CSF tau- increased (dying neurons release extracellularly) - higher concentration= greater cognitive impairment in normal-MCI-AD spectrum - increased CSF tau not specific for AD - similar increase not seen in pure tauopathies, indicate role of Abeta

CSF abeta- decreases over time - Abeta42 aggregated, retained within brain, not released in soluble form into CSF - low concentrations would match clinical diagnosis of AD

Lecture 7- Translational applications Flashcards by Thanuja Premkumar

drug development phases

phase 1- healthy volunteers, safety and dosage
phase 2- small no. patients, effectiveness, side effects
phase 3- more patients, effectiveness, adverse reactions
phase 4-additional post-marketing testing

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biomarkers

can help diagnose pre-symptomatic cases

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tau CSF- biomarker

CSF tau- increased (dying neurons release extracellularly)

higher concentration= greater cognitive impairment in normal-MCI-AD spectrum
increased CSF tau not specific for AD
similar increase not seen in pure tauopathies, indicate role of Abeta

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CSF Abeta- biomarker

CSF abeta- decreases over time

Abeta42 aggregated, retained within brain, not released in soluble form into CSF
low concentrations would match clinical diagnosis of AD

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molecular neuroimaging- biomarker

study normal brain function, early disease states, longitudinal studies, treatment response

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PET (positron emission tomography)

inject chemical ligand labelled with radio isotope, detects gamma rays

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PiB

PET ligand for amyloid; cross BBB, bind to amyloid, detect amyloid

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PET signal and braak staging

correlation- Abeta deposition/plaque location progressed

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Abeta burden in dementia in AD, HC, MCI

AD- SUVR above cutoff, PiB positive–>Abeta burden
HC- SUVR below cutoff, PiB positive; pre clinical cases?
MCI- PiB positive (non memory MCI), PiB negative (amnestic MCI)

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SUVR

standardised uptake value ratio

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ApoE4 and PiB signal

higher PiB signal

-higher SUVR score, E4 is a risk factor for AD, greater amyloid deposition

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neurogenetic testing

identify gene mutations, must be done with genetic counselling

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genetic stratification

very important if you know who to treat, easier during drug trials

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Parkinsons disease treating dopaminergic pathway

L-dopa
MAO-B inhibitors
dopamine agonists
anti-cholinergic drugs- interfere with production/uptake of ACh–>reduces tremors and muscle stiffness

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cholinergic pathway

project to thalamus

important role in working memory, conscious awareness and attention

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AChesterase inhibitors (Aricept)

enhances cholinergic activity (since inhibiting breakdown of ACh)

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5 drug targets

alpha secretase activator
anti-oxidant
neuroprotectants
anti inflammatory 
tau aggregation inhibitor

tramiprosate (homotaurine)

sulfated glycosaminoglycan mimetic

oligomerisation inhibitor
maintain Abeta in non-fibrillar form
reduces Abeta42 induced cell death
transgenic mice- reduced amyloid plaque and soluble/insoluble Abeta 40/42 levels
clinical trials- failed to improve cognitive performance

MPACs

metal protein attentuating compounds- targets metals bound to Abeta
- e.g. Clioquinol, PBT2

Abeta, metals and async

Abeta interacts with metals, drive async toxicity

clioquinol

chelates Zn and Cu, disaggregation of amyloid into smaller pieces of Abeta
crosses the BBB
small phase 2 human trial -reduction in amyloid load

PBT2

follow up MPAC to clioquinol

oxygen and nitrogen groups provide chelating properties
phase 2a trial- positive outcomes
global financial crisis- not even funds, trial design wrong

semagacestat (eli lilly)

gamma secretase inhibitor

semagacestat (eli lilly)

lowered plasma, CSF and brain Abeta in animals
lower CSF and plasma Abeta in humans
changed both Abeta40/42 levels
phase 3 trials- NO slow AD progression, caused worsening of clinical measures of cognition
side effects- increased incidence of skin cancers, infections

problem with gamma secretase inhibitors

non selective | - cleaver other proteins as well e.g. NOTCH0- important protein

anti-Abeta vaccines for AD

- only seen as theoretical before someone did it Approach - immunize AD mouse model with Abeta antigen Result - reduction in amyloid plaques, and Abeta levels -Abs also crossed BBB

vaccine in active immunisation against AD

AN1792- aggregated Abeta42 peptide antigen -phase 2a trial- patients immunized -no significant differences between Ab responder and placebo groups -trials stopped- meningoencephalitis in 6% patients-T cell activation - some patients long term followup -Mean Abeta load 5 years later decreased -NO evidence for improved survival or improvement in time to severe dementia Ie- reduced amyloid plaque but no effect on progression of neurodegeneration

3 vaccines for passive immunisation for AD

preformed purified Abs 1- Bapineuzumab 2- Solanezumab 3- Aducanumab

Bapineuzumab

binds both soluble and fibrillary Abeta - reduced amyloid burden in transgenic mice - trials not promising results - phase 3 trials- failed in AD patients with or without ApoE4 allele

Solanezumab

preferentially binds soluble Abeta - mouse model- reversed memory deficits without affecting brain Abeta load - phase 2 trials- increased plasma and CSF levels of Abeta40/42- GOOD- plaque load decreasing - no effect on behavioural outcomes (cognition) - phase 3 trials- primary endpoints (congitive, functional) NOT met - secondary analysis - modest slowing in cognitive decline

Aducanumab

binds soluble oligomers and insoluble fibrils - included PET imaging of amyloid - phase 1b trial- reduced amyloid levels, slowed down cognitive decline - but not powered enough to determine effect on cognition - did bigger trials- no robust change

anti async Ab

Antibody- Syn303 - wire hang test- motor performance - did better with Syn303 - decreases number of async aggregates - increases survival of TH positive neurons (dopaminergic)

Syn303

anti asynuclein Ab

Syn506

Ab that recognises misfolded async found in LBs

anti tau Ab

Ab- HJ8.5 - P301S transgenic mice - increases in plasma tau levels, decrease in phospho-tau (hitting its target) - improves motor function

3 mechanisms of Ab mediated therapeutics

1- microglial phagocytosis 2- catalytic disaggregation 3- peripheral sink mechanism

microglial phagocytosis

microglial recruitment to opsonised Abeta | - Fc receptor mediated phagocytosis `

catalytic disaggregation

Abs binds to fibrillar Abeta | - solubilisation of Abeta fibrils, neutralise/disaggregate

peripheral sink mechanism

Ab sequestering to circulating Abeta in periphery | -increased efflux from parenchyma to blood system

failure of major clinical trials

- actual mouse models not true representation - drug target no longer critical for pathogenic/clinical phenotype - treating subjects too advanced in the disease pathway