Publications by authors named "Ilaria Casetta"

75 Publications

Association between perihematomal perfusion and intracerebral hemorrhage shape.

Neuroradiology 2021 Apr 14. Epub 2021 Apr 14.

Neuroradiology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.

Purpose: The pathophysiological determinants of irregular intracerebral hemorrhage (ICH) shape are unclear. We aimed at characterizing the relationship between perihematomal perfusion and ICH shape.

Methods: A single-center cohort of patients with primary ICH was analyzed. Patients underwent computed tomography perfusion within 6 h from onset. Cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were calculated in the manually outlined perihematomal low-density region. ICH shape was rated on baseline non-contrast CT following international consensus criteria, and predictors of irregular shape were explored with logistic regression.

Results: A total of 150 patients were included, of whom 66 (44%) had irregular shape. Perihematomal CBF was lower in irregular ICH (median 23 vs 35 mL/100 g/min, p<0.001). CBF<20 mL/100 g/min was independently associated with irregular shape (odds ratio 9.67, 95% CI 2.42-38.69, p=0.001).

Conclusion: Our findings suggest that perihematomal hypoperfusion may contribute to the CT appearance of acute ICH.
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http://dx.doi.org/10.1007/s00234-021-02709-8DOI Listing
April 2021

Hematoma Expansion in Intracerebral Hemorrhage With Unclear Onset.

Neurology 2021 05 1;96(19):e2363-e2371. Epub 2021 Apr 1.

From UO Neurologia (A.M.), Azienda Socio-Sanitaria Territoriale (ASST) Valcamonica, Esine, Italy; Neuroradiology Department (G. Boulouis), Centre Hospitalier Sainte-Anne, Paris, France; J.P. Kistler Stroke Research Center, Department of Neurology (A. Charidimou, Q.L., A.D.W., C.D.A., M.E.G., A.B., A.V., S.M.G., J.R., J.N.G.), Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston; Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica (L.P., A. Pezzini, A. Padovani), Università degli Studi di Brescia; UO di Neurologia (P.C.), Istituto Clinico Fondazione Poliambulanza, Brescia; UOC Neurologia (V.D.G.), ASST Cremona; UC Malattie Cerebrovascolari e Stroke Unit (E.L., F.M., A. Cavallini) and UC Neurologia d'Urgenza (E.L., F.M., G.M.), IRCCS Fondazione Mondino, Pavia; Dipartimento di Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Neuroradiologia, Università degliStudi di Firenze (G. Busto, E.F.), and Stroke Unit (F.A., A.Z.), Ospedale Universitario Careggi, Firenze; UOC Neurologia e Rete Stroke, Metropolitana (L.B., S.G.), and Unità di Neuroradiologia (L.S.), IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Maggiore; Clinica Neurologica, Dipartimento di Scienze Biomediche e Chirurgico Specialistiche (M.L., I.C.), Università degli studi diFerrara, Ospedale Universitario S. Anna, Ferrara; Neurologia e Stroke Unit (E.C.), Ospedale di Circolo, ASST Settelaghi, Varese; Stroke Unit (M.G., M.M.), Neurologia Vascolare, ASST Spedali Civili, Brescia, Italy; Division of Neurocritical Care and Emergency Neurology, Department of Neurology (C.D.A., J.R., J.N.G.), Harvard Medical School, Henry and Allison McCance Center for Brain Health (C.D.A., J.R., J.N.G.), and Department of Emergency Medicine (J.N.G.), Massachusetts General Hospital, Boston.

Objective: To investigate the prevalence, predictors, and prognostic effect of hematoma expansion (HE) in patients with intracerebral hemorrhage (ICH) with unclear symptom onset (USO).

Methods: We performed a retrospective analysis of patients with primary spontaneous ICH admitted at 5 academic medical centers in the United States and Italy. HE (volume increase >6 mL or >33% from baseline to follow-up noncontrast CT [NCCT]) and mortality at 30 days were the outcomes of interest. Baseline NCCT was also analyzed for presence of hypodensities (any hypodense region within the hematoma margins). Predictors of HE and mortality were explored with multivariable logistic regression.

Results: We enrolled 2,165 participants, 1,022 in the development cohort and 1,143 in the replication cohort, of whom 352 (34.4%) and 407 (35.6%) had ICH with USO, respectively. When compared with participants having a clear symptom onset, patients with USO had a similar frequency of HE (25.0% vs 21.9%, = 0.269 and 29.9% vs 31.5%, = 0.423). Among patients with USO, HE was independently associated with mortality after adjustment for confounders (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.43-4.89, = 0.002). This finding was similar in the replication cohort (OR 3.46, 95% CI 1.86-6.44, < 0.001). The presence of NCCT hypodensities in patients with USO was an independent predictor of HE in the development (OR 2.59, 95% CI 1.27-5.28, = 0.009) and replication (OR 2.43, 95% CI 1.42-4.17, = 0.001) population.

Conclusion: HE is common in patients with USO and independently associated with worse outcome. These findings suggest that patients with USO may be enrolled in clinical trials of medical treatments targeting HE.
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http://dx.doi.org/10.1212/WNL.0000000000011895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166446PMC
May 2021

Upregulation of Cortical A2A Adenosine Receptors Is Reflected in Platelets of Patients with Alzheimer's Disease.

J Alzheimers Dis 2021 ;80(3):1105-1117

Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.

Background: Alzheimer's disease (AD) is a neurodegenerative pathology covering about 70%of all cases of dementia. Adenosine, a ubiquitous nucleoside, plays a key role in neurodegeneration, through interaction with four receptor subtypes. The A2A receptor is upregulated in peripheral blood cells of patients affected by Parkinson's and Huntington's diseases, reflecting the same alteration found in brain tissues. However, whether these changes are also present in AD pathology has not been determined.

Objective: In this study we verified any significant difference between AD cases and controls in both brain and platelets and we evaluated whether peripheral A2A receptors may reflect the status of neuronal A2A receptors.

Methods: We evaluated the expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, in postmortem AD patients and control subjects, through [3H]ZM 241385 binding experiments. The same analysis was performed in peripheral platelets from AD patients versus controls.

