Lecture 21- Aging brain Flashcards
What is aging?
-Changes in brain function in last few decades of life aging: a bad thing
What are the two types of changes during aging?
-normal and pathological
When does the brain change?
-alway changing, starts early due to development and plasticity -brain changes constantly from before birth to death
What are the three stages of the brain?
- Development: setting up the structure of the brain 2. Plasticity: fine tuning, laying down procedural and declarative memories 3. Aging: non-adaptive changes that negatively impact function
When does brain development start?
-brain development starts around 3-4 weeks post conceptions
How much does the brain increase in size after birth?
-brain size doubles in 9 months after birth
When does the brain reach close to adult size?
-reaches 90% of adult size at 6 years
What are the two phases of brain development?
- In utero 2. After birth
What is the first phase of cortical development?
- In utero -genetically determined with environmental influences (maternal and fetal) -follows a blue print inherent in the DNA
What is the second phase of cortical development?
-cortex becomes sensitive to patterns of sensory stimulation -both spontaneous and after birth externally driven -modulates synaptic connectivity -after birth -brain shaped by experience -period of plasticity
Do different regions mature at different rates?
-yes
How does visual cortex mature?
- V1 early maturing path in the brain -primary visual cortex reaches adult thickness at 6 months -when go up, V2 V3 etc takes longer -same for cell density and other structure -visual association areas not at adult state until 10 years
What other regions of the brain take long to mature?
-frontal and parietal lobes mature at 11-12 years of age -temporal lobe matures at 16 years
Are there differences between hemispheres in the rates of maturation?
-inter-hemispheric differences exist -up to 1 year old, right hemisphere frontal and anterior prefrontal cortex layer V dendrites are longer -by 6-8 years old, left side dendrites become longer
What is synaptic maturation like throughout development?
-synaptic density increases to 2 years, reaches peak and then declines over time (visual cortex) -frontal cortex peak at 5 years and then decrease, pruning of not useful connections -maturation sees decrease in synapses -visual cortex maximum at 6 months, declines after 1 year -frontal cortex reaches max at 1 year, adult levels at about 16 years
What is the summary of brain development?
-brain continues to develop for a decade and a half, late into adolescence -synapse elimination characterises most of this period -sensory input crucial in structuring and guiding late development
What is aging characterised by?
-aging is characterised by negative changes in function -this includes: -motor function -sensory function -sleep -memory -problem solving -some changes due to effector receptor changes (like in the visual system= clouding of the lens)
What are some specific brain functions that don’t change?
-vocabulary, information, comprehension
What are some specific brain functions that change during aging?
-working memory -long term memory -visuospatial abilities -verbal fluency
Is aging individual?
-yes, to an extend -when take a cognitive test, some people don’t decline over the years -cognitive decline is the average, it is not inevitable
Is cognitive decline something that happens in everyone?
-on average an age related decline -individually shows a wide range -same for humans and animals
Do individuals age at different rates?
-individuals tracked over long periods change cognitive abilities at different rates
What is the cognitive decline in individuals?
-some people decline a lot -some maintain their level of cognitive ability
What underlies normal versus pathological cognitive decline?
-neurons die, and you have fewer neurons -decline in neurons underlies the cognitive decline -there are fewer neurons in old brains -this is not true!!!
How do you count neurons?
-the old methods were bad -new methods say, old brains have the same number of neurons as in young brains
Do you have changes in the number of neurons in some parts of the brain?
-yes, in the hippocampus but it doesn’t account for the decline in some people
How do cognitive skills change in rats?
-age individually -some old ones as good as young
What are the differences in young versus old rats?
-differences in hippocampal learning young rats vs old rats -like humans individual variability -some old rats as good as the young
Do the worst performing rats have the fewest hippocampal neurons?
-count neurons in hippocampus and correlate with performance on maze -do the worst performing rats have the fewest hippocampal neurons -there is no difference in the number of neurons in young and old mice
Do parts of the hippocampus show minor losses of neurons?
-yes
Can decline in cortical performance occur without significant neuron loss?
-yes
Is aging a loss of neurons?
-no
What changes with age in the brain?
-intensity and frequency simulation needed to evoke LTP increases with age -LTP decays quicker -correlates with poorer performance of aged rats in spatial learning tasks -the LTP decline correlates with decline in performance -LTP- synaptic phenomena so the problem in synapses
What does not change with age in the brain?
-resting membrane potential -input resistance -spike amplitude and duration -peak magnitude of LTP
Does aging affect changes at synaptic level?
-yes -entorhinal cortex, fewer inputs to hippocampus than in young animals -this is the operational explanation -entorhinal cortex provides important inputs to hippocampus -these inputs selectively lost in aging -extent of loss correlates with memory deficits in rats
What is aging really like?
-aging not due to wide spread , nonspecific change across the brain -due to quite specific losses in particular pathways -affects multiple parts of the brain, e.g. frontal lobes
How is aging specific?
-as each brain is impacted differently, different pathways impacted in different people
What is aging about?
-synaptic phenomena not neuronal
What is the frontal lobe age-related loss? Is frontal lobe often connected to age related loss? How?
