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What is Alzheimers Disease and name 2 of the genes involved and what results from their mutation?
- Neurodegenerative disease affecting long and short term memory, Cognitive functions, behavior and motor skills.
- Mechanism of Alzheimers: Beta-amyloid buildup and tau tangles
- The two genes involved (Familial AD):
- 1. APP: Normal gene product is Amyloid-beta A4 protein. A mutation in this gene Changes location of ALPHA secretase cleavage site, leading to INcrease in BETA cleavage occurrence = increase in AB42 production.
- 2. PSEN1 and PSEN2: these mutations cause a change in GAMMA secretase and shifts APP towards AB42 production.
- Describe how APP can be differentially processed and identify the resulting products. (ie, What is responsible for the processing of APP, how does it result in different products etc...)
- Two pathways (one healthy, one not):
- 1. Alpha: healthy pathway, in which APP cleaved by Alpha secretase, then gamma secretase. After these are cleaved, p3 subunit is released
- 2. Beta: DISEASE causing, in which APP cleaved by beta secretase, then gamma secretase. The end result is ABeta42 production. This ABeta42 is what causes the buildup of plaque in the brain.
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What is PET and how is it used? How can it help diagnose a patient with AD?
- PET stands for POSITON EMISSION TOMOGRAPHY. This produces a 3D image of parts of the body to identify various functions. In relation to AD, it measures glucose metabolism and Abeta deposits in the BRAIN.
- In diagnosis, there are two markers:
- 1. DECREASE in glucose metabolism in the brain: FDG-PET used
- 2. INCREASE in Abeta deposits in brain: PIB-PET used
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What are the PET findings when comparing the brain of an unaffected elderly patient with the brain of an AD patient?
- 1. DECREASE in glucose metabolism in the brain: FDG-PET used
- 2. INCREASE in Abeta deposits in brain: PIB-PET used.
- PET showed shrinking of brain tissue and neural and synaptic brain loss in AD patient vs control
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What were the methods used in the study of Clinical and Biomarker changes in Dominantly inherited Alzheimers disease?
- 6 Methods used:
- 1. Clinical biomarkers: including family and medical history*
- 2. Cognitive assessment: Dementia rating, based on mental state and memory
- 3. MRI: used to detect brain atrophy
- 4. FDG-PET: used to analyze cerebral glucose metabolism
- 5. PIB-PET: look at Abeta deposits in brain (increase meaning AD)
- 6. Biochemical measures: look at Ab42 and tau proteins
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What are these AD Clinical and Biomarkers and what was the relative order of the changes before ADAD onset? Describe how these biomarkers change over time.
- 1. Clinical Dementia rating-Sum of boxes: CDR = 0 for cognitive function, and 18 is MAX cognitive impairment
- 2. Mini-mental state exam: 30 indicates NO impairment, 0 = SEVERE impairment
- 3. Wechsler Memory Scale-Revised Logical memory: 0 = NO recall of memory, 25 = complete recall (from 25 bits of info)
- Other levels were tested in laboratory:
- DECREASE in cerebral glucose metabolism over time
- INCREASE in Ab42 in plasma, Tau protein and brain atrophy over time
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