L9, Brain Aging Flashcards
What broad anatomical changes take place in the ageing brain?
- Loss of brain weight
- Shrinkage of grey matter
- Loss of cells
- Loss of synapses
Demographic changes in dementia:
Prevalence and incidence, sex differences
- Increased prevalence in older people general
- 20 fold increase in incidence from 65 to 89 (across various studies)
- 16% incidence above 90 yrs
- These proportions have been decreasing despite an increase in total cases
- Affects sexes in similar proportions
Types of dementia in women vs men:
- Alzheimer’s (AD), the most prevalent ND overall, is more frequent in women
- Parkinson’s (PD) is more frequent in men
Issues around natural ageing and dementia studies:
Bias, risk factors, model organisms
- Age is a major risk factor for neurodegenerative diseases
- NDs must be excluded in ‘natural brain ageing’ in humans is to be studied
- Pre-clinical forms of these diseases may also need to be excluded but they are hard to detect
- Collection bias, participation bias
- Domestic pets (dogs) can be useful model organisms in aging studies (similar mechanisms and environment to humans)
Primary impairments and pathology of AD
- Memory and language
- Plaques and tangles
Primary impairments and pathology of Vascular Dementia:
- Poor concentration, physical symptoms (limb paralysis/weakness)
- Hypertension and mini-strokes
Primary impairments and pathology of DLB:
- Hallucinations, fluctuating memory impairment
- Lewy bodies throughout cortex
Primary impairments and pathology of Parkinson’s dementia:
- PD with dementia (movement disorder)
- Lewy bodies, neural degeneration
Primary impairments and pathology of frontal lobe dementia:
- Personality and behavioural changes
- Frontal lobe degeneration
Primary impairments and pathology of alcohol-related dementia:
- Memory, planning, social skills, judgement, balance
- Excessive alcohol intake
Is natural brain ageing a major cause of dementia? - Arguments in favour
- <3% of dementia cases cannot be attributed to a particular type fo the disease
- Key features of well-known NDs can be seen in ‘naturally aging’ brains
- e.g. Protein aggregates and tangles are observed in old brains (as in AD)
- e.g.Dopaminergic synapses are lost with age (as in PD)
ND pathologies by region:
AD, PD, ALS
- AD: Hippocampal ageing
- PD: Substantia Nigra ageing
- ALS: Spinal chord ageing
Most NDs are diagnosed based on symptoms revealing region-specific impairments
…But natural ageing combined with regional susceptibility may underly NDs
Discussion: Age related changes at regional, cellular and molecular level
- Regional: Loss of grey or white matter in different regions
- Cellular: Astrocytes, neurons, microglia
- Molecular: Iron accumulation, synaptic perturbation, impaired protein degradation, altered translation, Mitochondrial dysfunction, calcium dysregulation
Mature Adult brain features
Adult brain cortex:
* 1.2 to 1.34 kg
* 1x10^11 neurones
* 2.5x10^15 synaptic connections
* 1:1 glia to neuron ratio
…Neurones live as long as we do and glial cells are just as abundant
Organ and tissue level changes to brain with age
- Brain grows 25% in volume between 2 and 15 yrs
- Brain weight and volume decrease with age
- This is mostly due to a loss in grey matter -> contains most of cell bodies whereas white matter contains mostly axons
- Between 16-80 yrs, brain shrinks to the size of 2-3 yrs
- Cerebrospinal fluid (CSF) volume increases with age
Gray matter and white matter makeup
- Gray: Dendrites, axon terminal of presynaptic cell, cell body
- White: Myelinated cells and oligodendrocytes (making myelin)
Frontal lobe studies in brain ageing
- Cross-sectional MRI in 148 healthy volunteers (in vivo)
- Prefrontal gray matter declined most with age
- Volume of temporal and parietal cortices, and hippocampus decreases too, but less so
- Sensory and motor region, including occipital cortex. tend to be preserved
-> definitely regional changes - Frontal lobes mature last but are amongst first to decline
Orbitofrontal/Pre-frontal cortex ageing:
- The prefrontal cortex updates and stores information about outcomes that will follow choices
- It thus impacts learning and memory, emotion control/social behaviours and decision-making processes
- The PFC is most affected by age
- It is a key subregion, strongly affected in AD
Episodic memory: Changes in AD vs normal ageing
- There are changes in cognition in the ‘disease-free’ elderly population, but this is not inevitable
- Memory impairment occurs across all species (e.g. rats, monkeys, humans) some of which do not develop AD
- Ability to encode new memories of events or facts show decline in both cross-sectional and longitudinal studies
- Episodic memory is especially impaired in normal ageing (recall of personal experiences at particular time and place)
Neuronal cell loss hypothesis for grey matter loss:
- Grey matter mostly made-up of neuron cell bodies -> grey matter loss due to cell loss
