Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke.

Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

Correction to: Novel mutations in KMT2B offer pathophysiological insights on childhood-onset progressive dystonia.

Rapid progress has recently been made in the elucidation of the genetic basis of childhood-onset inherited generalized dystonia (IGD) due to the implementation of genomic sequencing methodologies. We identified four patients with childhood-onset IGD harboring novel disease-causing mutations in lysine-specific histone methyltransferase 2B gene (KMT2B) by whole-exome sequencing. The main focus of this paper is to gain novel pathophysiological insights through understanding the molecular consequences of these mutations.The disease course is mostly progressive, evolving from lower limbs into generalized dystonia, which could be associated with dysarthria, dysphonia, intellectual disability, orofacial dyskinesia, and sometimes distinct dysmorphic facial features. In two patients, motor performances improved after bilateral implantation of deep brain stimulation in the globus pallidus internus (GPi-DBS). Pharmacotherapy with trihexyphenidyl reduced dystonia in two patients.We discovered three novel KMT2B mutations. Our analyses revealed that the mutation in patient 1 (c.7463 A > G, p.Y2488C) is localized in the highly conserved FYRC domain of KMT2B. This mutation holds the potential to alter the inter-domain FYR interactions, which could lead to KMT2B instability. The mutations in patients 2 and 3 (c.3602dupC, p.M1202Dfs*22; c.4229delA, p.Q1410Rfs*12) lead to predicted unstable transcripts, likely to be subject to degradation by non-sense mediated decay.Childhood-onset progressive dystonia with orofacial involvement is one of the main clinical manifestations of KMT2B mutations. In all, 26% (18/69) of the reported cases have T2 signal alterations of the globus pallidus internus, mostly at a younger age. Anticholinergic medication and GPi-DBS are promising treatment options and shall be considered early.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Novel mutations in KMT2B offer pathophysiological insights into childhood-onset progressive dystonia.

Rapid progress has recently been made in the elucidation of the genetic basis of childhood-onset inherited generalized dystonia (IGD) due to the implementation of genomic sequencing methodologies. We identified four patients with childhood-onset IGD harboring novel disease-causing mutations in lysine-specific histone methyltransferase 2B gene (KMT2B) by whole-exome sequencing. The main focus of this paper is to gain novel pathophysiological insights through understanding the molecular consequences of these mutations. The disease course is mostly progressive, evolving from lower limbs into generalized dystonia, which could be associated with dysarthria, dysphonia, intellectual disability, orofacial dyskinesia, and sometimes distinct dysmorphic facial features. In two patients, motor performances improved after bilateral implantation of deep brain stimulation in the globus pallidus internus (GPi-DBS). Pharmacotherapy with trihexyphenidyl reduced dystonia in two patients. We discovered three novel KMT2B mutations. Our analyses revealed that the mutation in patient 1 (c.7463A > G, p.Y2488C) is localized in the highly conserved FYRC domain of KMT2B. This mutation holds the potential to alter the inter-domain FYR interactions, which could lead to KMT2B instability. The mutations in patients 2 and 3 (c.3596_3697insC, p.M1202Dfs*22; c.4229delA, p.Q1410Rfs*12) lead to predicted unstable transcripts, likely to be subject to degradation by non-sense-mediated decay. Childhood-onset progressive dystonia with orofacial involvement is one of the main clinical manifestations of KMT2B mutations. In all, 26% (18/69) of the reported cases have T2 signal alterations of the globus pallidus internus, mostly at a younger age. Anticholinergic medication and GPi-DBS are promising treatment options and shall be considered early.

Rechargeable Internal Pulse Generators as Initial Neurostimulators for Deep Brain Stimulation in Patients With Movement Disorders.

