Andrew D. Mackinnon

Asymptomatic Embolization Detected by Doppler Ultrasound Predicts Stroke Risk in Symptomatic Carotid Artery Stenosis

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 >50% 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 (P=0.001) and the combined endpoint of stroke and TIA (P=0.00001). This remained significant, with an odds ratio of 4.67 (95% CI, 1.99 to 11.01; P<0.0001) 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 embolization in carotid stenosis predicts short-term ipsilateral stroke risk. This supports use of the technique to identify patients at high-risk for recurrent stroke for therapeutic interventions and as a surrogate marker to evaluate antithrombotic medication.

Rates and Determinants of Site-Specific Progression of Carotid Artery Intima-Media Thickness: The Carotid Atherosclerosis Progression Study

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 (n=3383), ICA-IMT, BIF-IMT, CCA-IMT, and vascular risk factors were evaluated at baseline and at 3-year follow-up. Results— Mean (SD) IMT progression was significantly greater at the ICA (0.032 [0.109] mm/year) compared with the BIF (0.023 [0.108] mm/year) and the CCA (0.001 [0.040] mm/year) (P <0.001). 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.

Internet-based CBT for depression with and without telephone tracking in a national helpline: randomised controlled trial.

Background Telephone helplines are frequently and repeatedly used by individuals with chronic mental health problems and web interventions may be an effective tool for reducing depression in this population. Aim To evaluate the effectiveness of a 6 week, web-based cognitive behaviour therapy (CBT) intervention with and without proactive weekly telephone tracking in the reduction of depression in callers to a helpline service. Method 155 callers to a national helpline service with moderate to high psychological distress were recruited and randomised to receive either Internet CBT plus weekly telephone follow-up; Internet CBT only; weekly telephone follow-up only; or treatment as usual. Results Depression was lower in participants in the web intervention conditions both with and without telephone tracking compared to the treatment as usual condition both at post intervention and at 6 month follow-up. Telephone tracking provided by a lay telephone counsellor did not confer any additional advantage in terms of symptom reduction or adherence. Conclusions A web-based CBT program is effective both with and without telephone tracking for reducing depression in callers to a national helpline. Trial Registration Controlled-Trials.com ISRCTN93903959

Cerebral Microbleeds and Cognition in Patients With Symptomatic Small Vessel Disease

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 after controlling for T2-lesion load, brain volume, lacune count, and mean diffusivity (b=−0.51; P=0.043). Conclusions— In symptomatic small vessel disease, CMB number was weakly associated with executive dysfunction. There seemed to be a threshold effect with the association being largely accounted for by an association of impaired executive function with high CMB count. No association of CMBs with other cognitive domains, including processing speed, was found.

Long-Term Ambulatory Monitoring for Cerebral Emboli Using Transcranial Doppler Ultrasound

Background and Purpose— Transcranial Doppler (TCD) monitoring for asymptomatic cerebral emboli is currently limited to short recordings by equipment size, restricting its clinical usefulness. We have developed a first ambulatory TCD system, evaluated it in at-risk patient groups, and used it to study the pattern of embolization in patients with symptomatic carotid stenosis. Methods— The system comprises an 18×11.5×3.2 cm battery-powered Doppler unit (425 g) and a 13-mm servo-controlled 2 MHz transducer probe. The quadrature raw Doppler signal is stored on flash-disk. An autosearch algorithm restores vessel insonation should signal quality fall. Initial evaluation was in 20 ambulatory stroke patients. Subsequently, 12 recently symptomatic carotid patients had recordings for ≥5 hours. Results— Recordings were well tolerated and a median of 96% of Doppler signal was suitable for analysis. Embolic signals were detected in 11 of the 12 symptomatic carotid patients. There was marked temporal variability in embolization and prolonging the recording increased the yield of embolic signal positive patients from 58% at 30 minutes to 92% at 150 minutes. In 3 subjects with frequent embolic signals, significant temporal clustering of embolic signals was observed. Conclusions— We have developed the first ambulatory TCD system. Good-quality recordings of ≥5 hours can be obtained. In view of the demonstrated temporal variability in embolization, this technique is likely to improve the predictive value of recording for asymptomatic embolic signals and may be particularly useful in patients in whom embolic signals are relatively infrequent, such as those with asymptomatic carotid stenosis and atrial fibrillation.

Mechanisms of Cognitive Impairment in Cerebral Small Vessel Disease: Multimodal MRI Results from the St George's Cognition and Neuroimaging in Stroke (SCANS) Study

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.

Ambulatory Transcranial Doppler Cerebral Embolic Signal Detection in Symptomatic and Asymptomatic Carotid Stenosis

Background and Purpose— Transcranial Doppler (TCD) ultrasound can detect asymptomatic emboli in carotid stenosis. Current systems are nonportable and can only record for short durations. A novel ambulatory TCD system allows prolonged recording. We applied this to patients with symptomatic and asymptomatic carotid stenosis to determine patterns of embolization in the 2 conditions and optimal recording protocols. Methods— Ambulatory TCD recordings were performed in 12 symptomatic and 15 asymptomatic carotid stenosis (≥50%) patients for 8 hours and then repeated on a second occasion. Results— Nine (75%) of symptomatic subjects had embolic signals during the first recording. In this group, repeating the recording did not increase the proportion of positive patients. In asymptomatic patients, 4 (26.7%) had embolic signals on 1 recording, and this proportion increased to 46.7% after 2 recordings. There was significant clustering of embolic signals demonstrating that the process was nonrandom. Conclusions— Ambulatory TCD is possible in patients with carotid artery stenosis. By increasing the duration of recording, additional information is provided, particularly in asymptomatic patients. Our results also demonstrate clustering of embolic signals. Our study provides baseline data to allow studies in both asymptomatic and symptomatic carotid stenosis to be planned.

Progression of MRI markers in cerebral small vessel disease: Sample size considerations for clinical trials

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.

Strategic lacunes and their relationship to cognitive impairment in cerebral small vessel disease.

Objectives Lacunes 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. Methods One 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. Results Lacune 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. Conclusion Lacunes 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.

Carotid Intima-Media Thickness is Greater but Carotid Plaque Prevalence is Lower in Black Compared with White Subjects

BACKGROUND AND PURPOSE: Carotid IMT is widely used as a surrogate marker for atherosclerosis. Prospective studies in largely white populations demonstrate that it is strongly associated with carotid plaque and is an independent predictor of stroke. There are few data from black populations. In a previous study, we showed that carotid IMT is increased in black individuals in the UK. The purpose of this study was to confirm this with a larger sample size and to establish whether raised IMT in black stroke-free individuals is associated with increased carotid plaque. MATERIALS AND METHODS: High-resolution sonography was used to measure the CCA-, BIF-, and ICA-IMT and plaque in 306 black and 281 white healthy individuals recruited by random community sampling from London, U.K. Mean CCA-IMT was determined by using a semiautomated computer program that detects the blood/intima borderline and the media/adventitia borderline with the use of a gray-value algorithm. RESULTS: CCA-IMT was higher in black compared with white individuals after controlling for cardiovascular risk factors and socioeconomic status (β = 0.050; 95%CI, 0.024–0.076; P < .001). BIF- and ICA-IMT were also increased in black subjects. In contrast, carotid plaque was more common in white individuals (OR, 2.90; 95%CI, 1.41–5.96; P = .004). CONCLUSIONS: The lack of correlation between increased IMT and carotid plaque in black individuals implies that IMT should not currently be used as a surrogate marker of atherosclerosis in black populations. It suggests that the increased IMT seen in black individuals may not represent early atherosclerosis.