BB2 Revision4 Flashcards
Pathogenesis of Alzeimers DIsease (AD)
Name the genes [3] and proteins [3] that are critical for early onset AD [3]
Genes for early onset AD (not common). caused by the following genes
* Amyloid precursor protein (APP)
* Presenellin 1 (PSEN1)
* Presenellin (PSEN2)
Describe the difference in APP processing between the amyloidogenic and non-amyloidogenic pathway
APP protein has 3 cleaving sites. Depending on combination of secretases have will cause different payhways
Non-amyloidogenic pathway:
* alpha-secretases and gamma-secretases
Amyloidogenic pathway:
* Beta-secretases and gamma-secretases
* Generates: AB peptide with two isoforms:AB 40 and AB 42.
Which gene is associated with late onset AD? [1]
Late onset (60+ years of age)
* Apolipoprotein E (Ch.19)
Which molecule is APOE involved in the metabolism of? [1]
What are the three isoforms of APOE? [3]
Which is the greatest risk for AD and why? [2]
Involved in cholesterol metabolism
APOE2; APOE3 & APOE4
APOE4 has greatest risk factor and decreases clearance of extracellular Aβ.
Which change in AD pathophysiology relates to cognitive decline? [1]
Hyperphosphorylated tau tangles correlate to cognitive decline (Amyloid plaques does not)
Which gene encodes tau? [1]
Are mutations to this gene linked to familial AD? [1]
MAPT gene
NOT linked to familial AD; instead to frontotemporal dementia (FTD) and several other Tauopathies.
Treatment strategies in AD
Name the drug class [1] and 3 drug examples you prescribe for mild - moderate AD? [3]
Name the drug class [1] and 3 drug examples you prescribe for severe AD? [1]
Mild-Moderate AD:
* Acetylcholinesterase inhibitors(e.g. donepezil, galantamine and rivastigmine)
Severe AD:
* NMDA receptor antagonists (e.g. memantine)
Which other drugs may AD patients be described based off their symptoms? [3]
But what needs to be considered about these? [1]
Antidepressant drugs
Antipsychotic drugs
Mood stabilisers
But overuse of anti-pyschotics can increase in mortality
Pathogenesis of Alzeimers DIsease (AD)
What is the final product of amyloid precursor protein being cleaved? [1]
Aβ peptides (this is a normal metablic event)
Presenilin 1 & 2 are responsible for making which secretase? [1]
Presenilin 1 & 2 proteins is one part (subunit) of a complex called gamma- (γ-) secretase.
Describe the inflammatory response caused by familial forms of AD pathogenesis (from early AD genes) [2]
Describe the effect of amyloid plaques within neurons (caused by familial forms of AD pathogenesis) [2]
Inflammatory response:
* Microglial activation - inability to clear AP causes chronic inflammation of microglia
* Astrocytosis (increase in amount) and acute phase protein release
Progressive neuritic injury within amyloid plaques
* Disruption of neuronal metabolism and ionic homeostasis:
* Oxidative Stress
Which posttranslational modification does the microtubule-binding protein, tau undergo which contributes to Alzheimer’s pathology? [1]
Which amino acids can undergo this specific post translational modification? [3]
Hyperphosphorylation.
Tyrosine, serine and threonine.
Describe effect of AD on cholinergic pathways? [2]
What can be given to reverse this effect? [1]
Cholinergic forebrain pathways innervating cortical and limbic structures degenerate in AD
Blockade of acetylcholinesterase increases the failing cholinergic signal
AD can be associated with a slow form of [] due to increased glutamate
AD can be associated with a slow form of excitotoxicity due to increased glutamate
Name 6 potential new mechanisms for AD treatment
- β-secretase inhibitors
- Notch-sparing γ-secretase inhibitors or modulators
- Aβ vaccines and monoclonal antibodies
- Aβ aggregation inhibitors
- Tau lowering/anti aggregation compounds
- Regulation of abnormal anti-inflammatory mechanisms
Define:
Dysarthria [1]
Dysphonia [1]
Dysarthrophonia [1]
What stays the same throughout each of the above? [1]
Dysarthria: disorder affecting articulation (slurred / unclear speech)
Dysphonia voice disorder (voice might be weak / distorted)
Dysarthrophonia: voice and articulation disoder
Language and cognition is normal
A 60-year-old female has non-fluent aphasia characterized by good comprehension but poor repetition. What is the best description of this condition?
A. Wernicke aphasia
B. Broca aphasia
C. Anomic aphasia
D. Mixed transcortical aphasia
A 60-year-old female has non-fluent aphasia characterized by good comprehension but poor repetition. What is the best description of this condition?
