bluuebunny/crossref_metadata_2025 huggingface dataset:
A National Study of the Quantity and Cost of Informal Caregiving for the Elderly with Stroke
Authors: Hickenbottom Susan L , Langa Kenneth M , Kutcher Jeffrey S , Kabeto Mohammed U , Fendrick A. M , Katz Steven J
Published: July 2021

56

Background:
As the US population ages, increased stroke incidence will result in higher stroke-associated costs. While estimates of direct costs exist, little information is available regarding informal caregiving costs for stroke patients. Objective: To determine a nationally representative estimate of the quantity and cost of informal caregiving for elderly stroke patients.
Methods:
We used data from the first wave (1993) of the Asset and Health Dynamics (AHEAD) Study, a longitudinal study of people over 70 living in the community, to determine average weekly hours of informal caregiving. Multivariate and logistic regression analyses were performed to examine association of stroke and other covariates and assess the probability of receiving informal care. Average annual cost for informal caregiving was calculated.
Results:
Of the 7443 respondents, 656 (6%) reported a history of stroke. Of those, 375 (57%) reported stroke-related health problems (SRHP). After adjusting for cormorbid conditions, social support and sociodemographics, the proportion of patients receiving informal care increased with stroke severity, and there was a significant association of weekly hours of caregiving with stroke category (p<0.01). Using the mean 1998 wage for a home health aide ($8.20/hr.) as the value for family caregiver time, the expected yearly caregiving cost per stroke ranged from $3500 to $7600, which would result in an annual cost of more than $5.7 billion for stroke-related informal caregiving in the US.
Conclusions:
The economic burden of informal caregiving following stroke has not been studied previously. Informal caregiving occurs frequently; associated costs are substantial and should be considered when estimating the cost of stroke treatment.
A pooled analysis of individual patient data from trials of endarterectomy for symptomatic carotid stenosis: efficacy of surgery in important subgroups
Authors: Dr Peter M Rothwell , Dr Sergei A Gutnikov , Professor Marc R Mayberg , Professor Charles P Warlow , Professor Henry Jm Barnett
Published: July 2021

65

Benefit from carotid endarterectomy (CEA) depends on the degree of symptomatic stenosis, but is also likely to be influenced by other clinical and angiographic characteristics. However, individual trials have been too small to allow reliable subgroup analysis. We therefore studied pooled individual patient data from the European Carotid Surgery Trial, the North American Symptomatic Carotid Endarterectomy Trial and the Veterans Administration trial #309. We determined the effect of CEA in 11 predefined subgroups: age (<65, 65–74, 75+), sex, type of presenting event (cerebral vs ocular; TIA vs stroke; lacunar vs non-lacunar), side of presenting event, months since last event (<1, 2–3, 4+), diabetes, plaque surface irregularity, near-occlusion, and contralateral carotid occlusion. There were statistically significant interactions between the risk of ipsilateral ischaemic stroke in the medical group and 8 of the 11 subgroup variables. In the surgery group, there were interactions between the operative risk of stroke and death and 6 subgroup variables. We therefore assessed heterogeneity of overall treatment effect (any ipsilateral ischaemic stroke and surgical stroke/death) in these subgroups. There was clinically and statistically significant heterogeneity within 5 subgroups: benefit from surgery increased with age, was greater in men than women; decreased with time since presenting event; was greater after stroke than TIA, and was absent in cases of near-occlusion. For example, in patients with 50–69% stenosis, the 5 yr absolute risk reduction was 10% (95% CI = 3–10, P=0.0005) in men and -3% (95% CI = -8 - 2, P=0.8) in women (overall interaction, P=0.003). There were also important differences in the effect of surgery for lacunar and non-lacunar stroke. Patients who are most likely to benefit from CEA cannot be identified using the degree of symptomatic carotid stenosis alone. Several other clinical and angiographic characteristics influence the efficacy of surgery. Optimal selection of patients will require a risk-modelling approach using multiple baseline characteristics.
Smoking Cessation After Stroke: Education and its Effect on Behavior
Authors: Sauerbeck Laura R , Khoury Jane C , Woo Daniel , Kissela Brett M , Moomaw Charles J , Broderick Joseph P
Published: July 2021

69

Background and Purpose:

Smoking is a strong independent environmental risk factor for stroke. We sought to prospectively examine the impact of the diagnosis of stroke on smoking behavior at three months.
Design
: Patients admitted to 17 hospitals in the Greater Cincinnati area with a confirmed diagnosis of stroke were interviewed in the acute period after their event. A standardized questionnaire was utilized to collect detailed smoking history. Risk factor reduction was discussed with the patient and/or family members and printed risk reduction information was provided. Patients or their proxies were then contacted at three months and current smoking status was recorded.

Results:

Of 365 stroke patients, 99 were current smokers at baseline. There were no differences between the smokers and the non-smokers based on gender, race, age, and education. At three months, 44% of the baseline smokers had quit smoking (p<0.001), and the overall amount of daily cigarette use had decreased (p<0.001). Factors independently associated with reduction of smoking were white race(OR=2.3, 95% CI 1.0–5.5) and male gender (OR= 2.2, 95% CI 1.0–5.2).

