Lecture 5 - Parkinson's Disease Flashcards
What is an axon?
An axon is a continuation of the cell body
Most of the time the length of the brain cell is a representation of the length of the axon
Longer axon=Longer cell body=has to maintain the whole fibre
Where does the basal ganglia lie?
deep in the forebrain
What makes the human brain so special?
unparallel complexity and organisation
What is Parkinson’s disease?
Progressive disorder of the CNS
effects Basal Ganglia
typically affects victims aged =around 60ish
90% of people experience parkinson’s disease
Dopamine producing neurons degenerate
thought to be due to absence of dopamine production
or
concentration between ACh:DA
exact cause is unknown (idiopathic parkinsons disease)
probable: toxic chemicals (herbicide spray absorbed through skin) & intentance
List the 5x symptoms of Parkinson’s Disease.
Mood Tremor Rigidity Bradykinesia Hypokinesia
How does Parkinson’s Disease affect a person’s mood?
“Parkinsonian Stare”
absent of any emotion
emotionally flat = cannot express emotion through facial expression
due to impaired mood and movement function of the basal ganglia
cannot read /communicate externally, even though feeling the same emotions
SLOWER THINKING
What is the most characteristic symptom of Parkinson’s Disease?
Tremor
then Brady/Hypokinesia
+ Slower THINKING
“often involuntary skeletal muscle contractions interfere with voluntary movements”
What does the Parkinson’s Disease related symptom of Tremor involve?
INvoluntary Tremor AT REST
side OPPOSITE the Basal Ganglia
Muscles of the UPPER limbs may ALTERNATIVELY contract/relax which causes the hand to shake
involuntary m. interferes with voluntary m.
What does Kinesia mean?
movement
What does the Parkinson’s disease related symptom of Bradykinesia involve?
Brady=Slow
Slowness (pace) of movement
Motor Performance is impaired
Slower THINKING
shaving more difficult
slow to get going
What does the Parkinson’s disease related symptom of Hypokinesia involve?
Hypo=Smaller
Reduced muscular movements DECREASE RANGE of motion
handwriting illegibly SMaller
walking steps shorter
What does the Parkinson’s Disease related symptom of Rigidity involve?
is the Rigidity(^muscle tone) of FACIAL muscles
face gets a MASK like appearance
UNBLINKING stare (parkinsonian stare in mood)
OPEN mouth
uncontrolled DROOLING
INcrease in muscle TONE
What is the impaired role of the Basal Ganglia in Parkinson’s disease?
Integration of Mood and Movement
= vacant stare
What is the pathway which degenerates in Parkinson’s disease?
Dopaminergic Nigrostriatal pathway
S.Nigra –> Striatum’s Putamen
What cells are affected by Parkinson’s Disease and where are they located in the brain?
Dopamine cells in the anterior part of the MidBrain
-black pigmented cells in the Substantia Nigra Pars Compacta (SNc) (very COMPACT) die
black –> more pale
start dying on one cell –> spread to other side (becomes a bilateral disease)
spreading is variable dependant on the person
When do Parkinson’s symptoms start appearing?
after 60 ish percent of the dopamine cells in the Substantia Nigra(Basal Ganglia) have died
substantial amount have been killed
What is the term for when death of dopamine cells has spread over both sides? and of what area?
BiLateral Disease
Substantia Nigra
What are the components of the Nigro-striatal pathway?
Substantia Nigra Pars Compacta (compact)–> Putamen in Striatum (disperse)
Nerves extending from SNc have axons terminating in the Striatum(SNc–>Striatum)
SNc neurons release the neurotransmitter dopamine (made in cell body and transported up thro microtubules) to the striatum (putamen)
gives the black pigment (m.c. to melanin)
What are features of dopamine?
is the reason for the black pigmentation of cells in the SNc (metabolically converted to melanin)
complex
excites and inhibits
regulates GABA secretion into the VA-VL of the Thalamus
concentrations of dopamine selectively lowest in parkinson’s disease
NON-universal transmitter(only utilised by 4/5 other pathways)
excitatory or inhibitory effect depends on the which of the 5x receptors dopamine acts on
acts as the activity/discharge/membrane potential
-alters firing rate
-modulates activity of GP and going to back to SN
-then modulates activity of cells goings to thalamus which release GABA
Which part of the Substantia Nigra contain the pigmented cells?
substantia nigra Pars Compact
SNc
What is the metabolic pathway to make dopamine?
Tyrosine –> Dopamine –> Melanin
Un-utilised Dopamine = Melanin = Black
Where is dopamine found in the highest concentration?
In the Basal Ganglia
is ONLY found in 4-6ish OTHER areas (less commonly found than other neurotransmitters)
How is Dopamine released?
in a Pulsiple Gradual way
lack of dopamine in the Globus Pallidus and back to the Nigra
What did the first attempt to fix dopamine involve?
Putative Dopamine
No effect
Nauseus + Vomit
HCl in stomach broke it down and was NEVER ABSORBED into the blood, therefore never got to brain
What is the name of the Pre-cursor chemical which gets turned into dopamine and why is it needed?
L-DOPA
The putative form of dopamine cannot be absorbed through the blood brain barrier (blood-/->brain) and is broken down by stomach acid HCl
therefore replaces dopamine in the striatum
What is L-DOPA?
Precursor to dopamine
CAN reach the brain as it CAN be ABSORBED and then converted to dopamine after it has crossed the blood brain barrier
(one metabolic step away from being converted into dopamine decarboxylose in SNc)
sometimes given Intravenously
Wonder drug for Parkinsons (main)
can come in different forms/combinations
Can L-DOPA be used as a long term treatment? Why or Why-not?
