Background and Purpose
Functional magnetic resonance imaging (fMRI) studies could provide crucial information on the neural mechanisms of motor recovery in stroke patients. Resting-state fMRI is applicable to stroke patients who are not capable of proper performance of the motor task. In this study, we explored neural correlates of motor recovery in stroke patients by investigating longitudinal changes in resting-state functional connectivity of the ipsilesional primary motor cortex (M1).
A longitudinal observational study using repeated fMRI experiments was conducted in 12 patients with stroke. Resting-state fMRI data were acquired four times over a period of 6 months. Patients participated in the first session of fMRI shortly after onset, and thereafter in subsequent sessions at 1, 3, and 6 months after onset. Resting-state functional connectivity of the ipsilesional M1 was assessed and compared with that of healthy subjects.
Compared with healthy subjects, patients demonstrated higher functional connectivity with the ipsilesional frontal and parietal cortices, bilateral thalamus, and cerebellum. Instead, functional connectivity with the contralesional M1 and occipital cortex were decreased in stroke patients. Functional connectivity between the ipsilesional and contralesional M1 showed the most asymmetry at 1 month after onset to the ipsilesional side. Functional connectivity of the ipsilesional M1 with the contralesional thalamus, supplementary motor area, and middle frontal gyrus at onset was positively correlated with motor recovery at 6 months after stroke.
Resting-state fMRI elicited distinctive but comparable results with previous task-based fMRI, presenting complementary and practical values for use in the study of stroke patients.
Resting-state fMRI; Stroke; Motor recovery; Functional connectivity
Background and Purpose
Few dietary protein sources have been studied prospectively in relation to stroke. We examined the relation between foods that are major protein sources and risk of stroke.
We prospectively followed 84,010 women aged 30–55 years at baseline and 43,150 men aged 40–75 years at baseline without diagnosed cancer, diabetes, or cardiovascular disease. Diet was assessed repeatedly by a standardized and validated questionnaire. We examined the association between protein sources and incidence of stroke using a proportional hazard model adjusted for stroke risk factors.
During 26 and 22 years of follow-up in women and men, respectively, we documented 2,633 and 1,397 strokes, respectively. In multivariable analyses, higher intake of red meat was associated with an elevated risk of stroke, while a higher intake of poultry was associated with lower risk. In models estimating the effects of exchanging different protein sources, compared to one serving/day of red meat, one serving/day of poultry was associated with a 27% (95% CI: 12% to 39%) lower risk of stroke, nuts with a 17% (95% CI: 4% to 27%) lower risk, fish with a 17% (95% CI: 0% to 30%) lower risk, low-fat dairy with an 11% (95% CI: 5% to 17%) lower risk, and whole-fat dairy with a 10% (95% CI: 4% to 16%) lower risk. We did not see significant associations with exchanging legumes or eggs for red meat.
These data suggest that stroke risk may be reduced by replacing red meat with other dietary sources of protein.
men; women; diet; protein; nutrition; stroke
Determinants of successful recanalization likely differ for Merci thrombectomy(MT) and intra-arterial pharmacologic fibrinolysis interventions. While the amount of thrombotic material to be digested is an important consideration for chemical lysis, mechanical debulking may be more greatly influenced by other target lesion characteristics.
In consecutive acute ischemic stroke patients treated with MT for middle cerebral artery M1 occlusions, we analyzed the influence on recanalization success and clinical outcome of target thrombus size (length) and shape (curvature and branching) on pretreatment T2* gradient echo magnetic resonance imaging (MRI).
Among 65 patients, pretreatment MRI showed susceptibility vessel signs (SVS) in 45 (69%). Thrombus length averaged 13.03 mm (range 5.56–34.91) and irregular shape (curvature or branching) was present in 17/45 (38%). Presence and length of SVS did not predict recanalization or good clinical outcome. Substantial recanalization (TICI 2b or 3) and good clinical outcome (mRS ≤2) were more frequent with regular than irregular SVS shape (57% vs 18%, P=0.013; 39% vs 6%, P=0.017). On multiple regression analysis, the only independent predictor of substantial recanalization was irregular SVS (OR, 0.16; 95% CI, 0.04 to 0.69; P=0.014); and leading predictors of good clinical outcome were baseline NIHSS (OR, 1.20; 95% CI, 1.03 to 1.40; P= 0.019) and irregular SVS (OR, 9.36; 95% CI, 0.98 to 89.4; P=0.052).
