Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology.

BACKGROUND AND PURPOSE: Guidelines on monogenic cerebral small-vessel disease (cSVD) diagnosis and management are lacking. Endorsed by the Stroke and Neurogenetics Panels of the European Academy of Neurology, a group of experts has provided recommendations on selected monogenic cSVDs, i.e. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), autosomal dominant High Temperature Requirement A Serine Peptidase 1 (HTRA1), cathepsin-A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), Fabry disease, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and type IV collagen (COL4)A1/2. METHODS: We followed the Delphi methodology to provide recommendations on several unanswered questions related to monogenic cSVD, including genetic testing, clinical and neuroradiological diagnosis, and management. RESULTS: We have proposed 'red-flag' features suggestive of a monogenic disease. General principles applying to the management of all cSVDs and specific recommendations for the individual forms of monogenic cSVD were agreed by consensus. CONCLUSIONS: The results provide a framework for clinicians involved in the diagnosis and management of monogenic cSVD. Further multicentre observational and treatment studies are still needed to increase the level of evidence supporting our recommendations.

The association between systolic blood pressure variability with depression, cognitive decline and white matter hyperintensities: the 3C Dijon MRI study.

BACKGROUND: Accumulating evidence links blood pressure variability (BPV) with white matter hyperintensities (WMH) and stroke. The longitudinal association between BPV with late onset depression (LOD) and cognitive decline remains unexplored. METHODS: Prospective cohort study of 2812 participant's age ⩾65 years (median age 72 years, 63.6% female) without dementia or stroke. Serial clinic visits assessed blood pressure, cognitive function, depression disorder, and depressive symptoms. A brain magnetic resonance imaging (MRI) substudy was performed in 1275 persons to examine possible associations with WMH. RESULTS: The interaction between symptomatic LOD and systolic BPV was associated with cognitive decline on the Isaac Set Test [slope -4.45; 95% confidence interval (CI) -8.92 to -0.16, p = 0.04], Benton Visual Retention Test (slope -0.89; 95% CI -1.77 to -0.01, p = 0.049), Mini Mental State Examination (slope -1.08; 95% CI -1.86 to -0.30, p = 0.007) and Finger Tapping Test (slope -7.53; 95% CI -13.71 to -1.34, p = 0.017) but not Trail Making Test-A or -B/A. The MRI substudy demonstrated that systolic BPV was associated with cognitive decline via interactions with depression and total WMH volume, but this was not dependent on either deep or periventricular WMH volumes. CONCLUSIONS: The findings show that the interaction between systolic BPV with symptomatic depression and WMH increases cognitive decline in persons ⩾65 years of age. Future work could extend these findings by examining systolic BPV in relation to cognitive decline and WMH in older populations with depression.

GWAS for executive function and processing speed suggests involvement of the CADM2 gene.

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Are migraine and non-migrainous headache risk factors for stroke in the elderly? Findings from a 12-year cohort follow-up.

BACKGROUND AND PURPOSE: There is evidence that migraine is a risk factor for stroke but little is known about this association in elderly people. Furthermore, non-migrainous headache (NMH) has received little attention despite being the most frequently reported type of headache. Late-life migraine and NMH were examined as candidate risk factors for stroke in a community-dwelling elderly sample over a 12-year follow-up. METHODS: One thousand nine hundred and nineteen non-institutionalized subjects aged 65+, without dementia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, DSM-IV criteria) and with no stroke history at baseline, were drawn from the Three-City Montpellier cohort (recruitment 1999-2001) for longitudinal analysis. Ischaemic and haemorrhagic stroke was reported at baseline and at each of the five follow-ups, with cases validated by a panel of experts, according to ICD-10 criteria (International Classification of Diseases, 10th revision). Migraine and NMH were determined at baseline during a neurological interview and examination using 1988 International Headache Society criteria. RESULTS: A total of 110 (5.4%) cases of migraine and 179 (8.9%) cases of NMH were identified at baseline. During the median 8.8-year follow-up, incident stroke was observed in 1.9% of baseline migrainers, 6.2% of NMH and 3.6% of those with no lifetime history of headache. Cox proportional hazard models indicated that migraine was not a risk factor for stroke; however, NMH sufferers were twice as likely to have a stroke (hazard ratio 2.00, 95% confidence interval 1.00-3.93, P = 0.049). CONCLUSIONS: This study is one of the first to suggest that late-life NMH rather than migraine could be an independent risk factor for stroke and a warning sign. The incidence of stroke in elderly migrainers, seldom reported, is particularly low.

