Antidepressant use and stroke or mortality risk in the elderly.

BACKGROUND AND PURPOSE: Current evidence on antidepressant-related stroke or mortality risk is inconsistent. Because the elderly have the highest exposure to antidepressants, the aim was to quantify their association with stroke and mortality risks in this vulnerable population. METHODS: Persons over 65 years old and registered in the Information System for Research in Primary Care of Catalonia during 2010-2015 comprised the study population. Antidepressant exposure was categorized into current-users, recent-users, past-users and antidepressant non-users (controls). The effect of antidepressant exposure on stroke or death, whichever came first, was analyzed by Cox regression adjusted for established risk factors. RESULTS: Of the 1,068,117 participants included, 20% had antidepressant reimbursements during follow-up, 17% had a stroke and 3% died. The risk of experiencing stroke or death was higher in antidepressant current-users (hazard ratio [HR] 1.04; 95% confidence interval [CI] 1.02-1.06), recent-users (HR 3.34; 95% CI 3.27-3.41) and past-users (HR 2.06; 95% CI 2.02-2.10) compared to antidepressant non-users. Antidepressant current-use was associated with increased stroke (HR 1.56; 95% CI 1.50-1.61) but decreased mortality risk (HR 0.93; 95% CI 0.91-0.94). During antidepressant recent-use and past-use, both stroke and mortality risks were significantly increased compared to no antidepressant use. CONCLUSIONS: Antidepressant use may be associated with increased stroke risk in the elderly. When using antidepressants in this population, the potential risks should be considered.

Effect of late-onset epilepsy on cognitive functioning in patients with small vessel disease.

RATIONALE: Late-onset epilepsy (LOE) often has underlying cerebrovascular cause and has been associated with neurocognitive deficits and dementia. Nevertheless, the interplay between these factors has not been studied thus far. Hence, we conducted a retrospective cross-sectional study aimed to explore how unprovoked epileptic seizures along with vascular-related factors contribute to neurocognitive impairments in patients with cerebral small vessel disease. METHODS: Twenty-seven patients with LOE aged > 60 years with concomitant cerebral small vessel disease (cSVD) and a matched group of cSVD without epilepsy were cognitively assessed. Demographic, clinical, and vascular information were obtained and vascular burden score was calculated for each patient. Multiple linear regression models were used to explore the relationship between epilepsy and cognitive measures adjusting for demographic and vascular risk factors. RESULTS: Compared with cSVD, cSVD-LOE group showed a poorer performance on verbal memory measures, visuomotor tracking and speed processing and phonetic fluency. In the multiple regression analysis, the presence of epilepsy was found to be the major predictor for verbal memory dysfunction, specifically in verbal short recall (p = 0.008) and verbal learning (p < 0.001). No interactions between vascular burden and epilepsy were found. CONCLUSION: Patients who had cSVD with concurrent LOE showed poorer performance on memory function compared with patients with cSVD without epilepsy, and they showed a different cognitive profile from that typically manifested by patients with cSVD. The presence of epilepsy, but not seizure localization nor vascular burden, was the major contributor to the decrease in verbal memory.

Obstructive sleep apnea and silent cerebral infarction in hypertensive individuals.

Obstructive sleep apnea syndrome is very prevalent in hypertensive subjects. Moreover, obstructive sleep apnea syndrome activates multiple processes that might be associated with silent cerebral infarct independently of established risk factors. Our aim is to estimate the frequency of obstructive sleep apnea syndrome in hypertensive patients with and without silent cerebral infarct, and to determine whether obstructive sleep apnea syndrome is an independent risk factor of silent cerebral infarct and/or lacunar silent cerebral infarct in patients with hypertension. In this matched cross-sectional study performed in hypertensive subjects, each patient with silent cerebral infarct detected by magnetic resonance imaging was matched with two patients without silent cerebral infarct. Polysomnographic studies were performed, and the apnea-hypopnea index was calculated. Severe obstructive sleep apnea syndrome was considered in those with apnea-hypopnea index >30. One-hundred and eighty-three patients, 61 with silent cerebral infarct and 122 without silent cerebral infarct, were evaluated. The mean age was 64.1 ± 4.5 years, and 72.1% were men. The frequency of severe obstructive sleep apnea syndrome was 44.3% in patients with silent cerebral infarct and 38.5% in the control group. An adjusted conditional logistic regression model did not show a significant increased risk of silent cerebral infarct in patients with severe obstructive sleep apnea syndrome (odds ratio 1.362; 95% confidence interval: 0.659-2.813; P = 0.404). Forty-three patients (70.5%) of the silent cerebral infarct were lacunar. The presence of severe obstructive sleep apnea syndrome was significantly higher in lacunar silent cerebral infarct when compared with patients without lacunar infarcts (55.8% versus 35.7%, P = 0.019), being independently associated on an adjusted logistic regression model (odds ratio 2.177; 95% confidence interval: 1.058-4.479; P = 0.035). In conclusion, severe obstructive sleep apnea syndrome is highly prevalent among hypertensive subjects, and is independently associated with lacunar silent cerebral infarct.

