PARKINSONS DISEASE

BY- UTKARSHA DIKSHIT 11408052 B.TECH GENETIC ENGG. SRM UNIVERSITY

INTRODUCTION
Parkinsonism is a clinical syndrome characterised by diminished facial expression,stooped posture,slowness of voluntary movement,festinating gait,rigidity and a pill-rolling tremor. This type of motor disturbance is seen in a number of conditions that share damage to dopaminergic neurons of substantia nigra or to their projection to the striatum . ( ROBBINS PATHOLOGY) Parkinsonism is the general term used to describe a large number of movement disorders, of which PD is the most common form, with a specific group of symptoms. In general, any disease that has some of the symptoms of PD is included in the larger parkinsonism group. Parkinson's disease (PD) is a neurodegenerative disorder of the central nervous system It is associated with degeneration of the basal ganglia of the brain and a deficiency of the neurotransmitter dopamine The second most common neurodegenerative disorder after Alzheimers Disease (AD)

HISTORY
AYURVEDA
Describes symptoms of Parkinson's Disease, known as Kampavata as far back as 5000 B.C .To treat they used a tropical legume called Mucuna Pruriens, which they called Atmagupta. The seeds of Mucuna Pruriens are a natural source of therapeutic quantities of L-dopa Mucuna pruriens is certainly the oldest known method of treating the symptoms of Parkinson's Disease, and is still being used to treat Parkinson's Disease.

HISTORY contd..
Leonardo da Vinci (1452-1519) saw people whose
symptoms coincided with the tremors seen in Parkinson's Disease. Leonardo wrote "you will see.....those who.....move their trembling parts, such as their heads or hands without permission of the soul; (the) soul with all its forces cannot prevent these parts from trembling.

There are examples of references to the symptoms of Parkinson's Disease in the plays of William Shakespeare (1564-1616). There is a reference to shaking palsy in the second part of Henry VI, during an exchange between Dick and Say. Say explains to Dick that it is shaking palsy rather than fear that was causing his shaking. Dick asks Say : "Why dost thou quiver, man ?" Say responds : "The palsy, and not fear, provokes me."

HISTORY contd..
Disease was first formally described in modern times in "An Essay on THE SHAKING PALSY Published in 1817 by a London physician named James Parkinson (1755-1824) .

THE FIRST CLAIMED CURE The English physician John Elliotson (1791-1868) published made the first known claimed cure. He suggested that many young patients could be cured, although unreliably, using the carbonate of iron. On another occasion, he reported that the disease instantly and permanently gave way when he treated with iron a patient who had proved resistant to all other forms of therapy. This was well over a century before iron was found to be essential for the formation of L-dopa.

HISTORY contd..
THE FIRST NAMED PATIENT Wilhelm von Humboldt (1767-1835), a philosopher and diplomat, described in his letters from 1828 until his death in 1835, his own medical history, which gave a more complete description of the disease than had James Parkinson . Noticed his typical parkinsonian posture

THE NAMING OF PARKINSON'S DISEASE It was not until 1861 and 1862 that Jean-Martin Charcot (1825-1893) with Alfred Vulpian (18261887) added more symptoms to James Parkinson's clinical description (Charcot and Vulpian, 1861, 1862) and then subsequently confirmed James Parkinson's place in medical history by attaching the name Parkinson's Disease to the syndrome.

SYMPTOMS
Four main symptoms : Resting tremor Rigidity Bradykinesia Postural instability

SYMPTOMS contd
Resting Tremor: The tremor consists of a shaking or oscillating movement, and usually appears when a person's muscles are relaxed, or at rest, hence the term "resting tremor." The affected body part trembles when it is not performing an action.

Rigidity: Rigidity causes stiffness and inflexibility of the limbs, neck and trunk. Muscles normally stretch when they move, and then relax when they are at rest. In Parkinsons rigidity, the muscle tone of an affected limb is always stiff and does not relax. People with PD most commonly experience tightness of the neck, shoulder and leg.

Bradykinesia: Bradykinesia means slow movement. Its a general reduction of spontaneous movement .Due to bradykinesia, a person with Parkinsons may have difficulty performing everyday functions,such as buttoning a shirt, cutting food or brushing his or her teeth,may walk with short, shuffling steps.

