Lecture Week Four: Parkinson's Disease Flashcards
What is the Basal Ganglia, and where is it?
BG is a group of grey matter sub-cortical structures, adjacent to the thalamus.
What are the two subcortical motor systems that project to the cortex via the thalamus?
- BGTC (basal ganglia thalamo-cortical) motor circuit
- The Cerebellar motor system
What are the three major components of the motor system in the brain?
- Motor Cortex
- Basal Ganglia
- Cerebellum
Basal ganglia includes what structures? (5)
- Caudate
- Putamen
- Globus pallidus
- Subthalamic nucleus
- Substantia nigra
All cerebellar output originates in the ____ ____ _____
All cerebellar output originates in the DEEP CEREBELLAR NUCLEI
The BGTC motor circuit is responsible for…
controlling the preparation and execution of motor plans/schemata
What is a motor program?
a set of motor commands needed to execute a simple motor act.
What BG circuit is involved in simultaneous movements, & execution of learned motor programs (e.g. walking)?
BGTC Motor Circuit
Without BG output, what is affected?
initiation, execution, & sequencing of automatic actions are affected.
How does the BG motor circuit work?
There are two pathways for the BG motor circuit:
- Direct: Premotor areas -> Putamen -> GPi/SNr -> Brainstem -> Spinal cord
- Indirect: Premotor areas -> Putamen -> GPe -> STN -> GPi/SNr -> Brianstem -> Spinal cord
In the BG motor circuit, what inhibits the thalamus?
the GPi and SNr
In terms of the BG motor circuit, (direct and indirect pathway), which pathway is mediated by D1-type dopamine receptors, and which is mediated by D2-type dopamine receptors?
Direct pathway = D1-type dopamine receptors
Indirect pathway = D2-type dopamine receptors
What are D1 and D2-type dopamine receptors responsible for?
D1 = initiating behavioural responses D2 = inhibiting behavioural responses
Is the Direct or Indirect BG pathway affected by early Parkinson’s Disease?
Direct pathway is affected
Is the Direct or Indirect BG pathway affected by early Huntington’s Disease?
Indirect pathway is affected
What does SNpc stand for?
The Substantia Nigra pars compacta (SNpc)
What is the SNpc?
A brain structure that is densely packed with large dopamine-containing
neurons.
• It receives GABAergic inhibitory input from the striatum.
• SNpc neurons project back to the caudate and putamen in a topographic manner.
• Action of the dopamine depends on the type of receptors -> dopamine then acts to modulate the excitatory corticostriatal input
The 5 parallel, segregated ‘basal ganglia thalamocortical (BGTC) circuits’ include:
- Skeletomotor circuit
- Oculomotor circuit
- DLPF circuit
- LOF circuit
- AC circuit
What kind of input occurs in the skeletomotor circuit?
premotor and somatosensory cortical input
What kind of input occurs in the oculomotor circuit?
Frontal eye field & cortical input
What kind of input occurs in the DLPF circuit?
input from the dorsolateral prefrontal cortex
What kind of input occurs in the LOF circuit?
input from the lateral orbitofrontal cortex
What kind of input occurs in the AC circuit?
input from the anterior cingulate and medial OFC
What is the organisation/order of the skeletomotor circuit?
SMA + cortical inputs -> Putamen -> GPi/SNr -> Thalamus
What is the organisation/order of the oculomotor circuit?
FEFs + cortical inputs -> Caudate -> GPi/SNr -> Thalamus
What is the organisation/order of the Dorsolateral Prefrontal Cortical circuit?
DLPFC + cortical inputs -> Caudate -> GPi/SNr -> Thalamus
What is the organisation/order of the Lateral Orbitofrontal Cortical circuit?
LOFC + cortical inputs -> Caudate -> GPi/SNr -> Thalamus
What is the organisation/order of the Anterior Cingulate circuit?
AC + cortical inputs -> Ventral Striatum -> GPi/SNr -> Thalamus
What are the main/only causes of BG dysfunction and/or damage?
Parkinson’s and Huntington’s Diseases
Which disease is associated with damage to SNpc neurons?
Parkinson’s Disease, onset often occurs at age 65-70.
In terms of Parkinson’s Disease-related degeneration of the SNpc, at what % of cell loss do symptoms normally appear?
Symptoms typically appear after around 70-80% of SNpc cell loss
What is the main deficit or consequence that results due to PD?
The main deficit is dopaminergic cell loss in substantia nigra (which projects to the striatum), and the formation of Lewy bodies
What neuroanatomical regions are affected by PD? (8)
Putamen (part of the motor loop) Medial olfactory area, Lateral hypothalamus, Amygdala, Entorhinal, Cingulate, Hippocampal Frontal cortices
What is the most characteristic pathological marker of PD?
Lewy Bodies; which are abnormal aggregations of protein that develop inside nerve cells. They have a spherical structure, and contain filaments and degenerating organelles.