Conclusions:

After a stroke, patients are motivated to change smoking behavior, as has been found with other life threatening diagnoses. Longer follow-up is needed to see if this behavior continues.
HEME OXYGENASE-1 GENE THERAPY FOR PREVENTION OF VASOSPASM IN RATS
Authors: Dr. Robert L Macdonald , Dr. Shigeki Ono
Published: July 2021

78

This study tested the hypothesis that adenovirus expressing heme oxygenase-1 (HO-1), the enzyme that metabolises hemoglobin, would reduce contractions of cerebral arteries to hemoglobin and decrease vasospasm after subarachnoid hemorrhage (SAH). Rats underwent injection of vehicle or replication defective adenovirus expressing HO-1 (Ad5HO-1) or β-galactosidase (Ad-βGal) into the cisterna magna. Transgene expression was assessed by reverse transcriptase polymerase chain reaction for messenger ribonucleic acid (mRNA) levels, immunoblotting for protein levels, immunohistochemistry, response of the basilar artery to pure, ferrous hemoglobin and carboxyhemoglobin production 1 day after virus injection. Effects of Ad5HO-1 and Ad-βGal on vasospasm were assessed in a rat double hemorrhage model. Injection of Ad5HO-1 significantly increased HO-1 mRNA, protein and activity in basilar artery compared to Ad-βGal and vehicle. Injection of Ad-βGal result in low level expression and activity of HO-1 but this was significantly less than after injection of Ad5HO-1. HO-1 immunoreactivity was present in the basilar artery adventitia after injection of Ad5HO-1 and Ad-βGal. Injection of Ad5HO-1 and Ad-βGal increased basilar artery diameter and brainstem blood flow compared to control (P < 0.001, ANOVA). Ad5HO-1, however, significantly and selectively prevented contraction of the basilar artery and reduction in brainstem cerebral blood flow due to hemoglobin and significantly increased carboxyhemoglobin concentration compared to Ad-βGal and vehicle. Basilar artery diameter 7 days after SAH was significantly greater after injection of Ad5HO-1 (380 ± 36 μm) compared to Ad-βGal (282 ± 44 μm) and vehicle (287 ± 31μm, P < 0.001, ANOVA). In conclusion, injection of Ad5HO-1 into the cisterna magna of rats results in expression of functional HO-1 in the adventitia of the basilar artery. This is associated with an increase in basilar artery diameter. HO-1 expression with Ad5HO-1 inhibits arterial contractions to hemoglobin and after SAH.
Acute Hyperglycemia in Stroke leads to increased brain lactate production and greater final infarct size.
Authors: Parsons Mark W , Barber P Alan , Darby David G , Yang Qing , Desmond Patricia M , Gerraty Richard P , Tress Brian M , Davis Stephen M
Published: July 2021

88

Background:
Diabetes and stress hyperglycemia occur in about 1/3 of stroke patients and are associated with worse stroke outcome. In animal stroke, MR spectroscopy (MRS) studies have established a relationship between hyperglycemia, increased brain lactate level, and larger final infarct size following reperfusion. We therefore used 1H-MRS to measure regional lactate, and MR diffusion-weighted (DWI) and perfusion-weighted imaging (PWI) to assess reperfusion of the ischemic penumbra.
Methods:
Forty-two hemispheric stroke patients were studied with DWI and PWI within 24 hours of symptom onset, and again at days 3 and 90. A subgroup of 24 patients had acute and day 3 MRS to determine lactate level in the ischemic region. Blood glucose was measured acutely within 1 hour of the acute scan.
Results:
Twenty-two patients were identified as not yet having undergone major reperfusion (acute PWI lesion > acute DWI lesion). The extent of the acute PWI lesion that did not progress to infarction was termed “penumbral salvage”. In the 22 patients who had not reperfused at time of acute scan, a correlation was found between acute blood glucose and final infarct size (r=0.62, p<0.01). Furthermore, hyperglycemia was associated with reduced penumbral salvage (r=0.75, p<0.01). Fourteen patients in the group yet to undergo reperfusion had MRS to measure lactate level in the ischemic region before reperfusion (mean 7 hours), and following reperfusion at day 3 (which may provide an indication of the amount of lactate generated during reperfusion). In these patients, acute blood glucose correlated strongly with day 3 lactate levels (r=0.85, p<0.01). Day 3 lactate level was also strongly associated with reduced penumbral salvage (r=0.90, p<0.01).
Conclusions:
In acute stroke, hyperglycemia may lead to increased lactate production during reperfusion, thus contributing to reperfusion injury, resulting in reduced penumbral salvage and increased final infarct size. These findings are the first reported in human stroke and help explain the worse outcome in diabetic stroke patients. Future research should evaluate the effects of glycemic control on these determinants.
Anticoagulation for Atrial Fibrillation: Physicians’ Readiness to Change Practices
Authors: Goldstein Larry B , Samsa Gregory P , Bonito Arthur J , Cohen Stuart J , Matchar David B
Published: July 2021

