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Background: The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood-cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction., Methods: The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40-60 and 9.0 over 60 years., Results: 1209 subjects were included in the study. 718 females and 491 males (age: 15-88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease subgroups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivariable linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group., Conclusions: Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach.

We investigated whether computed tomography (CT) perfusion can identify intracerebral hemorrhage patients at high risk of hematoma growth (HG). A total of 155 subjects underwent CT perfusion on admission. Variables associated with log-transformed absolute HG were explored with multivariable linear regression. Perihematomal cerebral blood volume (CBV) was inversely associated with HG (B = -0.20; p < 0.001), independently from blood pressure, hematoma volume, and other confounders. This association was not dose dependent, and only very low CBV (<1.4 ml/100 g) was significantly associated with HG (B = 0.25; p < 0.001). In conclusion, reduced perihematomal CBV is associated with HG, suggesting a potential role of the perihematomal region in the pathophysiology of hematoma enlargement. ANN NEUROL 2019;85:943-947., (© 2019 American Neurological Association.)

Intravenous thrombolysis (IVT) is the treatment of choice for most patients with acute ischemic stroke. According to the recently updated guidelines, IVT should be administered in absence of absolute exclusion criteria. We aimed to assess the proportion of ischemic strokes potentially eligible and actually treated with IVT, and to explore the reasons for not administering IVT. We prospectively collected and analyzed data from 1184 consecutive ischemic stroke patients admitted to the 22 Stroke Units (SUs) of the Veneto region from September 18th to December 10th 2017. Patients were treated with IVT according to the current Italian guidelines. For untreated patients, the reasons for not administering IVT were reported by each center in a predefined model including absolute and/or relative exclusion criteria and other possible reasons. Out of 841 (71%) patients who presented within 4.5 h of stroke onset, 704 (59%) had no other absolute exclusion criteria and were therefore potentially eligible for IVT according to the current guidelines. However, only 323 (27%) patients were eventually treated with IVT. Among 861 (73%) untreated patients, 480 had at least one absolute exclusion criterion, 283 only relative exclusion criteria, 56 only other reasons, and 42 a combination of relative exclusion criteria and other reasons. Our study showed that only 46% (323/704) of the potentially eligible patients were actually treated with IVT in the SUs of the Veneto region. All healthcare professionals involved in the acute stroke pathway should make an effort to bridge this gap between eligibility and reality.

Background: Hip Osteoarthritis (OA) causes pain and disability. Here we evaluate abobotulinumtoxinA (Dysport ® ) (AboBoNT-A) injections versus placebo as a novel treatment option to improve hip range of motion, pain and quality of life. Methods: This prospective randomized double-blind multicenter study (EudraCT # 2012-004890-25) recruited 46 outpatients with hip OA who were randomized 2:1 to the Treatment Group (TG; 31 subjects), or the Placebo Group (PG; 15 subjects). The TG received 400 U of AboBoNT-A injected into the adductor muscles, and the PG received placebo solution. The primary endpoints were the difference in Harris Hip Score (HHS) and Visual Analogic Scale for pain (VAS) at Week 4 between groups (TG vs. PG). Secondary endpoints were the change from baseline in HHS, VAS pain, Medical Research Council scale for muscle strength (MRC) and Short Form scale (SF-36) scores. Results: In TG at Week 4, the HHS and VAS score were significantly improved compared to PG, and pairwise assessments showed significant improvements in HSS and VAS pain at each time point compared to baseline for TG. No significant changes were observed in MRC and SF-36 over time, though SF-36 showed a positive trend. There were no significant differences from baseline in the PG. No adverse events were detected in either treatment group. Conclusions: AboBoNT-A injections in hip OA improve range of motion and pain without any significant side effects.