Long-Term Treatment with Citicoline Prevents Cognitive Decline and Predicts a Better Quality of Life after a First Ischemic Stroke.

Stroke, as the leading cause of physical disability and cognitive impairment, has a very significant impact on patients' quality of life (QoL). The objective of this study is to know the effect of citicoline treatment in Qol and cognitive performance in the long-term in patients with a first ischemic stroke. This is an open-label, randomized, parallel study of citicoline vs. usual treatment. All subjects were selected 6 weeks after suffering a first ischemic stroke and randomized into parallel arms. Neuropsychological evaluation was performed at 1 month, 6 months, 1 year and 2 years after stroke, and QoL was measured using the EuroQoL-5D questionnaire at 2 years. 163 patients were followed during 2 years. The mean age was 67.5 years-old, and 50.9% were women. Age and absence of citicoline treatment were independent predictors of both utility and poor quality of life. Patients with cognitive impairment had a poorer QoL at 2 years (0.55 vs. 0.66 in utility, p = 0.015). Citicoline treatment improved significantly cognitive status during follow-up (p = 0.005). In conclusion, treatment with long-term citicoline is associated with a better QoL and improves cognitive status 2 years after a first ischemic stroke.

Triflusal and aspirin in the secondary prevention of atherothrombotic ischemic stroke: a very long-term follow-up.

BACKGROUND: The mean follow-up in the clinical trials of antiplatelet drugs in the secondary prevention of ischemic atherothrombotic stroke ranges from 1 to 5.5 years. Thus, the safety and efficacy of these drugs in the very long term is not totally documented. We have assessed the safety and effectiveness of triflusal and aspirin for a very long-term period in the secondary prevention of patients with ischemic atherothrombotic stroke. METHODS: Patients with atherothrombotic ischemic stroke, including TIA, who participated in randomized clinical trials of triflusal versus aspirin were included in the study. The period of recruitment was between 1983 and 1999. After finishing their participation in the clinical trials, patients were followed up in the Neurology Department of our hospital. All patients were treated with aspirin or triflusal during a mean period of 17.2 years. Groups were comparable with respect to sex, age, risk factor and etiology of the stroke. Adverse events and vascular events (including stroke recurrence, ischemic heart disease and vascular death) that appeared throughout the study were registered. Statistical analysis was performed using the statistical package SPSS 15.0 for Windows. Kaplan-Meier curves and the log-rank test were used to compare treatments. RESULTS: A total of 441 patients (305 men) with a mean age (±SD) of 51.1±12.4 years were included in the study; 288 patients (65.3%) were treated with triflusal and 153 with aspirin. There were no statistically significant differences between aspirin and triflusal concerning new vascular events (72.5 vs. 60.4%; p=0.28), stroke recurrence (49.7 vs. 46.5%; p=0.53), ischemic heart events (54.9 vs. 55.6%; p=0.90), vascular death (25.5 vs. 24%; p=0.73) and global mortality (42.5 vs. 42%; p=0.92). The incidence of serious bleeding (upper digestive tract hemorrhage and cerebral hemorrhage) was 18.3% in aspirin-treated patients and 5.5% in triflusal-treated patients (p<0.001). In reference to other adverse events, no significant differences were found between aspirin and triflusal. CONCLUSIONS: In the secondary prevention of ischemic stroke, very long-term treatment with triflusal or aspirin seems to have a similar efficacy, but triflusal is safer with a lower hemorrhagic risk. Triflusal may be an alternative therapy, particularly in patients who present aspirin resistance.

Stroke-associated pneumonia according to mCDC criteria: impact on prognosis and antibiotic therapy.

