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| Pregunta | Respuesta |
| What percentage of the government's research budget is spent on alzheimer's research? | 2% |
| What is the annual cost of dementia in the UK? | 17 billion |
| How is the money spent on dementia distributed? (Highest first) | 1) Care homes 2) Informal care 3) Community care 4) Home care |
| Which sex is more likely to get dementia? | Women |
| What are three things are dementia characterised by? | 1) Cognitive impairment 2) No loss/clouding of consciousness 3) Irreversible and progressive |
| What are the cognitive impairments associated with dementia?1 | 1) Memory 2) Loss of ability to solve day-to-day tasks 3) Loss of perceptuo-motor skills 4) Correct use of social skills 5) Inability to control emotions |
| When was the pathology of alzheimer's disease first recorded? By who? | 1906 Alois Alzheimer |
| What percentage of people over the age of 65 have Alzheimer's? Over 85? | 10% 50% |
| What precentage of dementia does alzheimer's account for in the UK? | 70% |
| How many dementia cases are there in the UK? | 600,000 |
| How many dementia cases are there in under 25s? | 20,000 |
| What is average length of survival after diagnosis? What is the range of length of survival? | 8 years 3-13 years. |
| How do the symptoms in Alzheimers progress? | 1)Deficits in short term memory 2)Disruption of normal living - social skills intact 3) Problems with long term memory/recognition 4)Deficits in higher cognitive function (Abstract reasoning, judgement and language) 5) Spatial and temporal disorientation 6) Problems with skilled motor movement (Dyspraxia) 7) Apathy, depression, agitation, anxiety, paranoia and delusions. |
| What are the four ways of diagnosing AD? | 1) Pet/Spect fMRI 2) Pupil dilation test 3)Altered CSF tau and AB proteins 4) Post mortem |
| What does a PET/Spect fMRI look for? | Changes in blood flow/metabolism |
| Which drug is used in a pupil dilation test? Why is the pupil dilation test used? | Tropicamide Pupil dilation is unusually rapid in alzheimer's patients. |
| How are TAU and AB proteins altered? | Tau is increases AB decreases |
| What are the signs of AD post mortem? | 1) Brain atrophy 2) Symmetrical swelling of ventricles 3) Neurofibrillary tangles 4) Senile plaques |
| Describe neurofibrillary tangles | protein-riched paired helical filaments in the cytoplasm of affected cells. |
| Describe senile plaques. | B-amyloid core, degenerating neurons and synaptic loss with active glia surrounding the mass. |
| Which are the three areas most affected by AD? (Lobes) | Frontal Temporal Parietal |
| How thick are the protein fibres in plaques? | 7-10nM |
| What are the four hypotheses for AD pathophysiology? | 1) Cholinergic 2) Glutamatergic 3) Amyloid 4) Tau |
| What is the reasoning behind the cholinergic hypothesis? | Decrease in acetylcholine - first system targeted in treatment of AD. |
| What is the reasoning behind the glutamatergic hypothesis? | Over-activation of NMDA receptors by glutamate leads to cell death. |
| What is the reasoning behind the amyloid hypothesis? (2) | Plaques formation is the primary cause of AD. Triggers the formation of TAU tangles and leads to neuronal death and dementia. |
| What is the reasoning behind the TAU hypothesis? (2) | Tau hyperphosphorylation leads to the production of neurofibrillary tangles>>> Loss of cellular function in the brain. Tau aggregates can form wholly independently of B-Amyloid plaques. |
| Which cholinergic pathway(s) are affected in AD? | Septal nucleus > hippocampus Nucleus basalis of Meynert > cortex |
| Which is one of the first areas in the brain to be affected by AD? Which pathway does this therefore affect? | Locus coeruleus Noradrenergic |
| Which other pathway/peptide is effect? | 5-HT - Raphe nucleus > cortex |
| Where is choline acetylcholinesterase (CAT) lost from in AD? | Temporal and parietal lobe. Hippocampus. |
| What else is lost in relation to acetylcholine? | Choline uptake. |
