Lecture 39: Memory, Alzheimer's Disease Flashcards
What are the structures associated with memory?
Certain memories are not in defined structure in the brain, they are linked with connections/pathways of the brain (association, repetition, visualisation, geographic localisation of memories).
Trafficking of memories are important, which involves hippocampal formation, medial temporal cortex structure (most prone to tissue loss in Alzheimer’s disease). We can manage memories without one or the other, but not both.
By memory, we mean episodic information that is historic (time stamped), not implicit information such as motor memories (automatic, relearnt, overlearnt behaviours), which are in different areas from brain.
Describe the relationship between ageing and memory
- Increased variability between individuals
- Reduced speed of processing, some reduction in attention, divided-switching attention (better at concentrating with one task)
- Reduced working memory (e.g. fresh memory from recent conversation)
- Reduced retrieval of episodic (e.g. birthday, news) and to a lesser extent semantic memory (common knowledge).
What is Dementia?
Dementia is like brain failure (cf. heart, kidney, liver failures). It is a chronic or persistent disorder of the mental processes caused by brain disease or input.
- It is a syndrome (a sign symptom complex, not a formal diagnosis) that shows a decline (often gradual) from individual’s previous level of function in terms of 2+ domains:
- Memory disorders (must have!);
- Impairement of one or more other higher cognitive functions such as abstract thinking/reasoning, judgment, _language difficultie_s, changes in praxis (e.g. cannot copy drawings), or personality changes
- This change must be severe enough to interfere with patient’s normal activities of daily living.
- Need to exclude delirium, depression etc.
What is delirium?
Delirium is a relatively acute deterioration of cognitive function associated with known or presumed organic cause.
Describe the most common type of Alzheimer’s
SDAT (Senile Dementia of Alzheimer’s) is most common type of dementia, with a gradual progressive dementia not explained by other known factors
Strictly speaking, SDAT is a pathological diagnosis with clinical diagnosis being an educated guess, partly by excluding other causes. Pathology of SDAT is what distinguishes it from other dementias, and provides starting points for research into disease process and possible therapies.
We can use volumetric CT/MRI analysis, light and fluorescence (antibodies) microscopic analysis, positron emission tomography (fluoridated or carbon binding compound, e.g. PDG) analysis for SDAT brain. Key characteristics of the SDAT brain are: (1) extensive and progressive loss of neurons; and (2) histological findings of tangles and plaques.
What is praxis?
Apraxia is defined as the inability to carry out a previously learned motor activity, despite normal function of all the component parts (muscles, nerves, joints, etc.).
Describe the Gross pathology of Alzheimer’s
Atrophy
Compared with non-SDAT controls, the brains of SDAT patients examined at post-mortem show several gross changes related to widespread atrophy of the cortex.
- Shrinkage of the gyri*, with widened sulci*
- Enlarged ventricles*
- Shrinkage of the amygdala* and hippocampus
Image techniques (CT, MRI) have enabled researchers to do volumetric analysis to quantify neuron loss at ~30% patients (aged 70-90). SDAT has tissue loss around all edges of brain, Creutzfeldt-Jakob disease (CJD) has tissue loss mainly around cerebellum.
Describe the Intracellular pathology of Alzheimer’s
Neurofibrillary tangles (NFT) are found in great concentrations within neurons of SDAT brains, particularly in cortex and hippocampus, and are very rare in normal elderly.
Tangles correlate well with cognitive impairment.
Tangles are made up of paired helical filaments (PHFs), which are entwined polymers mostly composed of tau protein (τ protein).
- In healthy neurons, tau protein binds to tubulin to stabilize microtubules, which help maintain cell shape and structure.
- In SDAT brains, tau protein becomes excessively phosphorylated* and this impairs its ability to bind to tubulin. The hyperphosphorylated polymer aggregates into paired helical filaments and larger tangles.
In some parts of SDAT brain (particularly limbic system), there are tangles outside cells, which are apparently left over from neurons that have been destroyed. This suggests they may be neurotoxic.
But in other parts of the brain, extensive cell death can occur without the presence of tangles, which suggests that other factors are involved, which have yet to be identified.
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Why do Tangles excessively build up in patients with SDAT?
- Tangles are made up of paired helical filaments (PHFs), which are entwined polymers mostly composed of tau protein (τ protein).
- In healthy neurons, t_au protein binds to tubulin_ to stabilize microtubules, which help maintain cell shape and structure.
- In SDAT brains, t_au protein becomes excessively phosphorylated*_ and this impairs its ability to bind to tubulin. The hyperphosphorylated polymer aggregates into paired helical filaments and larger tangles.
In some parts of SDAT brain (particularly limbic system), there are tangles outside cells, which are apparently left over from neurons that have been destroyed. This suggests they may be neurotoxic.
But in other parts of the brain, extensive cell death can occur without the presence of tangles, which suggests that other factors are involved, which have yet to be identified.
Aside from CT and MRI what could you do to test for Alzihemer’s
PET- trag a biomarker that binds into tangles.
Describe the progressive changes in dynamic biomarkers of the Alzheimer’s Disease pathological cascade
- First, β-amyloid deposits in the brain very early before Alzheimer’s disease (normal people have it as well).
- Second, τ protein also starts to grow, usually confined to the medial temporal cortex structures. This is a better predictor than β-amyloid for Alzheimer’s disease.
- Then, if there is enough interactions between β-amyloid and τ protein, τ protein will escape and deposit in frontal neocortex, therefore brain starts to undergo atrophy and memory starts to fade.
- Clinical functions progress relatively late in Alzheimer’s disease.
Describe the Extracellular pathology of Alzheimer’s
Extracellular plaques, along with intracellular tangles, are defining feature of SDAT and were identified by Alzheimer himself in the first patient he described.
Like tangles, plaques are a histological finding, visible in stained tissue samples examined under the microscope.
- These plaques are small (up to 200um) spherical deposits, found in extracellular spaces in SDAT brains, particularly in cortex and hippocampus.
- They are composed of dead neurons and β-pleated sheets of an insoluble protein known as β-amyloid. The term “senile plaques” is often used, but they are found in SDAT cases irrespective of age.
Describe the treatment options for people with Alziehmer’s
No treatment.
The drugs for Alzhiemer’s is purely for the symptoms (e.g. enhance neurotransmitter pathways for cognitive function)
At present, ______________ is only explanation of SDAT which has produced approved treatments specific for SDAT
At present, cholinergic hypothesis is only explanation of SDAT which has produced approved treatments specific for SDAT
To be frank, the theory is unlikely to generate a “cure” for SDAT, it still provides a useful working model of SDAT.
Describe the Cholinergic Theory
- In SDAT brains, cholinergic nerves in cortex are significantly and selectively depleted, so progressive ¯ACh.
- Progressive loss of cholinergic neurons
- Progressive drecreases in available ACh
- Impairment in ADL behaviour and cognition
- Blockage of cholinergic receptors in normal humans causes memory loss.
Following on from these observations, it was suggested that SDAT is a disease of central cholinergic nerves, and SDAT plaques might result from degeneration of cholinergic nerve fibres.
The therapeutic implication is that improving cholinergic neurotransmission might alleviate symptoms and/or slow down disease progression.
