Ian Clark's first degree was in Veterinary Science at the University of Queensland in Australia, for which he was awarded a University Medal. After success in solving an inland cattle disease that had been a long-standing puzzle, and a PhD in basic immunology at the Royal College of Surgeons in London, he undertook further research in innate immunity and disease pathogenesis at the MRC Clinical Research Centre at Harrow, for which he was awarded a DSc (Lond.). It was during this period he began to develop the then novel view that infectious disease is caused not directly by the invading pathogen, but by the host's innate immunity to it. The host-derived mediators of this response, such as TNF and IL-1, when produced excessively, were argued to generate disease through disrupting the normal homeostatic physiological roles of these cytokines. On returning to Australia he has continued to develop this idea of excessive production of these cytokines, particularly TNF, being central to pathogenesis of non-infectious as well as infectious diseases. Present interest focuses on a number of chronic brain diseases that may exhibit reduced cognition, behavioral changes, neuropathic pain and fatigue, including the encephalopathies such as post-stroke syndromes, post-cerebral malaria syndrome, Parkinson’s disease, cerebral palsy, traumatic brain injury and Alzheimer’s disease. He has focused on the concept of these and similar conditions have a fundamental similarity in their pathogenesis that is best regarded as manifestations of chronic cerebral inflammation. This is characterised by excess cerebral production of potentially pro-inflammatory cytokines that at low levels are essential components of normal cerebral physiology. A corollary is that specific anti-TNF agents such as etanercept, when administered appropriately, can lower cytokine levels and thus be usefully employed in the treatment of these conditions.
- Brain diseases that share cognitive and behavioral changes (eg, post-cerebral malaria syndrome, Alzheimer’s disease, stroke, and traumatic brain injury)
- Inflammatory encephalopathic conditions
- Specific anti-TNF (Tumor necrosis factor) agents, such as etanercept.
Clark, I. A. and Vissel, B. (2019). Neurodegenerative disease treatments by direct TNF reduction, SB623 cells, maraviroc and irisin and MCC950, from an inflammatory perspective - a Commentary. Expert Review of Neurotherapeutics 19: 535-543.
Morris, G. P., Clark, I. A. and Vissel, B. (2018) Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer's disease. Acta Neuropathologica 136 (5):663-689.
Clark I. A. and Vissel B. (2018). Therapeutic implications of how TNF links APOE, P-tau, a-synuclein, b-amyloid, and insulin resistance in neurodegenerative diseases. British Journal of Pharmacology 175 (20):3859-3875.
Clark I. A. and Vissel B. (2018). The inflammatory nature of post-surgical delirium predicts benefit of agents with anti-TNF effects, such as Dexmedetomidine. Frontiers in Neuroscience 12: 127.
- Clark I. A. and Vissel B. (2017). The meteorology of cytokine storms, and the clinical usefulness of this knowledge. Seminars in Immunopathology, 39(5), 505-516 DOI 10.1007/s00281-017-0628-y
- Clark, I. A. (2017). Editorial: An unsound AAN Practice Advisory on poststroke etanercept. Expert Review of Neurotherapeutics, 17 (3) 215-217.
- Clark, I. A. (2016). Letter by Clark regarding article, "Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study." Stroke 47(12): e268.
- Clark, I. A. and B. Vissel (2016). Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents. J Neuroinflammation 13(1): 236.
- Clark, I. A. and Vissel, B. (2015) Amyloid β: one of three danger-associated molecules that are secondary inducers of the proinflammatory cytokines that mediate Alzheimer’s disease. British Journal of Pharmacology, 172, 3714-3727.
- Clark, I. A. and Vissel, B. (2015) A neurologist's guide to TNF biology, and to the principles behind the therapeutic removal of excess TNF in disease. Neuronal Plasticity, Volume 2015, Article ID 358263.
- Morris, G. P., Clark, I. A. and Vissel, B. (2014) Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer's disease. Acta Neuropathologica Communications 2: 135.
- Clark, I. A. and Vissel, B. (2014) Inflammation-sleep interface in brain disease: TNF, Insulin, Orexin. Journal of Neuroinflammation 11: 51.
- Wright A.L., Zinn R., Hohensinn B., Konen L.M., Beynon S.B., Tan R.P., Clark I,A., Abdipranoto A. and Vissel B. (2013) Neuroinflammation and neuronal loss precede Aβ plaque deposition in the hAPP-J20 mouse model of Alzheimer's disease. PLoS One 8: e59586.
- Morris G.P., Clark I.A., Zinn R., Vissel B. (2013) Microglia: A new frontier for synaptic plasticity, learning and memory and neurodegenerative disease research. Neurobiology of Learning and Memory 105:40-53.
- Clark, I. A. and Vissel, B. (2013) Treatment implications of the altered cytokine-insulin axis in neurodegenerative disease. Biochemical Pharmacology 86: 862-871.
- Clark, I, Atwood, C. Bowen, R. Paz-Filho, G, and Vissel, B. (2012) Tumor necrosis factor-induced cerebral insulin resistance in Alzheimer’s disease links numerous treatment rationales. Pharmacological Reviews 64, 1004-1026.
- Clark, I. (2012) Invited Commentary: New hope for survivors of stroke and traumatic brain injury. CNS Drugs 12: 1071-1072.
- Alleva, L. M., Guolani, R. C. and Clark, I. A. (2011) Current work and future possibilities for the management of severe influenza: using immunomodulatory agents that target the host response. Future Virology 6, 843-854.
- Clark, I. A., Alleva, L. M, and Vissel, B. (2011) TNF and leptin tell essentially the same story in Alzheimer's disease. Journal of Alzheimer’s Disease 26, 201-205.
- Clark, I. A. and Atwood, C. S. (2011) Is TNF a link between aging-related reproductive endocrine dyscrasia and Alzheimer's disease? Journal of Alzheimer’s Disease 27, 691-699.
- Clark, I. A., Alleva, L. M, and Vissel, B. (2010) The roles of TNF in brain dysfunction and disease. Pharmacology and Therapeutics 128, 519-548.
- Clark, I. A., Budd, A. and Alleva, L. A. (2008) Sickness behaviour pushed too far – the basis of the syndrome seen in severe protozoal, bacterial, and viral diseases, and post-trauma. Malaria Journal 7:208.
- Clark, I. A. (2007). How TNF was recognized to be a key mechanism of disease. Cytokine and Growth Factor Reviews 18: 335-343.
- Clark, I. A., Alleva, L. E., Mills, A. C., and Cowden W. B. (2004) Disease pathogenesis in malaria and clinically similar conditions. Clinical Microbiology Reviews 17:509-539.
- Clark, I. A. and Cowden W. B. (2003) The pathophysiology of falciparum malaria. Pharmacology and Therapeutics 99: 221-260.