Prognostic significance of pulsatile tinnitus in cervical artery dissection.

BACKGROUND AND PURPOSE: Our aim was to investigate whether pulsatile tinnitus (PT) in cervical artery dissection (CeAD) has prognostic significance. METHODS: All CeAD patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study with documentation of PT were analysed. The presence of PT was systematically assessed using a standardized questionnaire. Stroke severity at admission was defined according to the National Institutes of Health Stroke Scale (NIHSS). Excellent outcome after 3 months was defined as a modified Rankin Scale of 0-1. RESULTS: Sixty-three of 778 patients (8.1%) reported PT. PT+ patients presented less often with ischaemic stroke (41.3% vs. 63.9%, P < 0.001), more often with dissection in the internal carotid artery (85.7% vs. 64.2%, P = 0.001), less often with vessel occlusion (19.0% vs. 34.1%, P = 0.017) and more often with excellent outcome at 3 months (92.1% vs. 75.4%, P = 0.002). Logistic regression analysis identified PT as an independent predictor of excellent outcome after 3 months [odds ratio (OR) 3.96, 95% confidence interval (CI) 1.22-12.87] adjusted to significant outcome predictors NIHSS on admission (OR 0.82, 95% CI 0.79-0.86), Horner syndrome (OR 1.95, 95% CI 1.16-3.29) and vessel occlusion (OR 0.62, 95% CI 0.40-0.94) and to non-significant predictors age, sex, pain and location of CeAD. CONCLUSION: The presence of PT in CeAD is associated with a benign clinical course and predicts a favourable outcome.

Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility.

Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.

Anemia in young patients with ischaemic stroke.

BACKGROUND AND PURPOSE: To investigate the association of anemia on admission with ischaemic stroke (IS), stroke severity and early functional outcome in patients with cervical artery dissection (CeAD) or with IS of other causes (non-CeAD-IS patients). METHODS: The study sample comprised all patients from the Cervical Artery Dissection and Ischaemic Stroke Patients (CADISP) study without pre-existing disability and with documentation of stroke severity and hemoglobin (Hb) concentration on admission. Anemia was classified as mild (Hb < 12 g/dl in women and Hb < 13 g/dl in men) or moderate to severe (Hb < 10 g/dl in women and Hb < 11 g/dl in men). Stroke severity on admission was assessed with the National Institutes of Health Stroke Scale (NIHSS). Outcome after 3 months was assessed with the modified Rankin Scale (mRS-3mo). Unfavorable outcome was defined as mRS-3mo ≥ 3. RESULTS: Amongst 1206 study patients (691 CeAD and 515 non-CeAD), 87 (7.2%) had anemia, which was moderate to severe in 18 (1.5%) patients. Anemia was associated with female sex in both study samples, but no further associations with risk factors or comorbidities were observed. In CeAD patients, anemia was associated with occurrence of stroke (P = 0.042). In both study samples, anemic patients had more severe strokes (CeAD, P = 0.023; non-CeAD, P = 0.005). Functional outcome was not associated with anemia in general, but moderate to severe anemia was significantly associated with unfavorable outcome (P = 0.004). CONCLUSION: Anemia on admission was associated with stroke in CeAD patients and with more severe strokes in both study samples. Moderate to severe anemia may predict unfavorable outcome.

Stroke in first-degree relatives of patients with cervical artery dissection.