Results: The expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, revealed a density (Bmax) of 174±29, 219±33, and 358±84 fmol/mg of proteins, respectively, in postmortem AD patients in comparison to 104±16, 103±19, and 121±20 fmol/mg of proteins in controls (p < 0.01). The same trend was observed in peripheral platelets from AD patients versus controls (Bmax of 214±17 versus 95±4 fmol/mg of proteins, respectively, p < 0.01).

Conclusion: AD subjects show significantly higher A2A receptor density than controls. Values on platelets seem to correlate with those in the brain supporting a role for A2A receptor as a possible marker of AD pathology and drug target for novel therapies able to modify the progression of dementia.
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http://dx.doi.org/10.3233/JAD-201437DOI Listing
January 2021

Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion.

Biomedicines 2021 Feb 9;9(2). Epub 2021 Feb 9.

Laboratory for Technologies of Advanced Therapies, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy.

Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening, and damage-associated molecular pattern (DAMP) release place mitochondria in the center of an intricate series of chance interactions. Depending on the degree to which mitochondria are affected, they promote different pathways, ranging from inflammatory response pathways to cell death pathways. In this review, we will explore the principal mitochondrial molecular mechanisms compromised during ischemic and reperfusion injury, and we will delineate potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis.
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http://dx.doi.org/10.3390/biomedicines9020169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914955PMC
February 2021

Direct thrombectomy for stroke in the presence of absolute exclusion criteria for thrombolysis.

J Neurol 2020 Dec 25;267(12):3731-3740. Epub 2020 Jul 25.

Azienda Ospedaliero-Univeristaria, Padua, Italy.

Background: Intravenous thrombolysis (IVT)-ineligible patients undergoing direct thrombectomy tended to have poorer functional outcome as compared with IVT-eligible patients undergoing bridging therapy. We aimed to assess radiological and functional outcomes in large vessel occlusion-related stroke patients receiving direct thrombectomy in the presence of absolute exclusion criteria for IVT vs relative exclusion criteria for IVT and vs non-exclusion criteria for IVT.

Methods: A cohort study on prospectively collected data from 2282 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke cohort for treatment with direct thrombectomy (n = 486, absolute exclusion criteria for IVT alone; n = 384, absolute in combination with relative exclusion criteria for IVT; n = 777, relative exclusion criteria for IVT alone; n = 635, non-exclusion criteria for IVT).

Results: After adjustment for unbalanced variables (model 1), ORs for 3-month death was higher in the presence of absolute exclusion criteria for IVT alone (vs relative exclusion criteria for IVT alone) (1.595, 95% CI 1.042-2.440) and in the presence of absolute exclusion criteria for IVT alone (vs non-exclusion criteria for IVT) (1.235, 95% CI 1.014-1.504). After adjustment for predefined variables (model 2: age, sex, pre-stroke mRS ≤ 1, NIHSS, occlusion in the anterior circulation, onset-to-groin time, and procedure time), ORs for 3-month death was higher in the presence of absolute exclusion criteria for IVT alone (vs relative exclusion criteria for IVT alone) (1.235, 95% CI 1.014-1.504) and in the presence of absolute exclusion criteria for IVT alone (vs non-exclusion criteria for IVT) (1.246, 95% CI 1.039-1.495). No significant difference was found between the groups as regards any type of intracerebral hemorrhage and parenchymal hematoma within 24 h, successful and complete recanalization after procedure, and modified Rankin Scale score 0-2 at 3 months. After adjustment for predefined variables of model 2, ORs for death were higher in the presence of recent administration of IV heparin (OR: 2.077), platelet count < 100,000/mm (OR: 4.798), bacterial endocarditis (OR: 15.069), neoplasm with increased hemorrhagic risk (OR: 6.046), and severe liver disease (OR: 6.124).

Conclusions: Radiological outcomes were similar after direct thrombectomy in patients with absolute, relative, and non- exclusion criteria for IVT, while an increase of fatal outcome was observed in the presence of some absolute exclusion criterion for IVT.
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http://dx.doi.org/10.1007/s00415-020-10098-wDOI Listing
December 2020

Endovascular Thrombectomy for Acute Ischemic Stroke Beyond 6 Hours From Onset: A Real-World Experience.

Stroke 2020 07 17;51(7):2051-2057. Epub 2020 Jun 17.

Stroke Unit and Neurosonology Lab (A.P.), Padua University Hospital.

Background And Purpose: To evaluate outcome and safety of endovascular treatment beyond 6 hours of onset of ischemic stroke due to large vessel occlusion in the anterior circulation, in routine clinical practice.

Methods: From the Italian Registry of Endovascular Thrombectomy, we extracted clinical and outcome data of patients treated for stroke of known onset beyond 6 hours. Additional inclusion criteria were prestroke modified Rankin Scale score ≤2 and ASPECTS score ≥6. Patients were selected on individual basis by a combination of CT perfusion mismatch (difference between total hypoperfusion and infarct core sizes) and CT collateral score. The primary outcome measure was the score on modified Rankin Scale at 90 days. Safety outcomes were 90-day mortality and the occurrence of symptomatic intracranial hemorrhage. Data were compared with those from patients treated within 6 hours.

Results: Out of 3057 patients, 327 were treated beyond 6 hours. Their mean age was 66.8±14.9 years, the median baseline National Institutes of Health Stroke Scale 16, and the median onset to groin puncture time 430 minutes. The most frequent site of occlusion was middle cerebral artery (45.1%). Functional independence (90-day modified Rankin Scale score, 0-2) was achieved by 41.3% of cases. Symptomatic intracranial hemorrhage occurred in 6.7% of patients, and 3-month case fatality rate was 17.1%. The probability of surviving with modified Rankin Scale score, 0-2 (odds ratio, 0.58 [95% CI, 0.43-0.77]) was significantly lower in patients treated beyond 6 hours as compared with patients treated earlier No differences were found regarding recanalization rates and safety outcomes between patients treated within and beyond 6 hours. There were no differences in outcome between people treated 6-12 hours from onset (278 patients) and those treated 12 to 24 hours from onset (49 patients).

