Cerebral small vessel disease (SVD) is a common cause of vascular cognitive impairment. A number of disease features can be assessed on MRI including lacunar infarcts, T2 lesion volume, brain atrophy, and cerebral microbleeds. In addition, diffusion tensor imaging (DTI) is sensitive to disruption of white matter ultrastructure, and recently it has been suggested that additional information on the pattern of damage may be obtained from axial diffusivity, a proposed marker of axonal damage, and radial diffusivity, an indicator of demyelination. We determined the contribution of these whole brain MRI markers to cognitive impairment in SVD. Consecutive patients with lacunar stroke and confluent leukoaraiosis were recruited into the ongoing SCANS study of cognitive impairment in SVD (n = 115), and underwent neuropsychological assessment and multimodal MRI. SVD subjects displayed poor performance on tests of executive function and processing speed. In the SVD group brain volume was lower, white matter hyperintensity volume higher and all diffusion characteristics differed significantly from control subjects (n = 50). On multi-predictor analysis independent predictors of executive function in SVD were lacunar infarct count and diffusivity of normal appearing white matter on DTI. Independent predictors of processing speed were lacunar infarct count and brain atrophy. Radial diffusivity was a stronger DTI predictor than axial diffusivity, suggesting ischaemic demyelination, seen neuropathologically in SVD, may be an important predictor of cognitive impairment in SVD. Our study provides information on the mechanism of cognitive impairment in SVD.

Background and Purpose-Carotid intima-media thickness (IMT) progression rates are increasingly used as an intermediate outcome for vascular risk. The carotid bifurcation (BIF) and internal carotid artery (ICA) are predilection sites for atherosclerosis. IMT measures from these sites may be a better estimate of atherosclerosis than common carotid artery (CCA) IMT. The study aim was to evaluate site-specific IMT progression rates and their relationships to vascular risk factors compared with baseline IMT measurements. Methods-In a community population (nϭ3383), ICA-IMT, BIF-IMT, CCA-IMT, and vascular risk factors were evaluated at baseline and at 3-year follow-up. Only ICA-IMT progression significantly correlated with baseline vascular risk factors (age, male gender, hypertension, diabetes, and smoking). Change in risk factor profile over follow-up, estimated using the Framingham risk score, was a predictor of IMT progression only. For all arterial sites, correlations were stronger, by a factor of 2 to 3, for associations with baseline IMT compared with IMT progression. Conclusions-Progression rates at the ICA rather than the CCA yield greater absolute changes in IMT and better correlations with vascular risk factors. Vascular risk factors correlate more strongly with baseline IMT than with IMT progression. Prospective data on IMT progression and incident vascular events are required to establish the true value of progression data as a surrogate measure of vascular risk. Results-Mean

Detecting treatment efficacy using cognitive change in trials of cerebral small vessel disease (SVD) has been challenging, making the use of surrogate markers such as magnetic resonance imaging (MRI) attractive. We determined the sensitivity of MRI to change in SVD and used this information to calculate sample size estimates for a clinical trial. Data from the prospective SCANS (St George’s Cognition and Neuroimaging in Stroke) study of patients with symptomatic lacunar stroke and confluent leukoaraiosis was used (n = 121). Ninety-nine subjects returned at one or more time points. Multimodal MRI and neuropsychologic testing was performed annually over 3 years. We evaluated the change in brain volume, T2 white matter hyperintensity (WMH) volume, lacunes, and white matter damage on diffusion tensor imaging (DTI). Over 3 years, change was detectable in all MRI markers but not in cognitive measures. WMH volume and DTI parameters were most sensitive to change and therefore had the smallest sample size estimates. MRI markers, particularly WMH volume and DTI parameters, are more sensitive to SVD progression over short time periods than cognition. These markers could significantly reduce the size of trials to screen treatments for efficacy in SVD, although further validation from longitudinal and intervention studies is required.

