Risk Profile of Symptomatic Lacunar Stroke Versus Nonlobar Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Although lacunar stroke (LS) and deep intracerebral hemorrhage (dICH) represent acute manifestations of the same pathological process involving cerebral small vessels (small vessel disease), it remains unclear what factors predispose to one phenotype rather than the other at individual level. METHODS: Consecutive patients with either acute symptomatic LS or dICH were prospectively enrolled as part of a multicenter Italian study. We compared the risk factor profile of the 2 subgroups using multivariable logistic regression. RESULTS: During a time course of 9.5 years, 1931 subjects (1434 LS and 497 dICH; mean age, 71.3±13.3 years; males, 55.5%) qualified for the analysis. Current smoking was associated with LS (odds ratio [OR], 2.17; P<0.001). Conversely, dICH cases were more likely to be hypertensive (OR, 1.87; P<0.001), excessive alcohol consumers (OR, 1.70; P=0.001), and more frequently under treatment with warfarin (OR, 2.05; P=0.010) and statins (OR, 3.10; P<0.001). Hypercholesterolemia, diabetes mellitus, and antiplatelet treatment were not associated with a specific small vessel disease manifestation. CONCLUSIONS: The risk factor profile of dICH differs from that associated with LS. This might be used for disease risk stratification at individual level.

Serum cholesterol levels, HMG-CoA reductase inhibitors and the risk of intracerebral haemorrhage. The Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy).

OBJECTIVE: Although a concern exists that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) might increase the risk of intracerebral haemorrhage (ICH), the contribution of these agents to the relationship between serum cholesterol and disease occurrence has been poorly investigated. METHODS: We compared consecutive patients having ICH with age and sex-matched stroke-free control subjects in a case-control analysis, as part of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy), and tested the presence of interaction effects between total serum cholesterol levels and statins on the risk of ICH. RESULTS: A total of 3492 cases (mean age, 73.0±12.7 years; males, 56.6%) and 3492 control subjects were enrolled. Increasing total serum cholesterol levels were confirmed to be inversely associated with ICH. We observed a statistical interaction between total serum cholesterol levels and statin use for the risk of haemorrhage (Interaction OR (IOR), 1.09; 95% CI 1.05 to 1.12). Increasing levels of total serum cholesterol were associated with a decreased risk of ICH within statin strata (average OR, 0.87; 95% CI 0.86 to 0.88 for every increase of 0.26 mmol/l of total serum cholesterol concentrations), while statin use was associated with an increased risk (OR, 1.54; 95% CI 1.31 to 1.81 of the average level of total serum cholesterol). The protective effect of serum cholesterol against ICH was reduced by statins in strictly lobar brain regions more than in non-lobar ones. CONCLUSIONS: Statin therapy and total serum cholesterol levels exhibit interaction effects towards the risk of ICH. The magnitude of such effects appears higher in lobar brain regions.

Obesity and the risk of intracerebral hemorrhage: the multicenter study on cerebral hemorrhage in Italy.

BACKGROUND AND PURPOSE: The effect of obesity on the risk of intracerebral hemorrhage (ICH) may depend on the pathophysiology of vessel damage. To further address this issue, we investigated and quantified the correlations between obesity and obesity-related conditions in the causal pathways leading to ICH. METHODS: A total of 777 ICH cases ≥ 55 years of age (287 lobar ICH and 490 deep ICH) were consecutively enrolled as part of the Multicenter Study on Cerebral Hemorrhage in Italy and compared with 2083 control subjects by a multivariate path analysis model. Separate analyses were conducted for deep and lobar ICH. RESULTS: Obesity was not independently associated with an increased risk of lobar ICH (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.58-1.01) or deep ICH (OR, 1.18; 95% CI, 0.95-1.45) when compared with control subjects. The path analysis confirmed the nonsignificant total effect of obesity on the risk of lobar ICH (OR, 0.77; 95% CI, 0.58-1.02) but demonstrated a significant indirect effect on the risk of deep ICH (OR, 1.28; 95% CI, 1.03-1.57), mostly determined by hypertension (OR, 1.07; 95% CI, 1.04-1.11) and diabetes mellitus (OR, 1.04; 95% CI, 1.01-1.07). Obesity was also associated with an increased risk of deep ICH when compared with lobar ICH (OR, 1.62; 95% CI, 1.14-2.31). CONCLUSIONS: Obesity increases the risk of deep ICH, mostly through an indirect effect on hypertension and other intermediate obesity-related comorbidities, but has no major influence on the risk of lobar ICH. This supports the hypothesis of different, vessel-specific, biological mechanisms underlying the relationship between obesity and cerebral hemorrhage.