Conclusions: This real-world study suggests that in patients with large vessel occlusion selected on the basis of CT perfusion and collateral circulation assessment, endovascular treatment beyond 6 hours is feasible and safe with no increase in symptomatic intracranial hemorrhage.
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http://dx.doi.org/10.1161/STROKEAHA.119.027974DOI Listing
July 2020

General Anesthesia Versus Conscious Sedation and Local Anesthesia During Thrombectomy for Acute Ischemic Stroke.

Stroke 2020 07 10;51(7):2036-2044. Epub 2020 Jun 10.

Interventional Neuroradiology Unit and Stroke Unit, Azienda Ospedaliera-Universitaria, Padova, Italy (F.C., C.B.).

Background And Purpose: As numerous questions remain about the best anesthetic strategy during thrombectomy, we assessed functional and radiological outcomes in stroke patients treated with thrombectomy in presence of general anesthesia (GA) versus conscious sedation (CS) and local anesthesia (LA).

Methods: We conducted a cohort study on prospectively collected data from 4429 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke.

Results: GA was used in 2013 patients, CS in 1285 patients, and LA in 1131 patients. The rates of 3-month modified Rankin Scale score of 0-1 were 32.7%, 33.7%, and 38.1% in the GA, CS, and LA groups: GA versus CS: odds ratios after adjustment for unbalanced variables (adjusted odds ratio [aOR]), 0.811 (95% CI, 0.602-1.091); and GA versus LA: aOR, 0.714 (95% CI, 0.515-0.990). The rates of modified Rankin Scale score of 0-2 were 42.5%, 46.6%, and 52.4% in the GA, CS, and LA groups: GA versus CS: aOR, 0.902 (95% CI, 0.689-1.180); and GA versus LA: aOR, 0.769 (95% CI, 0.566-0.998). The rates of 3-month death were 21.5%, 19.7%, and 14.8% in the GA, CS, and LA groups: GA versus CS: aOR, 0.872 (95% CI, 0.644-1.181); and GA versus LA: aOR, 1.235 (95% CI, 0.844-1.807). The rates of parenchymal hematoma were 9%, 12.6%, and 11.3% in the GA, CS, and LA groups: GA versus CS: aOR, 0.380 (95% CI, 0.262-0.551); and GA versus LA: aOR, 0.532 (95% CI, 0.337-0.838). After model of adjustment for predefined variables (age, sex, thrombolysis, National Institutes of Health Stroke Scale, onset-to-groin time, anterior large vessel occlusion, procedure time, prestroke modified Rankin Scale score of <1, antiplatelet, and anticoagulant), differences were found also between GA versus CS as regards modified Rankin Scale score of 0-2 (aOR, 0.659 [95% CI, 0.538-0.807]) and GA versus LA as regards death (aOR, 1.413 [95% CI, 1.095-1.823]).

Conclusions: GA during thrombectomy was associated with worse 3-month functional outcomes, especially when compared with LA. The inclusion of an LA arm in future randomized clinical trials of anesthesia strategy is recommended.
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http://dx.doi.org/10.1161/STROKEAHA.120.028963DOI Listing
July 2020

Adenosinergic System Involvement in Ischemic Stroke Patients' Lymphocytes.

Cells 2020 04 25;9(5). Epub 2020 Apr 25.

Department of Morphology, Surgery and Experimental Medicine, Pharmacology Section, University of Ferrara, 44121 Ferrara, Italy.

Adenosine modulates many physiological processes through the interaction with adenosine receptors (ARs) named as A, A, A and AARs. During ischemic stroke, adenosine mediates neuroprotective and anti-inflammatory effects through ARs activation. One of the dominant pathways generating extracellular adenosine involves the dephosphorylation of ATP by ecto-nucleotidases CD39 and CD73, which efficiently hydrolyze extracellular ATP to adenosine. The aim of the study is to assess the presence of ARs in lymphocytes from ischemic stroke patients compared to healthy subjects and to analyze changes in CD39 and CD73 expression in CD4 and CD8 lymphocytes. Saturation binding experiments revealed that AARs affinity and density were significantly increased in ischemic stroke patients whilst no differences were found in A, A and AARs. These results were also confirmed in reverse transcription (RT)-polymerase chain reaction (PCR) assays where AAR mRNA levels of ischemic stroke patients were higher than in control subjects. In flow cytometry experiments, the percentage of CD73 cells was significantly decreased in lymphocytes and in T-lymphocyte subclasses CD4 and CD8 obtained from ischemic stroke patients in comparison with healthy individuals. These data corroborate the importance of the adenosinergic system in ischemic stroke and could open the way to more targeted therapeutic approaches and biomarker development for ischemic stroke.
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http://dx.doi.org/10.3390/cells9051072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290971PMC
April 2020

Subarachnoid Extension Predicts Lobar Intracerebral Hemorrhage Expansion.

Stroke 2020 05 23;51(5):1470-1476. Epub 2020 Mar 23.

Dipartimento di Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Neuroradiologia, Università degli Studi di Firenze, Ospedale Universitario Careggi, Firenze, Italia (G.B., E.F.).

Background and Purpose- We investigated whether subarachnoid extension (SAHE) of intracerebral hemorrhage (ICH) is associated with hematoma expansion (HE). Methods- Retrospective analysis of patients with primary spontaneous ICH admitted at 3 academic hospitals in Italy. The study population was divided into a development and a replication cohort. SAHE was rated on baseline noncontrast computed tomography by investigators blinded to clinical data. The main outcome of interest was HE, defined as ICH growth >33% mL and/or >6 mL. Predictors of HE were explored with multivariable logistic regression stratified by ICH location (lobar versus nonlobar). Results- A total of 360 and 192 patients were included in the development and replication cohort, respectively. SAHE was identified with good interrater reliability (=0.82), and its frequency was 27.8% in the development and 24.5% in the replication cohort. In univariate analysis, HE was more common in patients with SAHE (52.0% versus 27.3%; <0.001). When controlling for confounders in logistic regression, SAHE was an independent predictor of lobar HE (odds ratio, 6.00 [95% CI, 2.16-16.64]; =0.001) whereas there was no association with HE in nonlobar ICH (odds ratio, 0.55 [95% CI, 0.17-1.84]; =0.334). The increased risk of HE in lobar ICH with SAHE was confirmed in the replication cohort (odds ratio, 3.46 [95% CI, 1.07-11.20]; =0.038). Conclusions- SAHE predicts HE in lobar ICH. This may improve the stratification of HE risk in clinical practice or future trials targeting HE. Further research is needed to confirm our findings and characterize the underlying biological mechanisms.
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http://dx.doi.org/10.1161/STROKEAHA.119.028338DOI Listing
May 2020

Association Between Perihematomal Perfusion and Intracerebral Hemorrhage Outcome.

