Search

Background and Purpose: Studies of carotid artery disease have suggested that high-grade stenosis can affect cognition, even without stroke. The presence and degree of cognitive impairment in such patients have not been reported and compared with a demographically matched population-based cohort. Methods: We studied cognition in 1000 consecutive CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) patients, a treatment trial for asymptomatic carotid disease. Cognitive assessment was after randomization but before assigned treatment. The cognitive battery was developed in the general population REGARDS Study (Reasons for Geographic and Racial Differences in Stroke), involving Word List Learning Sum, Word List Recall, and Word List fluency for animal names and the letter F. The carotid stenosis patients were >45 years old with ≥70% asymptomatic carotid stenosis and no history of prevalent stroke. The distribution of cognitive performance for the patients was standardized, accounting for age, race, and education using performance from REGARDS, and after further adjustment for hypertension, diabetes, dyslipidemia, and smoking. Using the Wald Test, we tabulated the proportion of Z scores less than the anticipated deviate for the population-based cohort for representative percentiles. Results: There were 786 baseline assessments. Mean age was 70 years, 58% men, and 52% right-sided stenosis. The overall Z score for patients was significantly below expected for higher percentiles ( P P =0.015). Lower performance was attributed largely to Word List Recall ( P P ≤0.01). The scores for left versus right carotid disease were similar. Conclusions: Baseline cognition of patients with severe carotid stenosis showed below normal cognition compared to the population-based cohort, controlling for demographic and cardiovascular risk factors. This cohort represents the largest group to date to demonstrate that poorer cognition, especially memory, in this disease. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02089217.

Introduction: Cognitive decline and dementia after stroke is a major public healthcare problem, with dementia risk doubling over time, affecting more than 2M people in the US, with no current treatment. Silent brain infarction has been associated with cognitive decline, especially among those at risk for cardio-embolism. The therapeutic challenge is to prevent the occurrence of silent infarction to mitigate proactively the loss of cognitive function. Methods: The NINDS-funded ARCADIA-CSI is an ancillary study to ARCADIA, a randomized trial comparing apixaban vs aspirin to prevent recurrent clinical stroke in patients with cryptogenic stroke and left atrial cardiopathy. The aim of ARCADIA-CSI is to address whether apixaban might also reduce the incidence of silent infarction and be associated with better cognitive function over time compared to aspirin. Five hundred patients will be enrolled at least 90 days after the ARCADIA index stroke and undergo cognitive assessments at baseline and yearly thereafter using a telephone-based cognitive battery. We are testing the hypothesis that the slope of change in cognitive function is less steep during the follow-up period in patients on apixaban compared to patients on aspirin therapy. We will also collect an initial MRI around the time of the qualifying stroke and a follow-up MRI at the time that the subject completes participation in the ARCADIA parent study to assess the occurrence of new silent infarction. Results: As of August 12, 2021, the study has enrolled 188 subjects from 78 ARCADIA sites which have been green-lighted for enrollment in ARCADIA-CSI. A total of 61 sites have enrolled at least one subject. To date, there is a 95% completion of baseline cognitive exams and 98% completion at the 1-yr follow-up. We have obtained 91% of the clinical scans of the index stroke of which 95% have undergone central reading and interpretation. Conclusion: ARCADIA-CSI is designed to identify the most favorable medical approach to prevent the occurrence of silent infarction and cognitive decline in the setting of secondary stroke prevention. An update will be provided regarding the number of patients enrolled, centers green-lighted, and the completion rates of cognitive assessments, and MRIs obtained and interpreted.

Introduction: Associations between post-stroke vascular risk factors levels with post-stroke cognitive decline are uncertain. We determined associations between systolic blood pressure (BP), glucose, and low-density lipoprotein (LDL) cholesterol levels with post-stroke cognitive decline. Hypothesis: Higher post-stroke systolic BP, glucose, and LDL cholesterol levels are associated with faster post-stroke cognitive decline. Methods: This cohort study pooled data from 832 participants 18 and older with incident stroke and free of dementia before stroke (50% women and 32% Black) from 4 cohort studies from 1971-2019: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Offspring Study, and REasons for Geographic and Racial Differences in Stroke Study. Linear mixed-effects models were used to estimate longitudinal changes in cognition after incident stroke. The primary outcome was change in global cognition. Global cognition was harmonized across studies and standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median (IQR) follow-up was 5.5 (3.3-8.3) years. Results: In separate models, higher post-stroke glucose and LDL levels, but not systolic BP, were associated with faster declines in global cognition (Models M1a, M1b, and M1c, Table 1). In a model with all three vascular risk factors, higher post-stroke mean glucose and LDL levels were associated with faster global cognition decline, though not to traditional levels of statistical significance; however, post-stroke mean systolic BP was not associated with global cognition decline (Model M2, Table 1). Older age was associated with faster cognitive decline in all models. Conclusions: Our results suggest that higher post-stroke glucose and LDL levels are associated with faster post-stroke cognitive decline. We found no evidence that post-stroke BP levels are associated with post-stroke cognitive decline.

A healthy brain is critical for living a longer and fuller life. The projected aging of the population, however, raises new challenges in maintaining quality of life. As we age, there is increasing compromise of neuronal activity that affects functions such as cognition, also making the brain vulnerable to disease. Once pathology-induced decline begins, few therapeutic options are available. Prevention is therefore paramount, and primary care can play a critical role. The purpose of this American Heart Association scientific statement is to provide an up-to-date summary for primary care providers in the assessment and modification of risk factors at the individual level that maintain brain health and prevent cognitive impairment. Building on the 2017 American Heart Association/American Stroke Association presidential advisory on defining brain health that included “Life’s Simple 7,” we describe here modifiable risk factors for cognitive decline, including depression, hypertension, physical inactivity, diabetes, obesity, hyperlipidemia, poor diet, smoking, social isolation, excessive alcohol use, sleep disorders, and hearing loss. These risk factors include behaviors, conditions, and lifestyles that can emerge before adulthood and can be routinely identified and managed by primary care clinicians.

