an increase in muscle tone resulting in stiffness and inability to move their joints (7).
In addition to pain from their resting tremor the resulting stiffness is another early indicator of PD, most frequently found in the shoulder.
When these limbs are moved by another individual a “cogwheel rigidity” (difficult movement initially, then a period of less resistance repeating) is often noted (8). This rigidity may be found in the wrists, ankles, neck, shoulder, or hips. Studies found that the presence of stiffness were associated with increased development of PD (8).
!
Bradykinesia is the slowness of movement, a common clinical trait in which PD causes. This is
the most common symptom of basal ganglia disorders which causes difficulty in numerous aspects of planning movement through its execution (8). These symptoms first appear in daily activities and decreased reaction times. Further development of bradykinesia causes increased difficulty with fine motor skills (eg, tying shoes, penmanship) (7). Changes in the ability to swallow cause an individual to drool accompanied by lack of facial expression. Of all signs and symptoms of PD, bradykinesia is best explained by dopamine deficiency (8). Bradykinesia is not consistent as it depends heavily on …show more content…
the individuals emotional state or activity being performed (eg, ability to ride a bike and unable to walk).
When a PD patient is excited for something (eg, seeing a grandchild or old friend) their excitement often supersedes bradykinesia symptoms and are able to move at a faster pace.
! instability is caused by the destruction of postural reflexes which typically present after
Postural
other clinical indications of PD. This instability is often the cause of falls, resulting in fractures for these
PD patients (8). Given the typical age of PD patients these falls are a significant health risk. Tests for postural instability are conducted to determine the progression of the disease. A PD patient will be quickly
pulled forward or backward to access the degree to which the individual needs to respond (how many steps forward or backward to correct) (7). Instability is also caused by other common disease factors; orthostatic hypotension, or changes in cognition (8). The instability is infrequent in the younger PD population and increases with age (thought to be associated with normal loss of balance). Postural instability is used to test for PD 's progression.
! are many other symptoms of PD which are not related to motor function. Cognitive
There
defects and memory function are impaired patients often finding it difficult to recall memories, though cues of memories aids their recall (6). PD patients are six times more likely to develop dementia with its incidence increasing after 75 years of age (3). Depression is the most common non motor symptom of PD affecting 50% of patients often combined with anxiety (4). Impulse control disorders are more frequently recognized in patients with PD relating to gambling, eating, sexual behavior, or buying (3). Hallucinations and delusional thought processes can also be seen in PD patients. Psychosis is often related to dopamine therapy (5). Sleep disorders are also common, though the influence could be contributed to their medications. Insomnia, alterations in REM cycles, and excessive daytime somnolence are the typical manifestations. These non motor symptoms of PD can influence the life expectancy of the PD patient (6).
In some cases these symptoms can overshadow the motor disabilities making a diagnosis more difficult.
!
The primary cause of PD has not been found, though there are many risk factors that have been identified. As mentioned previously, incidences of PD increase with age mostly after 60. Additionally, males are more likely to get PD than females the reasoning may be due to environmental exposure to toxins or a possible X-linked component to the disease (8). Though females who do not use hormone replacement therapy are at greater risk. Another genetic link is through α-synuclein in which the carriers of the gene are 1.5x more likely to develop PD (1). There have been some connections supporting the genetic predisposition to PD if one or more immediate relatives have PD. Environmental toxins that inhibit dopamine production or initiate free radicals within the body are also believed to be a cause of PD, often years after exposure (8). Head trauma has also been linked to PD with upper cervical damage due to these injuries (7). Though there are many risk factors PD is not well understood. There are many people who align with multiple risk factors and never develop PD. This goes to show the amount of research needed in order to develop a further understanding of PD to connect with prevention.
!