Neurocrit Care 2020 10;33(2):525-532

Neuroradiology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.

Background: The prognostic impact of perihematomal hypoperfusion in patients with acute intracerebral hemorrhage (ICH) remains unclear. We tested the hypothesis that perihematomal hypoperfusion predicts poor ICH outcome and explored whether hematoma growth (HG) is the pathophysiological mechanism behind this association.

Methods: A prospectively collected single-center cohort of consecutive ICH patients undergoing computed tomography perfusion on admission was analyzed. Cerebral blood flow (pCBF) was measured in the manually outlined perihematomal low-density area. pCBF was categorized into normal (40-55 mL/100 g/min), low (< 40 mL/100 g/min), and high (> 55 mL/100 g/min). HG was calculated as total volume increase from baseline to follow-up CT. A modified Rankin scale > 2 at three months was the outcome of interest. The association between cerebral perfusion and outcome was investigated with logistic regression, and potential mediators of this relationship were explored with mediation analysis.

Results: A total of 155 subjects were included, of whom 55 (35.5%) had poor outcome. The rates of normal pCBF, low pCBF, and high pCBF were 17.4%, 68.4%, and 14.2%, respectively. After adjustment for confounders and keeping subjects with normal pCBF as reference, the risk of poor outcome was increased in patients with pCBF < 40 mL/100 g/min (odds ratio 6.11, 95% confidence interval 1.09-34.35, p = 0.040). HG was inversely correlated with pCBF (R = -0.292, p < 0.001) and mediated part of the association between pCBF and outcome (proportion mediated: 82%, p = 0.014).

Conclusion: Reduced pCBF is associated with poor ICH outcome in patients with mild-moderate severity. HG appears a plausible biological mediator but does not fully account for this association, and other mechanisms might be involved.
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http://dx.doi.org/10.1007/s12028-020-00929-zDOI Listing
October 2020

Increased age and male sex are independently associated with higher frequency of blood-cerebrospinal fluid barrier dysfunction using the albumin quotient.

Fluids Barriers CNS 2020 Feb 5;17(1):14. Epub 2020 Feb 5.

Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Via Aldo Moro 8, Settore 1C3, 44124, Ferrara, Italy.

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.
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http://dx.doi.org/10.1186/s12987-020-0173-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003357PMC
February 2020

Specific antibodies reacting to JC polyomavirus capsid protein mimotopes in sera from multiple sclerosis and other neurological diseases-affected patients.

J Cell Physiol 2020 07 3;235(7-8):5847-5855. Epub 2020 Feb 3.

Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, School of Medicine, University of Ferrara, Ferrara, Italy.

Published data support the hypothesis that viruses could be trigger agents of multiple sclerosis onset. This link is based on evidence of early exposure to viral agents in patients affected by this neurologic disease. JC (JC polyomavirus [JCPyV]), BK (BKPyV), and simian virus 40 (SV40) neurotropic polyomavirus footprints have been detected in brain tissue specimens and samples from patients affected by different neurological diseases. In this investigation, serum samples from patients affected by multiple sclerosis and other inflammatory and noninflammatory neurologic diseases, as well as healthy subjects representing the control, were investigated for immunoglobulin G (IgG) antibodies against JCPyV. To this end, an immunologic approach was employed, which consists of employing indirect enzyme-linked immunosorbent assay testing with synthetic peptides mimicking viral capsid protein 1 antigens. A significantly lower prevalence of IgG antibodies against JCPyV VP1 epitopes, with a low titer, was detected in serum samples from patients with multiple sclerosis (MS) and other neurologic diseases than in healthy subjects. Our study indicates that the prevalence of JCPyV antibodies from patients with multiple sclerosis is 50% lower than in healthy subjects, suggesting specific immune impairments. These results indicate that patients affected by neurological diseases, including MS, respond poorly to JCPyV VP1 antigens, suggesting specific immunologic dysfunctions.
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http://dx.doi.org/10.1002/jcp.29533DOI Listing
July 2020

Comparison of perihematomal perfusion in deep and lobar intracerebral hemorrhage.

Neuroradiology 2020 Feb 20;62(2):257-261. Epub 2019 Dec 20.

Neuroradiology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.

Purpose: Hypoperfusion in the perihematomal rim is common in acute intracerebral hemorrhage (ICH) but its determinants remain incompletely characterized. Despite known biological differences between deep and lobar ICH, the association between ICH location and cerebral perfusion has not been investigated. We tested the hypothesis that perihematomal perfusion differs between deep and lobar ICH.

Methods: Prospectively collected cohort of subjects with primary spontaneous ICH undergoing CT perfusion on admission. Cerebral blood flow (CBF), blood volume (CBV), and mean transit time (MTT) were measured in the manually outlined perihematomal low-density area. The association between perihematomal perfusion and ICH location was explored with multivariable linear regression.

Results: A total of 155 patients were enrolled (59 with a lobar bleeding). In univariate analysis, median perihematomal CBF and CBV were lower in lobar ICH compared with deep ICH (23.8 vs 33.4 mL/100 g/min, p = 0.001 and 1.7 vs 2.3 mL/100 g, p = 0.001, respectively). Lobar ICH location remained inversely associated with CBF (β = - 0.17, p = 0.038) and CBV (β = - 0.19, p = 0.023) after adjustment for confounders in linear regression.

Conclusion: Lobar ICH location is inversely related with perihematomal CBF and CBV. Further studies are needed to confirm this association and define the underlying biological mechanisms.
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http://dx.doi.org/10.1007/s00234-019-02331-9DOI Listing
February 2020

Detection of serum soluble HLA-G levels in patients with acute ischemic stroke: A pilot study.

