Intravenous Thrombolysis Guided by Perfusion CT with Alteplase in >4.5 Hours from Stroke Onset.

INTRODUCTION: The benefit of intravenous thrombolysis (IVT) in wake-up stroke (WUS), stroke of unknown time of onset (SUKO), or when time exceeds 4.5 h from last-seen-normal (LSN) guided by CT perfusion (CTP) or MRI has been recently suggested. However, there is limited information of IVT in those patients in real-world studies. OBJECTIVE: Our aim was to evaluate safety and efficacy of IVT selected by CTP in patients with WUS, SUKO, or stroke of time onset beyond 4.5 h. MATERIAL AND METHODS: We studied a prospective cohort of patients who underwent IVT from January 2010 to December 2017. Two groups were defined: standard of care group (SC) included patients with time onset <4.5 h and CTP group included patients with WUS, SUKO, or onset beyond >4.5 h from LSN with penumbra area in CTP. We evaluated baseline characteristics, functional outcomes according to modified Rankin Scale (mRS) at discharge and at 90 days, and intracranial hemorrhages rates. RESULTS: 657 patients were studied: 604 (92%) were treated in the SC group and 53 (8%) in the CTP group. The mean NIHSS score was 9.8 in the CTP group versus 13 in the SC group (p = 0.001). Seventeen patients in the CTP group (32.1%) received bridging therapy with mechanical thrombectomy (MT). Last time seen well-to-needle time was 538 versus 155 min (p < 0.001). The incidence of symptomatic intracranial hemorrhage was equal in both groups (3.8 vs. 3.8%, p = 1). Good functional outcome (mRS < 2) was achieved in both groups (72 vs. 60.4%, p = 0.107). CONCLUSIONS: IVT in patients with WUS, SUKO, or stroke beyond >4.5 h from LSN, with salvageable brain tissue on CTP, seems to be safe and has similar functional outcomes at 90 days to the standard therapeutic window, even when combined with MT.

Predictive Value of Serum Antibodies and Point Mutations of AQP4, AQP1 and MOG in A Cohort of Spanish Patients with Neuromyelitis Optica Spectrum Disorders.

The detection of IgG aquaporin-4 antibodies in the serum of patients with Neuromyelitis optica (NMO) has dramatically improved the diagnosis of this disease and its distinction from multiple sclerosis. Recently, a group of patients have been described who have an NMO spectrum disorder (NMOsd) and who are seronegative for AQP4 antibodies but positive for IgG aquaporin-1 (AQP1) or myelin oligodendrocyte glycoprotein (MOG) antibodies. The purpose of this study was to determine whether AQP1 and MOG could be considered new biomarkers of this disease; and if point mutations in the gDNA of AQP4, AQP1 and MOG genes could be associated with the etiology of NMOsd. We evaluated the diagnostic capability of ELISA and cell-based assays (CBA), and analyzed their reliability, specificity, and sensitivity in detecting antibodies against these three proteins. The results showed that both assays can recognize these antigen proteins under appropriate conditions, but only anti-AQP4 antibodies, and not AQP1 or MOG, appears to be a clear biomarker for NMOsd. CBA is the best method for detecting these antibodies; and serum levels of AQP4 antibodies do not correlate with the progression of this disease. So far, the sequencing analysis has not revealed a genetic basis for the etiology of NMOsd, but a more extensive analysis is required before definitive conclusions can be drawn.

Association of candidate genetic variants and circulating levels of ApoE/ApoJ with common neuroimaging features of cerebral amyloid angiopathy.

Introduction: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid-ß (Aß) in brain vessels and is a main cause of lobar intracerebral hemorrhage (ICH) in the elderly. CAA is associated with magnetic resonance imaging (MRI) markers of small vessel disease (SVD). Since Aß is also accumulated in Alzheimer's disease (AD) in the brain parenchyma, we aimed to study if several single nucleotide polymorphisms (SNPs) previously associated with AD were also associated with CAA pathology. Furthermore, we also studied the influence of APOE and CLU genetic variants in apolipoprotein E (ApoE) and clusterin/apolipoprotein J (ApoJ) circulating levels and their distribution among lipoproteins. Methods: The study was carried out in a multicentric cohort of 126 patients with lobar ICH and clinical suspicion of CAA. Results: We observed several SNPs associated with CAA neuroimaging MRI markers [cortical superficial siderosis (cSS), enlarged perivascular spaces in the centrum semiovale (CSO-EPVS), lobar cerebral microbleeds (CMB), white matter hyperintensities (WMH), corticosubcortical atrophy and CAA-SVD burden score]. Concretely, ABCA7 (rs3764650), CLU (rs9331896 and rs933188), EPHA1 (rs11767557), and TREML2 (rs3747742) were significantly associated with a CAA-SVD burden score. Regarding circulating levels of apolipoproteins, protective AD SNPs of CLU [rs11136000 (T) and rs9331896 (C)] were significantly associated with higher HDL ApoJ content in the lobar ICH cohort. APOEε2 carriers presented higher plasma and LDL-associated ApoE levels whereas APOEε4 carriers presented lower plasma ApoE levels. Additionally, we observed that lower circulating ApoJ and ApoE levels were significantly associated with CAA-related MRI markers. More specifically, lower LDL-associated ApoJ and plasma and HDL-associated ApoE levels were significantly associated with CSO-EPVS, lower ApoJ content in HDL with brain atrophy and lower ApoE content in LDL with the extent of cSS. Discussion: This study reinforces the relevance of lipid metabolism in CAA and cerebrovascular functionality. We propose that ApoJ and ApoE distribution among lipoproteins may be associated with pathological features related to CAA with higher ApoE and ApoJ levels in HDL possibly enhancing atheroprotective, antioxidative, and anti-inflammatory responses in cerebral ß-amyloidosis.

