WEEK 4 Flashcards
HOW DO cholinesterase inhibitors work
these increase brain acetylcholine levels by inhibiting CNS acetylcholinesterase . effective in Demetia with LB and parkinsons demetia but not FTD/vascular demetian. effective in mild/moderate AD
what is glutamate
an amino acid , the major excitatory neurotransmitter
characteristics of NMDA receptors
permeable to calcium ions
the ion channel is blocked by magnesium - voltage dependent blockade
long term potentiation - slow gated kinetics
Clinical features of Alzheimers disease
*failing memory- episodic mem affected
*cognitive decline
*psychiatric - personality changes
*neurological - primitive reflexes and postural abnormalities
impairment of organising planning and sequencing . there is visuospatial difficulties
pathological changes in the brain - preclinical AD
signs of AD first noticed in the entorhinal cortex, then the hippocampus . AD spreads through the rbain , the cerebral cortex begins to atrophy with more neuronal loss . affected regions begin to atrophy with associated neuronal loss . memory loss is the first sign .
mild AD
memory loss, confusion, trouble handling money , poor judgement , anxiety , mood changes
moderate AD
increased mem loss and confusion problems recognising people , difficulty with language and thoughts
wandering
repetitive statements
severe AD
- Severe cortical atrophy. Pathology throughout the neocortex.
- Patients are completely dependent requiring nursing home care.
- Weight loss, seizures, increased sleeping, loss of bladder and bowel control.
- Death usually occurs from pneumonia.
PATHOLOGY hall marks for AD
- Deposition of β-amyloid (Aβ) in amyloid plaques in the cortex
- Tau containing intracellular neurofibrillary tangles.
- These proteins aggregates damage synapses and ultimately lead to neuronal death.
- Amyloid may also be laid down in cerebral blood vessels, leading to amyloid angiopathy
WHAT is amyloid precursor protein
is a glycoprotein molecule that sits in the cytoplasm - essential component of neuronal membranes . it has 3 parts and thus can be cleaved off by the enzyme secretase , there are types of secretase - alpha beta gamma
possible mutations of APP
- Point mutations in the APP gene.
- Mutations in the presenilins 1 & 2 (affect gamma secretase)
- Polymorphism of the E4 allele of the apopliprotein E is associated with a 20x higher risk of developing AD
cleavage of APP releases what
beta-amyloid in the extracellular matrix , these then aggregate into plaques , which are harmful to neurons. beta amyloid may also be laid down in cerebral blood vessels leading to amyloid angiopathy
what is amyloid angiopathy
Aβ may also be laid down in cerebral blood vessels,
mutation of tau protein
- Within neurones, the transport system is organised in orderly parallel strands. biomolecules and cell parts move along these strands.
- However, when there is hyper-phosphorylation of the tau protein, it collapses into twisted strands called tangles. The strands can no longer stay straight and thus fall apart and disintegrate. Nutrients and other essential supplies can no longer move through the cells, which eventually die.
- The tau strands then aggregate into neurofibrillary strands
what is vascular demeNtia
Effectively a series of mini strokes , causing damage to the brain thus memory. patient often has a series of trasient ischaemic attacks to the brain.
demetia with lewy bodies pathophysiology
• The lewy bodies formed are aggregates of the protein α-synuclein. This is due to the protein misfolding into a β-pleated sheet structure. These then further aggregate into higher-order insoluble structures (fibrils), which are the building blocks for Lewy bodies.
clinical features of demetia with lewy bodies
visual hallucinations , fluctuating consciousness . shares features with parkinsonism . mem loss may not occur till later but delusions and transient loss of consciousness wil occur occur
fronto-temporal dementia
a group of neurodegenerative disorders characterised by frontal lobe and temporal lobe atrophy on MRI
often seen in younger patients - 45-65
sporadic/inherited .
- frontal lobe dysfunction , behavioural/personality changes , disinhibition , depressio, agitation
temporal dysfunction - progressive impairment of language function. Progressive loss of word-finding ability but fluent speech relatively lacking in meaningful content and difficulty with comprehension of language.
Tau accumulation causing Pick’s bodies ->picks disease
what are the events that occur at a cholinergic synapse
- An arriving action potential depolarises the synaptic knob.
- Calcium ions enter the cytoplasm, and after a brief delay, ACh is release through the exocytosis of synaptic vesicles
- Ach binds to sodium channel receptors on the postsynaptic membrane, producing a graded depolarisation.
- Depolarisation ends as ACh is broken down into acetate and choline by AChEsterase (AChE)
- The synaptic knob reabsorbs choline from the synaptic cleft and uses it to synthesise new ACh
why are cholinesterases not useful in frontotemporal dementia
because there are no cholinergic deficits . in FTD there are more serotonin deficits so SSRIs are useful
what does glutamate act on
AMPA and NMDA receptors on the post synaptic membrane
when is memantine used
in moderate /severe AD or when cholinesterase inhibs are not tolerated . there is a build up of glutamate in AD brains , thus memantine is used to block NMDA receptors and stop the overactivity of the glutaminergic system
what is BPSD
behavioural and psychological symptoms of dementia - refer to the often distressing non-cognitive symptoms of dementia and include agitation and aggressive behaviour. BPSD have been defined as symptoms of disturbed perception, mood or behaviour, frequently occurring in patients with dementia
in dementia what is depression associated with
reduced monoaminergic function