INTRODUCTION: Rechargeable internal pulse generators (r-IPGs) for deep brain stimulation (DBS) promise a longer battery life and cost effectiveness compared to non-rechargeable IPGs. However, patients need to learn to check the battery capacity and perform the recharging process to ensure continuous therapy. METHODS: n = 35 consecutive adult patients with movement disorders that underwent DBS electrode placement with implantation of a r-IPG were assessed with a questionnaire. They were asked to report on their recharging routine, user confidence, satisfaction, and adverse events. Patients were asked to assess the level of difficulty of the individual steps and the overall recharging process on an ordinal scale awarding 1-5 points. RESULTS: 89% (n = 31) patients responded and were available for data analysis. n = 21 patients received DBS for Parkinson's Disease, n = 8 for essential tremor and n = 2 for dystonia at a mean age of 63.3 years. The mean follow-up was 21.2 months. n = 7 patients have partners or nursing services check and recharge the IPG. The recharging takes an average of 57.6 min. 90.3% felt confident using their IPG after a mean of 2.1 weeks and 1.6 training sessions. 97% of patients prefer their r-IPG over a conventional one. n = 3 patients experienced inability to recharge their IPG at some point. One patient experienced battery depletion and interruption of stimulation because of inability to recharge. The overall recharging process was rated as "easy" with a score of 4.0 out of 5 points. Each individual step was also rated as "easy" with a median score of 4.0 out of 5. Old age was not associated with more adverse events or a lower rating for the recharging process. CONCLUSIONS: Choosing a r-IPG during initial DBS surgery is safe and associated with a low number of adverse events even in older patients. The vast majority of patients consider handling and recharging the IPG as "easy." Most of the patients undergoing DBS for movement disorders will benefit from the advantages of r-IPGs.

Genetic Imbalance in Patients with Cervical Artery Dissection.

BACKGROUND: Genetic and environmental risk factors are assumed to contribute to the susceptibility to cervical artery dissection (CeAD). To explore the role of genetic imbalance in the etiology of CeAD, copy number variants (CNVs) were identified in high-density microarrays samples from the multicenter CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study and from control subjects from the CADISP study and the German PopGen biobank. Microarray data from 833 CeAD patients and 2040 control subjects (565 subjects with ischemic stroke due to causes different from CeAD and 1475 disease-free individuals) were analyzed. Rare genic CNVs were equally frequent in CeAD-patients (16.4%; n=137) and in control subjects (17.0%; n=346) but differed with respect to their genetic content. Compared to control subjects, CNVs from CeAD patients were enriched for genes associated with muscle organ development and cell differentiation, which suggests a possible association with arterial development. CNVs affecting cardiovascular system development were more common in CeAD patients than in control subjects (p=0.003; odds ratio (OR) =2.5; 95% confidence interval (95% CI) =1.4-4.5) and more common in patients with a familial history of CeAD than in those with sporadic CeAD (p=0.036; OR=11.2; 95% CI=1.2-107). CONCLUSION: The findings suggest that rare genetic imbalance affecting cardiovascular system development may contribute to the risk of CeAD. Validation of these findings in independent study populations is warranted.

Cerebral Small Vessel Disease Is Associated with Dysregulation in the Ubiquitin Proteasome System and Other Major Cellular Pathways in Specific Brain Regions.

BACKGROUND/AIMS: Cerebral small vessel disease (SVD) is characterized by periventricular white matter (WM) changes and can lead to vascular dementia, the second most common form of age-dependent dementia. The pathogenesis of the disease remains poorly understood, and studies of its molecular basis are limited. By profiling gene expression of dissected postmortem brain tissue in SVD patients and comparisons with tissue of nonneurological controls, we aimed to identify genes and processes that are involved in the pathogenesis of SVD to gain new pathogenetic insights. METHODS: We performed genome-wide expression analyses in postmortem brain tissue samples dissected from frontal, temporal, and occipital lobes as well as basal nuclei comprising thalamus, basal ganglia, and hippocampus from 5 SVD cases and 5 nonaffected control cases. Cellular pathways associated with differently expressed genes were identified in each brain region individually. RESULTS: This analysis disclosed regional differences, with frontal lobe and thalamus showing the highest numbers of genes with significantly altered expression. Biological functions and pathways associated with changed gene expression depicted brain area-specific defective pathways. Vessel-associated functions, such as increased extracellular matrix-receptor interactions and cell adhesion molecules, were enhanced in all regions. Inflammation and apoptosis were induced particularly in basal nuclei and temporal and occipital regions. Interestingly, genes associated with the ubiquitin-dependent proteolysis (ubiquitin proteasome system) pathway were downregulated in the frontal lobe and in the thalamus, leading to the formation of protein aggregates. CONCLUSION: This analysis deciphers brain region-specific molecular processes to increase the present knowledge of SVD pathology and determine new potential therapeutic targets.

