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Content archived on 2024-04-30

Chronic microvascular disease in the brain and mechanisms of age related functional impairments

Objective

Objectives:
The project would test the following hypotheses concerning the mechanisms leading to deve!opment of leukoaraiosis:
1. Leukoaraiosis results from diffuse decreases in subcortical capillary density that lead to chronic subcortical ischaemia.
2. Axonal damage or loss is a major cause of the chronic functional impairments associated with leukoaraiosis
3. Microvascular disease leading to leukoaraiosis is associated both with altered coupling of local haemodynamic responses to neuronal activation and with altered functional connectivities between cortical networks activated during cognitive tasks.

Chronic microvascular disease of the brain is a major cause of motor impairment and dementia with aging. Early diagnosis and treatment have been limited by the lack of reliablenon-invasive markers of disease. Although widespread periventricular white matter changes described as leukoaraiosis are characteristic of the MRI brainscans of affected individuals, the significance of these changes is uncertain, as they also can be found with apparently healthy aging. Such variable severity of clinical deficits associated with similar appearances by conventional imaging must reflect considerable pathological heterogeneity underlying the changes of leukoaraiosis. This proposal would link expertise in four European research centres for the coordinated application of positron emission tomooraphy (PET), magnetic resonance imaging (MRI) and spectroscopy (MRS), and functional magnetic resonance imaging (FMRI) for better characterisation of the pathophysiology of aging-related chronic microvascular disease of the brain. The healthy aging patients with leukoaraiosis with or without dementia and patients with chronic hypertension who are at risk of developing leukoaraisosis would be studied. Correlations would be made between neuroimaging measures and clinically-relevant functional impairments.

The project would test the following hypotheses concerning the mechanisms leading to development of leukoaraosis:
1. Leukoaraiosis results from diffuse decreases in subcortical capillary density that lead to chronic subcortical ischaemia;
2. Axonal damage or loss is a major cause of the chronic functional impairments associated with leukoaraiosis;
3. Microvascular disease leading to leukoaraiosis is associated both with altered coupling of local haemodvnamic responses to neuronal activation and with altered functional connectivity between cortical networks activated during cognitive tasks.

In the course of our work we would assess whether PET or advanced MR techniques could be used as sensitive and specific surrogate markers for monitoring the progression of this disease process. Availability of such markers would provide a powerful tool for enhancing the efficiency of drug development studies and for assessment of the risks of disability from this disease. By working together, the project partners would be able to integrate clinical data and technical expertise to an extent not possible in any single European centre. The partnership would enhance research training, particularly in the areas of neuroimaging and image analysis. Positive results from the work would encourage the dissemination of sophisticated new brain imaging technologies currently being developed and marketed by major European industries.05 05

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Coordinator

The Chancellor, Masters and Scholars of the University of Oxford
EU contribution
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Total cost

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Participants (3)

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