Objective: The modified Centers for Disease Control and Prevention (mCDC) criteria have been proposed for diagnosing and managing stroke-associated pneumonia (SAP). The objective was to investigate the impact of SAP on stroke outcome depending on whether or not it conforms to mCDC criteria. Our secondary objective was to identify the responsible factors for antibiotic initiation in stroke patients. Methods: We conducted a prospective, multicenter, observational study of ischemic stroke patients with moderate to severe stroke (NIHSS≥4) admitted within 24 h. For 7 days, mCDC criteria were assessed daily, and infections and antibiotics were recorded. Pneumonias were divided into those fulfilling mCDC criteria (mCDC-SAP) or not (other pneumonias, OPn). The effect of each type of pneumonia on 3-month outcome was evaluated in separated logistic regression models. Factors associated with antibiotic initiation were explored using a random forest analysis. Results: Of the 342 patients studied, infections were diagnosed in 72 (21.6%), including 39 (11.7%) cases of pneumonia. Of them, 25 (7.5%) fulfilled mCDC criteria. Antibiotics were used in 92% of mCDC-SAP and 64.3% of OPn. In logistic regression analysis, mCDC-SAP, but not OPn, was an independent predictor of poor outcome [OR, 4.939 (1.022-23.868)]. The random forest analysis revealed that fever had the highest importance for antibiotic initiation. Interpretation: The mCDC criteria might be useful for detecting clinically relevant SAP, which is associated with poor outcomes. Isolated signs of infection were more important for antibiotic initiation than compliance with pre-defined criteria. Therefore, adherence to mCDC criteria might result in antibiotic saving without compromising clinical outcome.

Long-term treatment with citicoline may improve poststroke vascular cognitive impairment.

BACKGROUND: Cognitive decline after stroke is more common than stroke recurrence. Stroke doubles the risk of dementia and is a major contributor to vascular cognitive impairment and vascular dementia. Nonetheless, few pharmacological studies have addressed vascular cognitive impairment after stroke. We assessed the safety of long-term administration and its possible efficacy of citicoline in preventing poststroke cognitive decline in patients with first-ever ischemic stroke. METHODS: Open-label, randomized, parallel study of citicoline vs. usual treatment. All subjects were selected 6 weeks after suffering a qualifying stroke and randomized by age, gender, education and stroke type into parallel arms of citicoline (1 g/day) for 12 months vs. no citicoline (control group). Medical management was similar otherwise. All patients underwent neuropsychological evaluation at 1 month, 6 months and 1 year after stroke. Tests results were combined to give indexes of 6 neurocognitive domains: attention and executive function, memory, language, spatial perception, motor speed and temporal orientation. Using adjusted logistic regression models we determined the association between citicoline treatment and cognitive decline for each neurocognitive domain at 6 and 12 months. RESULTS: We recruited 347 subjects (mean age 67.2 years, 186 male (56.6%), mean education 5.7 years); 172 (49.6%) received citicoline for 12 months (no significant differences from controls n = 175). Demographic data, risk factors, initial stroke severity (NIHSS), clinical and etiological classification were similar in both groups. Only 37 subjects (10.7%) discontinued treatment (10.5% citicoline vs. 10.9% control) at 6 months; 30 (8.6%) due to death (16 (9.3%) citicoline vs. 14 (8.0%) control, p = 0.740), 7 lost to follow-up or incorrect treatment, and 4 (2.3%) had adverse events from citicoline without discontinuation. 199 patients underwent neuropsychological evaluation at 1 year. Cognitive functions improved 6 and 12 months after stroke in the entire group but in comparison with controls, citicoline-treated patients showed better outcome in attention-executive functions (OR 1.721, 95% CI 1.065-2.781, p = 0.027 at 6 months; OR 2.379, 95% CI 1.269-4.462, p = 0.007 at 12 months) and temporal orientation (OR 1.780, 95% CI 1.020-3.104, p = 0.042 at 6 months; OR 2.155, 95% CI 1.017-4.566, p = 0.045 at 12 months) during the follow-up. Moreover, citicoline group showed a better functional outcome (modified Rankin scale ≤2) at 12 months (57.3 vs. 48.7%) without statistically significant differences (p = 0.186). CONCLUSIONS: Citicoline treatment for 12 months in patients with first-ever ischemic stroke is safe and probably effective in improving poststroke cognitive decline. Citicoline appears to be a promising agent to improve recovery after stroke. Large clinical trials are needed to confirm the net benefit of this therapeutic approach.

Investigating silent strokes in hypertensives: a magnetic resonance imaging study (ISSYS): rationale and protocol design.

