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Question 1

what are the functions of the 4 main players in the brain?

Answer 1

cerebral hemisphere

• where sensory information is processed
• controls voluntary movement
• regulates conscious thought and activity

cerebellum: in charge of balance and coordination
brainstem: relays and recieved messages to and form the brain to other organs
hippocampus: short term memories converted to long term - affected in AD

Question 2

what are β-amyloid plaquesand how do they form?

Answer 2

• β-amyloid plaques = dense deposits of protein and cellular material that accumlate outside and around nerve terminals
• amyloid precursor protein (APP) is the precursor to amyloid plaque:
  
  1. APP sticks through the neuron membrane
  2. enzymes cut the APP into fragments of protein, including β-amyloid
  3. β-amyloid fragments come together in clumps to form plaques

Question 3

how do β-amyloid plaques –> AD?

Answer 3

• β-amyloid generation –> 2o events –> death of neurons
• plaques disrupt the work of neurons - affects hippo and other areas of cerebral cortex
• accumulation due to failure to clearance mechanisms

Question 4

describe the metabolism of APP.

Answer 4

• cleaved at A/B domain at N-terminal
• then cleaved at A/B domain at C-terminal end –> pathological part i.e. β-amyloid

Question 5

what are the features of neurofibrillar tangles (NFTs)

Answer 5

• twisted fibres that build up inside the nerve cells
• neurons have internal support structure - partly made up of MTs, tau helps to stabilise them
• NTFs:
  
  • hyperphosphorylation of tau disrupts its normal function –> aggregation of tau into NFTs
  • paired helical filaments of abnormally phosphorylated tau

Question 6

what is the cholinergic hypothesis in AD?

Answer 6

• AD caused by deficiency of ACh
• not cause: anti-chlinesterases do not slow disease, just treat symptoms
• loss of ACh correlates with AD cholinergic systems are important in learning, memory, cognition
• atrophy of nucleus basalis of Meynert (source of acetyltransferase) –> actual deficieny

Question 7

what are the aims of therapy?

Answer 7

• improve cognitive function
  
  • treat decreases choline acetyltransferase in cortex and hippocampus
  • enhance cholingeric func may stabilise cog function
• limit progression
• symptom control

Question 8

what are the feature of Donepezil?

Answer 8

• AD treatment
• non-competitive cholinesterase inhbitior
• decreases breakdown
• generally well tolerated
• metabolised by Cyt P450
• once daily dose
• adverse effects:
  
  • nausea, vomiting, anorexia, depression, urinary incontinance

Question 9

what are the features of Galantamine?

Answer 9

• competitive chlinesterase inhibitor and allosteric modulator of nic R’s
• AD drug
• dual mechanism
• lower levels of ACh required to sensitise NR’s
• may increase release of ACh and have neuroprotective effect

Question 10

what are Rivastigmine, Tacrin and Mamatine and their properties?

Answer 10

AD drugs

• Rivastigmine: chloinesterase inhibitor
• Tacrine: chloinesterase inhibitor (can –> liver toxicity)
• mamatine: NMDAR antagonist
  
  • reduce glu-induced neuronal degradation
  • prevents mitochondrial dysfunction, inflammation

Question 11

what role to seretases play in AD?

Answer 11

• β secretase: membrane-tethered aspartyl protease, amyloid precursor protein amino terminus
• γ secretase: cleaves APP within its TM segment
• presenilin: affects APP processing, if mutation –> amyloid plaques
• secretase inhibitors do NOT work in trials

Question 12

describe the use of vaccinations in AD.

Answer 12

amyloid vaccine:

• reduced plaque burden and memory loss in mice modes
• trials halted due to deaths
• vaccine showed less declune in neurons, slower cognition fall

Question 13

describe how Zn-treatment and MAb’s can be used in AD treatment.

Answer 13

MAb’s

• humanised MAb: bapineusumab (anti- Aβ)
• given i.v.
• slowed memory loss, conclusions undefined

Zn2+

• Cu2+ and Zn2+ involved in sequestering Aβ –> clearance, degradation
• decreased levels of Zn2+ in cleft
• possible treatment?

Question 14

describe the pathology of PD.

Answer 14

• degeneration of DAergic neurons in the substantia nigra compacta
• lewy bodies present
  
  • Parkin gene implicated in lewy bodies

Question 15

what is the current treatment managing in PD?

Answer 15

• drugs provide symptomatic relief (not curative)
• restore DA deficiency
  
  • increase synthesis and release
  • DA agonists
  • decrease DA metabolism
• restore DAergic /cholinergic balance in striatum
  
  • cholinergic antags

Question 16

describe DA synthesis, metabolism etc in CNS.

