VIDA DTC: The associations and impact of brain mineral deposition as a marker of vascular dysfunction and inflammation in neurovascular diseases

Iron is involved in oxygen transport, DNA synthesis, cell division, metabolism, and neurotransmission.  However, an excess of iron in brain tissue can lead to oxidative stress damage to biomolecules, and cellular dysfunction. With age, iron and other minerals like calcium, accumulate ‘physiologically’ in deep brain structures, but with a wide variation in the amount: we previously found in older people that excess mineral deposition, which is visible and quantifiable by magnetic resonance imaging (MRI), is associated with cerebral small vessel disease (SVD) on MRI, worse cognitive decline, and increased risks of other neurodegenerative diseases, but the mechanisms are unknown. On pathology, the iron has been associated with blood-brain barrier (BBB) leakage and inflammation, both of which are features of SVD, the commonest cause of vascular dementia. For example, in neuro-immune disorders, dystrophic microglia may be accompanied by iron-laden, perivascular macrophages, suggesting a role of inflammation in iron accumulation. Insoluble mineral deposition has been also observed in perivascular astrocytes, as well as increased perivascular fibrinogen, both implicating BBB disturbance. However, these studies relied on post-mortem tissue, were typically small and reflect end stage disease.

In this project, we will use in vivo MRI from several large longitudinal cohort studies (n~1400) in Edinburgh and London with MRI data on iron, SVD features, and most also with BBB function, to assess relationships of brain iron deposition to SVD features, cognitive and clinical measures, MRI measures of BBB leakage, blood markers of inflammation, and disease progression, with tissue samples available for some subjects. Analysis of MRI-detected iron, BBB leakage, and SVD severity, with blood and cellular biomarkers of vascular and neurodegenerative diseases, longitudinal clinical, cognitive, and demographic data, in four large cohort studies, will help determine the vascular and inflammatory associations and impact of brain iron deposition in neurovascular disease. Secondarily it will identify patterns of iron deposition that may indicate increased risk of vascular dementia. Iron deposition is easily seen on commonly-used clinical MRI sequences meaning that the findings will translate readily to clinical practice and research. The student will learn about imaging in vascular and neurodegenerative diseases including AI techniques, neuroanatomy, a range of MRI image analysis methods, how to manage large data samples, clinical observational and biomarker methods, state of the art statistical analysis, tissue histology, and benefit from training provided by the DPUK and DRI, including Vascular Theme ECR Network, and the two host institutions.

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Row Fogo Centre for Research into Ageing and The Brain: https://clinical-brain-sciences.ed.ac.uk/row-fogo-centre-for-research-into-ageing-and-the-brain/about-the-row-fogo-centre

Joanna M. Wardlaw: https://www.ed.ac.uk/profile/professor-joanna-wardlaw, https://ukdri.ac.uk/team/joanna-wardlaw

Maria del C. Valdés Hernández: https:/www.research.ed.ac.uk/en/persons/maria-valdes-hernandez

Blanca Díaz Castro: https://ukdri.ac.uk/team/blanca-diaz-castro

Fatemeh Gerenmayeh: https://profiles.imperial.ac.uk/fatemeh.geranmayeh00

https://www.dementiaresearcher.nihr.ac.uk/vascular-and-immune-contributors-to-dementia/

https://www.alzheimers.org.uk/research/our-research/alzheimers-society-doctoral-training-centres/vascular-and-immune-contributors-dementia