Parkinson’s disease is noted by the degeneration of dopamine producing neurons. Dopamine is a neurotransmitter in the brain that is involved in rewards and pleasure, many addictive drugs simulate its effects. Dopamine is an organic catecholamine chemical, produced in the basal ganglia and of which epinephrine and norepinephrine are made from the dopamine base. Degeneration is found in the basal ganglia’s substantia nigra and dorsal stratum where α-synuclein point mutations or misfolds decreases dopamine production (8). This results in uncontrolled excitatory or inhibitory flow in the basal ganglia.
Dopamine moderates and individuals response by moderating the amount of effort needed to achieve an action. The decreased amounts of dopamine in PD patients create an atmosphere within the body where to achieve an action larger amounts of effort are required. However, with a large stimulus of the sympathetic nervous system an action can easily be achieved. Changes to the α-synuclein production varies in the individual with PD (2); younger patients degradation of the substantia nigra occurs over a longer time period than older patients (2). These differences are believed to be the difference of dementia’s
onset between the different age classes.
!
Remaining neurons are often taken over by Lewy bodies which accumulate abnormal proteins in
the neurons. Each of these factors contributes to the hallmark attributes of PD (3). These appear after most of the degradation to dopamine production and are required for the clinical diagnosis of PD (3). The formation of Lewy bodies is not limited to the basal ganglia and occur in the diencephalon, spinal cord, and neocortex. The accumulation of α-synuclein as an insoluble fibril is the primary protein within the
Lewy body in addition to synphilin, another protein associated with α-synuclein (8). The presence of αsynuclein is also found in Lewy body Alzheimer patients that is one of the key overlaps between the two diseases. These bodies are spherical masses that compromise other cellular components further reducing the original function of the cell.
!
Sadly there is no cure for PD at this time. Numerous forms of treatment are available that can reduce the symptoms, yet not the progression of the disease (1). There are many options ranging from over-the-counter medications to surgical procedures. Treatment will often encompass many medications that either directly affect symptoms or are designed to make other medications more effective. Many PD patients find it difficult to follow their prescriptions due to their quantity and cognitive defects associated with PD (7). Most treatments look to stimulate remaining dopamine production or enhance the bodies use of its remaining dopamine. Progression of PD often lessens the treatments affects and becomes more difficult to treat.
! most common treatment of PD is administration of levodopa (L-DOPA), the precursor of
The
catecholamines (7). L-DOPA has the ability to cross the blood-brain barrier where its presence helps the remaining cells of the basal ganglia produce dopamine (5). Synthetic dopamine or treatment with dopamine itself is not a beneficial treatment as it cannot cross the blood-brain barrier. L-DOPA is converted into dopamine by aromatic L-amino acid decarboxylase with vitamin B6 as a cofactor (5).
Pyridoxine is typically administered with L-DOPA to provide B6 and facilitate optimal dopamine production. L-DOPA is commonly prescribed as Sinemet or Atamet which combines L-DOPA with carbidopa to negate the nausea caused by L-DOPA (1). There is no clear timeline in which this medication is most effective, though most neurologists suggest earlier treatment. Prolonged use and increasing doses can cause adverse side effects and the loss of effectiveness.
! from L-DOPA medications the other main prescriptions are dopamine agonists,
Aside
antichollnergics, MAO-B and COMT inhibitors. Dopamine agonists stimulate dopamine susceptible areas of the brain which causes the cells to activate as they would under dopamine (1). These drugs are not as potent as the L-DOPA medications with decreased incidences of dyskinesia. Apomorphine is a fast-acting dopamine agonist lasting 30 to 60 minutes relieving PD symptoms typically used when other medications lose effectiveness (1). Anticholinergics are used to aid tremors and dystonia liked to other medications effects and have few effects on PD symptoms (5). MAO-B and COMT inhibitors are used in conjunction with L-DOPA to moderate its breakdown within the brain (5). These allow for decreased doses and more effective use of L-DOPA medication and have no direct effect on PD symptoms.