94

PURPOSE.
Determine physicians’ readiness to change anticoagulation practices for patients with non-valvular atrial fibrillation (NVAF).
BACKGROUND.
Only half of eligible NVAF patients receive warfarin. Interventions to alter physicians’ anticoagulation practices must consider their motivation to change.
METHODS.
As part of a US national survey (1993–94), physicians were asked their current practices for patients over age 65 with NVAF, and whether they were comfortable, considering change, or expecting to change those practices.
RESULTS.
Overall, 67% of eligible physicians fully responded to the survey (n=1006). Seventy-three percent (72% of non-internist primary care physicians [PCPs], 76% of internists, 69% of neurologists and 37% of surgeons) responded that they often or always anticoagulate patients over age 65 with NVAF. The majority (73%) indicated they were comfortable with their practices, with the rates differing by specialty (68% PCPs, 76% internists, 82% neurologists, 87% surgeons; p<0.001). Regardless of specialty, 78% of physicians who seldom or never anticoagulate this type of patient were comfortable with this practice. An identical proportion of physicians indicating they always or often use anticoagulants for patients with NVAF were comfortable with their practices.
CONCLUSION.
Although differing by specialty, these data show that the majority of physicians are not expecting or planning to change their anticoagulation practices for patients over age 65 with NVAF. Although the majority believe they anticoagulate such patients and are comfortable with their practices, their actual treatment patterns may differ as several studies show that high proportions of eligible AF patients do not receive warfarin. Utilization review coupled with the identification of specific practice barriers and tailored educational programs may address this discrepancy. A high proportion of physicians who responded that they seldom or never anticoagulate these patients were also comfortable with their practices. Providing current treatment guidelines reinforced by other educational strategies might motivate them to consider a change in practice.
Cortical reorganization of the visual system in post-stroke hemianopia studied with fMRI
Authors: Nelles Gereon , Widmann Guido , Esser Joachim , Meistrowitz Anette , Weber Johannes , Forsting Michael , Diener H. Christoph
Published: July 2021

102

Introduction:
Restitution of unilateral visual field defects following occipital cortex lesions occurs rarely. Partial recovery, however, can be observed in patients with incomplete lesion of the visual cortex. Our objective was to study the neuroplastic changes in the visual system that underlie such recovery. Methods and
Results:
Six patients with a left PCA-territory cortical stroke and 6 healthy control subjects were studied during rest and during visual stimulation using a 1.5 T fMRI with a 40 mT gradient. Visual stimuli were projected with a laptop computer onto a 154 x 115 cm screen, placed 90 cm in front of the gantry. Subjects were asked to fixate a red point in the center of the screen during both conditions. During stimulation, a black-and-white checkerboard pattern reversal was presented in each hemifield. For each side, 120 volumes of 48 contiguous axial fMRI images were obtained during rest and during hemifield stimulation in alternating order (60 volumes for each condition). Significant differences of rCBF between stimulation and rest were assessed as group analyses using statistical parametric mapping (SPM 99; p<0.01, corrected for multiple comparison). In controls, strong increases of rCBF (Z=7.6) occurred in the contralateral primary visual cortex V1 (area 17) and in V3a (area 18) and V5 (area 19). No differences were found between the right and left side in controls. During stimulation of the unaffected (left) visual field in hemianopic patients, activation occurred in contralateral V1, but the strongest increases of rCBF (Z>10) were seen in contralateral V3a (area 18) and V5 (area 19). During stimulation of the hemianopic (right) visual field, no activation was found in the primary visual cortex of either hemisphere. The most significant activation (Z=9.2) was seen in the ipsilateral V3a and V5 areas, and contralateral (left) V3a.
Conclusions:
Partial recovery from hemianopia is associated with strong ipsilateral activation of the visual system. Processing of visual stimuli in the hemianopic side spares the primary visual cortex and may involve recruitment of neurons in ipsilateral (contralesional) areas V3a and V5.
Motor cortex activation in hemiparetic stroke patients
Authors: Cramer Steven C , Stegbauer Keith C , Mark Angela , Price Robert , Barquist Kristin , Bell Kathleen R , Esselman Peter C , Odderson Ib R , Maravilla Kenneth R
Published: July 2021

100

Little is known about the function of surviving motor cortex after hemiparetic stroke. Though the corticospinal tract may be damaged, function may persist via intact intracortical connections. We probed motor cortex function using paradigms unrelated to genesis of paretic limb movement. Seven patients with chronic post-stroke hemiparesis, including total hand plegia, were studied with functional MRI (fMRI). Brain activation was achieved by alternating between rest and one of several stimuli. For the plegic hand, stimuli were passive index finger movement, or viewing active movements; for the non-plegic hand, active or passive index finger movement. Brain activation maps (p<.001) were generated, after which anatomical landmarks were used to identify regions of interest within non-infarcted tissue. Tasks were rehearsed before fMRI, during which surface EMG leads were placed on 5 muscles in each arm. Patients were median 5 months post-stroke, median age 66 years. Median NIH stroke scale score was 9; Rankin, 3; and arm motor Fugl-Meyer score, 18 (normal=66); Motor Activity Log confirmed no plegic hand use. Studies with excess head movement were excluded, including all plegic hand tasks for 1 patient. Plegic hand tasks (10 studies across 6 patients) activated the stroke hemisphere in all patients, including primary motor cortex (5 patients), primary sensory cortex (5 patients), premotor cortex (4 patients), and supplementary motor area (3 patients). Non-stroke hemisphere was also activated, particularly primary motor cortex (5 patients). In a few instances, EMG disclosed paretic arm muscle activity, but this had no relationship to fMRI activation. Non-plegic hand tasks (9 studies across 7 patients) activated the stroke hemisphere ipsilaterally, including supplementary motor area in all 7 patients, and primary motor cortex in 6 patients. In patients with post-stroke hemiparesis, passive stimulation activates surviving motor cortex regions within the stroke-affected hemisphere. After corticospinal tract damage, motor cortex can still be activated during tasks unrelated to paretic limb movement. The results may suggest therapeutic avenues for improving motor function after stroke.
Optimizing Transcranial Doppler Screening for Vertebro-Basilar Stenosis
Authors: Okon Nicholas J , El-Mitwalli Ashraf , Malkoff Marc , Alexandrov Andrei V
Published: July 2021

