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Understanding neuroplasticity counteracting brain ageing

Primary Supervisor: Professor Johannes Boltze, School of Life Sciences

Secondary supervisor: Dr Sascha Ott

PhD project title: Understanding neuroplasticity counteracting brain ageing

University of Registration: University of Warwick

Project outline:

Background and hypotheses:The cerebral vasculature continuously changes as we age. There is an age-related, steady increase in systolic blood pressure (BP) which is so frequent that it is considered part of the “normal” ageing process1. The BP increase causes small artery remodelling, characterised by a decrease of vessel diameter, and increased wall thickness. Affected vessels, predominantly those situated in deep cortical grey matter and subcortical white matter areas and lacking substantial collaterals, become less capacious. As a result, cerebral blood flow (CBF) to downstream areas declines. Moreover, increasing arterial stiffness and neurovascular uncoupling are seen during ageing2. These impair autoregulatory CBF increases as a response to local demands during mental activities: a metabolic mismatch arises.

Sooner or later this mismatch affects the brain. When vascular remodelling comes to an extreme (vessel occlusion) and/or additional comorbidities such dyslipidemaemia-associated atherosclerosis join in, stroke or vascular dementia based on cerebral small vessel disease might result3. However, brain mass slowly declines even during normal ageing.

Many individuals age without or with only very mild cognitive impairments despite even macroscopically visible brain changes, while others exhibiting comparable brain changes show accelerated cognitive decline. This implicates the existence of (a) a powerful endogenous compensatory reserve (ECR) that can counter age-related CBF and subsequent structural brain decline and (b) factors causing individual differences in brain ageing.

The mental correlate of the ECR is the famous ‘cognitive reserve’ which has been described in neuropsychological studies. The neurobiological ECR representation is poorly understood. We hypothesise that neuroplasticity is the central ECR element, but is not equally effective in individuals. We also have an animal model at hand that can properly model human cerebrovascular and brain ageing, but in accelerated fashion.

Objectives:

  • to longitudinally describe cerebrovascular and structural brain ageing in an animal model, including individual differences
  • to characterise endogenous responses the ageing
  • to investigate brain plasticity as an attempt to counter age-related decline
  • to develop an in silicomodel identifying factors that may foster and impair the ECR in brain ageing, and to predict individual brain ageing.

Methods and approach: Spontaneously hypertensive rats (SHR) exhibit mildly to moderately elevated BP. They show vascular remodelling, structural brain changes and mild cognitive impairment (Fig.) similar to those observed in human ageing4. The phenotype, though subtle, develops spontaneously and continuously without the need for special diets or surgeries. However, animals differ in speed and extent of brain ageing, indicated by large standard deviations in cognitive tests.

An animal cohort will be monitored longitudinally for cognitive performance over 12 months, starting at the age of 3 months. Randomly selected subjects will be investigated for structural brain changes at 9, 12, and 15 months. We will measure brain volume and ventricle enlargement, neuronal and white matter (myelin index) density, small vessel density, vascular remodelling, perivascular amyloidosis, glial reactivity, and intracerebral peripheral immune cell distribution. We will also assess markers associated with neuroplasticity such neuronal and oligodendroglial precursor proliferation, synaptophysin expression, neurite/dendrite length, branching etc., and growth factor concentrations. A unique aspect of this project is the longitudinal description of brain changes and the ability to directly correlate them with cognitive function, providing a deeper understanding of the neurobiological ECR correlate and its role in brain ageing. A mathematical model will be developed to identify factors related to slow or absent cognitive decline and increased neuroplasticity to ultimately predict the individual course of brain ageing.

References:

  1. Prog Cardiovasc Dis 53:68-78
  2. Subcell Biochem 91:477-499
  3. Lancet Neurol 12:483-497
  4. Acta Neuropathol Commun 2:169

BBSRC Strategic Research Priority: Integrated Understanding of Health: Aging & Understanding the rules of life: Neuroscience and behaviour

Techniques that will be undertaken during the project:

  • Animal husbandry
  • Behavioural (cognitive) phenotyping
  • Histology & immunohistochemistry
  • Single cell analysis
  • Molecular biology
  • Mathematical modelling

Contact: Professor Johannes Boltze, University of Warwick