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Background. Lacunar strokes account for 25% of all ischaemic stroke but the exact nature of the causative cerebral small vessel abnormality remains unknown. Pathological studies are technically difficult and brain imaging cannot adequately characterise the cerebral small vessels. The retinal blood vessels are of similar size and physiology to the cerebral small vessels and may act as a surrogate marker for these cerebral small vessels. We therefore investigated retinal microvascular abnormalities in lacunar stroke. Methods. We performed a systematic review of retinal microvascular abnormalities in lacunar stroke to clarify associations and identify where further research was required. We then established a cohort of patients presenting with lacunar stroke with cortical stroke controls to investigate differences in retinal microvascular abnormalities between stroke subtypes. All patients had MRI brain at presentation and digital retinal photography of both eyes. We investigated the prevalence of retinopathy (hard and soft exudates or haemorrhages/microaneurysms), focal arteriolar narrowing and arteriovenous nicking . We developed, validated and used novel semi-automated techniques for measuring retinal arteriolar and venular widths, retinal arteriolar geometry (branching co-efficients (change in arteriolar cross sectional area across a bifurcation) and branching angles) and fractal dimensions (reflecting branching complexity) of the vasculature. We also assessed MRI parameters in lacunar stroke. We used multivariable analysis to correct for baseline imbalances in vascular risk factors. Results. From the systematic review we demonstrated that retinal microvascular abnormalities are associated with incident and prevalent stroke but that in general, strokes were inadequately characterised and there were no data regarding retinal microvascular abnormalities in ischaemic stroke subtypes. We recruited 253 patients, 129 lacunar strokes and 124 cortical strokes, mean age 68 years. We found no difference in the prevalence of retinopathy, arteriovenous nicking, focal arteriolar narrowing or arteriolar widths between lacunar and cortical stroke subtypes. We found that venules were wider in lacunar stroke. We found no differences in arteriolar branching co-efficients or arteriolar branching angles between lacunar and cortical strokes but found that deep white matter white matter hyperintensities on MRI were associated with increased branching co-efficients and periventricular white matter hyperintensities associated with decreased branching co-efficients. We found that the fractal dimension of the vascular tree was decreased in lacunar stroke. Furthermore we found that enlarged perivascular spaces on MRI are associated with lacunar stroke and white matter disease. Conclusions. We have clearly demonstrated that retinal microvascular abnormalities differ between lacunar and cortical stroke suggesting that a distinct small vessel vasculopathy may cause lacunar stroke. We have also identified MR markers of lacunar stroke. These results suggest that venular disease (a hitherto underresearched area) may play a role in the pathophysiology of lacunar stroke. Retinal microvascular abnormalities can act as markers for cerebral small vessel disease. We plan collaborative analyses with colleagues who have performed similar studies to further assess retinal abnormalities in lacunar stroke.

This thesis first explored the effects of concurrent spatial attention and working memory task performance on over-ground gait in healthy young and older adults. It then compared over-ground gait parameters and working memory performance in mild Alzheimer’s Disease (AD) and normal controls (NC) and investigated costs of dual-tasking on working memory performance and cadence during treadmill walking at preferred walking speed in the two groups. Furthermore, it explored these differences in AD and NC groups in relation to their subcortical hyperintensities (SH) that were rated using standardized scales on MRI. Reaction times and accuracy on working memory performance measures were collected under single and dual task conditions. Over-ground gait parameters were measured on an automated walkway. Costs of dual-tasking on gait parameters and working memory performance were measured at a constant velocity on a treadmill. The hypotheses that working memory influences gait performance and that a higher SH burden negatively influences over-ground gait and costs of dual-task conditions, were supported in a series of experiments. Gait slowed down while performing working memory and spatial attention tasks in young and older adults. Patients with mild AD, compared to NC, had a slower gait velocity, shorter stride length and lower cadence on the walkway. When the two groups were subdivided into higher and lower SH groups based on their median SH score, the NC group with lower SH burden walked significantly faster with a higher cadence and a longer stride length than the other three groups. Lastly, a higher SH burden negatively influenced working memory performance in NC while in mild AD patients, it had negative influences on adaptive changes in gait while dual-tasking. These results suggest that, in dual-task condition, SH interfere with processing speed in NC and on gait in AD. These findings provide new insights in to tradeoffs during dual tasking in relation to cerebrovascular disease. This has ecological implications because of the prevalence of small vessel disease in aging and dementia, may impact on predicting falls in AD.