Hum Immunol 2020 Apr 15;81(4):156-161. Epub 2019 Nov 15.

Section of Microbiology and Medical Genetics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

The aim of this study was to investigate the potential role of soluble Human Leukocyte Antigen-G (sHLA-G) molecules as biomarkers predicting outcome in acute ischemic stroke (AIS). Serum levels of total sHLA-G (sHLA-G1/HLA-G5) and its soluble isoforms sHLA-G1 and HLA-G5/G6 were measured by enzyme-linked immunosorbent assay (ELISA) in 92 AIS patients and healthy donors (HD). Incidence of hemorrhagic transformation (HT), size of final infarct volume (FIV) and clinical outcome at 3 months were recorded in AIS patients. Detectable serum levels of sHLA-G1/HLA-G5, HLA-G5/G6 and sHLA-G1 were present in a small proportion of AIS patients (26.1%, 17.4% and 16.3%, respectively) and HD (12.5%, 10.7% and 10.7%, respectively) and were more elevated in AIS patients without HT than in those with HT (p < 0.01; p < 0.05; p < 0.01, respectively). HT was less frequent (p < 0.01) in AIS patients with measurable serum concentrations of sHLA-G1/HLA-G5 and HLA-G5/G6. Serum levels of sHLA-G1/HLA-G5 and sHLA-G1 were inversely correlated to FIV (p < 0.02), whereas good outcome was more common (p < 0.01) in AIS patients with detectable serum concentrations of sHLA-G1/HLA-G5. Taken together, these findings suggest that total sHLA-G could exert a protective effect in a subset of AIS patients, irrespective of its soluble isoforms sHLA-G1 and HLA-G5/G6, and indicate that the prognostic value of serum levels of sHLA-G remains to be established.
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http://dx.doi.org/10.1016/j.humimm.2019.11.004DOI Listing
April 2020

Correlation between auto/mitophagic processes and magnetic resonance imaging activity in multiple sclerosis patients.

J Neuroinflammation 2019 Jun 27;16(1):131. Epub 2019 Jun 27.

Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.

Background: An alteration of autophagy and mitophagy, two highly conserved lysosome-dependent degradation pathways involved in the maintenance of cellular homeostasis, has been associated with multiple sclerosis (MS).

Objective: To search the level of autophagy-related 5 (ATG5) and Parkin proteins, as markers of autophagy and mitophagy respectively, and lactate in a cohort of MS patients.

Methods: Cerebrospinal fluid (CSF) and serum samples from 60 MS patients were analyzed: 30 with magnetic resonance imaging (MRI) evidence of disease activity, gadolinium (Gd)-based contrast agent positive (Gd+), and 30 without MRI evidence of disease activity (Gd-). ATG5, Parkin, and lactate were measured using commercially available products.

Results And Conclusions: Serum levels of ATG5, Parkin, and lactate were more elevated in Gd+ than in Gd- MS patients (p < 0.0001), and CSF concentrations of ATG5 and Parkin were greater in Gd+ than in Gd- MS (p < 0.0001). Our results demonstrated that molecular markers of autophagy and mitophagy are increased in CSF of MS patients during the active phases of the disease and that these catabolic markers, together with lactate, are also remarkably augmented in blood suggesting a role of these processes in MS pathogenesis and the possible use of these molecules as biomarkers of disease activity.
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http://dx.doi.org/10.1186/s12974-019-1526-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598368PMC
June 2019

Combined intravenous and endovascular treatment versus primary mechanical thrombectomy. The Italian Registry of Endovascular Treatment in Acute Stroke.

Int J Stroke 2019 12 24;14(9):898-907. Epub 2019 May 24.

Stroke Unit, University Hospital "Umberto I", Rome.

Background: Whether mechanical thrombectomy alone may achieve better or at least equal clinical outcome than mechanical thrombectomy combined with intravenous thrombolysis is a matter of debate.

Methods: From the Italian Registry of Endovascular Stroke Treatment, we extracted all cases treated with intravenous thrombolysis followed by mechanical thrombectomy or with primary mechanical thrombectomy for anterior circulation stroke due to proximal vessel occlusion. We included only patients who would have qualified for intravenous thrombolysis. We compared outcomes of the two groups by using multivariate regression analysis and propensity score method.

Results: We included 1148 patients, treated with combined intravenous thrombolysis and mechanical thrombectomy therapy (n = 635; 55.3%), or with mechanical thrombectomy alone (n = 513; 44.7%). Demographic and baseline clinical characteristics did not differ between the two groups, except for a shorter onset to groin puncture time (p < 0.05) in the mechanical thrombectomy group. A shift in the 90-day modified Rankin Scale distributions toward a better outcome was found in favor of the combined treatment (adjusted common odds ratio  = 1.3; 95% confidence interval: 1.04-1.66). Multivariate analyses on binary outcome show that subjects who underwent combined treatment had higher probability to survive with modified Rankin Scale 0-3 (odds ratio = 1.42; 95% confidence interval: 1.04-1.95) and lower case fatality rate (odds ratio = 0.6; 95% confidence interval: 0.44-0.9). Hemorrhagic transformation did not differ between the two groups.

Conclusion: These data seem to indicate that combined intravenous thrombolysis and mechanical thrombectomy could be associated with lower probability of death or severe dependency after three months from stroke due to large vessel occlusion, supporting the current guidelines of treating eligible patients with intravenous thrombolysis before mechanical thrombectomy.
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http://dx.doi.org/10.1177/1747493019851279DOI Listing
December 2019

Incidence study of Guillain-Barré syndrome in the province of Ferrara, Northern Italy, between 2003 and 2017. A 40-year follow-up.

Neurol Sci 2019 Mar 7;40(3):603-609. Epub 2019 Jan 7.

Department of Biomedical and Specialty-Surgical Sciences, Section of Neurology, Psychology and Psychiatry, University of Ferrara, Via Aldo Moro 8, 44124, Cona, Ferrara, Italy.

Background: Guillain-Barré syndrome (GBS) is an acute/subacute autoimmune inflammatory polyradiculoneuropathy. Previous epidemiological studies carried out in the province of Ferrara, Italy, from 1981 to 2002 indicated that GBS incidence had tendency of increase in the period considered.

