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Module 2 > Alzheimer's > Flashcards

Alzheimer's Flashcards

1
Q

What initial memory deficits occur in Alzheimer’s and this is secondary to dysfunction of which brain areas?

A

Episodic memory.

This is for dysfunction of medial temporal lobe structures. (Entorhinal cortex, hippocampus)

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2
Q

What are other impairments as the disease progresses?

A 
Short term memory
Visuospatial function, executive function, attention
Motor skills
Long term memory loss
Disorientated
Bedridden

Neuropsychiatric involvement:
Hallucinations
Delusions
Agitation

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3
Q

What are some atypical presentations of AD?

A

Speech disturbance/Aphasia
Behavioural symptoms
Progressive visuospatial symptoms

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4
Q

What are some other forms of dementia?

A

Lewy Body dementia
Visual Hallucinations
Vasculae dementia
FTLD (Behavioural, Semantic, Progressive non-fluent)

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5
Q

Which areas are targeted by AB pathology?

A

Entorhinal, hippocampal, limbic structures (medial temporal lobe structures). Also, network hubs (DMN).

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6
Q

What are some risk factors for AD?

A 
Past 65
2x more in women
Trauma
Genetics 
Lifestyle

Protective factors are Mediterranean diet, exercise and educational level (cognitive reserve).

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7
Q

What are the key genes in sporadic vs familial AD?

A

Sporadic:
APOE4. (Cholesterol transport protein involved in AB clearance. e4 allele greater risk, e2 delays deposition). Chromosome 19.

Trisomy 21: By 40, all patients acquire AD like pathology.

Familial:
PSEN 1 & 2. (Encode for y-secretase subunits which cleaves APP.) Chromosome 14. Role in intracellular signalling & dettermines cell fate w/Notch signaling.

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8
Q

What can be measured/seen in the pre symptomatic stages of AD?

A

Brain scans and lumbar punctures.
Gradual increase in AB load in brain. Gradual decrease in hippocampal volume 10 years before symptom onset.

There is an increase in dementia symptoms before clinical onset.

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9
Q

What is mild and subjective cognitive impairment?

A

Mild: Intermediate stage where subjects have more cognitive problems than expected for their age. No functional impairment however. Can be amnestic or non amnestic. This is only an artificial construct however.

Subjective: Pathogenesis has begun, patient may feel symptoms but there are no measured cognitive changes. There is episodic memory loss associated with positive for CSF AD biomarkers.

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10
Q

What are the diagnostic methods and their pros/cons?

A

Neuropsychology: Low cost and portable, but lacks specificity & sensitivity, and there is also lots of variance in population.

Structural imaging: CT, MRI

Functional imaging: FDG PET, Amyloid PET, Tau PET.

CSF examination (CSF Tau & AB)

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11
Q

What are the management strategies for Alzheimer’s?

Chiltern music academy

A

Diagnosis->Behavioural intervention->Dynamic care plans->drugs.

Cholinergic therapy: Acetyl cholinesterase inhibitors. Acetylcholine has a key role in learning and memory, dementia severity correlates with cholinergic loss. RIVASTIGMINE, DONEPAZIL & GALANTAMINE are NICE approved.

Memantine: Affects glutamatergic transmission, interacts with NMDA transmitter. Moderate affinity. Improves condition and function in severe dementia.

Antipsychotics: Used as a last resort. Riperidone.

Also important to treat other conditions that could worsen the condition e.g dehydration, thyroid disease.
Also withdraw medications that could worsen the disease (sleeping tablets)

Future strategies: Monoclonal antibodies to AB. (Aducanumab shown to clear AB load and slow cognitive decline)
B-secretase inhibitors: Verubexestat
Tau aggregation inhibitors.

Tau and AB vaccines.

LEARN FLOW CHART DIAGRAM.

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12
Q

What is the cholinergic hypothesis of AD?

A

ACh turnover decreases with age, and there are defects in cholinergic transmission underlying memory loss and other cognitive problems. Decrease in cholinergic markers correlates with dementia severity. Restoration of function could reduce cognitive loss.

