Parkinson’s Disease

(PD)

Natalie Diaz, MD
Pacific Neuroscience Institute
Providence Little Company of Mary Medical Center
424-212-5361

PACIFICNEURO.ORG
Introduction to PD
• A chronic neurological condition that develops
slowly over many years.

• Currently incurable, but good symptomatic

therapies are available..

• More than 10 million people with PD worldwide.

• Reported that number of people with PD will

double by year 2040.
Who Gets Parkinson’s Disease
Average age of onset 60, 10% diagnosed
before age 50.
Symptoms of Parkinson’s disease
Classic motor  Loss of facial expression
symptoms  Low volume or hoarse voice
 Tremor of the limbs Small handwriting
when at rest  Problems swallowing
 Slow movement  Trouble getting out of a chair
(bradykinesia)
 Stooped posture
 Muscular stiffness
(rigidity)  Loss of arm swing

 Change in walking and  Short, shuffled steps

balance  Freezing when walking
 Problems with balance
Non Motor Symptoms of Parkinson’s disease
• Loss of smell
• Fatigue, excessive daytime
sleepiness
• Apathy
• Depression/ Anxiety
• Problems with memory,
concentration
* The collection of and intensity of symptoms varies from person to person.
 Cont…

• Acting out dreams while asleep

• Lightheadedness when standing
• Constipation
• Urinary frequency or urgency
• Oily skin and dandruff
How is Parkinson’s disease diagnosed?
 No specific blood or imaging
test available to diagnose
PD.

 Diagnosis based on medical

history, a neurological
examination and response to
dopamine- based medications.

 Sometimes blood test, brain MRI or

DAT scan may be performed to
rule out other conditions that have
similar symptoms.
Is Parkinson’s disease hereditary?
 Less than 10% of cases of
Parkinson’s disease are directly
inherited (due to specific gene
mutations).

 Directly inherited genes -

Alpha- synuclein, Parkin and
LRRK2 genes

 In most inherited cases, there is a

strong family history (more than
one family member) and most
start at a young age (under age
40).
Genetic Susceptibility in PD
• Genome-wide association studies (GWAS) –
compare genome of large groups of people
with PD to those without.

• To date >90 variations in the humane

genome identified in PD as compared to
those without PD.

• Individually, genetic variations have

very low contribution as risk factor.

• Genetic variations give clues as to impaired

cellular processes
Environmental Exposures and PD
• Head Injury – repeated or associated with
altered consciousness
• Heavy metals exposure – higher incidence of PD
in welders
• Chronic amphetamine use
• Solvents
• Long term pesticide/herbicide exposure
**Based on studies that show an association and have not proven causality.
What causes PD
Protective Factors

Risk Factors
*Exercise

Aging Caffeine

Genetic Nicotine
Susceptibility
Education
Environmental
exposures Dietary factors

Low vitamin D
What’s happening in the brain
• Slow loss of dopamine producing
cells in the brain.

• Dopamine deficiency leads to

classic motor
(physical )symptoms:
 Tremor with limbs at rest
 Muscular rigidity
 Slow movements
 Changes in walking and
What’s happening in the brain
• Lewy Bodies - accumulations of
abnormally folded proteins

• Alpha synuclein = main protein

• Lewy bodies also found in other affected

brain areas. Other brain centers affected,
alterations in other brain chemicals that
may affect:
 Serotonin – mood, motivation
 Acetylcholine – memory
 Norepinephrine – cardiovascular
control, gait and attention
Where Does PD start?
• Evidence has suggested that PD may start in the little nerves
of the gut or the nose then spread to the brain.

• Constipation and loss of smell may predate the diagnosis of

PD by 10 years or more.
J of Park 11/7/2019

• The brain-gut axis – bidirectional communication regulated

by neural, hormonal and immunological factors.

• Abnormal gut bacterial environment (microbiome) may

alter communication with the brain.

• Gut-first vs. brain-first

PD Therapies in the Pipeline - early2020
Symptomatic therapies 55% (35% motor, 20% non motor
symptoms) Therapies for advanced stage complications
(fluctuations and dyskinesias) 5% Disease modifying
therapies 40%

40%

55%

5%
Disease modifying therapies (DMT)
• Aim to slow or halt the progression of PD.
• No current DMT available at this time.
• Current research targets for disease
modification:
Alpha Neurotrophic Genetic Lifestyle
synuclein and factors targets modification
Lewy Bodies

   
Prevent mis-folding Enhance natural Correct abnormal Diet
protective factors i.e. function
Prevent protein clumping BDNF, GDNF Exercise
Vaccinations Cognitive training
Mind-body practices
Parkinson’s Disease Vaccines
 Active immunization – introduces man-made molecule
similar to alpha-synuclein to trigger body to produce
antibodies.
 2 antibodies being studied
 AFFITOPE PD01A - Phase I study – safe and well tolerated, did produce
antibodies

 Passive immunization – pre-formed antibodies given

that target alpha-synuclein.
 4 antibodies being studied
 PASADENA study – phase II, placebo controlled, 316 patients.
Did not meet the defined combined clinical endpoints. But
did meet secondary endpoints – clinician rating of improved
motor function.
 SPARK study – phase II
Insulin Resistance in the Brain
• Patients with type 2 diabetes have a higher risk (1.5 times) of developing PD.
• Risk of PD up to 60% lower in diabetic patients on certain medications (GLP1
agonists).
• GLP1 agonists shown in animal models to improve brain glucose use and
decrease inflammation
• Exenatide trial
– 60 people, treated for 48 week, 1x/week injection exenatide versus
placebo
– In off state, treated group had improved motor function as compared to
placebo group had worsened since start of trial
– Phase II trial underway
• Others in trials - Liraglutide, Lixisenatide
Nilotinib
• Currently used for treatment of leukemia
• In animal models – reduces abnormal, mis-folded proteins and improves motor function
• 2016 small open label study
– 12 PDD and DLBD, no placebo group, treated for 24weeks
– Positive changes dopamine production and reduction of toxic alpha synuclein in
CSF
– Mild improvement in motor and cognitive symptoms, worsened once nilotinib
stopped
• 2 recent Phase II studies (Georgetown and PSG) yielded conflicting results
– Georgetown – 75 PD patient x12 months treatment – mild improvement in CSF
markers and clinical scores in low dose but not high dose group
– Parkinson study group – 76 patient x 6 months. No effect in CSF markers and
worsening clinical scores when off medication

**Current black warning of increased cardiovascular effects and death

Exercise and Parkinson’s disease

• Growing evidence over > 10 years that exercise, specifically

vigorous exercise, provides neuroprotection and enhances
brain plasticity.

• Exercise :
– enhance dopamine transmission
– increase release of neurotrophic factors
– increase blood flow
– reduce inflammation
– promotes new brain cell growth

Courtesy of APDA
• Goal-directed or dual tasking may provide additional benefits
In Summary

• Parkinson’s disease is a chronic and slowly progressive neurological conditions that spans
decades.

• Most cases are not directly inherited by likely due to a combination of genetic and
environmental risk factors.

• Loss of dopamine causes classic motor symptoms but other brainc centers and brain chemical
can explain the non motor symptoms.

• Parkinson’s disease may start outside of the brain in some people.

• Extensive research looking at different possible mechanisms for disease modifying therapies.
Courtesy of SharonSpence.com