Objective:To determine whether MRI markers, including diffusion tensor imaging (DTI), can predict cognitive decline and dementia in patients with cerebral small vessel disease (SVD).Methods:In the prospective St George's Cognition and Neuroimaging in Stroke study, multimodal MRI was performed annually for 3 years and cognitive assessments annually for 5 years in a cohort of 99 patients with SVD, defined as symptomatic lacunar stroke and confluent white matter hyperintensities (WMH). Progression to dementia was determined in all patients. Progression of WMH, brain volume, lacunes, cerebral microbleeds, and a DTI measure (the normalized peak height of the mean diffusivity histogram distribution) as a marker of white matter microstructural damage were determined.Results:Over 5 years of follow-up, 18 patients (18.2%) progressed to dementia. A significant change in all MRI markers, representing deterioration, was observed. The presence of new lacunes, and rate of increase in white matter microstructural damage on DTI, correlated with both decline in executive function and global functioning. Growth of WMH and deterioration of white matter microstructure on DTI predicted progression to dementia. A model including change in MRI variables together with their baseline values correctly classified progression to dementia with a C statistic of 0.85.Conclusions:This longitudinal prospective study provides evidence that change in MRI measures including DTI, over time durations during which cognitive change is not detectable, predicts cognitive decline and progression to dementia. It supports the use of MRI measures, including DTI, as useful surrogate biomarkers to monitor disease and assess therapeutic interventions.

Background and Purpose-Asymptomatic cerebral emboli can be detected using transcranial Doppler ultrasound (TCD).These embolic signals have potential as a marker of stroke risk and as a surrogate marker to evaluate antiplatelet agents. Small studies have demonstrated that they predict the combined endpoint of stroke and transient ischemic attack (TIA), but no studies have shown that they predict the more important endpoint of stroke alone. Methods-TCD was used to record for 1 hour from the ipsilateral middle cerebral artery in 200 patients with Ͼ50% symptomatic carotid stenosis. The Doppler audio signal was recorded for later analysis blinded to clinical details. Subjects were followed-up prospectively until surgical intervention, stroke, or study end at 90 days. Results-Embolic signals (ES) were detected in 89 (44.5%). During follow-up, 31 subjects experienced recurrent ipsilateral ischemic events: 7 strokes and 24 TIAs. The presence of ES predicted stroke alone (Pϭ0.001) and the combined endpoint of stroke and TIA (Pϭ0.00001). This remained significant, with an odds ratio of 4.67 (95% CI, 1.99 to 11.01; PϽ0.0001) after Cox regression to control for age, sex, smoking, hypertension, time from last symptoms, and degree of stenosis. The absence of ES identified a group at low risk for stroke alone and stroke and TIA during follow-up: 0% and 7.5%, respectively, versus 3.5% and 15.5% in all 200 subjects. Conclusions-Asymptomatic

Observations performed with a Rayleigh lidar and an Advanced Mesosphere Temperature Mapper aboard the National Science Foundation/National Center for Atmospheric Research Gulfstream V research aircraft on 13 July 2014 during the Deep Propagating Gravity Wave Experiment (DEEPWAVE) measurement program revealed a large-amplitude, multiscale gravity wave (GW) environment extending from~20 to 90 km on flight tracks over Mount Cook, New Zealand. Data from four successive flight tracks are employed here to assess the characteristics and variability of the larger-and smaller-scale GWs, including their spatial scales, amplitudes, phase speeds, and momentum fluxes. On each flight, a large-scale mountain wave (MW) having a horizontal wavelength~200-300 km was observed. Smaller-scale GWs over the island appeared to correlate within the warmer phase of this large-scale MW. This analysis reveals that momentum fluxes accompanying small-scale MWs and propagating GWs significantly exceed those of the large-scale MW and the mean values typical for these altitudes, with maxima for the various small-scale events in the range~20-105 m 2 s À2.

