Parkinson’s Disease Flashcards
What is Parkinson’s Disease?
• Parkinson’s disease (PD) is a long-term degenerative disorder of
the central nervous system
- Symptoms generally come on slowly, over time
- Mainly affects the motor system
- Average life expectancy following diagnosis is between 7 and 14 years
- Currently no cure for PD
Epidemiology of PD
In 2015, PD affected ~6.2 million people worldwide and resulted in about 117,400 deaths
• In Canada, ~1 in every 500 people are affected by PD - ~6,600 new cases per year
• Typically, PD occurs in people over 60 years of age - Prior to age of 50, considered young-onset PD
• Males are more often affected than females
Clinical Presentation – Motor Symptoms
Remember TRAP!
These are the most recognizable symptoms of PD:
(Resting) Tremor Rigidity
Akinesia (aka Bradykinesia) Postural instability
Motor Symptoms: Resting tremor
- At rest!
- Slow velocity
- Asymmetrical
- Tremors may affect chin, jaw, arms, legs
- “Pill-rolling”
- The most common presenting symptom
- 30% of PD patients do not show tremor
Motor Symptoms: Rigidity
- Occurs in over 90% of patients
- Characterized by increased resistance - The “cogwheel” phenomenon
- Increased muscle tone and contraction
- Present through the range of passive movements of a limb
- E.g. flexion, extension, or rotation about a joint
- Can occur in neck, shoulders, hips, wrists, ankles - Proximally & distally
Motor Symptoms: Bradykinesia
- The most characteristic clinical feature - Present in every single case of PD
- Slowness in performing activities of daily living
- Loss of spontaneous movements & gesturing
- Monotonic and hypophonic dysarthria (speech)
- Loss of facial expressions (hypomimia) and decreased blinking
- Drooling
- Reduced arm swing while walking
Motor Symptoms: Postural Instability
- Loss of postural reflexes
- Generally, manifestation of late stage PD
- Can lead to impaired balance and frequent falls
- Most common cause of falls
- Along with freezing of gait
- Contributes significantly to risk of hip fractures
Clinical Presentation – Non-Motor Symptoms
Psychiatric Disturbances
Autonomic Disturbances
Cognitive Impairment
Sleep Disturbances
Sleep Disturbances
Insomnia/fractured sleep
- Narcolepsy
- REM behavior disorder (RBD)
Cognitive Impairment
- Executive function deficit
- Dementia
- Hallucinations
Autonomic Disturbances
- Constipation
- Sexual dysfunction
- Orthostatic hypotension
Psychiatric Disturbances
Depression
- Anxiety
- Apathy
How does Parkinson’s Disease all happen?
Let’s start with the Basal Ganglia (BG) What is the BG? Dorsal Striatum Globus Pallidus Substantia Nigra Subthalamic Nucleus
Dorsal Striatum
- Caudate
* Putamen
Globus Pallidus
• Externa, Gpe • Interna, Gpi
Substantia Nigra
- Pars compacta
* Pars reticula
What does the BG do?
Sets the overall “tone” or
“motivation” for action
- Part of a system that focuses actions - Picks the correct ones
- Output of BG dictates the likelihood that movements will occur
- BG is organized into loops
- Speaks to different brain regions,
integrates information
BG Loops
Cognitive Loop
Visual/Oculomotor Loop
Affective Loop
Motor Loop
Motor Loop
- To move or not to move?
- Putamen, Globus Pallidus and
Substantia Nigra
Affective Loop
- Emotional component
- Desire, apathy, impulse
Visual/Oculomotor Loop
Scanning environment
- Spatial recognition
Cognitive Loop
- Turns on/off regions of frontal lobe
- Task switching
- Priority setting
What happens to the BG in PD patients?
Main pathological characteristics of PD are cell death in the BGà Substantia Nigra
- Up to 70% of the dopamine (DA) secreting neurons in the SN are affected
- Leads to DA depletion in the SN and the nigrostriatal DA pathway
- Dysfunctional motor loop of the BG
- TRAP
What’s Dopamine’s role?