109

Background and Purpose:
Intracranial vertebrobasilar (VB) stenosis carries a high risk of stroke. Transcranial Doppler (TCD) has lower sensitivity and specificity for VB lesions compared to anterior circulation. We performed a case-controlled study to develop additional criteria to optimize predictive value of TCD velocity criteria for VB stenosis.
Methods:
We performed TCD in consecutive patients with stroke or TIA symptoms using a standard insonation protocol and a priori established mean flow velocity (MFV) criteria for VB stenosis (≥50 and ≥60 cm/sec cut-offs). Patients who had abnormal VB TCD findings and angiography were selected. Age-matched patients with normal angiograms (DSA) who also had TCD were used for comparison.
Results:
Of 1289 patients screened, 115 had abnormal VB findings on TCD (9%). Of these, 50 patients had angiography including 24 DSAs. A total of 24 age-matched controls with TCD and DSA were identified among patients with normal VB results. When MFV criteria were applied alone, MFV cut-offs had sensitivity of 92%, specificity 44%, PPV 44%, NPV 92%. False-positive MFV elevation occurred mostly due to flow collateralization with carotid or VB occlusions (64% of false positive studies). The only two false negative TCD results were found with long irregular terminal VA plaques. When additional criteria for flow collateralization and focal MFV elevation (stenotic : pre- or post-stenotic VB MFV ratio ≥2 : 1) were used, TCD sensitivity was 82%, specificity 92%, PPV 82%, NPV 92%.
Conclusions:
Criteria for flow collateralization and velocity ratios can reduce the number of false positive TCD findings in patients with VB stenosis when velocity cut-offs are used alone. Although limited to a single center, our study suggests that the predictive value of TCD can be optimized to allow accurate noninvasive screening of patients for isolated VB stenoses.
Cooling for Acute Ischemic Brain Damage (COOL AID): Preliminary Efficacy Data of Moderate Hypothermia For Acute Ischemic Stroke
Authors: Abou-Chebl Alex , A De Georgia Michael , Krieger Derk W
Published: July 2021

114

Introduction:
Pharmacological neuroprotection has not been shown to be effective in improving outcomes of patients with acute ischemic stroke. Hypothermia is effective experimentally in reducing infarct volumes and improving outcome. We present the preliminary efficacy data of moderate hypothermia in patients with severe middle cerebral artery (MCA) territory stroke.
Methods:
Patients with severe (NIHSS ≥ 15) MCA territory ischemic stroke who presented within 6 hours of onset were screened. Patients who failed to improve after thrombolysis or attempted thrombolysis (i.e. still had an NIHSS > 8) were enrolled and hypothermia initiated by cooling blanket and ice water-alcohol bath to a core temperature of 32° C ± 1°. Hypothermia was maintained for 12 to 72 hours depending on sonographic or angiographic MCA patency status. Follow-up modified Rankin Scale scores (mRS) were assessed at 3 months. Patients treated with hypothermia were compared with eligible patients who were screened for the study but excluded for logistical reasons.
Results:
Seventeen patients were screened between October, 1999 to June 2000 and 9 enrolled with a mean NIHSS score of 20.6 ± 3.0. The mean time to initiation of hypothermia from the time of stroke onset was 6.2 ± 1.3 hours and the mean duration of hypothermia was 48.6 ± 21.2 hours. Target temperature was achieved within 3.6 ± 1.6 hours. The mean NIHSS score of the control patients was 20.0 ± 2.7. Pre-hypothermia, the MCA was occluded in 3 patients and open in 6. Among control patients the MCA was occluded in 4, open in 4 and unknown in 1. The mean mRS score at 3 months was 2.8 ± 2.2 for the hypothermia patients. Five patients had a mRS score 0–2 (55.5 %) and 4 had a mRS ≥3 (44.5 %). Control patients had a mean mRS score of 4.4 ± 1.7 (p = 0.11). Only one control patient had a mRS score 0–2 (12.5 %) while 7 patients had a mRS ≥3 (87.5%, p=0.13).
Conclusion:
This pilot study suggests that adjunct moderate hypothermia may benefit patients with severe acute ischemic stroke. The efficacy of hypothermia combined with thrombolytic therapy needs to be tested in a Phase II randomized controlled trial.
Systemic Thrombolysis Data from the German Stroke Database
Authors: Knoll Thomas , Weimar Christian , Haberl Roman L , Busse Otto , Hamann Gerhard F , Koennecke Hans C , Diener Hans C
Published: July 2021

