L9 Flashcards
what is dementia
Dementia is the term used when a person experiences a gradual loss
of brain function due to physical changes in the structure of their
brain.
what are some of the causes of dementia
the most common is
Alzheimer’s disease. Other causes include vascular dementia, dementia with Lewy bodies and fronto-temporal dementia.
All of them are slightly different but they cognitive symptoms are simmerler
what are some symptoms of dementia
loss of memory
impaired reasoning
reduced language skills
loss of daily living skills.
what are the mild symptoms of alzheimer’s disease
Confusion and memory loss
Disorientation; getting lost in familiar surroundings
Problems with routine tasks
Changes in personality and judgment
what are the moderate symptoms of alzheimer’s disease
Difficulty with activities of daily living, such as feeding and bathing
Anxiety, suspiciousness, agitation
Sleep disturbances
Wandering, pacing
Difficulty recognizing family and friends
how long does it take to go from mild to moderate symptoms of alzheimer’s disease
this disease is progressive therefore over a period of 1 to 2 years
what are the severe symptoms of alzheimer’s disease
Loss of speech
Loss of appetite; weight loss
Loss of bladder and bowel control
Total dependence on caregiver
how long does it take from when you see the first sign of cognitive symptoms until death (the progression of the disease)
5 -6 years
what are phonemic and semantic verbal fluency (SVF) tests used for
Tests of phonemic and semantic verbal fluency (SVF) are widely used
in the assessment of individuals with memory complaints and in the
clinical diagnosis of Alzheimer’s disease.
what consists of phonemic and semantic verbal fluency (SVF) tests
Patients are asked to generate as many words as they can either starting with a certain letter of the alphabet (phonemic fluency)
or belonging to a certain semantic category e.g. animals (semantic fluency).
they measure the number of correct words spoken by the patient in one minute.
what is the longitudinal change in semantic verbal fluency in dementia patients
the results decline as time goes on.
what is the primary risk factor of alzhimers
age
The likelihood of developing the condition doubles every five years after you reach 65
years of age
describe the prevalence of Alzheimer’s disease
At 60 the proportion is very low (almost 0) and then it grows exponentially
The age that people are living to is longer therefore there are more people are getting this
On the right is the number of cases world wide and this is also growing exponentially
This increases is because of a change in demographics
in NZ what is the current prevalence of people at age 85 or above
20%
what are brain changes observed in AD
extreme shrinking of the hippocampus
enlarged ventricles
shrinking of tissue (the gaps between the folds are enlarged)
what do we think causes AD
plaques and neurofibrillary tangles
there is also a loss in cholinergic projection neurons of the basal forebrain
where are plaques and neurofibrillary tangles located
plaques are located outside the neurons in the extracellular space
tangles are inside the neurons
what is the effects of the loss in cholinergic projection neurons of the basal forebrain
the nuclei here have axons that projects out to wider areas and release ACh
ACh enhances memory as it facilitates transmission strengthening the synapse. therefore less ACH = less strong synapses
what is ACh broken down by
cholinesterase
what is used to treat mild to moderate AD
cholinesterase inhibitors
how do cholinesterase inhibitors work
They block cholinesterase, giving the acetylcholine extra time to transmit messages
what are some examples of cholinesterase inhibitors
Donepezil (Aricept),
Rivastigmine (Exelon)
Reminyl (Galantamine)
are cholinesterase inhibitors an effective treatment for AD
no, they don’t have too much of a dramatic effect and they only show that small effect for the first 2 years of AD development
what is Amyloid Precursor Protein (APP)
Amyloid Precursor Protein (APP) is a protein that appears to
have an important role in synaptic plasticity and it appears in many areas of the brain
what is Beta Amyloid (Aβ)
Beta Amyloid (Aβ) is produced when APP is cut into segments (cleaved) by secretases.
what is APPs and Aβs effect on AD
In AD, Beta Amyloid is overproduced. It clumps together and forms fibrillar plaques on the outside surface of cells. these plaques are distributed throughout the cortex and are toxic (they start to kill neurons)
why is Beta Amyloid not over produced in a healthy brain
because AAP is usually cleaved by alpha scrotase at the part of the protein which would become the middle of Aβ
getting cleaved in the middle of Aβ means that it wouldn’t never be able to form
what causes the over production of Aβ in AD
beta and gamma secretase cleave AAP in a way that Aβ is formed
what does the distribution of Aβ across the brain tell us
Amyloid Plaque location doesn’t map well onto symptoms
therefore when you look at the distribution of Aβ and where they are damaging in the brain it doesn’t add up to what the symptoms of AD are
what is Aducanumab (2021)
New drug that has just received FDA approval for treatment of AD
What it is effective in is removing the plaques from the brain but removing these doesn’t appear to have any effect on the cognition of the individuals
what is the role of tau proteins in a healthy brain
they hold the microtubules together it their tubal structure
what is Taus effect in AD
Microtubules are the scaffold of the neurons.