| What correlates with the formation of plaques? | Loss of Choline Acetyltransferase (CAT) |
| Which receptors are affected in the cholinergic hypothesis? | M1 (post) - mainly spared M2 (pre) - Lost Nicotinic (mainly pre) - lost |
| What effect does the knockout of nACHR have on the cognitive ability of mice? | No impairments |
| How does the degree of cell loss vary between post mortem and biopsy? | NA, 5-HT and ACh all similarly reduced at post mortem (Locus coeruleus, Raphe nucleus and nucleus basalis) Biopsy shows that ACh is the most effected. |
| Which other brain regions are effected in AD? Markers for which transmitter and what type of neuron is lost? | Amygdala and cortex Presynaptic glutamatergic markers Pyramidal |
| What type of AD is genetically linked? Which chromosome is effected which also turns up in which disease? Which other chromosomes are linked? | Early onset 21 - down's syndrome 1,10,14 and 19 |
| What are the other 4 potential causes of AD? | Environmental Transmissible Amyloid-precursor protein (APP) misprocessing Tau-misprocessing |
| What could be the environmental factors that lead to AD? | Aluminium and other toxins |
| What are the transmissible agents which could cause AD? How do they spread? | Prion-like agents Through highly connected areas - like the hippocampus and the entorhinal cortex. |
| What results from the misprocessing of APP? | Pathway overload and deposition of B-amyloid, leads to AD |
| What is soluble APP essential for in the cholinergic system? | Expression and activity of the choline transporter. |
| Why does the cleavage of APP to B-amyloid occur? | Altered gene expression/proteolytic processing of large amounts of APP |
| What happens to the normal metabolic pathway and what does this result in? | Normal pathway is overloaded - deposition of B-amyloid |
| What do Y40 and Y42 correspond to? | The length of the B-amyloid protein |
| Which enzyme cleave APP in normal processing? | a-secretase followed by Y-secretase |
| Which enzyme is involved in the misprocessing of APP? | B-secretase |
| What are the two main proteins/genes in a-secretase? | ADAM10 ADAM17 |
| What is the target for y-secretase after 1) a-secretase has cleaved APP? 2) B-secretase has cleaved APP? | 1) a-CTF 2) B-CTF |
| What are the five genes/proteins which make up y-secretase? | 1) Presenilin 1 2) Presenilin 2 3) nicastrin 4) aph-1 5) pen-2 |
| In familial alzheimer's which proteins/genes in y-secretase are mutated? | Presenilin 1 Presenilin 2 |
| What is APP cleaved into by normal processing? Abnormal? | P3 and AICD AB and AICD |
| Other than in Y-secretase mutations of what are associated with APP misprocessing? | APP |
| What two type of AB are produced? Which is more toxic? | AB40 and AB42 |
| What happens after the formation of plaques? | Inflammatory response- 1) Microglial activation + Cytokine release 2) Tau hyperphosphorylation 3) Wide spread neuronal/neuritic dysfunction leads to cell death with transmitter deficits. |
| What is the function of Tau usually? | Stabilizes microtubules |
| What is responsible for 1) phosphorylation and 2) dephosphorylation of tau? | 1) Kinases 2) Phosphotases |
| Why does the detachment of hyperphosphorylated Tau lead to cell death? | 1) Microtubules become unstable and dissociate - not transport to and from cells 2) Neurofibrillary tangles block cell transport |
| What are the three components of neurofibrillary tangles? | 1) Straight filaments 2) Paired helical filaments 3) Twisted ribbons |
| What are the five direct events that are involved in the hyperphosphorylation of TAU? | 1) Up regulation or aberrant activation of Kinases 2) Down regulation of Phosphatases 3) Mutations 4) Covalent bonding 5) Other? |
| What are the four main indirect effect that lead to Tau hyperphosphorylation? | 1) AB-mediated toxicity 2) Inflammation 3) Oxidative stress 4) Others? |
| What happens to normal Tau when it comes into contact with a NFT? | Becomes part of NFT |
