Cerebral small vessel disease (SVD) includes white matter lesions (WML) and lacunar infarcts and is a frequent finding on computer tomography (CT) and magnetic resonance imaging (MRI) scans of elderly people . It is associated with vascular risk factors, such as hypertension, atherosclerosis, diabetes mellitus and atrial fibrillation [2–4]. In cerebral SVD symptoms are due to either complete (lacunar syndromes) or incomplete infarction (WML) of subcortical structures leading to accompanying complaints including the lacunar syndromes, cognitive, motor (gait) and/or mood disturbances . The prevalence of WML and lacunar infarcts varies considerably across studies from 5-95% and 8-28% respectively, depending on the population studied and the imaging technique used [1, 6]. There is evidence of an increased risk of cognitive decline, dementia, gait and balance disturbances and parkinsonism among individuals with SVD, although prospective studies are scarce [7–10].
However, individuals with a virtually identical WML burden on conventional FLuid Attenuated Inversion Recovery (FLAIR) imaging present with a wide variance in cognitive and motor performance ranging from no complaints at all to subjective cognitive complaints and mild parkinsonian signs to dementia and parkinsonism. Apparently there are other factors that determine whether identical appearing WML on FLAIR lead to for example cognitive or motor decline in one person, while leaving others unaffected.
One of the other factors could be the presence the coexisting manifestations of cerebral SVD on conventional MRI such as lacunar infarcts and cerebral microbleeds which might influence the cognitive and motor performance .
As identical appearing WML on conventional MRI are actually histopathologically heterogeneous , it could be that only the WML with a high loss of microstructural integrity are related to cognitive and motor impairment. It is also important to realize that only a small proportion of the white matter (usually less than a few percent) is affected by SVD, even among individuals with severe SVD . As conventional MRI is not sensitive to early loss of microstructural integrity in the normal appearing white matter (NAWM), possible changes in this largest part of the white matter cannot be assessed [14, 15]. These limitations of conventional MRI can potentially be overcome with the use of Diffusion Tensor Imaging (DTI) which allows us to assess the microstructural integrity of the whole white matter . DTI, amongst others, provides two parameters; mean diffusivity (MD), a measure of the magnitude of diffusion of water in the white matter, and fractional anisotropy (FA), which provides information about the directionality of water diffusion. Damage to the white matter is supposedly accompanied roughly by an increase in MD and a decrease in FA .
Another explanation for the clinical diversity due to WML could be the efficiency of compensation mechanisms that prevent further cognitive and motor (gait) deterioration. Support for the existence of compensatory mechanisms comes from a study among young carriers of a pre-senilin mutation (at risk for genetically determined Alzheimers' disease (AD), but still without cognitive impairment) who showed altered functional connectivity (assessed with fMRI) compared with controls . With innovative resting state fMRI techniques the strength of functional connectivity between brain regions can be investigated . In that way it might be that these compensation mechanisms also play a role in the variety of clinical presentation of individuals with SVD.
In the RUN DMC (Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort) study we prospectively investigate the effect of SVD on the transition from non-demented, independently living elderly people with cerebral SVD between 50 and 85 years towards cognitive and motor (gait) decline, and ultimately dementia and parkinsonism in a population with cerebral SVD. The primary objective of the RUN DMC study is to prospectively investigate the risk factors for and cognitive and motor (gait) consequences of longitudinal functional and structural changes in the integrity of the cerebral white matter as assessed by DTI, resting state fMRI and conventional structural MRI. To the best of our knowledge there are no other prospective cohort studies investigating the development of incident dementia and parkinsonism using these novel imaging techniques. Here we describe the study design and protocol of the RUN DMC study.