Extension thrombus into MCA division branches and curving shape of the MCA stem, but not thrombus length, decrease technical and clinical success of Merci thrombectomy in M1 occlusions.
stroke; acute; thrombectomy; endovascular treatment; magnetic resonance imaging; outcome
Background and Purpose
Human albumin has been shown to exert neuroprotective effects in animal models of cerebral ischemia and humans with various intracranial pathologies. We investigated the safety and tolerability of 25% human albumin (ALB) in patients with subarachnoid hemorrhage (SAH).
The ALISAH (Albumin in Subarachnoid Hemorrhage) Pilot Clinical Trial was an open-label, dose-escalation study. We intended to study 4 different dosages of ALB of increasing magnitude (0.625 g/kg: tier 1; 1.25 g/kg: tier 2; 1.875 g/kg: tier 3; and 2.5 g/kg: tier 4). Each dosage was to be given to 20 adult patients. Treatment was administered daily for 7 days. We investigated the maximum tolerated dose of ALB based on the rate of severe-to-life-threatening heart failure and anaphylactic reaction, and functional outcome at 3 months.
We treated 47 adult subjects: 20 in tier 1; 20 in tier 2; and 7 in tier 3. We found that doses ranging up to 1.25 g/kg/day × 7 days were tolerated by patients without major dose-limiting complications. We also found that outcomes trended towards better responses in those subjects enrolled in tier 2 compared to tier 1 (OR: 3.0513; CI: 0.6586 – 14.1367) and to the International Intra-operative Hypothermia for Aneurysm Surgery Trial cohort (OR: 3.1462; CI: 0.9158 – 10.8089).
ALB in doses ranging up to 1.25 g/Kg/day × 7 days was tolerated by patients with SAH without major complications and may be neuroprotective. Based on these results, planning of the ALISAH II, a Phase III, randomized, placebo-controlled trial to test the efficacy of ALB is underway.
Clinical Trial Registration Information: NCT00283400 (clinicaltrials.gov) http://clinicaltrials.gov/ct2/show/NCT00283400?term=subarachnoid+hemorrhage+houston&rank=1
subarachnoid hemorrhage; albumin; neuroprotection; outcome; delayed ischemic deficit
Background and Purpose
Swallowing screens after acute stroke identify those patients who do not need a formal swallowing evaluation and who can safely take food and medications by mouth. We conducted a systematic review to identify swallowing-screening protocols that met basic requirements for reliability, validity, and feasibility.
We searched MEDLINE and supplemented results with references identified through other databases, journal tables of contents, and bibliographies. All relevant references were reviewed and evaluated with specific criteria.
Of 35 protocols identified, four met basic quality criteria. These four had high sensitivities of 87% or greater and high negative predictive values of 91% or greater when a formal swallowing evaluation was used as the gold standard. Two protocols had greater sample sizes and more extensive reliability testing than the others.
We identified only four swallowing-screening protocols for patients with acute stroke that met basic criteria. Cost effectiveness of screening--including costs associated with false positives and impact of screening on morbidity, mortality, and length of hospital stay--requires elucidation.
dysphagia; swallowing; screening; evaluation; stroke
Background and Purpose
American Indians suffer high rates of stroke. Improved risk stratification could enhance prevention, but the ability of biochemical and echocardiographic markers of preclinical disease to improve stroke prediction is not well defined.
We evaluated such markers as predictors of ischemic stroke in a community-based cohort of American Indians without prevalent cardiovascular or renal disease. Laboratory markers included C-reactive protein (CRP), fibrinogen, urine albumin-creatinine ratio (UACR), and glycohemoglobin (HbA1c), while echocardiographic parameters comprised left atrial (LA) diameter, left ventricular mass, mitral annular calcification (MAC), and mitral E/A ratio. Predictive performance was judged by indices of discrimination, reclassification and calibration.
After adjustment for standard risk factors, only HbA1c, albuminuria, and LA diameter were significantly associated with first ischemic stroke. Addition of HbA1c, though not UACR, to a basic clinical model significantly improved the C-statistic (0.714 vs. 0.695, p=0.044), whereas LA diameter modestly enhanced integrated discrimination improvement (IDI=0.90%, p=0.004), but not the C-statistic (0.701, p=0.528). When combined with HbA1c, LA diameter further increased IDI (1.81%, p<0.001), though not the C-statistic (0.716). No marker achieved significant net reclassification improvement (NRI).
In this cohort at high cardiometabolic risk, HbA1c emerged as the foremost predictor of ischemic stroke when added to traditional risk factors, affording substantially improved discrimination, with a more modest contribution for LA diameter. These findings bolster the role of HbA1c in cardiovascular risk assessment among persons with glycometabolic disorders, and provide impetus for further study of the incremental value of echocardiography in high-risk populations.