BACKGROUND AND PURPOSE: Patients with ischaemic stroke (IS) caused by a spontaneous cervical artery dissection (CeAD) worry about an increased risk for stroke in their families. The occurrence of stroke in relatives of patients with CeAD and in those with ischaemic stroke attributable to other (non-CeAD) causes were compared. METHODS: The frequency of stroke in first-degree relatives (family history of stroke, FHS) was studied in IS patients (CeAD patients and age- and sex-matched non-CeAD patients) from the Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) database. FHS ≤ 50 and FHS > 50 were defined as having relatives who suffered stroke at the age of ≤50 or >50 years. FHS ≤ 50 and FHS > 50 were studied in CeAD and non-CeAD IS patients and related to age, sex, number of siblings, hypertension, hypercholesterolemia, smoking and body mass index (BMI). RESULTS: In all, 1225 patients were analyzed. FHS ≤ 50 was less frequent in CeAD patients (15/598 = 2.5%) than in non-CeAD IS patients (38/627 = 6.1%) (P = 0.003; odds ratio 0.40, 95% confidence interval 0.22-0.73), also after adjustment for age, sex and number of siblings (P = 0.005; odds ratio 0.42, 95% confidence interval 0.23-0.77). The frequency of FHS > 50 was similar in both study groups. Vascular risk factors did not differ between patients with positive or negative FHS ≤ 50. However, patients with FHS > 50 were more likely to have hypertension and higher BMI. CONCLUSION: Relatives of CeAD patients had fewer strokes at a young age than relatives of non-CeAD IS stroke patients.

Elevated peripheral leukocyte counts in acute cervical artery dissection.

BACKGROUND AND PURPOSE: It has been suggested that inflammation may play a role in the development of cervical artery dissection (CeAD), but evidence remains scarce. METHODS: A total of 172 patients were included with acute (< 24 h) CeAD and 348 patients with acute ischaemic stroke (IS) of other (non-CeAD) causes from the Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study, and 223 age- and sex-matched healthy control subjects. White blood cell (WBC) counts collected at admission were compared across the three groups. RESULTS: Compared with healthy control subjects, CeAD patients and non-CeAD stroke patients had higher WBC counts (P < 0.001). Patients with CeAD had higher WBC counts and were more likely to have WBC > 10 000/µl than non-CeAD stroke patients (38.4% vs. 23.0%, P < 0.001) and healthy controls (38.4% vs. 8.5%, P < 0.001). WBC counts were higher in CeAD (9.4 ± 3.3) than in IS of other causes (large artery atherosclerosis, 8.7 ± 2.3; cardioembolism, 8.2 ± 2.8; small vessel disease, 8.4 ± 2.4; undetermined cause, 8.8 ± 3.1; P = 0.022). After adjustment for age, sex, stroke severity and vascular risk factors in a multiple regression model, elevated WBC count remained associated with CeAD, as compared with non-CeAD stroke patients [odds ratio (OR) = 2.56; 95% CI 1.60-4.11; P < 0.001) and healthy controls (OR = 6.27; 95% CI 3.39-11.61; P < 0.001). CONCLUSIONS: Acute CeAD was associated with particularly high WBC counts. Leukocytosis may reflect a pre-existing inflammatory state, supporting the link between inflammation and CeAD.

Vascular risk factors and cognitive disorders.

Delaying the onset of dementia by just a few years could have a major impact on the prevalence of the disease at the population level. Vascular risk factors are modifiable and may offer an important opportunity for preventive approaches. Several studies have shown that diabetes, hypertension, obesity, and smoking are associated with an increased risk of cognitive decline and dementia, but other groups have not observed such a relation. Positive associations were observed mainly in studies where risk factors were assessed in midlife, suggesting that age is an important modulator in the relation between vascular risk factors and cognition. The population attributable risk of dementia is particularly high for hypertension. Associations of vascular risk factors with cognitive decline and dementia are probably mediated largely by cerebrovascular disease, including both stroke and covert vascular brain injury, which can have additive or synergistic effects with coexisting neurodegenerative lesions. To date, randomized trials have not convincingly demonstrated that treating vascular risk factors is associated with a reduction in cognitive decline or dementia risk. Of eight randomized trials testing the effect of antihypertensive agents on dementia risk, only one was positive, and another in a subgroup of individuals with recurrent stroke. In most trials, cognition and dementia were secondary outcomes, follow-up was short and treatment was initiated at an older age. No effect on cognitive decline or dementia could be demonstrated for statins and intensive glycemic control. Future areas of investigation could include differential class effects of antihypertensive drugs on cognitive outcomes and identification of high risk individuals as target population for clinical trials initiated in midlife.

