Dementia Syndromes- Vickers Flashcards
What is the definition of dementia?
• Change in functioning from previous levels
• Deterioration in cognition, personality and
behaviour
• Are diseases, not just due to brain ageing
What are some diseases which cause dementia?
– Alzheimer’s disease
– Frontotemporal dementia
– Lewy body dementia
– Vascular (multi-infarct) dementia
• Small vessel diseaseWhat is vulnerable to degeneration in Dementia?
Early research indicated that nerve cells that make a neurotransmitter called Acetylcholine vulnerable
to degeneration.”
Current therapeutic strategies make use of Acetylcholinesterase inhibitors - what are some of the names of the drugs used?
Acetylcholinesterase Inhibitors”
Tacrine (Cognex)
Donepezil (Aricept) -
Rivastigmine (Exelon) -
Other therapeutic strategies used in dementia
Estrogen" Vitamin E" Anti-oxidants" Anti-inflammatory agents" Statins"
Alzhimers disease
• Major cause of age-related dementia”
• Insidious onset”
• Progressive and degenerative condition”
Explain the histopathalogical changes that occur in Alzheimers disease -
there are 2 major proteins affected- what are these? which is inside and which is outside the nueronal cell
Only affect a certain type of neurons
So in Alzheimer’s disease they only lose 20-30% of neurons – but these are key in relation to function
Beta -amyloid plaques (outside)
Tau protein causing neurofibrillary tangles (inside)
Describe the formation of beta amyloid plaques
Beta-amyloid plaques
- Spherical deposits in the brain, outside the cells
- Extracellular spherical mass of fibrils composed of the beta-amyloid peptide
Beta-amyloid is derived from the AMYLOID PRECURSOR PROTEINn (APP) & is a normal component of the body.
Function of APP thought to be to do with something like stopping synapses. When something happens and APP gains 2 amino-acids, this increases its ability to stick to each other. These ‘oligomers’ are toxic. But then they keep aggregating into polymers (big clumps) which are insoluble
Dystrophic neurites – dendrites & axons that look abnormal
Beta-amyloid undergoes a conformational change to become insoluble, forming the fibrils of the plaque (distorts the architecture of the brain). Plaques can form within a few days.
These sit between the neurons, they are insoluble, they deposit & grow.
Describe the pathogenesis of the neurofibrillary tangles
2) Neurofibrillary tangles
- Inside the cells are neurofibrillary tangles
- Come from a protein called Tau
- TAU is a microtubule association protein – it stabilizes/connects together the microtubules. Recall microtubules are used for transport inside the cell.
Mutation causes the Tau to aggregate inside the cell body – becomes hyperphosphorylated & winds itself up into paired helical filaments which gums up the inside of the cell
Dementia is described as a disease of disconnection- why?
• Alzheimer’s disease attacks higher association areas of the neocortex
o So we can no longer communicate between these areas
• It is the long neurons that are affected
• We start off with changes around the hippocampus (area involved in memory)
o Start of here & then spread
There are two genetic traits which are ingrained with alzheimers, what are these?
• Familial Alzheimer’s Disease (FAD)
Genetic risk factors (for sporadic Alzheimers)
• Apolipoprotein E
What is FAD? What mutations are associated?
<10% of AD cases
Develop AD a lot earlier
Linked to mutations in
- Amyloid Precursor Protein Gene – Chr 21 (Down’s syndrome)
- Presenilin 1 gene – Chr 14
- Presenilin 2 gene – Chr 1
- Increase amount of gamma-secretase which increases Abeta amino acids so more bad amyloid
For sporadic Alzheimers, there are some genetic factors, what are these?
Apolipoprotein E
o Moves cholesterol around body, controls lipids& fats. ALLELIC VARIATIONS AFFECT RISK
- Apo-E2 – decreased risk of developing dementia
- Apo-E4 – increases risk (this is dependent on how many copies of the allele you have got – if you have more, you are more likely to develop a Dementia). Apo-E4 causes inflammation & leaky blood vessels & breaks down the BBB (leaky, harder to regulate what moves in & out)
Questions in AD still remain unanswered
What is the underlying neuronal deficit that leads to dementia?
- Neurofibrillary tangle formation?
- Frank neuronal loss?
- Change in synapses/synaptic physiology (change in structure, shape – cant communicate)
- Atrophy: loss of brain substance
• Shrinks, sulci expand, ventricles expand – could even be related to the myelin
What is the relationship between beta-amyloid & neuronal pathology
We know that Beta amyloid is important
Small subset of cases linked with mutation in amyloid precursor protein gene
Amyloid fibril deposition is an early feature of brain changes leading to dementia
Plaques cause damage to axons
What actually causes the damage?
- Beta-amyloid precursor protein
- OR Form oligomers & aggregated plaques. Oligomers can be directly neurotoxic.
Cortical Synapse loss actually exceeds neuronal loss in AD
• probably due to some toxic mechanism