118

Objectives:
To present data on systemic thrombolysis for acute ischemic stroke from a cooperative database of 23 german hospitals.
Methods:
All admitted stroke patients in the participating centers were prospectively recruited into a 599-item database including a telephone follow-up 3 months after stroke. Findings: From 01/1998 until 11/1999, 5279 patients with acute ischemic stroke were included in the database, 205 (3.9%) had systemic thrombolysis with 0.9mg/kg rt-PA (alteplase). Three hospitals did not perform thrombolysis (range of thrombolysis rate 0–11.3%). The median age of patients was 63 years (41% female, 59% male). The median National Institutes of Health Stroke Scale Score (NIHSSS) at admission was 14. Early high dose intravenous heparin after thrombolysis was given to 61.2% of patients. The rate of intracranial parenchymal hematoma (PH) until day 3 was 6.8%. In a logistic regression model including age, hypertension before stroke, NIHSSS, level of consciousness at admission, TOAST-classification, delay of thrombolysis and high dose intravenous heparin after thrombolyisis, PH was independently associated with high dose intravenous heparin after thrombolysis (p=.031) and hypertension before stroke (p=.042). Decompressive surgery was performed in 4.4% of thrombolysis patients. The median length of stay in the documenting hospital was 13 days, 4 in the ASU and 3 in the ICU. After 90 days, a Modified Rankin Scale Score (MRS) ≤1 was observed in 26.8%, ≤2 in 42.5% of patients (follow-up rate 66%). The mortality until day 90 was 18.3%.
Conclusions:
These uncontrolled multicenter data confirm published data on the frequency of use of systemic thrombolysis, risk of (symptomatic) PH and 3-month-mortality. The percentage of patients with favorable outcome (MRS ≤1) is lower than in the controlled trials. Early secondary prevention with high dose i.v. heparin was associated with increased frequency of PH and should therefore be avoided.
Unanticipated memory loss during superselective Wada testing for right cerebral arteriovenous malformation.
Authors: Lazar Ronald M , Marshall Randolph S , Mohr J P , Young William L , Pile-Spellman John
Published: July 2021

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, p<.00001). Attention was unaltered. After dissipation of the anesthesia at 12 minutes, memory returned to baseline levels in every case.
Conclusions:
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.
ADHESION MOLECULE (ICAM-1) SERUM LEVELS ARE RELATED TO SPONTANEOUS RECANALIZATION IN HUMAN ISCHEMIC STROKE.
Authors: Montaner Joan , Molina Carlos A , Abilleira Sonia , Arenillas Juan , Alvarez-Sabin Jose
Published: July 2021

P6

Background:
There is active migration of leukocytes into the brains of patients with cerebral infarctions directed by several classes of cell surface glycoproteins. Among the most studied adhesion molecules is ICAM-1 (intercellular adhesion molecule-1) which is located on the endothelial surface. As the extent of the infarction and timing of recanalization largely vary between patients these may be some of the reasons for the differences found in the soluble adhesion molecule field in previous human studies. Transcranial Doppler (TCD) offers a continous means of monitoring vessel patency, therefore we have chosen this tool to correlate the development of adhesion molecules mediated injury with the recanalization after middle cerebral artery stroke
Objectives:
To study adhesion molecules temporal profile in the acute phase of an homogeneus sample of stroke patients. To correlate adhesion molecule levels with the time-to-spontaneous-recanalization.
Methods:
From all consecutive stroke patients attended during a year period we selected and prospectively studied those presenting as a cardioembolic stroke involving the MCA territory. In 45 patients, serum levels of soluble ICAM-1 were repeatedly determined by ELISA in the acute phase. Serial TCD studies were performed to determine the time course of spontaneous recanalization, at study entry and at 12, 24 and 48 hours of the symptoms onset, when the blood sample for adhesion molecules determination was obtained.
Results:
ICAM-1 levels peaked at baseline determination (414,44 ng/ml) and decreased by the following determinations (12h=401,25 ng/ml; 24h=392,08 ng/ml; 48h=379,34 ng/ml). ICAM-1 levels at 12h of stroke onset were closely related with the MCA recanalization (p=0,032). Low ICAM-1 levels at 12h (356,81 ng/ml) are associated with the finding of a patent MCA at the 48h TCD, conversely high ICAM-1 levels (459,97 ng/ml) are associated with a persistent MCA occlussion.
Conclusions:
Patients who develop postischemic adhesion molecules upregulation are less prone to spontaneous recanalization. Antiadhesion therapies could facilitate reperfusion strategies.
False-Negative Tests in CADASIL
Authors: R de Freitas Gabriel , Miklossy Judith , Christen-Zäch Stephanie , Reichhart Marc , Bogousslavsky Julien
Published: July 2021

P14

Background:
The diagnosis of CADASIL is normally confirmed by screening DNA for mutations of Notch 3 gene or by skin biopsy. The pathological hallmark of this disease is the presence of characteristic granular osmiophilic material within the basal membrane of vascular smooth-muscle cells.
Objective:
We report the first CADASIL case with negative results for both genetic analysis and skin biopsy.
Methods:
A 69-year-old woman presented with recurrent TIA and strokes, seizures, and dementia. MRI revealed diffuse periventricular white matter abnormalities. Extensive investigation failed to reveal the cause of the disease. Analysis for CADASIL were performed.
Results:
The patient had no mutations in the Notch 3 gene, had a normal skin biopsy, but showed characteristic CADASIL abnormalities on brain pathological examination. Ultrastructural analysis of the brain showed marked destruction of smooth muscle cells with an accumulation of granular osmiophilic material in the muscular layer.
Conclusion:
Our findings suggest that negative results in the skin biopsy and genetic test do not exclude the disease, and a leptomeningeal biopsy should be considered in such cases. CADASIL may be more common than previously reported.
High Precision Measurement of Mean Transit Time for Pharmacological MRI
Authors: Brunecker Peter , Kerskens Christian M , Endres Matthias , Schultze Joerg , Doege Claudia A , Mueller Bianca , Dirnagl Ulrich , Villringer Arno
Published: July 2021