Stroke; Echocardiography; Biomarkers
Background and Purpose
Argatroban is a direct thrombin inhibitor that safely augments recanalization achieved by tPA in animal stroke models. The Argatroban tPA Stroke Study was an open-label, pilot safety study of tPA plus Argatroban in patients with ischemic stroke due to proximal intracranial occlusion.
During standard dose IV tPA, a 100μg/kg bolus of Argatroban and infusion for 48 hours was adjusted to a target partial thromboplastin time of 1.75 times baseline. The primary outcome was incidence of significant intracerebral hemorrhage defined as either symptomatic intracerebral hemorrhage (sICH) or parenchymal hemorrhage-type 2 (PH-2). Recanalization was measured at 2 and 24 hours by transcranial Doppler (TCD) or CT angiography.
Sixty-five patients were enrolled (45% men, mean age 63±14 years, median NIHSS = 13). The median (IQR) time tPA to Argatroban bolus was 51 (38, 60) minutes. Target anticoagulation was reached at a median (IQR) of 3 (2, 7) hours. Significant intracerebral hemorrhage occurred in 4 patients (6.2%, 95% CI 1.7–15.0). Of these, 3 were symptomatic (4.6%, 95% CI 0.9–12.9). Seven patients (10%) died in the first 7 days. Within the 2 hour monitoring period, TCD recanalization (n=47) occurred in 29 (61%) patients: complete in 19 (40%) and partial in another 10 (21%).
The combination of Argatroban and IV tPA is potentially safe in patients with moderate neurological deficits due to proximal intracranial arterial occlusions, and may produce more complete recanalization than tPA alone. Continued evaluation of this treatment combination is warranted.
Anticoagulation; acute stroke; thrombolysis; Argatroban; thrombin-inhibition
Background and Purpose
Our objective was to examine the agreement between adult patients with stroke and family member or clinician proxies in Activity Measure for Post Acute Care (AM-PAC) summary scores for daily activity, basic mobility, and applied cognitive function.
This study involved 67 patients with stroke admitted to a hospital within the Kaiser Permanente of Northern California system and were participants in a parent study on stroke outcomes. Each participant and proxy respondent completed the AM-PAC by personal or telephone interview at the point of hospital discharge and/or during one or more transitions to different post-acute care settings.
The results suggest that for patients with a stroke proxy AM-PAC data are robust for family or clinician proxy assessment of basic mobility function, clinician proxy assessment of daily activity function, but less robust for family proxy assessment of daily activity function and for all proxy groups’ assessment of applied cognitive function. The pattern of disagreement between patient and proxy was, on average, relatively small and random. There was little evidence of systematic bias between proxy and patient reports of their functional status. The degree of concordance between patient and proxy was similar for those with moderate to severe strokes compared with mild strokes.
Patient and proxy ratings on the AM-PAC achieved adequate agreement for use in stroke research where using proxy respondents could reduce sample selection bias. The AM-PAC data can be implemented across institutional as well as community care settings while achieving precision and reducing respondent burden.
stroke outcome; stroke assessment; disability evaluation; rehabilitation
Background and Purpose
Perihematomal edema formation and consequent cell death contribute to the delayed brain injury evoked by intracerebral hemorrhage (ICH). In this study we aimed to evaluate the effect of α7 nicotinic acetylcholine receptor (α7nAChR) stimulation, on behavior, brain edema and neuronal apoptosis. Furthermore we aimed to determine the role of the pro-apoptotic glycogen synthase kinase-3β (GSK-3β) after experimental ICH.
Male CD-1 mice (n=109) were subjected to intracerebral infusion of autologous blood (n=88) or sham surgery (n=21). ICH animals received either vehicle administration, 4 or 12 mg/kg of α7nAChR agonist PHA-543613, 12 mg/kg of α7nAChR agonist PNU-282987, 6 mg/kg of α7nAChR antagonist methyllycaconitine (MLA), 15 μg/kg of phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin or PHA-543613 combined with MLA or wortmannin. Behavioral deficits and brain water content were evaluated at 24 and 72 hours after surgery. Western blotting and immunofluorescence staining were utilized for the quantification and localization of activated Akt (p-Akt), GSK-3β (p-GSK-3β) and cleaved caspase-3 (CC3). Neuronal cell death was quantified via terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL).
α7nAChR stimulation improved neurological outcome and reduced brain edema at 24 and 72 hours after surgery (p<0.05 compared to vehicle). Furthermore, PHA-543613 treatment increased p-Akt and decreased p-GSK-3β and CC3 expressions in the ipsilateral hemisphere (p<0.05, respectively), which was reversed by MLA and wortmannin. P-Akt, p-GSK-3β and CC3 were generally localized in neurons. PHA-543613 reduced neuronal cell death in the perihematomal area (p<0.05).
