PARKINSON DISEASE

Scott J Sherman MD, PhDThe University of Arizona

LEARNING OBJECTIVES

The Course Participant will:1. Be familiar with the pathogenesis of

Parkinson’s Disease (PD)

2. Understand clinical and neuroimaging criteria

for the diagnosis of PD

3. Be proficient in choosing medications for

symptomatic treatment of PD

4. Understand the role of surgical treatment for

PD

Parkinson’s disease

Movement symptoms-

Tremor

Bradykinesia

Rigidity

Balance

Etiology of Parkinson disease

Pathogenesis

free mitochondrial oxidative protein radicals dysfunction stress aggregation

Parkinson's disease(s)

Environmentalor endogenous

toxins

Single or multiple

genes

etiology

Environmental influences PD

Most PD cases are not inherited

Risk factors

Pesticide exposure

Rural area

Protective factors

Gender (Female hormones)

Caffeine intake

Nicotine

Monogenic causes of PD are rare but

scientifically important

• Protein Aggregation

• α-synuclein

• Mitochondrial maintenance

• Parkin, PINK-1

• LRRK2

• 5% Ashkenazi Jews with

PD

What causes typical PD?

Damaged protein α-synuclein

forms clumps

May spread from cell to cell

via “exosomes”

Impairs cellular function- esp.

mitochondria

0

20

40

60

80

100

0 20 40 60 80 100

age

% d

op

am

iner

gic

neu

ron

s

Environmental

exposure

Normal aging

Other process

Parkinsonian Symptoms

Age: a PD risk factor

Environmental factors

Age, smoking, gender

Caffeine reduces risk of PDBoth caffeine and nicotine interact within dopamine system

Drug develop opportunities:

Adenosine receptor antagonists, under development

Nicotinic Acetylcholine Receptor agonists

New drug class: Adenosine antagonists

(still investigational)

Istradefylline is approved in Japan

More of these drugs are in testing

Related to caffeine

Reduces dyskinesia

Spread of Lewy bodies: PD

progression

Manifestations at PD Onset Tremor at rest

Bradykinesia

Rigidity

Micrographia

Hypophonia

Masked face

Stooped, shuffling gait

Slowing of activities of daily living

Decreased arm swing when walking

Barbosa et al. Psychiatr Clin North Am. 1997;20:769-90.

Playfer. Postgrad Med. 1997;73:257-64.

Parkinson’s disease

Non-movement symptoms- less response

Dizziness/ hypotension

Postural instability-balance

Swallowing problems

Soft voice-speech

Depression–Anxiety-Apathy

Memory problems

Difficulty with mental concentration

Shulman et al. Mov Disord. 2001;16:507-10.

Exercise-Phys Ther.

MAO Inhibitor

Dopamine agonist

Levodopa

Ancillary medications

Deep Brain Stimulation

The continuum of

treatment in PD

Dopamine

replacement

MAO-B inhibitors

Selegeline

Generic available

Rasagaline (Azilect)

Better evidence for neuroprotection

Not converted to amphetamine

Safinamide (Xadago)

Warnings about drug interactions

Dopamine Agonists

Oral

Pramipexole (Mirapex)

Ropinirole (Requip)

Injectable

Apomorphine (Apokyn)

Transdermal

Rotigotine – (Neupro)

Years

Su

rviv

al

dis

trib

uti

on

fu

nct

ion

0.00

0.20

0.40

0.60

0.80

1.00

0 1 2 3 4

L-dopa

Ropinirole

*

P < 0.0001

Years

Su

rviv

al

dis

trib

uti

on

fun

ctio

n

0.00

0.20

0.40

0.60

0.80

1.00

0 1 2 3 4

L-dopa

Ropinirole

*

P < 0.0001

Dopamine agonists reduce dyskinesia: either as monotherapy or in combination with

levodopa

Intention to TreatMonotherapy

Dopamine Agonists

Advantages

Long duration of effect

Do not cause dyskinesia

Allow reduction of

levodopa and smooth out

fluctuations

Can improve

sleep/depression/sensory

sx’s

Disdavantages

Numerous side effects

Drowsiness

Sleep attacks (rare)

Low blood pressure

Leg swelling

Visual illusions

Compulsive behavior

Gambling

Sex addiction

Eating

Levodopa

DOPAMINELEVODOPA

CARBIDOPA

COMT-inhibition

Entacapone

Stages of levodopa effect

Stage 1: “Honeymoon”-works great

Stage 2: “Wearing off” –end of dose

Stage 3: Dyskinesia- at peak dose

Stage 4: Motor fluctuations- Effects become erratic and unpredictable

Dyskinesia

Normal

PD Symptoms8 AM 12 2PM 4PM

L-D

OP

A l

evel

Dyskinesia

Normal

PD Symptoms8 AM 12 2PM 4PM

L-D

OP

A l

evelDyskinesia

8 AM 12 2PM 4PM

L-D

OP

A l

evel

PD Symptoms

Normal

Dyskinesia

8 AM 12 2PM 4PM

L-D

OP

A l

evel

PD Symptoms

Normal

Pharmocokinetic strategies

Rytary

Pharmacokinteic strategies

Duopa: continuous enteral delivery

Carbidopa/Levodopa

Advantages

Most potent

Few side effects

Almost always

necessary

Inexpensive

Disadvantages

Short duration/frequent

dosing needed

Poor absorption by gut

Interference by food

Erratic effects

Stored and converted

by brain cells

Causes dyskinesia

When to start levodopa?

Advantages to early start:

Most efficacious

Few side effects in early stages

Advantages to delayed start

Ultimately require polypharmacy for optimum

treatment

Levodopa have smoother action when added later

Ancillary medications

Movement symptoms

Amantadine 100-300 mg daily

Anticholinergic medications

Trihexyphenidyl (artane) 2-4 mg tid

Benztropine (Cogentin) 1-2 mg daily

Ancillary medications

Non-Movement symptoms

Hypotension

Midodrine

Fludrocortisone

Droxidopa (Northera)

Cognition

Memantine

Cholinesterase Inhibitors

Okay to use these, paradoxically they do not

worsen tremor

What is DBS-how does it work?

Deep Brain Stimulation (DBS)

uses high frequency (HF)

electrical stimulation to mask

abnormal neuronal activity

leading to symptomatic benefit

Benefits of DBS

Increase Periods of Good Mobility*

27% Good

Mobility

73% Poor

Mobility

74% Good

Mobility 26% Poor

Mobility

*Source: The Deep-Brain Stimulation for Parkinson’s Disease Study Group. Deep-brain stimulation of

the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med. 2001;345:956-

963.

Good mobility: “on” time without dyskinesia

Poor mobility: “off ” time and “on” time with dyskinesia

Before DBS After DBS

DBS can effectively control tremor

Tremor can be relatively

resistant to medical

treatment compared to

other PD symptoms

STN STIMULATION

Psychosis and Hallucinations

• “Atypical”

Antipsychotics

• Ideally no dopamine

receptor activity

• Quetiapine

• 25-100 mg daily

• Clozapine

• Requires frequent

labs

• Pimavanserin

• “Nuplazid”

• FDA approved

Summary

PD diagnosis can be aided by DAT scans

Carbidopa/levodopa remains the most potent

medical treatment

Ancillary medications are important therapies

Surgical treatment DBS can be treatment of

choice in carefully selected patients