Genetics of common polygenic ischaemic stroke: current understanding and future challenges.

Stroke is the third commonest cause of death and the major cause of adult neurological disability worldwide. While much is known about conventional risk factors such as hypertension, diabetes and incidence of smoking, these environmental factors only account for a proportion of stroke risk. Up to 50% of stroke risk can be attributed to genetic risk factors, although to date no single risk allele has been convincingly identified as contributing to this risk. Advances in the field of genetics, most notably genome wide association studies (GWAS), have revealed genetic risks in other cardiovascular disease and these techniques are now being applied to ischaemic stroke. This paper covers previous genetic studies in stroke including candidate gene studies, discusses the genome wide association approach, and future techniques such as next generation sequencing and the post-GWAS era. The review also considers the overlap from other cardiovascular diseases and whether findings from these may also be informative in ischaemic stroke

The Brief Memory and Executive Test (BMET) for detecting vascular cognitive impairment in small vessel disease: a validation study.

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.The BMET study was funded by The Stroke Association (TSA2010/08). Recruitment to BMET was supported by the NIHR Stroke Clinical Research Network. Hugh Markus is supported by an NIHR Senior Investigator award and his work is supported by the Cambridge University Hospitals NIHR Comprehensive BRC. Matthew Hollocks is supported by a Stroke Association/British Heart Foundation Grant (TSA BHF 2010/01). Robin Morris receives consultancy fees for P1Vital Limited. The authors disclose no competing interests financial or otherwise

Prognosis of carotid dissecting aneurysms: Results from CADISS and a systematic review.

OBJECTIVE: To determine the natural history of dissecting aneurysm (DA) and whether DA is associated with an increased recurrent stroke risk and whether type of antithrombotic drugs (antiplatelets vs anticoagulants) modifies the persistence or development of DA. METHODS: We included 264 patients with extracranial cervical artery dissection (CAD) from the Cervical Artery Dissection in Stroke Study (CADISS), a multicenter prospective study that compared antiplatelet with anticoagulation therapy. Logistic regression was used to estimate age- and sex-adjusted odds ratios. We conducted a systematic review of published studies assessing the natural history of DA and stroke risk in patients with non-surgically-treated extracranial CAD with DA. RESULTS: In CADISS, DA was present in 24 of 264 patients at baseline. In 36 of 248 patients with follow-up neuroimaging at 3 months, 12 of the 24 baseline DAs persisted, and 24 new DA had developed. There was no association between treatment allocation (antiplatelets vs anticoagulants) and whether DA at baseline persisted at follow-up or whether new DA developed. During 12 months of follow-up, stroke occurred in 1 of 48 patients with DA and in 7 of 216 patients without DA (age- and sex-adjusted odds ratio 0.84; 95% confidence interval 0.10-7.31; p = 0.88). Published studies, mainly retrospective, showed a similarly low risk of stroke and no evidence of an increased stroke rate in patients with DA. CONCLUSIONS: The results of CADISS provide evidence suggesting that DAs may have benign prognosis and therefore medical treatment should be considered

Effect of Standard vs Intensive Blood Pressure Control on Cerebral Blood Flow in Small Vessel Disease The PRESERVE Randomized Clinical Trial