α7nAChR stimulation improved functional and morphological outcomes after experimental ICH in mice. PHA-543613 reduced the expression of pro-apoptotic GSK-3β via the PI3K-Akt signaling pathway.
α7 nicotinic acetylcholine receptor; glycogen synthase kinase-3; intracerebral hemorrhage; apoptosis; caspase-3; PHA-543613; PHA-282987
Background and Purpose
The aim of this study was to test whether arterial spin labeling (ASL) can detect significant differences in relative cerebral blood flow (rCBF) in the core, mismatch, and reverse-mismatch regions, and whether rCBF values measured by ASL in those areas differ from values obtained using DSC MRI.
Acute stroke patients were imaged with diffusion (DWI) and perfusion (ASL and DSC) MRI. An expert reader segmented the ischemic lesion on DWI and the DSC time-to-peak (TTP) maps. Three regions were defined: core (DWI+, TTP+), mismatch (DWI−, TTP+) and reverse-mismatch (DWI+, TTP−). For both ASL and DSC, rCBF maps were created with commercially available software, and the ratio was calculated as the mean signal intensity measured on the side of the lesion to that of the homologous region in the contralateral hemisphere. Values obtained from core, mismatch, and reverse-mismatch were used for paired comparison.
Twenty-eight patients were included in the study. The mean age was 65.6 (16.9) years with a median baseline NIHSS of 10 (IQR 4-17). Median time from last known normal to MRI was 5.7 hours (IQR 2.9-22.6). Mean rCBF ratios were significantly higher in the mismatch 0.53 (0.23) versus the core 0.39 (0.33) and reverse-mismatch 0.68 (0.49) versus the core 0.38 (0.35). Differences in rCBF measured with DSC and ASL was not significant.
ASL allows for the measurement of rCBF in the core and mismatch regions. Values in the mismatch were significantly higher than in the core, suggesting there is potential salvageable tissue.
acute stroke; cerebral blood flow; perfusion quantification
Background and Purpose
Coil compaction is thought to be the main mechanism for recurrence in cerebral aneurysms with previously successful coil embolization. We hypothesize that sac growth may be equally or more important. The objective is to study the relative roles of coil compaction and sac growth as explanations for aneurysm recurrence requiring re-treatment in a study population using quantitative three-dimensional image processing methods.
From July 2009 to December 2010, 175 aneurysms were coiled at the University of Iowa Hospitals and Clinics. Eight aneurysms had major recurrence requiring re-treatment (4.4 to 12.1 months between procedures; mean 7.2 months). The 3-dimensional structures of the vessel and coil mass were reconstructed using rotational angiography data scanned before and after both initial coil embolization and retreatment. Changes in the sac and coil mass over time were visualized using model registration techniques and quantified using volume calculations.
All eight coiled aneurysms with major recurrence had significant aneurysm sac growth (15–102% increase in volume), independent of change in coil volume. Five aneurysms with major recurrence had sufficient data for assessment of coil compaction. The Coil mass volume decreased in one aneurysm (12% compaction by volume), did not change significantly in one aneurysm (increased by 1%) and significantly increased in three aneurysms (8%, 21%, and 25%) between the first treatment and before the second treatment.
In this study population, aneurysm sac growth, not coil compaction was the primary mechanism associated with recurrence following initial coil embolization.
cerebral aneurysm; recurrence; image analysis; sac growth; coil compaction
Disruption of the blood-brain barrier (BBB) and edema formation play a key role in the development of neurological dysfunction in acute and chronic cerebral ischemia. Animal studies have revealed the molecular cascades that are initiated with hypoxia/ischemia in the cells forming the neurovascular unit (NVU) and that contribute to cell death. Matrix metalloproteinases (MMPs) cause reversible degradation of tight junction proteins (TJPs) early after the onset of ischemia and a delayed secondary opening during a neuroinflammatory response occurring from 24 to 72 hrs. Cyclooxgyenases (COX) are important in the delayed opening as the neuroinflammatory response progresses. An early opening of the BBB within the three-hour therapeutic window for tissue plasminogen activator (tPA) can allow it to enter the brain and increase the risk of hemorrhage. Chronic hypoxic hypoperfusion opens the BBB, which contributes to the cognitive changes seen with lacunar strokes and white matter injury in subcortical ischemic vascular disease (SIVD). This review will describe the molecular and cellular events associated with BBB disruption and potential therapies directed toward restoring the integrity of the NVU.
