What is the difference between upstream and downstream prevention strategies?
Upstream: large government campaigns that affect populations, e.g. quit smoking or wipe off 5.
Downstream: individual lifestyle, e.g. smoking, drinking, speeding, etc.
What are the 11 obstacles to prevention in health?
- Not enough drama
- Success is invisible
- Requires persistent behaviour change
- May be long delayed
- Statistical lives have low emotional effect
- Benefits do not accrue to the payer (e.g. a hospital who runs successful prevention programs will see less patients)
- Avoidable harm is accepted as normal (e.g. smoking)
- Preventive advice may be inconsistent (e.g. harmfulness of butter)
- bias against errors of commission may be a deterrent (mistakes made by those “in the know”)
- prevention is expected to produce a financial return whereas treatment is only expected to be worth its cost
- commercial interests and personal, cultural and religious beliefs may conflict with disease prevention
Examples of prevention strategies; identify steps involved
Stop smoking campaign; increasing legal buying age to 18; increasing tax on cigarettes; stopping
Outline 9 hallmarks of ageing
- Telomere attrition - reduction of telomeres over multiple replications.
- Mitochondrial dysfunction - build-up of ROS due to ineffectiveness of ETC (particularly I and IV).
- Epigenetic modifications - during ageing, histones are lost and hypomethylation (global) and hypermethylation (focal) occur.
- Loss of proteostasis - loss of mechanisms that dispose of misfolded proteins; e.g. proteosomes and autophagy.
- Deregulated nutrient sensing - mechanistic target of rapamycin (mTOR) pathway inhibition extends lifespan; IGF-1 signalling pathway attenuation also extends life span.
Calorie restriction also extends lifespan.
Candidate longevity genes in humans:
- Sir 1, 2 and 3
- FOXO1 and 3 TF
- Akt1 - Cellular sensescence
- Stem cell exhaustion
- Altered intercellular communication
- Genomic instability
Describe the phenotype and common neuropathological features of neurodegenerative diseases (5)
- delayed onset (age)
- selective neuronal vulnerability: Alzheimer’s (cholinergic neurons spanning from basal forebrain to hippocampus); Parkinson’s (dopaminergic neurons spanning from substantia nigra to striatum)
- abnormal protein processing and aggregation
- cellular toxic effects involving both cell-autonomous and cell-cell interaction mechanisms
- most neurodegenerative mechanisms have unknown aetiology
Outline diagnostic steps for Alzheimer’s Disease (4)
Cognitive performance (dementia): * ADAS-cog scale * MMSE * CDR scores No reliable biomarkers of disease in CSF * total tau/ phosphoTau * amyloid beta42 Neuroimaging * PIB-PET (amloid pathology) * 18FDG-PET (hypometabolism) * MRI (hippocampal atrophy) Post-mortem confirmation of pathology
Outline steps involved in the processing and deposition of amyloid beta
Normal: APP protein is cleaved by alpha-secretase to result in C83, which is then cleaved by gamma-secretase to p3 (neuroprotective)
Amyloidogenic: APP protein cleaved by beta secretase to C99, which is then cleaved by gamma secretase to amyloid beta 1-40 or amyloid beta 1-42.
* amyloid beta 1-40 has a lower tendency to aggregate and thought to have neurotrohic tendency
* amyloid beta 1-42 prone to formation of oligomers, main form in amyloid fibrils
Describe how tau-hyperphosphorylation causes synaptic dysfunction
Hyperphosporylated tau detaches from microtubules; soluble tau aggregates and with increasing phosphorylation forms NEUROFIBRILLARY TANGLES which aggregate in the hippocampus
List genetic and environmental risk factors of AD
Genetic
Early onset - Familial AD (FAD)
* mutations in APP (amyloid precursor), presenelin 1 and 2 (components of gamma secretase)
Late onset AD (LOAD)
* ApoE, clusterin, ABCA7 - cholesterol metabolism
* complement receptor 1, CD33, TREM2 - immune response
* BIN1, PICALM, CD2AP, EPHA1, SORL1 - endocytosis
* rare variants APP, presenellin 1 and 2
TAU protein
* silent mutations of MAPT gene = hyperphosphorylation
* missense mutations of MAPT = inherited cases of frontotemporal dementia, NOT AD
Environmental
* age
* head trauma
* vascular health
* obesity & diabetes
* physical and mental inactivity
* smoking
* low education attainment
Agents currently being used in treatment of AD, including mechanisms of action
Symptomatic
* cholinesterase inhibitors (increase cholinesterases)
* NMDA receptor antagonist
Disease-modifying (4)
* amyloid plaque formation - amyloid beta vaccine, gamma secretase inhibitors
* tau hyperphosphorylation - kinase inhibitors, phosphatases
* synaptic dysfunction - neuroprotective agents
* hippocampal atrophy
The ONLY approved therapies are cholinergic neuron-treating symptoms
Describe the animals models used to study AD
Single transgenic - APP mutations
Double transgenic - APP and PS1 mutations
Triple transgenic - APP, PS and tau [unpredictable; mutation can drop out during transbreeding]
Tau transgenic - tau mutations
Problem: animals that express tau tangles have frontotemporal disease, not AD
animals that express amyloid have plaques, no tau tangles
Outline clinical features and diagnostic steps for Parkinson’s disease
TRAP: T: tremors R: rigidity A: akinesia P: postural instability Post-mortem pathology: - Degeneration of the substantia nigra pars compacta - Lewy bodies [accumulation of degenerated alpha synuclein bodies] and Lewy neurites
Susceptible pathway in PD?
Nigro-striatal dopaminergic neurons - depletion
% of people in AU that experienced some form of a MD in their lifetime?
45.5%
% of people who experienced major depression?
6%
To which category does depression belong?
Affective/ mood disorders
Female: male ratio of major depression?
1.5-3:1
% of people who experienced bipolar?
1-2%
Female: male ratio of bipolar?
1:1
Causes of bipolar? (5)
- genetics
- serotonin abnormality (main)
- environmental
- medical illness
- pregnancy
What duration of persistence applies to GAD (generalised anxiety disorder)?
> 6 months
Female:male ratio of GAD?
2:1
% of AU who reported PTSD?
6.4%
% of women with PTSD? Men?
W: 8.3%: men 4.6%