! procedures for PD consist of deep brain stimulation (DBS) that helps control PD
Surgical
symptoms and improve the patient’s quality of life (5). Electrical stimulation of the brain is directed by electrodes placed into the brain while under MRI to target specific areas. DBS is best use to treat PD patients with tremor, rigidity, and bradykinesia as their primary symptom (5). The area of the brain stimulated by DBS is subject of the patients symptoms and desired outcome. Like all surgeries there is a possibility of complications, predominantly hemorrhaging and infection (1). DBS is the most recent treatment for PD and progress continues towards more effective treatment and prevention.
!
Parkinson 's Disease is better documented and understood than ever before. The multifactorial and
undocumented cause of PD also contribute towards it’s increasing research. PD in the United States was most publicly brought into the spotlight when actor Michael J. Fox was diagnosed in 1991 and didn’t make it public until 1999. His foundation and others have furthered the research and spread of information regarding this life changing disease. Hopefully their research will provide greater insight to the incidence of PD. Further determination of risk factors and causes will initially decrease incidence rates while a cure is obtained. With our increasing aging population it is paramount that we further understand the disease to lessen the strain on our health care system and to provide insight to the many families who watch their loved ones through the many trying stages of the disease.
!
References:
! Halliday, G. M., & McCann, H. (2009). The progression of pathology in Parkinson’s disease. Annals
(1)
! of the New York Academy of Sciences, 1184(2010) pp. 188-195.
(2) Jankovic, J. (2007). Parkinson’s disease: clinical features and diagnosis. Journal of Neurological,
Neurosurgery and Psychiatry, 79: 368-376. doi:10.1136/jnnp.2007.131045
! Kano, O., Ikeda, K., Cridebring, D., Takazawa, T., Yoshii, Y., & Iwasaki, Y. (2011). Neurobiology of
(3)
Depression and Anxiety in Parkinson’s Disease. Parkinson’s Disease. Vol. 2011, Article ID 143537, 5 pages. doi:10.4061/2011/143547
! Parkinson’s Disease Foundation. www.pdf.org/en/index Accessed July 20, 2013.
(4)
! Rao, S. S., Hoffmann, L. A., & Shakil, A. (2006). Parkinson’s Disease: Diagnosis and Treatment.
(5)
American
74:2046-56.
! Rektorova,Family Physician,Chaudhuri, K. R., & Strafella, A.P. (2011). Nonmotor symptoms of
(6)
I., Aarsland, D.,
Parkinson’s Disease. Parkinson’s Disease. Vol. 2011, Article ID 351461, 2 pages. doi:
10.4061/2011/351461
! Weintraub, D., Comella, C. L., & Horn, S. (2008). Parkinson’s Disease: Quality Assessment and
(7)
Improvement of Care. The American Journal of Managed Care, vol. 14. http://www.ajmc.com/ publications/supplement/2008/2008-03-vol14-n2suppl Accessed July 20, 2013
! Zigmond, M. J., & Burke, R. E. (2002). Pathophysiology of Parkinson’s Disease. In
(8)
Neuropsychoparmacology: The Fifth Generation of Progress (pp. 1781-1793). Lippincott Williams &
Wilkins.
Pathophysiology
Research Paper - Parkinson’s Disease
7/20/13
!
Parkinson’s disease (PD) is a common neurodegenerative disorder second to Alzheimer’s disease in prevalence (1). PD is marked by rigidity, a tremor at rest, unstable posture, and bradykinesia. Incident rates of PD increase with age the earliest occurring around 40 years with a significant increase after 60 years (7). Approximately 1 in 272 people have PD in the United States though it is believed that there are many undiagnosed, or improperly diagnosed individuals who have PD (7). The population with PD and increasing efficiency in diagnosis coupled with longer lifespans pose a potential burden on the individuals and health care system for their cumulative costs. …show more content…
!
There are four hallmark motor symptoms of PD: 1) resting tremor, 2) bradykinesia, 3) rigidity with “cogwheel” properties, and 4) unstable posture (8). These symptoms may not be found in all individuals, though most do occur at some point throughout their life with postural instability typically occurring last. All symptoms are bilateral though they first exhibit themselves on one side of the body and become apparent in the other as PD further develops. The side where symptoms were first pronounced continue to be more affected than the other side (5).