Systemic thrombolysis in patients with acute ischemic stroke and Internal Carotid ARtery Occlusion: the ICARO study.

BACKGROUND AND PURPOSE: The beneficial effect of intravenous thrombolytic therapy in patients with acute ischemic stroke attributable to internal carotid artery (ICA) occlusion remains unclear. The aim of this study was to evaluate the efficacy and safety of intravenous recombinant tissue-type plasminogen activator in these patients. METHODS: ICARO was a case-control multicenter study on prospectively collected data. Patients with acute ischemic stroke and ICA occlusion treated with intravenous recombinant tissue-type plasminogen activator within 4.5 hours from symptom onset (cases) were compared to matched patients with acute stroke and ICA occlusion not treated with recombinant tissue-type plasminogen activator (controls). Cases and controls were matched for age, gender, and stroke severity. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale, dichotomized as favorable (score of 0-2) or unfavorable (score of 3-6). Safety outcomes were death and any intracranial bleeding. RESULTS: Included in the analysis were 253 cases and 253 controls. Seventy-three cases (28.9%) had a favorable outcome as compared with 52 controls (20.6%; adjusted odds ratio (OR), 1.80; 95% confidence interval [CI], 1.03-3.15; P=0.037). A total of 104 patients died, 65 cases (25.7%) and 39 controls (15.4%; adjusted OR, 2.28; 95% CI, 1.36-3.22; P=0.001). There were more fatal bleedings (2.8% versus 0.4%; OR, 7.17; 95% CI, 0.87-58.71; P=0.068) in the cases than in the controls. CONCLUSIONS: In patients with stroke attributable to ICA occlusion, thrombolytic therapy results in a significant reduction in the proportion of patients dependent in activities of daily living. Increases in death and any intracranial bleeding were the trade-offs for this clinical benefit.

Intravenous thrombolysis for acute ischemic stroke associated to extracranial internal carotid artery occlusion: the ICARO-2 study.

BACKGROUND AND PURPOSES: In a case-control study in patients with acute ischemic stroke and extracranial internal carotid artery (eICA) occlusion, thrombolytic treatment was associated with increased mortality. The aim of this cohort study was to assess the efficacy and safety of thrombolysis in patients with eICA occlusion compared to those without eICA occlusion. METHODS: Consecutive patients treated with intravenous tissue-type plasminogen activator within 4.5 h from symptom onset included in the Safe Implementation of Thrombolysis in Stroke - International Stroke Thrombolysis Registry (SITS-ISTR) in 20 Italian centres were analyzed. Acute carotid occlusion was diagnosed using ultrasound examination, angio-CT scan or angio-MRI. Since the SITS-ISTR database did not plan to report the site of vessel occlusion, each participating center provided the code of the patient with eICA occlusion. Patients were divided into 2 groups, those with and those without eICA occlusion. Main outcome measures were: death, disability (modified Rankin Scale, mRS, 3-6) and any intracranial bleeding at 3 months. Multiple logistic regression analysis was performed to reveal predictors for main outcomes. The following variables of interest were included in the analysis: presence of eICA occlusion, age, gender, diabetes mellitus, hyperlipidemia, atrial fibrillation, congestive heart failure, previous stroke, current smoking, antiplatelet treatment at stroke onset, baseline NIHSS score, baseline blood glucose, cholesterol and blood pressure, history of hypertension and stroke onset to treatment time. RESULTS: A total of 1,761 patients without eICA occlusion and 137 with eICA occlusion were included in the study. At 3 months, 42 patients were lost to follow-up (3 with eICA occlusion). Death occurred in 30 (22.4%) patients with eICA occlusion and in 175 (10.2%) patients without (p < 0.0001). Death or disability at 3 months occurred in 91 of 134 patients with eICA occlusion (67.9%) compared with 654 of 1,722 patients without eICA occlusion (37.9%, p < 0.0001). No or minimal disability at 3 months (mRS 0-1) was reported in 25 (18.7%) patients with eICA occlusion and in 829 (48.2%) patients without (p < 0.0001). Any intracranial bleeding detected by CT or MRI at posttreatment imaging was seen in 16 (11.7%) patients with eICA occlusion and in 314 (17.8%) of those without (p = 0.09). The proportion of symptomatic intracerebral hemorrhage was 5.8% for patients with eICA occlusion and 8.0% for patients without (p = 0.16). At logistic regression analysis, eICA occlusion was associated with mortality (odds ratio, OR 5.7; 95% confidence interval, CI 2.9-11.1) and mortality or disability (OR 5.0; 95% CI 2.9-8.7) at 90 days. CONCLUSIONS: This cohort study in patients with acute ischemic stroke treated with thrombolysis showed an association between eICA occlusion and adverse outcome.