Gender and cervical artery dissection.

BACKGROUND AND PURPOSE: To analyze previously established gender differences in cervical artery dissection (CeAD). METHODS: This case-control study is based on the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) population comprising 983 consecutive CeAD patients (mean age: 44.1 ± 9.9 years) and 658 control patients with a non-CeAD ischemic stroke (IS) (44.5 ± 10.5 years). RESULTS: Cervical artery dissection was more common in men (56.7% vs. 43.3%, P < 0.001) and men were older (46.4 vs. 41.0 years, P < 0.001). We assessed putative risk factors for CeAD including vascular risk factors, recent cervical trauma, pregnancies, and infections. All gender differences in the putative risk factors and outcome were similar in the CeAD and the non-CeAD IS groups. CONCLUSION: Our analysis of the largest collection of CeAD patients to date confirms male predominance and differences in age at dissection between men and women. Gender differences in putative risk factors may explain the higher frequency of CeAD in men and their older age, but the putative risk factors are probably not specific for CeAD.

Thrombolysis in cervical artery dissection--data from the Cervical Artery Dissection and Ischaemic Stroke Patients (CADISP) database.

OBJECTIVE: To examine whether thrombolysis for stroke attributable to cervical artery dissection (CeAD(Stroke) ) affects outcome and major haemorrhage rates. METHODS: We used a multicentre CeAD(Stroke) database to compare CeAD(Stroke) patients treated with and without thrombolysis. Main outcome measures were favourable 3-month outcome (modified Rankin Scale 0-2) and 'major haemorrhage' [any intracranial haemorrhage (ICH) and major extracranial haemorrhage]. Adjusted odds ratios [OR (95% confidence intervals)] were calculated on the whole database and on propensity-matched groups. RESULTS: Among 616 CeAD(Stroke) patients, 68 (11.0%) received thrombolysis; which was used in 55 (81%) intravenously. Thrombolyzed patients had more severe strokes (median NIHSS score 16 vs. 3; P < 0.001) and more often occlusion of the dissected artery (66.2% vs. 39.4%; P < 0.001). After adjustment for stroke severity and vessel occlusion, the likelihood for favourable outcome did not differ between the treatment groups [OR(adjusted) 0.95 (95% CI 0.45-2.00)]. The propensity matching score model showed that the odds to recover favourably were virtually identical for 64 thrombolyzed and 64 non-thrombolyzed-matched CeAD(Stroke) patients [OR 1.00 (0.49-2.00)]. Haemorrhages occurred in 4 (5.9%) thrombolyzed patients, all being asymptomatic ICHs. In the non-thrombolysis group, 3 (0.6%) patients had major haemorrhages [asymptomatic ICH (n = 2) and major extracranial haemorrhage (n = 1)]. CONCLUSION: As thrombolysis was neither independently associated with unfavourable outcome nor with an excess of symptomatic bleedings, our findings suggest thrombolysis should not be withheld in CeAD(Stroke) patients. However, the lack of any trend towards a benefit of thrombolysis may indicate the legitimacy to search for more efficient treatment options including mechanical revascularization strategies.

Heritable and non-heritable uncommon causes of stroke.

Despite intensive investigations, about 30% of stroke cases remains of undetermined origin. After exclusion of common causes of stroke, there is a number of rare heritable and non-heritable conditions, which often remain misdiagnosed, that should be additionally considered in the diagnosis of cryptogenic stroke. The identification of these diseases requires a complex work up including detailed clinical evaluation for the detection of systemic symptoms and signs, an adequate neuroimaging assessment and a careful family history collection. The task becomes more complicated by phenotype heterogeneity since stroke could be the primary or unique manifestation of a syndrome or represent just a manifestation (sometimes minor) of a multisystem disorder. The aim of this review paper is to provide clinicians with an update on clinical and neuroradiological features and a set of practical suggestions for the diagnostic work up and management of these uncommon causes of stroke. The identification of these stroke causes is important to avoid inappropriate and expensive diagnostic tests, to establish appropriate management measures, including presymptomatic testing, genetic counseling, and, if available, therapy. Therefore, physicians should become familiar with these diseases to provide future risk assessment and family counseling.