| What type of disease is a mutation of chromosome 17 associated with? Which protein does this mutation implicate? | Frontotemporal dementia with Parkinson's. Tau. |
| EVIDENCE FOR AB (7) 1) What percentage of alzheimer's is familial/early onset? Where are the mutations found? Which implicates more plaques? | 2-5% Presenilin 1/2 & APP AB42 |
| 2) What happen to people with Downs Syndrome by the time they reach their 40s? Why? | Alzheimer's like symptoms - carry APP mutation gene (extra copy) on chromosome 21. |
| 3) What is APOE4? How is it related to AD? | Major serum lipoprotein involved in cholesterol metabolism. Mutation leads to large build up of AB before onset of AD symptoms. |
| 4) What happened in APP transgenic mice phenotypes? | Build up of plaques some loss of cognitive ability but no cell death. |
| 5) The close proximity of what also implicates AB as being the main cause of AD? | Close proximity of neurodegradation to plaques. |
| 6) What can AB plaques cause in vitro? Why might this not be a valid argument for the AB hypothesis? | Neurodegeneration. Much higher levels of AB used to test in vitro than in human AD brains. |
| 7) A positive mutation of what was found to have a protective effect on AD? | APP. |
| What are the main issues with AB and AD? (4) | 1) Presence of AB plaques in non-demented elderly 2) APP TMice - cognitive impairment can occur before AB plaques. Memory impairments also sometimes occurred without neurodegeneration. 3) Weak correlations between no. AB plaques and clinical manifestations. 4) Neurodegeneration can occur in areas without AB plaques |
| Which arguments show support for Tau being the most important in AD? | 1) Good correlation between no. tangles and cognitive impairments 2) Tau-opathies related to AD but with no AB deposits 3) Tau is elevated in cerebrospinal fluid 4) Tangles occur in places critical for memory - amygdala and hippocampus |
| What are the two different pathways which combine Tau and AB pathology? | Serial Model and Dual Model. |
| From which study is AB thought to bring about Tau hyperphosphorylation? | APP transgenic mice |
| What could be a common upstream driver of AB plaques and Tau hyperphosphorylation? | APoE4 |
| What are three target pathways? | APoE4 GSK3 Retromer |
| What happens first: Neuronal death or synaptic loss? | Synaptic loss |
| How does tau hyperphosphorylation cause neuronal cell death? | 1) Tangles physically block cell transport 2) Microtubules dissociated without tau structural support - reduced cell transport. |
| What can be seen in PET scans before full symptoms of AD occur? | Increase in AB plaques. |
| What is the main system targeted for treatment of AD? | Cholinergic. |
| What are the three potential targets of new treatment for AD? | 1) Immunotherapy/vaccines 2) Inhibition of B and y secretase 3) Preventing ABy42 aggregation |
| What are the main effects of acetylcholinesterase inhibitors? | Increase ACh levels - GI side effects |
| What are the three cholinesterase inhibitors used to treat AD? | Donepezil Galantamine Rivastigmine |
| What is MEMANTINE used for? Is it effective? | Memantine is an un-competitive NMDA use-dependent partial antagonist - neuroprotective in AD but not always very effective. |
| Why are cholinesterase inhibitors only useful for a limited period of time? | Once ACh producing cells start dying off in ernest, ACh is too low in synapses regardless of inhibition acetylcholinesterases. |
| When is Memantine used in AD? | Very early stages. |
| How is B-amyloid involved in glu excitotoxicity? (3) | 1) Augments NMDA mediated transmission 2) Enhances depolarisation-mediated transmission 3) Inhibits Glu uptake by glial cells |
| What are some of the future targets for dementia treatment? | Reduce a-beta production Increase a-beta clearance Increase cell survival Stop/reverse plaques Replace cells Reduce oxidative stress Cholinergics - M1 |
| XANOMELINE | M1 and M4 agonist Significant effect of cognition Serious CV side effects Transdermal patch in trials |
| AF102B | M1 agonist in phase 3 trials in USA |