Serum Neurofilament Light Chain Levels Are Associated with Clinical Characteristics and Outcome in Patients with Cervical Artery Dissection.

BACKGROUND: Serum neurofilament light chain (sNfL) levels represent a promising marker of neuroaxonal injury. They are elevated in several neurological conditions, but their importance in cerebrovascular diseases remains unclear. In a proof of concept study, we compared sNfL levels with clinical characteristics and outcome in patients with cervical artery dissection (CeAD). METHODS: A total of 49 non-traumatic CeAD patients were included. sNfL levels were measured by high-sensitivity electrochemiluminescence immunoassay. Levels were compared with regard to (i) type of presenting symptoms (local symptoms only (n = 8), transient ischemic attack (TIA; n = 10) or ischemic stroke (n = 31)), (ii) stroke severity quantified by National Institute of Health Stroke Scale (NIHSS), (iii) time interval between onset of symptoms and blood sampling and (iv) 3-month outcome as measured by the modified Rankin Scale score. Analyses were performed using univariate and multivariate linear and ordinal regression models. RESULTS: CeAD patients presenting with stroke had significantly higher sNfL levels (median 108.9 pg/ml, interquartile range (37.8-427.7)) than patients with TIA (16.4 pg/ml (8.7-36.3), p = 0.002) or local symptoms (23.4 pg/ml (17.8-30.8), p = 0.0007). Among stroke patients, sNfL levels were positively associated with both NIHSS (p = 0.0002) and time between stroke onset and serum sampling (p = 1.9 × 10-6). Higher sNfL levels were associated with unfavorable outcome at 3 months (OR 4.67, 95% CI 1.69-12.95, p = 0.003). However, this association lost significance after adjustment for NIHSS. The highest sNfL level was observed in a TIA patient who had ischemic stroke 1 day after serum sampling for sNfL measurement. CONCLUSION: sNfL levels were increased in CeAD patients presenting with stroke, correlated with clinical severity and were influenced by the time point of blood sampling. The prognostic meaning of sNfL in CeAD deserves further testing.

Parkinson's Disease Case Ascertainment in the EPIC Cohort: The NeuroEPIC4PD Study.

BACKGROUND/AIMS: Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. METHODS: The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of 'definite', 'very likely', 'probable', or 'possible' PD. RESULTS: A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last follow-up. CONCLUSIONS: This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.

Primary preventive potential for stroke by avoidance of major lifestyle risk factors: the European Prospective Investigation into Cancer and Nutrition-Heidelberg cohort.

BACKGROUND AND PURPOSE: Because primary prevention of stroke is a priority, our aim was to assess the primary preventive potential of major lifestyle risk factors for stroke in middle-aged women and men. METHODS: Among 23,927 persons, 551 (195 women and 356 men) had a first diagnosis of stroke during an average follow-up of 12.7 years. Using Cox proportional hazards models, we estimated the associations of adiposity, smoking, physical activity, alcohol consumption, and diet with risk of developing stroke. A competing risk model built from cause-specific proportional hazards models accounting for concurrent risk of death was used to calculate relative and absolute reductions in stroke occurrences that could have been achieved by maintaining a healthy lifestyle pattern. RESULTS: Obesity, smoking, alcohol consumption, diet, and physical inactivity were each identified as modifiable lifestyle risk factors for stroke. About 38% of stroke cases were estimated as preventable through adherence to a healthy lifestyle profile (never smoking, maintaining optimal body mass index and waist circumference, performing physical exercise, consuming a moderate quantity of alcohol, and following a healthy dietary pattern). Age-specific estimates of 5-year incidence rates for stroke in the actual cohort and in a hypothetical, comparable cohort of individuals following a healthy lifestyle would be reduced from 153 to 94 per 100,000 women and from 261 to 161 per 100,000 men for the age group 60 to 65 years. CONCLUSIONS: Our analysis confirms the strong primary prevention potential for stroke based on avoidance of excess body weight, smoking, heavy alcohol consumption, unhealthy diet, and physical inactivity.

Characteristics and outcomes of patients with multiple cervical artery dissection.