Postural Instability: One of the most important signs of Parkinsons , it is a tendency to be unstable when standing upright.

SYMPTOMS contd..
Other symptoms:
Depression Emotional changes Difficulty with swallowing and chewing Speech changes Urinary problems or constipation Skin problems Sleep problems. Muscle cramps and dystonia. Fatigue and loss of energy Sexual dysfunction

PREVELANCE

WORLD'S HIGHEST PREVALENCE

The world's highest prevalence of Parkinson's Disease by far has been found among the Amish community, where Parkinson's Disease is two to three times more prevalent than anywhere else in the world.

The prevalence of Parkinson's Disease amongst the Amish community is 970 per 100,000, which is enormously high.
They are afflicted by genetic disorders. So it was thought that the cause might be genetic. However, the more closely related they were, the less they were affected.

PREVELANCE contd..
The world's next highest prevalence of Parkinson's Disease is in the vicinities of ferromanganese plants near Brescia in Italy, with 407 people per 100,000 population.

The next highest prevalence of Parkinson's Disease of any region is in Nebraska, U.S.A. with 329.3 people per 100,000 population

The Parsi community of Mumbai, India have a prevalence of Parkinson's Disease of 328.3 per 100,000 population, which is almost in excess of that found in Nebraska. This is despite India as a whole having a low prevalence

PREVELANCE contd..

Ethiopia has the world's lowest recorded prevalence of Parkinson's Disease.

At a rate of only 7 per 100,000 GENDER DIFFERENCES:There are more men than women with Parkinson's Disease.

RACIAL DIFFERENCES:In the U.S.A.,

the proneness to Parkinson's Disease was highest amongst whites, with an incidence of 45 per 100,000. Latinos were the next most prone with an incidence of 40 per 100,000. Least prone of all were African-Americans with an incidence of only 23 per 100,000.

PREVELANCE contd..

HAIR COLOUR:The risk of Parkinson's Disease increases according to hair colour. People with black hair were found to be least prone to Parkinson's Disease. People with brown hair were 40% more likely to develop Parkinson's Disease. People with blonde hair were found to be around 60% more likely to develop Parkinson's Disease. Worst at risk were people with red hair, for whom the risk of Parkinson's Disease is nearly doubled. Hair colour and Parkinson's Disease share a common biochemistry. The dopamine needed to relieve Parkinson's Disease is initially made from L-tyrosine turning in to L-dopa. Coincidentally, Melanin, the pigment that colours hair is also initially made by turning L-tyrosine in to L-dopa.

PREVELANCE contd..
Parkinson's Disease in the Parsi Community of Bombay, India A door-to-door survey was carried out to screen a community of 14010 people (Parsis living in colonies in Bombay, India) for possible neurologic diseases. Neurologists used defined diagnostic criteria to evaluate individuals positive on the screening survey. There were 46 people (25 men, 21 women) who suffered from Parkinson's disease (328.3 cases per 1000 population).. In december 1988 Parkinson disease in the city of Kolkata, India A door-to-door survey. This study was undertaken between 2003 to 2007. A total population of 100,802 was screened. The age-adjusted prevalence rate (PR) and average annual incidence rate were 52.85/100,000 and 5.71/100,000 per year, respectively.. The adjusted average annual mortality rate was 2.89/100,000 per year. The relative risk of death was 8.98. The case-control study showed that tobacco chewing protected and hypertension increased PD occurrence.

CAUSES
INITIAL CAUSES:Parkinson's Disease consequently occurs when the effect of dopamine is less than that of acetylcholine. There is eventually a massive loss of cell activity. lack of those substances needed for the production and action of dopamine (L-tyrosine, ferrous iron, zinc, pyridoxine, nicotinamide, folic acid, manganese) would lead to low levels of dopamine and the cell damage. TOXIC CAUSES:Includes toxins like Paraquat (herbicide), Rotenone (pesticide), 6-hydroxydopamine (6-OHDA),Maneb (fungicide), Manganese, MPTP (drug by product), Toluene (solvent), N-hexane (solvent), Carbon disulfide (usually in solvents or pesticides), Carbon monoxide, Mercury, Cyanide, and Copper. HEAD TRAUMA: A prior head injury with amnesia or loss of consciousness was associated with an increased risk of developing Parkinson's Disease DRUG INDUCED: Some of the Anti-psychotics - drugs that are used to treat
schizophrenia and psychosis - can induce the symptoms of Parkinson's disease by lowering dopaminergic activity, as can Trimetazidine.

