Lecture 5 - Parkinson's Disease

Question 1

What is an axon?

Answer 1

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

Question 2

Where does the basal ganglia lie?

Answer 2

deep in the forebrain

Question 3

What makes the human brain so special?

Answer 3

unparallel complexity and organisation

Question 4

What is Parkinson’s disease?

Answer 4

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

Question 5

List the 5x symptoms of Parkinson’s Disease.

Answer 5

Mood
Tremor
Rigidity
Bradykinesia
Hypokinesia

Question 6

How does Parkinson’s Disease affect a person’s mood?

Answer 6

“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

Question 7

What is the most characteristic symptom of Parkinson’s Disease?

Answer 7

Tremor
then Brady/Hypokinesia
+ Slower THINKING
“often involuntary skeletal muscle contractions interfere with voluntary movements”

Question 8

What does the Parkinson’s Disease related symptom of Tremor involve?

Answer 8

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.

Question 9

What does Kinesia mean?

Answer 9

movement

Question 10

What does the Parkinson’s disease related symptom of Bradykinesia involve?

Answer 10

Brady=Slow
Slowness (pace) of movement
Motor Performance is impaired
Slower THINKING

shaving more difficult
slow to get going

Question 11

What does the Parkinson’s disease related symptom of Hypokinesia involve?

Answer 11

Hypo=Smaller
Reduced muscular movements DECREASE RANGE of motion

handwriting illegibly SMaller
walking steps shorter

Question 12

What does the Parkinson’s Disease related symptom of Rigidity involve?

Answer 12

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

Question 13

What is the impaired role of the Basal Ganglia in Parkinson’s disease?

Answer 13

Integration of Mood and Movement

= vacant stare

Question 14

What is the pathway which degenerates in Parkinson’s disease?

Answer 14

Dopaminergic Nigrostriatal pathway

S.Nigra –> Striatum’s Putamen

Question 15

What cells are affected by Parkinson’s Disease and where are they located in the brain?

Answer 15

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

Question 16

When do Parkinson’s symptoms start appearing?

Answer 16

after 60 ish percent of the dopamine cells in the Substantia Nigra(Basal Ganglia) have died
substantial amount have been killed

Question 17

What is the term for when death of dopamine cells has spread over both sides? and of what area?

Answer 17

BiLateral Disease

Substantia Nigra

Question 18

What are the components of the Nigro-striatal pathway?

Answer 18

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)

Question 19

What are features of dopamine?

Answer 19

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

Question 20

Which part of the Substantia Nigra contain the pigmented cells?

Answer 20

substantia nigra Pars Compact

SNc

Question 21

What is the metabolic pathway to make dopamine?

Answer 21

Tyrosine –> Dopamine –> Melanin

Un-utilised Dopamine = Melanin = Black

Question 22

Where is dopamine found in the highest concentration?

Answer 22

In the Basal Ganglia

is ONLY found in 4-6ish OTHER areas (less commonly found than other neurotransmitters)

Question 23

How is Dopamine released?

Answer 23

in a Pulsiple Gradual way

lack of dopamine in the Globus Pallidus and back to the Nigra

Question 24

What did the first attempt to fix dopamine involve?

Answer 24

Putative Dopamine
No effect
Nauseus + Vomit
HCl in stomach broke it down and was NEVER ABSORBED into the blood, therefore never got to brain

Question 25

What is the name of the Pre-cursor chemical which gets turned into dopamine and why is it needed?

Answer 25

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

Question 26

What is L-DOPA?

Answer 26

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

Question 27

Can L-DOPA be used as a long term treatment? Why or Why-not?

Answer 27

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

Question 28

What is Diskinesia?

Answer 28

Uncontrolled/Unexpected Involuntary Movement | Worse than the disease themselves - but occurrence is dependant on the patient

Question 29

What doesN'T L-DOPA do?

Answer 29

Doesn't stop the dying of dopamine making cells in the SNc

Question 30

What does L-DOPA require?

Answer 30

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

Question 31

What is idiopathic Parkinsons?

Answer 31

``` Unknown cause toxic chemicals (e.g. herbicide spray) or stroke or trauma (boxing(kills brain cells in general)) = intentnance = probable cause ```

Question 32

What are the treatments for Parkinson's Disease?

Answer 32

Drug Surgical Lesions Deep Brain Stimulation New Novel Treatments

Question 33

How have treatments for Parkinson's developed?

Answer 33

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)

Question 34

What is Pallidotomy?

Answer 34

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

Question 35

What were the results of Pallidotomy?

Answer 35

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

Question 36

How is Pallidotomy carried out?

Answer 36

(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

Question 37

What is Thalamotomy? which part of the brain does it involve?

Answer 37

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

Question 38

Compare usage of Pallidotomy and Thalamotomy

Answer 38

both effective treatments | as imagine improved PALLIdotomy became PREFERREd

Question 39

What is Deep Brain Stimulation?

Answer 39

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

Question 40

What does each Nucleus have?

Answer 40

Recording | Characteristic profile recording pattern of impulses passing through

Question 41

What is a benefit of the Deep Brain Stimulation Procedure?

Answer 41

can monitor frequency and amplitude until gets exact amount of stimulation required of the subthalamic nucleus + can vary it

Question 42

What are some of the New Novel Treatments for Parkinson's Disease?

Answer 42

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

Question 43

What is the gene to make Dopamine?

Answer 43

Tyrosine Hydroxylase gene