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Molecular mechanisms in delirium and dementia

This project aims at investigating the molecular mechanisms involved in the development of delirium, or “acute confusion”, and dementia, and the link between these two conditions.

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About the project

Little is known regarding the pathophysiology of delirium and the links between delirium and dementia. We will study brain mechanisms causing delirium and thereby dementia, utilizing patient samples (with blood and cerebrospinal fluid), animal models, imaging and brain autopsies.

Delirium, or “acute confusional state”, is characterized by a sudden impairment in memory, orientation and alertness, and is precipitated by an acute somatic illness. Delirium is common in the elderly, and has the potential to precipitate dementia in patients that are cognitively intact, and to induce a more rapid pace of deterioration in those already demented.

Objectives

The aim of this project is to:  

  • Characterize the impact of neurotransmitters (acetylcholine, monoamines, serotonin, glutamate, GABA) and their precursor amino acids (such as tyrosine, tryptophan and glutamine) on the development of delirium and dementia and their associated symptoms.
  • Investigate pathofunctional roles of pro-inflammatory and anti-inflammatory mediators, and their contribution to delirium and dementia associated impairment of brain functions and neurodegeneration.
  • Gain insight into the molecular and cellular basis of cognitive reserve and its contribution for the development of delirium and dementia.
  • Identify therapeutic targets. We will investigate the potential of clonidine (α2 agonist) and ondansetron (5HT-3 antagonist) in research and treatment of delirium and dementia.

Background

This project requires a multidisciplinary approach. We have therefore established a consortium consisting of basic neuroscientists, clinicians and investigators with prior experience in translational and/or therapeutic interventions. The project will be led by Professor Farrukh A Chaudhry (chair) and professor Torgeir Bruun Wyller (co-chair). Chaudhry has vast experience with studies of neuronal signaling in animal models. Wyller and Watne has comprehensive experience in sampling CSF and clinical data from patient cohorts. Watne is the leader of Oslo Delirium Research Group. ODRG will host the 12th annual meeting in the European Delirium Association at Hotel Bristol, Oslo November 16th - 17th 2017.

Collaboration

  • Professor Alasdair MacLullich, University of Edinburgh, President of European Delirium Association
  • Professor Henrik Zetterberg, University of Gothenburg
  • Professor Lars Nordsletten, Dept. of Orthopaedics, Oslo University Hospital
  • Professor Johan Ræder, Dept. of Anaesthesiology, Oslo University Hospital
  • Dr Colm Cunningham, Trinity College Dublin, Irland
  • Professor Johannes Attems, Newcaslte Brain Tissue Resource, Newcastle University
  • Professor Henrik Zetterberg, Professor Kaj Blennow, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. 
  • Wender Figved, Marius Myrstad, Ullrich Sprang. Dept of Orthopedics/Dept of Anaesthesiology, Vestre Viken, Bærum, Norway
  • Einar Sivertsen, Ole Christian Roald, Aasmund Godø. Dept of Orthopedics/Dept of Anaesthesiology. Diakonhjemmet hospital, Norway
  • Professor Asbjørn Årøen, Adam Essack, Christian Pollman. Dept of Orthopedics/Dept of Anaesthesiology. AHUS, Norway
  • Professor Anders Fjell, Professor Kristine Walhovd, Research Group for Lifespan Changes in Brain and Cognition, Departemnt of Pscychology, UIO, Norway

Financing

Norwegian Health Association

Tools

- HPLC analyses of serum and cerebrospinalfluid from patients with and without delirium. We will also use HPLC to analyse serum/CSF from mousemodels.
- Laser scanning confocal microscopy
- Immunogold electron microscopic analyses
- Laser Microbeam System and catapulted into LPC-Microfuge tube caps
- Quantitative immunoblotting and proteomics.
- Mousemodels: behavioural analysis and EEG
- Extracellular recordings on brain slices
- MRI of the brain with specific references to hippocampus, white matter changes, cortical atrophy, locus coeruleus and thalamus

Start - finish: 

01.03.2015 -01.03.2018

Publications

  • CSF biomarkers in delirium: a systematic review. Hall RJ, Watne LO, Cunningham E, Zetterberg H, Shenkin SD, Wyller TB, MacLullich AMJ. Int J Geriatr Psychiatry. 2017 Jun 6. doi: 10.1002/gps.4720. Hall and Watne contributed equally PMID: 28585290
  • Increased CSF levels of aromatic amino acids in hip fracture patients with delirium suggests higher monoaminergic activity. Watne LO, Idland AV, Fekkes D, Raeder J, Frihagen F, Ranhoff AH, Chaudhry FA, Engedal K, Wyller TB, Hassel B. BMC Geriatr. 2016 Aug 2;16:149. doi: 10.1186/s12877-016-0324-0.
  • Preclinical Amyloid-β and Axonal Degeneration Pathology in Delirium. Idland AV, Wyller TB, Støen R, Eri LM, Frihagen F, Ræder J, Chaudhry FA, Hansson O, Zetterberg H, Blennow K, Bogdanovic N, Brækhus A, Watne LO. J Alzheimers Dis. 2016 Sep 20.
  • Cerebrospinal fluid levels of neopterin are elevated in delirium after hip fracture. Hall RJ, Watne LO, Idland AV, Raeder J, Frihagen F, MacLullich AM, Staff AC, Wyller TB, Fekkes D. J Neuroinflammation. 2016 Jun 29;13(1):170. doi: 10.1186/s12974-016-0636-1. Hall and Watne contributed equally
Tags: Nordic
Published Feb. 20, 2015 1:19 PM - Last modified Apr. 24, 2018 10:04 AM

Contact

Farrukh A. Chaudhry (leader)

Torgeir Bruun Wyller

 

Visiting address

Department of Molecular Medicine

Sognsvannsveien 9,

Domus Medica

0372 Oslo