BACKGROUND AND PURPOSE: Little is known about factors contributing to multiple rather than single cervical artery dissections (CeAD) and their associated prognosis. METHODS: We compared the baseline characteristics and short-term outcome of patients with multiple to single CeAD included in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study. RESULTS: Among the 983 patients with CeAD, 149 (15.2%) presented with multiple CeAD. Multiple CeADs were more often associated with cervical pain at admission (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.10-2.30), a remote history of head or neck surgery (OR, 1.87; 95% CI, 1.16-3.00), a recent infection (OR, 1.71; 95% CI, 1.12-2.61), and cervical manipulation (OR, 2.23; 95% CI, 1.26-3.95). On imaging, cervical fibromuscular dysplasia (OR, 3.97; 95% CI, 2.04-7.74) and the presence of a pseudoaneurysm (OR, 2.91; 95% CI, 1.86-4.57) were more often seen in patients with multiple CeAD. The presence of multiple rather than single CeAD had no effect on functional 3-month outcome (modified Rankin Scale score, ≥3; 12% in multiple CeAD versus 11.9% in single CeAD; OR, 1.20; 95% CI, 0.60-2.41). CONCLUSIONS: In the largest published series of patients with CeAD, we highlighted significant differences between multiple and single artery involvement. Features suggestive of an underlying vasculopathy (fibromuscular dysplasia) and environmental triggers (recent infection, cervical manipulation, and a remote history of head or neck surgery) were preferentially associated with multiple CeAD.

Demographic and geographic vascular risk factor differences in European young adults with ischemic stroke: the 15 cities young stroke study.

BACKGROUND AND PURPOSE: We compared among young patients with ischemic stroke the distribution of vascular risk factors among sex, age groups, and 3 distinct geographic regions in Europe. METHODS: We included patients with first-ever ischemic stroke aged 15 to 49 years from existing hospital- or population-based prospective or consecutive young stroke registries involving 15 cities in 12 countries. Geographic regions were defined as northern (Finland, Norway), central (Austria, Belgium, France, Germany, Hungary, The Netherlands, Switzerland), and southern (Greece, Italy, Turkey) Europe. Hierarchical regression models were used for comparisons. RESULTS: In the study cohort (n=3944), the 3 most frequent risk factors were current smoking (48.7%), dyslipidemia (45.8%), and hypertension (35.9%). Compared with central (n=1868; median age, 43 years) and northern (n=1330; median age, 44 years) European patients, southern Europeans (n=746; median age, 41 years) were younger. No sex difference emerged between the regions, male:female ratio being 0.7 in those aged <34 years and reaching 1.7 in those aged 45 to 49 years. After accounting for confounders, no risk-factor differences emerged at the region level. Compared with females, males were older and they more frequently had dyslipidemia or coronary heart disease, or were smokers, irrespective of region. In both sexes, prevalence of family history of stroke, dyslipidemia, smoking, hypertension, diabetes mellitus, coronary heart disease, peripheral arterial disease, and atrial fibrillation positively correlated with age across all regions. CONCLUSIONS: Primary preventive strategies for ischemic stroke in young adults-having high rate of modifiable risk factors-should be targeted according to sex and age at continental level.

Familial occurrence of cervical artery dissection--coincidence or sign of familial predisposition?