Objectives: We aimed at updating the epidemiology of GBS in the years 2003-2017 and carrying on the work started in the 1980s.

Methods: We conducted an incidence study, by adopting a complete enumeration approach. Cases were identified from administrative, medical records, and database of the Ferrara Hospital and other provincial structures of the study area. Case ascertainment and definition are analogous to those adopted in previous surveys.

Results: In the period 1 January 2003 to 31 December 2017, 73 patients living in the province of Ferrara (mean population 353,142) were found to be new cases of GBS fulfilling the NINCDS criteria. Male/female ratio 1.15. The mean incidence rate was 1.38 per 100,000 (95% CI 1.08-1.74), 1.54 per 100,000 for men and 1.23 per 100,000 for women, a nonsignificant difference. During the period considered, the rates had slow increase or mild decrease, without nonsignificant difference. The highest rates were observed for the age groups 70-79 years for both sexes. A half of patients reported infectious events in the weeks before the onset of symptoms.

Conclusion: In line with many epidemiological data, in the whole period 2003-2017, we observed a trend towards increase or decrease in incidence and periods of relative stability. Similar temporal heterogeneity with the comparison to our previous works was found.
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http://dx.doi.org/10.1007/s10072-018-3688-4DOI Listing
March 2019

Migraine improvement after spontaneous cervical artery dissection the Italian Project on Stroke in Young Adults (IPSYS).

Neurol Sci 2019 Jan 21;40(1):59-66. Epub 2018 Sep 21.

Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, P.le Spedali Civili, 1,, 25123, Brescia, Italy.

Objective: Whether migraine modifies after spontaneous cervical artery dissection (sCeAD) more than after other stroke etiologic subtypes has never been adequately investigated.

Methods: In the setting of the Italian Project on Stroke in Young Adults (IPSYS), we compared the course of migraine before and after acute brain infarct in a group of migraine patients with sCeAD and a group of migraine patients whose ischemia was due to a cause other than CeAD (non-CeAD IS), matched by sex, age (± 3 years), and migraine subtype.We applied linear mixed models to evaluate pre-event vs post-event changes and differences between sCeAD and non-CeAD IS patients.

Results: Eighty-seven patients per group (migraine without aura/migraine with aura, 67/20) qualified for the analysis. After the acute event, migraine headaches disappeared in 14.0% of CeAD patients vs 0.0% of non-CeAD IS patients (p ≤ 0.001). Migraine frequency (patients suffering at least 1 attack, from 93.1 to 80.5%, p = 0.001), pain intensity (from 6.7 ± 1.7 to 4.6 ± 2.6 in a 0 to 10 pain scale, p ≤ 0.001), and use of acute anti-migraine medications (patients taking at least 1 preparation, from 81.6 to 64.4%, p = 0.007) also improved significantly after CeAD as opposed to that observed after non-CeAD IS.

Conclusion: The spontaneous improvement of migraine after sCeAD reinforces the hypothesis of a pathogenic link between the two conditions.
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http://dx.doi.org/10.1007/s10072-018-3578-9DOI Listing
January 2019

Bilateral Hypoglossal Nerve Palsy in an Adult Patient With Repaired Tetralogy of Fallot.

Neurologist 2018 Sep;23(5):155-156

Department of Neuroscience and Rehabilitation, Ferrara University Hospital, Italy.

Introduction: Spontaneous cervical artery dissection (sCAD) is a major cause of ischemic stroke in young and middle-aged adults, but the occurrence of multiple sCADs could suggest the presence of an underlying arteriopathy. Bilateral hypoglossal nerve palsy caused by extracranial internal carotid artery dissections have been rarely described. We present the case of a 3-vessel sCAD in a patient with repaired tetralogy of Fallot (ToF).

Case Report: A 50-year-old man was admitted to our stroke unit for a sudden onset of left cervical pain, mild left ptosis, dysarthria, and dysphagia. His medical history was remarkable for surgically repaired ToF. Neurological examination showed left Claude-Bernard-Horner syndrome and bilateral hypoglossal palsy. Diffusion-weighted magnetic resonance imaging excluded parenchymal lesions while magnetic resonance angiography showed a pattern of bilateral extracranial internal carotid and right vertebral dissection.

Conclusions: This is the first case of multiple-vessel sCAD, and more associated with an unusual clinical presentation, in a patient with surgically repaired ToF, supporting the hypothesis that defective large artery elastogenesis plays a role in this congenital disorder, and suggesting the importance of continuous long-term vascular follow-up.
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http://dx.doi.org/10.1097/NRL.0000000000000190DOI Listing
September 2018

Multiple Sclerosis in Italy: A 40-Year Follow-Up of the Prevalence in Ferrara.

Neuroepidemiology 2018 21;51(3-4):158-165. Epub 2018 Aug 21.

Multiple Sclerosis Research Center, Section of Neurological Sciences, Department of Biochemical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy.

Background: To assess a longitudinal follow-up of the prevalence of multiple sclerosis (MS) through 4 decades in the province of Ferrara, northern Italy, and reappraise the current rates on December 31, 2016.

Methods: We conducted a community-based intensive prevalence study, by adopting a complete enumeration approach. MS cases were identified from administrative health data and medical records from the Units of Neurology and Motor Rehabilitation, Ferrara University Hospital, from other provincial neurological structures and from archives of the National Pension Institute and National Health Insurance scheme of the study area. Case ascertainment method and case definition are analogous to those adopted in previous surveys in the same area of study.

Results: On December 31, 2016, 685 patients (478 women and 207 men) affected by definite or probable MS (Poser's criteria) were living in the province of Ferrara (population 386,896), yielding a crude prevalence ratio of 194.91 (95% CI 180.4-209.6) per 100,000, 260.8 (95% CI 238.10-285.82) for women and 123.1 (95% CI 106.98-141.21) for men The prevalence ratio was 26.9 per 100,000 in 1978, increased to a value of 46.1 per 100,000 in 1981, 69.4 per 100,000 in 1993, 120.9 per 100,000 in 2004. Female to male ratio was 2.31 (1.2 on December 31, 1978). The mean duration of the disease at prevalence day was 17.5 ± 11.9 years (13.9 ± 10.8 years in 1978). The mean age at prevalence day was 52.04 ± 10.8 years (13.8 ± 10.8 years in 1978).