What happens in AD is the the Tau protein gets phosphorylated and the tou forms clumps inside the cell called neurofibrillary tangles (NFTs)
You then have a disruption in the microtubules as they fall apart and no longer make connections with other neurons
This degeneration does map well with the symptoms
what are the clumps of Tau protein called
neurofibrillary tangles (NFTs)
where do neurofibrillary tangles (NFTs) initially appear in AD progression
and then as it progresses
As Alzheimer’s progresses NFTs appear initially in the
transentorhinal (perirhinal) cortex. this is where information from the cortex goes into the hippocampus
As the disease progresses then the tangles start to go into the hippocampus and then in neighbouring regions.
NFT progression parallels cognitive deficits
is the relationship between NFTs and the symptoms of AD seemingly casual
why
the more NFTs you have the worse cognitive impairments you have on a Mini mental state exam
what are the major risk factors
age (5% < 65 years)
Family history/genetic disposition
- People with relatives who developed Alzheimer’s disease are more likely to develop the disease themselves.
Familial (early onset)
- only makes up 2-3% of cases BUT if someone in your family has it it increases your likelihood by 50% chance for early onset
what are the genetic factors of AD linked to
linked to mutation on PSEN1, PSEN2, APP genes
when is AD classified as early onset
when you see symptoms before 65
what is late onset (sporadic) AD risk factors related to
risk is related to variations of the APOE gene on chromosome 19
how do variations of the APOE gene on chromosome 19 increase your chances of developing late onset (sporadic) AD
There are three major variations (alleles) of the APOE gene- called APOE2, APOE3
and APOE4.
We are each born with two alleles at the APOE gene that we inherit from our parents. We can have any combination of the three variations.
Having one E4 confers 2-3 x higher risk
Having E4/E4 confers 5-8 x higher risk
what does the APOE gene cause
These APOE gene alleles produce slightly different forms of the Apolipoprotein E (ApoE)
protein. ApoE is mainly produced by astrocytes, and transports cholesterol to neurons
APOE possibly has more effect on females than males
i’m not sure theres a graph in the lecture but IDK what it wants from me
what is the problem with APOE in astrocytes
reduction in APOE level causing cholesterol accumulation and impaired beta amylase clearance
what is the problem with APOE in microglia like cells
they become immune prone (over reactive) and have impaired beta amylase clearance
what is the problem with APOE in neurons
increased synapps formation
elevated rely endosomes
increases formation of beta amylase
what is the blood brain barrier
The BBB separates the circulation from the brain, allowing for protection from and transport regulation of serum factors and neurotoxins.
The BBB is not just a physical barrier but also acts more selectively as a transport interface, a secretory body, and a metabolic barrier (containing and releasing certain enzymes locally)
what is APOE4s effect on the BBB
The gene variant APOE4 is associated with a disruption of tight junctions, which opens up the BBB
APOE4 was associated with higher BBB permeability in hippocampus and
parahippocampal gyrus – independent of amyloid and Tau accumulation
capillaries are usually just the basement membrane and the endothelial cells which have an intracellular space separating them
what is different about capillaries in the brain
then endothelial cells are held together via tight junctions
the capillaries is also covered by astrocytes for support and then pericytes for maintaining that support
how does APOE4 cause AD
the BBB is leaky which leads to elevated levels of a marker for pericyte injury predicts cognitive decline
what is the progression of AD
you see the first cognitive symptoms after 1-2 years (therefore it is developing for about 1-2 years before you get a diagnosis)
what was the nun study
The University of Minnesota ‘Nun Study’ is a longitudinal study of aging and Alzheimer’s disease. Participants were 678 American members of the School Sisters of Notre Dame religious congregation who were aged 75 to 102 years of age .
why is the nun study so good
because early life autobiographies were obtained at average age 22
They had been in this order for a long period of time. They have had the same diet and the same environmental exposure because they have lived in the nunnery since that were 20
what did the nun study find
The more ideas they had when they were 20 years old the less likely they were to develop AD
therefore this suggests that the things you did in your 20s has an effect on if you were developing AD
Therefore we believe that having a good education protects you from AD (more ideas)
what is the cognitive reserve hypothesis
that education is a protective factor against AD