- Various studies -> cell loss is minimal during brain ageing
Dendrite and synapse loss hypothesis for grey matter loss:
- Grey matter hosts most synapses, with cortical brain layers characterised by high dendritic density
- Performant cognition enabled by synaptic network rather than absolute cell numbers
- Age-related decline in cognition is more likely to be due to loss of dendrites and synapses
- Many studies have shown this including studies into aged rats -> loss of pyramidal neurons with age, shrinkage of cell body, loss of basal dendritic branches (NOT apical)
Aberrant dendritic growth in man, mice and worms…
- In man, hippocampal neurones grow more dendrites in mid to old age, although they seem to lose dendrites after 90
- In mice, retina rod bipolar cells also increase their dendritic length with age in mouse models
- In worms, ageing neurons sprout new dendrites but synapses dynamics are not compromised
-> Supports hyperfunction theory of ageing
Plasticity vs synapse stability
- The aged brain largely retains plasticity but synapses lose stability
- Density of ‘en passant’ boutons are similar
- But EPBs more dynamic/less stable and shorter-lived
- Less presynaptic contacts or vesicles may explain lesser synaptic stability/strength with age
Measuring synaptic strength
- Long term potentiation: Basis of long term memory; synapse repeatedly stimulated -> more dendritic receptors -> more transmitter molecules -> stronger link at the synapse
- Memory is stored in the brain through changes in the strength of synaptic connections
- Results in larger electrical response in post-synaptic cell -> Measure of synaptic strength
LTP decrease in age:
Studies in rats
- LTP decay is faster in older rats (strength lost quicker)
-> Results in lesser synaptic stability
-> Reflected in poorer spatial memory performance
–> Ageing neurons: Not much cell loss, similar branch dynamics and complexity, shrunk cell bodies, less stable synapses, LTP decay
Neurone key qualities in relation to ageing effects: (2 advantages and one disadvantage)
- Neurones are highly-specialised and long-lived; don’t divide so telomere dysfunction does not affect them
- They are naturally good at clearing protein damage since they strongly rely on efficient proteostasis and endolysosomal functions (autophagy, exophers)
- However, they do not do well in energy depletion/ starvation/ metabolic shifts
-> require effective energy supply
-> rely critically on other brain cells and the brain milieu
How do myeloid cells become energy depleted with age?
Effects of energy depletion:
- Myeloid cells become energy-depleted with age (PGE2-EP2 signalling)
- Cells can use various substrates as fuel; however myeloid cells in aged mice lose the capacity to use fuels other than glucose
-> PGE2 signalling increases with age -> PGE2 signalling on EPR2 lowers available glucose
-> Myeloid cells starve and become pro-inflammatory -> increased cytokine secretion by brain and plasma myeloid cells in vivo
-> Leads to cognitive decay
Key systemic factors involved in age-associated brain dysfunction (inflammation of brain):
Increased…
- TNF
- IL-1beta
- CCL2
- Type 1 interferon
Decreased…
- IL-4
- Type II interferon
- IL10
-> All these may contribute to brain inflamm-ageing
Cellular and subcellular hallmarks of brain ageing
- Mitochondrial dysfunction
- Impaired molecular waste disposal
- Impaired DNA repair
- Aberrant neuronal network activity
- Stem cell exhaustion
- Glial cell activation and inflammation
- Impaired adaptive stress response signalling
- Dysregulated neuronal calcium homeostasis
- Oxidative damage
…All interlinked; largely due to systemic issues, possibly also hyperfunction issue
Is natural brain ageing unavoidable?
Differences between individuals, blood rejuvenation
- Heterogeneity; Some individuals can utilise certain compensatory mechanisms (eg. centenarians)
- Examples of counteracting age-related cognitive decline by plastic reorganisation of existing neural pathways (i.e. bilateral results in high performing aged individuals vs right lateral otherwise)
- Milieu shown to reverse brain ageing
Pharmacological Interventions into metabolism
- Keto diet: Improves kidney and brain function but difficult to achieve ,kidney stone and muscle loss issues
- Rapamycin: Pleiotropic effects; recently failed clinical trials
- Metformin: beneficial effects in cancer, diabetes, processed by microbiota (clinical trials ongoing)
- Senolytics; removing senescent cells?
Gut microbiota
- Healthy gut improve brain ageing (Restoring a youthful gut microbiota)
- Shifts in gut microbiota robustly linked to NDs and neuropsychiatric disorders
- Linked to inflamm-ageing
Lifestyle interventions for brain aging
- Exercise Improves brain ageing
-> Considerable evidence in athletes as well as general population
-> Strongly linked with nutrition (especially protein intake in older age) - Diet (more protein)
- Good Sleep (8 hrs)
