Ellen Van Der Holst

Cerebral small vessel disease (CSVD), a disease of the small perforating cerebral arteries, arterioles, venules and capillaries, is very common in the elderly population, with a prevalence of >90% in individuals aged 60 years and over. On a cerebral magnetic resonance imaging (MRI), this disease is visible as white matter hyperintensities (WMH), lacunes, microbleeds and brain atrophy. These imaging markers are considered as the traditional CSVD markers. Main risk factors are longstanding arterial hypertension, smoking and diabetes. CSVD is associated with a broad clinical spectrum, including cognitive disturbances, dementia, depression, stroke, as well as motor problems, including gait disturbances and mild parkinsonian signs. It is assumed that these clinical symptoms are the result of disruption of white matter tracts and loss of connectivity between brain areas by CSVD. However, the traditional CSVD markers do not explain the whole clinical spectrum. Therefore, other factors, such as the underlying white matter microstructural integrity, which can be assessed by diffusion tensor imaging (DTI), may play a role in the development of clinical symptoms in CSVD.

In this thesis, I mainly focused on the brain changes in CSVD associated with the development of motor disturbances over time, including gait decline and the development of parkinsonism. In addition, I studied the determinants of 8-year mortality in CSVD. All studies described in this thesis are conducted as part of the RUN DMC study, a prospective cohort study among 503 older adults, aged 50-85 years with CSVD on neuroimaging, which started in 2006. Follow-up assessment took place in 2011-2012. This study is designed to investigate the risk factors and clinical consequences of brain changes assessed by conventional MRI and DTI. In this chapter I will summarize the main findings of each chapter.

Part II: Cerebral small vessel disease and cognitive performance
In chapter 2 we reported on the association between the white matter integrity, assessed by DTI, and cognitive performance, including verbal memory performance. Verbal memory failure may eventually result in cognitive decline and dementia in some. With a region of interest (ROI) approach and a Tract-Based Spatial Statistics (TBSS) analysis, we demonstrated that the microstructural integrity of the cingulum is specifically associated with verbal memory performance at the cross-sectional level, independent of the presence of traditional CSVD markers. The cingulum is a white matter bundle, which connects the medial temporal lobe structures (e.g. hippocampus) and the posterior cingulate cortex, and has a pivot role in memory function. In addition, we showed that microstructural integrity of the cingulum is associated with the structural integrity of the hippocampus. The cingular integrity was significantly lower in participants with a low structural integrity of the hippocampus compared to those with a high structural integrity of the hippocampus. These results might indicate that cingular microstructural integrity could serve as a surrogate marker for (the development of) impaired verbal memory and possibly also dementia in individuals with CSVD.

Part III: Cerebral small vessel disease and motor performance
This part of the thesis reports on the motor consequences of CSVD after 5 years of follow-up. Traditional CSVD markers (WMH volume, lacunes, microbleeds and white and grey matter volume), as well as DTI measures of the white matter were related to gait decline and the development of parkinsonism after 5 years. A TBSS analysis was used in each chapter, to study the microstructural integrity of important white matter tracts.

In chapter 3 we investigated the associations between baseline CSVD and gait decline and the development of incident gait impairment, defined as a gait speed below 1.0m/s. We found no significant associations between baseline imaging markers and gait decline or incident gait impairment after 5 years in our population. In addition, the TBSS analysis revealed no significant differences in DTI measures between participants with and those without incident gait impairment after additional adjustments for the traditional CSVD markers. In chapter 4 we extended this study and investigated whether changes in these MRI and DTI markers are associated with gait decline after 5 years. We found that white matter atrophy and loss of white matter integrity were associated with gait decline. Gait decline was affected by a smaller stride length and not with a decline in cadence. Progression of the other markers of CSVD (WMH volume, lacunes and microbleeds) was not associated with gait decline. Changes in DTI measures, especially an increase in mean diffusivity and radial diffusivity, were associated with stride length decline. The strongest associations were found in the corpus callosum and posterior and anterior corona radiata and were independent of traditional CSVD markers. These findings suggest that progression of white matter pathology, especially white matter atrophy and loss of white matter structural integrity, should be considered as a possible cause of gait decline in older adults with CSVD.

In chapter 5 we reported on the association between baseline CSVD and incident parkinsonism. Of our 503 baseline participants, parkinsonism developed in 20 participants after 5 years. The cumulative 5-year risk for parkinsonism was 3.5% (95% CI 1.9-5.2). We found that a high WMH volume and a high number of lacunes were associated with an increased 5-year risk of parkinsonism. For vascular parkinsonism, this risk was also increased by the presence of microbleeds and a low grey matter volume. Moreover, participants with vascular parkinsonism had a lower structural integrity in bifrontal white matter tracts in comparison to those without, independent of the presence of traditional CSVD markers. These findings are building the case for a role of CSVD in the aetiology of parkinsonism.

Part IV: Long-term mortality in cerebral small vessel disease
In chapter 6 we studied the 8-year mortality in CSVD and investigated potential clinical and imaging factors associated with mortality. 80 Participants of the 503 died during the follow-up period (mean 7.8 years (SD 1.5)). All-cause mortality was highest in participants with the presence of lacunes and microbleeds, with the highest WMH volume and mean diffusivity of the white matter, and with the lowest white and grey matter volumes. In the prediction of mortality, older age, lower gait speed, lower grey matter volumes and greater mean diffusivity of the white matter were factors that best predicted 8-year mortality in our population with older adults with CSVD aged 50-85 years. Cognitive performance and other traditional CSVD markers were not retained in the prediction model. The predictive factors are probably a reflection of the vital health status of our population.

Conclusion
The studies described in this thesis showed that several brain changes are associated with the development of motor disturbances after 5 years, as well as functional outcome in older adults with CSVD. The presence of traditional CSVD markers at baseline imaging increased the 5-year risk of incident parkinsonism, as well as the 8-year mortality. In addition, impaired white matter microstructural integrity at baseline was associated with incident vascular parkinsonism, and was an important predictor of 8-year mortality, next to age, gait speed and grey matter volume in our population. The development of gait impairment or gait decline after 5 years was, however, not associated with baseline CSVD. Though, gait decline was associated with white matter atrophy and loss of white matter microstructural integrity after 5 years in our population.

Our findings suggest that DTI holds promise for unravelling the underlying mechanisms, as well as for serving as a surrogate marker in the development of motor disturbances and functional outcome (e.g. mortality) in CSVD. More studies are needed to investigate the reproducibility of our results and further elucidate the mechanisms of the development of clinical deficits in CSVD by using novel imaging techniques and network analysis. Furthermore, future research should also be directed at whether preventive strategies, e.g. on CSVD and gait decline, could improve motor and cognitive performance and functional outcome.