On the origin of cerebral small vessel disease

Cerebral small vessel disease includes an ever expanding spectrum of white
matter hyperintensities, lacunar infarcts, microbleeds and loss of
microstructural integrity of on conventional FLAIR imaging normal appearing
white matter. Its presence and incidence has found to be related with vascular
risk factors.
Cerebral small vessel disease plays an important role in the development of
cognitive and motor decline, ultimately leading to dementia and parkinsonism.1
Remarkably, the clinical picture can usually not be explained by subcortical
small vessel disease alone. This coincides with increasing awareness for the
role the cortex in patients with small vessel disease with regards to these
disabling diseases. The cortex, before the emergence of subcortical small
vessel disease, being connected with other parts of the brain, may have been
affected by loss of input/connectivity due disconnection of white matter tracts
residing in areas of small vessel disease.
One of the remaining mysteries of cerebral small vessel disease is its origin.
Although the occurrence of neurological deficits due to a lacunar infarction is
well recognized, in most patients the progression of small vessel disease
(including the emergence of lacunes) goes unnoticed as it is usually not
accompanied by recognizable clinical symptoms.
Therefore our current knowledge is mainly based on *interval* small vessel
disease lesions, detected long (often years) after their occurrence by follow
up imaging, usually within the framework of a longitudinal study. From that
approach we know that the incidence of lacunar infarcts is about 10%/year in
both stroke populations and populations based studies. The average increase of
white matter hyperintensities is about 0.5ml/year.
Recently, this view has dramatically been challenged by findings from a
high-frequency (weekly) MR imaging study in which investigators showed that, in
contrast to current understanding, progression of WMH was due acute cerebral
ischemia, with each incident WMH showing corresponding lesions on a Diffusion
Weighted Image (DWI) scan.2,3 The rate of progression of WMH was in line with
the average degree of progression of WMH as estimated from large prospective
studies on patients with SVD. This was completely different from current
thoughts on a chronic cerebral ischemia
However, in this study only five patients with a recent TIA or lacunar stroke
had been assessed. Remarkably, patients didn*t experience any clinical symptom,
although detailed serial neuropsychological examinations had not been
performed.2
We therefore propose to perform both high frequency serial imaging and
neuropsychological examinations among non-demented survivors of our RUNDMC
study, with already known moderate to severe SVD, from whom already nine years
of follow up imaging and neuropsychological assessments were available.

The objective of the current study proposal is therefore to investigate *the
origin of cerebral small vessel disease*

prospective cohort study

Patients will undergo serial MR imaging, with which they are already familiar.
In addition during each visit there will be a short cognitve and motor
assessment. The total "burden" will be about 24 hours during the course of the
whole project. When succesful, we feel that this "burden" outweighs the
possible benefits future people may have.