Ahead of the curve: Parkinson s Disease 101. Luisa Solis-Cohen, MD Movement Disorders Specialist Colorado Neurodiagnostics Littleton, CO

Ahead of the curve: Parkinson s Disease 101 Luisa Solis-Cohen, MD Movement Disorders Specialist Colorado Neurodiagnostics Littleton, CO

Our goals for discussion... 1. Recognize the motor symptoms of Parkinson s disease (PD) 2. Review the non-motor symptoms of PD 3. Discuss what is known about the underlying cause of PD 4. Discuss possible diagnostic tests 5. Learn about available medical and surgical therapies 6. Highlight recently approved therapies and future treatments 7. Connect you with ways to get involved and/or obtain further information

The many faces of Parkinson s disease.

Parkinson s disease is NOT uncommon.

What is Parkinson s disease? Progressive, neurodegenerative disorder affecting the body s ability to move fluidly. Motor symptoms Non-motor symptoms Dopamine dysfunction in the brain

Motor Symptoms 1. Bradykinesia 2. Tremor 3. Rigidity +/- Postural instability

Bradykinesia = slow movement The DEFINING feature of Parkinson s disease. Often described as weakness, clumsiness, incoordination. Here are some of the ways it affects voluntary and automated movements:

Tremor in Parkinson s disease Classically starts on one hand or leg Most prominent at rest Particularly bothersome if Dominant hand Action tremor also present Limits one s ability to fall asleep

Rigidity = stiffness Reaching across the body Getting out of a car or chair Turning over or repositioning in bed

Motor Symptoms 1. Bradykinesia 2. Tremor 3. Rigidity +/- Postural instability

Gait Dynamics Stooped posture Reduced arm swing Shuffling stride Freezing Unwanted accelerations Postural instability & tendency to fall +/- Tremor

Other motor symptoms... Dystonia: cramping and posturing due to involuntary muscle twisting and contraction despite being at rest. Dyskinesia: uncontrolled, involuntary movement. Commonly regarded as wiggling, head bobbing and fidgeting.

Non-motor symptoms Loss of sense of smell Constipation REM Sleep Disorder Anxiety and/or depression Mood changes Impulsivity Apathy Fatigue Bladder habit changes Restless legs syndrome Cognitive issues memory difficulties, slowed thinking, confusion Vision changes Orthostatic hypotension Sexual problems Drooling Skin changes Excessive sweating Pain

What causes Parkinson s disease?

Alpha-synuclein plays a role in Parkinson s disease Alpha-synuclein is a normal protein we all have. Likely plays a role in cell to cell communication. Overabundant and/or misfolded in Parkinson s leading to certain genetic forms of PD and L ewy Bodies. A H O T T O PI C in PD research. Alpha-synuclein antibody therapy is being studied.

Braak Hypothesis Braak, Heiko; Tredici, Kelly Del; Rüb, Udo; Vos, Rob A. I. de; Steur, Ernst N. H. Jansen; Braak, Eva (2003-03-01). "Staging of brain pathology related to sporadic Parkinson s disease". Neurobiology of Aging. 24 (2): 197 211.

Does Parkinson s originate in the gut? - Truncal vagotomy trends towards decreased likelihood of Parkinson s disease - Bacteria populating the gut appears to be different in people with Parkinson s disease, but poor consistency between studies - Constipation often precedes motor symptoms - Alpha synuclein found in enteric nervous system No conclusions yet! Keep your eyes on the gut!

Barreto et al. Front. Aging Neurosci., 09 January 2015

How did my doctor make the diagnosis of PD? Do I need further testing? Diagnosis is made based on a clinical examination (bradykinesia, rigidity, tremor). M R I is N O T necessary for the diagnosis, but may be obtained in certain individuals, especially if the pattern of symptoms atypical. M R I brain imaging is often normal. Genetic testing is offers limited additional information, but can be beneficial in young onset Parkinsonism. D at scan looks at dopamine transport in the brain, but is not specific to Parkinson s disease.

DaT Scan (Dopamine transporter scan) Most helpful in distinguishing Parkinson s disease from essential tremor or drug induced Parkinson s disease. Not specific to Parkinson s disease. Does not distinguish PD from some forms of Parkinsonism such as PSP, MSA, etc. FDA approved 2011 Small amount of radioactive material used Determines amount of dopamine in brain

Symptomatic Treatment of Parkinson s disease treat symptoms by directly or indirectly compensating for loss of dopamine Carbidopa/levodopa (Sinemet), pramipexole (Mirapex), etc. Exercise Disease modifying Slow ongoing loss of dopamine-producing brain cells among others Neuroprotective Prevents loss of dopaminergic neurons. Restorative Replace lost cells or connections Stem cells, growth factors, gene therapy

Everyone should exercise! Overall well being Heart and bone health Motor symptoms improve Coordination, gait/balance, stiffness Non-motor symptoms improve improve mood & sleep lessen constipation Best exercise? Yoga and Tai Chi - Balance Dancing - Coordination Boxing Swimming Cycling Golf Best exercise is the one you will stick with!

