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Greg Pontone, MD, MHSDirector, Parkinson’s Neuropsychiatry Cl inical Programs

Johns Hopkins University School of Medicine

Parkinson’s Disease: Moving Toward Improved Understanding and Treatment

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DisclosuresDr. Pontone is a consultant for Acadia Pharmaceuticals Inc

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Learning Objectives•Explain the pathophysiology of Parkinson’s disease, including the motor and non-motor symptoms.

•Summarize new data on current and emerging therapies for Parkinson’s disease•Apply available modalities to patient cases using evidence-based medicine•Describe the impact of OFF periods on patient daily life•Formulate strategies for improving education regarding OFF periods in patients with Parkinson’s disease

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Pathophysiology of Parkinson’s disease

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Parkinson’s DiseaseParkinson’s disease is a progressive neurodegenerative disorder characterized by aggregates of misfolded ⍺-synuclein called Lewy bodies

Parkinson’s disease has a complex clinical phenotype that includes motor and non-motor symptoms that vary not only in severity but also in terms of presence or absence from case to case

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Parkinson’s Disease – Substantia Nigra

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Dopamine Deficiency in the Nigrostriatal Pathway

Basal ganglia – “extrapyramidal system” includes substantia nigra, striatum (caudate and putamen), globus pallidus, subthalamic nucleus, and thalamus

Parkinson’s disease 60% - 80% reduction in dopamine producing neurons in the substantia nigra

Two output pathways from the striatum: indirect pathway in which dopamine (D2) has an inhibitory influence and the direct pathway in which dopamine (D1) has an excitatory influence

In the context of dopamine depletion the indirect inhibitory pathway mediated via D2 striatal receptors is thought to be overactive, whereas the direct inhibitory pathway mediated via D1 striatal receptors is underactive

As a consequence, the main pallidal-thalamic outflow pathway provides excessive inhibitory input to the thalamus, which causes suppression of thalamo-cortical-spinal pathway, causing slowness of movement (bradykinesia)

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Clinical Diagnosis of PDRequires Only Motor SymptomsFirst essential criterion: • Slowing of physical movement (bradykinesia)

Plus at least one of the following:• Tremor (4-7hz)• Muscle rigidity

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Postuma RB et al Mov Disord 2015

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Stage and Severity of Parkinson’s DiseaseHoehn and Yahr Stage

Stage 1 – unilateral involvement only, usually with no functional disability

Stage 2 – bilateral involvement without impairment of balance

Stage 3 – bilateral involvement with impairment of postural reflexes (balance)

Stage 4 – severely disabling disease; still able to walk with assistive device or stand unassisted

Stage 5 – confinement to bed or wheelchair unless aided

Unified Parkinson’s Disease Rating Scale – part 3 motor exam, example for rigidity

0: normal: no rigidity

1: slight: rigidity detected only with activation maneuver

2: mild: rigidity detected without activation maneuver, but full range of motion easily achieved

3: moderate: rigidity detected without activation and full range of motion is achieved with effort

4: severe: rigidity detected without activation and full range of motion not achieved

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Now let me tell you the rest of the story…Non-motor symptoms of Parkinson’s diseaseNeuropsychiatric: apathy, anxiety, depression, psychosis, impulse control disorders

Cognitive impairment, ≤40% have MCI at diagnosis and 80% demented within 20 years of motor symptom onset

Olfactory loss ≤90%

Dysautonomia ≤70%

Sleep disturbances >30%

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11BRAAK ET AL.

