Background and Purpose-Cerebral small vessel disease (SVD) is the most common cause of vascular dementia. Interest in the use of surrogate markers is increasing. The aims of this study were to determine if brain volume was different between patients with SVD and control subjects, whether it correlated with cognition in SVD, and whether changes in brain volume could be detected during prospective follow-up. Methods-Thirty-five patients (mean age, 68.8 years) who had a lacunar stroke and radiological evidence of confluent leukoaraiosis and 70 age-and gender-matched control subjects were recruited. Whole-brain T1-weighted imaging and neuropsychological testing were performed after 1 year on all patients and after 2 years for the control subjects. Fully automated software was used to determine brain volume and percentage brain volume change. An executive function score was derived. Results-There was a significant difference in brain volume between the patients with SVD and control subjects (meanϮSD [mL] 1529Ϯ84 versus 1573Ϯ69, Pϭ0.019). In the patients with SVD, there was a significant association between brain volume and executive function (rϭ0.501, PϽ0.05). The meanϮSD yearly brain atrophy rate for patients with SVD and control subjects was significantly different (Ϫ0.914%Ϯ0.8% versus Ϫ0.498%Ϯ0. 4%, respectively, Pϭ0.017). No change in executive function score was detected over this period. Key Words: brain atrophy Ⅲ cerebral small vessel disease Ⅲ cognitive impairment Ⅲ longitudinal study Ⅲ MRI Ⅲ surrogate marker C erebral small vessel disease (SVD) is a major cause of stroke, age-related cognitive decline, and vascular dementia. 1 Despite its importance, few studies have specifically investigated treatment in this stroke subtype. 2,3 This is due to a number of issues that complicate assessment of treatment efficacy: the risk of recurrent stroke is relatively low with an annual rate of 0.25%, 4 the rate of progression to dementia is slow, 4 and repeated cognitive testing is associated with a learning effect that reduces sensitivity to longitudinal decline. Therefore, large sample sizes are required to determine treatment efficacy when using stroke and dementia as end points. This has led to the suggestion that imaging may provide useful surrogate markers for SVD to assess therapeutic approaches at an early stage. 5 A number of criteria have been proposed for the definition of an effective surrogate marker for treatment trials. 6 The first criterion is that the marker must be able to predict the natural course of the disease, that is, it should correlate with relevant clinical features, for example, cognitive function, in both crosssectional and longitudinal studies. Conclusions-Brain volume is reduced in SVD andIn multiple sclerosis, imaging parameters have been demonstrated to have high sensitivity for detection of disease activity, which is better than clinical scores. 7 Brain atrophy has been used as an outcome measure in treatment trials. 8,9 In comparison to multiple sclerosis, there are less data on br...

Background and Purpose-Cerebral small vessel disease is the most common cause of vascular dementia. Interest in using MRI parameters as surrogate markers of disease to assess therapies is increasing. In patients with symptomatic sporadic small vessel disease, we determined which MRI parameters best correlated with cognitive function on cross-sectional analysis and which changed over a period of 1 year. Methods-Thirty-five patients with lacunar stroke and leukoaraiosis were recruited. They underwent multimodal MRI (brain volume, fluid-attenuated inversion recovery lesion load, lacunar infarct number, fractional anisotropy, and mean diffusivity from diffusion tensor imaging) and neuropsychological testing. Twenty-seven agreed to reattend for repeat MRI and neuropsychology at 1 year. Results-An executive function score correlated most strongly with diffusion tensor imaging (fractional anisotropy histogram, rϭϪ0.640, Pϭ0.004) and brain volume (rϭ0.501, Pϭ0.034). Associations with diffusion tensor imaging were stronger than with all other MRI parameters. On multiple regression of all imaging parameters, a model that contained brain volume and fractional anisotropy, together with age, gender, and premorbid IQ, explained 74% of the variance of the executive function score (Pϭ0.0001). Changes in mean diffusivity and fractional anisotropy were detectable over the 1-year follow-up; in contrast, no change in other MRI parameters was detectable over this time period. Conclusion-A multimodal MRI model explains a large proportion of the variation in executive function in cerebral small vessel disease. In particular, diffusion tensor imaging correlates best with executive function and is the most sensitive to change. This supports the use of MRI, in particular diffusion tensor imaging, as a surrogate marker in treatment trials.

Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and small vessel disease show a similar pattern of cognitive deficits. This suggests that CADASIL provides a model of pure vascular dementia relevant for sporadic small vessel disease vascular dementia.

These results suggest there is cognitive impairment in hypertension. Treated hypertension was associated with deficits in memory while untreated hypertension revealed a more 'subcortical' pattern of cognitive impairment.

In patients with cerebral small vessel disease (SVD) diffusion tensor imaging (DTI) is sensitive to white matter damage and correlates better with cognitive function than conventional imaging. It has been proposed as a surrogate marker for treatment trials. However, the pathological changes underlying DTI are not known. The purpose of this study was to use magnetic resonance spectroscopy (MRS) to determine the pathological changes underlying DTI abnormalities in a range of patients from asymptomatic white matter hyperintensities to symptomatic cerebral SVD. 29 SVD patients, 63 hypertensive subjects, and 42 normotensive controls were recruited. The relationship between the DTI and MRS parameters in the centrum semiovale white matter was determined. There was a significant reduction in N-acetylaspartate (NAA; 2.067 ؎ 0.042 vs 2.299 ؎ 0.029 and 2.315 ؎ 0.036, P ‫؍‬ 9 ؋ 10 ؊6 ) and increase in mean diffusivity (mm 2 /s ؋ 10 ؊3 ; 0.942 ؎ 0.123 vs 0.822 ؎ 0.064 and 0.792 ؎ 0.057, P ‫؍‬ 1 ؋ 10 ؊8 ) in symptomatic SVD patients compared with the other two groups. DTI parameters correlated with NAA in all three groups, in a graded manner depending on severity of disease (r ؊SVD ؊0.827, hypertensive subjects ؊0.457, controls ؊0.317). NAA is a marker of axonal loss/dysfunction. These findings are consistent with axonal loss/dysfunction being the principal process causing the DTI changes found in cerebral SVD and ageing. Magn Reson Med 59:528 -534, 2008.