BACKGROUND: Silent brain infarcts are detected by neuroimaging in up to 20% of asymptomatic patients based on population studies. They are five times more frequent than stroke in general population, and increase significantly both with advancing age and hypertension. Moreover, they are independently associated with the risk of future stroke and cognitive decline.Despite these numbers and the clinical consequences of silent brain infarcts, their prevalence in Mediterranean populations is not well known and their role as predictors of future cerebrovascular and cardiovascular events in hypertensive remains to be determined.ISSYS (Investigating Silent Strokes in Hypertensives: a magnetic resonance imaging study) is an observational cross-sectional and longitudinal study aimed to: 1- determine the prevalence of silent cerebrovascular infarcts in a large cohort of 1000 hypertensives and to study their associated factors and 2-to study their relationship with the risk of future stroke and cognitive decline. METHODS/DESIGN: Cohort study in a randomly selected sample of 1000 participants, hypertensive aged 50 to 70 years old, with no history of previous stroke or dementia.On baseline all participants will undergo a brain MRI to determine the presence of brain infarcts and other cerebrovascular lesions (brain microbleeds, white matter changes and enlarged perivascular spaces) and will be also tested to determine other than brain organ damage (heart-left ventricular hypertrophy, kidney-urine albumin to creatinine ratio, vessels-pulse wave velocity, ankle brachial index), in order to establish the contribution of other subclinical conditions to the risk of further vascular events. Several sub-studies assessing the role of 24 hour ambulatory BP monitoring and plasma or genetic biomarkers will be performed.Follow-up will last for at least 3 years, to assess the rate of further stroke/transient ischemic attack, other cardiovascular events and cognitive decline, and their predictors. DISCUSSION: Improving the knowledge on the frequency and determinants of these lesions in our setting might help in the future to optimize treatments or establish new preventive strategies to minimize clinical and socioeconomic consequences of stroke and cognitive decline.

Impact of telemedicine on acute management of stroke patients undergoing endovascular procedures.

BACKGROUND: Telemedicine is improving acute stroke care in remote areas. Delay in hospital-to-hospital transfer is a common reason why acute ischemic stroke patients are excluded from interventional therapy. The progressive implementation of these procedures, requiring highly specialized professionals in comprehensive stroke centers, will certainly challenge even more the geographic equity in the access to the best acute stroke treatments. We aimed to assess the benefits of telemedicine in selecting stroke patients for endovascular treatments. METHODS: In our Reference Comprehensive Stroke Center (RCSC), we perform urgent intra-arterial procedures in acute stroke patients. Patients may be primarily admitted (PA) or referred from community hospitals with (TMHs; 2 centers) or without telemedicine (nonTMHs; 7 centers). We prospectively studied all consecutive stroke patients undergoing urgent endovascular recanalization procedures in the RCSC. We studied different outcome measures according to the patients' initial admission: PA patients, TMH patients or nonTMH patients. For all patients, demographic and outcome data including serial National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores at 3 months were recorded. Clinical improvement was defined as a decrease ≥4 points on the NIHSS at 7 days or discharge and favorable outcome as mRS ≤2 at 3 months. Whether an endovascular procedure was indicated was decided according to clinical, radiological and transcranial Doppler (TCD) data, independently of the patient's initial admission center. RESULTS: During a 2-year period, 119 patients received endovascular treatment: PA patients 74 (63.1%), TMH patients 25 (20.5%), nonTM patients 20 (16.4%). The mean distance to the RCSC was 52 ± 15 km for TMHs and 34.5 ± 12 km for nonTMHs (p = 0.4). There were no differences in baseline characteristics including age (71, 71.6 and 66.5 years; p = 0.25), baseline NIHSS (18.5, 19 and 18; p = 0.57) and previous use of intravenous tissue plasminogen activator (56.5, 56.5 and 57.9%; p = 0.95). The rate of recanalization (modified Thrombolysis in Cerebral Infarction Score ≥2a) was similar in all groups (75, 66.6 and 68.4%; p = 0.682). TMH and PA patients had similar clinical improvement (61 vs. 63.8%; p = 0.51) and good functional outcome (36.8 vs. 35.3%; p = 0.722). Conversely, nonTMH patients presented a lesser degree of clinical improvement (31.3%) and poorer functional outcome (15.8%) than TMH (p = 0.019 and p = 0.046) and PA patients (p = 0.05 and p = 0.013). TMH patients had significantly shorter door-to-groin puncture times (47 vs. 69 min; p = 0.047). CONCLUSIONS: Telemedicine assessment to select patients for endovascular procedures improves the efficiency in stroke management and possibly the early and long-term outcome in patients receiving intra-arterial reperfusion treatment.

Lipoprotein-associated phospholipase A(2) activity is associated with large-artery atherosclerotic etiology and recurrent stroke in TIA patients.

BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has emerged as a novel biomarker in cardiovascular diseases due to its ability to predict stroke in population-based studies. We aimed to investigate Lp-PLA(2) levels in transient ischemic attack (TIA) patients and to study their relationship with stroke recurrence. METHODS: Lp-PLA(2) mass and activity were measured by means of the PLAC test with an automated Olympus analyzer and by a colorimetric activity method (diaDexus) in 166 TIA patients and 144 healthy controls. Vascular risk factors and stroke etiology were assessed. Outcome was defined as the presence of recurrent stroke/TIA within 7 and 30 days after the index TIA. Multivariate analyses were performed to identify potential predictors of recurrence. RESULTS: Both Lp-PLA(2) mass and activity (p < 0.05) were higher in TIA than in controls. Several risk factors or previous treatments were associated with Lp-PLA(2) mass and activity level. During follow-up, 20 strokes/TIA (12%) occurred within the first 30 days and the presence of a large-artery atherosclerosis etiology of stroke (HR 3.28, p = 0.011), together with the past medical history of hyperlipidemia (HR 3.68, p = 0.008) and Lp-PLA(2) activity of >207 nmol/ml/min (HR 2.7, p = 0.042) were all significant predictors for recurrent stroke/TIA. CONCLUSIONS: Lp-PLA(2) activity might add significant prognostic information in the early evaluation of TIA patients.