Background: Data from the CDC show that approximately one-quarter of adults have elevated triglyceride (TG) levels. Recent trials have demonstrated that pharmacologic treatment of high TG levels, in patients already on statin therapy, reduces the rate of major vascular events such as myocardial infarction and stroke (REDUCE-IT trial). We sought to assess how often patients with asymptomatic carotid stenosis (CS) have elevated TG levels and factors associated with high TG values. Methods: Patients enrolled in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST 2) were analyzed. Baseline lipid profiles were evaluated to determine high TG treatment eligibility as per the REDUCE-IT trial. We also evaluated baseline use of pharmacologic treatment for high TG levels. Demographic factors and baseline medical conditions were studied in relation to high (>150 mg/dl) TG values. Chi square and t tests were used to assess baseline factors and abnormal TG values. Results: As of August 10, 2020, 1655 of 1689 randomized patients (mean age 69.7 years, 61% men) had baseline lipid profiles suitable for analysis. Treatment eligibility according to REDUCE-IT (LDL 41-100 mg/dl, TG>150 mg/dl) was present in 21% (345) of subjects. In these patients, the median TG value was 205 (IQR 93) mg/dl. Fibrate medications were used at baseline in 4.5% of patients. Analysis of demographic and medical history factors and TG values greater than 150 mg/dl is found in the Table. There was significant positive correlation between baseline hemoglobin A1C and triglyceride values (p Conclusions: One in five patients in CREST 2 has TG values that potentially justify pharmacologic treatment. Elevated TG levels are most correlated with diabetes, hypertension, obesity, decreased physical activity, and heart disease. Clinicians should investigate treatment of elevated TG levels as a component of intensive medical therapy for stroke prevention.

Introduction: The Emergency Medical Stroke Assessment (EMSA) is a six point stroke severity scale with one point each for gaze preference, facial droop, arm drift, leg drift, abnormal naming, and abnormal repetition that was developed to help emergency medical services (EMS) providers identify acute ischemic stroke (AIS) patients with large vessel occlusion (LVO). We hypothesized that the EMSA would detect left hemisphere LVO with a higher sensitivity than right hemisphere LVO. Methods: We trained 24 trauma system-based emergency communication center (ECC) paramedics in the EMSA. ECC-guided EMS in performance of the EMSA on patients with suspected stroke. We compared the sensitivity, specificity, area under the curve (AUC), and 95% confidence interval (CI) of ECC-guided prehospital EMSA for right versus left hemisphere ICA or M1 occlusion. Results: We enrolled 569 patients from September 2016 through February 2018, out of which 236 had a discharge diagnosis of stroke and 173 had a diagnosis of AIS. We excluded patients with bilateral (n=21) and brainstem (n=21) AIS. There were 64 patients with left hemisphere AIS including 19 with LVO. There were 67 patients with right hemisphere AIS including 22 with LVO. A score of ≥ 4 points yielded a sensitivity of 84.2 (95% CI = 60.4-96.6) and specificity of 66.7 (51.1-80.0) for left hemisphere LVO compared to a sensitivity of 68.2 (45.1-86.1) and specificity of 73.9 (58.9-85.7) for right hemisphere LVO. For predicting a left hemisphere LVO, the AUC was 0.77 (0.65-0.90) compared to 0.66 (0.50-0.82) for right-sided LVO. Assigning 2 points for abnormal gaze yielded an AUC of 0.78 (0.66-0.91) versus 0.67 (0.52-0.83) for left and right hemisphere LVO, respectively. Conclusions: The EMSA, like the National Institutes of Health Stroke Scale (NIHSS) upon which it is based, is more sensitive to left compared to right hemisphere LVO. More heavily weighting abnormal gaze did not improve the sensitivity of the EMSA for right hemisphere LVO. There is no comparable data on the right versus left hemisphere performance of other prehospital scales. There is a need to develop sensitive tests of right hemisphere dysfunction that are suitable for use in the field.

Objective: To determine if aortic stenosis (AS) is associated with altered cerebral hemodynamics and impaired neurocognition, and whether TAVR improves hemodynamics and cognition. Background: AS results in higher systolic pressure to overcome resistance from the stenotic valve, leading to heart failure and decline in cardiac output. There has been no baseline assessment of CBF with neurocognition in AS, or the effects of valve replacement. Methods: In 40 patients with planned TAVR, transcranial Doppler (TCD) assessed bilateral MCA mean flow velocity (MFV); abnormality was < 30cc/sec. The neurocognitive battery assessed memory, language, attention, visual-spatial skills, and executive function, yielding an average Z-score. Impairment was < 1.5 SD’s below the normative mean. Results: The mean age was 78 years, 59% male, and the mean valve gradient was 46.87%. Mean follow-up was 36 days post-TAVR (range 27 - 55). Before TAVR, the average MFV was 42 cc/sec (SD=10.22), and the mean cognitive score was -0.22 SD’s (range -1.99 to 1.08) below the normative mean. Of the 5 with abnormal MFV’s, none had abnormal cognition (average=0.19 SD’s above the normative mean). After TAVR, the MFV was 43 cc/sec, not different from baseline (p=0.56). The post-TAVR average Z-score was 0.01 SD’s above the normative mean, also not different from baseline (p=0.29). There was no correlation between the change scores in MFV and in neurocognition (r = 0.08, p= 0.69). Conclusions: Among patients with severe AS, there was no correlation at baseline between abnormal MFV’s on TCD and abnormal neurocognition. It was therefore unsurprising that there was little impact of valve replacement on these measures of cerebral blood flow and brain function. Prior assumptions about diminished CBF and the relationship to cognitive function may not be supported.

