AD Flashcards
(33 cards)
outline and describe the main histopathological features of AD
Severe atrophy of neurons. looking at a brain i postmortem it will have large sulci and enlarged lateral ventricle.
severe atrophy of the HPC is also a sign related to early spatial memory deficits
Extracellular depostions of amyloid beta plaques. Large insoluble aggregates fromed from the abberant proteolysis of precursor APP.
A-beta deposition is also visualised in cerebral amyloid angiopathy (CAA) where plaques form in the walls of blood vessels.
Intracelular inclusions of NeuroFibillary Tangles. These consist of hyper phosphorylated microtuble associated protein Tau. (MAPT). look like Whispy Flames.
Neuroinflamation. This can be seen by the surrounding of plaques by microglia that have undergone hypertrophy to enter a Ramified state.
briefly outline the Thal phases of AD compare this to BRAAK staging of AD.
THAL phases tracks the progression of AD through the depostion of AMYLOID BETA. spread being anterograde transmission to regions innervated by infected regions.
1- neocortical depostion
2- inclusions of allocortical regions
3- involvement of striatum, cholinergic nuclei of basal forebrain, diencephallic nuclei
4- inclusion of several brain stem nuceli
5- the final phase with inclusion of the cerebellum.
Phases 1-3 are associated with the preclinical phases and phase 4+5 with the clinical symptoms.
Braak staging tracks the deposition of tau pathology (neuro fibilliary tangles)
1+2- these involve primarily the entorhinal cortex and hippocampus.
3+4- these involve the inclusion of limbic structures
5+6- nemerous regions of the cortex now included.
1+2 confer a non symptomatic stae with the onset of symptoms in stages 3+4 and 5+6 conferring severe stages of AD.
Tau progression has been shown to correlate with the progression of AD. However, Amyloid beta depostion has not with many dying with abundant amyloid beat deposits and no symptoms. Hence, Braak staging may be more reliable in AD.
provide a breif descripion of the clinical progression of AD and its correlation pathological changes.
The progression of AD follows a predictable pattern of atrophy.
atrophy can be visualised by MRI far before the symptomapric phase in a preclinical phase. early on here atrophy can be seen in the EC and HPC, are associated with spatial cognition, something that can be seen in ealry phase AD patients.
soon atrophy in limbic and later cortical areas is observed. conferring with the onset of symptoms like memory loss and later confusion, and the detrioation of intelectual capacity associated with dementia.
Although a hall mark of AD histopathology this does not correlate with the spread of AB pathology. However, it does correlate with the predictable spreading pattern of tau pathology described in Braak staging.
1+2- this being the preclinical phase where there is accumualtion in EC and HPC areas, confers with spatial cognition deficits.
3+4- There is inclusion of limbic areas and the onset of symptoms like memory loss confer with this.
5+6 this is where multiple cortical regiosn begin to be involved, this is seen in late stage AD and correlates with the progressive severity of dementia.
what are the main therapeutic targets in AD?
stop amyloid plaque formation
stop the formation of hyperphosphorylated Tau tangles
reduce neuroinflamation (thought to be a cause of issues with synaptic efficacy, a early contributon to neurodegenerative cascades)
modulate neurotransmission
use genetics to identify novel targets
what are the early behvaioural warning signs of AD?
memory loss, in particular issues with spatial memory as the hippocampus is degenerated early on, we can assess this through the 3 peaks study which test both spatial memory and perception (perception is normally fine)
changes in personality issues with pallning and decision making. misplacing things, change in mood disorientiation is space an time. difficutly performing familiar tasks.
what risk of bias can be associated with randomised studies of neruodegenrative disease like AD, what is the issue of the currently known markers?
In neruodegenrative conditions the rate of progression can vary alot.
Randomised smapling runs the risk of having fast progressor and slow porgressors dominantly in placebo vs test trials. this can cause false positive/negative results when analysing the progression od symptoms in tertiary studies or disease markers in secondar trials.
The issue with current biomarkers is there are alot of RETROSPECTIVE markers that provde inof on risk of onset but very few that tell uss how a disease will progress. making it hard to distinguish between fast and slow progressors.
Tertiary efficacy outline a test used to measure the change in AD patient cognition? Give an example of a clinically meaningful exam.
ADAS-COG (Alzheimers disease assessment scale cognitive subscale) this is used to assess the changes in cognitive symptoms. the score ranges between 1-70 with normally elderly individuals scoring 0-1 and AD patients score usually increasing yearly. (score is number of errors
A clinically meaniful exam would be the Clinical interview based impression of change with carer input (CBIC-plus). this is a score of improvement between 1-7
either halting of worsening or improvement is considered successful.
importance of placebo efficacy on AD trials for tertiary cures
Here improvement in test drug and decline in placebo is a sign of efficacy.