Minor allele of the factor V K858R variant protects from venous thrombosis only in non-carriers of factor V Leiden mutation.

Factor V serves an important role in the regulation of blood coagulation. The rs6025 (R534Q) and rs4524 (K858R) polymorphisms in the F5 gene, are known to influence the risk of venous thrombosis. While the rare Q534 (factor V Leiden) allele is associated with an increased risk of venous thrombosis, the minor R858 allele is associated with a lower risk of disease. However, no study has deeply examined the cumulative impact of these two variations on venous thrombosis risk. We study the association of these polymorphisms with the risk of venous thrombosis in 4 French case-control populations comprising 3719 patients and 4086 controls. We demonstrate that the Q534 allele has a dominant effect over R858. Besides, we show that in individuals not carrying the Q534 allele, the protective effect of the R858 allele acts in a dominant mode. Thrombin generation-based normalized activated protein C sensitivity ratio was lower in the 858R/R homozygotes than in the 858K/K homozygotes (1.92 ± 1.61 vs 2.81 ± 1.57, p = 0.025). We demonstrate that the R858 allele of the F5 rs4524 variant protects from venous thrombosis only in non-carriers of the Q534 allele of the F5 rs6025. Its protective effect is mediated by reduced factor VIII levels and reduced activated protein C resistance.

Fourth European stroke science workshop.

Lake Eibsee, Garmisch-Partenkirchen, 16 to 18 November, 2017: The European Stroke Organisation convened >120 stroke experts from 21 countries to discuss latest results and hot topics in clinical, translational and basic stroke research. Since its inception in 2011, the European Stroke Science Workshop has become a cornerstone of European Stroke Organisation's academic activities and a major highlight for researchers in the field. Participants include stroke researchers at all career stages and with different backgrounds, who convene for plenary lectures and discussions. The workshop was organised in seven scientific sessions focusing on the following topics: (1) acute stroke treatment and endovascular therapy; (2) small vessel disease; (3) opportunities for stroke research in the omics era; (4) vascular cognitive impairment; (5) intracerebral and subarachnoid haemorrhage; (6) alternative treatment concepts and (7) neural circuits, recovery and rehabilitation. All sessions started with a keynote lecture providing an overview on current developments, followed by focused talks on a timely topic with the most recent findings, including unpublished data. In the following, we summarise the key contents of the meeting. The program is provided in the online only Data Supplement. The workshop started with a key note lecture on how to improve the efficiency of clinical trial endpoints in stroke, which was delivered by Craig Anderson (Sydney, Australia) and set the scene for the following discussions.

Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk.

ESSENTIALS: Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk. SUMMARY: Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n = 2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, ß = -25.9 mU mL-1 per minor allele; FVIIa-AT, ß = -26.6 pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, ß = 7.8 mU mL-1 per minor allele; FVIIa-AT, ß = 9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95% CI, 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in variation in circulating FVIIa and FVIIa-AT. The findings suggest FVIIa is a risk factor for ischemic stroke in older adults, whereas higher FVIIa-AT may reflect mortality risk.

Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study.

BACKGROUND: The relationships of thrombin generation (TG) with cardiovascular disease risk are underevaluated in population-based cohorts. OBJECTIVES: To evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways ex vivo with common single-nucleotide polymorphisms (SNPs) and incident cardiovascular disease and stroke. PATIENTS/METHODS: We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (n = 5411), both with and without inhibitory anti-factor XIa antibody (pTG/FXIa(-) ). We evaluated their associations with ~ 50 000 SNPs by using the IBCv2 genotyping array, and with incident cardiovascular disease and stroke events over a median follow-up of 13.2 years. RESULTS: The minor allele for an SNP in the FXII gene (F12), rs1801020, was associated with lower pTG in European-Americans (ß = - 34.2 ± 3.5 nm; P = 3.3 × 10(-22) ; minor allele frequency [MAF] = 0.23) and African-Americans (ß = - 31.1 ± 7.9 nm; P = 9.0 × 10(-5) ; MAF = 0.42). Lower FXIa-independent pTG (pTG/FXIa(-) ) was associated with the F12 rs1801020 minor allele, and higher pTG/FXIa(-) was associated with the ABO SNP rs657152 minor allele (ß = 16.3 nm; P = 4.3 × 10(-9) ; MAF = 0.37). The risk factor-adjusted ischemic stroke hazard ratios were 1.09 (95% confidence interval CI 1.01-1.17; P = 0.03) for pTG, 1.06 (95% CI 0.98-1.15; P = 0.17) for pTG/FXIa(-) , and 1.11 (95% CI 1.02-1.21; P = 0.02) for FXIa-dependent pTG (pTG/FXIa(+) ), per one standard deviation increment (n = 834 ischemic strokes). In a multicohort candidate gene analysis, rs1801020 was not associated with incident ischemic stroke (ß = - 0.02; standard error = 0.08; P = 0.81). CONCLUSIONS: These results support the importance of contact activation pathway-dependent TG as a risk factor for ischemic stroke, and indicate the importance of F12 SNPs for TG ex vivo and in vivo.