Background: Autoantibodies to apolipoprotein A-1 (anti-ApoA-1 IgG) were shown to predict major adverse cardiovascular events and promote atherogenesis. However, their potential relationship with clinical disability and ischaemic lesion volume after acute ischaemic stroke (AIS) remains unexplored., Materials and Methods: We included n = 76 patients admitted for AIS and we investigated whether baseline serum anti-ApoA-1 IgG levels could predict (i) AIS-induced clinical disability [assessed by the modified Rankin Scale (mRS)], and (ii) AIS-related ischaemic lesion volume [assessed by Computed Tomography (CT)]. We also evaluated the possible pro-apoptotic and pro-necrotic effects of anti-ApoA-1 IgG on human astrocytoma cell line (U251) using flow cytometry., Results: High levels of anti-ApoA-1 IgG were retrieved in 15·8% (12/76) of patients. Increased baseline levels of anti-ApoA-1 IgG were independently correlated with worse mRS [β = 0·364; P = 0·002; adjusted odds ratio (OR): 1·05 (95% CI 1·01-1·09); P = 0·017] and CT-assessed ischaemic lesion volume [β = 0·333; P < 0·001; adjusted OR: 1·06 (95% CI 1·01-1·12); P = 0·048] at 3 months. No difference in baseline clinical, biochemical and radiological characteristics was observed between patients with high vs. low levels of anti-ApoA-1 IgG. Incubating human astrocytoma cells with anti-ApoA-1 IgG dose dependently induced necrosis and apoptosis of U251 cells in vitro., Conclusion: Anti-ApoA-1 IgG serum levels at AIS onset are associated with poorer clinical recovery and worse brain lesion volume 3 months after AIS. These observations could be partly explained by the deleterious effect of anti-ApoA-1 IgG on human brain cell survival in vitro and may have clinical implication in the prediction of poor outcome in AIS., (© 2016 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: The relevance of human leukocyte antigen (HLA)-G in dimeric form in multiple sclerosis (MS) is still unknown., Objective: To investigate the contribution of cerebrospinal fluid (CSF) HLA-G dimers in MS pathogenesis., Methods: CSF amounts of 78-kDa HLA-G dimers were measured by western blot analysis in 80 MS relapsing-remitting MS (RRMS) patients and in 81 inflammatory and 70 non-inflammatory controls., Results: CSF amounts of 78 kDa HLA-G dimers were more frequent in RRMS than in inflammatory (p<0.01) and non-inflammatory controls (p<0.001) and in magnetic resonance imaging (MRI) inactive than in MRI active RRMS (p<0.00001)., Conclusion: Our findings suggest that HLA-G dimers may be implicated in termination of inflammatory response occurring in MS., (© The Author(s), 2015.)

Introduction: The capability of CT perfusion (CTP) Alberta Stroke Program Early CT Score (ASPECTS) to predict outcome and identify ischemia severity in acute ischemic stroke (AIS) patients is still questioned., Methods: 62 patients with AIS were imaged within 8 hours of symptom onset by non-contrast CT, CT angiography and CTP scans at admission and 24 hours. CTP ASPECTS was calculated on the affected hemisphere using cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) maps by subtracting 1 point for any abnormalities visually detected or measured within multiple cortical circular regions of interest according to previously established thresholds. MTT-CBV ASPECTS was considered as CTP ASPECTS mismatch. Hemorrhagic transformation (HT), recanalization status and reperfusion grade at 24 hours, final infarct volume at 7 days and modified Rankin scale (mRS) at 3 months after onset were recorded., Results: Semi-quantitative and quantitative CTP ASPECTS were highly correlated (p<0.00001). CBF, CBV and MTT ASPECTS were higher in patients with no HT and mRS ≤ 2 and inversely associated with final infarct volume and mRS (p values: from p<0.05 to p<0.00001). CTP ASPECTS mismatch was slightly associated with radiological and clinical outcomes (p values: from p<0.05 to p<0.02) only if evaluated quantitatively. A CBV ASPECTS of 9 was the optimal semi-quantitative value for predicting outcome., Conclusions: Our findings suggest that visual inspection of CTP ASPECTS recognizes infarct and ischemic absolute values. Semi-quantitative CBV ASPECTS, but not CTP ASPECTS mismatch, represents a strong prognostic indicator, implying that core extent is the main determinant of outcome, irrespective of penumbra size.