However, improvement with drug and no decline in placebo is not strng evidence of efficacy. as this could simply mean that trial drug is beinmg tested on slow progressors.
In secondary studies what is seen as a sign of effectiveness, what do you need to assess this.
Secondary studies a sign of effectiveness in the halting of progression of a dynamic biomarker (cannot uno damage)
In order to assess this you need a dynamic biomarker who changes correlate with the progression of symptoms. in PD this is MRI to investigate atrophy of neural tissue that racks decline in cognition.
Why is amyloid plaque accumualtion not a good biomarker of disease progression, How can we visualise it and what is it used for?
amyloid plaques do accumualte throughout the disease and indeed accumualtion can be seen even 15 years before onset as a toxic threshold is need for disease.
This can be visusalised using postiron emisiion tomography using a Amyloid specific radioactive marker.
Give the best cuurent exmaple of a dynamic marker that can be used to track changes in disease pogression for secondary trials of AD?
currently the best marker is magnetic resonance imaging of the brain.
There used to be some issues as movement of the head could make images appear to be shifted and the images never where done with the exact same point of reference.
Now days a computer program can precisely sperimpose several images alllwoing the visualisation and calculation of the prgressive atrophy. we now Know in a healthy 40 year old this is 0.2% a yar and rises to 2.8% a year in AD hence this is a rnage of reference for reductions in progression.
severe atrophy is is seen far before the onset of symptoms and Atrophy does correlate with the progression of cognitve deffiencies.
How do you overcome issues of bias in secondary efficacy trials?
In secondary trial the risk of fast and slow progressos still exists so instead STRATIFIED SAMPLES are used.
The take individuals once they have been analysed and are confirmed fast or slow progressors.
Although logic suggest using fast progressors as the change in disease progression will be most visible.
It is also importnat to test in slow progressors as fats progressors once identified may have already passed a irreversible threshold and thus may produce false negatives.
issues with using Event related pottentials (ERP) as a marker of impairment and progression in AD, equally wat are the weakness of EGG.
ERP work as declines have been both correlated with cognitve deffiencies and disease progression in AD. usually tested using a constat repeated tone with infrequent changes to investigate the neuronal reponse. this is reduced in amplitude and latency
Issue is this is aslo observed in PD, schizophrenia and dyslexia and so is not a specific AD test.
simmilarly testing for EEG in which in AD patients we observe a progressive INCREASE in slow wAVE THETA AND DELTA WAVE AND reduction IN FAST BETA AND ALPHA WAVES. this is also observed with normal aging in elederly and several othe rpathological isues.
Benefits of double blind
In these trial neither the patient o experimenter Know who has the placebo and who has the dru. ence, ths can reduce psychological or experimental bias, improving the validity of findings.
Can we diagnose AD in life?
NO given the biomarkers today we can predict the likelihood of AD onset and the probability that somebody has AD but we cannot diagnose it as AD until postmortem studes are done.
outline the process by which Amyloid beta plaques from APP and how Neurofibilliary tangles form from TAU.
Amyloid beta is produced by the from th precursor APP.
APP is usually cleaved by alpha-secretase and then gamma-secretase this produces the normal peptides.
However, it can be alternatively cleaved by Beta-secretase and them gamma secretase froming the toxic amyloid beta peptides. gamma secretase can cleave at multiple points primrily producing amyloid beta 40 or 42. These will then form plaques. 42 has MORE hydrophobic amino acids and further promotes aggregation. (Idea is that then mutations in APP or subunits of gamma-secretase will increase the cleaving to produce amyloid beta)
NFTs- Tau is a microtuble associated proteina (MAPT) stabilises microtubules. It binds via c-terminal repeats of which there are 2 (3R+4R). The Reverisble binding is regulated by phophorylation.However, in pathogenic state there is hyperphosphorylation of MAPT resulting in the formation of Paired helical filaments of MTs and TAU. These are deposited intracelluarly as NFTS.
Note there are normally equall amounts of 3 and 4 but in AD taus express the C-terminal repeat 4 more than 3.
what is the social importance of treating alzheimers?
We have an aging population and the greatest risk f AD is age. hence, the AD population is growing.
forms of dementia like this are evermore prevalent with 1:3 being ascoiated with someone with dementia.
The estimates cost to society is 26billion a year.
Hence is is of great soceital importance to treat this condition.
what are the main risk factors of AD out side of genetics?
