22. Dementia Flashcards
What is meant by ‘dementia’?
Dementia is a term used to describe a syndrome that can be caused by a number of illnesses where there is a progressive decline in multiple areas of function:
Decline in memory and reasoning
Decline in communication skills
Inability to carry out daily activities
What are some common symptoms of dementia?
Agitation Aggression Wandering Shouting Repeated questioning Sleep disturbance Depression and psychosis
What are the different types of dementia and which is the most common type?
Alzheimer's disease Vascular dementia Dementia with Lewy body Parkinson's disease Frontal temporal
Alzheimer’s disease is the most common type
What are the non-modifiable risk factors for dementia?
Age (greatest risk factor)
Genetic predisposition
Family history
Downs-syndrome
What are the modifiable risk factors for dementia?
Vascular risk factors such as high cholesterol, hypertension, diabetes
Cognitive inactivity (low education attainment)
Environmental i.e. increased head injury
Depression and other psychiatric diseases
What changes occur in the brain of someone suffering from AD?
Increased deposition of protein B-amyloid in the form of amyloid plaques - primarily in the parietal lobe and hippocampus
Increased prevalence of neurofibrillary tangles composed of protein Tau - occurs due to hyper-phosphorylation of Tau
Increased neuronal loss
Cerebral atrophy
Excessive synaptic loss - particularly of cholinergic cells
Why do such changes occur in the brain of someone with AD? - Give the pathophysiology of AD
Amyloid hypothesis:
Mutations in the APP (amyloid) gene on chromosome 21 is associated with early onset AD
This can increase the deposition and accumulation of B-amyloid in the brain
There are 29 mutations all associated with increased deposition
(Downs syndrome - increased risk of AD - chromosome 21)
Presence of E4 allele of the ApoE gene on chromosome 19 - increased risk of late onset AD
Presence of ApoE2 allele has a protective role of the development of AD
Hyper-phosphorylation of Tau protein
Tau generally acts to stabilise microtubules (mt are responsible for passage of neuronal structures to where they are required in the grey matter)
Hyper-phosphorylation causes the Tau to dissociate off of the microtubules and so they dissociate and the structures do not get to where they are required and neurones cannot function like normal
Increased oxidative stress to the brain
Abnormal inflammatory reactions
Which three genes predispose to the development of early onset AD and why?
Early onset AD occurs if there is a mutation in the structure of the APP protein (amyloid precursor protein - transmembrane protein) - there are 29 genes which result in this mutation - this APP is cleaved to form AB peptides
APP - encodes for the APP protein and a mutation in this genes results in an altered structure of the APP protein
PSEN1 - encodes presenilin-1 which is a subunit of y-secretase and this cleaves the APP to form the AB peptide - mutations in this causes the cleaving to occur pathologically and alters the structure of the APP protein - these are the most common cause of early onset AD
PSEN2 - encodes presenilin-2 which is another subunit of y-secretase and the same pathology occurs in as the above gene but on a different location on the APP protein - this is a rare cause of early onset AD
What does abnormal cleaving of the APP proteins result in?
APP proteins, once cleaved, then go down either a non-amyloidogenic pathway or an amyloidogenic pathway
The non-amyloidogenic pathway occurs if the APP protein is cleaved by a-sec and y-sec
The amyloidogenic pathway occurs if the APP protein is cleaved by B-sec and y-sec and this results in the formation of AB-amyloid peptide which is deposited in the brain - this is a pathogenic pathway
What is an oligama and what is the consequence of this?
This is produced when you have the amyloidogenic pathways occuring
This is an insoluble species and is also a toxic species which leads to the death of neurones
What occurs in the brain as a result of the B-amyloid deposition?
B-amyloid plaque deposition results in a neuro-inflammatory response - there is microglial activation and they release things such as TNF-a
There is also a increased level of oxidative stress
There is disruption to the phosphotase activity - hyper-phosphorylation of Tau
Where specifically in the brain does neuronal death and dysfunction occur in AD?
Neuronal death and dysfunction occurs specifically in the hippocampus and the cerebral cortex
What are the different biomarkers and investigations for dementia and AD?
Lumbar puncture to look at the CSF - in advancing AD there will be low levels of B-amyloid in the CSF and high levels of Tau
MRI and CT - to exclude other cerebral pathologies such as a tumour or hydrocephalus and also used to confirm presence of brain atrophy, neuronal loss and enlarged ventricles
Blood test - to identify if there is any other cause for the dementia rather than AD e.g. thyroid tests, B12 level, electrolyte level
What is the effect on cholinergic neurones in AD?
How is this treated and when is this adminstered?
In AD, the cholinergic forebrain pathways that innervate cortical and limbic structures degenerate
SO administer acetylcholinesterase inhibitors to inhibit the breakdown of the acetylcholine and increase their signal
What other treatment options are there for AD?
NMDA glutamate receptor antagonists - because the neurones are dying in AD, this results in a state of hyper-excitability of the remaining neurones and they fire at a much greater rate - this can cause damage to the remaining neurones
SO the NMDA glutamate antagonist e.g. memantine acts to reduce the Ca2+ entering the neurones to reduce their excitability