Matrix Metalloproteases (MMPs) and cytokines have been involved in the pathogenesis of multiple sclerosis (MS). However, no studies have still explored the possible associations between the two families of molecules. The present study aimed to evaluate the contribution of active MMP-9, active MMP-2, interleukin- (IL-) 17, IL-18, IL-23, and monocyte chemotactic proteins-3 to the pathogenesis of MS and the possible interconnections between MMPs and cytokines. The proteins were determined in the serum and cerebrospinal fluid (CSF) of 89 MS patients and 92 other neurological disorders (OND) controls. Serum active MMP-9 was increased in MS patients and OND controls compared to healthy subjects (p < 0.001 and p < 0.01, resp.), whereas active MMP-2 and ILs did not change. CSF MMP-9, but not MMP-2 or ILs, was selectively elevated in MS compared to OND (p < 0.01). Regarding the MMPs and cytokines intercorrelations, we found a significant association between CSF active MMP-2 and IL-18 (r = 0.3, p < 0.05), while MMP-9 did not show any associations with the cytokines examined. Collectively, our results suggest that active MMP-9, but not ILs, might be a surrogate marker for MS. In addition, interleukins and MMPs might synergistically cooperate in MS, indicating them as potential partners in the disease process.

Background and Aims: Different adipokines have been associated with atherosclerotic plaque rupture and cardiovascular events, such as acute ischaemic stroke (AIS). However, the potential role of these molecules in postischaemic brain injury remains largely unknown., Methods and Methods: We performed a substudy analysis on nonobese patients with first atherothrombotic stroke (n = 35) from a recently published prospective cohort. Primary endpoint was to investigate the predictive value of serum leptin/adiponectin ratio on neurological recovery at 90 days after AIS. The secondary endpoint was the predictive value of serum adipokine levels of clinical and radiological outcomes at a shorter follow-up (at days 1 and 7 after AIS). The radiological evaluation included ischaemic lesion volume and haemorrhagic transformation (HT). The clinical examination was based on National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS)., Results: At day 1 after AIS, serum leptin and leptin/adiponectin ratio were increased and inversely correlated with both radiological and clinical parameters at all follow-up time points. Once identified the best cut-off points by receiver operating characteristic (ROC) analysis, risk analysis showed that higher circulating leptin improved neurological recovery at day 90. In addition, leptin/adiponectin ratio maintained statistical significance after adjustment for age, gender and thrombolysis, also predicting the occurrence of HT in the first 7 days after AIS (adjusted OR 0·15 [95% CI 0·03-0·83); P = 0·030])., Conclusions: Higher leptin/adiponectin ratio at day 1 predicted better neurological outcomes in patients with atherothrombotic AIS and might be potentially useful as a prognostic biomarker of the disease., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

We investigated the practical clinical utility of the CT perfusion (CTP) cerebral blood volume (CBV) parameter for differentiating salvageable from non-salvageable tissue in acute ischemic stroke (AIS). Fifty-five patients with AIS were imaged within 6 h from onset using CTP. Admission CBV defect (CBVD) volume was outlined using previously established gray and white matter CBV thresholds for infarct core. Admission cerebral blood flow (CBF) hypoperfusion and CBF/CBV mismatch were visually evaluated. Truncation of the ischemic time-density curve (ITDC) and hypervolemia status at admission, recanalization at 24-h CT angiography, hemorrhagic transformation (HT) at 24 h and/or 7-day non-contrast CT (NCCT), final infarct volume as indicated by 3-month NCCT defect (NCCTD) and 3-month modified Rankin Score were determined. Patients with recanalization and no truncation had the highest correlation (R = 0.81) and regression slope (0.80) between CBVD and NCCTD. Regression slopes were close to zero for patients with admission hypervolemia with/without recanalization. Hypervolemia underestimated (p = 0.02), while recanalization and ITDC truncation overestimated (p = 0.03) the NCCTD. Among patients with confirmed recanalization at 24 h, 38 % patients had an admission CBF/CBV mismatch within normal appearing areas on respective NCCT. 83 % of these patients developed infarction in admission hypervolemic CBF/CBV mismatch tissue. A reduction in CBV is a valuable predictor of infarct core when the acquisition of ITDC data is complete and hypervolemia is absent within the tissue destined to infarct. Raised or normal CBV is not always indicative of salvageable tissue, contrary to the current definition of penumbra.