CSF Alzheimer's disease-like pattern in corticobasal syndrome: evidence for a distinct disorder.

BACKGROUND: Corticobasal syndrome (CBS) has a heterogeneous neuropathological spectrum, ranging from the classical corticobasal degeneration to Alzheimer's disease (AD). The neuropathology of CBS is still unpredictable. CSF tau/abeta ratio is a reliable marker of AD. OBJECTIVE: To evaluate the presence of a distinct clinical and neuroimaging CBS phenotype according to CSF pattern. METHODS: 30 patients fulfilling current clinical criteria for CBS entered the study. Each patient underwent a clinical and standardised neuropsychological assessment, and CSF analysis (total tau and abeta42 dosages). CSF AD-like pattern and CSF non-AD like pattern (nAD-like) were identified. In 23 CBS cases, (99m)Tc-ECD single photon emission computed tomography (SPECT) scan was performed and analysed by statistical parametric mapping. RESULTS: CSF AD-like pattern was reported in six cases (20%). The two subgroups did not differ in demographic characteristics or global cognitive impairment. The AD-like group showed greater impairment of memory performances, language and psychomotor speed while the nAD-like group had more severe extrapyramidal syndrome with comparable apraxia scores. Voxel by voxel analysis on SPECT images demonstrated that CBS AD-like patients had greater hypoperfusion in the brain areas typically affected by AD-namely, precuneus, posterior cingulate and hippocampus, bilaterally-compared with nAD-like patients (p<0.001). No clusters above the pre-established threshold were detected when nAD-like were compared with AD-like patients. CONCLUSIONS: CSF AD-like profile in CBS is associated with earlier memory impairment and brain abnormalities typically found in classical AD. These findings argue for the usefulness of CSF testing to identify AD in CBS, and might suggest a different pharmacological approach on the basis of biological data.

Risk of recurrent cerebrovascular events in patients with cryptogenic stroke or transient ischemic attack and patent foramen ovale: the FORI (Foramen Ovale Registro Italiano) study.

BACKGROUND: The optimal management of patients with cryptogenic ischemic stroke found to have a patent foramen ovale (PFO) at diagnostic workup remains unclear. The aims of this observational multicenter study were to evaluate: (1) the risk of recurrent cerebrovascular events in patients with cryptogenic minor ischemic stroke or transient ischemic attack (TIA) and PFO who either underwent percutaneous PFO closure or received only medical treatment, and (2) the risk factors associated with recurrent events. METHODS: Consecutive patients (aged 55 years or less) with first-ever cryptogenic minor ischemic stroke or TIA and PFO were recruited in 13 Italian hospitals between January 2006 and September 2007 and followed up for 2 years. RESULTS: 238 patients were included in the study (mean age 42.2 ± 10.0 years; 118 males); 117 patients (49.2%) received only antithrombotic therapy while 121 patients underwent percutaneous PFO closure (50.8%). Stroke as the qualifying event was more common in the medical treatment group (p = 0.01). The presence of atrial septal aneurysm and evidence of 20 bubbles or more on transcranial Doppler were more common in the PFO closure group (p = 0.002 and 0.02). Eight patients (6.6%) experienced a nonfatal complication during PFO closure. At the 2-year follow-up, 17 recurrent events (TIA or stroke; 3.6% per year) were observed; 7 of these events (2.9% per year) occurred in the percutaneous PFO closure group and 10 events (4.2% per year) in the medical treatment group. The rate of recurrent stroke was 0.4% per year in patients who underwent percutaneous closure (1 event) and 3.4% per year in patients who received medical treatment (8 events). On multivariate analysis, percutaneous closure was not protective in preventing recurrent TIA or stroke (OR = 0.1, 95% CI = 0.02-1.5, p = 0.1), while it was barely protective in preventing recurrent stroke (OR = 0.1, 95% CI = 0.0-1.0, p = 0.053). CONCLUSIONS: The results of this observational, nonrandomized study suggest that PFO closure might be superior to medical therapy for the prevention of recurrent stroke. Periprocedural complications were the trade-off for this clinical benefit. Controlled randomized clinical trials comparing percutaneous closure with medical management are required.

