Multiple sclerosis: It is now thought that the progression of multiple sclerosis is not determined by relapsing and remitting brain plaques of demyelination but rather by ‘smouldering’ lesions that do not enhance on MRI but show microglial activation on TSPO PET and iron deposition on SWI. High sensitivity WB PET will allow these smouldering lesions in brain and particularly spinal cord to be detected with DPA714 PET, a programme being set up by Dr Joe Guadagno MRCP PhD. He is exploring the possibility of getting a CARP award.
Histone deacetylase changes in neurodegenerative and psychiatric disorders. Martinostat binds to HDACs 1,2,and 3 which regulate gene function. Dr Stephen Hobson and Dr Jon Sellars are developing 18F-martinostat to study changes in HDAC activity in Parkinsons’ disease and DLB.
Lithium is the most effective treatment for bipolar depression but its effect on brain function are complex. Dr Vicky Wing in the NU Dept of Psychiatry is interested to study bipolar depression cases before and after successful Li treatment with DPA714 PET to determine whether it excites a glial reaction. She is also interested in accessing the mitochondrial complex 1 marker, 18F-BCPP-EF, and Stephen is looking into sourcing the precursor.
It is now believed that aging leads to an increasing number of senescent cells which are toxic and increase in dementias. Post radiotherapy cases also show increased levels of brain cell senescence. Senolytic drugs are now available and we are looking to synthesise 18F-PyGal, a marker of senescence cell load. Dr Satomi Miwa, Lecturer in the Bioscience Institute NU, will drive this programme.
The orphan receptor G-protein coupled receptor 6 (GPR-6) regulates dopamine transmission. Inverse agonists are now available which may have a theapeutic role in treating psychoses and parkinsonian disorders. CVN424 suppresses activity of GPR-6 sites on striatal neurones expressing D2 receptors. We are developing the tracer 18F-CVN424 in partnership with Aarhus University and Lundbeck.
The mitochondrial cytopathy MELAS leads to strokes and dementia in some gene carriers. Prof Grainne Gorman heads the Mitochondrial Centre at NU and is interested to image the brains (and hearts) of MELAS 3423 mutation gene carriers with 18F-BCPP-EF PET to determine whether their complex 1 activity is predictive of outcome in early cases. These cases will also have DPA714 scans. She is discussing the project with one of her supporting charities.