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Parkinson’s as a Disease Model for Neuropsychiatric Symptoms

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m edu lla ry raphe nuc le i

nuc leus subcoeru leus

stag es 5 & 6

stag e 1

stag e 2

stag e 3

stag e 4

Dysautonomia:gastrointestinaldisturbances,constipation,genito-urinarydysfunction,sexualdysfunction,orthostatichypotension,cardiacsympatheticdenervationOlfactoryloss;hyposmia:impairmentsinodordetection,identification&discrimination

Sleepdisturbances:REMbehaviordisorder;excessivedaytimesleepiness,insomnia,restlesslegssyndrome

Motorsymptoms:bradykinesia,rigidity,tremor

Cognitivedisorders:mildcognitiveimpairmentanddementia

Mooddisorders:

Anxiety

Depression

au tonom ic nervous sys tem

dorsa l m oto r X nuc leus

o lfac to ry nerve

substan tia n ig ra

am ygda la

basa l nuc leus

h ippocam pus

fron ta l co rtex

parie ta l co rtex

Psychosis:hallucinations,delusions

F igure 1 .C lin ica lcorre la teso fpatho log ica lstag ing in PD .

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13KALIA AND LANG ET AL.

Parkinson’s as a Disease Model for Neuropsychiatric Symptoms

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New Landscape of Parkinson’s Disease

Prodromal PD Symptomatic PD PD Dementia

PD diagnosed by motor symptoms

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New ‘stages’ of Parkinson’s disease

Prodromal: pre-motor, hyposmia, RBD, cardiac sympathetic denervation

Symptomatic: motor symptom onset and progression

Dementia: progressive cognitive decline due to Lewy body disease or comorbidity

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Key Points

• Parkinson’s disease, in most cases, starts years before motor symptoms are present

• Non-motor symptoms such as autonomic dysfunction, REM sleep behavior disorder, and loss of smell are biomarkers of early disease

• Going forward, early recognition and disease modifying treatments will likely significantly lower the burden of PD

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Current and emerging therapies for Parkinson’s disease

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Interventions for Parkinson’s disease

1. Prevention or delay of disease progression (‘disease modifying’)

2. Symptomatic monotherapy

3. Adjunctive therapies

4. Prevent or delay of motor complications

5. Motor complication therapies

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Disease Modifying InterventionsExercise – has insufficient evidence and considered investigational, but is widely recommended

No clinically useful interventions to prevent or delay disease progression (Fox SH et al 2018)

Notable negative studies – MAOIs, CoQ10, creatine, vitamin D, dopamine agonists

Promising candidates – BIIB054 (cinpanemab) targets abnormal alpha-synuclein, BIIB094 (LRRK2 ASO) antisense oligonucleotide helps reduce LRRK2 protein, small molecules may also be helpful, agents that down regulate inflammation especially via type-2 astrocytes

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Symptomatic MonotherapyEfficacious – clinically useful• Dopamine agonists – non-ergot, ergot• Levodopa + peripheral decarboxylase inhibitor – immediate release, controlled

release, extended release

• Monoamine oxidase inhibitors – B-selective, eg, rasagiline, selegiline

Likely efficacious – clinically useful or possibly useful• Anticholinergics• Amantadine

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Adjunctive TherapiesEfficacious – clinically useful• Dopamine agonists• Rasagiline

Likely efficacious – clinically useful or possibly useful• Anticholinergics• Amantadine

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Okun MS. N EnglJ Med 2012;367:1529-1538.

Electrode Implantation for Deep-Brain Stimulation.

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Deep Brain StimulationPotential benefits:• Reduces motor signs of the disease• Improves off time• Improves dyskinesia, especially GPi DBS• STN may allow dopamine reduction

Potential adverse effects:• Speech and cognitive impairment• Gait changes

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Key Points

• Symptomatic therapies are predominantly focused on motor symptoms and are based on increasing dopamine levels

• Adjunctive therapies are used when patients are deemed to be “undertreated” with monotherapy

• Deep brain stimulation is a viable option for many and earlier use and broader application of this intervention is being explored

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Motor complications of dopaminergic therapy

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Levodopa Induced DyskinesiaHyperkinetic involuntary movements of upper and lower limbs, trunk, and less often facial muscles