ObjectivesLacunes are an important disease feature of cerebral small vessel disease (SVD) but their relationship to cognitive impairment is not fully understood. To investigate this we determined (1) the relationship between lacune count and total lacune volume with cognition, (2) the spatial distribution of lacunes and the cognitive impact of lacune location, and (3) the whole brain anatomical covariance associated with these strategically located regions of lacune damage.MethodsOne hundred and twenty one patients with symptomatic lacunar stroke and radiological leukoaraiosis were recruited and multimodal MRI and neuropsychological data acquired. Lacunes were mapped semi-automatically and their volume calculated. Lacune location was automatically determined by projection onto atlases, including an atlas which segments the thalamus based on its connectivity to the cortex. Lacune locations were correlated with neuropsychological results. Voxel based morphometry was used to create anatomical covariance maps for these ‘strategic’ regions.ResultsLacune number and lacune volume were positively associated with worse executive function (number p < 0.001; volume p < 0.001) and processing speed (number p < 0.001; volume p < 0.001). Thalamic lacunes, particularly those in regions with connectivity to the prefrontal cortex, were associated with impaired processing speed (Bonferroni corrected p = 0.016). Regions of associated anatomical covariance included the medial prefrontal, orbitofrontal, anterior insular cortex and the striatum.ConclusionLacunes are important predictors of cognitive impairment in SVD. We highlight the importance of spatial distribution, particularly of anteromedial thalamic lacunes which are associated with impaired information processing speed and may mediate cognitive impairment via disruption of connectivity to the prefrontal cortex.

C erebral ischemic small vessel disease (SVD) is associated with stroke and cognitive impairment. Magnetic resonance imaging (MRI) characteristics of SVD include lacunar infarcts, T2 hyperintensities (leukoaraiosis), and cerebral microbleeds (CMBs).1,2 CMBs are signal voids on T2*-weighted gradient echo MRI, resulting from paramagnetic properties of focal deposits of hemosiderin-containing macrophages, 3 ranging in diameter between 0.82 and 1.5 mm. 4 CMB incidence is up to 80% in patients with subcortical vascular dementia.5 They are also common in the monogenic form of SVD, cerebral autosomal-dominant angiopathy with subcortical infarcts and leukoencephalopathy. 6 SVD is associated with a characteristic cognitive impairment, with prominent impaired executive function and information processing speed, but relatively preserved episodic memory. 7 The correlation of cognition with T2-lesion load is weak, 8 but stronger correlations have been detected with diffusion tensor imaging (DTI). 9 The association between DTI and cognition has been regarded as support for SVD causing cognitive impairment via white matter tract disruption causing a disconnection syndrome. Associations have also been reported between cognition and both brain atrophy 9 and lacunar infarct count. 10 Recent studies suggest CMBs play a role in cognitive impairment, although results have been inconsistent. CMB frequency increases with age, reported in 17.8% of those aged 60 to 69 years and 38.3% of those aged 80 to 99 years.2 Healthy adults with CMBs showed a reduction in the attention and calculation section of the Mini-Mental State Examination (MMSE) 11,12 and information processing and motor speed. 13 In elderly normal subjects, CMBs were associated with cognitive impairment and dementia. 13 This relationship was weakened, but still significant, Background and Purpose-Cerebral microbleeds (CMBs) are common in cerebral small vessel disease. They may cause cognitive impairment, possibly via white matter tract disruption but previous studies have produced inconsistent results. We determined whether CMB number and location are associated with impaired cognition in symptomatic small vessel disease and whether any association was independent of other magnetic resonance imaging markers of small vessel disease. Methods-One hundred sixteen patients with lacunar stroke and radiological leukoaraiosis were studied. Neuropsychological assessment was performed. CMBs on gradient echo images were assessed using the Brain Observer Microbleed Rating Scale criteria. Magnetic resonance imaging measures, including diffusion tensor imaging, were also analyzed. Associations between cognitive function and the presence, number, and location of CMBs were determined. Results-CMBs were present in 46 (39.7%) patients. CMB number correlated weakly with executive function (r=0.22; P=0.022) but not with other cognitive indices. CMBs count in the top decile (≥9 CMB, N=12) was more strongly associated with poor executive function; this association remained significant ...