Background and Purose
Disruption of the blood-brain barrier (BBB) has been proposed to be important in vascular cognitive impairment (VCI). Increased cerebrospinal fluid (CSF) albumin and contrast-enhanced MRI provide supporting evidence, but quantification of the BBB permeability in patients with VCI is lacking. Therefore, we acquired dynamic contrast-enhanced MRI (DCEMRI) to quantify BBB permeability in VCI.
We studied 60 patients with suspected VCI. They had neurological and neuropsychological testing, permeability measurements with DCEMRI and lumbar puncture to measure albumin index (Qalb). Patients were separated clinically into subcortical ischemic vascular disease (SIVD), multiple and lacunar infarcts (MI/LAC), and leukoaraiosis (LA). Twenty volunteers were controls for the DCEMRI studies, and control CSF was obtained from 20 individuals undergoing spinal anesthesia for non-neurological problems.
Thirty-six patients were classified as SIVD, 8 as MI/LAC and 9 as LA. The Qalb was significantly increased in the SIVD group compared to 20 controls. Permeabilities for the VCI patients measured by DCEMRI were significantly increased over controls (p<0.05). Patient age correlated with neither the BBB permeability nor Qalb. Highest Qalb values were seen in SIVD group (p<0.05), and were significantly increased over MI/LAC. Ki values were elevated over controls in SIVD, but were similar to MI/LAC.
There was abnormal permeability in white matter in patients with SIVD as shown by DCEMRI and Qalb. Future studies will be needed to determine the relationship of BBB damage and development of WMHs.
Albumin; blood-brain barrier; vascular cognitive impairment; MRI; cerebrospinal fluid
Background and Purpose
S-nitrosylated hemoglobin (S-nitrosohemoglobin) has been implicated in the delivery of O2 to tissues through the regulation of microvascular blood flow. This study tested the hypothesis that enhancement of S-nitrosylated hemoglobin by ethyl nitrite inhalation improves outcome after experimental subarachnoid hemorrhage (SAH).
A preliminary dosing study identified 20 ppm ethyl nitrite as a concentration that produced a 4-fold increase in S-nitrosylated hemoglobin concentration with no increase in methemoglobin. Mice were subjected to endovascular perforation of the right anterior cerebral artery and were treated with 20 ppm ethyl nitrite in air, or air alone for 72 hours, after which neurologic function, cerebral vessel diameter, brain water content, cortical tissue PO2, and parenchymal red blood cell flow velocity were measured.
At 72 hours after hemorrhage, air- and ethyl nitrite– exposed mice had similarly sized blood clots. Ethyl nitrite improved neurologic score and rotarod performance; abated SAH-induced constrictions in the ipsilateral anterior, middle cerebral, and internal carotid arteries; and prevented an increase in ipsilateral brain water content. Ethyl nitrite inhalation increased red blood cell flow velocity and cortical tissue PO2 in the ipsilateral cortex with no effect on systemic blood pressure.
Targeted S-nitrosylation of hemoglobin improved outcome parameters, including vessel diameter, tissue blood flow, cortical tissue PO2, and neurologic function in a murine SAH model. Augmenting endogenous PO2-dependent delivery of NO bioactivity to selectively dilate the compromised cerebral vasculature has significant clinical potential in the treatment of SAH.
brain; mouse; subarachnoid hemorrhage; S-nitrosylated hemoglobin; ethyl nitrite
Background and Purpose
The piwi-interacting RNA (piRNA) is the most predominant RNA species in eukaryotes. The piRNA are a class of non-coding (nc) RNA that bind and degrade the RNA formed by the transposons to control the transposon -induced gene mutations. The role of piRNA after focal ischemia is not yet evaluated.
We profiled 39,727 piRNAs in the cerebral cortex of adult rats subjected to transient focal ischemia using microarrays. The RT targets of stroke-responsive piRNAs were identified with bioinformatics. To understand how piRNA are controlled, we analyzed the transcription factor (TF) binding sites in the putative promoters of 10 representative stroke-responsive piRNAs.
In the ipsilateral cortex of ischemic rats, 105 piRNAs showed altered expression (54 up- and 51 down-regulated; >2.5 fold) compared to sham. Twenty five of those showed >5-fold change. A bioinformatics search showed that the transposon targets of the highly stroke-responsive piRNAs are distributed among the 20 autosomal chromosomes and there is a redundancy in the targets between the piRNAs. Furthermore, the transposon targets were observed to be highly repetitious for each piRNA across the chromosome length. Of the 159 TFs observed to have binding sites in the piRNA gene promoters, 59% belonged to 20 major families indicating that TFs control stroke-responsive piRNAs in a redundant manner.
The present study is the first to show that many piRNAs are expressed in adult rodent brain and several of them respond to focal ischemia.