P36

Introduction Pharmacological MRI based on BOLD contrast is difficult since drug induced signal intensity changes are small. An alternative is bolus track MRI using a paramagnetic contrast agent which, however, has limitations regarding quantitation, one reason is the poor definition of the arterial input curve (AIC). Although AIC in principle can be determined from contrast agent induced signal intensity changes in larger arteries, the conversion into concentration time courses is inprecise. In this study a new approach was employed correcting the AIC before deconvolution. For evaluation cerebral perfusion was assessed before and after application of L-Arginine (L-Arg). Methods Bolus Track MRI (TE 54 ms; TR 0.8 s; 128x128x8) was performed after i.v. administration of 0.2 mmol/kg GdDTPA in four volunteers before and after L-Arg (500 mg/kg, i.v.). In one slice a white matter ROI was selected and AIC was taken from 6 different groups of arterial pixels and averaged. Concentrations were calculated and part of first passage in AIC was replaced with a fitting function that has been varied in an optimization procedure. The goal was to find the best prediction of time courses in tissue by model-dependent convolution in a transport-diffusion-model. ”Improved“ AIC determined in this way were used as most probable AIC at high concentrations for MTT determination. Results For the ”standard“ AIC, the MTT values were 2.7 ± 0.6 s before and 2.3 ± 0.5 s after L-Arg, the ratio of MTT in the same tissue regions after/before L-Arg was 0.8 ± 0.2. The MTT shortening indicated a CBF increase but not significantly. Using model-dependent deconvolution, the ”improved“ MTT values were similar, but less noisy. MTT values were 3.0 ± 0.5 s before and 2.5 ± 0.5 s after L-Arg. The improvement in SNR was particularly evident when assessing the after/before ratios of MTT which were 0.83 ± 0.02. Conclusion The improved definition of the input function significantly reduced the noise in our data as indicated by smaller standard deviations. As illustrated by the measurement of L-Arg-induced CBF increase, this improvement should make the assessment of rather small pharmacologically induced perfusion changes more precise.
Cerebral Vasomotor Reserve in Hypertension during Head-up Tilt
Authors: Novak Vera , Slivka Andrew , Kanard Roly , Novak Peter , Binkley Phillip
Published: July 2021

P44

Objective:
To evaluate cerebral vasomotor reserve in hypertension during head-up tilt with hypo- and hypercapnia.
Background:
Cerebral vasoregulation determines degree of perfusion during increased metabolic demands such as orthostatic stress, hypo- and hypercapnia. With hypertension, silent hypoperfusion may develop if vasomotor reserve is compromised due to remodeling of the vessel wall and impaired vasodilation.
Methods:
We studied 15 mild hypertensive (BP 145/95 mm Hg) and 15 control men and women (aged 35–65 years) using Transcranial Doppler. Blood flow velocities (BFV) from both middle cerebral arteries (MCA), brachial artery (BRA), heart rate, blood pressure (BP), respiration and carbon dioxide (CO
2
) were simultaneously recorded during: hyperventilation (3 min), apnea (1 min) and CO
2
rebreathing (3 min) in supine rest and head-up tilt at 80
O
. Vasomotor reserve (VMR) was calculated from systolic (VMRS), diastolic (VMRD) and mean BFVs (VMRM) using regression analysis as percentual increment between hypo-, normo- and hypercapnia.
Results:
In controls, BFVs and VMR reserve were symmetric in both MCAs and there were no significant differences between rest and head-up tilt. In hypertensive patients, VMRM and were significantly reduced during supine rest (p<0.05) and head-up tilt (p<0.01) compared to the controls by about 50% (Table 1)in both MCAs. In controls, VMRD doubled during hypercapnia, while no significant increment was found in hypertensive patients. Systolic BFVs and VMR were similar in both groups.
Conclusions:
Vasomotor reserve was reduced even with mild hypertension due to impaired vasodilation. Impaired vasoregulation during orthostatic stress may be associated with silent cerebral hypoperfusion.
Lesion defined by Multiparametric MRI ISODATA correlates well with neurological deficit and PWI
Authors: Hammoud Rabih , Mitsias Panayiotis D , Patel Suresh C , Pasnoor Mamatha , Soltanian-Zadeh Hamid , Santhakumar Sunitha , Papamitsakis Nikolaos Ih , Jacobs Michael A , Peck Donald J , Lu Mei , Duhaini Ibrahim , Chopp Michael
Published: July 2021