Background: Presence of atherosclerotic disease in more than one vascular bed (polyvascular disease) is associated with an increased risk of long-term vascular events. In the setting of asymptomatic carotid stenosis, the predictors of disease in other vascular beds is not well delineated. Objective: To identify the frequency and predictors of disease in other vascular beds the CREST 2 randomized trial population with hemodynamically significant stenosis. Methods: Recorded baseline characteristics among CREST 2 participants included: demographics, past medical history, lifestyle factors, and laboratory studies. Each variable was tested against three potential definitions of disease in other beds (cardiac, peripheral arterial disease (PAD) or disease in cardiac + PAD). Statistical analysis was done with Chi square and t tests as appropriate. Results: Data from 1447 patients were available for analysis. In these subjects with carotid disease, 51% also had cardiac disease, 24% also had PAD, and 16% had disease in in both cardiac and PAD. There was no relationship between age or race and presence of disease in other beds. Those with cardiac disease were more likely to be male. Diabetes, hypertension, hypercholesterolemia, and former history of smoking were all more common in those with either cardiac and PAD (TABLE). Elevated triglyceride and low HDL levels were also associated with all three definitions of disease in other beds. Those with either PAD or cardiac + PAD were more likely to be current smokers. Conclusions: Among CREST 2 participants, several medical conditions and lifestyle factors were associated with an increased frequency of disease in other vascular beds. Smoking, in particular, appears to be more common in those with PAD. Future analyses will address whether those with disease in other beds have higher rates of stroke or death.

Background: Perfusion weighted imaging on MRI (MRP) and computerized tomography perfusion (CTP) are increasingly required to manage large vessel disease. Computerized algorithms can quantify perfusion data, but the programs are expensive and not widely used outside acute stroke evaluation. We aimed to determine how well human observers can identify asymmetries in cerebral perfusion images compared with an automated computer algorithm. Methods: Ten clinicians experienced in treating carotid artery disease (4 vascular neurologists, 3 neuroradiologists, 1 vascular surgeon, 1 neurosurgeon, 1 interventional radiologist) were given 28 post-processed, color-coded, axial-slice MRP scans from patients in the Carotid Revascularization Endovascular versus Stenting Trial - Hemodynamics (CREST-H) study. All patients had >70%, unilateral, asymptomatic carotid artery stenosis and had varying degrees of time-to-peak (TTP) delay on the side of stenosis, ranging from 0 to 2 secs, quantified by a semi-automated system that computes quantitative perfusion maps, using deconvolution of tissue and arterial signals (Olea, Cambridge, MA). A minimum volume of 10cc was required for a given TTP delay. Clinicians were asked to determine asymmetry (y/n) and side of occlusion for each case. Number of correct responses that matched the computer output were tallied. Results: We averaged correct responses by the 10 clinicians for cases at each increment of TTP delay; (Figure). At TTP delays ≥1.5 seconds, accuracy was ≥80%. At 1.25 sec accuracy fell to 60%, and at ≤ 1 sec, accuracy was ≤50%. For TTP=0 (no asymmetry), accuracy was 71%. Conclusions: Visual impression of hemodynamic asymmetry among experienced clinicians was reasonably accurate for TTP delays ≥1.5 seconds, but declined with more subtle asymmetries. Depending on the clinical impact of TTP delays (for CREST-H: correlation with cognitive decline), experienced clinicians may perform as well as an automated algorithm.

Stroke is the second leading cause of death and the third leading cause of disability-adjusted life years worldwide. Although numerous therapies have been developed over the past 10 years to treat acute ischemic stroke, the stark reality remains that only 5% of these patients are so treated in the United States,1 in part, because of treatment window times 7 million stroke survivors …

Background: The importance of physical activity in preventing major vascular events has received increased attention in the past decade. Due to the inclusion of the INTERVENT lifestyle modification program, the CREST2 trial provides a unique opportunity to study physical activity profiles in patients with severe asymptomatic extracranial carotid stenosis. Hypothesis: Based on data from a trial of intracranial stenosis patients, we aimed to evaluate the hypothesis that Methods: We analyzed 1087 CREST2 participants with baseline data on physical activity. The Physician-based Assessment and Counseling for Exercise (PACE) score is recorded for each patient and dichotomized as “in target” (4-8 points) or “out of target” ( Results: The mean age of the study population is 69.5±7.8 years (60% male). The median PACE score at baseline is 4.0 (mean 3.8±2.1; IQR 2 to 6). The Table shows baseline characteristics of patients by mean PACE score. Being male, not having diabetes mellitus, having a body mass index Conclusions: We have defined several patient groups with asymptomatic carotid stenosis that have suboptimal physical activity. These results provide opportunities for targeted efforts to improve primary stroke prevention. These baseline data will also allow investigators to determine if trial involvement and the INTERVENT program leads to improvement in the level of physical activity.

Background: In CREST2, intensive medical management of subjects’ vascular risk factors is overseen by the site Principal Investigator (PI) and implemented by a designated Medical Management Physician (MMP) and coordinator. These physicians have different specialties and experience with risk factor management. We sought to determine the relationship between risk factor control and PI and MMP specialty. Methods: Data on 613 patients with at least 1 follow-up visit from 105 CREST2 sites were used for these analyses. CREST2 sites were categorized based on both PI specialty and MMP specialty. Specialty of the site-designated primary MMP was used for sites with more than one MMP. We compared the percentage of patients in target at last follow-up visit for the primary risk factors, LDL < 70 mg/dL and SBP Results: The table shows the number of patients by PI and MMP specialty, as well as their control of SBP and LDL. There were no significant differences in control of SBP or LDL by PI specialty. There was a trend toward an association between LDL control and MMP specialty, with higher rates of LDL control at sites with Internal Medicine MMP specialists and lower rates of control with Vascular Surgery MMPs. SBP control rates were not significantly different across MMP specialties. Conclusions: In this early analysis of risk factor control in the CREST2 study, site PI and MMP specialty did not have a significant effect on LDL and SBP during follow-up. This suggests that protocol care pathways are generalizable to diverse physicians.