UNLABELLED: BACKGROUNDAND PURPOSE: The etiology of spontaneous cervical artery dissection (CeAD) is poorly understood in most patients. Mild cervical trauma preceding the dissection event is a common finding, but many CeAD occur spontaneously. It is likely that genetic factors may increase the risk for CeAD. However, familial cases are excedingly rare. Familial clustering of CeAD may be accidental or associated with genetic or environmental risk factors shared between affected relatives. In this explorative study, we aim to show that specific risk factors for familial CeAD exist. METHODS: Age of onset, sex, affected artery and number of recurrent CeAD were documented for familial patients and compared with published findings from patients with sporadic CeAD. Concordance of age, sex and dissected artery within the families was analyzed by correlation analysis and by analysis of variance or Kruskal-Wallis testing. RESULTS: The study sample consisted of 9 new patients with a family history of CeAD enrolled in the Neurology Department of the University of Heidelberg or referred to Heidelberg from other centers. The study sample also included published findings from another 23 patients, in total 32 patients. The mean age of the patients with familial CeAD at their first dissections was 38.4 ± 13.3 years. Twenty (62.5%) patients were female and 12 patients (37.5%) suffered multiple dissections. Four patients (12.5%) presented with recurrent dissections after >1 year. Patients with a familial history of CeAD were younger (p = 0.023) and presented more often with multiple dissections (p = 0.024) and recurrent dissections (p = 0.018). Age at the first event (correlation analysis p = 0.026; analysis of variance p = 0.029) and site of the dissection (correlation analysis p = 0.032; Kruskal-Wallis test p = 0.018) differed between the families, and there was no concordance of gender of affected family members (correlation analysis p = 0.500; Kruskal-Wallis test p = 0.211). CONCLUSIONS: The high prevalence of multiple dissection events and of long-term (>1 year) recurrent dissections in patients with a familial history of CeAD indicates that a specific predisposition for familial CeAD exists. Since age of onset and affected vessel differ between families, the risk profile for familial CeAD is heterogeneous. A large-scale (whole exome) sequencing analysis of 14 patients from 7 of the analyzed families is currently being performed in order to identify causative genetic variants.

Is improvement in the quality of life after subthalamic nucleus stimulation in Parkinson's disease predictable?

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) significantly improves quality of life (QoL) in PD. However, QoL fails to improve in a relevant proportion of patients. We studied clinical baseline and progression parameters associated with improvement in QoL after DBS. Data from a German randomized, controlled study comparing DBS (60 patients) with best medical treatment (59 patients) were analyzed. Changes in patients' QoL were assessed using the Parkinson's Disease Questionnaire (PDQ-39) at baseline and at the 6-month follow-up. For the STN-DBS patients, the changes in PDQ-39 were correlated with predefined clinical preoperative and progression parameters. Scores for QoL improved after STN-DBS for 57% of the patients, and for 43% patients, they did not improve. Patients with improvement in QoL showed significantly higher cumulative daily "off" time. Changes in the PDQ-39 showed a significant positive correlation with the cumulative daily off time at baseline. Logistic regression analysis revealed that 1 additional hour off time at baseline increases the odds for improvement on PDQ-39 by a factor of 1.33 (odds ratio). In the postoperative course, changes in the PDQ-39 significantly correlated with the reduction of cumulative daily off time, an improvement on the UPDRS (UPDRS III off), and positive mood changes. Among the baseline parameters, the cumulative daily off time is the strongest predictor for improvement in disease-related QoL after DBS. Improvement in QoL after STN-DBS is also correlated with changes in motor functions and changes in depression and anxiety.

Risk factors for executive dysfunction after subthalamic nucleus stimulation in Parkinson's disease.

A slight decline in cognitive functions and especially in executive functioning after deep brain stimulation (DBS) of the nucleus subthalamicus (STN) in patients with Parkinson's disease (PD) has been described. This study evaluated baseline parameters that contribute to a deterioration of cognitive functioning after DBS. We analyzed data from the neuropsychological protocol in a randomized controlled study comparing DBS with best medical treatment (BMT). Change scores were calculated for the cognitive domains "global cognitive functioning," "memory," "working memory," "attention," and "executive function." These domain-specific change scores were correlated with previously defined preoperative parameters. Compared with the BMT group (63 patients), the STN-DBS group (60 patients) showed a significant decline only in the domain executive function 6 months after DBS, which was significantly correlated with age, levodopa-equivalence dosage (LED) and axial subscore of the UPDRS in the off-medication state at baseline. Multiple regression analysis showed that these three factors explained, however, only about 23% of the variance. Patients with higher age, higher baseline LED, and/or higher axial subscore of the UPDRS at baseline have an increased risk for worsening of executive function after STN-DBS. High scores of these factors might reflect an advanced stage of disease progression. As these baseline factors explained the variance of the change score executive function only to a minor proportion, other factors including the surgical procedure, the exact placement of the electrode or postsurgical management might be more relevant for a decline in executive functioning after STN-DBS.

Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial).

