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"Normal" age-related cognitive decline has been associated with cardiovascular risk factors. Framingham Vascular Age is age-normed cardiovascular risk which may help communicate risk to patients and identify those at relatively higher risk. We aim to assess the association between Framingham Vascular Age and cognition. 346 "healthy" participants (57±10 years) without neuropsychiatric disorders or clinical manifestations of cardiovascular disease were studied. Cognition was evaluated using the Brief Memory and Executive Test and Framingham Vascular Age was calculated. The association between Framingham Vascular Age and cognitive performance was determined through General Linear Models to control for covariates. Framingham Vascular age was associated with poorer Memory and Executive Function/Processing Speed indices (p= 0.019 and p

Background and Purpose— A variant in the histone deacetylase 9 ( HDAC9 ) gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate. Methods— Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long-term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression. Results— A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P =0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3–0.7; P =0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29–0.77; P =0.003). Conclusions— These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke.

Cerebral small vessel disease (SVD) is associated with deficits in working memory, with a relative sparing of long-term memory; function may be influenced by white matter microstructure. Working and long-term memory were examined in 106 patients with SVD and 35 healthy controls. Microstructure was measured in the uncinate fasciculi and cingula. Working memory was more impaired than long-term memory in SVD, but both abilities were reduced compared to controls. Regression analyses found that having SVD explained the variance in memory functions, with additional variance explained by the cingula (working memory) and uncinate (long-term memory). Performance can be explained in terms of integrity loss in specific white matter tract associated with mnemonic functions., Highlights • Working and long-term memory are both impaired in SVD compared to healthy adults. • SVD explained a significant proportion of the variance in both mnemonic functions. • Variance in working memory was explained by microstructure of the cingula. • Variance in long-term memory was explained by microstructure of the uncinate.

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— Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic form of cerebral small vessel disease leading to early-onset stroke and dementia, with younger patients frequently showing subclinical deficits in cognition. At present, there are no targeted cognitive screening measures for this population. However, the Brief Memory and Executive Test (BMET) and the Montreal Cognitive Assessment (MoCA) have shown utility in detecting cognitive impairment in sporadic small vessel disease. This study assesses the BMET and the MoCA as clinical tools for detecting mild cognitive deficits in CADASIL. Methods— Sixty-six prospectively recruited patients with CADASIL, and 66 matched controls completed the BMET, with a subset of these also completing the MoCA. Receiver operating characteristic curves were calculated to examine the sensitivity and specificity of clinical cutoffs for the detection of vascular cognitive impairment and reduced activities of daily living. Results— Patients with CADASIL showed more cognitive impairment overall and were poorer on both executive/processing and memory indices of the BMET relative to controls. The BMET showed good accuracy in predicting vascular cognitive impairment (85% sensitivity and 84% specificity) and impaired instrumental activities of daily living (92% sensitivity and 77% specificity). The MoCA also showed good predictive validity for vascular cognitive impairment (80% sensitivity and 78% specificity) and instrumental activities of daily living (75% sensitivity and 76% specificity). The most important background predictor of vascular cognitive impairment was a history of stroke. Conclusions— The results indicate that the BMET and the MoCA are clinically useful and sensitive screening measures for early cognitive impairment in patients with CADASIL.

Background: cerebral small vessel disease (SVD) is the most common cause of vascular cognitive impairment (VCI). Despite this, there is a paucity of rapid simple screening tools to identify cognitive impairment in SVD and differentiate it from other common dementia types. Objective: to validate a new screening test for cognitive impairment in SVD, the Brief Memory and Executive Test (BMET) battery, and examine its ability to detect SVD and differentiate it from Alzheimer's disease (AD). Subjects: 45 patients with SVD, 27 patients with AD and 80 normal controls. Methods: the BMET includes brief tests of executive functioning and processing speed, with comparative tests of memory and orientation. Group discrimination was calculated using discriminant function analysis. Results: the BMET took an average of 10 min to administer. It showed high sensitivity (91%) and specificity (85%) in differentiating SVD patients with cognitive impairment from AD patients. As a comparison the mini-mental state examination had lower sensitivity (63%) and specificity (62%). Conclusions: the BMET is a simple and quick to administer clinical tool for the detection of VCI in SVD and its differentiation from AD impairment. Further multicentre studies are required to evaluate and compare it with other existing screening tests.

