Macro and microstructural damage within the brain in relation to cognitive decline:
: a population based study

Student thesis: Doctoral ThesisDoctor of Philosophy


Understanding the links between neurological damage, imaging markers and cognition is important for understanding aetiology and also for diagnosis, prognosis, and rehabilitation. This is often investigated through the use of information at the macrostructural level which is visible to the naked eye. The Rotterdam study, amongst others, has investigated the importance of macrostructural markers seen on MR imaging in relation to a whole variety of clinical cognitive features and future events (Cees De Groot et al., 2000; Vermeer et al., 2003). Investigating these markers in more detail and over time with more focal measures investigating with greater anatomical precision is important in relation to damage and its effect on cognition. This thesis addresses this need through the use of multiple measures of white matter microstructural markers, individual tract structure and hippocampal structure within the large prospective cohort study, The Rotterdam Study.

The first analysis in the thesis investigates white matter microstructure at a global level using diffusion-MRI in relation to risk of future focal events such as stroke. This analysis highlights the importance of white matter microstructure as an early marker, even globally, showing an increased risk of incident stroke over a mean follow-up of 5.5 years.

Secondly, this thesis focuses on structural markers which have been related to cognition previously (Mueller et al., 2011; Yassa et al., 2011; Tamnes et al., 2014; Cremers et al., 2016). Specifically, the focus narrows to individual white matter tracts and the hippocampal formation in relation to cognitive tests and disease which involve its decline. This is done through the use of more detailed measures on a smaller scale than in past research focusing on white matter microstructure within tracts and subregion volumes of the hippocampus. Results within these studies found location-specific associations with cognition which was seen to be dynamic over cognitive decline. Additionally, hippocampal subregion-specific associations with dementia risk were observed. When combining multimodal measures from structural MRI quantifying volumetric metrics and diffusion MRI differential associations were observed within the network of hippocampal subregions and white matter tracts in relation to memory processes. These analyses found specifically that diffusion changes within the fornix may precede changes within the hippocampal subregion the subiculum, and possibly drive memory decline.

These studies display the importance of specific white matter tracts and their dynamic associations with cognition within the trajectory of decline. Thus, analysis into location specific damage within white matter tracts in relation to cognitive change was investigated. These analyses show a location specific relationship between lesions in white matter and decline in cognitive functions.

This thesis highlights the importance of white matter imaging markers and the dynamic role of white matter in relation to cognition. The importance of greater anatomical specification when investigating damage and degeneration is stressed in relation to prognosis and the trajectory of cognitive decline. This could aid in producing individual rehabilitation programmes dependent on location of neurological damage.
Date of Award1 Mar 2019
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorMichael O'Sullivan (Supervisor) & Steven Williams (Supervisor)

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