Genetic, psychosocial and clinical factors associated with hippocampal volume in the general population.

The hippocampus--crucial for memory formation, recall and mood regulation--is involved in the pathophysiology of dementia and depressive disorders. Recent genome-wide association studies (GWAS) have identified five genetic loci associated with hippocampal volume (HV). Previous studies have described psychosocial and clinical factors (for example, smoking, type 2 diabetes and hypertension) to have an impact on HV. However, the interplay between genetic, psychosocial and clinical factors on the HV remains unclear. Still, it is likely that genetic variants and clinical or psychosocial factors jointly act in modifying HV; it might be possible they even interact. Knowledge of these factors might help to quantify ones individual risk of or rather resilience against HV loss. We investigated subjects (N=2463; 55.7% women; mean age 53 years) from the Study of Health in Pomerania (SHIP-2; SHIP-TREND-0) who underwent whole-body magnetic resonance imaging (MRI) and genotyping. HVs were estimated with FreeSurfer. For optimal nonlinear model fitting, we used regression analyses with restricted cubic splines. Genetic variants and associated psychosocial or clinical factors were jointly assessed for potential two-way interactions. We observed associations between HV and gender (P<0.0001), age (P<0.0001), body height (P<0.0001), education (P=0.0053), smoking (P=0.0058), diastolic blood pressure (P=0.0211), rs7294919 (P=0.0065), rs17178006 (P=0.0002), rs6581612 (P=0.0036), rs6741949 (P=0.0112) and rs7852872 (P=0.0451). In addition, we found three significant interactions: between rs7294919 and smoking (P=0.0473), rs7294919 and diastolic blood pressure (P=0.0447) and between rs7852872 and rs6581612 (P=0.0114). We suggest that these factors might have a role in the individual susceptibility to hippocampus-associated disorders.

The genetics of small-vessel disease.

Cerebral small-vessel disease (SVD) is a well-known cause of stroke, dementia and death, but its pathogenesis is not yet completely understood. The spectrum of neuroradiological manifestations associated with SVD is wide and may result from chronic and diffuse or acute and focal ischemia (leukoaraiosis and lacunar infarction) as well as from small-vessel rupture (cerebral microbleeds and intracerebral hemorrhage). Several lines of evidence from family and twin studies support the hypothesis that genetic factors may contribute to SVD pathogenesis. Identification of genetic susceptibility factors for SVD may improve our knowledge of SVD pathogenesis and help to identify new therapeutic targets to reduce the burden of SVD-related cognitive decline and stroke disability. A number of monogenic conditions presenting with clinical features of SVD have been described. Although monogenic disorders account for only a small proportion of SVD, study of these diseases may provide further insight into the pathogenesis of SVD. In most cases, however, SVD is thought to be a multifactorial disorder. Several genetic association studies, conducted using the candidate gene and, more recently, the genome-wide approach, have so far failed to demonstrate a convincing association between SVD and genetic variants. Methodological issues, particularly related to inaccurate or heterogeneous phenotyping and insufficient sample sizes, have been invoked as possible reasons for this. Large collaborative efforts and robust replication, as well as implementation of new genetic approaches, are necessary to identify genetic susceptibility factors for complex SVD.