| What positive effects might nicotine have on cognitive factors? What doesn't it affect? | Attention and information processing Doesn't affect memory |
| How is M1 agonists thought to help treat AD? | Coupled to Gq, increase PLC, increase PKC 1) Increases ADAM 17 (for correct APP processing). Decreases BACE1 (B-sec), decreasing misprocessing. 2)Inhibits GSK3B therefore decreasing apoptosis 3) Breaks up AB oligomers which are neurotoxic when bound to PrPc (by increasing ERK1 and ADAM17) |
| What was the aim of vaccination therapies for AD? Why didn't it work? | Stimulates immune response to remove AB plaques - overactive in humans, makes plaques worse. |
| How are B- and Y-secretase inhibitors meant to help treat AD? | Reduce production of AB |
| How are statins meant to help help treat alzheimer's? | Increase processing of APP by a-secretase |
| What is Clionquinol (PBT-2) and how is meant to help treat AD? | Copper/Zinc chelator Decreases interaction of copper/zinc with plaque - decreasing their formation and increasing clearance. |
| Give an example of NSAIDs. How are they meant to treat alzheimers? | Ibuprofen, Sulindac. Inhibit production of AB42 peptide. |
| What was and what went wrong in the AN-1792 trial? | Immunotherapy - inject small amount of synthetic B-amyloid drug. Dangerous autoinflammatory immune response in some patients (eg brain swelling) |
| What is the mechanism of statins that is thought to help with AD, why? | Lipid raft partitioning > relieve oxidative stress via microvasculature. |
| What is solanezumab? How does it work? | Monoclonal antibody targeting B-amyloid. Stop AB clumping together |
| What happened in the first human trial? | Drug had no effect. |
| Why was the first trial wrong? | 1) Lots of patients had been misdiagnosed - never got full blown alzheimer's 2) Many patients didn't have any alzheimer's pathology 3) Split alzheimer's group into early stages of and late stages of alzheimer's - later found that those who received treatment in early stages benefited from treatment. |
| How have they modified the trial? | Scan for AB plaques/load to check that patients are at the right stage. |
| What is Bapineuzumab? | Monoclonal antibody to AB |
| What else is being developed as an immune therapy? | AB42 antibody |
| Why has B-secretase inhibitors been hindered so far? | Pharmacokinetics |
| What is semagacestat? What did it show in clinical trials? | y-secretase inhibitor. Increased cognitive decline - probably do to decreased production of P3. Also increased risk of skin cancer. |
| What else does y-secretase effect? What does blocking y-secretase also cause? | Tyrosinase. Change of hair colour. |
| What does notch usually suppress? What effect did semagacestat have? | Suppresses tumour Semagacestat caused increased risk of skin cancer. |
| What is an important target of y-secretase? What is it involved in? | Notch, cell and tissue development. |
| What does tarenflurbil do? Why did it perform badly in phase III trials? | Modulates y-secretase, worked to produce smaller, less toxic AB fragments. Unable to enter CNS. |
| What is tramiprostate? How did it do in clinical trials | Indirect inhibitor of y-secretase - failed trials. |
| How does lithium potentially treat AD? | Inhibition of GSK3 (which hyperphosphorylates TAU. |
| What is paclitaxel? What was it first used in? | Microtubule modifier (stabilises them to prevent diving/dissociation). Cancer treatment. |
| What is TauRX | Tau aggregation inhibitor. |
| How does TauRx prevent Tau aggregates? | 1) Prevent formation of oligomers 2) Prevents conversion of oligomers to paired helical filaments 3) Dissolves Tau plaques. |
| What is the benefit of TauRX (Rember/methylthioninium chloride) | Doesn't affect normal tau-tubulin interactions. |
| What have phase II clinical trials of Rember/Methylthioninium chloride shown? | 80% of patients with mild/moderate alzheimer's shows a decrease in cognitive decline. |
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