Week 11 Flashcards
(47 cards)
Macroscopic brain ages
Ventricular enlargement, cortical thinning, decreased post mortem weight, the accumulation of white matter hyperintensities
Cellular changes ageing
Synaptic pruning, axonal loss, mitochondrial changes, alterations glial cell numbers
Molecular changes ageing
Altered gene expression, disrupted calcium signalling, epigenetic changes
Clinically ageing brain
Cognitive decline (information processing speed, memory, reasoning, and executive function)
Decreased well being
Increased symptoms low mood
Increase neurodegenerative disease
Changes in brain as we age
Volume decline 5% per decade from 40 years
Neuronal volume loss not number
Prefrontal cortex most affected
Hippocampus, striatum, temporal lobes, cerebellum
Don’t tend to get changes in brain stem or primary visual cortex
Changes in cell types in brain as we age
Neuronal cell, stable no. Reduced volume
Oligodendrocyte, increases
Astrocytes stable
Microglia increased. Inflammatory phenotype, senescent MHCII but primed
Microglia
Phagocytes: clear debris such as beta amyloid and damage to myelin
Release growth factors and neurotrophins such as BDNF
Trigger repair by astrocyte stimulation and stem cell recruitment
Activated in inflammation, in response produce inflammatory cytokines which help bring in Th1 helper cells
Damage to astrocytes or damage to synapses will also activate microglial cells
Once they do their jobs they go back to being quiescent
Microglial senescence
Changes in microglia distribution: increase in numbers/density in neural parenchyma. Decreases regularity in distribution, translocation into ares not previously occupied by microglial (outer layers by retina)
Changes in microglial morphology: decreases in individual ramification (dendritic arbor area, branching and total process length). Appearance of morphological changes suggestive of increased activation state (eg perinuclear cytoplasmic hypertrophy, retraction of processes) sporadic appearance of dystrophic microglial in aged human brains
Changes in microglial dynamic behaviour: decrease in rate of process movement, decrease in rate of migration to focal tissue injury
How does ageing microglial affect function at synapses
At the presynaptic neurone the mitochondria dont function as well with age
They produce less ATP so there’s less energy to get nT out presynaptic neurone
Changes in gene expression of transporters in presynaptic neurones
Post synaptic neurone: get changes in number and affinity of post synaptic neurone receptors and changes in calcium homeostasis- normally important for triggering AP
Changes in neurotransmitters with age
Dopamine: 10% decrease per decade from 20, frontal cortex to striatum affected, Parkinsonism
Serotonin and BDNF changes
ACh: reduction enzyme CAT (greater in hippocampus) which converts precursors Ach to ACh so less ach in neurone less in synaptic cleft. Reduction M1, M2 receptors, loss cells produce ach, Alzheimer’s disease
GABA: reduced GAD enzyme produces GABA and reduced GABA receptors. Huntingtons disease
Mitochondrial dysfunction, ROS, calcium dysregulation
Memory and parts of the brain
Semantic: medial temporal lobe (incl hippocampus) and cortex
Episodic: medial temporal lobe (incl hippocampus and cortex)
Procedural: cerebellum, striatum, putamen tend not to change with age
Emotional: amygdala
Working
Different areas more affected lead to different clinical features
Prefrontal cortex firstly and most affected by age
See changes in hippocampus, striatum, temporal love, cerebellum
Don’t tend to get changes in brainstem or primary visual cortex
Working memory may reduce with age- perceptual speed
Verbal ability associated with long term memory- stays fairly constant with age
Brain predicted age
Brain PAD: brain predicted age difference
Positive brain PAD ‘older appearing brain’
Negative brain PAD ‘younger’ appearing brain
Brain PAD predicts survival over 8 years so good marker of physiological age as opposed to chronological age
Alzheimer’s take home messages
Alzheimer’s disease is the most significant disease in an ageing population and as yet there are no pharmacological treatments to modify or prevent the disease
Amyloid hypothesis describes accumulation beta amyloid Ab as the event that triggers AD
Ab is a derivative of the larger amyloid precursor protein APP. The roles of a, B and gamma secretase play an essential part in this model
Intellectual failure type
Mild cognitive impairment: when people have cognitive defect but not dementia doesn’t get in the way everyday life
Dementia: cognitive development gets in the way of everyday functioning
Delirium: common in developing brains and ageing brains, sudden change in someone’s intellect (cognition) and their arousal usually due to infection
Intellectual failure broad presentation
Forgetful not usual self
Acuteness of symptoms is key affect on everyday function
Intellectual failure intervention
Diagnosis: dementia often underdiagnosed
By diagnosing offer support
Non pharmacological support
Pharmacological support: cholinesterase inhibitors increase Ach in synaptic cleft
Dementia
Chronic syndrome
Impairs cognition not just memory global impairment
Affects everyday function
Causes: Alzheimer’s, vascular disease, lewy body dementia, frontal-temporal dementia, posterior cortical atrophy (pratchett)
Intervention: diagnosis, drugs, support
Rise in UK ageing population
Amyloid cascade hypothesis
Missense mutations in APP, PS1, PS2 genes
Increased Ab42 production and accumulation
Ab42 oligomerisaiton and deposition as diffuse plaques
Oligomers weaken communication and plasticity at synapses which could be what stops brain forming and retrieving memories
Ab leads to ROS production that damages neurons changes in excitotoxicity of cell
Astrocytes and microglial activated (complement factors, cytokines etc)
Progressive synaptic and neuritic injury
Altered neuronal ionic homeostasis; oxidative injury
Altered kinase/phosphatase activities- tangles
Widespread neuronal/neuritic dysfunction and cell death with transmitter deficits
Dementia
Another key feature is neurodegeneration
Neuronal death and damage is triggered by Ab but some of its affects are mediated by another protein called tau
In health neurone molecules are carried along axon on series of tracts made of microtubules and stabilised by tau protein
In Alzheimer’s tau in modified causing it to dissociate from microtubules and adopt an abnormal shape and it move from axon to cell body
These remains stick together and deposit
Eventually these process kill neurone
Also misfolded tau proteins spread across synapses into healthy neurones where they make healthy tau proteins misfold spreading pathology across Brain
Forms of AD
Dominantly inherited forms AD: Missense mutations in APP or PS1or PS2 genes -> increased relative Ab42 production throughout life
Non dominant forms AD: includes sporadic AD. Failure of Ab clearance mechanisms (ApoE4 inheritance , faulty Ab degradation etc)-> gradually rising AB42 levels in brain
risk factors through the life course: modifiable and non modifiable
Risk factors for dementia- lots occur throughout life course
65% risk developing dementia related to things cant change non modifiable
35% potentially modifiable
Early life: less education
Midlife: hearing loss, hypertension, obesity
Late life: smoking, depression, physical inactivity, social isolation, diabetes
Basic principles of anaesthesia
“Triad of general anaesthesia”
-need for unconsciousness
-need for analgesia
-need for muscle relaxation (loss of reflexes)
Work by depression CNS activity
Structure of inhalational anaesthetics
Simple unreactive compounds
Short chain molecules
No one chemical class