<p>In recent years, the emergence of diffusion tensor imaging (DTI) has provided a unique means via water diffusional characteristics to investigate the white matter integrity in the human brain, and its impact on neuronal functions. However, since the characterization of white matter integrity using DTI often lacks tissue specificity, most research studies report changes in anisotropy that are not explicitly correlated with particular cellular origins. To improve the utility of DTI in translational neuroimaging, it is critical to develop DTI acquisition techniques that are quantitative and tissue specific.</p><p>There are, nevertheless, existing methods for tissue specificity. For example, myelin water images can be generated using multiple echo time (TE) or magnetization transfer techniques. These techniques can detect changes in the concentration of myelin associated markers, but not in their spatial organization. Most white matter pathologies however start with early microstructural changes in the myelin sheaths during which the tissue contents remain similar and are thus not differentiable on a conventional MR image. Thus, the ability to construct a diffusion tensor that is myelin specific can have an immediate impact on our better understanding myelin physiology and pathophysiology during brain development. </p><p>Unfortunately, the myelin water signal decays rapidly because of its short transverse relaxation time constant (T2 < 50 ms), especially in DTI experiments where the echo time (TE) can be as large as 100ms. Even in special cases where the TE is shorter, the lack of myelin selectivity in conventional DTI techniques makes assessment of myelin microstructure extremely challenging. Thus we need to develop a DTI methodology that will greatly shorten the TE and allow myelin selectivity.</p><p>To address these challenges we have developed innovative DTI acquisition methodologies that can specifically assess myelin microstructural changes in white matter. To preserve more signal from myelin water we used a stimulated echo DTI implementation. In our initial approach we integrated this sequence with a magnetization transfer preparation to achieve additional differentiating sensitization to myelin water and derive a myelin water weighted (MWW) diffusion tensor. Our results indicate that, compared to the conventional DTI, myelin water diffuses along the axis of the fiber, but has the same has larger fractional anisotropy (FA) due to significantly smaller radial diffusivity. The limited specificity of MT and high radio frequency power deposition of MT-DTI restrict its applicability in clinical studies. </p><p>To obtain increased myelin specificity we implemented a robust stimulated echo DTI sequence with segmented spiral-out readout trajectory for achieving minimal TE on clinical MRI scanners. To ensure high spatial accuracy throughout the DTI scan we further develop a methodology for inherently and dynamically correcting both motion induced phase errors and off-resonance effects due to magnetic field inhomogeneities (including eddy currents) in the reconstructed image. We the used this technique to conduct an unprecedented experiment in which we collected DTI images at multiple echo times (as short as 18ms) and characterized the dependence of anisotropy on the T2 components including myelin water. The results confirmed the anisotropy characteristics of myelin water found with our initial previous approach. </p><p>Building on this new information, we designed a MWW-DTI method based on the simultaneous acquisition of DTI images at two different echo times within clinical practical durations. It is hoped that this new DTI technique sensitized myelin microanatomy will find wide applications in monitoring healthy brain development in pediatric populations, as many developmental brain disorders start with microstructural changes in white matter.</p> / Dissertation

This thesis first explored the effects of concurrent spatial attention and working memory task performance on over-ground gait in healthy young and older adults. It then compared over-ground gait parameters and working memory performance in mild Alzheimer’s Disease (AD) and normal controls (NC) and investigated costs of dual-tasking on working memory performance and cadence during treadmill walking at preferred walking speed in the two groups. Furthermore, it explored these differences in AD and NC groups in relation to their subcortical hyperintensities (SH) that were rated using standardized scales on MRI. Reaction times and accuracy on working memory performance measures were collected under single and dual task conditions. Over-ground gait parameters were measured on an automated walkway. Costs of dual-tasking on gait parameters and working memory performance were measured at a constant velocity on a treadmill. The hypotheses that working memory influences gait performance and that a higher SH burden negatively influences over-ground gait and costs of dual-task conditions, were supported in a series of experiments. Gait slowed down while performing working memory and spatial attention tasks in young and older adults. Patients with mild AD, compared to NC, had a slower gait velocity, shorter stride length and lower cadence on the walkway. When the two groups were subdivided into higher and lower SH groups based on their median SH score, the NC group with lower SH burden walked significantly faster with a higher cadence and a longer stride length than the other three groups. Lastly, a higher SH burden negatively influenced working memory performance in NC while in mild AD patients, it had negative influences on adaptive changes in gait while dual-tasking. These results suggest that, in dual-task condition, SH interfere with processing speed in NC and on gait in AD. These findings provide new insights in to tradeoffs during dual tasking in relation to cerebrovascular disease. This has ecological implications because of the prevalence of small vessel disease in aging and dementia, may impact on predicting falls in AD.