Cognitive function is an important component of aging and predicts quality of life, functional independence, and risk of institutionalization. Advances in our understanding of the role of cardiovascular risks have shown them to be closely associated with cognitive impairment and dementia. Because many cardiovascular risks are modifiable, it may be possible to maintain brain health and to prevent dementia in later life. The purpose of this American Heart Association (AHA)/American Stroke Association presidential advisory is to provide an initial definition of optimal brain health in adults and guidance on how to maintain brain health. We identify metrics to define optimal brain health in adults based on inclusion of factors that could be measured, monitored, and modified. From these practical considerations, we identified 7 metrics to define optimal brain health in adults that originated from AHA’s Life’s Simple 7: 4 ideal health behaviors (nonsmoking, physical activity at goal levels, healthy diet consistent with current guideline levels, and body mass index 2 ) and 3 ideal health factors (untreated blood pressure

Objective: To determine whether cognition among those with carotid occlusive disease independently affects Quality of Life (QoL). Introduction: Carotid occlusion may result in stroke, TIA, and reduction in cognition. QoL has been studied in stroke patients but less is known about QoL in patients with carotid occlusive disease without stroke or significant depression. Methods: Subjects, selected from an NIH study of carotid occlusive treatment, included those with with history of TIA or a remote history of minor stroke, and excluded those with a history of stroke within 4 months prior, major deficits in ADL’s, and dementia. Because the relationship between depression and OoL is well-established, we excluded with moderate-severe depression. Patients underwent cognitive examination (memory, language, motor, executive function skills), completed depression and QOL questionnaires (Center for Epidemiological Studies-Depression (CES-D), Stroke Specific Quality of Life (SSQOL), and were rated for stroke severity (NIHSS). Age-corrected Z-scores for cognitive tests were calculated and averaged into a composite cognitive Z-score (Cog-Z). The SSQOL scores were averaged across subgroup domains. Correlation analyses were performed to determine univariate relationships between the variables, with significant values put into in a regression model to predict SSQOL. Results: Among 24 subjects (mean age=58.38 (2.01); 10 women), mean Cog-Z was –1.06 SD (Low Average range), mean CES-D score was 10.77 (normal range), mean NIHSS was 0.46 (normal range), and the mean SSQOL score was 3.92 (needing “a little help”). The correlations between NIHSS, history of prior stroke, and SSQOL were nonsignificant. In a regression model including Cog-Z and CES-D, Cog-Z was an independent predictor of SSQOL (Beta=.389, p=.038). Conclusions: In patients with carotid occlusive disease without major stroke, cognitive scores were independently associated with QOL. Even minor reductions in cognition influenced QoL and were distinct from the influence of depression. These data further establish the clinical relevance of cognitive decline among patients with cerebrovascular conditions.

Objective: Cortical thinning has been reported in patients with cerebrovascular disease and degenerative dementia, but the direct impact of regional hypoperfusion on cortical pathology has been difficult to establish. We examined the association between regional cerebral blood flow (rCBF) and regional cortical thickness (rCT) in a cohort of patients with unilateral high-grade internal carotid artery (ICA) disease without history of stroke. Methods: Twenty-seven patients age 73±10yrs, 11F with unilateral ICA stenosis ≥80% or occlusion but no stroke underwent MRI, including high resolution T1 (MPRAGE) and tissue specific pseudocontinuous arterial spin labeling (ts-pCASL) to assess cortical thickness and gray matter resting CBF. Cortical thickness was measured in each hemisphere in the primary motor cortex (M1--Brodmann Area 4) by a blinded investigator using Freesurfer software ( http://surfer.nmr.mgh.harvard.edu/ ), and in visual cortex (V1, Brodmann area 17) as a control for nonspecific effects in the posterior circulation. Paired t-tests were used to assess hemispheral asymmetry for rCBF and for rCT in M1 on the occluded vs unoccluded side. Linear regression was used to predict the effect of rCBF on rCT in M1 on the occluded side. Results: Cortex was 0.08mm thinner on the side of ICA occlusion in M1 (95%CI=0.04-0.11, p=0.0003). There was no rCT asymmetry in V1 (p=.276). rCBF was 9.3 ml/100gm*min -1 lower in M1 of the occluded hemisphere (95%CI=5.1-13.5, p2 =.128, p=.038). Conclusion: Cortical thinning occurred in M1 on the side of carotid occlusion in the absence of stroke, and correlated with lower rCBF. Brodmann area 4 was chosen to represent the distal field of the carotid artery. Our finding demonstrates an important effect of chronically reduced blood flow on brain pathology, and suggests that a broader definition of “symptomatic” carotid artery disease may be needed.

Background: Cerebral blood flow (CBF) regulation is a critical element in cerebrovascular pathophysiology, particularly in large vessel disease. Different methods to assess hemodynamics may represent different aspects of blood flow regulation, however, uniquely affecting outcomes and management. We examined 4 different blood-flow related measures in patients with high-grade unilateral carotid disease, assessing asymmetry between the occluded vs non-occluded side, and the correlations among the measures. Methods: Thirty-three patients (age 50-93, 19M) with unilateral 80-100% ICA occlusion but no stroke underwent: 1) quantitative resting CBF using continuous arterial spin labeling (CASL) MRI, 2) mean flow velocity (MFV) in both middle cerebral arteries (MCAs) by transcranial Doppler, 3). Vasomotor reactivity (VMR) in response to 2 minutes of 5% CO2 inhalation, and 4) Dynamic cerebral autoregulation (DCA) using continuous insonation of both MCAs for 10 minutes at depth 56mm with a standard head frame. Phase shift (PS) between spontaneous oscillations in blood pressure (measured with finger photoplethysmography) and MCA MFV at frequencies .06-.12 Hz was calculated for each hemisphere using transfer function analysis. Lower PS indicated worse autoregulation. Paired T-tests and Pearson correlations were used to look for side-to-side differences within each measure, and correlations between measures (SPSS v.22). Results: CASL CBF (p=.001), MFV (p0.09). Conclusions: These 4 measures showed high sensitivity to the occluded carotid artery, but appear to represent independent aspects of cerebral blood flow (CASL: resting gray matter CBF; MFV: whole-hemisphere CBF; VMR: cerebrovascular reserve, and DCA: homeostatic blood flow regulation) suggesting that any given measure only partially characterizes hemodynamic state. Further investigation will use these 4 measures to predict outcomes including vascular cognitive impairment.