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13
Q
  1. What are neurofibrillary tangles?

2. How does AB pathology manifest?

A
  1. Tangles composed of paired helical filaments. Made of Tau, a microtubule stabilising protein which is hyperphosphorylated.

Correlates much better with the clinical picture.

  1. Senile plaques, classic plaques with dense protein core and a halo of difuse staining.

Cerebral amyloid angiopathy.

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14
Q

What are the 6 Braak stages of AD pathology?

TETTPS: Tell everyone to take party string

A 
I: Transentorhinal region. Anterior hippocampal block.
II: Entorhinal region. 
III: Temporal-occipital gyrus
IV: Temporal cortex
V: Peristriatal cortex
VI: Striatal cortex
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15
Q

What is the normal vs pathogenic cleavage of AB peptide?

A

Normal: Cleavage occurs by a-secretase within AB sequence so aggregate not produced. APPs-a and peptide p3 produced. Amyloid intracellular domain also produced, thought to act like a TF.

Pathological: Aminoterminus cleavage to produce CTFB, followed by carboxy terminus cleavage by gamma secretase. AICD & APPs-a also produced.

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16
Q

What is the amyloid cascade hypothesis?

A

Anything that can alter APP metabolism to favour AB production may be a driving factor in AD development/. AB deposition->Vascular amyloid & Neuritic plaques-> Neuronal damage, tangles, dementia.

17
Q

What are some possible therapeutic strategies?

A 
Prevent AB aggregation
Clear existing AB deposits
Reduce APP expression
ALter APP metabolism
Control APP regulators
Anti inflammatories
Growth factors
Tissue transplants

Secretases:
(a secretase- TNF-a converting enzyme)
B secretase : BACE 1
G secretase: Presenilin

Peptide was used in animals, cleared AB pathology. Caused many side effects in patients and no change to disease course however.

18
Q

What are 2 different tau protein kinases?

A

Glycogen synthase kinase-3
Cyclin dependent kinase

Phosphatases also cause increased phosphorylation of Tau.

19
Q

What other ways can cause pathological processing of APP?

A

APP reinternalised in endosomes, where the majority of B-secretase cleavage occurs.

Can also be reinserted into membrane where B-secretase can cleave.

Either way this releases Aß & APPs-ß into the extracellular space.

20
Q

What is some extra info about the 3 secretases?

A

B-secretase (BACE-1) is a transmembrane protein. Also able to cleave neuregulin, so B-secretase KOs had problems forming myelin.

a-secretase is an ADAM family protein. APP region cleaver can also cleave TNFa. ADAM10 & ADAM17 are proteins most . involved in APP cleavage.

y-secretase is a complex of proteins. Active catalytic site is presenilin-1. Important in regulating and trafficking presenilin to membrane.

21
Q

What are some mechanisms of Aß clearance from the brain?

A 
Microglial phagocytosis
Neprilysin
Insulin degrading enzymes
Glial cells (receptors for amyloid)
ApoeE
22
Q

What are the signs for prion like spreading?

A

Aß pathology starting in lateral and outermost brain structures and moving inwards to limbic and brainstem structures in late pathology.

Cadaveric pituitary GH extracts used and caused high Aß load particularly around pituitary gland.

SEE ICA

23
Q

What are some mutations in APP?

A

Gamma secretase site: London mutation
B secretase: Swedish mutation
Middle of APP: Iowa, Dutch and Flemish.

24
Q

List some disease modifying strategies.

A

Aß synthesis inhibitors . (BACE & y-secretase)
Aß modulators
Catabolism inducers
Aggregation inhibitors

Immunotherapy:
Injecting Aß (vaccination). Patients died in clinical trials.
Passive immunisation: Aß antibodies directly injected into individual, and different types of antibody recognise different forms of AB. Aducanumab recognises AB plaques and oligomers.

Tau based therapeutics:
Microtubule stabilisers
Tau assembly inhibitors
Autophagy enhancers
HSP90 inhibitors
NMDA antagonists

NSAIDS decrease risk and progression. Targets are COX-1 & 2. NFkB also a target, a key TF in inflammatory processes. Can also target PPAR-y which is another nuclear receptor. This may suppress BACE-1 expression.

