Case studies Flashcards
4 tactile? tests to test for Alzheimers (AD)
Blood tests, electroencephalography (EEG), MRI
What is electroencephalography (EEG)
measures cortical activity = sum of each neuron firing. Measures sleep disorders, epilepsy, coma, brian death
What does MRI measure
Cerebrovascular damage = blood flow and the blood vessels in the brain
Structure of Mini-cog test for DA
3 word registration (repeat 3 words), clock drawing + draw hands at time, word recall of 3 word registration. Gives a score of likelihood of cognitive impairment
4 examples of dementia
Alzheimers dis, Vascular dem, frontotemporal dem, dem with Lewy bodies
Info on frontotemporal dementia
Global cognitive impairment + motor deficits - fatal after aorund 8 years. Early onset dementia (<65 yrs). Deterioration of behaviour, loss of empathy, OCD, dietary changes
What is the frontal love and temporal lobe associated with in the brain
Frontal: Movement, decision making, emotional behaviour. Temporal: Auditory processing
Info on demential with Lewy Bodies (DWL)
In Alzheimers + Parkinsons. Formation of Lewy bodies containing α-synuclein originating from brain stem -> progressing to limbic system (emotions) and cerebral cortex. Changes in cognition, hallucinations, rapid eye movement
Info on Vascular dementia
Variable cognitive impairment - cause not determined. Associated with demographic, genetic, stroke related risk factors.
4 stages of AD
Mild, moderate, late, advanced
What happens on macroscopic level to brain in Alzheimers
Widening of sulcal spaces + narrowing of gyri. Cortical atrophy. Enlarged frontal + temporal horns of lateral ventricles (some holes in middle of brain)
What happens on microscopic level to brain in Alzheimers
- Amyloid plaques formed from Aβ40 and Aβ42 (mainly).
- Neurofibrillary tangles: Composed of filamentous tau protein. In AD: they become hyperphosphorylated + abnormally folded -> loss in tau function. (death of neurons - tau stabilises neuron skeleton)
Aetiology meaning
Cause of a disease or condition
Aetiology of AD (1 genetic reason)
Apolipoprotein E (APOE) transports cholesterol to neurons to support their normal function. ε2, ε3, ε4 alleles. Heterozygous and homozygous ε4 (APOE4) leads to increased risk of AD
Challenges of treading mild AD
Delay in efficacy, improves but doesn’t treat, side-effect of medicine is confusion
How does acetyl choline NT work w cholinesterase in neurone
- Synthesis of Acetyl chlone by Acetyl CoA + Choline by emzyme. 2. Storage in synaptic vesicles. 3. They move to pre-synaptic nerve terminal. Fuse with pre-synap terminal. 4. Release of NT (acetyl choline) to synpatic cleft. 5. Some acetyl choline bind to its receptors on post-synap (muscarinic or nicotinic). Some broken down by acetylcholineesterase -> acetate + choline. 6. Choline reused as precursor of acetyl choline. Acetate removed.
What is donepezil
A colinesterase inhibitor
3 medicines used for mild AD
Donepezil (tablet), Rivastigmine (patch), Galantamine (extended release formulation)
Why is colinesterase inhibitor used for AD
Lower concs of acetylcholine in AD. “Cholinergic hypothesis”
Memantine use + action in body
NMDA receptor antagonist for moderate/severed AD. Protects against excessive glutamate realeased from excitotoxicity.
What is excitotoxicity relating to glutamate
Occurs following excessive exposure to glutamate/overstimulation of glutamate receptors -> neuronal death
Theories for why memantine works for AD
- β-amyloid peptide -> glutamate excitotoxicity through interaction with NMDA receptors.
- Tau protein + glutamade excitotox link - glutamate-induced neurodegeneration
Mechanism + non-mechanism based approaches for future research of AD
Mech: Targer amyloid, tau, APOE, neuroprotective therapies. Non-mech: cognitive enhancers, prevention
Angiogenesis meaning
Formation of new blood vessels from pre-existing vascular into avascular (due to VEGF-stimulus)
2 types of tumours
Benign, Malignant
Info about benign tumours
Do not metastasise, usually encapsulated, in any tissue - resembels original tissue, well differentiated (slow growing), often relatively harmless
Metastasise meaning
(of a cancer) spread to other sites in the body
Info about malignant tumours
Intravasation then metastasis, poorly differentiated - frequent cell devisions = fast growing
What is intravasation
When tumour enters circulation (into vessel especially blood)
What can cause mutagenic initiation
Chemicals, radiation, viruses, spontaneous change, genome instability
What mutations can be caused in dna
Nonsense, silent mutations or chromosomal alterations: deletions, insertions, translocation
Epigenetic (genes) alterations
Acetylations, methylation
Steps of metastasis cascade
- Primary tumour formation.