Background: Prior studies have shown a correlation between the National Institutes of Health Stroke Scale (NIHSS) score and infarct volume on diffusion weighted imaging (DWI); however data are limited in patients with minor stroke whose treatment is controversial. Our aim is to determine the association between DWI lesion(s) volume and the (1) total NIHSS score and (2) NIHSS components in a population of patients with minor ischemic stroke. Methods: We included all patients with minor stroke (NIHSS 0-5) who were enrolled in the prospective Stroke Warning Information and Faster Treatment (SWIFT) study. All patients were admitted to the hospital with a final diagnosis of stroke. We calculated lesion(s) volume (cm 3 ) on DWI sequence using Medical Image Processing, Analysis, and Visualization (MIPAV, NIH, Version 7.1.1). Based on the distribution of lesion volume, we summarized the explanatory value into median cm 3 . We used non-parametric tests to study the association between the primary outcome, DWI lesion(s) volume, and the predictors (NIHSS score and its components). Results: 894 patients had a discharge diagnosis of ischemic stroke; 709 underwent MRI and 510 were DWI positive. There was a weak graded relationship between NIHSS score and median DWI lesion volume in cm 3 : (NIHSS 0: 7.1, NIHSS 1: 8.0, NIHSS 2: 17.1, NIHSS 3: 11.6, NIHSS 4: 19.0, NIHSS 5: 23.6). We also noted highly significant relationships between lesion volume and certain NIHSS components. Compared to patients without the deficit, the median lesion volume was significantly higher in patients with neglect (105.6 vs. 12.5,p=0.025), language disorder (34.6 vs. 11.9,p Conclusion: In patients with minor stroke, the nature of the neurological deficit improves prediction of infarct volume when added to the total NIHSS score. This may lead to clinical and therapeutic implications.

Background: High grade internal carotid artery (ICA) disease can alter cerebral autoregulation and thus increase risk for ischemia. We aimed to differentiate two types of autoregulation - dynamic cerebral autoregulation (DCA), thought to be a homeostatic process, and vasomotor reactivity (VMR), which determines cerebrovascular reserve - in patients with asymptomatic ICA stenosis. Methods: Twenty-two patients (age 50-93, 16M) with unilateral 80-100% ICA occlusion but no stroke underwent quantitative CBF measurements using continuous arterial spin labeling (CASL) MRI. DCA was performed by continuous insonation of both middle cerebral arteries with transcranial Doppler for 10 minutes at depth 56mm using a standard head frame. Phase shift (PS) between spontaneous oscillations in blood pressure (measured with finger photoplethysmography (Finapres)) and MCA mean flow velocities (MFV) at frequencies .06-.12 Hz was calculated for each hemisphere using transfer function analysis. Lower degree of PS indicated worse autoregulation (abnormal Results: MCA MFV (p Conclusions: DCA but not VMR correlated with a low flow state produced by high grade ICA disease in asymptomatic patients. Our results suggest that in ICA stenosis dynamic/homeostatic mechanisms may be affected without substantially altering the static/protective mechanism of cerebrovascular reserve. Ongoing studies will investigate the effect of these two autoregulatory mechanisms on vascular cognitive impairment. 1 Ortega-Gutierrez S, et al. J Neuroimaging. 2014 24:379-86

Background: While imaging is useful in confirming the diagnosis of ischemic stroke, negative diffusion weighted imaging (DWI) is reported in up to 10% of patients. We aim to (1) identify predictors of MRI-positive stroke from the itemized NIHSS, and (2) to correlate subsets with infarct volume. Methods: Data were derived from the Stroke Warning Information and Faster Treatment study from 2006 to 2009 among patients with mild deficits (NIHSS 0-5) and attending physician final diagnosis of stroke. Using Medical Image Processing, Analysis, and Visualization (MIPAV, NIH) (Version 7.1.1), we calculated lesion volume (cm3) from DWI sequence. Univariate models studied the association between itemized NIHSS subsets, including cortical deficits (visual field cut, aphasia, or neglect), and presence of DWI hyperintensity and lesion volume. Multivariable regression assessed factors predicting DWI-positive strokes; p Results: Of 611 patients with a discharge diagnosis of stroke, 498 underwent MRI and 29.5% were DWI negative. On multivariate analysis, predictors of a positive DWI were NIHSS score of 3-5 (OR= 2.5, 95%CI:1.1-5.5), motor deficits (OR= 1.9, 95%CI:1.1-3.4), and ataxia (OR=3.0, CI:1.5-6.1). All patients with neglect and visual deficits were DWI positive (table). The mean lesion volume in cm3 was larger in patients with NIHSS 3-5 vs. NHSS 0-2 (49.0 vs. 17.3, p=0.002), cortical deficits (112.6 vs. 22.9, p Conclusion: NIHSS score subsets predict DWI positivity and lesion volume in mild strokes. The presence of neglect or visual field deficit on the NIHSS subsets is highly likely to have an MRI correlate even in patients with low NIHSS.

Background: High grade carotid stenosis produces hemodynamic effects on the brain, but the relationship between cerebral autoregulation, absolute CBF and neurovascular coupling has not been well-delineated. Methods: Twelve subjects (age 74±9, 3F) with unilateral ICA stenosis (80-100% occluded) but no infarct (asymptomatic or TIA only) underwent dynamic cerebral autoregulation (DCA) testing with transcranial Doppler by comparing phase shift (PS) of spontaneous oscillations in blood pressure (measured with finger photoplethysmography (Finapres)) versus MCA flow velocities at frequencies .06-.12 Hz using transfer function analysis, lower degree of PS indicating worse autoregulation.Neurovascular coupling was assessed by amplitude of absolute increase in CBF in bilateral Brodman area (BA) 4 during a bilateral repetitive hand closure task using continuous arterial spin labeling (CASL) MRI. Four activation (ON) periods were averaged and subtracted from 4 rest (OFF) periods. Resting CBF for each hemisphere’s motor cortex was determined by averaging the OFF periods. Results: All subjects showed: 1) hemispheric asymmetry in baseline CBF with the occluded side being on average 25mL/100g*min (+/- 14 mL/100g*min) lower than the unoccluded hemisphere. 2) hemispheric asymmetry in motor activation: unoccluded hemisphere average activation (mean_CBF_ON - mean_CBF_OFF) in BA4 was 23.7mL/100g*min, representing a 21% increase in local CBF due to activation; occluded hemisphere mean activation was 14 mL/100g*min, representing 18% percent increase in local CBF. 3) Hemispheric asymmetry in DCA, PS=33.1 deg ± 31 on the occluded side vs. 43.5 deg±23 on the non-occluded side. Both the hemispheral difference in baseline CBF (impaired flow) and the difference in DCA measurement (impaired autoregulation) were good predictors of the lower activation (neurovascular coupling) on the occluded hemisphere: R 2 = 0.85 and 0.80, respectively. Conclusion: Both impaired resting CBF and impaired cerebral autoregulation appear to contribute to decreased neurovascular coupling in carotid artery occlusive disease, representing a potential mechanism for occult neuronal dysfunction such as mild cognitive impairment in this patient population.