Non-coding RNA; Stroke; Transposons; Brain damage; Bioinformatics; Expression profiling
Background and Purpose
Although cigarette smoking is known to be a risk factor for ischemic stroke, there are few data on the dose-response relationship between smoking and stroke risk in a young ethnically diverse population.
We used data from the Stroke Prevention in Young Women Study, a population-based case-control study of risk factors for ischemic stroke in women aged 15 to 49 years to examine the relationship between cigarette smoking and ischemic stroke. Historical data, including smoking history, was obtained through standardized interviews. Odds ratios (OR) were estimated using logistic regression. Cases (n=466) were women with stroke in the greater Baltimore-Washington area, and controls (n=604) were women free of a stroke history identified by random digit dialing.
After multivariable adjustment, the OR comparing current smokers to never smokers was 2.6 (P<0.0001); no difference in stroke risk was observed between former smokers and never smokers. Adjusted OR increased with increasing number of cigarettes smoked per day (OR=2.2 for 1 to 10 cigs/d; 2.5 for 11 to 20 cigs/d; 4.3 for 21 to 39 cigs/d; 9.1 for 40 or more cigs/d).
These results suggest a strong dose-response relationship between cigarette smoking and ischemic stroke risk in young women and reinforce the need for aggressive smoking cessation efforts in young adults.
stroke; women; smoking
Background and Purpose
The cause of initial ischemic stroke in up to 30% of young patients remains unclear. Fabry disease, due to deficient α-galactosidase A (α-Gal A) activity, is a vascular endothelial glycosphingolipid storage disease typically presenting in childhood. With advancing age, patients develop renal, cardiac, and cerebrovascular disease and die prematurely. A European study suggested an increased prevalence of unrecognized Fabry disease in patients with cryptogenic stroke. We hypothesized that α-Gal A deficiency is a rare cause of initial early-onset ischemic stroke in men.
The Stroke Prevention in Young Men Study enrolled >550 men (15 to 49 years) with first ischemic stroke in the Baltimore–Washington area in 2004 to 2007. Frozen plasma samples were assayed for α-Gal A activity, and DNA from patients with consistently low plasma α-Gal A activities were sequenced.
The study sample consisted of 558 men (42% African-American; median age 44 years). Stroke was cryptogenic in 154 men (40% African-American). In 10 patients with low plasma α-Gal A activities, DNA sequencing identified alterations in the α-Gal A gene in 2 patients. The polymorphism, D313Y, which results in low plasma enzyme activity, but near normal levels of cellular activity was seen in one European-American male. The Fabry disease-causing A143T mutation was seen in an African-American male with cryptogenic stroke (0.18% of all strokes: upper 95% CI=0.53%; 0.65% of cryptogenic strokes: upper 95% CI=1.92%).
In this biracial population, unrecognized Fabry disease is a rare but treatable cause of initial ischemic stroke in young men.
brain infarction; genetic diseases; genetic screening; Fabry disease; stroke; X-linked
We report the case of a young man with recurrent posterior circulation strokes over the course of 6 years. Standard stroke evaluation was unremarkable until careful review of catheter angiogram and CT angiogram images revealed a bony protuberance from the occiput impinging on the left vertebral artery. Local vessel injury with thrombosis and distal embolization is the presumed etiology of the recurrent infarcts. Surgical removal of this developmental anomaly was accomplished, with no subsequent neurological events.
anatomy; angiography; neurosurgery; stroke; vertebrobasila
Background and purpose
Our objective was to investigate the associations between polymorphisms in representative genes of the renin angiotensin system with measures of cerebral blood flow regulation in older adults.
Participants in this analysis were white subjects (n=335) in the MOBILIZE Boston study, an observational study of community-dwelling elders who underwent transcranial Doppler while sitting and standing and during hypercapnea and hypocapnea. Autoregulation phenotype was the change in cerebrovascular resistance from sit to stand. Vasoreactivity (VR) phenotype was the slope of the change in cerebrovascular conductance vs change in end-tidal CO2. Total of 33 tagged single nucleotide polymorphisms (SNP) were selected in the angiotensinogen gene (AGT), the angiotensin converting enzyme (ACE) gene and the angiotensin receptor gene (AGTR). Regression analyses adjusted for age, gender, body mass index, mean arterial blood pressure, stroke and use of antihypertensives were conducted for each SNP and outcome. Bonferroni corrections were used to adjust p-values for multiple testing.
In the AGT gene, only the rs699 SNP was associated with VR after Bonferroni correction (p=0.00028). Homozygous carriers of the CC genotype of this SNP had lower VR compared to the CT or TT genotypes. There were no significant associations with autoregulation measures. None of the SNP’s in the other genes was associated with our phenotypes.
