Alzhiemer's and sleep Flashcards
What is a typical macroscopic clinical feature of Alzhiemer’s Disease?
Gross cerebral atrophy
What are the presences of Alzhiemer’s in the pop. at different ages?
Dementia affects 1 in 17,000 below 65; 1 in 50
jobetween 65 and 70 an 1 in 5 over 80.
What are the histopathological features that are diagnostic of Alzhiemer’s Disease?
Senile plaques
neurofibrillary tangles
neurone loss
What are the different neuronal cell types?
Spiny neurons - pyramidal cells and stellate cells
Non-spiny neurons - types of GABAergic and peptide-containing cells
Neurofibrillary tangles and AD?
- tangles (NFT) correlate with dementia
- found first in entorhinal cortex
- composed of paired helical filaments (PHF)
- PHF composed of highly phosphorylated tau
- tau normally stabilises microtubules
- tau mutated in FTD‐P 17
(Disturbance of enzymes which add and remove phosphate
Tau in normally as phosphate protein)
What is tau?
- 6 isoforms in CNS
- 1 gene
- phosphoprotein
What are the stages of degeneration in Alzhiemer’s?
Transentorinhal - stage I and II
Iimbic - stage III and IV
Neocortical changes - stages V+VI
(3-5 - dementia onset)
See pages 15-16 of neuropathology of Alzhiemer’s for diagrams
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Is Alzheimer’s genetic?
A small percentage of people with Alzheimer’s have autosomal dominant mutations on these chromosomes 1, 14, 21
Mutations in tau known to cause Alzhiemer’s
Apoe genotype e4 increases risk and makes onset earlier
What is the role of Amyloid Precursor Protein in Alzheimer’s?
Deposited in plaques
Beta-secretase
Fibrillisation
Which NTs are particularly deficient in Alzhiemer’s Disease?
Ach
5HT
NA
(Glutamate)
2 important nuclei in the major cholinergic pathways?
Septal nuclei
Nucleus basalis
What happens with hippocampal pyramidal neurones in AD?
• Normal human brain
‐ stain for glutamate and glutaminase.
• Alzheimer’s disease
‐ decreased numbers stain for glutamate and glutaminase.
‐ neurones have disorganised and shortened dendrites
‐ glutamate and glutaminase stained neurones contain tangles.
Why is the hippocampus important in AD?
Memory formation requires activation of hippocampal circuitry
Signalling between cortical areas and hippocampus is dysfunctional in AD
What drug treatment is available for Alzheimer’s and how effective is it?
• Based on the Acetylcholine deficiency model
(Aricept, Exelon and Remenyl) or glutamate (Ebixa).
- 60% of suffers gain some benefit.
- Improve over 6/12 then begin to decline again.
- Many more in the pipeline.
What are the valuable qualities of genetically modified animal models?
- Test genetic contribution to aetiology
- Recapitulate some features of human disease
- Allow examination of evolution of pathology and disease mechanisms.
- Examine influence of other genes/products
- Test novel therapies
Features of Alzhiemer’s Disease - list
Thioflavin S-positive Alpha-Beta deposits
Neuritic plaque
Synaptic loss
Astrocytosis
Microgliosis
Neurofibrillary tangles
Neuron loss
Progressive pathology (age dependent)
Pattern of pathology
Learning and memory impairment
LTP deficit
Neurotransmitter dysfunction
Is there hope for an AD vaccine?
Immunization with ABeta attenuates AD‐like pathology in the PDAPP mouse
Clinical trial using ABeta42 (AN‐1792) with the T helper 1 adjuvant QS‐21
What are the general effects of sleep on body physiology?
The entire body, is affected during sleep, not just the brain.
During sleeps there is a fall in the core body temperature (especially during REM sleep),
increased secretion of growth hormone secretion of growth hormone,
increased secretion of cortisol (activation of the hypothalamic-pituitary axis (HPA)
and a reduction in renal potassium secretion secretion.
With regard to the CNS, is sleep a uniform behaviour
No
Sleep can be divided into REM (Rapid Eye Movement) and non-REM phases that occur cyclically (typically 5-7 cycles) throughout the sleep period.
Non-REM sleep is further divided into 4 stages that can be identified by EEG characteristics
(Younger - larger proportion of REM and more defined pattern than older people)
What are the features of REM sleep?
- Characterized by rapid side-to-side movements of the eyes whilst closed
- Frequent ‘dreams’
- Near-awake levels of cortical neuronal activity
- Near-awake metabolic rate
- Brain temperature rises but body temperature falls overall
- Irregular autonomic activity (heart rate and BP variations) but net parasympathetic dominance, e.g. constricted pupils
- Selective paralysis and loss of muscle tone (eye, diaphragm movements remain intact, limbs are paralyzed)
- Loss of some homeostatic reflexes
What are the features of Non-REM sleep?
- Few ‘dreams’
- Associated with reduced neuronal activity
- Reduced metabolic rate
- Reduced brain temperature
- Autonomic output is dominated by parasympathetic tone (low B.P., low heart rate, constricted pupils)
- Muscle tone and reflexes are intact
What are the EEG frequencies of different depths etc of sleep?
Delta Theta - 1-4 Hz, 4-8Hz - deep sleep
Theta - 4-8Hz - light sleep
Alpha - 8-14Hz - relaxed
Beta - 15-30Hz and Gamma - 30-120Hz - awake, REM sleep
light sleep relaxed
awake, REM Gamma 30-120 Hz a a e,
Proposed physiological purposes of sleep
Metabolic reconstitution:
- restoring glycogen levels for energy, re-filling neurotransmitter stores, clearance of unwanted metabolic products.
Neuroplasticity:
- Consolidation and/or disassembly of new synaptic connections - (neural development, optimizing intellectual performance; filtering learning and memory)
Repair and restoration:
- tissue repair during quiescence; immune regulation.
