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Research Tags

Ageing, Older People and Healthcare Aging/Gerontology Alzheimer's Disease Amyotrophic Lateral Sclerosis (ALS) Animal Models Brain Dementia Dementia/ Alzheimer's Disease Depression Emotional/Mental Health--Geriatric Inflammation Neurodegeneration Neurodegenerative Diseases/Disorders Neurological Disorders Parkinson's Disease Senile Dementia Stress

Research Projects

Project Title

Towards and understanding of infection-induced delirium

From

23/10/06

22/10/10

Summary

Delirium is a transient disorder of orientation and cognition that is highly prevalent in the elderly population admitted to or resident in hospital (10-30%). The highest risk factors for episodes of delirium are ageing and dementia and these episodes are most commonly triggered by infection, injury or surgery. Thus, while the aetiology of delirium is unknown, it is clearly multi-factorial and may result from the interaction of prior pathology and superimposed inflammatory insults. We have shown that prion-diseased mice show cognitive impairments typical of dementia and show neurodegeneration and associated CNS inflammation in neural pathways that underlie cognitive processes. These mice also show exaggerated acute sickness behaviour responses to systemic inflammatory challenges and these are underpinned by acutely raised cytokines in the hippocampus. We hypothesise that prior CNS inflammation, such as that induced by neurodegeneration, is acutely exacerbated by systemic inflammation and precipitates episodes of delirium. In the current proposal we aim to establish a mouse model of infection-induced delirium. We will investigate whether systemic inflammatory insults have more severe cognitive consequences in animals with prior CNS inflammation than in normal animals. We will investigate the cellular and molecular mechanisms of delirium using the model developed during this work.

Funding Agency

The Wellcome Trust

Programme

Research Career Development Fellowship

Project Type

Fellowship in Basic Biomedical Science

Person Months

Project Title

Reconciling Cholinergic and inflammatory hypotheses of delirium: acute and lasting effects of systemic inflammation on chronic neurodegeneration

From

2010

2017

Summary

1) Reconciling inflammatory and cholinergic mechanisms of delirium. I propose that prior pathology in the basal forebrain cholinergic nuclei (BFCN) predisposes individuals to systemic inflammation-induced acute cognitive impairments. I will produce selective and limited lesions of the BFCN, with p75NTR-saporin that do not cause significant cognitive impairment. I predict that superimposed systemic inflammation will then induce acute cholinergic dysfunction specifically in lesioned animals. This will be a valuable model system with which to study aspects of cholinergic hypofunction-associated delirium and I will study inflammatory, behavioural and neurochemical aspects of this system. 2) Mechanisms of long-term decline. Using both the "ME7+systemic inflammation" and p75-saporin models of delirium during dementia I will study potential mechanisms of acute impairments and long-term decline resulting from inflammatory challenges. In so doing I will examine the idea that the acute cognitive dysfunction and the subsequent long-term cognitive impairment associated with delirium are two distinct processes: an acute neurochemical change and an acute pathological change that is superimposed on the existing pathological state. 3) Microglial priming. I predict that primed microglia have a role in both acute and long-term consequences of acute inflammatory episodes. I propose that priming of these CNS macrophages consists of hyper-responsiveness to a variety of inflammatory stimuli and I will investigate this with respect to receptor expression, cytosolic levels of key transcription factors and nuclear localization of these in response to inflammatory stimulation.

Funding Agency

Wellcome Trust

Programme

Senior Research Fellowship

Project Type

Fellowship in Basic Biomedical Science

Person Months

Project Title

Neuroinflammatory and cognitive consequences of losing cholinergic anti-inflammatory tone in the forebrain

