Parkinson’s Disease

Parkinson’s Disease

Degenerative disease of the nervous system

First described by James Parkinson (1817) Tremor Weakness Propensity to bend the

trunk forward Propensity to pass from a

walking to a ruunning pace Senses and intelect

uninjured 1841 – paralysis agitans

(Marshall Hall)

Parkinson’s Disease

Idiopathic Parkinson disease is observed in all ethnic groups and all socioeconomic classes Incidence in afroamericans is ¼ that in

whites In asians incidence is 1/3-1/2 that in whites

Incidence is about 1% in population over age 65 years (1 million patients in North America)

Parkinson’s Disease

Begins between 40 and 70 years, peak age of onset in the sixth decade

Incidence somewhat greater in menRisk for the first degree relatives about 5% Genetic aspects

Evidence of striatal dysfunction in 75% of asymptomatic monozygotic twins of Parkinson patients (pet scanning for dopamine metabolism)

Familial cases – there was identified forms with clear established genetic defects (less than 25% from all cases)

Progresion of Parkinsons Disease

Parkinson’s Disease

Familial cases - earlier onset (the fourth decade) and a relatively rapid course (10 years from onset to death)

Mutation in the gene enconding the protein α-synuclein (main component of the Levy body ) (crs 4q)

Mutations of exons in Park2 gene (chr 6q) – the commonest types are point mutations or deletions in exon 7 but abnormalities of the other 12 exons evince similar syndromes 50% of families with early onset of parkinson disease harbor

mutations in this gene Up to 2% of late onset cases and 18% of sporadic cases with early

onset are due to parkin mutations (Kahn et all)

Mutations in genes park 5, 6, 7, 8, NR4A2

Parkinson’s Disease

Lewy bodies (LB) are considered as the histological hallmark of Parkinson's disease; They were first described in

cholinergic neurons of substantia innominata

("unnamed substance") Then described in dopaminergic

neurons of substantia nigra (pars compacta) in association with cells depletion and replacement gliosis

There are two morphological types: classical (brain stem) Lewy bodies and cortical Lewy bodies.

A Lewy body is composed of the protein alpha-synuclein associated with other proteins such as ubiquitin, neurofilament protein and alpha B crystallin

Lewy bodies and Lewy neurites in PD

Parkinson’s Disease : Pathophysiology

The major neuropathologic findings in Parkinson disease are a loss of pigmented dopaminergic neurons in the substantia nigra and the presence of Lewy bodies

Primary neurochemical deficiency in Parkinson's disease is the loss of dopaminergic projections of the striatum.

There are also others pigmented an nonpigmeted neuronal population in midbrain and lower brainstam wich are affected

Other neurotransmitter deficiencies such as norepinephrine, serotonin, acetilcholine and gamma amino butyric (GABA) due to neuronal loss in locus ceruleous, lateral tegmental areas of the brain, nucleus basalis of Meynert, raphe nuclei may contribute to secondary symptoms

Recent data suggests that many neurodegenerative diseases (AD, PD) are overlaping

Loss of pigmented neurons in substantia nigra

Normal Parkinson Disease

Symmetrycal activity of striat (healthy volunteer)

Asymmetrycal decrease of striatal activity in a PD patient

Patients may follow or not dopaminergic therapy

Reprinted from Parkinson Study Group. Neurology. 2000;55:1540-1547.

Loss of pigmented neurons in substantia nigra

Clinical Features

Frequently unilateral onset, early symptoms may be overlooked by patient or family members

Initial symptoms in patients with PD (Hoehn and Yahr)

Tremor 70%

Gait disturbance 11%

Rigidity 10%

Slowness of voluntar movement 10%

Muscular aches 8%

Loss of dexterity 7%

Handwriting disturbance (micrographia) 5%

Depression, nervousness, other psychiatric disturbance 4%

Speech disturbance 3%

Clinical Features

Hipokynesia / bradykinesia

Resting tremor

Postural instability

Rigidity

Clinical Features

Tremor Frequently unilateral onset 4~6Hz frequency, Most conspicuous at rest, it increases at times of

emotional stress and often improves during voluntary activity.

Fluctuations of intensity - is aggravated by emotions or walk Frequency remains constant

“Pill-rolling” or “money-counting” character EMG – alternating burst of activity in agonist and

antagonist muscles Negro’s sign (cogwheel phenomenon)

Clinical Features

Rigidity It tends to appear in the more advanced stages of the

disease It can be felt by the palpating finger and seen as a

salience of muscle groups in active and pasive movements or even when the patient relaxes. It affects both the extensor and flexor groups.