Answer 16

• Tyr –> L-DOPA by tyrosine hydroxylase
• L-DOPA –> DA by Dopa decarboxylase\
  
  • inhibiting peripheral DDC>> more DA in CNS
• neuronal uptake by DAT
• MAO metabolism
• extraneuronal uptake (as not many DATs), metabolism by COMT

Question 17

what are the properties of Levodopa as a drug?

Answer 17

• 90% metabolised in periphery - large doses, peripheral inhibitors
  
  • peripheral conversion DA>>NA
  • carbidopa = DDC inhibitor
• effectiveness decreases over time: continued degen of DAergic neurons so must increase doses
• req some function of DAergic neurons
• 1st line treatment
• rapid half life

Question 18

what are the adverse effects of levodopa?

Answer 18

• anoerxia, nausea, vomiting
• tachcardia
• pupil dilation
• halluncinations
• mood changes, depression
• drug interactions - MAOIs

Question 19

what are the DA agonists used in PD and their properties?

Answer 19

• bromocriptine and cabergoline
• can be used as monotherapy - improves bradykinesia and rigidity
• preferred in younger patients - gradual increase dose
• pergolige - only as addition to L-dopa
• side effects:
  
  • similar to L-dopa but hallucinations, nausea, hypotension more common
  • arrthymias, MCI
  • dyskinesias less prominent

Question 20

dicuss MAO_B inhibitors as PD drug treatment.

Answer 20

• selegiline
• decrease metabolism of DA
• no hypertensive crises like MAOA inhibsm - at recommended doses
• early use may delay disease progression - decrase free radical prod

Question 21

dicuss amantadine as an anti-PD agent.

Answer 21

• antiviral used in influenza - observed to decr rigidity and bradykinesia
• enhances DA release
• less efficacious than L-DOPA and more rapid tolerance
• adverse effects:
  
  • restlessness, agitation, confusion, halluncinations
  • postural hypotension, urinary retention
  • dry mouth
• less-anticholinergic act (not good)

Question 22

discuss DBS and COMT-inhibitors as PD treatments.

Answer 22

DBS

• electrode in brain, adjust symptoms and mitigates side effect
• MOA unclear

COMT inhibitors

• Entacapone
• decrease metabolism of L-dopa
• adjunct to L-dopa - increase CNS levels

Question 23

dicuss how the DAergic/cholinergic balance is restore in PD patients.

Answer 23

• muscarinic R antag’s - Bezhexol, benztropine, biperiden
• adjunct to L-dopa ONLY
  
  • modest effect on tremor, rigidity
• adverse effects: SLUD
  
  • dry mouth, blurred vision, constipations, vomiting
  • memory impairment, confusion

Question 24

what can we expect to see in the next 5, 10 and 20 years in PD drug development?

Answer 24

5 years

• adenosine A2A receptor antagonists: interacts with D2 receptor in BG to increase sensitivity to DA
  
  • increase effects of L-DOPA
• decrease glutamate levels with mGluR5 - allow L-DOPA to be given at higher levels

5-10 yrs

• optogenetics- integrating light-sen proteins into partiuclar neurons in brain (similar to DBS)

10-20 yrs

• genetics
• cell replacement therapy: pluripotent stem cells, reprogrammed to DAergic neurons and put back in

Question 25

what are the links between alpha-synuclein and mitochondria to PD?

Answer 25

alpha-synuclein * mutations in this gene --\> PD disease * found in large amounts in Lewy bodies * mutations --\> mitochondrial fragmentation mitochondria * mito dysfunction involved in PD pathogeneis * damage by toxins --\> ROS prod, CytC release --\> cell death * several mito-related genes are linked to PD pathogenesis when mutated

Question 26

describe the links to PD with smoking, drinking, pesticides and your gut and nose.

Answer 26

smoking and dranking * protective link? lower incidence pesticides * farmers have high incidence: paraquat and rotenone exposure link gut and nose * first signs of PD = loss of smell * suggests environmental exposure to toxin

Question 27

what is the link between PD and age?

Answer 27

* bigger risk factor as you age * increase damaged mitochondria - more oxidative stress * decrease ability to dispose of harmful alpha-synuclein * less HSP, HSF1 chaperons to destroy abnormal proteins

Question 28

describe the significance of the MPTP toxin.

Answer 28

* toxin affecting neuronal cell body * leads to PD symptoms * depletes DA at terminals * lipid soluble * enters astrocytes and is converted --\> MPP+ by MAO_B * MPP+accumulates in DAergic cells of substantia nigra via DAT reuptake system * MPP+ enters mito's and blocks respiration --\> neuronal cell death * PARP-1 KO mice have reduced sensitivity to MPTP - suggests PARP-1 inhibitors may be used to treat PD