Acute hyperglycemia and early hemorrhagic transformation in ischemic stroke.

BACKGROUND: Hyperglycemia has been claimed to be associated with hemorrhagic transformation (HT) in patients with acute ischemic stroke treated with thrombolysis. The aim of this study was to assess whether the admission blood glucose level is related to HT in a prospective study in consecutive patients with acute ischemic stroke. METHODS: Consecutive patients admitted for ischemic stroke to 4 Italian hospitals were included in this prospective cohort study. RESULTS: Among 1,125 consecutive patients included in the analysis, 98 (8.7%) had HT: 62 (5.5%) had hemorrhagic infarction (HI) and 36 (3.2%) parenchymal hematoma (PH). A blood glucose level >110 mg/dl was found in 42.4% of the patients, a level between 110 and 149 mg/dl in 25.2%, and a level >150 mg/dl in 17.2%. At 3 months, 7 patients were lost at follow-up, 326 patients (29.2%) were disabled (modified Rankin score > or = 3) and 129 died (11.5%). PH was associated with an increased risk of death or disability (OR 15.29, 95% CI 2.35-99.35). However, this was not the case for HT overall and HI. At logistic regression analysis, PH was predicted by high levels of admission blood glucose (OR 1.01, 95% CI 1.00-1.01 for 1 added mg/dl). The rate of PH was 2.1% in patients with <110 mg/dl, 3.6% in patients with a level between 110 and 149 mg/dl and 6.4% in patients with a level >150 mg/dl. The curve estimation regression model showed a significant linear increase in the risk of PH related to an increase in blood glucose levels (R(2) = 0.007, p = 0.007). CONCLUSIONS: Hyperglycemia during acute ischemic stroke predisposes to PH, which in turn determines a non-favorable outcome at 3 months. This relationship seems to be linear.

Cerebrospinal fluid biomarkers and prediction of conversion in patients with mild cognitive impairment: 4-year follow-up in a routine clinical setting.

Mild cognitive impairment (MCI) is a very common syndrome in elderly people, with a high risk of conversion to dementia. Several investigations have shown the usefulness of cerebrospinal fluid (CSF) biomarkers (Abeta42, total tau [T-tau], and phosphorylated tau [P-tau]) in predicting the progression to Alzheimer's disease (AD). We report a 4-year follow-up of MCI patients who underwent CSF evaluation for biomarker assessment, in order to further evaluate the usefulness of CSF analysis in predicting the conversion to dementia in a routine clinical setting. We identified 55 patients with MCI among the consecutive patients, referred from 2001 to 2003 to our Memory Clinic for cognitive disorders, who underwent a complete diagnostic assessment, including lumbar puncture (n = 273). At the end of the follow-up, 31 MCI patients (56%) did not progress to dementia (stable MCI), while 24 (44%) developed a dementia condition. At baseline, the mean levels of CSF Abeta42, T-tau, and P-tau were significantly altered in MCI patients who were converting to dementia with respect to those with stable MCI. All MCI patients with the three altered CSF biomarkers developed dementia within 1 year. Among the stable MCI patients, none showed all three pathological values and only one subject had the pathological value of P-tau. Early diagnosis of dementia and, specifically, a correct prediction of MCI outcome represent a primary goal. To this respect, the role of CSF biomarkers seems to be crucial in a routine clinical setting.

Early hemorrhagic transformation of brain infarction: rate, predictive factors, and influence on clinical outcome: results of a prospective multicenter study.