Rigidity and cogwheel feature can be elicited or enhanced by having the patient engage the the opposite limb in a motor task requiring some degree of concentration

In the muscle of the trunk, postural hypertonuspredominates in yhe flexor groups and confers on the patient the characteristic flexed posture

Muscle aches (back, neck, shoulders, hips)

Clinical Features

Bradykinesia – slowness in initiation and execution of a movement

Hypokinesia – reduced frequency and amplitude of movement Infrequency of blinking (associated with widening of the palpebral

fissures – stelwag sign), infrequency of swallowing, slowness of chewing,

Limited capacity to make postural adjustments Absence of arm swing in walking, lack of small “movements of

cooperation” Difficulty in executing two motor acts simultaneously, alternating

movements become progressively impeded and finally are blocked completely or adopt the the rhythm of the patient alternating tremor

Micrographia: small, tremulous, cramped handwriting (Charcot) “hypokinetic dysarthria” (Caekebeke): voice softens, speech seems

hurried, monotonous and mumbling

Kinesis paradoxica – in the excitement of some unusual circumstance, the patient is capabil of brief but remarkably effective movement

Clinical Features

Gait disturbance Walking is shuffled, the patient frequently loses

balance, walking forward and backward may seem to be “chasing” the body’s center of gravity with a series of short steps in order to avoid falling (festination)

Defence and righting reactions are faulty Falls occur surprisingly infrequently given the degree

of postural instability Gait is typically improved by sensory guidance, as by

holding yhe patient at the elbow Obstacles such as door tresholds causes the patient

to”freeze” in place

Clinical Features

Dementia – 10-15% of oatients (Mayeux) Incidence increases with advancing age aproaching

65 percent in patients above 80 years of age Sometimes associated with lesions in white matter

Hypersalivation (failure to swallow with normal frequency), seborheea, excessive sweating

Other involuntary movements (dystonias)

Compensatory changes in dopaminergic synapse in PD

Presynaptic: Hiperactivity of

restant dopaminergic neurons (increasing of dopamine turnover)

Postsynaptic Increasing of

receptor’s sensitivity for dopamine

100%

80%

60%

40%

20%

0%

Compensate (no simptoms)

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Un

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Mild simptomatologyImportant simptomatology

Most symptoms do not appear until striatal DA levels decline by at least 70-80%. 

Stimulating the release of dopamine (amantadine)

Increasing the synthesis of dopamine (levodopa)

Stimulating the dopamine receptor sites directly (agonists)

Inhibiting the catabolism of dopamine (MAO B and COMT inhibitors)

Treatment of Parkinson’s Disease

Drug Therapy Against ParkinsonDisease

D1

D2PRESYNAPTIC

POSTSYNAPTIC

Levodopa metabolismIn

test

inal

wall

Levodopa

Levodopa

CO

MT

Inhibited by Entacapone, Tolcapone

Dopamine

Inhibited by Carbidopa,Benserazided

eca

rboxy

lase

3-Ο methyl dopa

MA

O-

B

MAO-B inhibitors (Selegiline)

Deaminated

metabolites

BB

B

Levodopa Dopaminedecarboxylase

CO

MT

Inhibata de Tolcapone

3-Ο methyl dopa

MA

O-

B

Inhibitori de MAO B

Deaminatedmetabolites

MA

O-

B

Deaminatedmetabolites

methoxytyramine

MA

O-

B

Homovanillic acid

CO

MT

L-Dopa therapy

Action: L Dopa fairly effective in eliminating most of the symptoms of Parkinson

disease bradykinesia > rigidity > tremor

L Dopa less effective in eliminating postural instability, shuffling gait, dysarthria, vegetative disturbance meaning other neurotransmitters are involved in Parkinson disease

Decrease of action: frequently after 3-5 years motor fluctuations and dyskinesias may occur

Delivers to restant neurons in substantia nigra the substrate for dopamine sinthesis

Drugs: L-Dopa andBenserazide: Madopar 125/250 tb., 62,5/125 cps.,

Madopar LT tb. (125mg), Madopar 125 Depot-Kapseln; L-Dopa and Carbidopa: NacomR 100/250 tb., Nacom retard 100/200 tb.;

Isicom 100/250 tb., StriatonR 200 tb.

Effects of chronic levodopa administration

End-of-dose wearing-off effect

On/off oscillations

Freezing during movement

Dose failure (drug resistance)

Dyskinesia at peak dose

Complications of long-term therapy with L-dopa

Motor Fluctuations: beneficial effects of levodopa last a few hours and

then diminish: "wearing-off" Rapid and unpredictablechange from a state of

relative freedomof symptoms to one of complete immobility: "on-off"

Off-period dystonia and early morning dystonia : painful contractions of ankle muscles

“Delayed on” : long interval between administration of pill and onset of on effect

“No on” : no response to l-dopa administration "freezing“ phenomenon

Motor complications of long-term therapy with L-dopa

Dyskinesias (choreic, athetosic, dystonic, balistic movements) “peak-dose” dyskinesia (choreic

movement) “end-of-dose" dyskinesia (dystonic aspect) diphasic dyskinesia (choreic and balistic

movements)

Almost always dyskinesias are combined with on-off fluctuations

Catechol-O-methyltransferase inhibitors (COMT)

Action: inhibits metabolisation of L-Dopa to 3-Ο methyl dopa in peripheral tissues (Tolcapone acts in periphery and also centraly, Entacapone only in periphery )

Increases the duration of effect of levodopa doseDrugs :

Entacapone (Comtan) tb. 200mg; Tolcapone (Tasmar) tb. 100/200mg;

Hepatic toxicity

STALEVO – combination 1:4:8 of carbidopa, levodopa and entacapone (tablets 50, 100 and 150 mg)

Inhibitors of Monoamine Oxidase B (MAO-B)

Action: inhibits the metabolic breakdown of dopamine.