GENETIC CAUSES Protein and genes associated with parkinsons disease are PARK1 (alpha-synuclein),PARK 2 (Parkin), PARK 6 (PINK 1), PARK 7 (DJ-1), SNCA, LRRK2, UCHL1, SNCAIP, GBA, NR4A2, CYP2D6, PARK 3; PARK 4, PARK 8, PARK 10 and PARK 11. Mutations in the Alpha-Synuclein, LRRK2 (Leucine-Rich Repeat Kinase-2) and UCHL1 (Ubiquitin C-terminal hydrolase L1) genes cause dominant forms of Familial PD. In contrast, mutations in Parkin, DJ1 and the newly identified PINK1 (PTEN-induced Kinase-1) are responsible for recessive forms of familial PD .

 The majority of Parkinsons disease is Sporadic. oxidative stress (Glutathione depletion, Iron deposition, increased markers of lipid peroxidation, ROS (Reactive Oxygen Species), oxidative DNA damage, and protein oxidation) and mitochondrial dysfunction play prominent roles in the death of DA (Dopamine) neurons.

GENETIC CAUSES contd..

PARK1 1)The first Parkinsons disease gene to be identified. It encode the presynaptic nerve terminal protein AlphaSynuclein. 2)It consist of 140 amino acid represents about 1% of the cytosolic protein in the brain. 3)It is believed to play an important role in killing cells by accumulation of toxic aggregates, inhibition of Proteasomal function, induction of apoptotic death machinery, autophagy and interference with cell survival pathways. 4) Oxidative stress and heavy metal toxicity potentiates AlphaSynuclein aggregation and toxicity. 5)In Parkinsons disease, Alpha-Synuclein accumulates in the cell bodies and neurites of degenerating neurons as a major component of Lewy bodies.

GENETIC CAUSES contd..

PARK2

The second Parkinsons disease gene, PARK2, is caused by mutations in the gene for Parkin, and it leads to AR-JP (Autosomal Recessive Juvenile Parkinsonism). Parkin protein is an E3 Ubiquitin Ligase. The Parkin gene has an estimated genomic size of 500 kb and consists of 12 coding exons with an open reading frame of 1395 bp. It is divided into three parts: the Amino-terminal Ubl domain, the Carboxy-terminal RING-box and the linker region, which connects the former two segments. PARK5, caused by mutations in the UCHL1 gene which codes for the protein ubiquitin carboxy-terminal hydrolase L1. It is a deubiquitinating enzyme that hydrolyzes bonds between ubiquitins that have been attached to other proteins, to create monomeric (single) ubiquitin molecules.

PARK2 gene location:

GENETIC CAUSES contd..

PARK6 , caused by mutations in PINK1 which codes for the protein PTEN-induced putative kinase PARK7 caused by mutations in DJ-1 It may be involved in oxidative stress responses Mutations in DJ1.

PARK8 caused by mutations in LRRK2(leucine-rich repeat kinase 2 ) which codes for the protein dardarin. In vitro, mutant LRRK2 causes protein aggregation and cell death, possibly through an interaction with parkin .LRRK2 mutations, of which the most common is G2019S, cause autosomal dominant Parkinson disease, with a penetrance of nearly 100% by age 80.G2019S is the most common known genetic cause of Parkinson disease, found in 1-6% of U.S. and European PD patients.It is especially common in Ashkenazi Jewish patients, with a prevalence of 29.7% in familial cases and 13.3% in sporadic.
PARK12 ,maps to the X chromosome

Genetic forms of parkinsonism

Pathophysiology:

Basal Ganglia Neuroanatomy:

Contd..

The basal ganglia and the cerebellum transmit information via the thalamus to the cerebral cortex in order to regulate movement. In a healthy brain, the neurons based in the substantia nigra extend into the putamen and caudate (which both comprise the striatum). These cells release dopamine in the striatum, which modulates neuronal activity. Movement disorders such as Parkinson's disease are conditions that involve changes in the basal ganglia and its associated structures. Basal ganglia disorders are typically due to neurotransmitter changes that affect the output of the striatum into the globus pallidus as well as into the thalamus and cerebral cortex beyond.