BACKGROUND AND PURPOSE: Early hemorrhagic transformation (HT) is a complication of ischemic stroke but its effect on patient outcome is unclear. The aims of this study were to assess: (1) the rate of early HT in patients admitted for ischemic stroke, (2) the correlation between early HT and functional outcome at 3 months, and (3) the risk factors for early HT. METHODS: Consecutive patients with ischemic stroke were included in this prospective study in 4 study centers. Early HT was assessed by CT examination performed at day 5+/-2 after stroke onset. Study outcomes were 3-month mortality or disability. Disability was assessed using a modified Rankin score (> or = 3 indicating disabling stroke) by neurologists unaware of the occurrence of HT in the individual cases. Outcomes in patients with and without early HT were compared by chi(2) test. Multiple logistic regression analysis was used to identify predictors for HT. RESULTS: Among 1125 consecutive patients (median age 76.00 years), 98 (8.7%) had HT, 62 (5.5%) had hemorrhagic infarction, and 36 (3.2%) parenchymal hematoma. At 3 months, 455 patients (40.7%) were disabled or died. Death or disability was seen in 33 patients with parenchymal hematoma (91.7%), in 35 patients with hemorrhagic infarction (57.4%) as compared with 387 of the 1021 patients without HT (37.9%). At logistic regression analysis, parenchymal hematoma, but not hemorrhagic infarction, was independently associated with an increased risk for death or disability (OR 15.29; 95% CI 2.35 to 99.35). At logistic regression analysis, parenchymal hematoma was predicted by large lesions (OR 12.20, 95% CI 5.58 to 26.67), stroke attributable to cardioembolism (OR 5.25; 95% CI 2.27 to 12.14) or to other causes (OR 6.77; 95% CI 1.75 to 26.18), high levels of blood glucose (OR 1.01; 95% CI 1.00 to 1.01), and thrombolytic treatment (OR 3.54, 95% CI 1.04 to 11.95). CONCLUSIONS: Early HT occurs in about 9% of patients. Parenchymal hematoma, seen in about 3% of patients, is associated with an adverse outcome. Parenchymal hematoma was predicted by large lesions attributable to cardioembolism or other causes, high blood glucose, and treatment with thrombolysis.

Nimodipine and its use in cerebrovascular disease: evidence from recent preclinical and controlled clinical studies.

Nimodipine is a 1,4-dihydropyridine-derivative Ca(2+)-channel blocker developed approximately 30 years ago. It is highly lipophilic, crosses the blood-brain barrier, and reaches brain and cerebrospinal fluid. Early treatment with nimodipine reduces the severity of neurological deficits resulting from vasospasm in subarachnoid haemorrhage (SAH) patients. In SAH, nimodipine reduced spasm-related deficits of all severities, but no spasm-unrelated deficits. This paper has reviewed preclinical studies on the influence of nimodipine in various animal models of cerebral ischemia, with particular attention toward investigations published in the last 10 years. These studies further support the main indication of nimodipine, by clarifying some mechanisms of the anti-ischemic activity of the compound. Papers reporting a possible role of nimodipine in epileptogenesis were also examined. Clinical studies on nimodipine were grouped into subarachnoid hemorrhage, acute ischemic stroke, cerebral ischemia without stroke, dementia disorders, and migraine. Clinical investigations have shown that the drug improves neurological outcome by reducing the incidence and severity of ischemic deficits in patients with SAH from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition. No relevant effects of treatment with nimodipine were reported for acute ischemic stroke, cerebral ischemia without stroke, and migraine, except than for cluster headache. The less pronounced cardiovascular effects of nimodipine compared to other dihydropyridine-type Ca(2+)-channel blockers probably accounts for its use out of label for treating patients affected by chronic cerebral ischemia and vascular cognitive impairment. However, the blood pressure-lowering effects of nimodipine should not be minimized, as clinical studies have documented lowering blood pressure in small groups of patients, including cases of withdrawn due to pronounced hypotension induced by nimodipine administration. In the area of vascular cognitive impairment, short-term benefits of nimodipine do not justify its use as a long-term anti-dementia drug, and benefits obtained in elderly patients affected by subcortical vascular dementia require to be confirmed by other groups and in larger scale trials. In conclusion, nimodipine is a safe drug with an important place in pharmacotherapy and with the main documentation for reduction in the severity of neurological deficits resulting from vasospasm in SAH patients.