DA neurons in the SN form strong connections with the dorsal striatum, globus pallidus and the motor cortex - These are excitatory connections - Dorsal striatum (motor) has dense expression of (D1 and D2) dopamine receptors - DA is main driver of motor cortex activation There are a number of compensatory mechanisms that can mask early symptoms of PD
Noradrenergic
- Urinary frequency
- Erectile dysfunction
Serotonergic
- Sleep disturbances
- REM Behavioral disorder
Cholinergic
- Constipation
Understanding PD progression
There are 4 stages
Stage 1 of PD
Olfactory bulb
Dorsal motor nucleus
Stage 2 of PD
Locus coeruleus
Stage 3 of PD
Substantia nigra
Stage 4 of PD
Cortex
PD progression Neuronal cell loss
Subtle, non-motor symptoms
PD progression 5 years
Diagnosis
First clinical symptoms appear when around 70% of neurons are lost
PD progression 10 years
Neuronal cell loss continues
Symptoms Progress
Wearing off phenomena
Random fluctuations
PD progression 15 years
Severe presynaptic cell loss
Decreasing response to L-dopa
What Causes Cell Death in PD?
PD is mostly idiopathic we don’t know what causes it!
Environmental
Genetic
Environmental PD
- Toxins and/or pollutants (e.g. insecticides, herbicides) - Head injuries (e.g. boxing)
- Infections (e.g. encephalitis, syphilis)
- Side effects of drugs (e.g. MPTP)
- Injury (e.g. stroke, lesions)
Genetic
- Typically early onset (>50) PD is associated with genetic factors
- 15% of individuals with PD have a first-degree relative with the disease
- 5% – 10% of PD cases are known to occur because of mutation in one of several specific genes
- SNCA,encodesalpha-synuclein
- Genetic testing for some of the genes is possible, but
interpretation is difficult
Lewy bodies
Both genetic and environment lead to Lewy bodies
Affected neurons show presence of Lewy Bodies
• Abnormal aggregates of the alpha-synuclein protein that develop inside neurons
- Pathological alpha-synuclein acts as a template that corrupts normal alpha-synuclein
- Leads to spherical masses located in the cytoplasm
- Displace other cell components
• Can be identified under the microscope
- Appear in the olfactory bulb, medulla oblongata, pontine
tegmentum
- As disease progresses, substantia nigra, midbrain, basal forebrain and finally neocortex
• Leads to apoptosis of affected neurons
- Signs of programmed cell death are evident
Current Treatment Options
Levodopa (L-DOPA)
COMT Inhibitors & MAO-B Inhibitors
DopamineAgonists
Non-PharmacologicalTreatment
Levodopa (L-DOPA)
- Precursor to dopamine
- Only 5-10% crosses BBB
- Improvement (temporarily) in motor symptoms
- Long-term, leads to involuntary movements called dyskinesias, hallucinations, agitation
- Fluctuations occur and patient will cycle through phases with good responses to medication and poor responses to medication
COMT Inhibitors & MAO-B Inhibitors
Catechol-O-Methyltransferase (COMT) and monoamine oxidase (MAO) B are enzymes that degrades dopamine
- Can be used to compliment L-DOPA in early stages
- Modest symptomatic relief when used alone
DopamineAgonists
- Bind to DA receptor, and reduce motor symptoms of PD
- Less effective than L-DOPA, but can be used in early stages
- Side effects include hallucinations, insomnia, nausea, constipation, impulse control issues
Non-PharmacologicalTreatment
- Education, support, exercise, nutrition
Management through surgery
Deep Brain Stimulation (DBS)
Stem Cell Treatment
Stem Cell Treatment
- Healthy DA cells can be plugged into the SN
- Many obstacles in the way before this is a mainstream treatment option
- Healthy DA cells can be plugged into the SN
- Many obstacles in the way before this is a mainstream treatment option