Importance: Blood pressure lowering is considered neuroprotective in patients with cerebral small vessel disease, however more “intensive” regimens may increase cerebral hypoperfusion. We examined the effect of intensive vs. standard blood pressure treatment on cerebral perfusion in severe small vessel disease patients. Objective: To determine whether intensive vs. standard blood pressure lowering over 3 months causes decreased cerebral perfusion. Design, Setting and Participants: This randomised, parallel, controlled, blinded-outcomes clinical trial took place in 2 English university medical centres. A central, online randomisation system (1:1 ratio) allocated grouping. 70 hypertensive patients with MRI confirmed symptomatic lacunar infarct and confluent white matter hyperintensities were recruited between 2012 and 2015, and randomised (36/34 in standard/intensive arms). Analysable data were available in 62 patients, 33/29 in the standard/intensive groups respectively, for intention to treat analysis. This experiment examines the 3 month follow-up period. Intervention: Patients were randomised to “standard” (systolic=130-140mmHg) or “intensive” (systolic=<125mmHg) blood pressure targets, to be achieved through medication regimen changes. Main Outcome and Measure: Cerebral perfusion was determined using arterial spin labelling; the primary end point was change in global perfusion between baseline and 3 months, compared between treatment groups by ANOVA. Linear regression compared change in perfusion against change in blood pressure. MR scan analysis was blinded to treatment arm. Results: Patients were 69.3 years old (mean) and 59.7% male. Mean(SD) systolic blood pressure reduced by 8(12) and 27(17)mmHg in the standard/intensive groups, respectively (p<0.001), with achieved pressures of 141(13) and 126(10) mmHg respectively. Change in global perfusion did not differ between treatment arms: standard, mean(SD) (ml/min/100g)= -0.5(9.4); intensive, 0.7(8.6), partial ETA2= 0.004, 95% CI= -3.6–5.8, p= 0.63. No differences were observed when analysis examined grey/white matter only, or was confined to those achieving target blood pressure. The number of adverse events did not differ between treatment groups (standard/intensive mean(SD)= .21(.65)/.32(.75), p=.44). Conclusions and Relevance: Intensive blood pressure lowering did not reduce cerebral perfusion in severe small vessel disease.This study was funded by a joint Stroke Association/British Heart Foundation program grant (TSA BHF 2010/01). The study received additional support from the Newcastle Biomedical Research Centre, which is funded by the National Institute for Health Research (NIHR). Drs O’Brien, Ford, and Markus are supported by NIHR Senior Investigator awards. Drs O’Brien and Markus are also supported by the Cambridge University Hospitals NIHR Comprehensive Biomedical Research Centre

Stroke genetics: prospects for personalized medicine.

Epidemiologic evidence supports a genetic predisposition to stroke. Recent advances, primarily using the genome-wide association study approach, are transforming what we know about the genetics of multifactorial stroke, and are identifying novel stroke genes. The current findings are consistent with different stroke subtypes having different genetic architecture. These discoveries may identify novel pathways involved in stroke pathogenesis, and suggest new treatment approaches. However, the already identified genetic variants explain only a small proportion of overall stroke risk, and therefore are not currently useful in predicting risk for the individual patient. Such risk prediction may become a reality as identification of a greater number of stroke risk variants that explain the majority of genetic risk proceeds, and perhaps when information on rare variants, identified by whole-genome sequencing, is also incorporated into risk algorithms. Pharmacogenomics may offer the potential for earlier implementation of 'personalized genetic' medicine. Genetic variants affecting clopidogrel and warfarin metabolism may identify non-responders and reduce side-effects, but these approaches have not yet been widely adopted in clinical practice

Novel intelligent wavelet filtering of embolic signals from TCD ultrasound

Transcranial Doppler ultrasound can be used to detect emboli in blood flow for predicting stroke. Embolic signals have characteristic transient chirps suitable for wavelet analysis. We have implemented and evaluated the first on-line intelligent wavelet filter to amplify embolic signals building on our previous work in detection. Our intelligent wavelet amplifier uses the matching filter properties of the Daubechies 8th order wavelet to amplify embolic signals. Even the smallest embolic signal is enhanced without affecting the background blood flow signal. We show an increase of over 2db (on average) in embolic signal strength and an improvement in detection of 10-20%

Mechanisms and treatment of ischaemic stroke: insights from genetic associations

The precise pathophysiology of ischaemic stroke is unclear, and a greater understanding of the different mechanisms that underlie large-artery, cardioembolic and lacunar ischaemic stroke subtypes would enable the development of more-effective, subtype-specific therapies. Genome-wide association studies (GWASs) are identifying novel genetic variants that associate with the risk of stroke. These associations provide insight into the pathophysiological mechanisms, and present opportunities for novel therapeutic approaches. In this Review, we summarize the genetic variants that have been linked to ischaemic stroke in GWASs to date and discuss the implications of these associations for both our understanding and treatment of ischaemic stroke. The majority of genetic variants identified are associated with specific subtypes of ischaemic stroke, implying that these subtypes have distinct genetic architectures and pathophysiological mechanisms. The findings from the GWASs highlight the need to consider whether therapies should be subtype-specific. Further GWASs that include large cohorts are likely to provide further insights, and emerging technologies will complement and build on the GWAS findings