Age is the main risk factor of AD.
outline and decribe some of the identified genetic causes and risk factors (not including GWAS) of AD. (3)+(2)
Monogenic EOAD: less tan 5% of cases are fammilial.
APP mutations- this is the precursor of amyloid beta and muations here promote cleavage via the beta-gamma pathway and thus increase the production of AMyloid beta.
Trisonomy 21- this is the cause of down syndrome and chromosome 21 in the location of the APP gene. Hence, this is a dose dependat increase in APP and subsequently in Amyloid beta.
PSEN1+PSEN2- these are subunits of gamma secretase and mutations promote the lesion to produce the aggreagation-enhanced Amyloid beta 42.
- Lee et al 2010 report effects besides this showing that PS1 KO in cells prevented the provision of a proton transporter to lysosomes causing dysfucntion with their acididification and disrupting autophagy. Studies reproted that this led to axonal swelling filled with autophagic vacuoles containg incompletely degraded proteins.
- Issues with autophagy have been previously related to increased Plaques and boosting it has been related to partial recovery of cognitive deficits in mouse models.
- It may be that the lifelong reduction in the efficacy of Autophagy reproted by CUERVO ET AL 2008 may expalin largely the increased risk with age.
Risk factors (removal)
APOE4- there are 4 allels of this gene, APOE2 asscoaited with protection against AD, APOE3 which is AD neutral and APOE4 whcih increases the risk of AD. These are involved with the transport of cholesterol to neuron and APOE4 is thought to slow A-BETA removal.
TREM2- triggering receptor on myeloid cells 2. This is associated with the response to amyloid beta by microglia.Thus mutations inhibit the immune removal (phagocytosis) of toxic amyloid beta.
- There is also evidence that APOE4 and TREM2 intercat to this same effect.
- This suggests that dysfucntion of microglia is not a secondary fetaure of AD but is instead a primary factor.
- Alteration in TREM2 levels in the CSF are now being investoigated as a biomarker of AD.
what is dementia
Dementia is caused by several diseases and is defined by the detrioration of intelectual capacity. (Judgement , memory e.t.c)
outline the amyloid beta theory and the brief evidence behind it. include varied roles of tau an amyloid in pathology.
The amyloid beta theory states that abberant proteolysis of APP froms toxic species of amyloid beta. These then act ia 3 mechanisms.
1- they intefear with the kinases asscoiates with MAPT an drive the formations of hyperphosphorylated tau and NFTs, leading to neruonal death.
2- AB plaques form and drive the subsequent dysfunction of neruons and contributes to neuronal death.
3- the fromation of soluble AB oligomer causes synaptic dysfunction (shown in mouse models) and contributes to neuronal death.
hence within this theory AB acts upstream of NFT formation and neuronal death.
evidnece:
Mutations related to the fromation of AB can cause familial AD suggesting it is the driver of the disease.
Crossing APP mutant mice with a tau KO was unable to cause pathology, neuronal death or cognitive deficits. But APP cross with WT did. This suggests Tau pathology is key to the neurotoxic aspects of the disease and AB is key to the onset. (Hence need to target both)
MAPT mutations do not cause AD (although they do cause deeneration asscoiated with FTD shown by P301 mutation mouse models)
Clavaguera et al 2015
Injection of Mutant Tau fibrils homogenates from human tissue into mouse models was able to induce the misfolding of endogenous tau creating simmilar inclusions to those injected. Using human specific and murine specific antibodies they showed that murine Tau has indded misfolded. This suggestsed that ince misfolded Tau pathology an become self maintaing.
They also reported that the crossing of APP muatant mice with the ALZMice model. The APP mutation could pottentiate th spread of tau.
Do Tau mutations have varied impacts of AD an FTD.
MAPT muations do not cause AD. However, they have identified roles in FTD.
discuss the efficacy and usefullness of early mouse line trials in targetting Tau kinases in therpeutics?
GSK3beta and CDK5 are both kinases that have been associated with the phophoryaltion of tau. trials have been run in mice attemtping to stop this to stop the formation of NFTs.
This was able to reduce progression of cognitive defects.
But these are not clinnically useful because the fucntion of Tau phosphryaltion and the function of these kinases besides tau is important and thus this has severe off target effects.
discuss the importance of critical periods of actions to therapeutics. Imapact of likely hood of certain targets being effective.
amyloid beta accumualtion and atrophy can be seen 15+20 years, respectively before symptoms onset. hence this offers a critical period of action in which we can stop AB action efore it is too late.
aafter a period tau pathology became self-maintaining. thus there is a periodin which inhibtiing the formation of AB would not stop disease progression and thus stopping the action of tau is also important.