OBJECTIVES: Cognitive impairment, predominantly affecting processing speed and executive function, is an important consequence of cerebral small vessel disease (SVD). To date, few longitudinal studies of cognition in SVD have been conducted. We determined the pattern and rate of cognitive decline in SVD and used the results to determine sample size calculations for clinical trials of interventions reducing cognitive decline.METHODS: 121 patients with MRI confirmed lacunar stroke and leukoaraiosis were enrolled into the prospective St George's Cognition And Neuroimaging in Stroke (SCANS) study. Patients attended one baseline and three annual cognitive assessments providing 36 month follow-up data. Neuropsychological assessment comprised a battery of tests assessing working memory, long-term (episodic) memory, processing speed and executive function. We calculated annualized change in cognition for the 98 patients who completed at least two time-points.RESULTS: Task performance was heterogeneous, but significant cognitive decline was found for the executive function index (pCONCLUSIONS: The pattern of cognitive decline seen in SVD over three years is consistent with the pattern of impairments at baseline. Rates of decline were slow and sample sizes would need to be large for clinical trials aimed at halting decline beyond initial diagnosis using cognitive scores as an outcome measure. This emphasizes the importance of more sensitive surrogate markers in this disease.

Background Cognitive impairment is common in patients with cerebral small vessel disease, but is not well detected using common cognitive screening tests which have been primarily devised for cortical dementias. We developed the Brief Memory and Executive Test (BMET); a rapid screening measure sensitive to the impaired executive function and processing speed characteristic of small vessel disease (SVD). To assess the BMET’s validity for general use, we evaluated it when administered by non-psychologists in a multicentre study and collected control data to derive normative scores. Methods Two-hundred participants with SVD, defined as a clinical lacunar stroke and a corresponding lacunar infarct on MRI, and 303 healthy controls aged between 40–90 years old were recruited. The BMET, as well as the Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE), were performed. Overall, 55 SVD participants underwent repeat testing at 3 months to assess the BMET test-retest reliability. Results Administering the BMET took a mean (SD) of 12.9 (4.7) in cases and 9.5 (2.6) minutes in controls. Receiver Operator Curve analysis showed the BMET was a good predictor of cognitive impairment in SVD (AUC = 0.94) and performed significantly better than both the MoCA (AUC = 0.77) and the MMSE (AUC = 0.70). Using a cut-off score of 13, the BMET had a sensitivity of 93% and specificity of 76% for detecting cognitive impairment in SVD. Conclusions The BMET is a brief and sensitive tool for the detection of cognitive impairment in patients with SVD. Electronic supplementary material The online version of this article (doi:10.1186/s12916-015-0290-y) contains supplementary material, which is available to authorized users.

Background Cerebral small vessel disease causes lacunar stroke, and more recently has been implicated as a cause of depression. Factors causing reduced quality of life in small vessel disease, including the relative contributions of disability and depressive symptoms, remain uncertain. Methods One hundred patients with small vessel disease and 55 controls completed the Stroke-Specific Quality of Life scale. The protocol was repeated in 40 patients with the young-onset genetic form of small vessel disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy, and 35 controls. Disability, activities of daily living, cognition and depression were measured. Results Quality of life was significantly lower in small vessel disease versus controls: mean (standard deviation), 196·8 (35·2) vs. 226·8 (15·3), P < ·0001. Depressive symptoms were the major predictor of quality of life, explaining 52·9% of variance. The only other independent predictor was disability, explaining an additional 18·4%. A similar pattern was found in the young-onset genetic group, with reduced quality of life 202·0 (29·7) vs. controls 228·6 (13·1) P < ·0001, and depressive symptoms accounting for 42·2% of variance. Disability explained an additional 17·6%. Relationships between depression and quality of life, and disability and quality of life were independent of one another. Conclusions Depressive symptoms, often unrecognized, are a major determinant of reduced quality of life in small vessel disease. They account for greater reduction than, and are independent of, disability. This relationship may reflect the proposed causal association between white matter disease and depression. Treatment of depressive symptoms might significantly improve quality of life in small vessel disease.