Conclusion: Our study has confirmed the province of Ferrara is an area at high risk for MS, in line with epidemiological data from the regions of continental and insular Italy. The sharp increase in MS prevalence over time in this population can be imputed in part to a greater exposition to risk factors in genetically susceptible subjects but also to an increased survival and improved ascertainment. So, the results suggest that both methodologic and environmental factors are essential in determining the real distribution of MS. The need to get reliable estimates of MS prevalence must be highlighted as a public health and research priority, essential to support planning and prioritization of care services and to reduce the overall burden of chronic disease.
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http://dx.doi.org/10.1159/000491548DOI Listing
September 2019

Multiple sclerosis in the Republic of San Marino, Italian peninsula: an incidence and prevalence study from a high-risk area.

Neurol Sci 2018 Jul 18;39(7):1231-1236. Epub 2018 Apr 18.

Department of Biomedical and Specialty-Surgical Sciences, Section of Neurology, Psychology and Psychiatry, University of Ferrara, Via Aldo Moro 8, 44124, Ferrara, Italy.

Epidemiological studies on multiple sclerosis (MS) carried out in Southern Europe in the last years have shown a significant increase in the disease frequency. Previous surveys conducted in the Republic of San Marino, Northern Italian peninsula, identified that the population is at high risk for MS, with a prevalence of 51.6 per 100,000 population in 1982 and of 166.7 in 2005 and with a mean annual incidence of 7.9 per 100,000 for the period 1990-2005. The present work is a community-based intensive prevalence and incidence survey, by a complete enumeration approach, to update the prevalence and incidence of MS in the Republic of San Marino. The mean annual incidence for the period 2005-14 was 7.7 (95% CI 4.9-11.4) per 100,000, 3.3 (95% CI 1.1-7.6) for men and 11.9 (95% CI 7.2-18.6) for women. On 31 December 2014, 67 patients (19 men and 48 women), suffering from definite or probable MS and living in the Republic of San Marino, yielded a crude prevalence of 204.3 (95% CI 158.4-259.5) per 100,000, 117.8 (95% CI 70.9-183.7) for men and 288.2 (95% CI 212.4-383.3) for women. Our study has confirmed San Marino is an area at high risk for MS, in line with epidemiological data from continental Italy. The marked increase in MS prevalence over time in this population can be ascribable to increased survival and improved ascertainment, in the presence of a substantially stable, yet high, incidence rate.
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http://dx.doi.org/10.1007/s10072-018-3402-6DOI Listing
July 2018

Selective intrathecal enrichment of G1m1-positive B cells in multiple sclerosis.

Ann Clin Transl Neurol 2017 10 27;4(10):756-761. Epub 2017 Sep 27.

Department of Immunology and Transfusion Medicine Faculty of Medicine University of Oslo and Oslo University Hospital Rikshospitalet Oslo Norway.

Immunoglobulin gamma (IgG) heavy chain genes are associated with susceptibility to multiple sclerosis (MS) and IgG levels in the cerebrospinal fluid (CSF). However, how these variants are implicated in disease mechanisms remains unknown. Here, we show that proliferating plasmablasts expressing the G1m1 allotype of IgG1 are selectively enriched in CSF of G1m1/G1m3 heterozygous MS patients, whereas plasmablasts expressing either G1m1 or G1m3 are evenly distributed in blood. Moreover, there was a preferential intrathecal synthesis of oligoclonal IgG1 of the G1m1 allotype in heterozygous patients, whereas controls with Lyme neuroborreliosis displayed oligoclonal IgG1 of both allotypes. This points to a disease-specific mechanism involved in B-cell establishment within the central nervous system in MS.
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http://dx.doi.org/10.1002/acn3.451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634349PMC
October 2017

Autophagy and mitophagy elements are increased in body fluids of multiple sclerosis-affected individuals.

J Neurol Neurosurg Psychiatry 2018 Apr 2;89(4):439-441. Epub 2017 Sep 2.

Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.

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http://dx.doi.org/10.1136/jnnp-2017-316234DOI Listing
April 2018

Epidemiological Study of Huntington's Disease in the Province of Ferrara, Italy.

Neuroepidemiology 2017 12;49(1-2):18-23. Epub 2017 Aug 12.

Department of Biomedical and Specialty Surgery, Section of Neurology, University of Ferrara, Ferrara, Italy.

Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of CAG triplet repeat. We aimed to reappraise HD epidemiology in a northern Italian population, in relation to introduction of genetic testing.

Methods: Through ICD-9M code 333.4 and medical fare exemption code RF0080, HD cases were identified from administrative health data and medical records from the Units of Neurology and Genetics, Ferrara University Hospital, and from other provincial neurological structures.

Results: HD mean annual incidence rate in 1990-2009 was 0.3 per 100,000 (95% CI 0.2-0.5). All incident cases were found to have symptoms of the disease's classic form, and neither juvenile nor the rigid Westphal variant was detected. The mean (SD) age at onset was 50.2 (12.7 years; range 32-82 years), 54.9 (14.6) for men and 45.8 (9.4) for women. On prevalence day, December 31, 2014, HD prevalence was 4.2 per 100,000 (95% CI 2.4-7.0), with a male:female ratio of 1:2.

Conclusions: The prevalence and incidence of HD in our population were lower than the prevalence and incidence reported for other European and Italian populations, but higher compared to those of Asia, Africa, and Eastern Europe. Compared to previous studies, HD incidence and prevalence did not change significantly.
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http://dx.doi.org/10.1159/000479697DOI Listing
May 2018

Monocyte count at onset predicts poststroke outcomes during a 90-day follow-up.

Eur J Clin Invest 2017 Oct 2;47(10):702-710. Epub 2017 Sep 2.

First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.

Background: Acute ischaemic stroke (AIS) triggers both systemic and neurovascular inflammation, influencing poststroke recovery. In smokers with AIS, inflammation might be further upregulated, increasing ischaemia/reperfusion injury. Here, the predictive value of leucocyte and adhesion molecules levels on poststroke outcomes was investigated.

