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CCNI Journal Club

Explore the neurobiological changes induced by MPTP in marmosets through MRI imaging, study cognitive changes in 'parkinsonian' monkeys, attempt reversal with novel cognitive enhancers, and assess mechanisms with fMRI. Dive into the monkey model of PD, MPTP toxicity background, and potential future studies at CCNI.

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CCNI Journal Club

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  1. CCNI Journal Club Parkinsonian monkeys: imaging, motor function & cognition

  2. Parkinson’s disease • 1.5 million sufferers in USA • Generally has onset around late 50s - early 60s • Some familial (genetic) forms known, these often have earlier age of onset • Motor symptoms best known, but are cognitive symptoms too

  3. Parkinsonian symptoms

  4. Features of PD patients’ brains F-DOPA scans: Decreased dopamine in PD patient Can reverse with transplant fetal DA tissue MRI: PD regions Normal PD patient pre-treatment PD patient post-graft fetal tissue

  5. Progress of nigral degeneration

  6. Future studies at the CCNI?! • Grant proposal: NIH call for – “Basic and translational research on the cognitive sequelae of Parkinson’s disease” • Our proposal: to administer MPTP to marmosets, track the neurobiological changes induced using MRI, study cognitive changes in ‘parkinsonian’ monkeys, attempt reversal with novel cognitive enhancers and assess mechanisms with fMRI.

  7. MPTP background: • 1980s – California – rash of apparent cases of Parkinson’s disease in young people • Displayed symptoms, i.e. rigidity, bradykinesia, tremor, postural instability • Symptoms responded to L-DOPA, major drug of choice for Parkinson’s disease • Unusual (PD usually seen in late 50s/early 60s) • Heroin users

  8. MPTP toxicity • 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine • Lipid soluble • MAO-B conversion to MPP+ • DA neurones active uptake • Concentrated in mitochondria • Impairs oxidative metabolism • Causes cell degeneration • Substantia nigra particularly susceptible, probably due to low VMAT2 levels

  9. Monkey model of PD: • MPTP given to primates, including humans, causes PD-like symptoms • Marmoset monkeys become ataxic, inco-ordinated, and have postural difficulties • MPTP causes damage to the substantia nigra (+projections to striatum), no damage to noradrenaline or serotonin systems • Similar profile to PD, but no Lewy bodies in neurones and some subtle differences in profile of dopaminergic damage (e.g. VTA) • MPTP in monkeys causes nigral damage that can be followed with imaging • As well as motor changes, cognitive symptoms are seen - as in the patients

  10. MPTP damage • Marmoset normal posture, compared with posture post-MPTP treatment • As well as posture, movement is unco-ordinated and fine motor control is impaired • Grasping and reaching affected

  11. In rhesus monkeys, chronic low dose MPTP produces cognitive deficits without significant motor problems Cognitive deficits are on similar tasks to those on which PD patients are impaired Frontal cortical functions Attentional shifting Planning “Executive functions” Fronto-striatal pathway functions Motor planning ?other cognitive tasks? Chronic low dose MPTP treatment

  12. Cognitive tasks CANTAB touchscreen apparatus • Attentional set shifting, visuospatial memory etc. - same tasks as PD patients show impairments • BUT can we present these tasks in the magnet somehow?? • Or find some way to show whether marmosets cognitive function changes correlate with MRI changes??

  13. Discussion: • What kind of imaging should we do to track the effects of MPTP? • Can we do cognitive tasks in the magnet? How would we go about starting to develop this technology? • Any other ideas for this grant?! • Thanks!

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