! symptoms are paramount to the diagnosis of PD. A resting tremor is the most frequently
These
occurring early presentation of PD (5), typically found in the patients thumb or wrist. Resting tremors can also be seen in the legs or oral region (chin, lips, jaw) and infrequently involve the neck or head (7).
Supination-pronation “Pill-rolling” is a feature of this tremor causing a circular motion between the index finger and thumb approximately 4-6 times per second (3). This tremor is usually apparent during times of rest and absent with voluntary movement or sleep. Individuals may have a long history of tremors before the parkinsonian tremor manifests. Postural tremors also occur in PD patients which present like an essential tremor. These tremors can also be the first indications of PD which are severely disabling (3).
These tremors are the easiest recognizable trait of PD.
! to these tremors PD patients incur increased muscle tone causing rigidity. Continued and
Due
excessive contractions of muscle cells because of their tremor or otherwise cause an increase in muscle tone resulting in stiffness and inability to move their joints (7).
In addition to pain from their resting tremor the resulting stiffness is another early indicator of PD, most frequently found in the shoulder.
When these limbs are moved by another individual a “cogwheel rigidity” (difficult movement initially, then a period of less resistance repeating) is often noted (8). This rigidity may be found in the wrists, ankles, neck, shoulder, or hips. Studies found that the presence of stiffness were associated with increased development of PD (8).
!
Bradykinesia is the slowness of movement, a common clinical trait in which PD causes. This is
the most common symptom of basal ganglia disorders which causes difficulty in numerous aspects of planning movement through its execution (8). These symptoms first appear in daily activities and decreased reaction times. Further development of bradykinesia causes increased difficulty with fine motor skills (eg, tying shoes, penmanship) (7). Changes in the ability to swallow cause an individual to drool accompanied by lack of facial expression. Of all signs and symptoms of PD, bradykinesia is best explained by dopamine deficiency (8). Bradykinesia is not consistent as it depends heavily on …show more content…
the individuals emotional state or activity being performed (eg, ability to ride a bike and unable to walk).
When a PD patient is excited for something (eg, seeing a grandchild or old friend) their excitement often supersedes bradykinesia symptoms and are able to move at a faster pace.
! instability is caused by the destruction of postural reflexes which typically present after
Postural
other clinical indications of PD. This instability is often the cause of falls, resulting in fractures for these
PD patients (8). Given the typical age of PD patients these falls are a significant health risk. Tests for postural instability are conducted to determine the progression of the disease. A PD patient will be quickly
pulled forward or backward to access the degree to which the individual needs to respond (how many steps forward or backward to correct) (7). Instability is also caused by other common disease factors; orthostatic hypotension, or changes in cognition (8). The instability is infrequent in the younger PD population and increases with age (thought to be associated with normal loss of balance). Postural instability is used to test for PD 's progression.
! are many other symptoms of PD which are not related to motor function. Cognitive
There
defects and memory function are impaired patients often finding it difficult to recall memories, though cues of memories aids their recall (6). PD patients are six times more likely to develop dementia with its incidence increasing after 75 years of age (3). Depression is the most common non motor symptom of PD affecting 50% of patients often combined with anxiety (4). Impulse control disorders are more frequently recognized in patients with PD relating to gambling, eating, sexual behavior, or buying (3). Hallucinations and delusional thought processes can also be seen in PD patients. Psychosis is often related to dopamine therapy (5). Sleep disorders are also common, though the influence could be contributed to their medications. Insomnia, alterations in REM cycles, and excessive daytime somnolence are the typical manifestations. These non motor symptoms of PD can influence the life expectancy of the PD patient (6).
In some cases these symptoms can overshadow the motor disabilities making a diagnosis more difficult.
!
