Neurogenerative Disorders Flashcards
what is the estimated burden of neurological disorders in Europe
35%
what is the average life expectancy of MND
3 years
Alzheimers disease
this is 70% of all cases of dementia
- female predominance
- 10% familial
- Presents with early memory disturbance, progressing to dyspraxia and dysphasia, eventually immobile and mute
dyspraxia
lack of coordination - lack of ability to plan and act out movements
what are the three main types of dementia
- alzheimers
- fronto temporal dementia
- Lewy body dementia
histologically outside the cells, what can be seen in dementia patients
- plaques outside the cells, these are known as extracellular proteinaceous deposits and are largely composed of Abeta peptides
people believe these are toxic to the immune system
what can be seen histologically within the cells, in dementia patients
neurofibrillary tangles:
- predominantly composed of tau
- microtubule stabilising protein
- tau in tangles is hyperphosphorylated + forms paired helical filaments
Abeta peptide (that makes up the protein deposits)
is made from the precursor amyloid precursor peptide (APP) which goes through the secretory pathway after being processed through the Golgi
and is cleaved at different stages by enzymes called secretases and normally the alpha and gamma ones cut the APP and you get fragments but if BETA secretes acts the fragments are 38-42 amino acids and therefore are less soluble and aggregate extracellularly to make fibres plaques
genome scan for risk factors
ApoE4 - Alzheimers by 10 fold, lipoprotein effects SORL1 trafficking)
TREM2 (binds to ApoE4 and effects the functions in recycling)
SORL1 (endocytic sorting via retromer)
what can be seen in the early stages of Alzheimers
- endosome enlargement occurs earlier than tau or amyloid
- key components of the sorting complex retromer, are depressed in the hippocampus of AD patients
- when retromer is dysfunctional this leads to aberrant trafficking, which leads to mixing of beta secretes and APP which leads to Abeta proteins increasing which is BAD
biomarkers fro AD
- thinning of cortex in scans? potentially due to old age
- functional PET cerebral blood flow and metabolism, good for tracing changes
- amyloid PET and Tau PET, which are labelled and can quantitate the level of these proteins, VERY EXPENSIVE AND TAKES ALOT OF TIME
CSF studies
main CSF markers:
- amyloid -beta42
- Total tau
- phosphorylated tau
p-tau181 and p-217 in CSF increase in familial AD before diagnosis
peripheral blood flow biomarkers
- pTau181 assay = this can detect established Alzheimers disease and correlated tangles and plaques distinguished from other dementias
plasma pTau181 increases early in AD
this increases the risk of developing AD by 11 fold
what area of the brain in significantly hit by neurodegenerative disorders
marked loss of Act in nucleus basalis of meynert (this is believed to be where the learning and memory deficit comes from)
- GABA loss from the cortex secondary to neuronal loss
- serotonin (5HT) input from dorsal raphe nuclei reduced
- Noradrenaline input from locus coeruleus reduced
drugs that can aid in the memory and learning deficit
Galantamine
Donepezil
Rivastigmine
acting on receptors or act on EACh and breaks it down in the synaptic cleft