P59

OBJECTIVE:
To show that the lesion defined by ISODATA (Iterative Self Organizing Data Analysis Technique) has a greater correlation with the deficit on perfusion weighted image (PWI) and National Institute of Health Stroke Scale (NIHSS) compared to the lesion defined by diffusion weighted image (DWI) or T2 weighted image (T2WI).
BACKGROUND:
Early in the course of acute ischemic stroke, the PWI lesion area is usually larger than the DWI or T2WI lesion areas, and correlates best with clinical neurological deficit. The computer segmentation algorithm ISODATA integrates different MRI parameters (DWI, T2WI, T1WI) and provides complimentary information about status of the tissue.
METHODS:
We obtained MRI parameters of DWI, T2WI and T1WI from 11 patients at two time points after stroke, the acute (<12 hrs) and chronic (3 months). The clinical neurological deficit was graded by the NIHSS at each time point. PWI was obtained at the acute time point. Relative mean transit time images (rMTT) were used to define the perfusion deficit. We compared PWI deficit area with DWI, ISODATA and T2WI lesion of the same location. The lesion areas were also correlated with NIHSS at acute time point. At chronic time point T2WI and ISODATA lesion volumes were compared with NIHSS.
RESULTS:
In acute phase PWI lesion area correlated best with NIHSS (r=0.72, p<0.05), followed by ISODATA (r=0.62, p<0.05), DWI (r =0.51, p<0.05) & T2WI (r=0.21, p<0.05) lesion areas. ISODATA correlated best with PWI lesion (r=0.90, p<0.05), and outperformed DWI (r=0.63, p<0.05) and T2WI (r= 0.48, p<0.05). We also noticed at chronic time point that there is a good correlation between ISODATA and T2WI(r= 0.97, p<0.05), ISODATA and NIHSS (r= 0.70, p<0.0.5), T2WI and NIHSS (r=0.68, p<0.05).
CONCLUSION:
This preliminary study shows that the integrated ISODATA approach to tissue segmentation discriminates abnormal from normal tissue at each time point after stroke. The area of the ISODATA defined lesion correlates well with PWI at the acute and T2WI at the chronic time point and the clinical neurological status of the patient.
Effects of PS-519 combined with thrombolytic therapy in embolic stroke in rat
Authors: Zhang Li , Zhang Zheng G , Chopp Michael , Elliott Peter J , Adams Julian
Published: July 2021

P67

We evaluated the effect of a proteasome inhibitor (PS-519) which blocks the activation of NF-kB, alone or combination with thrombolysis, on ischemic cell damage after embolic stroke in rat. Male Wistar rats (n=44) were subjected to embolic middle cerebral artery (MCA) occlusion. Animals were randomly assigned into seven groups: PS-519 treatment groups (n=6 each group) were infused intravenously with PS-519(1.0 mg/kg) at 2 h, 4 h, or 6 h after MCA occlusion, respectively. Combination treatment groups (n=6 each group) PS-519(1.0 mg/kg) followed by rtPA (10 mg/kg) were administered at 2 h, 4 h, or 6 h after MCA occlusion. A control group (n=8) was administered saline at 2 h after MCA occlusion. Rats were sacrificed 7 days after MCA occlusion, infarct volume and gross hemorrhage were measured. In PS-519 treatment groups: infarct volume was significantly (p<0.05) reduced by PS-519 treatment at 2 (19”3.5%) and 4 h (22“3.1%) after MCA occlusion when compared with the control group (34”3.5%). However, no significant reduction of lesion volume was found in the 6 hour treated group (34“2.5%). In the combination treatment groups: infarction volume was significantly (p<0.05) reduced in all three groups compared with control: 2 h (18”4.3%), 4 h (21“3.6%), 6 h (21”4.4%). None of treated rats and 25% of control rats had intracerebral gross hemorrhage. Significant reductions (p<0.05) in neurological deficit and body weight loss were found in all treated groups except the group that treated with PS-519 alone at 6 h. Our results demonstrate that administration of PS-519 alone, or combination with rtPA significantly reduces ischemic cell damage. Moreover, combination treatment with PS-519 and rtPA expands the therapeutic window to at least 6 h after embolic stroke. This suggests that combination therapy might lead to improved neurological outcome beyond that which would occur with neuroprotective treatment or thrombolytics alone.
Extracellular Signal Regulating Kinase Phosphorylation and Diffusion Weighted Imaging: Dual Markers of Infarct Progression
Authors: Legos Jeffrey J , Erhardt Joseph A , Haimbach Robin E , Boland Patrick M , Chandra Sudeep , Lenhard Stephen C , Irving Elaine A , Hunter Jacqueline , Sarkar Susanta K , Ohlstein Eliot H , Barone Frank C , Parsons Andrew A
Published: July 2021

