Lecture 9: Parkinson's Disease Flashcards
What is Parkinson’s disease?
- a long-term degenerative disorder of the central nervous system
- Symptoms generally come on slowly, subtly, over time
- it is a progressive disease because it gets worse over time. Someone could have Parkinson’s for a decade or even two decades before they show symptoms
- Mainly affects the motor system; it affects other systems as well but the motor system one is the most noticeable
- Average life expectancy following diagnosis is between 7 and 14 years
- Currently no cure for PD
What is the epidemiology of PD?
- 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
What are the motor symptoms of PD?
Tremor (resting)
Rigidity
Akinesia (aka Bradykinesia)
Postural instability
What is the resting tremor symptom of PD?
- Slow velocity
- Asymmetrical; not same on both sides (one side is more affected)
- Tremors may affect chin, jaw, arms, legs
- “Pill-rolling”
- The most common presenting symptom; presenting means it makes the person present at the doctors office
- 30% of PD patients do not show tremor
What is the rigidity symptom of PD?
– 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
What is the akinesia (Bradykinesia) symptom of PD?
– 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 (speaking in one tone) and hypophonic (no pitches or changes in tone) dysarthria (speech)
– Loss of facial expressions (hypomimia) and decreased blinking
– Drooling
– Reduced arm swing while walking
What is the postural instability symptom of PD?
- 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; stuck mid-step
- —> Contributes significantly to risk of hip fractures (hip fractures can be fatal)
What are the non-motor symptoms of PD?
1) Psychiatric Disturbances
Depression
Anxiety
Apathy
2) Autonomic Disturbances
Constipation
Sexual dysfunction
Orthostatic hypotension (drop in blood pressure when you stand)
3) Cognitive Impairment (late-stage of PD)
Executive function deficit
Dementia
Hallucinations
4) Sleep Disturbances
Insomnia/fractured sleep (constantly waking up)
Narcolepsy (stimulation overload leading to falling asleep out of nowhere)
REM behavior disorder (RBD) –acting out your dreams
What does the Basal Ganglia consist of?
-- Dorsal Striatum Caudate Putamen -- Globus Pallidus Externa, Gpe Interna, Gpi -- Substantia Nigra Pars compacta Pars reticula -- Subthalamic Nucleus
What does the Basal Ganglia do?
- Sets the overall “tone” or “motivation” for action; BG helps decide which one is the best option for movement. It receives information from all parts of the brain and then decides an action (ex. running away instead of hiding)
- BG communicates directly with the motor cortex (the output of the BG will either turn on or not turn on the motor cortex); it basically tells the motor cortex what to do
- BG is organized into loops; Speaks to different brain regions, integrates information
What are the different loops of the Basal Ganglia?
1) Cognitive Loop
- Turns on/off regions of frontal lobe
- Task switching
- Priority setting; frontal lobe needs to be engaged (decides what your priorities are; if an emergency happens this loop is responsible for switching your priorities/focus)
2) Visual/Oculomotor Loop
- Scanning environment
- Spatial recognition
3) Affective Loop
- Emotional component
- Desire, apathy, impulse
4) Motor Loop
- To move or not to move?
- Putamen, Globus Pallidus and Substantia Nigra
the first three loops helps the basal ganglia decide to activate the motor loop (to move or not to move)
What happens to the BG in PD patients?
Main pathological characteristics of PD are cell death in the BG, specifically in the Substantia Nigra
- Up to 70% of the dopamine (DA) secreting neurons in the SN are affected; this is at the point of presenting to the doctor/seeing symptoms
- Leads to DA depletion in the SN and the nigrostriatal (between substantia nigra and dorsal striatum) DA pathway
- Dysfunctional motor loop of the BG
What’s the role of dopamine in the BG?
- 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 (D1 and D2 Medium Spiny Neurons)
- —> DA is main driver of motor cortex activation
What other NT are responsible for the non-motor symptoms of PD?
1) Noradrenergic Urinary frequency Erectile dysfunction 2) Serotonergic Sleep disturbances REM Behavioral disorder 3) Cholinergic Constipation
What are the progressive stages of PD?
Stage 1: Olfactory bulb, Dorsal motor nucleus
Stage 2: Locus coeruleus; autonomic function disturbances
Stage 3: Substantia nigra; motor symptoms, TRAP, clinical symptoms
Stage 4: Cortex; cognitive impairement behavioural/personality changes
What are the environmental causes of cell death in Parkinson’s Disease?
- 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)
What are the genetic causes of cell death in Parkinson’s Disease?
– 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, encodes alpha-synuclein)
– Genetic testing for some of the genes is possible, but interpretation is difficult
What factors reduce risk of PD?
exercise regularly, smoking (nicotine) and/or drink coffee or tea.
What are Lewy bodies and how do they cause cell death?
- Lewy Bodies: mass accumulation of protein
- Affected neurons (DA neurons in the SN) 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; they become charged and corrupt 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 (seen here before in the SN), medulla oblongata, pontine tegmentum
- —> As disease progresses, substantia nigra, midbrain, basal forebrain and finally neocortex
Leads to apoptosis of affected neurons
What are the treatment options for PD?
1) Levadopa (L-DOPA)
- -Precursor for dopamine synthesis
- - Only 5-10% crosses BBB so most is acting on the periphery and causing other symptoms
- - 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
2) COMT Inhibitors & MAO-B Inhibitors
- - Catechol-O-Methyltransferase (COMT) and monoamine oxidase (MAO) B are enzymes that degrades dopamine so the inhibitors inhibit them so that they cannot break down dopamine
- - Can be used to compliment L-DOPA in early stages
- - Modest symptomatic relief when used alone
3) Dopamine Agonists
- - Bind to DA receptor, and activate it, 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
4) Non-Pharmacological Treatment
- - Education (teach about what PD is which can help reduce the stress faced), support, exercise, nutrition
How can you manage PD with surgery?
Deep Brain Stimulation (DBS)
- Electrodes implanted in a target region (e.g. Globus Pallidus)
- Stimulated with a low-voltage current to facilitate behavior and reduce medication
- Can help relieve some PD motor-symptoms
- Has been used in treatment of depression, OCD, PD, recovery from TBI, and more.
Stem Cell Treatment
- Healthy DA cells can be plugged into the SN
- Many obstacles in the way before this is a mainstream treatment option
However these are not considered actual treatment options**