DOPAMINE PRODUCTION AND TRANSMISSION

Tyrosine hydroxylase(TH) is an enzyme within the substantia nigra that converts an amino acid, tyrosine into levodopa. Subsequently , other enzymes convert levodopa into the neurotransmitter dopamine. Activity of tyrosine hydroxylase is the rate -limiting factor in the production of dopamine. Dopa decarboxylase (DDC) is the enzyme that converts levodopa to dopamine.

BASAL GANGLIA NEUROCHEMISTRY:

Neurotransmitter : Dopamine GABA Acetyl choline Glutamate Endorphins Substance p

The chemical and electrical interactions among the neurons in the brain involves the maintenance of a complex balance between excitation and inhibition of nerve impulses.

DOPAMINE SYNTHESIS

Dopamine is synthesized from tyrosine, which is first catalysed to L-DOPA by tyrosine hyroxylase. L-DOPA is then decarboxylated to dopamine by dopadecarboxylase, and stored in the vesicles. When released into synaptic cleft, dopamine binds to receptors (D1-D5 in the figure), which activates different second messenger systems inside the cell causing changes in excitability, metabolism and gene expression.

Reuptake of dopamine is by dopamine transporter. If unstored in the cytosol, dopamine is oxidized by monoamine oxidase (MAO).

LEWY BODIES( Neuropathology of PD)

The main neuropathological feature of the disease consists of eosinophilic, round cytoplasmic inclusions called Lewy bodies and Lewy neurites, first described in 1912 by a German neuropathologist Friedrich Lewy. In 1919 it was shown that these inclusions are particularly numerous in the substantia nigra.

On the left a Lewy body of substantia nigra section from a PD patient. On the right cortical Lewy bodies of cingulate gyrus -synuclein accumulates in Lewy bodies in Parkinson's disease but not in Alzheimer's disease

 A picture of Alois Alzheimer and his co-workers in which Friedrich Lewy is standing to the very right side of the picture

SUBSTANTIA NIGRA AND THE EXTRAPYRAMIDAL SYSTEM

CORTEX
+ +

STRIATUM
D 1 D 2 D 1

SN c
SN r

GPe ST + N GP i

THALAMUS

Substantia nigra is part of so called extrapyramidal system which processes information coming from the cortex to the striatum, and returns it back to the cortex through the thalamus. One major function of the striatum, which is under the control of substantia nigra, is the regulation of posture and muscle tonus.

NORMAL MOTOR CONTROL

DIAGNOSIS UNIFIED PARKINSONS DISEASE RATING SCALE The most commonly used symptom questionnaire is the Unified Parkinson Disease Rating Scale (UPDRS). The UPDRS was developed to address the need for a comprehensive Parkinson's Disease measurement tool. It encompasses earlier rating scales : Hoehn and Yahr staging scale, and the modified Schwab and England activities of daily living scale.

Hoehn and Yahr Staging of Severity of Parkinsons Disease

0- No clinical signs evident

I- Unilateral involvement II- Bilateral involvement but no postural abnormalities III- Bilateral involvement with mild postural imbalance on examination or history of poor balance or falls; patient leads independent life IV- Bilateral involvement with postural instability; patient requires substantial help V- Severe, fully developed disease; patient restricted to bed or wheelchair

Schwab & England Activities of Daily Living Scale

100% Completely independent. Able to do all chores without slowness, difficulty or impairment. Essentially normal. Unaware of any difficulty 80% Completely independent in most chores. Takes twice as long. Conscious of difficulty and slowness 60% Some dependency. Can do most chores, but exceeding slowly and with much effort. Error; sometimes impossible 40% Very dependent. Can assist with all chores, but few alone 20% Nothing alone. Can be slight help with some chores. 0% Cannot swallow, bladder and bowel not functioning, Bed-ridden.

DIAGNOSIS contd..
History
Examination Administration of antiparkinsonian medications such as levodopa or other agent.