May occasionally have dystonic posturing

~40% experience dyskinesia after 4-6 years of levodopa treatment

Dyskinesia is associated with longer duration of PD and higher levodopa doses (more than length of time on levodopa therapy)

Dyskinesia is most likely at ‘peak’ dose—high levodopa concentrations

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On-off dopamine medication fluctuations

Stacey M. and Hauser R. 2007

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On-off Dopamine Medication Fluctuations

Most of end-of-dose deterioration (return of motor symptoms)

Occur in >50% of patients at 5 years and nearly 100% at 10 years

Disease duration, exposure to levodopa and cumulative dose, delayed or erratic gastric emptying, female sex, low body weight, and young disease onset

High protein meals interfere with absorption

In rare cases, can occur as early as 6 months after initiating dopaminergic therapy

Most associated with levodopa, but can occur with agonists

Non-motor fluctuations often occur in conjunction with motor fluctuations

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Recognizing Off-Periods (and Other Complications of Therapy)

Ask patients to keep a symptom journal

Suggest they anchor journal entries by noting the time they take PD medications

Do off-periods occur at every dosing interval? Or only after meals?

During what interval of time, relative to medication dosing, do off-periods occur? Dose failure? End-of-dose wearing off?

Do any other (non-motor) symptoms occur during off periods?

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Prevent or Delay of Motor ComplicationsEfficacious – clinically useful• Dopamine agonists

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Treatments for Motor FluctuationsEfficacious – clinically useful• Dopamine agonists

• Levodopa with peripheral decarboxylase inhibitor, several forms, standard, extended release, intestinal infusion

• COMT inhibitors, eg, entacapone• MAOI-B or MAOI-B plus channel blockers• Bilateral STN or GPi DBS

• Unilateral pallidotomy

Likely efficacious – possibly useful• Istradefylline (adenosine A2A antagonist)• Apomorphine SC

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Treatments for DyskinesiaEfficacious – clinically useful• Amantadine• Clozapine, but requires special monitoring• Bilateral STN or GPi DBS• Unilateral pallidotomy

Likely efficacious – clinically useful• Intestinal infusion of levodopa

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Key Points

• Motor complications of dopaminergic therapy include dyskinesia and on-off fluctuations

• Disease duration, rather than time of exposure to levodopa, is thought to be the main factor associated with the development of motor complications

• Motor complications are most typical of moderate to advanced disease

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Case vignettes

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63 year old right handed male with new onset rest tremor in left hand, mild bradykinesia and rigidity

carbidopa/levodopa 25/100mg 1 tablet 3 times daily

rasagiline 1 mg daily

rotigotine transdermal patch

trihexyphenidyl

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72 year old right handed male with an 8 year PD hx, no tremor, moderate bradykinesia and rigidity, severe dyskinesia on standard levodopa Q3 hours

amantadine

rasagiline 1 mg daily

surgery, eg, GPi DBS

transition to extended release levodopa

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56 year old right handed female with PD onset at age 42, now with bilateral symptoms, severe on-off fluctuations and moderate dyskinesia on levodopa 5/day

amantadine

bilateral deep brain stimulation

pramipexole extended release

COMT inhibitor

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Any Questions?

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ReferencesArmstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020 Feb 11;323(6):548-560. doi: 10.1001/jama.2019.22360. PMID: 32044947.

Fox SH, Katzenschlager R, Lim SY, Barton B, de Bie RMA, Seppi K, Coelho M, Sampaio C; Movement Disorder Society Evidence-Based Medicine Committee. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson's disease. Mov Disord. 2018 Aug;33(8):1248-1266. doi: 10.1002/mds.27372. Epub 2018 Mar 23. Erratum in: Mov Disord. 2018 Dec;33(12):1992. PMID: 29570866.

Reich SG, Savitt JM. Parkinson's Disease. Med Clin North Am. 2019 Mar;103(2):337-350. doi: 10.1016/j.mcna.2018.10.014. Epub 2018 Dec 3. PMID: 30704685.

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