P74

Background:
We have previously demonstrated a rapid and transient activation of p38 MAP Kinase following occlusion of the middle cerebral artery (MCAO). The aim of the present study was to evaluate the temporal progression of infarct development following distal and proximal MCAO using phosphorylation of Extracellular Signal Regulating Kinase (phospho-ERK) and MRI signatures.
Methods:
Spontaneously hypertensive (SHR) and normotensive (NTR) rats underwent either distal or proximal MCAO (n = 4–9/group). ERK activation was evaluated using western blots and immunohistochemistry in both ischemic and non-ischemic cortices at several time points. Imaging of infarct development was assessed by single slice analyses at several time points between 60–180min and again at 24h using diffusion weighted imaging (DWI) and gadolinium (Gd) enhanced bolus perfusion.
Results:
Following distal MCAO in SHR, ERK activation, in the ischemic cortex peaked at 15min (6.5±1.8 fold over sham-operated cortex) which remained significantly (p<0.05) elevated up to 1h (4.1±1.1 fold) post injury compared to non-ischemic (2.1±0.3 fold) tissue. In this model, there was no evidence of a mismatch at 60min post MCAO between Gd Peak Delay (140±15 pixels) and DWI (145±30 pixels). These early changes in DWI were identical to final infarct volume at 24h (148±15 pixels) indicating non-progressing stroke. Following proximal MCAO in NTR, increased phospho-ERK was observed up to 24h, and there was a mismatch in Gd Peak Delay and DWI at 60min (455±37 vs. 213±44 pixels), which was maintained up to 150min (494±29 vs. 321±46 pixels). By 24 hours, infarct volume, assessed by DWI (506±32 pixels), was identical to the early perfusion deficits suggesting a progression of infarct development in this model.
Conclusion:
Collectively, this data demonstrates that early changes in DWI can be predictive of final infarct volume only in an MCAO model where there is no early DWI/perfusion mismatch. The data also suggests that ERK activation can be a useful predictor of the progression of infarct development in certain models depicting early perfusion deficits.
Prediction of secondary ischemic lesions with diffusion-weighted imaging after transient middle cerebral artery occlusion in rats
Authors: Li Fuhai , Silva Matthew D , Meng Xiangjun , Sotak Christopher H , Fisher Marc
Published: July 2021

P75

Background and Purpose:
Previous studies demonstrated that secondary ischemic lesions documented by diffusion-weighted imaging might be smaller than, larger than or similar to initial lesions that occur during ischemia. The purpose of this study was to investigate if the size of secondary lesions can be predicted.
Methods:
Twelve rats underwent 30 minutes of transient middle cerebral artery occlusion with the intraluminal suture method. Diffusion- and perfusion-weighted images were performed just before reperfusion, 90 minutes and 24 hours after reperfusion. The ischemic lesion size was calculated by tracing visual abnormalities on the apparent diffusion coefficient (ADC) maps. Cerebral blood flow index (CBF
i
) ratio was calculated by dividing the ipsilateral CBF
i
by the contralateral CBF
i
. Based on difference between initial and secondary lesion volume, rats were assigned to reperfusion-benefit group (n=6) where secondary lesions were smaller than initial lesions (less than 85% of initial lesions) and reperfusion-nonbenefit group (n=6) where secondary lesions were similar to or larger than initial lesions (more than 85% of initial lesions).
Results:
At 90 minutes after reperfusion, the initial ischemic lesions almost disappeared in both groups. At 24 hours, secondary lesions were 54±11% (mean±SD) of the initial lesions in the reperfusion-benefit group and 100±14% of the initial lesions in the reperfusion-nonbenefit group (p<0.001). There was no difference in ADC values (47±2×10
-5
mm
2
/s vs 46±5×10
-5
mm
2
/s, p=0.7) and CBF
i
ratio (0.62±0.06 vs 0.67±0.04, p=0.2) between the two groups before reperfusion. However, the initial lesion volume was significantly smaller in the reperfusion-benefit group than in the reperfusion-nonbenefit group (125±54 mm
3
vs 195±36 mm
3
, p=0.037).
Conclusions:
Changes of ADC values and CBF before reperfusion are unable to predict if initial ischemic lesions will eventually shrink or not after reperfusion. Smaller size of initial lesions may suggest that secondary lesions will be smaller than initial lesions.
Delayed (6h) Intracarotid Treatment with TNK-tPA Improves Neurological Functional Recovery after Embolic Stroke in the Unanesthetized Rat
Authors: Zhang Ruilan , Zhang Li , Goussev Anton , Chopp Michael
Published: July 2021

P76

We tested the hypothesis that delayed intra-arterial administration of TNK-tPA increases functional recovery in a model of focal cerebral embolic ischemia in the unanesthetized rat. Male unanesthetized Wistar rats (n=22) were subjected to middle cerebral artery (MCA) occlusion using a single fibrin rich clot. TNK-tPA (1.5 mg/kg) was administered intraarterially via an internal carotid catheter at 2 h (n=4), 4 h (n=6) or 6 h (n=6) after MCA occlusion. Non-treated ischemic rats (n=6) were used as a control group. A battery of tests (1. Rotarod test, 2. Adhesive-removal test and 3. Footfault test) was used to evaluate neurological function. Animal body weights were measured before and after MCA occlusion. All rats were sacrificed 28 days after ischemia. Infract volume and gross hemorrhage was measured. Intra-arterial treatment with TNK-tPA at 2h after ischemia significantly (p<0.01) reduced infarct volume (18.6“2.6 % of the contralateral hemisphere) and improved neurological functional recovery compared with the control rats (37.5 ”0.7%). Although infarct volumes were not significantly reduced for rats treated with intra-arterial TNK-tPA at 4h (31.2“3.1 %) and at 6h (32.9”3.1 %) after ischemia, significant (p<0.05) improvements on sensorimotor functions (adhesive removal test at 4, 14, 21, and 28 d ) and significant increases in animal body weight (7 d) were detected in rats treated with TNK-tPA at 4 h and 6h. Gross hemorrhage was 25% (2h), 33% (4h) and 33% (6h), which was not significantly different from gross hemorrhage in the control group (17 %). This study demonstrates that intra-carotid treatment with TNK-tPA even at 6h of the onset of stroke improves neurological functional recovery from brain damage without significantly increasing the incidence of intra-cerebral hemorrhage in the unanesthetized ischemic rat.