Performance of a brain MRI (magnetic resonance imaging) or brain CT (computed tomography) scan.
Nuclear imaging such as PET (positron emission tomography) and SPECT (single photon emission computerized tomography) scans, which are used in rare diagnostic

History(For diagnosis)
Genetic background : A family history of neurodegenerative disease such as early-onset Parkinson's disease, ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig's disease), dementia, parkinsonism, tremor disorders, etc. Psychiatric history: include depression, anxiety, bipolar disorders, schizophrenia, and addiction disorders. Previous head trauma: significant head traumas resulting in loss of consciousness. Medication exposure: Medications such as metoclopramide (Reglan), amoxapine, and antipsychotics can induce a medication-induced parkinsonism. Exposure to environmental toxins : Exposure to carbon monoxide, manganese, the fungicide maneb, the pesticide rotenone, etc.

DIAGNOSIS contd..
Examination of Initially Presenting Symptoms : The physician will check for the four core symptoms of Parkinson's disease: tremor, rigidity, akinesia/bradykinesia, and postural changes Administration of levodopa and other agents:Patients are prescribed levodopa(L-dopa) or another pharmaceutical agent,such as dopamine agonist. Dopamine is often combined with another medication, carbidopa, to lessen the side effects of nausea. Combination product is known as SINEMET. It give relief from motor symptoms like muscle stiffness, tremor and slowness Imaging tests for parkinson's disease: various imaging scans may also be ordered as a component of the patient's evaluation for parkinson's disease.These scans are performed to exclude other potential causes for the patient's symptoms.

DIAGNOSIS contd..

PET scan(positron emission tomography):PET is a

type of nuclear study involves in the administration of radioactive chemicals that is detected by sensitive cameras. For parkinson's disease, Fluorodopa PET scanning is used.here radioactive compound fluorodopa (F-dopa), is taken to the branches of dopamine nerve cells in striatum.

MOLECULAR DIAGNOSIS:
MOLECULAR BIOMARKERS:Rare cases of familial PD are caused by missense mutations in the SNCA gene, which encodes -synuclein. Moreover, duplication and triplication of this gene give rise to late-onset and early-onset familial PD, respectively, indicating that the expression level of -synuclein might be an important determinant of disease onset and severity. DJ1, as loss-of-function mutations in PARK7, which encodes DJ1, can cause early-onset PD. Degree of blood contamination of cerebrospinal fluid: Determined by measuring the haemoglobin level. The researchers used sensitive and quantitative Luminex bead-based assays to measure the levels of -synuclein and DJ1 . cerebrospinal fluid levels of -synuclein and DJ1 are substantially reduced in patients with Parkinson disease compared with healthy controls or individuals with Alzheimer disease.

TREATMENT
Parkinsons disease Paralysis agitans; Shaking palsy Last reviewed: May 6, 2011. (PUBMED) There is no known cure for Parkinson's disease. The goal of treatment is to control symptoms. Medications control symptoms, mostly by increasing the levels of dopamine in the brain. At certain points during the day, the helpful effects of the medication often wears off, and symptoms can return. Your doctor may need to change the: Type of medication Dose Amount of time between doses How the medications are taken. Many medications can cause severe side effects, including hallucinations, nausea, vomiting, diarrhea, and delirium. Eventually, symptoms such as stooped posture, frozen movements, and speech difficulties may not respond very well to drug treatment.

CURRENT TREATMENT STRATEGIES

LEVODOPA

Late 1950s: L-dihydroxyphenylalanine (L-DOPA; levodopa), a precursor of DA that crosses the blood-brain barrier, could restore brain DA levels and motor functions in animals treated with catecholamine depleting drug (reserpine).

First treatment attempts in PD patients with levodopa resulted in dramatic but short-term improvements; took years before it become an established and succesfull treatment. Still today, levodopa cornerstone of PD treatment; virtually all the patients benefit.

Catechol-O-methyl-transferase (COMT) inhibitors, like entacapone, which increase the bioavailability of levodopa by inhibiting COMT enzyme peripherally and thus slow down the breakdown of levodopa.

Levodopa that enters the brain is rapidly converted into dopamine by the enzyme, dopa-decarboxylase, in neurons. This helps to restore the imbalance in the basal ganglia caused by the deficiency of dopamine. Its an oral drug when ingested does not required tyrosine hyroxylase synthetic levodopa travels to brain. they are converted to dopamine by dopa carboxylase,DDC.Dopamine is not able to cross the blood barrier.

 limitations of levodopa Does not prevent the continuous degeneration of nerve cells in the subtantia nigra, the treatment being therefore symptomatic

Neuroprotective agents-vitamin E,coenzyme Q10,anti- apoptic agent

such as minocycline,CEP1347.(slowing the progression of parkinsons disease.)

