Dementia & Alzheimers Flashcards
What are some symptoms of dementia?
- Confusion
- Memory loss
- Change in mood/ behaviour
- difficulties with every day tasks
Name types of dementia
- Alzheimers
- Vascular dementia (changes in vascular system/ peripheray lead to neuronal loss and dementia)
- Lewy Bodies
- Frontotemporal dementia
What causes dementia?
- Degenerative: Alzheimers, Lewy bodies disease
- Infection: prion, neuro-syphilis
- Intracranial: trauma to head, tumour
- Endocrine: Hypothyrodism, crushing’s, addisons
- Metabolic: Hypoglycaemia, Ca & Mg, folate
- Toxins: Prolonged alcohol misues, heavy metal posioning
What is Alzheimers?
Most common form of senile dementia. The disease leads to the inevitable destruction of neurons ultimately leading to death within 7 to 10 years.
Not normaly aging
What are risk factors for alzheimers disease?
- Advanced age (over 65)
- Genetic: Downsyndrome (C21), Presenillins, APoE4
- Messing with cerebral perfusion
- Head trauma
- Female
- Enviroment: pollition, toxins
What brain structures are at risk with dementia?
- Cerebral cortex: involved in conscious thoughts and language
- Basal forebrain: involved in memory and learning
- Hippocampus: essential to memory storage
How is dementia diagnosed?
Absolute diagnosis can only be done postmortem (after dead)
- Clincical criteria
- Cognitive testing: mini mental state examination
- Lab test dependent on history and clinical circumstances
- Exclusion of depression
- Use of imaging: MRI and SPECT
In Alzheimers what is neuronal loss associated with?
- Amyloid plaques
- Neurofibrillary tangles
- loss of cholinergic neurons
What is the amyloid hypothesis?
Amyloid protein generation is centetal to the disease. Risk factors affect metabolism of amyloid proteins and therefore deposition. Production of neurofibrillary tangles of hyperphosphorylated tau proteins associate with it.
Describe normal amyloid cleavage in relation to what happens in dementia
Normally amyloid protein attaches across the membrane. It has a C and N terminal.
There are secretases which cleave the protein at at particular place (a). a-secretase cleaves at positinon a. (see digram to see what forms)
However, there are other secretases which cleave at different positions: ß & y secretases. (See diagram). This cleavinf forms Aß amyloid which is neurotoxic when it accumulates.
Describe amyloid hypothesis
- AB40 & AB 42 aggregate and form amyloid plaque which leads to neuronal death (destory connections between nerves cells)
- This aggregation also stimulates phosphorylation of tau proteins leading to neurofibrillarty tangles. This is turn may lead to neuronal death.
What is the amyloid precursor protein hypothesis
(How do genetic factors affect amyloid production)
- APP and Presenilin mutations increase AB40 and AB42 formation
- APoE4 mutation enhance aggrigation
What are the aims for treatment in trials?
- Directly prevent aggrigation of Ab40 &Ab42 into insoluble plaques or enhance clearance from CNS
- Prevent/ hinder AB production (secretase inhibitors)
- Modulate Cholesterol homeostasis
- Modulate inflammatory immune response
Tell me how the following trial drugs work:
- BACE1 inhibitor verubecestat
- Antibody Aducanumab
- inhibits B secretases therefore less AB peptide
- Targets AB and helps to get out of system
What is the cholinergic hypothesis
Correlation between cognitive defects and cholinergic loss.
Lesions of cholinergic innervation of the hippocampus leads to memory/ learning difficulties. These defects can be restored by drugs enhancing cholinergic transmission
Scopolamine produces memory loss
