Future studies are needed to test the hypotheses generated in this thesis.
Firstly, as the observed associations between microbleeds, cortical thickness or the mi- crostructural integrity of the white matter and gait/MPS have not or only sporadically been reported previously, our results need to be replicated in other cross-sectional studies. Secondly, future studies are warranted to investigate the neural pathways disrupted in motor disturbances, particularly in parkinsonian signs, in more detail, using voxel-based methods, such as Tract-Based Spatial Statistics, instead of rather large regions-of interest such as the whole frontal lobe. Other ways to study these networks are motor imagery of walking in combination with functional MRI or resting state functional MRI. It would also be interesting to include the infratentorial regions in these analyses, such as the mesencephalic motor regions.
Thirdly, as our studies were all cross-sectional, which prevents us from making causal inference, longitudinal studies with serial neuroimaging assessments of all the MRI markers of SVD are of major importance. If a change in the severity of a MRI marker of SVD can be related to a change in motor performance, it would greatly enhance evidence for a causal relationship. This would also be interesting regarding the role of the location of the lesions: whether they play a causal role or are only related to other lesions at other
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important locations. The RUN DMC study has a longitudinal design and follow-up with both neuroimaging and motor assessment is already planned in 2011.
Fourthly, a major question to be answered is whether and which proportion of subjects with SVD will eventually progress to more extensive SVD with (vascular) parkinsonism. It is unclear whether MPS and parkinsonism represent categories within a single continuum versus truly distinct events with separate pathophysiologies. As our results could imply a vascular contribution to MPS, we suggest that MPS could be, to some extent, a prodromal stage of full-blown (vascular) parkinsonism. The follow-up of the RUN DMC study may clarify this issue.
If the transition from MPS to parkinsonism coincides with increasing severity of for example WMLs, this would further encourage studies on modifi able risk factors for the development and progression of SVD. Blood pressure for example is recognized as a major risk factor for WMLs, but evidence for the benefi t of antihypertensive therapy on WML progression is still scarce.198 Ultimately, future studies should unravel whether
adequate treatment of vascular risk factors in subjects with SVD may reduce the course of MRI lesions of SVD, and subsequently reduce the number of patients with impaired gait or parkinsonism.
Finally, our study and other studies suggest that MRI markers of SVD (WML volume or the mean MD of the white matter) could serve as a surrogate marker for (cognitive and) motor disturbances in future therapeutic trials. However, a requirement for a surrogate marker in SVD is the correlation with motor performance (and cognition) over time. Future studies are needed evaluating the effect of changes in WML volume and DTI markers in the white matter on motor performance, and which parameter shows the most rapid decrease or increase over time.
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Chapter 5.2
Box 1 Final conclusions and recommendations Final conclusions
• Cerebral SVD affects motor performance, with stride length being most affected.
• WMLs and lacunar infarcts are related to gait disturbances and (other) parkinsonian signs. Microbleeds also play a role, but to a lesser extent.
• Gait is not only explained by subcortical SVD, but also by cortical atrophy.
• The microstructural integrity of the WMLs themselves is related to motor performance. • The microstructural integrity of the normal-appearing white matter on conventional MRI is also
affected, especially in patients with moderate or severe WMLs, and is related to motor disturbances.
• Motor disturbances in patients with cerebral SVD seem to be the result of damage to widespread networks involved in motor control: the basal ganglia-thalamo-frontal cortical circuits, as well as networks located in the limbic area, parietal and temporal lobe and corpus callosum.
• DTI is a promising tool from a pathophysiological point of view (i.e. in investigating the underlying mechanisms of motor impairment in patients with SVD), but not yet from a clinical perspective.
Recommendations for clinical practice
MRI sequences needed to assess SVD:
• a T1-weighted and FLAIR sequence for the assessment of WML volume and number of lacunar infarcts
• a gradient-echo T2*-weighted or DTI sequence for clinical purpose is not helpful When to consider cerebral SVD as a cause of motor impairment:
• a WML volume >20 ml (i.e. an Age-Related White Matter Changes scale of ≥2 in the frontal regions and/or in the parieto-occipital regions)
• and/or a number of lacunar infarcts >2-3 • location of the lesions is not important
Recommendations for future research
• Investigate the disconnection and compensation of networks, including those in the infratentorial regions, in motor disturbances in SVD in more detail using techniques such as Tract-Based Spatial Statistics or (resting state) functional MRI.
• Perform a longitudinal study to assess causality between SVD-related MRI lesions and motor performance.
• Investigate whether a DTI parameter could be a surrogate marker for motor (and cognitive) decline in longitudinal studies.
• When a relationship between (progression of) SVD and the transition from mild parkinsonian signs to parkinsonism has been established, intervention studies with modification of risk factors of SVD are warranted.
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Discussion and future perspectives