Anti-diabetics.

PROBLEM: Patients have pathology for a long time before treatment, which is not reversible. Identify at risk populations e.g Yarumal in Colombia.

25
Q

What are in vitro and in vivo techniques to study AD?

A

In vitro:
Neuronal cell line that expresses APP.
iPSC technology- drug screening and cell replacement therapy.

In vivo:
Animal models- molecular interactions in vivo, efficacy of drugs in vivo.
PSEN1, TAU and human APP transgenic mice.

26
Q

What are the pros and cons of mice models for AD, and what are some other animal models?

A

Pros:
Similar brain anatomy to humans
NFT & Plaque staging, regional vulnerability addressed
Sophisticated behavioural tests possible

Cons:
Production and breeding time consuming and expensive
Ethical considerations
High throughput drug screening not possible.

C.elegans, D melanogaster.

27
Q

What are some tests that can be performed on mice?

A

Behavioural
Morris water maze, Y maze, radial maze, object recognition, fear reconditioning.

Electrophysiology
Assess long term potentiation, measure synaptic strength in hippocampus.

Brain imaging
PET and MRI.

AAV-Vectors
Mice developed plaques few weeks after injection but no neuronal loss. Have hyperphosphorylated WT tau, but no NFTs.

28
Q

What neuropathology is seen in Pick’s disease?

A 
Fronto-temporal atrophy (knife edge)
Marked gliosis
Balloon neurons
Tau positive pick bodies
It is a 3R tauopathy.
29
Q

What mutation in Ch17 can cause FTD, and what are the symptoms of this?

A

Progranulin mutation. Causes inclusions positive for ubiquitin but Tau negative. Cat eye inclusions.

Facial emotion recognition deficit.
Aphasia
Inability to name objects and make calculations.

30
Q

What are other mutations leading to FTDs?

A

TDP-43. Types A-D, with different symptoms. Ubiquitin positive.

FUS (Fused in sarcoma). Variety of inclusions. Ubiquitin positive.

C9ORF72. Ubiquitin positive, TDP-43 negative inclusions in cerebellum.

31
Q

What is the process of PET imaging?

A

Cyclotron bombardment produces highly charged particles.
Tracer synthesis
Dispensing and QC.
PET scanning- radioactivity from injected positrons detected.
Data modelling
Parametric brain image.

32
Q

What tracer binds to Amyloid?

A

11C-PIB. Selectively binds to fibrillar amyloid. Cerebellum is devoid of fibrillar amyloid. High radioactivity measured in frontal cortex.

Mild cognitive impairment, dementia with lewy bodies and parkinsons disease dementia all have amyloid pathology throughout.

  • 60% amnestic MCI patients show amyloid load similar to AD. 50% of these patients progress to AD in 2 years.
  • 80% DLB patients and 20% PDD patients have high amyloid.
33
Q

What tracer binds to microglia and how does it reveal AD?

A

11C-PK11195: Microglial binding tracer. microglia express translocator protein which has binding site (TSPO).

Patterns of amyloid load and microglial activation detected by PET accord with known distribution of neuropathological changes.
Microglial activation associated with neuronal dysfunction and cognitive impairment.

34
Q

What tracer is used for glucose?

A

18F-FDG-PET. Measures glucose metabolism and cortical glucose uptake.
Hypometabolism with AD disease progression (cell death).
Glucose metabolism is surrogate measure of assessing cognitive function. (good clinical correlate)

35
Q

What are the clinical indications for imaging and inappropriate uses?

A

Clinical indications:
Cognitive impairment
AD a possible diagnosis, but there is uncertainty.
Diagnostic certainty
Alteration of management
Unexplained MCI
Progressive dementia at atypically early age

Inappropriate use:
Patients satisfying symptoms, clinical age of onset
Insurance
Determination of dementia severity
Replacement for genetic testing
Cognitive complaint not assessed clinically
Solely based on family genetics (apoe4)

Module 2 (7 decks)

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