Individualized plan Patient goals Treatment considerations... Minimize falls and other health risks Feasibility of therapy (dosing, cost, transportation ) Age of patient, social dynamics, other medical issues, medication interactions Non-motor symptoms Need for advanced therapies Timing of therapy initiation Rehabilitative services are integral PT, OT, S&S, Lee Silverman Voice Training (BIG and LOUD) Social support systems

Medications for Motor Symptoms Levodopa C arbidopa/levodopa I R /C R ( Sinemet) C arbidopa/levodopa E R ( R ytary) C arbidopa/levodopa intestinal gel infusion ( D uopa) Orally disintegrating tablets ( Parcopa) C arbidopa/levodopa/entacapone ( Stalevo) D opamine agonists Apomorphine ( Apokyn) Pramipexole I R /E R ( M irapex) Ropinirole IR/XL (Requip) R otigotine patch ( N eupro) Bromocriptine ( Parlodel) MAO-B inhibitors Rasagiline (Azilect) Selegiline ( D eprenyl) Fast dissolving selegiline ( Zelepar) Safinamide ( X adago) COMT inhibitors E ntacapone ( C omtan) T olcapone ( T asmar) Anticholinergic T rihexyphenidyl ( Artane) Benztropine ( C ogentin) Other ( multiple mechanisms) Amantadine ( Symmetrel) Amantadine E R ( G ocovri) Amantadine E R ( Osmolex)

Non-motor symptom management Loss of sense of smell C onstipation R E M Sleep D isorder Anxiety and/or depression M ood changes I mpulsivity Apathy Fatigue Bladder habit changes R estless legs syndrome Cognitive issues memory difficulties, slowed thinking, confusion V ision changes Orthostatic hypotension Sexual problems D rooling Skin changes E xcessive sweating Pain

Parkinson s treatment, more than just a pill panini?

Maximizing the Benefits of your Medications... 1. Optimize your doctor s understanding of your goals, your bothersome symptoms and their response to medications. Document and bring to clinic! Journal, spreadsheet, calendar, graph. 2. Be honest about your real medication schedule and dosing at home! 3. Take doses on time 4. To eat or not to eat with your levodopa?

Motor fluctuations

Advanced therapies.

Deep Brain Stimulation (DBS) High frequency electrical stimulation of brain structures by electrodes surgically implanted deep inside the brain Mechanism of action: Disrupt the disruption FDA approved for Tremor 1997 Parkinson s disease 2002 Dystonia 2003 (HDE) Obsessive C ompulsive disorder 2009 ( H DE ) Over 150,000 individuals with DBS implanted worldwide, >⅔ with PD Okun, M. S. (2012). Deep-Brain Stimulation for Parkinson's Disease. New England Journal of Medicine, 367(16), 1529-1538.

Who can benefit from DBS therapy? Majority: PD symptoms for at least 4 years Motor fluctuations, with or without dyskinesias Levodopa offers a good response for at least part of the day Combinations of PD meds were tried without substantial improvement Minority: Medication-resistant tremor Bothersome dystonia PD medications are poorly tolerated at doses need to treat motor symptoms Significant implications to professional life

Smoothing out motor fluctuations Decrease off time Increased on time without bothersome dyskinesias Hickey P, Stacy M. Deep Brain Stimulation: A Paradigm Shifting Approach to Treat Parkinson s Disease. Frontiers in Neuroscience. 2016;10:173.

When is DBS surgery not recommended? Atypical Parkinsonism Primary motor symptoms of concern are not levodopa responsive (can exclude tremor) Psychiatric illness Psychosis Severe depression Dementia Other serious health conditions

DBS is a Team Approach Movement Disorders Neurologist Confirm PD diagnosis / Levodopa on-off evaluations / Medication optimization Discuss expectations and limitations with DBS therapy. Discuss DBS system options and neural targets. DBS programming Neurosurgeon Surgical candidacy consultation Discuss neurosurgical options and DBS systems DBS surgery itself: typically in 2 stages. Battery replacements Neuropsychologist Cognitive evaluation Psychiatrist, social worker, PCP, PT, OT, SLP

The DBS electrode is composed of several contacts.

DBS electrode generates a precise region of stimulation within the intended brain target.