From

2016

2021

Summary

Systemic inflammation can trigger acute cognitive dysfunction (including delirium) as well as accelerating long-term cognitive decline (including dementia) and this occurs with high prevalence in the aging population. It is accepted that prior neurodegeneration increases the risk of these adverse health outcomes but this is poorly understood and we now propose that loss of anti-inflammatory acetylcholinergic tone predisposes to exaggerated brain inflammatory responses to systemic inflammatory insults, resulting in excessive inflammatory mediator release and contributing to acute cognitive dysfunction and lasting brain injury. In the current proposal we will use p75NTR-saporin to produce partial and selective degeneration of basal forebrain cholinergic neurons, and will induce systemic inflammation with bacterial endotoxin or polymicrobial sepsis, in order to study the influence of pre-existing hypocholinergia on acute illness-induced brain inflammation, changes in brain energy metabolism and neurophysiology (time-synchronized to behaviour) and new brain injury leading to long-term cognitive decline.

Funding Agency

National Institutes of Health (USA)

Programme

R01

Project Type

R01

Person Months

Project Title

Fever & the brain in autism: temperature vs. inflammatory effects

From

April 2017

March 2019

Summary

We will investigate the hypothesis that fever can ameliorate symptoms of autism, and explore possible mechanisms in mouse models. We will: 1) Dissociate fever and inflammation (i.e. induce whole body hyperthermia in the absence of systemic inflammation and, in different animals, induce systemic inflammation not inducing fever). Compare inflammation and fever for differential patterns of brain activation using immediate early gene cFOS expression in (amygdala, frontal cortex, hippocampus, hypothalamus, striatum, nucleus accumbens, locus ceruleus and others). Compare Inflammation and fever for their effects on brain metabolism (brain oxygen, glucose and lactate levels measured in vivo, in real-time). 2) Assess the impact of these different paradigms on behavioral measures (both positive and negative symptoms), relevant to autism spectrum disorders in 3 model systems with complementary advantages a.C58/J: Natural mutant showing both positive and negative symptoms relevant to ASD (#000669). b.B6.129-Shank3tm2Gfng/J (# 017688; also known as Shank3B-) c.Tsc+/-: B6;129S4-Tsc2tm1Djk/J (#004686) 3) We will pursue preliminary evidence for: Involvement of specific inflammatory pathways (PGE2, IL-1β; TNF) and of altered autophagy

Funding Agency

SIMONS FOUNDATION

Programme

Simons Foundation Autism Research Initiative

Project Type

Project grant

Person Months

Project Title

The impact of acute systemic inflammation upon CSF and blood biomarkers of brain inflammation and injury in dementia: a study in acute hip fracture and memory clinic patients

From

Nov 2016

Nov 2018

Summary

We propose that acute inflammatory insults, such as trauma and surgery, cause new brain injury in older adults. The current project aims to identify the inflammatory biomarkers predictive of such injury and the neuronal and synaptic biomarkers that are demonstrative of such brain injury. We aim to collect cerebrospinal fluid and blood from patients who experience hip fractures (and who have spinal anaesthesia to facilitate hip-fracture repair surgery) in order to sample the circulating and brain levels of inflammatory mediators and of markers of neuronal damage. We will then assess cognitive decline and sample blood at 1, 3 and 6 months to assess the progression of cognitive decline in those who experienced this inflammatory trauma.. We predict that the severity of acute brain inflammation and the levels of specific neuronal injury markers will predict the rate of cognitive decline in the proceeding 6 months.

Funding Agency

Alzheimer's Research UK

Programme

Major research Grants

Project Type

Project grant to investigate biomarkers of inflammation and brain injury

Person Months

Representations

Details	Date
As a member of the Association Executive I have contributed to discussions leading to a consensus adopted by the European Delirium Association and the American Delirium Society (BMC Medicine 201412:141 DOI: 10.1186/s12916-014-0141-2) that with respect to "The DSM-5 criteria, level of arousal and delirium diagnosis: inclusiveness is safer". I was also part of an international panel of experts gathered to write a definitive report on the "Intensive Care Medicine Research Agenda on Delirium" for publication in INTENSIVE CARE MEDICINE. I am an editorial board member of 2 journals: Brain Behavior and Immunity. Journal of Neuroinflammation.