Selegiline: Deprenyl tb. 5mg; Stimulatory amphetaminic effect selectively inhibits monoamine oxidase B which metabolizes

dopamine, but does not inhibit monoamine oxidase a which metabolizes norepinephrine and serotonin

Rasagiline (Azilect) 1 mg/day rapidly absorbed, reaching peak plasma concentration in

approximately 1 hour. Monotherapy in early stages and combined with Levodopa in

advanced stages of disease (beneficial effects on dopaminergic motor dysfunction.)

There are some data wich suggests un possible neuroprotective efect Early use of rasagiline may delay the progression of symptoms Patients treated early with rasagiline have a lower functional decline

comparative with those patients who takes rasagiline with a delay of 6 months

Dopamine agonists

Action: the direct influence of the D1 and D2 receptor, dopamine independently different half-lives

Generics and preparations: Bromocriptine, Cabergolin; Lisurid;

Pergolid; α-dihidroergocriptine: Ropinirol: Requip cp

0,25/0,5/1/2/5mg; Ropinirol retard cp 2/4/8 mg Pramipexol: cp0,125/0,25/1mg.

Dopamine agonists

Effective even in monotherapy - postponing the need to introduce levodopa with 12-36 months

Symptomatic benefit less than levodopa

Delay / Reduce motor complications

May delay disease progression

Have a sparing effect of levodopa

• Start with a low dose and slowly increase

• Titrate to therapeutic efficacy

o pramipexole 1.5-4.5 mg/day

o ropinirole 3-24 mg/dayo bromocriptina 7.5-30

mg/dayo pergolide 1.5-4.5 mg/day

Acute side effects: nausea, dizziness, drowsiness, confusion

Not affected by dietary protein intake

NMDA antagonists

Low affinity blocker of the NMDA receptor channel, increases the release of dopamine, blocks up the dopamine reuptake and cholinergic effects

Amantadine: 100mg cpModest effects on tremor, hypokinesia and

postural symptoms May cause edema, worsen heart failure,

exaggerate cognitive impairment disorders ,worsen the glaucoma

Anticolinergics

Action: central and peripheral muscarinic receptor blockade

Clinical action especially on tremor and rigidityCognitive side effects, hallucinations, prostatic

obstruction The effect is cumulative and occurs after several

days of dosing. Dose titrated up to the best into balance between

effectiveness and side effectsGenerics and preparations:

Benzatropin: Cogentinol cp. 2mg; Biperiden: Akineton cp. 2mg, Trihexiphenidil: Artane cp. 2/5mg, Artane retard

Deep Brain Stimulation in Parkinsons Disease

In Parkinson's disease, the rest tremor seems to be caused by a neuronal group located in the thalamus and basal ganglia downloading signals synchronous

Under physiological conditions, these neurons download signals in a chaotic mode

It acts as a pacemaker and enables the premotor cortex, the motor cortex area, and the additional motor

Stimulation of thalamic / subthalamic with high frequency (high frequency periodic pulse - 4100 Hz) suppresses the activity of peace maker, and consequently the peripheral tremor

It was approved by FDA in 2002 Cost: £ 25-30000

Deep Brain Stimulation in Parkinsons Disease

Thalamic stimulation has a favorable effect on tremor especially =>seems to be particularly useful in patients with essential tremor

Pallidal stimulation is effective on dyskinesias, improves rigidity, increases periods "on", has minimal effect or worsens bradykinesia

Subthalamic stimulation is effective on tremor, rigidity, bradykinesia.

Could improve stability, walking, states "freezing"

Requires lower stimulation intensities (longer use)

Continuous Dopaminergic stimulation - DUODOPA

The concept of continuous dopaminergic stimulation reprezents a new trend in the PD pharmacology

The fundamental theory behind this concept consists in the fact that physiological striatal dopaminergic stimulation is constant and that the oral therapy with levodopa cand replace this constant stimulation in a intermitent and non pysiological way

This pulsatile stimulation of the dopaminergic receptors is belived to contribute to the development of the motor fluctuations, which are common after a few years of levodopa treated PD patients and can affect the quality of life

Levodopa – Duodenal Infusion

“Bypass“- stomach area

L-dopa infused directly in duoden/jejuni