Scott J Sherman MD, PhD The University of Arizona PARKINSON DISEASE

Scott J Sherman MD, PhD The University of Arizona PARKINSON DISEASE

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 Environmental or endogenous toxins etiology Single or multiple genes Pathogenesis free mitochondrial oxidative protein radicals dysfunction stress aggregation Parkinson's disease(s)

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

% dopaminergic neurons Age: a PD risk factor 100 80 60 Environmental exposure Normal aging 40 20 0 Parkinsonian Symptoms Other process 0 20 40 60 80 100 age

Environmental factors Age, smoking, gender

Caffeine reduces risk of PD Both 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 The continuum of treatment in PD Dopamine agonist Levodopa Dopamine replacement Ancillary medications Deep Brain Stimulation

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)

Survival distribution function Survival distribution function Dopamine agonists reduce dyskinesia: either as monotherapy or in combination with levodopa 1.00 0.80 0.60 0.40 0.20 Ropinirole L-dopa 0.00 0 1 2 3 4 Years Monotherapy P < 0.0001 * 1.00 0.80 0.60 0.40 0.20 Ropinirole L-dopa 0.00 0 1 2 3 4 Years P < 0.0001 Intention to Treat *

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 COMT-inhibition Entacapone LEVODOPA DOPAMINE CARBIDOPA

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 L-DOPA level Dyskinesia Normal L-DOPA level Dyskinesia Normal PD Symptoms 8 AM 12 2PM 4PM PD Symptoms 8 AM 12 2PM 4PM

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* Before DBS After DBS 27% Good Mobility 73% Poor Mobility 74% Good Mobility 26% Poor Mobility Good mobility: on time without dyskinesia Poor mobility: off time and on time with dyskinesia *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.

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