A. Wernicke aphasia
B. Broca aphasia
C. Anomic aphasia
D. Mixed transcortical aphasia
What is the name for saying the wrong words? [1]
Paraphasias
What is telegrammatism? [1]
Difficulty forming sentences
TBI injury mechanism:
What are the 3 causes of TBI? [3]
Penetrating injury
* Foreign object (e.g. bullet) enters into brain causing focal damage.
Closed head injury:
* Blow to the head (e.g. road traffic accident).
Blast injury
* Explosion (e.g. bomb) create fast moving pressure wave that passes through the brain and damages axons and vasculature.
Types of traumatic brain injury injury classification
Describe the injury classifications for TBI [2]
Focal injury:
- Coup: at site
- Contrecoup: opposite site
Diffuse injury:
- Diffuse axonal injury
Diagnosis of TBI
Which scale is used to classify TBI? [1]
Which critertia is it based on? [3]
What is the maximum score for each of the criteria? [1]
Glasgow Coma Scale (GCS):
Based on:
- eye opening [/4]
- motor response [/5]
- verbal response [/6]
What are mild, moderate and severe GCSs? [3]
Mild: 14-15
Moderate: 9-13
Severe: less than 8
Explain the two other scales that can be used to assess TBI? [2]
Loss of Consciousness (LOC) scale measures the time patient was unconscious
Post traumatic amnesia (PTA) scale measures the interval from injury until patient is orientated and can form and recall new memories.
.
Diagnosis of TBI: Imaging
What GCS would cause a CT to be given:
- straight away? [1]
- after 2 hrs of assessment [1]
GCS less than 13 on intial assessment
GCS less than 15 after 2 hours of injury assessment
1- Pathophysiology of TBI: Increase in intracranial pressure
How do you detect ICP? [1]
ICP bolt
1- Pathophysiology of TBI: Increase in intracranial pressure
Describe the Monro-Kellie Hypothesis [4]
Relationship between the contents of the cranium and intracranial pressure:
- Brain is enclosed in a fixed non-expandable skull.
- Increase in mass (e.g. haematoma) reduces CSF and cerebral blood flow in the brain.
- Decrease in brain blood and CSF causes ischemia and then brain cell death.
- Increase ICP can cause herniation.
3- Pathophysiology of TBI: herniation
Name the 6 types of brain herniation
Uncal
Central (transtentorial)
Cingulate (Subfalcine)
Transcalvarial
Upward cerebellar (transtentorial)
Downward cerebellar (Tosillar)
4- Pathophysiology of TBI (Sub Dural Haemotmoa)
Which layers do SDH occur in? [1]
Which blood vessel is commonly affected? [1]
How does SDH commonly occur in imaging?
Subdural haematoma (SDH) is a blood clot in the subdural space between the dura and arachnoid mater of the meninges.
SDH is mostly from damage bridging cortical veins (75%)
SDH is often in CT scan as ‘banana/crescent’ shape and can cause herniation.
5- Acute management of TBI (Mild TBI)
How would you acutely treat mild TBI? [2]
Describe the 3 categories of epileptic seizures? [3]
Focal onset (aka partial seizures)
* Cortical or subcortical effected
* They can remain localized or spread to large areas
* start in one of the brain hemisphere
Generalised onset:
* Both sides of brain at onset
* Cortical or subcortical effected
Unknown onset
* If the beginning of the seizure is uncertain
Which part of the brain undergoes structural changes during epilepsy? [1]
Which structural changes occur in this area? [4]
Reorganisation of the hippocampal tissue / hippocampal scleoris:
* Atrophy of CA2 and CA3 hippocampal areas
* Different tract orientation
* Compresion of layers
* Loss of neurones
Strucutral changes in epilepsy (I)
What are the consequences of hippocampal sclerosis / degeneration in epilepsy? [1]
Sprouting of axons & neurogenesis- may lead of excess synaptic conduct between neurons
Aberrant circuits may be created within the hippcampus
Overtime, there is transformation within neural networks that promote excitability.
Describe the phenomenon / profile of neurones in an epileptic focus [1]
Describe how this occurs [1]
Burst firing: aka paroxysmal depolarising shift phenomenon
- This leads to synchronous, hyperexcitable activity within a neuronal population
- Particularly NDMA glutamate receptor activation
Label A&B of the hippocampus [2]
A: CA2
B: CA3
Both undergo atrophy in epilepsy
Label the channels that are abnormally functioning in epilepsy
EAAT1
EAAT2
(causes more glutamate in synapse)
Name this cell [1]
What is the function of this cell [1]
Chanderlier cell
specialized GABAergic interneuron subtype that selectively innervates pyramidal neurons at the axon initial segment (AIS), the site of action potential generation
