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Systemic inflammation has negative effects on cognitive function in populations with dementia

(Note:This comes from the Nilvad Newsletter, an online publication monitoring the progress of Archer's Ph3 drug for Alzheimer's disease)

http://nilvad.newsweaver.com/InternalStudyNewsletter/18cfzm3khsf?a=1&p=34834365&t=21611585

by Colm Cunningham,
Delirium Basic Research Group, Trinity College Dublin [e-mail]


Colm Cunningham is a Wellcome Trust Senior Research Fellow in Neuroscience, with a strong interest in neuroinflammation. Research in his laboratory, in the Trinity College institute of Neuroscience, Trinity College Dublin, is dedicated to the development of animal models with which to study delirium during dementia and to examine its long-term consequences.

Delirium is a profound and serious acute neuropsychiatric syndrome that is especially prevalent in the elderly and demented population and is frequently triggered by acute systemic inflammation. It is now clear that delirium can accelerate cognitive decline in Alzheimer’s disease (Fong et al., 2009) and increases the risk for dementia generally (Davis et al., 2012). Over the last several years Dr Cunningham’s work, and that of collaborators and others in the field, has demonstrated that systemic inflammation has negative consequences for those with prior neurodegenerative disease. He has used animal models to show that a single systemic challenge with bacterial endotoxin can produce acute cognitive dysfunction, mimicking aspects of delirium, as well as driving progression of underlying disease (Cunningham, 2011). Among the key findings in this work is the observation that microglia (brain macrophages) are “primed” by neurodegenerative pathology to produce exaggerated responses to subsequent inflammatory insults (Perry et al., 2007), which may help us to understand how systemic inflammatory events produce CNS inflammation that is selectively amplified in those areas with prior brain pathology. Collectively these studies suggest that systemic inflammation leads to acute cognitive changes including delirium, and that even upon recovery from this acute event, patients may not recover their original baseline cognitive function (figure 1).



Figure 1

The Cunningham group is currently interrogating the mechanisms by which systemic inflammation acutely disrupts cognitive function and contributes to disease progression and these studies have lead to multiple collaborations with clinical colleagues investigating the role of particular pro-inflammatory cytokines in the development of delirium and the progression of dementia (Holmes et al., 2009; MacLullich et al., 2011). There is now a strong motivation to monitor the impact of such inflammatory insults in the NILVAD trial. Since this large multicentre trial will monitor patients with evolving Alzheimer type dementia for a period of 18 months, it is likely that a large number of patients will develop inflammatory events such as infections, surgeries or falls/injuries during this period, and such events may be associated with the development of delirium or other cognitive changes. As such, the occurrence of such events may have a significant impact on study outcomes in drug- and placebo-treated patients and capturing information about these events will be important both for the interpretation of variability in efficacy of nilvadipine and for the examination of the impact of nilvadipine on the consequences of such inflammatory exacerbations. In collaboration with Dr. Sean Kennelly, medical scientific advisor to the NILVAD project, it is now proposed that we capture such events via the adverse events checklist, through carer-informed reports at each visit, in particular noting unscheduled primary care or hospital visits, need for antibiotics, injuries, falls and other relevant inflammation-related ‘adverse events’. Since blood samples, and to a lesser degree CSF samples, will be collected at 4 times during the course of treatment, there are opportunities to assess biomarkers of inflammation and we will seek to do this. Such biomarker studies would facilitate the examination of inflammatory mediator association with these reported adverse events and the investigation of their relationship to the progression of disease in these patients.

It is becoming clear that acute and chronic co-morbidities can have a significant impact on the trajectory of dementia and, as such, the frequency and severity of these events in placebo- and drug-treated cohorts may have important implications for the trial. Our continuing animal model mechanistic studies will allow us to provide new data on key inflammatory pathways and to inform biomarker analysis as the trial progresses.



References

Cunningham, C. (2011) Systemic inflammation and delirium: important co-factors in the progression of dementia. Biochem Soc Trans, 39, 945-953.



Davis, D.H., Muniz Terrera, G., Keage, H., Rahkonen, T., Oinas, M., Matthews, F.E., Cunningham, C., Polvikoski, T., Sulkava, R., MacLullich, A.M. & Brayne, C. (2012) Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain, 135, 2809-2816.



Fong, T.G., Jones, R.N., Shi, P., Marcantonio, E.R., Yap, L., Rudolph, J.L., Yang, F.M., Kiely, D.K. & Inouye, S.K. (2009) Delirium accelerates cognitive decline in Alzheimer disease. Neurology, 72, 1570-1575.



Holmes, C., Cunningham, C., Zotova, E., Woolford, J., Dean, C., Kerr, S., Culliford, D. & Perry, V.H. (2009) Systemic inflammation and disease progression in Alzheimer's disease. Neurology, 73, 768-774.



MacLullich, A.M., Edelshain, B.T., Hall, R.J., de Vries, A., Howie, S.E., Pearson, A., Middleton, S.D., Gillies, F., Armstrong, I.R., White, T.O., Cunningham, C., de Rooij, S.E. & van Munster, B.C. (2011) Cerebrospinal Fluid Interleukin-8 Levels Are Higher in People with Hip Fracture with Perioperative Delirium Than in Controls. J Am Geriatr Soc, 59, 1151-1153.



Perry, V.H., Cunningham, C. & Holmes, C. (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol, 7, 161-167.