This analysis suggests that the AGT gene may be involved in vasoreactivity independent of blood pressure. Larger studies are needed to confirm the role of this gene in cerebrovascular health and aging.
Angiotensin; cerebral blood flow; vasoreactivity
Background and Purpose
Cerebral cavernous malformations (CCMs) are characterized by grossly dilated capillaries, associated with vascular leak and hemorrhage, and occur in sporadic or inherited (autosomal dominant) forms with mutations in one of three gene loci (CCM 1, 2 or 3). We previously reported that the CCM1 protein (KRIT1) localizes to endothelial cell-cell junctions and loss of KRIT1 leads to junctional instability associated with activation of RhoA and its effector Rho kinase (ROCK). Although ROCK inhibition has been proposed as potential therapy for CCM, there has been no demonstration of a therapeutic effect on CCM lesion genesis in vivo.
Our recently generated a model of CCM1 disease (Ccm1+/−Msh2−/−) was treated with ROCK inhibitor fasudil (100 mg/kg/day administered in drinking water from weaning to 5 months of age), or placebo, and blindly assessed CCM lesion burden by systematic survey of animals’ brains. For comparison, we also assessed therapeutic effect in previously described Ccm2+/−Trp53−/− mice, treated with the same dose and duration of fasudil and placebo.
Fasudil treated Ccm1+/−Msh2−/− mice had a significantly decreased prevalence of CCM lesions compared to placebo controls. Lesions in treated animals were smaller and less likely associated with hemorrhage, inflammation and endothelial proliferation, and exhibited decreased expression of ROCK activation biomarkers. A therapeutic effect was also documented in Ccm2+/−Trp53−/− mice.
This represents the first report of therapeutic benefit of pharmacological therapy in development and progression of CCMs, and indicates that ROCK activation is a critical step in CCM lesion genesis and maturation.
Cerebral cavernous malformation; cavernous angioma; ROCK; Fasudil; therapy
Background and Purpose
The Pediatric National Institutes of Health Stroke Scale (PedNIHSS), an adaptation of the adult NIH Stroke Scale, is a quantitative measure of stroke severity shown to be reliable when scored prospectively. The ability to calculate the PedNIHSS score retrospectively would be invaluable in the conduct of observational pediatric stroke studies. The study objective was to assess the concurrent validity and reliability of estimating the PedNIHSS score retrospectively from medical records.
Neurological examinations from medical records of 75 children enrolled in a prospective PedNIHSS validation study were photocopied. Four neurologists of varying training levels blinded to the prospective PedNIHSS scores reviewed the records and retrospectively assigned PedNIHSS scores. Retrospective scores were compared among raters and to the prospective scores.
Total retrospective PedNIHSS scores correlated highly with total prospective scores (R2=0.76). Interrater reliability for the total scores was “excellent” (intraclass correlation coefficient of 0.95, 95% confidence interval 0.94–0.97). Interrater reliability for individual test items was “substantial” or “excellent” for 14 of 15 items.
The PedNIHSS score can be scored retrospectively from medical records with a high degree of concurrent validity and reliability. This tool can be used to improve the quality of retrospective pediatric stroke studies.
arterial ischemic stroke; pediatric; NIH stroke scale
Background and Purpose
Severely elevated blood pressure (BP) and aggressive BP reduction are both associated with poor outcome in acute ischemic stroke (AIS). In non-tPA patients, the AHA recommends anti-hypertensive therapy only if BP is ≥220/120mmHg, with a goal of 15–25% reduction in the first 24hours. We hypothesized that AIS patients often receive anti-hypertensives in the emergency department (ED) below the recommended threshold, and that BP reduction is often greater than 20%.
In 2005, AIS cases were ascertained at all 16 hospitals in Greater Cincinnati. BP was recorded at ED presentation and before and after anti-hypertensive treatment. Hypertension was defined as BP ≥220/120mmHg. Chi square and Mann-Whitney U-tests were used for comparisons.
1739 AIS patients met inclusion criteria. Median age was 72years, with 43% male and 25% black. Of 218 treated with anti-hypertensives, 65 (30.0%) met treatment criteria immediately prior to treatment. Treated patients were younger (66 vs. 73years, p<0.001) with greater stroke severity than untreated patients (NIHSS 4 vs. 3, p=0.028). Median change in systolic BP was -25mmHg (range −96 to 25). Median percentage change in systolic BP was −12.3% (range −49.2 to 16.1). Systolic BP decreased more than 20% in 52 treated patients (23.7%).