Mendelian randomization study of the association between telomere length and risk of cancer and non-neoplastic diseases

$\textbf{Importance}$ The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain, due to the susceptibility of observational studies to confounding and reverse causation. $\textbf{Objective}$ To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. $\textbf{Data Sources}$ Genome-wide association studies (GWAS) published up to January 15 2015. $\textbf{Study Selection}$ GWAS of non-communicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of pre-existing diseases. Of 163 GWAS of non-communicable diseases identified, summary data from 103 were available. $\textbf{Data Extraction}$ Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. $\textbf{Main Outcomes}$ Odds ratios (ORs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. $\textbf{Results}$ Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420,081 cases (median 2,526 per disease) and 1,093,105 controls (median 6,789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations were observed for (ORs per 1-SD change in genetically increased telomere length): glioma 5.27 (3.15-8.81), serous low-malignant-potential ovarian cancer 4.35 (2.39-7.94), lung adenocarcinoma 3.19 (2.40-4.22), neuroblastoma 2.98 (1.92-4.62) , bladder cancer 2.19 (1.32-3.66), melanoma 1.87 (1.55-2.26), testicular cancer 1.76 (1.02- 3.04), kidney cancer 1.55 (1.08-2.23) and endometrial cancer 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division (P<0.05). There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic and other non-neoplastic diseases, except for coronary heart disease (0.78 [0.67-0.90]), abdominal aortic aneurysm (0.63 [0.49-0.81]), celiac disease (0.42 [0.28-0.61]) and interstitial lung disease (0.09 [0.05- 0.15]). $\textbf{Conclusions}$ It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.This work was supported by CRUK grant number C18281/A19169 (the Integrative Cancer Epidemiology Programme). Dr Haycock is supported by CRUK Population Research Postdoctoral Fellowship C52724/A20138. The MRC Integrative Epidemiology Unit is supported by grants MC_UU_12013/1 and MC_UU_12013/2. Dr Martin is supported by the National Institute for Health Research (NIHR), the Bristol Nutritional Biomedical Research Unit and the University of Bristol

Cardiovascular care of patients with stroke and high risk of stroke: The need for interdisciplinary action: A consensus report from the European Society of Cardiology Cardiovascular Round Table.

Comprehensive stroke care is an interdisciplinary challenge. Close collaboration of cardiologists and stroke physicians is critical to ensure optimum utilisation of short- and long-term care and preventive measures in patients with stroke. Risk factor management is an important strategy that requires cardiologic involvement for primary and secondary stroke prevention. Treatment of stroke generally is led by stroke physicians, yet cardiologists need to be integrated care providers in stroke units to address all cardiovascular aspects of acute stroke care, including arrhythmia management, blood pressure control, elevated levels of cardiac troponins, valvular disease/endocarditis, and the general management of cardiovascular comorbidities. Despite substantial progress in stroke research and clinical care has been achieved, relevant gaps in clinical evidence remain and cause uncertainties in best practice for treatment and prevention of stroke. The Cardiovascular Round Table of the European Society of Cardiology together with the European Society of Cardiology Council on Stroke in cooperation with the European Stroke Organisation and partners from related scientific societies, regulatory authorities and industry conveyed a two-day workshop to discuss current and emerging concepts and apparent gaps in stroke care, including risk factor management, acute diagnostics, treatments and complications, and operational/logistic issues for health care systems and integrated networks. Joint initiatives of cardiologists and stroke physicians are needed in research and clinical care to target unresolved interdisciplinary problems and to promote the best possible outcomes for patients with stroke