Techniques in disease

1. Phase II
2. Efficacy
3. better animal models

Annotations:

• that indicate the disease- and the affects of interventions

1. novel drug

1. improve current drug

1. transgenic manipulations

1. Transgenic overexpression of APP
   1. models familial mutations (only 10%)
   2. High levels of soluble Ab, Ab plaques, Memory deficits, elevated b-secretase
   3. Deficits in LTP (in some labs)- not representative
2. No perfect model
   1. 95% AD cases are sporadic
   2. elevated amyloid levels from early age point- not necessarily in AD
   3. No NFT
   4. No neurodegeneration
   5. Cannot test neuroprotective (against neural loss) in most
      1. See 4/5xFAD
3. APP + PS1 overexpression
4. APP + PS1 + tau
   1. NFT
   2. Ab diposition
   3. No neuronal loss
5. 5xFAD
   1. aggressive Ab
   2. reduced synaptic staining
   3. neuronal loss
6. 4xFAD
   1. aggressive Ab
   2. massive neuronal loss
7. Transgenic rats
   1. cleverer than mice, but less well characterised
8. Primates
   1. Biologically closer to humans

1. require long clinical trials to see effects of progression
2. improved cognitive tests
3. disease biomarkers- Ab
   1. Non-invasive Ab measurements required
      1. PET- metabolic changes
   2. Blood/urnine- not good
   3. CSF- better- invasove

Annotations:

• a prolonged seizure (termed status epilepticus or SE) is induced by either electrical stimulation or a chemoconvulsant, leading to injury as the “initial precipitating event.” 

1. kainic acid

   Annotations:

   • chemconvulsant-induced SE models
2. pilocarpine

   Annotations:

   • chemconvulsant-induced SE models

1. Replicate the underlying biology

1. Reflect the symptoms in man

1. Predict treatments which will be effective in the human condition

1. pathophysiological-based animal models
2. target pathways relevant for the disease
3. Disease relevant end-points
4. relevant biomarkers