Background and Purpose —Recovery from hemiparesis due to corticospinal tract infarction is well documented, but the mechanism of recovery is unknown. Functional MRI (fMRI) provides a means of identifying focal brain activity related to movement of a paretic hand. Although prior studies have suggested that supplementary motor regions in the ipsilesional and contralesional hemisphere play a role in recovery, little is known about the time course of cortical activation in these regions as recovery proceeds. Methods —Eight patients with first-ever corticospinal tract lacunes causing hemiparesis had serial fMRIs within the first few days after stroke and at 3 to 6 months. Six healthy subjects were used as controls. Statistically significant voxels during a finger-thumb opposition task were identified with an automated image processing program. An index of ipsilateral versus contralateral activity was used to compare relative contributions of the 2 hemispheres to motor function in the acute and chronic phases after stroke. Results —Controls showed expected activation in the contralateral sensorimotor cortex (SMC), premotor, and supplementary motor areas. Stroke patients differed from control patients in showing greater activation in the ipsilateral SMC, ipsilateral posterior parietal, and bilateral prefrontal regions. Compared with the nonparetic hand, the ratio of contralateral to ipsilateral SMC activity during movement of the paretic hand increased significantly over time as the paretic hand regained function. Conclusions —The evolution of activation in the SMC from early contralesional activity to late ipsilesional activity suggests that a dynamic bihemispheric reorganization of motor networks occurs during recovery from hemiparesis.

Objective: To assess predictors of cognitive dysfunction in a nationwide sample of adults 60 years or older with and without cardiovascular disease (CVD) Methods: In non-institutionalized US adults randomly selected to participate in the National Health and Nutrition Examination Survey (NHANES), we used the survey-collected digit symbol substitution test (DSST) score as a surrogate of cognitive function. Stratified analysis was performed to sort out the effects of CVD and vascular risk factors on the DSST score. Univariate logistic regression was used to identify significant associations that were used to create an adjusted multivariate analysis. Results: The studied sample included 1607 participants, mean age 70.1 ± 0.3 years, 43% men, 85% Non-Hispanic Whites, 7% Hispanic and 5% non-Hispanic Black. Vascular risk factors included hypertension (HTN) in 68%, Diabetes (DM) in 16%, Dyslipidemia in 75%, and current smoking in 12%. Cardiovascular disease was reported in 20.8% -- 3.2 % stroke, 16.5 % cardiac disease and 1.1% both. In univariate analysis, statistically significant predictors of a lower DSS score were age (β -0.92 per year), Hispanic and Non-Hispanic Black ethnicities compared to non-Hispanic whites (β -18.1 and β -15.0, respectively), HTN (β -6.1), DM (β -7.6) and CVD (β -7.5); greater education and income both predicted higher DSS scores (β 9.7 and 5.3, respectively). Multivariate analysis confirmed all associations with the exception of HTN (β -1.4, P=0.08). In this adjusted model, both stroke and cardiac disease were independent predictors of lower DSS score (β -5.3 and -2.2, respectively). Stratifying by CVD status using the same multivariate model, DM was the only modifiable vascular risk factor predicting lower DSS score in those without CVD (β -4.8, P=0.001), whereas HTN was associated with lower DSST score only in those who reported having CVD (β -4.6, P=0.05). Conclusion: We confirmed the deleterious effects of HTN and DM on cognition in this nationwide sample, but showed that DM was associated with worse cognition in those without reported CVD, while HTN had a significant negative impact on cognition only in those who already had CVD. The mechanisms underlying these differential associations need further study.

INTRODUCTION: Recovery of most hemiparetic patients at 90 days can be well predicted as a fixed proportion (70%) of initial motor deficit. However, recent work has shown considerable variability in the rate of recovery among proportional recoverers, prompting consideration of whether rate of recovery and recovery capacity are independent and whether a single rate dynamic governs proportional recovery. HYPOTHESIS: Among proportional recoverers, recovery rate variability can be accounted for by a single mathematical model in which: 1) recovery rate is independent of recovery capacity and 2) recovery has a sigmoid trajectory parameterized only by initial stroke severity. METHODS: We studied 23 patients with first-ever unilateral hemiparetic stroke previously identified as proportional recoverers. Fugl-Meyer Upper Extremity Motor Exam (FM-UE) had been measured at RESULTS: The model accounted for 86% of variability in motor recovery achieved by patients at 1 week after stroke onset (pseudo-R 2 =0.863, F 23,21= 418.0, p CONCLUSION: The model provides evidence that proportional recovery is governed by a single rate dynamic and that recovery rate is independent of recovery capacity. It provides a tool for predicting motor impairment at any time following stroke onset and suggests a framework for characterizing the biology of recovery and the role of therapeutic interventions as either capacity-enhancing or rate-enhancing.