Details

Date

As a member of the Association Executive I have contributed to discussions leading to a consensus adopted by the European Delirium Association and the American Delirium Society (BMC Medicine 201412:141 DOI: 10.1186/s12916-014-0141-2) that with respect to "The DSM-5 criteria, level of arousal and delirium diagnosis: inclusiveness is safer". I was also part of an international panel of experts gathered to write a definitive report on the "Intensive Care Medicine Research Agenda on Delirium" for publication in INTENSIVE CARE MEDICINE. I am an editorial board member of 2 journals: Brain Behavior and Immunity. Journal of Neuroinflammation.

Languages

Language	Skill Reading	Skill Writing	Skill Speaking
English	Fluent	Fluent	Fluent
Italian	Basic	Basic	Basic

Memberships

Membership of Professional Institutions, Associations, Societies

Details	Date From	Date To
Society for Neuroscience	2005	2015
European Delirium Association	2008	2017
Psychoneuroimmunology Research Society	2009	2014

Publications and other Research Outputs

Hough, K. and Verschuur, C.A. and Cunningham, C. and Newman, T.A., Macrophages in the cochlea; an immunological link between risk factors and progressive hearing loss, GLIA, 70, (2), 2022, p219-238 , Notes: [cited By 1], Journal Article, PUBLISHED TARA - Full Text DOI

Tsui, A. and Searle, S.D. and Bowden, H. and Hoffmann, K. and Hornby, J. and Goslett, A. and Weston-Clarke, M. and Hamill Howes, L. and Street, R. and Perera, R. and Taee, K. and Kustermann, C. and Chitalu, P. and Razavi, B. and Magni, F. and Das, D. and Kim, S. and Chaturvedi, N. and Sampson, E.L. and Rockwood, K. and Cunningham, C. and Ely, E.W. and Richardson, S.J. and Brayne, C. and Muniz Terrera, G. and Tieges, Z. and MacLullich, A. and Davis, D., The effect of baseline cognition and delirium on long-term cognitive impairment and mortality: a prospective population-based study, The Lancet Healthy Longevity, 3, (4), 2022, pe232-e241 , Notes: [cited By 4], Journal Article, PUBLISHED DOI

Paolicelli, R.C. and Sierra, A. and Stevens, B. and Tremblay, M.-E. and Aguzzi, A. and Ajami, B. and Amit, I. and Audinat, E. and Bechmann, I. and Bennett, M. and Bennett, F. and Bessis, A. and Biber, K. and Bilbo, S. and Blurton-Jones, M. and Boddeke, E. and Brites, D. and BrÃŽne, B. and Brown, G.C. and Butovsky, O. and Carson, M.J. and Castellano, B. and Colonna, M. and Cowley, S.A. and Cunningham, C. and Davalos, D. and De Jager, P.L. and de Strooper, B. and Denes, A. and Eggen, B.J.L. and Eyo, U. and Galea, E. and Garel, S. and Ginhoux, F. and Glass, C.K. and Gokce, O. and Gomez-Nicola, D. and GonzÃ¡lez, B. and Gordon, S. and Graeber, M.B. and Greenhalgh, A.D. and Gressens, P. and Greter, M. and Gutmann, D.H. and Haass, C. and Heneka, M.T. and Heppner, F.L. and Hong, S. and Hume, D.A. and Jung, S. and Kettenmann, H. and Kipnis, J. and Koyama, R. and Lemke, G. and Lynch, M. and Majewska, A. and Malcangio, M. and Malm, T. and Mancuso, R. and Masuda, T. and Matteoli, M. and McColl, B.W. and Miron, V.E. and Molofsky, A.V. and Monje, M. and Mracsko, E. and Nadjar, A. and Neher, J.J. and Neniskyte, U. and Neumann, H. and Noda, M. and Peng, B. and Peri, F. and Perry, V.H. and Popovich, P.G. and Pridans, C. and Priller, J. and Prinz, M. and Ragozzino, D. and Ransohoff, R.M. and Salter, M.W. and Schaefer, A. and Schafer, D.P. and Schwartz, M. and Simons, M. and Smith, C.J. and Streit, W.J. and Tay, T.L. and Tsai, L.-H. and Verkhratsky, A. and von Bernhardi, R. and Wake, H. and Wittamer, V. and Wolf, S.A. and Wu, L.-J. and Wyss-Coray, T., Microglia states and nomenclature: A field at its crossroads, Neuron, 110, (21), 2022, p3458-3483 , Notes: [cited By 25], Journal Article, PUBLISHED DOI