The primary cause of PD has not been found, though there are many risk factors that have been identified. As mentioned previously, incidences of PD increase with age mostly after 60. Additionally, males are more likely to get PD than females the reasoning may be due to environmental exposure to toxins or a possible X-linked component to the disease (8). Though females who do not use hormone replacement therapy are at greater risk. Another genetic link is through α-synuclein in which the carriers of the gene are 1.5x more likely to develop PD (1). There have been some connections supporting the genetic predisposition to PD if one or more immediate relatives have PD. Environmental toxins that inhibit dopamine production or initiate free radicals within the body are also believed to be a cause of PD, often years after exposure (8). Head trauma has also been linked to PD with upper cervical damage due to these injuries (7). Though there are many risk factors PD is not well understood. There are many people who align with multiple risk factors and never develop PD. This goes to show the amount of research needed in order to develop a further understanding of PD to connect with prevention.
!
Parkinson’s disease is noted by the degeneration of dopamine producing neurons. Dopamine is a neurotransmitter in the brain that is involved in rewards and pleasure, many addictive drugs simulate its effects. Dopamine is an organic catecholamine chemical, produced in the basal ganglia and of which epinephrine and norepinephrine are made from the dopamine base. Degeneration is found in the basal ganglia’s substantia nigra and dorsal stratum where α-synuclein point mutations or misfolds decreases dopamine production (8). This results in uncontrolled excitatory or inhibitory flow in the basal ganglia.
Dopamine moderates and individuals response by moderating the amount of effort needed to achieve an action. The decreased amounts of dopamine in PD patients create an atmosphere within the body where to achieve an action larger amounts of effort are required. However, with a large stimulus of the sympathetic nervous system an action can easily be achieved. Changes to the α-synuclein production varies in the individual with PD (2); younger patients degradation of the substantia nigra occurs over a longer time period than older patients (2). These differences are believed to be the difference of dementia’s
onset between the different age classes.
!
Remaining neurons are often taken over by Lewy bodies which accumulate abnormal proteins in
the neurons. Each of these factors contributes to the hallmark attributes of PD (3). These appear after most of the degradation to dopamine production and are required for the clinical diagnosis of PD (3). The formation of Lewy bodies is not limited to the basal ganglia and occur in the diencephalon, spinal cord, and neocortex. The accumulation of α-synuclein as an insoluble fibril is the primary protein within the
Lewy body in addition to synphilin, another protein associated with α-synuclein (8). The presence of αsynuclein is also found in Lewy body Alzheimer patients that is one of the key overlaps between the two diseases. These bodies are spherical masses that compromise other cellular components further reducing the original function of the cell.
!
Sadly there is no cure for PD at this time. Numerous forms of treatment are available that can reduce the symptoms, yet not the progression of the disease (1). There are many options ranging from over-the-counter medications to surgical procedures. Treatment will often encompass many medications that either directly affect symptoms or are designed to make other medications more effective. Many PD patients find it difficult to follow their prescriptions due to their quantity and cognitive defects associated with PD (7). Most treatments look to stimulate remaining dopamine production or enhance the bodies use of its remaining dopamine. Progression of PD often lessens the treatments affects and becomes more difficult to treat.
! most common treatment of PD is administration of levodopa (L-DOPA), the precursor of
The
catecholamines (7). L-DOPA has the ability to cross the blood-brain barrier where its presence helps the remaining cells of the basal ganglia produce dopamine (5). Synthetic dopamine or treatment with dopamine itself is not a beneficial treatment as it cannot cross the blood-brain barrier. L-DOPA is converted into dopamine by aromatic L-amino acid decarboxylase with vitamin B6 as a cofactor (5).
Pyridoxine is typically administered with L-DOPA to provide B6 and facilitate optimal dopamine production. L-DOPA is commonly prescribed as Sinemet or Atamet which combines L-DOPA with carbidopa to negate the nausea caused by L-DOPA (1). There is no clear timeline in which this medication is most effective, though most neurologists suggest earlier treatment. Prolonged use and increasing doses can cause adverse side effects and the loss of effectiveness.