Background and Purpose Focal neurological deficits (FNDs) in patients with arteriovenous malformations (AVMs) have been widely attributed to the phenomenon of “cerebral steal.” The incidence of focal deficits was investigated in a large prospective sample. Methods Using data from patient history and examination, CT or MRI, and transcranial Doppler sonography, we studied 152 consecutive, prospective AVM patients for evidence of FNDs unrelated to a hemorrhagic event. Feeding mean arterial pressure was measured during superselective angiography. Results Two (1.3%) of 152 patients met the criteria for a progressive FND. Nonprogressive FNDs were seen in 11 (7.2%) patients (stable in 4.6%, reversible in 2.6%). The median observation time period was 17 months (range, 1 to 60 months). There were no differences in transcranial Doppler mean velocities in feeding arteries in FND versus non-FND groups (118±44 versus 112±37 cm/s, P >.05) or pulsatility indexes (0.53±0.20 versus 0.55±0.15, P >.05). Feeding artery pressure was similar in FND (n=10) and non-FND (n=96) groups (39±16 versus 39±16 mm Hg at a systemic pressure of 82±18 versus 75±14 mm Hg, NS). Conclusions Nonhemorrhagic focal neurological syndromes in AVM patients are infrequent. Progressive deficits are especially rare. There was no relation between feeding artery pressure or flow velocities and FND. There does not appear to be sufficient evidence to assign steal as an operative pathophysiological mechanism in the vast majority of AVM patients.

Background and Purpose— A transient ischemic attack (TIA) in the brain is classically considered a syndrome lasting A agonist midazolam in recovered stroke patients can reinduce the acute clinical state, we determined whether TIA patients would demonstrate a similar effect. Methods— Four right-handed patients participated: 3 with clinical TIA presumed to have affected the left hemisphere within the previous 24 to 72 hours and no evidence of a new lesion on diffusion-weighted and fluid-attenuated inversion recovery imaging, and 1 patient with an asymptomatic temporal arteriovenous malformation. The TIA duration ranged from 30 minutes to 3 hours. Each patient underwent baseline testing for motor function and aphasia, after which intravenous midazolam was delivered until mild drowsiness was detected. Patients were tested during the peak drug effect and again after 2 hours when sedation had dissipated. Results— No patient showed weakness or aphasia at baseline. After administration of midazolam, all 3 TIA patients demonstrated re-emergence of features that characterized their recent transient neurological syndromes (right-sided weakness and/or aphasia) but no left-sided findings. The arteriovenous malformation patient who had never been symptomatic showed no drug effect. Two hours later, all TIA patients returned to their normal clinical state. Conclusions— Patients who had suffered recent transient cerebral ischemic episodes and were neurologically intact with negative diffusion-weighted imaging showed re-emergence of prior focal deficits after administration of a benzodiazepine in a dose that produces light sedation. These findings suggest that presumed TIA may produce neuronal dysfunction beyond the symptomatic period.

INTRODUCTION: Prior work has identified that the majority of acute hemiparetic patients recover a very predictable (adjusted R2=0.85) 70% of their maximum potential recovery on the Fugl-Meyer Upper Extremity Motor exam (FM) at 3-months. We examined these data to investigate whether the early recovery trajectory was uniform among these patients at 3 months. Among first-time acute stroke patients who recover motor function at 3 months, we assessed the hypothesis that the rate of recovery will be variable at one week after stroke. METHODS: We examined 30 patients with first-ever unilateral hemiparetic stroke using the FM score (max score=66) at 24-72 hours (FMinit), 1 week (FM1wk), and 3-months (FM3mo). Initial impairment was defined as 66 - FMinit. Recovery was defined as the change in FM over 3 months (FM3mo - FMinit). A Pearson correlation coefficient was calculated for predicted vs. observed change to assess how well (0.70 x initial impairment) predicted 3-month recovery, as well as to identify the subgroup of non-recoverers. A histogram was plotted for the recoverers to examine the distribution of patients based on the proportion of the 3-month recovery that had been achieved by 1-week. RESULTS: A strong correlation (R2=0.96) was demonstrated of predicted vs. observed recoveries, with non-recoverers (n=4) removed. Among recoverers, there was a bimodal distribution of patients by the proportion of 3-month recovery achieved at 1-week-- those who achieved >50% of 3-month recovery (fast to recover-- FTR, N=14) vs. those who achieved CONCLUSION: Patients who recover over the first 3 months follow distinct trajectories, either achieving approximately 90% of their total recovery by 1 week or making marginal recovery early, and only later achieving their total expected recovery ( Fig ). These findings have important implications for rehabilitation and predicting recovery after stroke. Future work must address the biological correlates of this dichotomy.

Background and Purpose — Patients who have sustained a neurological injury and then improved may experience transient reemergence of their syndromes when given benzodiazepines. As a step toward assessing whether neurotransmitter systems underlie poststroke clinical improvement, we selected midazolam, a γ-aminobutyric acid A (GABA A ) agonist, for systemic administration to measure general or stroke-specific effects in patients. Methods — Eight patients with image-verified stroke (5 with left-sided and 3 with right-sided cerebral lesions) participated. The strokes had occurred from 7 days to 6 years earlier, with patients showing clinical improvement from their initial syndromes. Each patient underwent baseline testing for motor function, aphasia, and left hemispatial neglect, after which intravenous midazolam was delivered until mild drowsiness was detected. Patients were tested during this period and again after 2 hours when sedation had dissipated. Results — After the administration of midazolam, the 5 patients with left hemisphere stroke demonstrated reemergence or worsening of their initial right hemiparesis and aphasia but showed no left neglect. The 3 patients with right cerebral stroke showed reemergence of left hemiparesis and left visual field neglect but no aphasia. All patients returned to baseline after 2 hours. Conclusions — Under conditions of light sedation, patients whose initial stroke syndrome had substantially improved clinically showed transient reemergence of their initial focal syndrome. These data suggest a possible role for GABA A -mediated neurochemical mechanisms in poststroke improvement and sensitivity to medication effects.

Vascular cognitive impairment has been traditionally defined by structural pathology, an accumulation of infarcts, leading to progressive cognitive decline. Recent evidence, however, suggests that cognitive impairment may be independently mediated by hemodynamic dysfunction, including global and hemispheral hypoperfusion and altered cerebral blood flow regulation. In this review, we examine evidence for the contribution of hemodynamic impairment to cognitive dysfunction in the setting of large vessel disease, cardiac failure, and microvascular disease. If there is a hemodynamic component of vascular cognitive impairment, then treatments proposed to correct impaired vascular physiology may reasonably be expected to treat the cognitive dysfunction as well.

