Dementia Flashcards
Dementia
Syndrome that may be caused by a number of illnesses in which there is progressive decline in multiple areas of function, including:
- -> decline in memory, reasoning + communication skills
- -> inability to carry out daily activities
Dementia definition
Clinical syndrome characterised by a cluster of symptoms manifested by difficulties in memory, language, behavioural, psychological changes and impairments in daily living
Mini Mental State Exam
Time orientation- what is date
Information- something that happened in news recently
Recall test- give name + address, want u to repeat it, will ask again in few minutes
Clock drawing task
5-8= mild impairment
<4= cognitive impairment
Degenerative or inherited
Alzheimer's 62% Lewy body dementia Huntington's Pick's MS
Vascular
Vascular dementia 17%
Cerebral vasculitis
Space-occupying lesions
Chronic hydrocephalus
Tumour
Infection
HIV-associated dementia
Abscess
Syphilis
Post-meningitis
Traumatic
Post head trauma
Boxing
Toxic
Cerebral anoxia
Alcohol + drugs
Metabolic or nutritional causes
Hypothyroidism
Hypocalcaemia
Vit B12/folic acid/niacin
Thiamine deficiency –> Korsakoff’s and Wernicke’s
Non-modifiable risk factors
Age
Genetics
Family history
Down’s
Modifiable RFs
Vascular (high cholesterol, hypertension, diabetes)
Cognitive inactivity (low education attainment)
Environment (head injury in boxers)
Depression
Alzheimer’s pathophysiology
Beta amyloid plaques Tau neurofibrillary tangles Neurotic dystrophy Synaptic loss Selective neuronal loss Significant loss cholinergic cells
Beta amyloid plaques
Extracellular deposits of Beta amyloid peptide in senile plaques
Deposits of Beta amyloid peptide in cerebral vessels
Tau tangles
Intraneuronal neurofibrillary tangles (hyper-phosphorylated tau protein) in cell bodies + neurites
Genetic factors - early onset AD
Amyloid precursor protein (APP)- chromosome 21 Presenilin 1 (PSEN1)- chromosome 4 Presenilin 2 (PSEN2)- chromosome 1
Genetic factors- late onset AD
Apolipoprotein E (APOE)- chromosome 19
APP
Single transmembrane polypeptide
APP abundantly expressed in neurones
Also expressed in glia and endothelial and smooth muscle cells
APP increase A beta production
Alzheimer’s pathology
Extreme shrinkage of hippocampus
Extreme shrinkage of cerebral cortex
Severely enlarged ventricles
APP processing
Cleaved by 3 secretases- alpha, beta and gamma secretase
Cleaved in non-amyloidogenic (alpha and gamma) and amyloidogenic (beta and gamma) pathway
Amyloidogenic pathway –> production of A beta 40-42, which form fibrillar insoluble plaques between neurones
PSEN
PSEN 1 + 2 are subunits of gamma secretase (responsible for A Beta generation)
PSEN 1- most common cause of early onset Alzheimer’s
PSEN 2- least common cause of early onset Alzheimer’s
APOE
Secreted lipoprotein Involved in cholesterol metabolism Strong RF for late onset APOE 2, 3 and 4 ApoE4- shown to decrease clearance of extracellular A beta
Tau
Microtubule-associated protein
Role in microtubule stabilisation + axonal transport
Phosphorylation of tau regulates its activity to bind to microtubules
Hyperphosphorylation of tau results in formation of neurofibrillary tangles - primarily composed of paired helical filaments
Nicotinic receptors
Ion-gated receptor channels
Selective for cations- K+, Na+ and Ca2+
Muscarinic receptors
G protein coupled receptors
ACh synthesis
Synthesised from choline and acetyl-CoA by choline acetyltransferase
ACh transferred into synaptic vesicles by…
Vesicular acetylcholine transporter
ACh hydrolysis
By acetylcholinesterase into choline and acetate
Recycled into pre-synaptic neurone by high affinity choline transporter (CHT1)
What neurones are main neurones affected in Alzheimer’s
Cholinergic neurones
AChE inhibitors
Increase ACh levels + reduce anxiety, improve motivation, memory and concentration, and improve ability to continue activities of daily living
Donepezil
AChE inhibitor
Rivastigmine
AChE inhibitor
Galantamine
AChE inhibitor
Memantidine
Moderate to severe Alzheimer’s
Intolerant to AChE inhibitors
Reduces glutamate excitatory neurotoxicity
NMDA receptor antagonist
Works on ion channel + extracellular surface of receptor
Anti-amyloid strategies
Inhibition or stimulation of secretases involved in APP metabolism
Selective reduction of ABeta42 synthesis
Prevention of amyloid aggregation
Anti-amyloid immunotherapy