The aim of the study was to investigate the efficacy of the antibiotic minocycline as a drug treatment in patients with Multiple-System-Atrophy Parkinson-type (MSA-P). Sixty-three patients were randomized to minocycline 200 mg/d (n = 32) or a matching placebo (n = 31). The primary outcome variable was the change in the value of the motor score of the Unified Multiple-System-Atrophy Rating-Scale (UMSARSII) from baseline to 48 weeks. Secondary outcome variables included subscores and individual Parkinsonian symptoms as determined by the UMSARS and the Unified-Parkinson's-Disease Rating-Scale (UPDRS). Health-related quality of life (HrQoL) was assessed using the EQ-5D and SF-12. "Progression rate" was assumed to be reflected in the change in motor function over 48 weeks. At 24 weeks and 48 weeks of follow-up, there was a significant deterioration in motor scores in both groups, but neither the change in UMSARSII nor in UPDRSIII differed significantly between treatment groups, i.e. "progression rate" was considered to be similar in both treatment arms. HrQoL did not differ among the two treatment arms. In a small subgroup of patients (n = 8; minocycline = 3, placebo = 5)[(11)C](R)-PK11195-PET was performed. The three patients in the minocycline group had an attenuated mean increase in microglial activation as compared to the placebo group (P = 0.07) and in two of them individually showed decreased [11C](R)-PK11195 binding actually decreased. These preliminary PET-data suggest that minocycline may interfere with microglial activation. The relevance of this observation requires further investigation. This prospective, 48 week, randomized, double-blind, multinational study failed to show a clinical effect of minocycline on symptom severity as assessed by clinical motor function.

Vascular injury biomarkers and stroke risk: A population-based study.

OBJECTIVE: Because little is known about associations between biomarkers of vascular injury and stroke risk, we evaluated associations between plasma concentrations of 6 novel biomarkers of vascular injury and stroke risk in a population-based study. METHODS: A case-cohort subset of EPIC-Heidelberg (European Prospective Investigation for Cancer and Nutrition-Heidelberg) including incident stroke cases (n = 335) and a random subcohort (n = 2,418) was selected. Concentrations of intercellular adhesion molecule 3 (ICAM3), soluble E-selectin and P-selectin, soluble thrombomodulin (sTM), thrombopoietin, and glycoprotein IIb/IIIa were measured in baseline plasma samples. Weighted Cox regression analyses were used to assess associations between biomarker levels and stroke risk. RESULTS: Median follow-up in the subcohort and among cases was 9.8 (range, 0.1-12.5) years and 6.2 (range, 0.01-12.1) years, respectively. ICAM3 levels were associated with increased risk of incident stroke after multivariable adjustment (hazard ratio, highest vs lowest quartile: 1.64 [95% confidence interval, 1.15-2.32]; p linear trend < 0.001). This association was more apparent for ischemic (1.65 [1.12-2.45]; p linear trend < 0.01) than for hemorrhagic stroke (1.29 [0.60-2.78]; p linear trend = 0.3). We further observed a borderline significant trend for a positive association between sTM and overall stroke risk (1.47 [0.99-2.19]; p linear trend = 0.05). CONCLUSIONS: In this population-based study, circulating levels of ICAM3, an adhesion molecule shed by leukocytes, were associated with increased risk of incident stroke. Further mechanistic studies are needed to elucidate the pathophysiology underlying this association. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma levels of ICAM3 are associated with increased stroke risk.

Artery occlusion independently predicts unfavorable outcome in cervical artery dissection.