Silent brain infarcts, peripheral vascular disease and the risk of cardiovascular events in patients with hypertension.

BACKGROUND AND AIMS: We aimed to study the relationship between cerebral small vessel disease (cSVD) lesions, as markers of subclinical target organ damage (TOD) in the brain, and incident cardiovascular events (CVE). METHODS: Data from the ISSYS (Investigating Silent Strokes in hYpertensives Study), which is a longitudinal and observational study conducted in patients with hypertension aged 50-70 years, and stroke-free at the inclusion. At the baseline visit, participants underwent a clinical interview, a brain MRI, urine and blood sampling collection and vascular testing studies. Therefore, we obtained markers of TOD from the brain [white matter hyperintensities, silent brain infarcts (SBI), cerebral microbleeds and enlarged perivascular spaces (EPVS)], from kidney (microalbuminuria, glomerular filtration) and regarding large vessels [ankle-to-brachial index (ABI), carotid-femoral pulse wave velocity]. Survival analyses were used to assess the relationship between these predictors and the incidence of cardiovascular events (CVE). RESULTS: We followed-up 964 individuals within a median time of 5 years (4.7-5), representing 4377.1 persons-year. We found 73 patients presenting incident CVE, which corresponds to a rate of 8.2%. We found ABI less than 0.9 [hazard ratio, 2.2; 95% confidence interval (CI) 1.17-4.13, P value = 0.014] and SBI (hazard ratio, 2.9; 95% CI 1.47-5.58, P value = 0.002) independently associated with higher risk of incident CVE. The inclusion of both variables in a clinical model resulted in an increased discrimination of individuals with new CVE of 4.72%, according to the integrated discrimination index. CONCLUSION: Assessment of SBI and ABI less than 0.9 may refine the cardiovascular risk stratification in patients with hypertension.

Extending the time window for endovascular procedures according to collateral pial circulation.

BACKGROUND AND PURPOSE: Good collateral pial circulation (CPC) predicts a favorable outcome in patients undergoing intra-arterial procedures. We aimed to determine if CPC status may be used to decide about pursuing recanalization efforts. METHODS: Pial collateral score (0-5) was determined on initial angiogram. We considered good CPC when pial collateral score<3, defined total time of ischemia (TTI) as onset-to-recanalization time, and clinical improvement>4-point decline in admission-discharge National Institutes of Health Stroke Scale. RESULTS: We studied CPC in 61 patients (31 middle cerebral artery, 30 internal carotid artery). Good CPC patients (n=21 [34%]) had lower discharge National Institutes of Health Stroke Scale score (7 versus 21; P=0.02) and smaller infarcts (56 mL versus 238 mL; P<0.001). In poor CPC patients, a receiver operating characteristic curve defined a TTI cutoff point<300 minutes (sensitivity 67%, specificity 75%) that better predicted clinical improvement (TTI<300: 66.7% versus TTI>300: 25%; P=0.05). For good CPC patients, no temporal cutoff point could be defined. Although clinical improvement was similar for patients recanalizing within 300 minutes (poor CPC: 60% versus good CPC: 85.7%; P=0.35), the likelihood of clinical improvement was 3-fold higher after 300 minutes only in good CPC patients (23.1% versus 90.1%; P=0.01). Similarly, infarct volume was reduced 7-fold in good as compared with poor CPC patients only when TTI>300 minutes (TTI<300: poor CPC: 145 mL versus good CPC: 93 mL; P=0.56 and TTI>300: poor CPC: 217 mL versus good CPC: 33 mL; P<0.01). After adjusting for age and baseline National Institutes of Health Stroke Scale score, TTI<300 emerged as an independent predictor of clinical improvement in poor CPC patients (OR, 6.6; 95% CI, 1.01-44.3; P=0.05) but not in good CPC patients. In a logistic regression, good CPC independently predicted clinical improvement after adjusting for TTI, admission National Institutes of Health Stroke Scale score, and age (OR, 12.5; 95% CI, 1.6-74.8; P=0.016). CONCLUSIONS: Good CPC predicts better clinical response to intra-arterial treatment beyond 5 hours from onset. In patients with stroke receiving endovascular treatment, identification of good CPC may help physicians when considering pursuing recanalization efforts in late time windows.