Background and Purpose— Cerebral vasodilatory capacity (CVC) testing with transcranial Doppler has been shown to be useful in the assessment of stroke risk in patients with symptomatic and asymptomatic internal carotid artery (ICA) stenosis and occlusion, but whether hemodynamic status improves, deteriorates, or remains the same over time is uncertain. Methods— Thirty-five patients with ≥80% carotid artery stenosis or complete occlusion underwent CVC testing at baseline and 6 months later. CVC was assessed by measuring the increase in ipsilateral middle cerebral artery mean flow velocity in response to 5% inhaled CO 2 . Continuous tracings of left and right middle cerebral artery flow velocity, heart rate, respiratory rate, and P co 2 were recorded and then analyzed offline. One-way analysis of variance was used to compare baseline CVC in symptomatic and asymptomatic patients with control subjects. A paired t test was used to compare CVC before and after revascularization. Also, χ 2 analysis was used to compare rates of cerebrovascular events in patients with low compared with normal CVC over the 6-month period and in 14 patients whose ICAs were revascularized. Results— Patients with high-grade stenosis or occlusion of the ICA who had ICA disease had an average CVC of 2.4±1.9%/mm Hg P co 2 ; control subjects averaged 4.2±1.1%/mm Hg P co 2 . ( P =0.01). In the revascularization group, CVC increased from an average of 1.4±1.7%/mm Hg P co 2 at baseline to an average of 2.8±1.0%/mm Hg P co 2 after revascularization, significantly different from the spontaneous change in the natural history group over 6 months ( P =0.003). Over the 6-month follow-up period, in the natural history group and in the treatment group after revascularization, 4 ischemic events occurred, all in patients with abnormal CVCs; abnormal CVC was associated with ischemic events (Fisher’s exact test, P =0.03). Conclusions— In a timeframe pertinent to clinical decision making and clinical trial outcomes, cerebral hemodynamic status may not be constant. A higher ischemic risk may be present in patients with severe carotid artery disease whose CVC is poor at baseline, becomes poor over 6 months, or fails to normalize after revascularization.

120 Background: A major concern in the treatment of cerebral AVMs is whether so-called eloquent regions occupy normal anatomic locations. Recently, we have shown with selective anesthetic injections that language has a wide and unusual distribution in patients with left cerebral AVM. Our Objective here was to determine whether superselective Wada testing in medial right-hemisphere arteries would produce verbal memory loss in patients with right cerebral AVM. Methods: Nine patients, 8 right- and 1 left-handed, had superselective injections of amobarbital sodium plus lidocaine into vessels near or feeding right medial AVMs. Five patients had AVMs supplied by PCA feeders and four had ACA feeders. Memory testing occurred in a no-anesthetic baseline, 1 minute after anesthetic injection, and 12 minutes after injection. A memory test consisted of 5 words presented on a computer screen which the patient had to read aloud. After 3 minutes, recall was tested. A maximum score was 15, with uncued recall of a word = 3 points, prompted recall = 2 points, and multiple choice = 1 point. Based on clinical considerations, various numbers of vessels were tested in each patient. Results: Superselective anesthetic testing in most vessels yielded memory scores no different than baseline, and embolization took place. In each patient, however, there was at least one vessel feeding the AVM in which significant short-term verbal memory loss took place. In these instances, the mean memory score at baseline was 14 (s.d. = 1.5). Following injection of anesthetics, the mean score fell significantly to 7.1 (t-test, pConclusions: In nine patients, superselective Wada injection into arteries feeding right medial AVMs produced unanticipated verbal memory deficits. Traditional assumptions about eloquent regions would have suggested that such testing would have been unnecessary, but embolization here would have yielded significant morbidity. Our findings also question established notions of verbal memory restricted to the left hemisphere.

P62 OBJECTIVE: Impaired cerebral vasomotor reactivity has been proposed as a measure of exhausted vascular reserve in patients with carotid artery stenosis or occlusion. We tested this hypothesis by measuring vasoreactivity in patients with asymptomatic or recently symptomatic severe carotid artery disease. METHODS: Fourteen patients with severe carotid artery disease (5 with occlusion, 9 with stenosis 80–99%, 8 symptomatic, 6 asymptomatic within 2 years) and 7 healthy controls had continuous bilateral monitoring of mean flow velocity (MFV) in the MCAs by transcranial Doppler (TCD). End-tidal CO2 was measured continuously with an in-line capnometer connected via snorkel mouthpiece, nasal airway occluded by noseclip. After baseline measurements, subjects held their breath for 30 seconds. A breath holding index (BHI) was calculated (% change in MFV/seconds held). After return to baseline MFV, subjects breathed a 5% CO2 gas mixture for 2 minutes. CO2 reactivity was calculated as percent rise in MFV per mmHg PCO2 once the MFV curve plateaued. ANOVA was used to calculate differences between symptomatic, asymptomatic and control groups for CO2 reactivity and BHI. RESULTS: There was a highly significant difference in vasoreactivity by CO2 inhalation in the symptomatic group (2.02±.80 %/mmHg) versus the asymptomatic group (4.45±1.9 %/mmHg) and controls (3.69±.95 %/mmHg) (F 2,18 =7.85, p=.004). A linear relationship was seen between MFV and PCO2, taking multiple MFV measurements at various PCO2 levels throughout the study period (average r 2 =.60 for patients, .77 for controls). BHI did not distinguish between the groups (p=.37). CONCLUSIONS: Measuring cerebral vasoreactivity by CO2 inhalation with continuous TCD monitoring provides an important physiological index of the clinical status of patients with carotid artery disease which may help guide treatment algorithms. The linear relationship between MCA MFV and end-tidal CO2 enables confirmation of the baseline and maximum measurements used to calculate CO2 reactivity, and provides the opportunity to investigate further the link between physiology and clinical state.