Materials And Methods: A total of 89 patients with AIS (n = 30 smokers and n = 59 nonsmokers) were recruited and evaluated 1, 7 and 90 days after the onset to assess stroke severity by the National Institute of Health Stroke Scale (NIHSS) score as well as clinical recovery at 90 days by the modified Rankin Scale (mRS). Lesion volume was assessed by noncontrast computed tomography. Haematological parameters, blood chemistry and soluble adhesion molecules were measured.

Results: Smokers experienced a more severe stroke and at a younger age with respect to nonsmokers, moreover, they had higher circulating levels of monocytes, neutrophils and soluble adhesion molecules. Baseline monocytes positively correlated with stroke severity and disability across all time points in the overall cohort. No correlation was shown between adhesion molecules and poststroke outcomes. A monocyte count >0·63 × 10 /L predicted worse stroke severity (defined as NIHSS ≥5) at day 90 independently of age, hypertension, thrombolysis and active smoking in the overall cohort. Similarly, a monocyte count >0·64 × 10 /L predicted poor neurological recovery at day 90 (defined as mRS > 2).

Conclusions: Smoker had more severe AIS and higher leucocytes and adhesion molecule levels. In the overall cohort, monocyte count was an independent predictor of worse poststroke outcome. Although larger trials are needed, monocyte count might be a cheap prognostic parameter in AIS.
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http://dx.doi.org/10.1111/eci.12795DOI Listing
October 2017

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

JAMA Neurol 2017 05;74(5):512-518

Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italia.

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.
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http://dx.doi.org/10.1001/jamaneurol.2016.5704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822194PMC
May 2017

Can the age at onset give a clue to the pathogenesis of ALS?

Acta Neurol Belg 2017 Mar 19;117(1):221-227. Epub 2016 Oct 19.

Neurological Clinic, biomedical and specialized surgery sciences department of the University of Ferrara, Ferrara, Italy.

Pathogenesis could play an important role in the mid- to late-life onset of symptoms in amyotrophic lateral sclerosis (ALS). An analysis of the age at onset of ALS among the incident cases occurring in the population in the Health District of Ferrara, Italy, in the period 1064-2009 was carried out. Two subsequent 23-year time intervals (1964-1986 and 1987-2009) were considered. The mean age at onset (MAAO) was estimated in relation to gender, onset type and area of residence (urban or extra-urban) at disease onset among the incident cases which occurred in the two subsequent time intervals. An uneven increase in the MAAO over time was observed as it was significant only among the female cases (from 56.7 95 % CI 51.6-61.7 years to 65.4 95 % CI 61.8-69.0 years), the overall bulbar onset cases (from 58.0 95 % CI 54.0-62.1 years to 69.3 95 % CI 66.2-72.4 years), the overall cases occurring in the extra-urban population (from 54.5 95 % CI 49.0-60.1 years to 65.1 95 % CI 60.4-69.8 years) and the bulbar onset cases occurring in the extra-urban population (from 57.1 95 % CI 53.5-60.7 years to 69.6 95 % CI 66.3-73.7 years). Although the increasing age of the population combined with improvements in ALS diagnosis among the elderly may have played a part, these uneven findings among the incident cases occurring in a well-defined homogeneous population with a stable ALS incidence would seem to suggest the involvement of risk factors associated with the extra-urban environment.
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http://dx.doi.org/10.1007/s13760-016-0704-4DOI Listing
March 2017

Decreased serum PCSK9 levels after ischaemic stroke predict worse outcomes.

Eur J Clin Invest 2016 Dec 10;46(12):1053-1062. Epub 2016 Nov 10.

First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy.

Background: Soluble mediators have been investigated to predict the prognosis of acute ischaemic stroke (AIS). Among them, proprotein convertase subtilisin/kexin type 9 (PCSK9) might have both clinical and pathophysiological relevance.

Materials And Methods: All available serum samples from a cohort of patients with first AIS (n = 72) were tested for PCSK9 and included in this substudy analysis. The primary endpoint investigated the predictive value of early PCSK9 level variations (ΔPCSK9) from AIS onset to day 7 or from day 1 to day 7, towards a 90-day outcome by modified Rankin Scale (mRS). The secondary endpoint explored the association between ΔPCSK9 and the risk of major adverse cardiovascular events (MACEs).

Results: Decreased serum PCSK9 levels at days 1 and 7 were associated with poor clinical outcomes at day 90. At the cut-off point identified by ROC curve analysis (-61·28 ng/mL), ΔPCSK9 day 7-day 1 predicted a poor mRS at day 90 after AIS. ΔPCSK9 day 7-day 1 ≤ -61·28 ng/mL was associated with an increased rate of MACEs.

Conclusion: A decrease in PCSK9 levels was a predictor for poor outcome and increased MACEs after AIS. Additional studies targeting post-AIS PCSK9 levels and activity are required to clarify the prognostic and pathophysiological relevance of PCSK9 after AIS.
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http://dx.doi.org/10.1111/eci.12692DOI Listing
December 2016

Negative interaction between smoking and EBV in the risk of multiple sclerosis: The EnvIMS study.

Mult Scler 2017 Jun 23;23(7):1018-1024. Epub 2016 Sep 23.

The Kristian Gerhard Jebsen Centre for MS-Research, Department of Clinical Medicine, University of Bergen, Bergen, Norway/The Norwegian Multiple Sclerosis Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Background: Results from previous studies on a possible interaction between smoking and Epstein-Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting.

Objectives: To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS.

Methods: Within the case-control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale.

Results: Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis ( p = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66-1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): -0.98, 95% CI: -2.05-0.15, p = 0.09).

Conclusion: Our findings indicate competing antagonism, where the two exposures compete to affect the outcome.
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http://dx.doi.org/10.1177/1352458516671028DOI Listing
June 2017

Anti-ApoA-1 IgG serum levels predict worse poststroke outcomes.

Eur J Clin Invest 2016 Sep;46(9):805-17

Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland.

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.
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http://dx.doi.org/10.1111/eci.12664DOI Listing
September 2016
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