No
L-DOPA is Not a long-term treatment as =over time =can lead to EXCESS L-DOPA =which can lead to NAUSEA and even worse disease of DISKINESIA
You want to increase dose as dopamine-producing-cells are dying, but then the side effect is an ^increased toxicity
“critical” nature of dopamine which has a very finely balanced between required and excessive level (low # enzymes due to dopamine neuron death = low levels of L-DOPA conversion to dopamine = higher (excessive) levels of un-converted L-DOPA
What is Diskinesia?
Uncontrolled/Unexpected Involuntary Movement
Worse than the disease themselves - but occurrence is dependant on the patient
What doesN’T L-DOPA do?
Doesn’t stop the dying of dopamine making cells in the SNc
What does L-DOPA require?
in order to be converted into dopamine it requires the critical enzymes which are only found in dopamine neurons
^death of dopamine cells = v enzymes for L-DOPA conversions = ^levels of unconverted L-DOPA =Diskinesia
What is idiopathic Parkinsons?
Unknown cause toxic chemicals (e.g. herbicide spray) or stroke or trauma (boxing(kills brain cells in general)) = intentnance = probable cause
What are the treatments for Parkinson’s Disease?
Drug
Surgical Lesions
Deep Brain Stimulation
New Novel Treatments
How have treatments for Parkinson’s developed?
research = dopamine treatment/levels
accidental = bleeding anurism / blood vessel at brain base near basal ganglia surgery=GPi cells become HYPERactive due to LOSS of dopamine=firs faster=more GABA release
Stimulate brain to find out if they were in the correct part of the brain(internal capsule = muscle movement)
What is Pallidotomy?
killing of neurons in the Globus Palladus Internus (GPi) by inserting an electrode to stop impulse conduction to the Thalamus
(small lesions in the Globus Pallidus)
^ v. INVASIVE
need to be PRECISE as it is close to the Internal Capsule and Visual Cortex (risk of Losing Vision)
GPi cells release GABA into VA-VL nucleus in Thalamus
v loss of dopamine = excited/hyperactive GPi cells = overactivation of GABA release
this Overactivated release of GABA INHIBITS communication b/w Thalamus and MotorCortex = Decreased excitation from cerebellum = Decreased impulses/info going to UMN = movements SLOWER and more GRADUAL
What were the results of Pallidotomy?
most patients = miraculous cure
negatives=
Issues starting movement=Basal Ganglia
Tremor=possible OSCILATION of thalamus
didn’t work for all patients
had to be very precise (GP small let alone GPi only)(could hit internal capsule or optic nerve(hit=visual defects))
need visual techniques/MRI and taxic co-ordinates/computerised neurosurgery reconstruction
very invasive procedure
How is Pallidotomy carried out?
(the brain itself is not sensitive no pain receptors)
Local Anaesthetise skin
Drill hole past periosteum
Electrode into brain
Continue killing(freezing) cells until tremor disappears
-reduce temp on tip of electrode
What is Thalamotomy? which part of the brain does it involve?
Killing of cells (Lesion) of the VA-VL nucleus in the Thalamus at back (vil)
VA-VL gets input from GPi via GPi axon terminals
thalamus is where the fibres PROJECT TOO
less precision=bigger target= less risk
(note: as imaging improved pallidotomy became preferred)
freeze cells via decreasing electrode temperature and then cells would regenerate
TARGET PROCESSing AREA (Thalamus) = stopped increased inhibition caused b the GABA released from abnormal activity in GPi
Compare usage of Pallidotomy and Thalamotomy
both effective treatments
as imagine improved PALLIdotomy became PREFERREd
What is Deep Brain Stimulation?
Stimulating GPi/Subthalamic Nucleus= as good as = Lesion
Improvements in symptoms
Electrode attached and wire brought out through skull and down to chest = acts as pacemaker = freq (f) and ampli. (A) can be altered by a remote for stimulation
First stimulations = to GPi
Current stimulations = to subthalamic nucleus = ^^ much more effective
=latest treatments
What does each Nucleus have?
Recording
Characteristic profile recording pattern of impulses passing through
What is a benefit of the Deep Brain Stimulation Procedure?
can monitor frequency and amplitude until gets
exact amount of stimulation required of the subthalamic nucleus
+ can vary it
What are some of the New Novel Treatments for Parkinson’s Disease?
dopamine producing cells die, so can you replace?
CELL REPLACEMENT
1. TRANSPLANTATION
- cannot transplant mature human brain cells as they die
a. IMMATURE neurons (fetal)
(Ethical/Technical problems(aborted fetus/baby 10 weeks old v small and only want from SN otherwise will form incorrect structure/tumour))
b. GENETICALLY ENGINEERED CULTURED Neurons to produce dopamine in affected striatum (technical problems could form tumour)
c. EMBRYONIC STEM CELLS
(from embryo, after 4 days old) (ethical problems)
d. Adult Stem Cells (SV2) (medial to caudate nucleus, ventral)
GENE THERAPY
- viral vectors
- Tyrosine Hydroxylase gene to make Dopamine
- for making GABA by INSERTING T.H.genes/GABA gene into the SN (SubThalamic Nucleus) which (Alters Activity) QUIETENS down overactivation of GABA by the hyperactivation of GPi in Parkinson’s
What is the gene to make Dopamine?
Tyrosine Hydroxylase gene