How does the brain try and compensate for the substantial Nigrostriatal Degeneration (70-80%) due to PD?
Remaining survivor neurons produce an increased dopamine output
What ways does PD affect the BG motor circuits? (3)
And, what is the overall net result?
• In PD there is an underactive motor circuit (not as excitable as it should be)
• Loss of dopamine from the SNpc leads to over inhibition of the GPe in the indirect pathway (so that output nuclei are over activated)
• Reduced dopamine also leads to reduced activity along the direct inhibitory projection from the putamen to GPi/SNR (causes akinesia and rigidity)
• Net result - decreased thalamic output –
hypokinesia or decreased motor activity
What are the suspected causes of PD?
Genetic predisposition (5-10% of cases are familial), and Genetic Mutation that forms the following abnormal proteins; parkin, ubiquitin, and a-synuclein.
What mutated protein is a major component of PD Lewy Bodies?
a-synuclein
What external factors can cause mutations in the a-synuclein gene?
toxins like industrial chemicals, carbon monoxide, herbicides, and pesticides
What is levodopa?
Also known as L-dopa, it is a precursor for dopamine. It crosses the blood brain barrier and directly metabolizes into dopamine and helps stimulate the release of dopamine. It alleviates tremors, bradykinesia, and rigidity.
When does L-dopa dose need to be increased?
More L-dopa is needed when more neurons die due to PD. More side-effects also occur.
What is Pallidotomy?
A surgical procedure that creates a lesion in the ventral or internal portion of the globus pallidus. PD-related dopamine decreases cause the pallidum to become overactive, lessioning the GP structure arrests this accessive activity.
who might have a Pallidotomy?
patients who are experiencing difficulty with the PD drugs
Patients receiving deep brain stimulation to the globus pallidus and subthalamic nucleus show…
- Improved motor functioning,
- Increased metabolism in the
premotor cortex and cerebellum. - Alleviates PD symptoms without negative effects.
What are stem cells?
A renewable source of tissue that can be coaxed to become different cell types of the body
What are the best-known stem cells?
Embryonic stem (ES) cells. found within an early-stage embryo. These cells can generate all the major cell types of the body (they are “pluripotent”).
What do adult stem cells do?
adult stem cells help with maintenance and repair by becoming specialized cells types of the tissue or organ where they originate
What has been the level of response (%) in PD patients who received Stem Cell Therapy?
After 3 years of stem cell therapy, recipients under 60 yrs had improved 30% and older patients by 14%
What is one major hurdle to stem cell therapy for Parkinson’s Disease?
Work is still needed to generate robust cells, in both quality and quantity, that can also survive and function appropriately in a host brain
How are cues used in rehabilitation therapies for PD?
Internal cueing mechanisms (via globus pallidus) are damaged and patients rely on cues to direct movements. Two major external cues are used in clinics:
- Tape cues on a walkway allow patients to increase their stride length
- Metronomes act as cues to initiate movements and also act as rhythmical music therapy for PD patient’s homes.
Finish these facts about PD:
– A form of _________ ___________ dementia
– Attacks the _____ ______ (mainly the _______ ______) and the _________ system
– Slowed _____ ______ and ______ function
– Is not common under ___ years
– Average age at onset is ___ years
– PD is a ______ disorder; there are a range of clinical features
FACTS:
– A form of sub-cortical neurodegenerative dementia
– Attacks the basal ganglia (mainly the substantia nigra) and the dopaminergic system
– Slowed general motor and cognitive function
– Is not common under 40 years
– Average age at onset is 65 years
– PD is a heterogeneous disorder; there are a range of clinical features
What are the 7 motor symptoms of PD?
– Resting tremor
– Bradykinesia (difficulty executing movements)
– Akinesia (difficulty initiating movements)
– Muscular rigidity & impaired balance
– Stooped posture, small, shuffling steps, poor arm swing
– Micrographia (progressive shrinking of writing)
– “Masked face” (expressionless face)
What are the 5 Executive Functioning difficulties in PD?
– changing mental set – maintaining mental set – set-shifting – verbal fluency – planning and organizing
What happens to language and speech in PD patients?
General language processing and sentence structure is intact (no aphasia or linguistic impairment). Some problems with: - Understanding grammatical complexity - Articulation - Bursts of speech - Compulsive word repetition
What happens to memory in PD patients?
Memory function is relatively spared in PD. May show recall deficits on:
- paired associative learning,
- visual reproduction of geometrical designs
(note: PD patients still show encoding and registration of this material, just impaired recall)
Do people with Parkinson’s Disease often have good insight on their problem?
Yes!
What happens to Visual-Spatial skills in PD patients? (4)
Evident impairment.
- Poor visual spatial activity on motor and non-motor tasks
- Impaired ability to do matching, drawing of lines, and following targets on a screen
- Slowed eye initiation and execution
- Overshoot targets and have hypo reflexivity