Lopez-Rodriguez, A.B. and Hennessy, E. and Murray, C.L. and Nazmi, A. and Delaney, H.J. and Healy, D. and Fagan, S.G. and Rooney, M. and Stewart, E. and Lewis, A. and de Barra, N. and Scarry, P. and Riggs-Miller, L. and Boche, D. and Cunningham, M.O. and Cunningham, C., Acute systemic inflammation exacerbates neuroinflammation in Alzheimer's disease: IL-1Î² drives amplified responses in primed astrocytes and neuronal network dysfunction, Alzheimer's and Dementia, 17, (10), 2021, p1735-1755 , Notes: [cited By 9], Journal Article, PUBLISHED TARA - Full Text DOI

McGarry, N. and Murray, C.L. and Garvey, S. and Wilkinson, A. and Tortorelli, L. and Ryan, L. and Hayden, L. and Healy, D. and Griffin, E.W. and Hennessy, E. and Arumugam, M. and Skelly, D.T. and Mitchell, K.J. and Cunningham, C., Double stranded RNA drives anti-viral innate immune responses, sickness behavior and cognitive dysfunction dependent on dsRNA length, IFNAR1 expression and age, Brain, Behavior, and Immunity, 95, 2021, p413-428 , Notes: [cited By 4], Journal Article, PUBLISHED TARA - Full Text DOI

O'Neill, E. and Griffin, Ã .W. and O'Sullivan, R. and Murray, C. and Ryan, L. and Yssel, J. and Harkin, A. and Cunningham, C., Acute neuroinflammation, sickness behavior and working memory responses to acute systemic LPS challenge following noradrenergic lesion in mice, Brain, Behavior, and Immunity, 94, 2021, p357-368 , Notes: [cited By 4], Journal Article, PUBLISHED TARA - Full Text DOI

Escartin, C. and Galea, E. and Lakatos, A. and Oâ Callaghan, J.P. and Petzold, G.C. and Serrano-Pozo, A. and SteinhÃ€user, C. and Volterra, A. and Carmignoto, G. and Agarwal, A. and Allen, N.J. and Araque, A. and Barbeito, L. and Barzilai, A. and Bergles, D.E. and Bonvento, G. and Butt, A.M. and Chen, W.-T. and Cohen-Salmon, M. and Cunningham, C. and Deneen, B. and De Strooper, B. and DÃaz-Castro, B. and Farina, C. and Freeman, M. and Gallo, V. and Goldman, J.E. and Goldman, S.A. and GÃ¶tz, M. and GutiÃ©rrez, A. and Haydon, P.G. and Heiland, D.H. and Hol, E.M. and Holt, M.G. and Iino, M. and Kastanenka, K.V. and Kettenmann, H. and Khakh, B.S. and Koizumi, S. and Lee, C.J. and Liddelow, S.A. and MacVicar, B.A. and Magistretti, P. and Messing, A. and Mishra, A. and Molofsky, A.V. and Murai, K.K. and Norris, C.M. and Okada, S. and Oliet, S.H.R. and Oliveira, J.F. and Panatier, A. and Parpura, V. and Pekna, M. and Pekny, M. and Pellerin, L. and Perea, G. and PÃ©rez-Nievas, B.G. and Pfrieger, F.W. and Poskanzer, K.E. and Quintana, F.J. and Ransohoff, R.M. and Riquelme-Perez, M. and Robel, S. and Rose, C.R. and Rothstein, J.D. and Rouach, N. and Rowitch, D.H. and Semyanov, A. and Sirko, S. and Sontheimer, H. and Swanson, R.A. and Vitorica, J. and Wanner, I.-B. and Wood, L.B. and Wu, J. and Zheng, B. and Zimmer, E.R. and Zorec, R. and Sofroniew, M.V. and Verkhratsky, A., Reactive astrocyte nomenclature, definitions, and future directions, Nature Neuroscience, 24, (3), 2021, p312-325 , Notes: [cited By 218], Journal Article, PUBLISHED TARA - Full Text DOI