Background: The activity of matrix metalloproteinase-9 (MMP-9) depends on two isoforms, an 82 kDa active MMP-9 modulated by its specific tissue inhibitor (TIMP-1), and a 65 kDa TIMP-1 resistant active MMP-9. The relevance of these two enzymatic isoforms in multiple sclerosis (MS) is still unknown., Objective: To investigate the contribution of the TIMP-1 modulated and resistant active MMP-9 isoforms to MS pathogenesis., Methods: We measured the serum levels of the 82 kDa and TIMP-1 resistant active MMP-9 isoforms by activity assay systems in 86 relapsing-remitting MS (RRMS) patients, categorized according to clinical and magnetic resonance imaging (MRI) evidence of disease activity, and in 70 inflammatory (OIND) and 69 non-inflammatory (NIND) controls., Results: Serum levels of TIMP-1 resistant MMP-9 were more elevated in MS patients than in OIND and NIND (p < 0.05, p < 0.02, respectively). Conversely, 82 kDa active MMP-9 was higher in NIND than in the OIND and MS patients (p < 0.01 and p < 0.00001, respectively). MRI-active patients had higher levels of TIMP-1 resistant MMP-9 and 82 kDa active MMP-9, than did those with MRI inactive MS (p < 0.01 and p < 0.05, respectively)., Conclusion: Our findings suggested that the TIMP-1 resistant MMP-9 seem to be the predominantly active isoform contributing to MS disease activity., (© The Author(s), 2015.)

Background: After an acute ischaemic stroke (AIS), several inflammatory biomarkers have been investigated, but their predictive role on functional recovery remains to be validated. Here, we investigated the prognostic relevance of biomarkers related to atherosclerotic plaque calcification, such as osteopontin (OPN), osteoprotegerin (OPG) and the receptor activator of nuclear factor kappa-B ligand (RANKL) in a cohort of patients with AIS (n = 90) during 90-day follow-up., Materials and Methods: Radiological and clinical examinations as well as blood sampling were performed at admission and at days 1, 7 and 90 from the event. Validated scores [such as modified Rankin scale (mRS) and the National Institutes of Health Stroke Scale (NIHSS)] were used to assess poststroke outcome. Serum levels of OPN, OPG and RANKL were measured by colorimetric enzyme-linked immunosorbent assay (ELISA)., Results: When compared to the admission, OPN serum levels increased at day 7. Serum OPN levels at this time point were positively correlated with both ischaemic lesion volume and NIHSS at days 7 and 90. A cut-off of 30.53 ng/mL was identified for serum OPN by receiver operating characteristic (ROC) curve analysis. Adjusted logistic regression showed that serum OPN levels at day 7 predicted worse mRS at day 90 [OR 4.13 (95% CI 1.64-10.36); P = 0.002] and NIHSS [1.49 (95% CI 1.16-1.99); P = 0.007], independently of age, gender, hypertension and thrombolysis., Conclusions: Serum levels of OPN, but not OPG and RANKL, peaked at day 7 after AIS and predicted worse neurological scores. Therefore, OPN might have a pathophysiological and clinical relevance after AIS., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)