- Localised invasion (towards blood vessel)
- Intravasation - into blood stream
- Transport through circulation
- Arrest in microvessels of organs eg Lungs, bone, brain (cells get stuck in tiny vessels)
- Extravasation - into tissue
- Formation of micrometastasis - too small for scan
- Colonisation: Formation of macrometastasis
6 original hallmarks of cancer
Resisting cell death, sustaining proliferative (growing) signalling, evading growth supressors, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis
4 new emerging + enabling hallmarks of cancer
Deregulating cellular energetics (put energy into what tumour needs), avoiding immune destruction, genome instability and mutation, tumour-promoting inflammation
Where is angeiogenesis used in normal processes in body
Development, menstrual cycle, wound healing
How does a normal cell transform into a cancer cell (short answer)
Accrual (accumulation) of multiple genetic mutations over time
What does leaky vessels mean and what does it casue
Fluid leaks from blood vessels into surrounding tissue. Causes drop in blood pressure
Differences between normal vs tumour angiogenesis
Normal: Controlled, regulated, organised, mature and low interstitial (outside vessels) pressure. Pathological (tumour) is the opposite
Negative effect of higher interstitial pressure
Medication can’t leave bc can’t go down pressure gradient as it is lower in tumour vascular
4 modes of vessel formation
Sprouting angiogenesis (2 vessels get connected), vasculogenesis (bone marrow differentiates - brand new vessel), intussuseption (hole in vessel expands to become 2), vessel co-option (tumour cells co-opt pre-existing vessels, sit by it)
What happens in sprouting engiogenesis (vessel brancing)
Angiogenic factors = stimulus to quiescent (normal) vessel (eg VEGF) - tells cell in vessel to change phenotype = tip-cell formation. Has little hairs that are sensors. Tip-cell signals to cells besides to follow tip-cell to stimulus and change phenotype = stalk cells + stalk elongation. Same happens in adjacent vessel. Blood flow starts coming behind it as moves out. Eventually blood vessels connect = quiescent phalanx resolution. Pericyte cells give protection + stability to growing + maturing blood vessel.
3 treatments for cancer
Surgery, chemotherapy and radiotherapy
Info about surgery for cancer
Invasive, facilitates further treatment (better access for chemo), prevention (removal of moles), debulking (remove bulk of tumour before chemo)
Info + types of chemotherapy
Alkylating-like agents, anti-metabolites, topoisomerase inhibitors, microtubule inhibitors. All interfere with cell cycle (s-phase) + attack rapidly proliferating cells EXCEPT microtubule - changes where chromosomes line up - don’t complete M phase of cell cycle.
What are some issued with chemotherapy
Bone marrow, GI tract, hair follicles are normal cells that are rapidly dividing, nausea, myelosupression (decrease blood cells), diarrhoea, cardiovascular toxicity
Info on radiotherapy
External beam target tissue. Can otherwise implant “seeds” in body. Can causes rash/burns to skin. Causes damage to normal tissue too.
Other ways to target cancer treatment
Target growth and death (tumour supressors etc), anti-oestrogen or androgen signalling, target cell signalling (angiogenesis inhibitor)
What is VEGF-A
Vascular endothelial growth factor. Protein, affects proliferation, cell survival… Regulated blood flow and vascular tone - more VEGF = more vasodilated
How does VEGF bind to receptor etc
Released by tumour (or something else). Dimerises then binds to receptor - VEGFR2 (3 diff types but focus on R2). Receptor dimersises: tyrosine kinase domain comes together. RTK become autophosphorylated. Then signalling starts
4 types of VEGF inhibition
- Inhib of VEGFA ligand (by an antibody that captures it). 2. VEGFR2 (receptor) - small molec inhibitor by crossing cell membrane and stopping phosporylation of RTK, 3. VEGFR2 downstream signalling. 4. anti-VEGFR1 or R2 antibodies
What does it mean if medicine ends in mab
Monoclonal antibody!
Name of medicine that inhibits VEGFA
Bevacizumab (or avastin)
Info and problems of inhibition of VEGFR2
Sunitinib, sorafenib. RTK inhibitors used. Competitive OR allosteric inhib. Multi-targeted - many side effects. Leads to resistance and toxicities. Left ventricle dysfunction-> onset of heart faliure
Consequences of VEGF inhibition
Hypertension, bad wound healing, cardiac dysfunction (hypertension), renal toxic effects, haemorrhage, blood clots