Bridging intravenous-intra-arterial rescue strategy increases recanalization and the likelihood of a good outcome in nonresponder intravenous tissue plasminogen activator-treated patients: a case-control study.

BACKGROUND AND PURPOSE: Safety and efficacy of the "bridging therapy" (intra-arterial [IA] reperfusion rescue for nonresponder intravenous [IV] tissue plasminogen activator [tPA]-treated patients) is a matter of debate. Our aim was to compare IV and IV-IA thrombolysis using a case-control approach. METHODS: Consecutive patients with proximal intracranial occlusion who received IA reperfusion procedures after unsuccessful IV tPA (lack of clinical improvement and arterial recanalization 1 hour after tPA bolus) were studied (IV-IA group). They were compared with occluded vessel, clot location, stroke severity, and time to treatment-matched 1 to 2 historical patients from our prospective IV tPA database with persistent occlusion 1 hour after IV tPA (IV-NR group). Arterial occlusion and recanalization were assessed with transcranial Doppler. Clinical evaluation was assessed by National Institutes of Health Stroke Scale at baseline, 24 hours, and at discharge. Symptomatic intracranial hemorrhage was defined according to the National Institute of Neurological Disorders and Stroke trial. Functional evaluation was determined by modified Rankin Scale, being functional independency defined by modified Rankin Scale score ≤2. RESULTS: Forty-two IV-IA patients were compared with 84 matched IV-NR. Mean age was 71.5±2.9 years, 58 (46%) were women, and baseline median National Institutes of Health Stroke Scale score was 20 (interquartile range, 5). Mean time from symptoms to IV tPA was 176.9±113 minutes. On transcranial Doppler, complete recanalization was significantly higher in IV-IA than control subjects (12 hours: 45.2% versus 18.1%, P=0.002; 24 hours: 46.3% versus 25.3%, P=0.016) with nonsignificant better clinical evolution at 24 hours (40.5% versus 30.1%, P=0.169) and discharge (52.5% versus 39.5%, P=0.123). Symptomatic intracranial hemorrhage was similar (IV-IA 11.9% versus IV-NR 6%, P=0.205). Mortality at 3 months was 50% in the IV-IA group and 35.8% in the IV-NR (P=0.154). Forty percent of IV-IA patients were functionally independent at 3 months and only 14.9% IV-NR (P=0.012). CONCLUSIONS: Bridging IV-IA treatment may improve recanalization and clinical outcome in nonresponder IV tPA-treated patients.

Serum low-density lipoprotein cholesterol level predicts hematoma growth and clinical outcome after acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Lower serum low-density lipoprotein cholesterol (LDL-C) levels have been associated with increased risk of death after intracerebral hemorrhage (ICH). Nevertheless, their link with hematoma growth (HG) is unknown. Therefore, we aimed to investigate the relationship between LDL-C levels, HG, and clinical outcome in patients with acute ICH. METHODS: We prospectively studied 108 consecutive patients with primary supratentorial ICH presenting within 6 hours from symptoms onset. National Institutes of Health Stroke Scale score and ICH volume on computed tomography scan were recorded at baseline and at 24 hours. Lipid profile was obtained during the first 24 hours. Significant HG was defined as hematoma enlargement >33% or >6 mL at 24 hours. Early neurological deterioration as well as mortality and poor long-term outcome (modified Rankin Scale score >2) at 3 months were recorded. RESULTS: Although LDL-C levels were not correlated with ICH volume (r=-0.18; P=0.078) or National Institutes of Health Stroke Scale score (r=-0.17; P=0.091) at baseline, lower LDL-C levels were associated with HG (98.1±33.7 mg/dL versus 117.3±25.8 mg/dL; P=0.003), early neurological deterioration (89.2±31.8 mg/dL versus 112.4±29.8 mg/dL; P=0.012), and 3-month mortality (94.9±37.4 mg/dL versus 112.5±28.5 mg/dL; P=0.029), but not with poor long-term outcome (109.5±31.3 mg/dL versus 108.3±30.5 mg/dL; P=0.875). Moreover, LDL-C levels were inversely related to the amount of hematoma enlargement at 24 hours (r=-0.31; P=0.004). In multivariate logistic regression analysis, LDL-C level <95 mg/dL emerged as an independent predictor of HG (OR, 4.24; 95% CI, 1.26-14.24; P=0.020), early neurological deterioration (OR, 8.27; 95% CI, 1.66-41.16; P=0.010), and 3-month mortality (OR, 6.34; 95% CI, 1.29-31.3; P=0.023). CONCLUSIONS: Lower serum LDL-C level independently predicts HG, early neurological deterioration, and 3-month mortality after acute ICH.

