Diseases of the brain and mind, including epilepsy, clinical depression, addiction and dementia now account for more than 40 per cent of all illness and are devastating for those affected, their families and the wider community. This makes the work of researchers employed behind the scenes in labs critical in understanding these diseases that could one day lead to a cure.
Researchers at ANSTO LifeScience are doing their bit through investigations that reveal processes and mechanisms in the brain with the aid of nuclear science techniques, including positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging.
Understanding neuroinflammation: Tools for Dementia research
A major research focus of ANSTO LifeScience in the Dementia space is the development of tools for imaging neurological disease progression in vivo (i.e. in living animals and humans) and in vitro (i.e. for post mortem or biopsy pathology samples). In particular, this is being achieved using molecular preclinical imaging (PET/CT and SPECT/CT) to monitor the response of the immune system of the brain in animal models of brain injury and disease.
Imaging Epilepsy
The following papers utilise these in vivo molecular imaging tools in the area of epilepsy research. The interest here is to be able to use molecular imaging to detect the ‘silent’ phase of epilepsy, where after a brain injury or unknown clinical event, an alteration in the physiology of key brain regions occurs that can lead to the development of chronic seizures. We can use PET/CT imaging to monitor disease progression in animal models of epilepsy during this ‘silent’ phase.
- Dedeurwaerdere S, Callaghan PD, Pham T, Rahardjo GL, Amhaoul H, Berghofer P, Quinlivan M, Mattner F, Loc'h C, Katsifis A, Gregoire MC (2012) PET imaging of brain inflammation during early epileptogenesis in a rat model of temporal lobe epilepsy. EJNMMI Res 2:60. http://www.ejnmmires.com/content/2/1/60
- Dedeurwaerdere S, Gregoire MC, Vivash L, Roselt P, Binns D, Fookes C, Greguric I, Pham T, Loc'h C, Katsifis A, Hicks RJ, O'Brien TJ, Myers DE (2009) In-vivo imaging characteristics of two fluorinated flumazenil radiotracers in the rat. Eur J Nucl Med Mol Imaging 36:958-965. http://www.ncbi.nlm.nih.gov/pubmed/19205698
- Vivash L, Gregoire MC, Lau EW, Ware RE, Binns D, Roselt P, Bouilleret V, Myers DE, Cook MJ, Hicks RJ, O'Brien TJ (2013) 18F-Flumazenil: A gamma-Aminobutyric Acid A-Specific PET Radiotracer for the Localization of Drug-Resistant Temporal Lobe Epilepsy. J Nucl Med 54:1270-1277 http://www.ncbi.nlm.nih.gov/m/pubmed/23857513/
- Shultz SR, Cardamone L, Liu YR, Hogan RE, Maccotta L, Wright DK, Zheng P, Koe A, Gregoire MC, Williams JP, Hicks RJ, Jones NC, Myers DE, O'Brien TJ, Bouilleret V (2013) Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome? Epilepsia 54:1240-1250. http://www.ncbi.nlm.nih.gov/pubmed/23718645
Developing tools for imaging neuro-inflammation
A significant focus of the group involves the development of new molecular imaging approaches (both imaging design and development of novel radiotracers) to study neuro-inflammation. These particular studies target excitotoxic brain injury, a core pathophysiological process that is involved in various dementias.
- Boutin H, Chauveau F, Thominiaux C, Kuhnast B, Gregoire MC, Jan S, Trebossen R, Dolle F, Tavitian B, Mattner F, Katsifis A (2007) In vivo imaging of brain lesions with [(11)C]CLINME, a new PET radioligand of peripheral benzodiazepine receptors. Glia 55:1459-1468. http://www.ncbi.nlm.nih.gov/pubmed/17680643
- Van Camp N, Boisgard R, Kuhnast B, Theze B, Viel T, Gregoire MC, Chauveau F, Boutin H, Katsifis A, Dolle F, Tavitian B (2010) In vivo imaging of neuroinflammation: a comparative study between [(18)F]PBR111, [ (11)C]CLINME and [ (11)C]PK11195 in an acute rodent model. Eur J Nucl Med Mol Imaging 37:962-972. http://www.ncbi.nlm.nih.gov/pubmed/20069292
Imaging Multiple sclerosis
Additionally, PET/CT and SPECT/CT molecular imaging of neuro-inflammation has shown utility in understanding multiple sclerosis disease processes, using radiotracers developed in house by Life Sciences.
- Mattner F, Bandin DL, Staykova M, Berghofer P, Gregoire MC, Ballantyne P, Quinlivan M, Fordham S, Pham T, Willenborg DO, Katsifis A (2011) Evaluation of [(1)(2)(3)I]-CLINDE as a potent SPECT radiotracer to assess the degree of astroglia activation in cuprizone-induced neuroinflammation. Eur J Nucl Med Mol Imaging 38:1516-1528.http://www.ncbi.nlm.nih.gov/pubmed/21484375
- Mattner F, Staykova M, Berghofer P, Wong HJ, Fordham S, Callaghan P, Jackson T, Pham T, Gregoire MC, Zahra D, Rahardjo G, Linares D, Katsifis A (2013) Central nervous system expression and PET imaging of the translocator protein in relapsing-remitting experimental autoimmune encephalomyelitis. J Nucl Med 54:291-298.http://www.ncbi.nlm.nih.gov/pubmed/23321458
Harm minimisation research: Prescribed and illicit drugs
The researchers also use in vitro imaging, to look at changes in proteins and physiological processes post mortem in drug induced brain injury. The following papers have used in vitro autoradiography to assess neuro-inflammation to determine the neurotoxic potential for the new party drug, ‘Meow Meow’.
These studies contribute to the harm minimisation advice from clinicians to recreational users of the drug about the potential risks to their health. Another application for these tools has used in vitro imaging to investigate changes in neurotransmitter systems in the brain of adolescent rats after chronic administration of the antidepressant ‘Paxil’.
This animal model displays the characteristics of the paradoxical effects of antidepressants in children and youths, where anxiety and depression can be extenuated by the drug treatment. The brain mechanisms for this are still not understood, and can limit treatment of depression in young people.
- Motbey CP, Clemens KJ, Apetz N, Winstock AR, Ramsey J, Li KM, Wyatt N, Callaghan PD, Bowen MT, Cornish JL, McGregor IS (2013) High levels of intravenous mephedrone (4-methylmethcathinone) self-administration in rats: Neural consequences and comparison with methamphetamine. J Psychopharmacol 27:823 836. http://jop.sagepub.com/content/early/2013/06/03/0269881113490325.abstract
- Motbey CP, Karanges E, Li KM, Wilkinson S, Winstock AR, Ramsay J, Hicks C, Kendig MD, Wyatt N, Callaghan PD, McGregor IS (2012) Mephedrone in adolescent rats: residual memory impairment and acute but not lasting 5-HT depletion. PLoS One 7:e45473. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045473
- Karanges E, Li KM, Motbey C, Callaghan PD, Katsifis A, McGregor IS (2011) Differential behavioural and neurochemical outcomes from chronic paroxetine treatment in adolescent and adult rats: a model of adverse antidepressant effects in human adolescents? Int J Neuropsychopharmacol 14:491-504. http://www.ncbi.nlm.nih.gov/pubmed/21329552