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Recovery of the aged brain after acquired injury
Closing date
Supervisors
Professor Adina T. MICHAEL-TITUS, a.t.michael-titus@qmul.ac.uk, Professor of Neuroscience, Queen Mary University of London
Dr Ping YIP, p.yip@qmul.ac.uk, Non-Clinical Lecturer in Neuroscience, Queen Mary University of London
Project Details

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The world is ageing, as shown by United Nations data indicating that by 2050 one in four persons in Europe and USA could be aged 65 or over. With an ageing population, the incidence of stroke is rising. Furthermore, for traumatic brain injury, whereas a first peak of incidence occurs in young adults, a second peak occurs in people aged 65 and over. These older patients have increased mortality and poorer functional outcome (Flanagan et al., 2006; Thompson et al., 2006). Increased incidence of these types of acquired brain injury is associated with increased health care costs. Elderly patients also have nutritional and metabolic deficiencies which can affect recovery. As ageing impairs the ability to recover after vascular and accidental brain injuries, the impact of such injuries on brain function in the elderly needs to be better understood in order to develop management approaches which limit disability and the high health costs. It is known that recovery after tissue damage is slow and limited in the elderly, but in spite of this awareness, there is no optimum management strategy at present to improve outcome.

Our aim is to examine the response of ageing brain tissue to injury and assess specific modalities to support neurorepair and recovery which would reduce the impact of injury-related disability in the aged population. We hypothesize that specific nutritional and metabolic support and rehabilitation will lead to optimum recovery.

We will model acquired brain injury (stroke and traumatic injury) in aged animals and focus on key processes altered with age, i.e. energy metabolism and neuroinflammation, and their influence on the repair and plasticity of brain circuits, including axonal growth, synapse formation and neurogenesis. Aged animals have reduced brain glucose uptake, an increased basal glial activation (astrocytes and microglia) and decreased neurogenesis (Marschallinger et al., 2015). We will study the recovery after injury using models of localized cortical impact or localised ischaemia in aged rats. We will compare the response to injury in young adults vs. aged animals using behaviour (motor and cognitive performance), imaging and post-mortem analysis (lesion volume, mitochondrial markers, neurogenesis, angiogenesis, axon regeneration and sprouting, glial scar, myelin inhibitors, neuroinflammation and synapse dynamics). To elucidate the interplay between alteration in energy metabolism and neuroinflammation and response to injury, we will model injury factors in vitro. We will characterize the alterations in energy metabolism following injury-relevant stimuli (e.g. hypoxia, excitotoxicity) of neuronal cultures. Subsequently, using pharmacological and nutrient manipulation, we will assess the contribution of different energy pathways and their ability to meet altered demands after injury. We can mimic the reduced glucose metabolism seen with old age, and provide nutrients targeting the remaining pathways, to compensate for the energy gap. Both energy metabolism and neuroinflammation are sensitive to nutrient status, therefore the in vitro exploration will allow us to identify nutrients that support energy metabolism and also target neuroinflammation.

It has been shown that the response of young animals to brain injury can be modified by sensory-motor stimulation (environmental enrichment) (Monaco et al., 2013; de la Tremblaye et al., 2019), exercise and task-specific rehabilitation (Maldonado et al., 2008), as well as specialised nutrients including antioxidants, phospholipids and alternative energy substrates (Thau-Zuchman et al., 2019, Thau-Zuchman et al., in press). A specific nutritional intervention developed in this project will be based on our in vitro findings. We will explore the impact of these various interventions (enrichment, rehabilitation, specific nutrients), alone or in combination, on the neurological recovery of the aged animals and on injury tissue markers, in order to identify an optimum management regime which could be translated to elderly patients. 

References

Supervisors’ most relevant publications

Thau-Zuchman O, Svendsen L, Dyall SC, Paredes-Esquivel U, Rhodes M, Priestley JV,  Feichtinger RG, Kofler B, Lotstra S, Verkuyl MJ, Hageman RJ, Broersen LM, van Wijk N, Silva JP, Tremoleda  JL, Michael-Titus AT. A new ketogenic formulation improves functional outcome and reduces tissue loss following traumatic brain injury in adult mice. in press, Theranostics.

Thau-Zuchman O, Ingram R, Harvey GG, Cooke T, Palmas F, Pallier PN, Brook J, Priestley JV, Dalli J, Tremoleda JL, Michael-Titus AT. A Single Injection of Docosahexaenoic Acid Induces a Pro-Resolving Lipid Mediator Profile in the Injured Tissue and a Long-Lasting Reduction in Neurological Deficit after Traumatic Brain Injury in Mice. J Neurotrauma. 2019 Sep 6. doi: 10.1089/neu.2019.6420. [Epub ahead of print] .

 Yip PK, Bowes AL, Hall JCE, Burguillos MA, Ip THR, Baskerville T, Liu ZH, Mohamed MAEK, Getachew F, Lindsay AD, Najeeb SU, Popovich PG, Priestley JV, Michael-Titus AT. Docosahexaenoic acid reduces microglia phagocytic activity via miR-124 and induces neuroprotection in rodent models of spinal cord contusion injury. Hum Mol Genet. 2019 Jul 15;28(14):2427-2448. doi: 10.1093/hmg/ddz073

Thau-Zuchman O, Gomes RN, Dyall SC, Davies M, Priestley JV, Groenendijk M, De Wilde MC, Tremoleda JL, Michael-Titus AT. Brain Phospholipid Precursors Administered Post-Injury Reduce Tissue Damage and Improve Neurological Outcome in Experimental Traumatic Brain Injury. J Neurotrauma. 2018 Jul 25. doi: 10.1089/neu.2017.5579.

Liu Z-H, Yip PK, Priestley JV, Michael-Titus AT. A Single Dose of Docosahexaenoic Acid Increases the Functional Recovery Promoted by Rehabilitation after Cervical Spinal Cord Injury in the Rat. J Neurotrauma 13 Jan 2017.

Tremoleda JL, Thau-Zuchman O, Davies M, Foster J, Khan I, Vadivelu KC, Yip PK, Sosabowski J, Trigg W, Michael-Titus AT. In vivo PET imaging of the neuroinflammatory response in rat spinal cord injury using the TSPO tracer [18F]GE-180 and effect of docosahexaenoic acid. Eur J Nucl Med Mol Imaging. 2016 Aug;43 (9):1710-22. doi: 10.1007/s00259-016-3391-8. Epub 2016 May 7.

Pallier PN, Poddighe L, Zbarsky V, Kostusiak M, Choudhury R, Hart T, Burguillos MA, Musbahi O, Groenendijk M, Sijben JW, DeWilde MC, Quartu M, Priestley JV, Michael-Titus AT. A nutrient combination designed to enhance synapse formation and function improves outcome in experimental spinal cord injury. Neurobiol Dis 82:504-515 Oct 2015

The injured aged brain AMT PY recording

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