Anticoagulants Resumption after Warfarin-Related Intracerebral Haemorrhage: The Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy).

Whether to resume antithrombotic treatment after oral anticoagulant-related intracerebral haemorrhage (OAC-ICH) is debatable. In this study, we aimed at investigating long-term outcome associated with OAC resumption after warfarin-related ICH, in comparison with secondary prevention strategies with platelet inhibitors or antithrombotic discontinuation. Participants were patients who sustained an incident ICH during warfarin treatment (2002-2014) included in the Multicenter Study on Cerebral Hemorrhage in Italy. Primary end-point was a composite of ischemic stroke/systemic embolism (SE) and all-cause mortality. Secondary end-points were ischemic stroke/SE, all-cause mortality and major recurrent bleeding. We computed individual propensity score (PS) as the probability that a patient resumes OACs or other agents given his pre-treatment variables, and performed Cox multivariable analysis using Inverse Probability of Treatment Weighting (IPTW) procedure. A total of 244 patients qualified for the analysis. Unlike antiplatelet agents, OAC resumption was associated with a lower rate of the primary end-point (weighted hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09-0.45), as well as of overall mortality (weighted HR, 0.17; 95% CI, 0.06-0.45) and ischemic stroke/SE (weighted HR, 0.19; 95% CI, 0.06-0.60) with no significant increase of major bleeding in comparison with patients receiving no antithrombotics. In the subgroup of patients with atrial fibrillation, OACs resumption was also associated with a reduction of the primary end-point (weighted HR, 0.22; 95% CI, 0.09-0.54), and the secondary end-point ischemic stroke/SE (weighted HR, 0.09; 95% CI, 0.02-0.40). In conclusion, in patients who have an ICH while receiving warfarin, resuming anticoagulation results in a favorable trade-off between bleeding susceptibility and thromboembolic risk.

Arterial hypertension and cognitive dysfunction in physiologic and pathologic aging of the brain.

Arterial hypertension is the most important modifiable cerebrovascular risk factor; its relationship with cerebrovascular disease is continuous, consistent, and independent. Different and probably converging pathophysiologic mechanisms explain the role of arterial hypertension in causing cognitive dysfunction in pathologic aging of the brain, specifically, vascular dementia and Alzheimer's disease.

Association Between Migraine and Cervical Artery Dissection: The Italian Project on Stroke in Young Adults.

Importance: Although sparse observational studies have suggested a link between migraine and cervical artery dissection (CEAD), any association between the 2 disorders is still unconfirmed. This lack of a definitive conclusion might have implications in understanding the pathogenesis of both conditions and the complex relationship between migraine and ischemic stroke (IS). Objective: To investigate whether a history of migraine and its subtypes is associated with the occurrence of CEAD. Design, Setting, and Participants: A prospective cohort study of consecutive patients aged 18 to 45 years with first-ever acute ischemic stroke enrolled in the multicenter Italian Project on Stroke in Young Adults was conducted between January 1, 2000, and June 30, 2015. In a case-control design, the study assessed whether the frequency of migraine and its subtypes (presence or absence of an aura) differs between patients whose IS was due to CEAD (CEAD IS) and those whose IS was due to a cause other than CEAD (non-CEAD IS) and compared the characteristics of patients with CEAD IS with and without migraine. Main Outcomes and Measures: Frequency of migraine and its subtypes in patients with CEAD IS vs non-CEAD IS. Results: Of the 2485 patients (mean [SD] age, 36.8 [7.1] years; women, 1163 [46.8%]) included in the registry, 334 (13.4%) had CEAD IS and 2151 (86.6%) had non-CEAD IS. Migraine was more common in the CEAD IS group (103 [30.8%] vs 525 [24.4%], P = .01), and the difference was mainly due to migraine without aura (80 [24.0%] vs 335 [15.6%], P < .001). Compared with migraine with aura, migraine without aura was independently associated with CEAD IS (OR, 1.74; 95% CI, 1.30-2.33). The strength of this association was higher in men (OR, 1.99; 95% CI, 1.31-3.04) and in patients 39.0 years or younger (OR, 1.82; 95% CI, 1.22-2.71). The risk factor profile was similar in migrainous and non-migrainous patients with CEAD IS (eg, hypertension, 20 [19.4%] vs 57 [24.7%], P = .29; diabetes, 1 [1.0%] vs 3 [1.3%], P > .99). Conclusions and Relevance: In patients with IS aged 18 to 45 years, migraine, especially migraine without aura, is consistently associated with CEAD. This finding suggests common features and warrants further analyses to elucidate the underlying biologic mechanisms.

Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin-K Oral Anticoagulants (RAF-NOACs) Study.

BACKGROUND: The optimal timing to administer non-vitamin K oral anticoagulants (NOACs) in patients with acute ischemic stroke and atrial fibrillation is unclear. This prospective observational multicenter study evaluated the rates of early recurrence and major bleeding (within 90 days) and their timing in patients with acute ischemic stroke and atrial fibrillation who received NOACs for secondary prevention. METHODS AND RESULTS: Recurrence was defined as the composite of ischemic stroke, transient ischemic attack, and symptomatic systemic embolism, and major bleeding was defined as symptomatic cerebral and major extracranial bleeding. For the analysis, 1127 patients were eligible: 381 (33.8%) were treated with dabigatran, 366 (32.5%) with rivaroxaban, and 380 (33.7%) with apixaban. Patients who received dabigatran were younger and had lower admission National Institutes of Health Stroke Scale score and less commonly had a CHA2DS2-VASc score >4 and less reduced renal function. Thirty-two patients (2.8%) had early recurrence, and 27 (2.4%) had major bleeding. The rates of early recurrence and major bleeding were, respectively, 1.8% and 0.5% in patients receiving dabigatran, 1.6% and 2.5% in those receiving rivaroxaban, and 4.0% and 2.9% in those receiving apixaban. Patients who initiated NOACs within 2 days after acute stroke had a composite rate of recurrence and major bleeding of 12.4%; composite rates were 2.1% for those who initiated NOACs between 3 and 14 days and 9.1% for those who initiated >14 days after acute stroke. CONCLUSIONS: In patients with acute ischemic stroke and atrial fibrillation, treatment with NOACs was associated with a combined 5% rate of ischemic embolic recurrence and severe bleeding within 90 days.

Diagnosing prodromal Alzheimer's disease: role of CSF biochemical markers.

Mild cognitive impairment (MCI) is an aetiologically heterogeneous syndrome. A correct prediction of MCI conversion to Alzheimer's disease (AD) represents a primary goal in routine clinical practice. Since the presence of pathological levels in >or=2 cerebrospinal fluid (CSF) biomarkers; amyloid protein (Abeta42), total tau (h-tau) and phospho-tau (p-tau) seems to reliably identifying MCI subjects converting to AD, we report our experience in a routine clinical setting. In the period from January 2001 to June 2003, 273 consecutive patients referred to our Memory Clinic for diagnostic assessment of cognitive impairment. Of them, 180 underwent a complete diagnostic evaluation including CSF dosage of fragment 1-42 of amyloid protein, total tau and phospho-tau (ELISA Method, Innogenetics, Gent, Belgium), after vascular or other secondary causes of dementia could be excluded. At baseline, 38% of the MCI subjects (20/55) showed pathological levels in >or=2 CSF biomarkers. After 1 year, 11 MCI patients converted to dementia, 33 remained stable, 11 showed a further progression of cognitive impairment still not fulfilling the diagnostic criteria for dementia. Of the 11 converters, 10 showed >or=2 pathological values CSF biomarkers and in all of them, p-tau was high. On the contrary, 29 out of 33 stable MCI (88%) showed no or one pathological CSF value. We confirm that pathological levels in >or=2 CSF biomarkers reliably predict MCI conversion to AD and correctly identify the stable form of MCI.

Treatment of Alzheimer's disease: from pharmacology to a better understanding of disease pathophysiology.