! from L-DOPA medications the other main prescriptions are dopamine agonists,
Aside
antichollnergics, MAO-B and COMT inhibitors. Dopamine agonists stimulate dopamine susceptible areas of the brain which causes the cells to activate as they would under dopamine (1). These drugs are not as potent as the L-DOPA medications with decreased incidences of dyskinesia. Apomorphine is a fast-acting dopamine agonist lasting 30 to 60 minutes relieving PD symptoms typically used when other medications lose effectiveness (1). Anticholinergics are used to aid tremors and dystonia liked to other medications effects and have few effects on PD symptoms (5). MAO-B and COMT inhibitors are used in conjunction with L-DOPA to moderate its breakdown within the brain (5). These allow for decreased doses and more effective use of L-DOPA medication and have no direct effect on PD symptoms.
! procedures for PD consist of deep brain stimulation (DBS) that helps control PD
Surgical
symptoms and improve the patient’s quality of life (5). Electrical stimulation of the brain is directed by electrodes placed into the brain while under MRI to target specific areas. DBS is best use to treat PD patients with tremor, rigidity, and bradykinesia as their primary symptom (5). The area of the brain stimulated by DBS is subject of the patients symptoms and desired outcome. Like all surgeries there is a possibility of complications, predominantly hemorrhaging and infection (1). DBS is the most recent treatment for PD and progress continues towards more effective treatment and prevention.
!
Parkinson 's Disease is better documented and understood than ever before. The multifactorial and
undocumented cause of PD also contribute towards it’s increasing research. PD in the United States was most publicly brought into the spotlight when actor Michael J. Fox was diagnosed in 1991 and didn’t make it public until 1999. His foundation and others have furthered the research and spread of information regarding this life changing disease. Hopefully their research will provide greater insight to the incidence of PD. Further determination of risk factors and causes will initially decrease incidence rates while a cure is obtained. With our increasing aging population it is paramount that we further understand the disease to lessen the strain on our health care system and to provide insight to the many families who watch their loved ones through the many trying stages of the disease.
!
References:
! Halliday, G. M., & McCann, H. (2009). The progression of pathology in Parkinson’s disease. Annals
(1)
! of the New York Academy of Sciences, 1184(2010) pp. 188-195.
(2) Jankovic, J. (2007). Parkinson’s disease: clinical features and diagnosis. Journal of Neurological,
Neurosurgery and Psychiatry, 79: 368-376. doi:10.1136/jnnp.2007.131045
! Kano, O., Ikeda, K., Cridebring, D., Takazawa, T., Yoshii, Y., & Iwasaki, Y. (2011). Neurobiology of
(3)
Depression and Anxiety in Parkinson’s Disease. Parkinson’s Disease. Vol. 2011, Article ID 143537, 5 pages. doi:10.4061/2011/143547
! Parkinson’s Disease Foundation. www.pdf.org/en/index Accessed July 20, 2013.
(4)
! Rao, S. S., Hoffmann, L. A., & Shakil, A. (2006). Parkinson’s Disease: Diagnosis and Treatment.
(5)
American
74:2046-56.
! Rektorova,Family Physician,Chaudhuri, K. R., & Strafella, A.P. (2011). Nonmotor symptoms of
(6)
I., Aarsland, D.,
Parkinson’s Disease. Parkinson’s Disease. Vol. 2011, Article ID 351461, 2 pages. doi:
10.4061/2011/351461
! Weintraub, D., Comella, C. L., & Horn, S. (2008). Parkinson’s Disease: Quality Assessment and
(7)
Improvement of Care. The American Journal of Managed Care, vol. 14. http://www.ajmc.com/ publications/supplement/2008/2008-03-vol14-n2suppl Accessed July 20, 2013
! Zigmond, M. J., & Burke, R. E. (2002). Pathophysiology of Parkinson’s Disease. In
(8)
Neuropsychoparmacology: The Fifth Generation of Progress (pp. 1781-1793). Lippincott Williams &
Wilkins.