Medtroni c Three FDA Approved DBS Systems Boston Scientific Abbott/SJM Images courtesy of Medtronic, Abbott and Boston

Levodopa Intestinal Gel Infusion (Duopa) FDA approved Jan 2015 Carbidopa/levodopa suspension is delivered continuously into the intestine for up to 16 hours Smooths out motor fluctuations (decreased off time, increased on time without dyskinesias). Some patients no longer take oral medications. Images from Abbvie Inc.

Our goals for discussion... 1. Recognize the motor symptoms of Parkinson s disease (PD) 2. Review the non-motor symptoms of PD 3. Discuss what is known about the underlying cause of PD 4. Learn about available medical and surgical therapies 5. Highlight recently approved therapies and future treatments 6. Connect you with ways to get involved and/or obtain further information

Recent approvals... March 21, 2017 2 clinical trials adjunct therapy to carbidopa/levodopa Mechanisms of action include blocking the enzyme monoamine oxidase B (more available dopamine), blocking sodium and potassium channels and reducing glutamate release Reduce off time Increase on time without dyskinesias Restrictions and a number of drug-drug interactions There are a number of other FDA approved MAO-B inhibitors. No head to head trials. Which is best?

Recent approvals... August 24, 2017 Reduction of time with bothersome dyskinesias 25-30% compared to placebo. R eduction of daily off time by approximately 1 hr per day. Studies compare placebo to amantadine E R. N o comparison to amantadine H C l.

Neuroprotection Israpidine Inosine In the Pipeline... H igh blood pressure medication. Potential for less oxidative stress and possibly less damage to dopaminergic neurons. Phase III STEADY-PD trial ongoing, estimated completion by mid 2019 D rug that elevates blood uric acid level ( higher in those with gout and some kidney stones) Phase III SURE-PD trial ongoing, estimated completion date Aug 2020 E xenatide Diabetes medication. Preclinical studies suggest a role in inhibiting cell death, reducing oxidative stress, enhancing mitochondria function, and promoting neuronal functioning Caffeine Nicotine U nclear if nicotine or another compotent of tobacco plays the integral role N ot permission to take up smoking

Neuroprotection in the Pipeline Anti - alpha-synuclein monoclonal antibody shown to be safe and tolerable phase 1 trials. O ngoing are 2 phase 2 trials looking at efficacy and safety of 2 such M ABs Pasadena and Spark trials. Both recruiting in D enver.

AAN Practice Parameter: Neuroprotection in Parkinson s Disease Levodopa does not accelerate disease progression N o treatment has been shown to be neuroprotective N o evidence that vitamin or food additives can improve motor function in PD

Potential future advanced therapies... High-frequency Focused Ultrasound In clinical trials for tremor (thalamotomy) and dyskinesia (pallidotomy) treatment FDA approved for essential tremor Unilateral lesions only Non-invasive, but permanent tissue destruction Closed-loop deep brain stimulation Stimulation is tailored in response to one s own neuronal activity Adapts to fluctuating symptoms and interpatient variability Potentially decreases side effects, decreases habituation, extends stimulator battery life

Our goals for discussion... 1. Recognize the motor symptoms of Parkinson s disease (PD) 2. Review the non-motor symptoms of PD 3. Discuss what is known about the underlying cause of PD 4. Learn about available medical and surgical therapies 5. Highlight recently approved therapies and future treatments 6. Connect you with ways to get involved and/or obtain further information

Clinical trial opportunities Fox Trial Finder: foxtrialfinder.michaeljfox.org National Institutes of Health: www.clinicaltrials.gov Educational, exercise & support group resources Parkinson Association of the Rockies www.parkinsonrockies.org Davis Phinney Foundation www.davisphinneyfoundation.org Parkinson s Foundation www.parkinson.org Aware in Care Kit www.awareincare.org or 1-800-4PD-INFO

Bonus slides

LRRK 2 (chromosome 12) Autosomal dominant I ncomplete penetrance ( ~50% develop PD by age 75%) 1-2% of all PD have this G 2019S mutation 5% of all familial PD 18% of all Ashkenazi Jews with PD 30% of all Ashkenazi Jews with PD 40% of all N. African Arabs with PD

Genetic testing for LRRK2 If parent has PD and NOT Ashkenazi Jewish: 2% of L R R K 2 mutation 50% penetrance by age 75 50% risk offspring inherits mutation R isk for offspring to inherit L R R K 2 mutation and get PD = 2% * 50%* 50% = 0.5% R isk for parent and another 1st degree relative and Ashkenazi Jewish = 30% of having mutation. R isk that off inheriting the mutation and get PD = 30% * 50% *50% = 7.5%