Professor Holmes’s clinical research programme consists of translational research that falls under 3 main themes.
The role of inflammation in the development of Alzheimer’s disease
In Alzheimer’s disease brain pathology is accompanied by an inflammatory response, neuroinflammation, characterized by activation of microglia. Work performed in Southampton on an animal model of chronic neurodegeneration showed that systemic inflammation (i.e. inflammation outside the CNS) led to an exaggeration of the symptoms of sickness behaviour, and an acceleration of CNS disease progression. This work led to the hypothesis that microglia in the diseased brain are ‘primed’ by ongoing neurodegenerative disease and are more susceptible to peripheral signals from ongoing systemic inflammation with further activation of the microglia contributing to disease onset and progression (Perry et al 2007). Clinical studies performed by Prof Holmes in Southampton have confirmed this. An cohort study of Alzheimer’s disease subjects showed that those with systemic inflammation, associated with a raised peripheral pro-inflammatory cytokine signal, had a more rapid long term cognitive decline and exaggerated sickness behaviour symptoms (Holmes et al, 2009; 2011). This finding, in conjunction with collaborative genome wide association studies (Harold et al 2009) identifying the importance of innate immunity in late onset AD, has important implications for our understanding of the factors that drive disease progression and to the development of new treatments. Further research by Prof Holmes is exploring the role of specific common inflammatory events e.g. chronic periodontitis; respiratory and urinary infections on disease progression; the effects of systemic drug therapies, aimed at attenuating the systemic pro-inflammatory cytokine signal, on disease progression and the development of a clinical sickness behaviour scale. Our primary goal is to discover how we can monitor, prevent and inhibit the detrimental effects of a systemic inflammatory event on the diseased brain.
The biological and clinical outcomes of immunotherapy in Alzheimer’s disease
Studies in animal models suggested that peripheral immunisation with Aβ protein may reduce brain Aβ. The first human clinical study (Bayer et al 2005) to explore the safety of Aβ immunotherapy in Alzheimer ’s disease was performed in our clinical trials unit the Memory Assessment and Research Centre in Southampton. Neuropathological examination of a single case from this cohort was the first study to demonstrate that Aβ immunization alters Alzheimer’s disease by removing Aβ plaques from the brain (Nicoll et al 2003). In 2006 this finding was identified by 34 leaders in the field as one of the most notable advances in Alzheimer’s Disease (Nature Medicine 2006) and has being quoted as the most highly cited case report in medicine (BMJ 2009). This finding has had a major impact on the development of new vaccination therapies by pharmaceutical companies. At the time the initial active immunisation protocol was halted due to unanticipated side effects. However, our observation that immunisation had indeed resulted in plaque removal was instrumental in encouraging several pharmaceutical companies to continue with programmes, that they had been about to abandon.
Professor Holmes established an independent long term clinico-neuropathological follow up study of the whole cohort with the co-operation of Elan Pharmaceuticals who provided unpublished data on treatment allocation and baseline antibody response. This has led to joint publications with industry (Nicoll et al 2005) and a highly cited Lancet study (Holmes et al 2008) showing the variable nature of Aβ plaque removal from the brain and, most importantly, that Aβ plaque removal was not sufficient to halt the cognitive decline. This finding has directly challenged the dominant pathogenetic hypothesis of AD; the amyloid cascade hypothesis; and clearly suggests that removing plaques late in the disease will not give benefits. Further work has elucidated the impact of A immunisation on other aspects of neuropathology including the possible side effects of immunotherapy e.g. on vascular pathology (Boche et al 2008); its impact on innate immunity (Boche and Nicoll 2008; Zotova et al 2010) and the effects on tau pathology (Boche at al 2010). Work is continuing to further explore the biological and clinical consequences of vaccination with ongoing pharmaceutical trials in our clinical trials unit and further neuropathological examination of immunized cases in the department of neuropathology.
The treatment of cognitive and behavioural symptoms in dementia
Professor Holmes has had a long standing interest in the treatment of cognitive and behavioural symptoms in Alzheimer’s disease and, in addition to immunomodulatory therapies, has performed a large number of RPCT trials in other pharmaceutical areas over the past 10 years. This has included a number of investigator initiated commercially funded studies examining the effects of cholinesterase inhibitors and neuroleptics on disease progression in Alzheimer’s Disease as well as major non pharmaceutically funded national collaborative RPCT’s. Recent examples include an MRC study (CALM-AD) examining the role of a cholinesterase inhibitor in the treatment of agitation in Alzheimer’s disease; a NIHR Study (SADD) examining the treatment of depression with anti-depressants in dementia and an MRC study (DOMINO) examining the treatment of dementia with a cholinesterase inhibitor and memantine. These studies have led to major publications in the NEJM and the Lancet.
Clinical and Experimental Sciences Academic Units
Affiliate academic unit(s)
Clinical Neuroscience Research group
Professor Clive Holmes
Phone: (023) 8047 5216 Fax: (023) 8046 3022 Email: email@example.com