Only one-third of AIS patients treated with anti-hypertensives met AHA recommended treatment criteria, and the rate of change of BP was frequently greater than recommended. Further studies are warranted to determine the impact of practice patterns on AIS outcomes.
Emergency Medicine; blood pressure; acute stroke; cerebral infarct
Stroke related tissue pressure increase in the core (Pcore) and penumbra (Ppen) determines regional cerebral perfusion pressure (rCPP) defined as a difference between local inflow pressure (Pi) and venous (Pv) or tissue pressure, whichever is higher. We previously showed that venous pressure reduction below the Pcore causes blood flow diversion - cerebral venous steal. Now we investigated how transition to collateral circulation after complete arterial occlusion affects rCPP distribution.
We modified two parallel Starling resistor model to simulate transition to collateral inflow after complete main stem occlusion. We decreased Pv from the arterial pressure (Pa) to zero, and investigated how arterial and venous pressure elevation augments rCPP.
When core pressure exceeded venous (Pcore>Pv), rCPP=Pi−Pcore. Venous pressure (Pv) decrease from Pa to Pcore caused smaller Pi to drop augmenting rCPP. Further drop of Pv to Ppen decreased rCPP in the core but augmented rCPP in penumbra. After transition to collateral circulation, lowering Pv below Ppen further decreased rCPP and collaterals themselves became pathway for steal. Venous pressure level at which rCPP in the core becomes zero we termed the “point of no reflow” (PONR). Transition from direct to collateral circulation resulted in decreased Pi, decreased rCPP, and a shift of PONR to higher venous loading values. Arterial pressure augmentation increased rCPP, but only after venous pressure exceeded PONR.
In the presence of tissue pressure gradients, transition to collateral flow predisposes to venous steal (collateral failure) which may be reversed by venous pressure augmentation.
Stroke; no reflow; hemodynamics; collaterals; venous; ischemia zero flow; perfusion pressure
Background and Purpose
Endoplasmic reticulum stress triggers apoptotic cascades in neurons of the central nervous system after subarachnoid hemorrhage (SAH). The aim of this work was to study the mechanism of neuroprotection conferred by targeting CHOP in the acute brain injury following SAH.
A total of 172 rats were used. SAH was induced by endovascular perforation. Two small interfering RNAs for CHOP were injected 24hrs before hemorrhage induction. At 24 or 72 hours rats were neurologically evaluated and euthanized. The brains were recovered for molecular biology and histology studies.
Western blot analysis revealed effective silencing of CHOP associated with suppression of Bim-Caspase-3 apoptotic pathway. Moreover, the anti apoptotic Bcl2 was found upregulated with CHOP siRNA treatment. Histological protection was reflected by a reduced number of TUNEL positive cells in the subcortex and in the hippocampus. CHOP siRNA treatment ameliorated intracranial sequelae of SAH and improved functional performance.
We conclude that CHOP silencing alleviates early brain injury following SAH via inhibiting apoptosis and that CHOP siRNA treatment has a clinical potential for patients with this type of hemorrhagic stroke.
Subarachnoid hemorrhage; siRNA; CHOP; Bim; Bcl2; Apoptosis
Elevated serum levels of brain natriuretic peptide (BNP) have been associated with cardioembolic (CE) stroke and increased post-stroke mortality. We sought to determine whether BNP levels were associated with functional outcome after ischemic stroke.
We measured BNP in consecutive patients aged ≥18 years admitted to our Stroke Unit between 2002–2005. BNP quintiles were used for analysis. Stroke subtypes were assigned using TOAST criteria. Outcomes were measured as 6-month modified Rankin Scale score (“good outcome” = 0–2 vs. “poor”) as well as mortality. Multivariate logistic regression was used to assess association between the quintiles of BNP and outcomes. Predictive performance of BNP as compared to clinical model alone was assessed by comparing ROC curves.
Of 569 ischemic stroke patients, 46% were female; mean age was 67.9 ± 15 years. In age- and gender-adjusted analysis, elevated BNP was associated with lower ejection fraction (p<0.0001) and left atrial dilatation (p<0.001). In multivariate analysis, elevated BNP decreased the odds of good functional outcome (OR 0.64, 95%CI 0.41–0.98) and increased the odds of death (OR 1.75, 95%CI 1.36–2.24) in these patients. Addition of BNP to multivariate models increased their predictive performance for functional outcome (p=0.013) and mortality (p<0.03) after CE stroke.
Serum BNP levels are strongly associated with CE stroke and functional outcome at 6 months after ischemic stroke. Inclusion of BNP improved prediction of mortality in patients with CE stroke.
Ischemic Stroke; Outcome; Biomarkers