Diabetes, Albuminuria and the Kidney-Brain Axis.

Cognitive decline and kidney disease are significant public health problems that share similar characteristics and risk factors. The pathophysiology of the kidney-brain axis is not completely understood, and studies analysing the relationship between the biomarkers of kidney damage and cognitive impairment show different results. This article focuses on the epidemiological and clinical aspects concerning the association of albuminuria, a marker for endothelial dysfunction and microvascular disease, and cognitive impairment in patients with chronic kidney disease, diabetic kidney disease and end-stage kidney disease. Most studies show a positive relationship between albuminuria and cognitive impairment in all groups, but evidence in type 2 diabetes (T2D) patients is limited. We briefly discuss the mechanisms underlying these associations, such as damage to the microvascular circulation, leading to hypoperfusion and blood pressure fluctuations, as well as increased inflammation and oxidative stress, both in the brain and in the kidneys. Further clinical and epidemiological studies developed to understand the interplay between the kidneys and brain diseases will hopefully lead to a reduction in cognitive impairment in these patients.

Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment.

CADASIL is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the EGF-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraine, psychiatric disturbances, recurrent strokes and dementia, being executive function characteristically impaired. The molecular pathways altered by this receptor aggregation need to be studied further. A genome-wide transcriptome study (four cases paired with three healthy siblings) was carried out, in addition to a qRT-PCR for validation purposes (ten new cases and eight new controls). To study the expression profile by cell type of the significant mRNAs found, we performed an in situ hybridization (ISH) (nine cases and eight controls) and a research in the Single-nuclei Brain RNA-seq expression browser (SNBREB). Pathway analysis enrichment was carried out with Gene Ontology and Reactome. Neuropsychological tests were performed in five of the qRT-PCR cases. The two most significant differentially expressed mRNAs (BANP, p-value = 7.23 × 10-4 and PDCD6IP, p-value = 8.36 × 10-4) were selected for the validation study by qRT-PCR. Additionally, we selected two more mRNAs (CAMK2G, p-value = 4.52 × 10-3 and E2F4, p-value = 4.77 × 10-3) due to their association with ischemic neuronal death. E2F4 showed differential expression in the genome-wide transcriptome study and in the qRT-PCR (p = 1.23 × 10-3), and it was upregulated in CADASIL cases. Furthermore, higher E2F4 expression was associated with worse executive function (p = 2.04 × 10-2) and attention and information processing speed (IPS) (p = 8.73 × 10-2). In situ hibridization showed E2F4 expression in endothelial and vascular smooth vessel cells. In silico studies indicated that E2F4 is also expressed in brain endothelial cells. Among the most significant pathways analyzed, there was an enrichment of vascular development, cell adhesion and vesicular machinery terms and autophagy process. E2F4 is more highly expressed in the skin biopsy of CADASIL patients compared to controls, and its expression is present in endothelial cells and VSMCs. Further studies are needed to understand whether E2F4 could be useful as a biomarker, to monitor the disease or be used as a therapeutic target.

Ambulatory Blood Pressure Levels in the Prediction of Progression of Cerebral Small Vessel Disease.

OBJECTIVES: We aimed to study the value of ambulatory blood pressure monitoring (ABPM) in predicting the global progression of cerebral small vessel disease (cSVD). DESIGN: Longitudinal cohort study. SETTING: Data from the population-based Investigating Silent Strokes in Hypertensives study. PARTICIPANTS: Individuals with hypertension who were 50 to 70 years of age and stroke free at baseline. In baseline and follow-up visits, patients underwent magnetic resonance imaging and ABPM. MEASUREMENTS: Ambulatory systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels were studied as continuous variables and dichotomized according to good or poor control on the basis of 125/75 (24 hours), 130/80 (day), and 110/65 (night) mm Hg cutoff values. Whole cSVD progression was qualitatively scored with 1 point when an incident lesion (incident lacunar infarcts, deep cerebral microbleeds, white matter hyperintensities, and basal ganglia enlarged perivascular spaces) was detected. The score ranged from 0 to 4. RESULTS: We followed up 233 participants with a median age of 65 years within 4 years. A total of 61 (26.2%) and 23 (9.9%) subjects showed cSVD progression in one and two or more markers, respectively. Baseline ambulatory SBP and DBP and nighttime pulse pressure (PP) values were positively correlated with the number of incident cSVD lesions. Interestingly, patients without incident lesions showed greater differences between office and ambulatory BP, thus suggesting an increased white coat effect. Poor DBP control, nighttime PP, and DBP white coat effect were independently associated with cSVD progression. The inclusion of these metrics in a clinical model resulted in a significant increase in the prediction of incident lesions (integrated discrimination improvement = 9.09%; P value <.001). CONCLUSION: ABPM may help assess cSVD risk of progression, especially by the identification of poor BP control, masked hypertension, and increased nighttime PP. J Am Geriatr Soc 68:2232-2239, 2020.