Anticholinergics-used in the treatment of tremor. Monoamine oxidase B inhibitors-used in mild or early parkinsons
disease to delay for further medications.

SURGICAL TREATMENTS

.Pallidial surgery:
Surgery on the internal pallidium contained within the globus pallidus. In pallidotomy, a permanent lesion is made, destroying a section of internal pallidium. Deep brain stimulation, electrical current is sent to the structure via an implanted electrode to supress akinesia, bradykinesia , dyskinesia or related symptoms. .Thalamic surgery: Similar to pallidial surgery. Alleviate contralateral limb tremor.

Transplantation: human/pig fetal cells have been experimentally transplanted in the striatum to restore the loss of dopamine - producing cell in substantia nigra. GDNF glial cell line- derrived neurotropic factor infusion into the brain has been used to help restore dopamine cells.

Gene Therapy The gold standard for treatment of both familial and sporadic Parkinson's disease is the peripheral administration of the dopamine precursor, levodopa. In addition, dopamine enhancement therapies are most useful when a portion of the nigrostriatal pathway is intact.

Employing either recombinant adeno-associated virus type 2 (rAAV2) or lentivirus vectors, these clinical trials are focused on three overarching approaches: augmentation of dopamine levels via increased neurotransmitter production. modulation of the neuronal phenotype. and neuroprotection. Intra striatal grafts of human embryonic mesencephalic tissue and human embryonic dopamine neurons reinnervate the striatum in patients with Parkinson's disease. Stem cell therapy for Parkinson's disease
In a recent study, scientists directed mouse embryonic stem cells to differentiate int oDA neurons by introducing the gene Nurr1. When transplanted into the brains of a rat model of PD, these stem cell-derived DA neurons reinnervated the brains of the rat Parkinson model, released dopamine and improved motor function. Regarding human stem cell therapy, scientists are developing a number of strategies for producing dopamine neurons from human stem cells in the laboratory for transplantation into humans with Parkinson's disease. The successful generation of an unlimited supply of dopamine neurons could make neurotransplantation widely available for Parkinson's patients at some point in the future.

Lifestyle changes that may be helpful for Parkinson's disease: Good general nutrition and health Exercising, but adjusting the activity level to meet changing energy levels Regular rest periods and avoiding stress Physical therapy, speech therapy, and occupational therapy Railings or banisters placed in commonly used areas of the house Special eating utensils Social workers or other counseling services to help cope with the disorder and get assistance (such as Meals-onWheels)

FAMOUS PEOPLE WITH PARKINSON'S DISEASE Muhammad Ali, Amerian boxer

Adolf Hitler, German Dictator

Pope John Paul II, Polish Pope

 World Parkinson's Disease Day is celebrated on April 11 in commemoration of Dr. James Parkinson'sbirthday (1755 - 1824) who established the disease as a clinical entity in a paper entitled An Essay on the Shaking Palsy

MOVIE LOVE AND OTHER DRUGS

STRANGE FACTS ABOUT PARKINSON'S DISEASE Many people in the Pacific island of Guam have developed Parkinson's Disease, due to feasting on flying foxes, a species of bat that can be as big as six feet across. This is because the bats eat cycad seeds which contain a potent neurotoxin.

In the seventeenth century, Nicholas Culppepper claimed a variety of substances to be useful in the treatment of symptoms of Parkinson's Disease that included "oil of winged ants" and earthworms.

 Yahya Ibn Sarafyun, a physician in medieval Damascus devised a formulation for treating symptoms of Parkinson's Disease that included frankincense, myrrh and frogs.

People are much less likely to get Parkinson's Disease if they smoke cigarettes, drink alcohol, have high cholesterol, and drink too much coffee.

 There are two films of Adolf Hitler's last public appearance, one that was shown in which he displayed no symptoms of Parkinson's Disease, and another that was purposefully not shown in which he was displaying the symptoms of Parkinson's Disease.

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