OBJECTIVE: To assess the impact of dissected artery occlusion (DAO) on functional outcome and complications in patients with cervical artery dissection (CeAD). METHODS: We analyzed combined individual patient data from 3 multicenter cohorts of consecutive patients with CeAD (the Cervical Artery Dissection and Ischemic Stroke Patients [CADISP]-Plus consortium dataset). Patients with data on DAO and functional outcome were included. We compared patients with DAO to those without DAO. Primary outcome was favorable functional outcome (i.e., modified Rankin Scale [mRS] score 0-1) measured 3-6 months from baseline. Secondary outcomes included delayed cerebral ischemia, major hemorrhage, recurrent CeAD, and death. We performed univariate and multivariable binary logistic regression analyses and calculated odds ratios (OR) with 95% confidence intervals (CI), with adjustment for potential confounders. RESULTS: Of 2,148 patients (median age 45 years [interquartile range (IQR) 38-52], 43.6% women), 728 (33.9%) had DAO. Patients with DAO more frequently presented with cerebral ischemia (84.6% vs 58.5%, p < 0.001). Patients with DAO were less likely to have favorable outcome when compared to patients without DAO (mRS 0-1: 59.6% vs 80.1%, p unadjusted < 0.001). After adjustment for age, sex, and initial stroke severity, DAO was independently associated with less favorable outcome (mRS 0-1: OR 0.65, CI 0.50-0.84, p = 0.001). Delayed cerebral ischemia occurred more frequently in patients with DAO than in patients without DAO (4.5% vs 2.9%, p = 0.059). CONCLUSION: DAO independently predicts less favorable functional outcome in patients with CeAD. Further research on vessel patency, collateral status and effects of revascularization therapies particularly in patients with DAO is warranted.

A randomized trial of deep-brain stimulation for Parkinson's disease.

BACKGROUND: Neurostimulation of the subthalamic nucleus reduces levodopa-related motor complications in advanced Parkinson's disease. We compared this treatment plus medication with medical management. METHODS: In this randomized-pairs trial, we enrolled 156 patients with advanced Parkinson's disease and severe motor symptoms. The primary end points were the changes from baseline to six months in the quality of life, as assessed by the Parkinson's Disease Questionnaire (PDQ-39), and the severity of symptoms without medication, according to the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III). RESULTS: Pairwise comparisons showed that neurostimulation, as compared with medication alone, caused greater improvements from baseline to six months in the PDQ-39 (50 of 78 pairs, P=0.02) and the UPDRS-III (55 of 78, P<0.001), with mean improvements of 9.5 and 19.6 points, respectively. Neurostimulation resulted in improvements of 24 to 38 percent in the PDQ-39 subscales for mobility, activities of daily living, emotional well-being, stigma, and bodily discomfort. Serious adverse events were more common with neurostimulation than with medication alone (13 percent vs. 4 percent, P<0.04) and included a fatal intracerebral hemorrhage. The overall frequency of adverse events was higher in the medication group (64 percent vs. 50 percent, P=0.08). CONCLUSIONS: In this six-month study of patients under 75 years of age with severe motor complications of Parkinson's disease, neurostimulation of the subthalamic nucleus was more effective than medical management alone. (ClinicalTrials.gov number, NCT00196911 [ClinicalTrials.gov].).

Pharmacogenetic testing for guiding de novo phenprocoumon therapy in stroke patients.

BACKGROUND: For many conditions causing transient ischemic attack or minor stroke, secondary prevention with early initiation of oral anticoagulation is indicated. The individual response to coumarins is known to vary widely and is not well predicted by clinical variables. Patients' discharge from hospital care is often delayed only because the therapeutic target range has not been reached yet. A feasible tool to guide coumarin dosing and thereby safely shortening time in hospital is required. METHODS: We established a polymerase chain reaction technique for rapid genotyping of the vitamin K epoxide reductase complex (VKORC1), which is the pharmaceutical target of the coumarins. C283 + 837C -> T (rs2359612) genotypes were determined in 49 patients who underwent de novo oral anticoagulation with phenprocoumon for cerebrovascular disease. Other variables potentially affecting phenprocoumon sensitivity were systematically evaluated. RESULTS: Of 49 genotyped patients, 47 were treated in hospital until an international normalized ratio (INR) of 2-3 was reached. The time and the cumulative dose of phenprocoumon necessary to achieve the target INR both were strongly dependent on the individual C283 + 837C -> T genotype (Kruskal-Wallis test p = 0.0002, and p < 0.0001, respectively). Carriers of the TT genotype reached an INR of 2-3 after a mean time of 3.2 days (n = 5), CT carriers after 4.4 days (n = 27), and CC carriers after 6.5 days (n = 15). No other variable, including body weight, was significantly correlated with the treatment response. CONCLUSION: In patients with cerebrovascular disease, genotyping for VKORC1 alone can strongly predict the individual response to de novo phenprocoumon treatment. The size of the pharmacogenetic test's potential effect on a more efficient use of hospital capacities remains to be shown by a controlled interventional study.