-frontal lobes support executive function -specific deficits seen with aging in how frontal lobe manipulates memory -can lose source of memory (Where did I learn that?) -can lose specific temporal memory capacity (remembering objects objects in order) -can lose specific temporal memory capacity (remembering objects in order)
How do you test the prefrontal lobe memory loss in monkeys? (age related)
-test where and when memory -show monkey food being hidden in one of number of possible places -after a delay, let monkey get food (if it can remember) -repeat many times: monkey has to keep last location seen in memory -compare young monkeys with hippocampal or frontal lobe damage with aged monkeys -young monkey do better than older monkeys -old monkey behave like a young monkey with hippocampal or frontal lobe damage
What is the morphology of the brain in the aged monkeys?
-monkeys with frontal cortex damage most similar to aged monkey
What are the frontal cortex age-related changes in monkeys that are old?
-no neuron loss in regions responsible for deficits -synaptic density, dendritic architecture and myelination all altered -specific deficits in parts of the frontal cortex not generalised changes
What is aging?
-not a single phenomena, individual -few effective interventions
What is human memory loss?
-fMRI/PET shows frontal lobe in aged individuals more affected than hippocampus -emerging view: different parts of the brain age independently with only a broad correlation -unlikely to be a single process underlying all changes
What are the changes in normal vs abnormal age related brains?
-age-related mental decline can interfere with normal functioning
What is senile dementia?
-memory loss in an otherwise alert person -loss of at least one other area of cognition, language, problem solving, judgment etc. -may be an inevitable outcome of living a long time, may be pathological
What is the most common pathological form of senile dementia?
-Alzheimer’s disease
What is the incidence of Alzheimer’s like?
-rare in sixty -1-3% of 60-70 y.o. -3-12% of 70-80 y.o. -25-35% of over 85 y.o. -early onset forms occur (both sporadic and familial)
What does Alzheimer’s affect?
-abnormalities common in: -memory -language -problem solving -judgment -calculation -visuospatial awareness -some show psychosis, hallucinations and delusions -end up mute, incontinent and bedridden -diagnose definitively by brain biopsy
What is the dramatic difference in abnormal pathological aging?
-dramatic neuron and synaptic loss: -neocortex -entorhinal cortex -hippocampus -amygdala -nucleus basalis -anterior thalamus -brainstem -loss of neurons, also synaptic changes -it affects almost all parts of the brain
What is the comparison of an Alzheimer’s and normal brain?
-massive loss of neurons, it is not standardized loss across the whole brain -hotspots= temporal lobe affected a lot -somatosensory not bad -parietal is bad
What is the microscopic pathology in Alzheimer’s brain?
-can see tangles and plaques -not clear what they do -independent pieces of pathology -intra neuronal neurofibrillary tangles of tau (microtubule-related protein) -plaques (extracellular deposits of Abeta amyloid)
What occurs first plaques or tangles in Alzheimer’s?
- plaques, synaptic loss and tangles precede first clinical signs
- get as many plaques as you will have before starting to show too bad signs
- plaques, synaptic loss and tangles precede first clinical signs
- mild cognitive impairment with full load plaques
- major brain changes also lag behind
What is Tau pathology?
-something goes wrong with it and forms a tangle -forms tangles -hyperphosphorylated form of tau -intracellular -exact role unknown -may act synergistically with Abeta amyloid
What is the plaque made of?
-a beta amyloid -comes from APP, it is in every cell in the body, not clear what it does -we do know that it is cleaved by enzymes and there is one way of cleaving that produces the a beta amyloid -Abeta amyloid comes from amyloid precursor protein -APP is present through neuronal cell membrane and is of unknown function (synapse formation?) -it is cleaved by secretases to produce various sized pieces (Abeta 1-40, Abeta 1-42, and Abeta 1-43) -Abeta 1-42 is toxic and leads to amyloid deposition
How is Abeta amyloid generated?
- number of secretases that cleave the APP -the key thing is how long the pink bit is
- neurons are specieal in that they lack the third enzyme (alpha secretase) which cuts it again and makes it harmless (all other cells have it)
- 42 amino acid length is the bad
- aggregates, sticks to itself and forms a plaque
- alpha secretase present in all cells but neurons cleaves Abeta into harmless fragments
What are some genetic risk factors?
-makes risk high or low -can have a mutation in APP gene (mutations makes Abeta 1-42 more likely) -can have mutation in Presenilin 1 and 2 that cut the APP (mutation makes Abeta 1-42 more likely) -can also have mutation in Alpha 2 that cleans up the a beta (polymorphism affects Abeta scavenging) -ApoE mutation? not clear why it is connected Apolipoprotein E (ApoE- cholesterol transport) -role of these genes in sporadic late onset Alzheimer’s unclear
What is the role of ApoE?
-ApoE enhances proteolysis of Abeta -ApoE alleles seems to predict late onset Alzheimer’s -Three alleles: 1: E2- frequency in normal population 0.08 2.E3 (0.78) 3. E4 (0.14) -in late onset Alzheimer’s population E4 is 0.54 -Individuals homozygous for E4 8 times more likely to develop Alzheimer’s than those homozygous for E2 -If no copies of E4 only 20% develop AD, two copies of E4 75-90% develop AD
What about curing alzheimer’s?
-major challenge for future -no cure, some drugs ease transition into disease state by maintaining function (cholinergic drugs) -research centres on modifying handling of Abeta 1-42 or APP processing -maybe modify action of the modifying genes -some drugs prolong normal function