Alzheimer's disease (AD) is the most common cause of cognitive impairment in older patients and is expected to increase greatly in prevalence in the next future. It is characterized by the development of senile plaques and neurofibrillary tangles, which are associated with neuronal loss affecting to a greater extent cholinergic neurons. A cascade of pathophysiological events is triggered in AD that ultimately involves common cellular signalling pathways and leads to cellular and neural networks dysfunction, failure of neurotransmission, cell death and a common clinical outcome. The process is asynchronous and viable neurons remain an important target for therapeutic intervention at each stage of disease evolution. At present symptomatic drugs inhibiting the degradation of acetylcholine within synapses and more recently glutamate receptor antagonists represent the mainstay of therapy. However, interventions able to halt or slow disease progression (i.e., disease-modifying agents) are necessary. Although much progress has been made in this area, there are currently no clinically approved interventions for AD classed as disease modifying or neuroprotective. This paper reviews the main symptomatic strategies available for treating AD and future strategies for improving our therapeutic approach to AD.

Neurotransmitter deficits in behavioural and psychological symptoms of Alzheimer's disease.

Behavioural and psychological symptoms of dementia (BPSD) occur in 50-90% of Alzheimer's disease (AD) patients. Imbalance of different neurotransmitters (acetylcholine, dopamine, noradrenaline and serotonin), involvement of specific brain regions responsible for emotional activities (parahippocampal gyrus, dorsal raphe and locus coeruleus) and cortical hypometabolism have been proposed as neurobiological substrate of BPSD. Compared to with respect to the neurochemical component, the cholinergic dysfunction seems to play a major role in contributing to BPSD occurrence. This view is also supported by the findings of recent trials with cholinesterase inhibitors, showing that these drugs are effective in controlling and/or improving BPSD, independent on effects on cognitive dysfunction. On the site of psychotropic drugs, atypical or novel antipsychotics represent the reference drugs for treating BPSD, whereas classic antipsychotic drugs for their profile and the potential side effects should be avoided.

Assessment of the Incremental Diagnostic Value of Florbetapir F 18 Imaging in Patients With Cognitive Impairment: The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study.

IMPORTANCE: Cerebral amyloidosis is a key abnormality in Alzheimer disease (AD) and can be detected in vivo with positron emission tomography (PET) ligands. Although amyloid PET has clearly demonstrated analytical validity, its clinical utility is debated. OBJECTIVE: To evaluate the incremental diagnostic value of amyloid PET with florbetapir F 18 in addition to the routine clinical diagnostic assessment of patients evaluated for cognitive impairment. DESIGN, SETTING, AND PARTICIPANTS: The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study is a multicenter study involving 18 AD evaluation units from eastern Lombardy, Northern Italy, 228 consecutive adults with cognitive impairment were evaluated for AD and other causes of cognitive decline, with a prescan diagnostic confidence of AD between 15% and 85%. Participants underwent routine clinical and instrumental diagnostic assessment. A prescan diagnosis was made, diagnostic confidence was estimated, and drug treatment was provided. At the time of this workup, an amyloid PET/computed tomographic scan was performed, and the result was communicated to physicians after workup completion. Physicians were asked to review the diagnosis, diagnostic confidence, and treatment after the scan. The study was conducted from August 5, 2013, to December 31, 2014. MAIN OUTCOMES AND MEASURES: Primary outcomes were prescan to postscan changes of diagnosis, diagnostic confidence, and treatment. RESULTS: Of the 228 participants, 107 (46%) were male; mean (SD) age was 70.5 (7) years. Diagnostic change occurred in 46 patients (79%) having both a previous diagnosis of AD and an amyloid-negative scan (P < .001) and in 16 (53%) of those with non-AD diagnoses and an amyloid-positive scan (P < .001). Diagnostic confidence in AD diagnosis increased by 15.2% in amyloid-positive (P < .001; effect size Cohen d = 1.04) and decreased by 29.9% in amyloid-negative (P < .001; d = -1.19) scans. Acetylcholinesterase inhibitors and memantine hydrochloride were introduced in 61 (65.6%) patients with positive scan results who had not previously received those drugs, and the use of the drugs was discontinued in 6 (33.3%) patients with negative scan results who were receiving those drugs (P < .001). CONCLUSIONS AND RELEVANCE: Amyloid PET in addition to routine assessment in patients with cognitive impairment has a significant effect on diagnosis, diagnostic confidence, and drug treatment. The effect on health outcomes, such as morbidity and mortality, remains to be assessed.