Neurodegenerative disorders

Question 0

what is a major problem with treating neurodegenerative disorders?

Answer 0

as the disease progresses the symptoms get worse

only have treatments for symptoms

Question 1

what are the characteristics of a neurodegenerative disorder ?

Answer 1

loss of neurones from CNS and some motor neurones
progressive
irreversible

Question 2

what are examples of neurodegenerative diseases ?

Answer 2

PD - onset can be any age but generally over 70
HD- onset is about middle life
AD- >60yrs, at >85yrs 20-25% people have it
FTD/picks- onset in old age
motor neurones- middle life
PSN
CBGD

Question 3

define dementia:

Answer 3

an acquired persistent intellectual impairment involving at least 3 of the following

• memory
• language
• visuospatial skills
• emotion/personality
• cognitive/executive functions

Question 4

general info on pd :

Answer 4

first described by james palsy in 1817 - shaking palsy
common worldwide
incidence increase >70yrs older you are the more likely you are to develop it
akinetic rigid syndrome= loss of movement and increased muscle tone

Question 5

what is the pathology of PD?

Answer 5

• loss of neurones in the substantia nigra
• dopaminergic neurones affected
• loss of nigro-striatal pathways direct/indirect
• direct pathway facilitates movement
• indirect pathway inhibits movement

Question 6

what does treatment often try to recover in PD?

Answer 6

tries to recover the loss of dopamine neurons in the stn

• increase the amount of DA in remaining neurons
• prevent breakdown of DA
• increase release of remaining DA
• use DA agonists
• alter acetylcholine activity in striatu

Question 7

what approaches are taken to increase DA activity ?

Answer 7

replace DA with L-DOPA
decrease DA breakdown with MAO inhibitors and COMT inhibitors
increase DA release with amantidine
DA agonists such as bromocriptine and pergolide

Question 8

what approaches are taken to decrease ACh activity ?

Answer 8

antimuscarinics such as benzhexol and orphenadrine

Question 9

why is L-DOPA given ?

Answer 9

tyrosine is the aa that forms DA but it cannot cross BBB
L-DOPA is the precursor of DA and it can cross BBB and be taken up by DA neurones
- taken up into neurons by carrier mechanism
- this increases the amount of DA in DA neurones so it releases mre DA upon AP
- it can also be taken up by glial cells

Question 10

why is L-DOPA not taken orally ?

Answer 10

although it can be taken orally, 90% of it is lost by the liver and even once it is absorbed by the intestine it can be broken down readily in the periphery causing the loss of another 9% so therefore only 1% reaches the brain

Question 11

what happens to 90% of L-DOPA?

Answer 11

it is metabolised in the intestinal wall by DOPA decarboxylase or MAO

Question 12

what is usually given alongside L-DOPA and why ?

Answer 12

carbidopa
- because it inhibits DOPA decarboxylase and it cannot cross the BBB so it enables the L-DOPA to reach the brain in sufficient amounts

Question 13

what are the adverse effects of L-DOPA ?

Answer 13

‘on-off’ effect - this is a serious side effect in which there is a worsening of PD symptoms aas DA concentration drops - the mechanism is unknown
nausea, vomitting, anorexia- activates the chemoreceptive trigger zone
dyskinesias- too much L-DOPA causing then too much movement
tachycardia, extrasystoles
hypotension - could be due to central sympathetic inhibition
insomnia,, confusion, schizophrenic effects- these are due to increase DA turnover

Question 14

what do PD patients become very adept in ?

Answer 14

in knowing how much L-DOPA they need to take and when

Question 15

what are often used to control the side effects caused by increased DA turnover ?

Answer 15

neuroleptics- with no D2 action

Question 16

what happens with the side effects of LDOPA ?

Answer 16

they are greater with time because the dose of L-DOPA needs to be increase and so therefore with time it is no longer effective

Question 17

what do MAO inhibitors do ?

Answer 17

they inhibit MAO and therefore reduce the breakdown of DA
useful first line therapy
e.g. selegiline

Question 18

what is selegiline ?

Answer 18

= deprenyl
MAO b inhibitor so has fewer side effects
may have neuroprotective effects - thought it may have antioxidative effects to slow nerve damage
few side effects
potentiates central side effects of L-DOPA
effective on its own in the early stages but ineffective in later stages

Question 19

what do COMT inhibitors do ?

Answer 19

block COMT to increase the concentration of DA and L-DOPA

e.g entacapone - first licensed in 1998

Question 20

when are COMT inhibitors often used ?

Answer 20

for patients with ‘on-off’ problems
usually used in combo with L-DOPA
it smooths out variations with DA levels

Question 21

what are the adverse effects of COMT inhibitors ?

Answer 21

aggravate L-DOPA dyskinesias
nausea- action at chemoreceptive trigger zone 
diarrhoea
abdo pain 
dry mouth

Question 22

what does amantadine do ?

Answer 22

increases DA release - it is an amphetamine
useful in the early stages
generally well tolerated
can cause confusion and hallucinations in the elderly

Question 23

what are bromocriptine and pergolide?

Answer 23

dopamine agonists 
bromocriptine is a d1 and d2 
pergolide is d2 selective 
given alone or with L-DOPA 
half life of 6-8 hours - need to take 2-3 times a day

Question 24

what are the adverse effects of bromocriptine and pergolide ?

Answer 24

dyskinesias
nausea, vomitting- chemoreceptive trigger zone
severe hypotensive effects
sometimes hallucinations

Question 25

what are antimuscarinics?

Answer 25

block muscarinic receptors
e.g benzhexol and orphenadrine
most effective on tremor and drooling

Question 26

what are the adverse effects of antimuscariniccs?

Answer 26

central effects- confusion, deluisions, hallucinations, drowsiness and mood changes

Question 27

what happens once youve been diagnosed with PD?

Answer 27

you see a neurologist to control and tailor the treatment to the patient

• effects of different drugs vary between individuals
• treatment has to be changed overtime

Question 28

what are the 3 main surgical procedures that can be used to treat PD?

Answer 28

lesions
implantable stimulators
grafts

Question 29

what are lesion surgeries ?

Answer 29

motor thalamus- thalamotomy
globus pallidus- pallidotomy
subthalamus- subthalamotomy
these are severe procedures and not that effective and as the disease progresses the symptoms return

Question 30

what are implantable stimulators ?

Answer 30

deep brain stimulators- done in absence of general anaesthesias

• electrode is advanced into the subthalamic nucleus and then look for lessening of symptoms
• effective for several years

Question 31

what are grafts ?

Answer 31

adrenal medulla- mixed results and not its been dropped as a treatment idea- take chromaffin cells into the striatum because only they produce catecholamines
foetal nigral tissue- fetus’ that have been aborted - shown limited success
GM fibroblasts- take skin cells from animals and modify them to produce DA and put them back into animals to see if DA produced- problem was that the cells kept dividing
stem cells- need to develop a way to differentiate them into DA neurons and also stop them continually dividing
xenografts - take DA tissue from another animal however this has ethical issues