Kealy, Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium, Journal of Neuroscience, 2020, p10.1523/JNEUROSCI.2876-19.2020 , Journal Article, PUBLISHED TARA - Full Text

Wilson, J.E. and Mart, M.F. and Cunningham, C. and Shehabi, Y. and Girard, T.D. and MacLullich, A.M.J. and Slooter, A.J.C. and Ely, E.W., Publisher Correction: Delirium (Nature Reviews Disease Primers, (2020), 6, 1, (90), 10.1038/s41572-020-00223-4), Nature Reviews Disease Primers, 6, (1), 2020, Notes: [cited By 0], Journal Article, PUBLISHED TARA - Full Text DOI

Oldham, M.A. and Slooter, A.J.C. and Cunningham, C. and Rahman, S. and Davis, D. and Vardy, E.R.L.C. and Garcez, F.B. and Neufeld, K.J. and de Castro, R.E.V. and Ely, E.W. and MacLullich, A., Characterising neuropsychiatric disorders in patients with COVID-19, The Lancet Psychiatry, 7, (11), 2020, p932-933 , Notes: [cited By 0], Journal Article, PUBLISHED TARA - Full Text DOI

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Donal Skelly, Eadaoin W Griffin, Carol Murray, Sarah Harney, Conor O'Boyle, Edel Hennessy, Nicholas Rawlins, David Bannerman, Colm Cunningham, Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms, bioRxiv, 2017, Dataset, PUBLISHED

Colm Cunningham, European Delirium Association annual meeting 2017, Oslo, Autumn, 2017, Invited Talk, APPROVED

Colm Cunningham, American Delirium Society Annual Meeting, Nashville, June, 2016, Invited Talk, PRESENTED

Colm Cunningham, Immunology research series, University of Cambridge, October, 2016, Invited Talk, PRESENTED

Colm Cunningham, Neurosciences in Intensive Care Symposium, Pasteur institute, Paris, June, 2016, Invited Talk, PRESENTED

Colm Cunningham, Keynote lecture, European Delirium Associaton/British Geriatric Society Meeting, London, September, 2015, BGS/EDA, Invited Talk, PRESENTED

Colm Cunningham, British Association for Psychopharmacology Conference, Bristol, August, 2015, BAP, Invited Talk, PRESENTED

Colm Cunningham, "Delirium in Older Adults: Finding Order in the Disorder", , NIH, Bethesda, Maryland, USA, February, 2014, National Institute of Aging & American Geriatrics Society, Invited Talk, PRESENTED

Robert Dantzer(ed.), Cytokines in the ageing brain, Trends in Neurosciences, Arcachon, France, 25, ((11)), June 2002, Elsevier, 2002, 546-547 p, Notes: [Author list: Colm Cunningham, Jan-Pieter Konsman and Tammy Cartmell], Proceedings of a Conference, PUBLISHED

Awards and Honours

Award	Date
Wellcome Trust Research Career Development Fellowship	2006
Wellcome Trust Senior Research Fellowship	2010

Trinity College Dublin, The University of Dublin

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Dr. Colm Cunningham

Dr. Colm Cunningham

Associate Professor - Neuroscience (Biochemistry)

Colm.Cunningham@tcd.ie

3531896 3964

Associate Professor - Neuroscience (Trinity Inst. of Neurosciences (TCIN))

Research Tags

Research Projects

Representations

Languages

Memberships

Membership of Professional Institutions, Associations, Societies

Publications and other Research Outputs

Publications

Awards and Honours