Kidney function changes and their relation with the progression of cerebral small vessel disease and cognitive decline.

AIMS: We aimed to study whether worsening in markers of kidney function parallels the progression in cerebral small vessel disease (cSVD) and cognitive decline. METHODS: Data from the ISSYS (Investigating Silent Strokes in Hypertensives Study), a longitudinal population-based study in hypertensives aged 50-70 and dementia and stroke-free at baseline. At both visits, patients underwent a brain MRI, a cognitive diagnosis (normal aging or mild cognitive impairment, [MCI]) and urine and blood sampling collection. We assessed the incidence of infarcts and cerebral microbleeds, and the progression of white matter hyperintensities at periventricular (PVH) and deep areas. We determined changes in albumin-creatinine ratio and estimated glomerular filtration rate (eGFR). These changes were dichotomized into microalbuminuria at follow-up -either in subjects with or without baseline microalbuminuria- and significant decline in eGFR -lowest quintile of eGFR change (-10.57 mL/min/1.73m2)-. RESULTS: 360 patients were followed-up for 4 years. 80 (23%) patients presented microalbuminuria at follow-up and 68 (20.1%) experienced a significant eGFR decline. Considering cSVD change, we found a relationship between microalbuminuria at follow-up and progression in PVH (ß = 0.31, P-value = .01). Regarding cognitive decline, presence of microalbuminuria at follow-up related to a steeper decrease in memory function (ß = -0.36, P-value<.01). Moreover, patients with significant decline in eGFR were at higher risk of incident MCI (OR = 3.54, P-value = .02). These associations were independent of progression of cSVD. CONCLUSION: The worsening in markers of kidney function paralleled the decrease in cognition and the progression of cSVD, and this may be explained by common shared underlying risk factors.

Nighttime hypoxia affects global cognition, memory, and executive function in community-dwelling individuals with hypertension.

STUDY OBJECTIVES: The objective of this study was to determine which respiratory and architectural sleep parameters are related to cognitive function and cognitive status (mild cognitive impairment [MCI] versus normal cognitive aging [NCA]) in community-dwelling individuals with hypertension. Additionally, it aimed to determine whether the results changed in the presence or absence of vascular brain lesions (silent brain infarcts and extensive white matter hyperintensities [WMHs]). METHODS: In a cohort of individuals with hypertension and without previous stroke or dementia, we conducted in-hospital polysomnography including electroencephalography, electro-oculography, electromyography, and magnetic resonance imaging to assess silent brain infarcts and WMHs. Cognitive testing was carried out with a screening test (Dementia Rating Scale version 2 [DRS-2]) and a complete cognitive visit. RESULTS: This study included 158 participants with a median age of 65.0 years; 32.3% were females, and the median apnea-hypopnea index was 22.3 events/h. MCI was diagnosed in 24 study participants, and the rest had NCA. Regarding respiratory parameters, total DRS-2 scores (ß; 95% CI) 0.121; 0.026, 0.215 were positively associated with mean O2 saturation, whereas total (-0.022; -0.036, -0.009), executive function (-0.016; -0.026, -0.006) and memory (-0.017; -0.029, -0.004) DRS-2 scores were all negatively associated with the percent of time with oxygen saturation < 90% after correcting for education, vascular risk factors, and magnetic resonance imaging lesions. Regarding sleep architecture, Attention DRS-2 scores (0.0153; 0.001, 0.306) were independently associated with total sleep time. Similar results were obtained in the absence of silent brain infarcts or WMHs in the stratified analysis. None of the sleep parameters were associated with cognitive status. CONCLUSIONS: Low oxygen saturation contributes to cognitive performance, and this effect appears even in the absence of vascular brain lesions in individuals with hypertension.

Is it time to reassess the SITS-MOST criteria for thrombolysis?: A comparison of patients with and without SITS-MOST exclusion criteria.

BACKGROUND AND PURPOSE: The Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) established guidelines to increase safety in acute stroke thrombolysis, but precluding treatment in an important proportion of patients. We aimed to assess safety/efficacy of thrombolysis in patients with SITS-MOST exclusion criteria. METHODS: 369 nonlacunar tPA-treated patients were studied. Patients were classified as SITS-MOST (SM) or non-SITS-MOST (NSM) according to SITS-MOST-criteria fulfilling. Clinical evaluation was assessed by NIHSS and functional outcome by mRS at 3 months (functional independency=mRS