Safety and efficacy of intra-arterial bone marrow mononuclear cell transplantation in patients with acute ischaemic stroke in Spain (IBIS trial): a phase 2, randomised, open-label, standard-of-care controlled, multicentre trial.

BACKGROUND: Pilot clinical trials have shown the safety of intra-arterial bone marrow mononuclear cells (BMMNCs) in stroke. However, the efficacy of different doses of intra-arterial BMMNCs in patients with acute stroke has not been tested in a randomised clinical trial. We aimed to show safety and efficacy of two different doses of autologous intra-arterial BMMNC transplantation in patients with acute stroke. METHODS: The IBIS trial was a multicentre phase 2, randomised, controlled, investigator-initiated, assessor-blinded, clinical trial, in four stroke centres in Spain. We included patients (aged 18-80 years) with a non-lacunar, middle cerebral artery ischaemic stroke within 1-7 days from stroke onset and with a National Institutes of Health Stroke Scale score of 6-20. We randomly assigned patients (2:1:1) with a computer-generated randomisation sequence to standard of care (control group) or intra-arterial injection of autologous BMMNCs at one of two different doses (2 × 106 BMMNCs/kg or 5 × 106 BMMNCs/kg). The primary efficacy outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 180 days in the intention-to-treat population, comparing each BMMNC dose group and the pooled BMMNC group versus the control group. The primary safety endpoint was the proportion of serious adverse events. This trial was registered at ClinicalTrials.gov, NCT02178657 and is completed. FINDINGS: Between April 1, 2015, and May 20, 2021, we assessed 114 patients for eligibility. We randomly assigned 77 (68%) patients: 38 (49%) to the control group, 20 (26%) to the low-dose BMMNC group, and 19 (25%) the high-dose BMMNC group. The mean age of participants was 62·4 years (SD 12·7), 46 (60%) were men, 31 (40%) were women, all were White, and 63 (82%) received thrombectomy. The median NIHSS score before randomisation was 12 (IQR 9-15), with intra-arterial BMMNC injection done a median of 6 days (4-7) after stroke onset. The primary efficacy outcome occurred in 14 (39%) patients in the control group versus ten (50%) in the low-dose group (adjusted odds ratio 2·08 [95% CI 0·55-7·85]; p=0·28), eight (44%) in the high-dose group (1·89 [0·52-6·96]; p=0·33), and 18 (47%) in the pooled BMMNC group (2·22 [0·72-6·85]; p=0·16). We found no differences in the proportion of patients who had adverse events or dose-related events, but two patients had a groin haematoma after cell injection in the low-dose BMMNC group. INTERPRETATION: Intra-arterial BMMNCs were safe in patients with acute ischaemic stroke, but we found no significant improvement at 180 days on the mRS. Further clinical trials are warranted to investigate whether improvements might be possible at different timepoints. FUNDING: Instituto de Salud Carlos III co-funded by the European Regional Development Fund/European Social Fund, Mutua Madrileña, and the Regional Ministry of Health of Andalusia.

Comparison of Plasma Lipoprotein Composition and Function in Cerebral Amyloid Angiopathy and Alzheimer's Disease.

Cerebral amyloid angiopathy (CAA) refers to beta-amyloid (Aß) deposition in brain vessels and is clinically the main cause of lobar intracerebral hemorrhage (ICH). Aß can also accumulate in brain parenchyma forming neuritic plaques in Alzheimer's disease (AD). Our study aimed to determine whether the peripheral lipid profile and lipoprotein composition are associated with cerebral beta-amyloidosis pathology and may reflect biological differences in AD and CAA. For this purpose, lipid and apolipoproteins levels were analyzed in plasma from 51 ICH-CAA patients (collected during the chronic phase of the disease), 60 AD patients, and 60 control subjects. Lipoproteins (VLDL, LDL, and HDL) were isolated and their composition and pro/antioxidant ability were determined. We observed that alterations in the lipid profile and lipoprotein composition were remarkable in the ICH-CAA group compared to control subjects, whereas the AD group presented no specific alterations compared with controls. ICH-CAA patients presented an atheroprotective profile, which consisted of lower total and LDL cholesterol levels. Plasma from chronic ICH-CAA patients also showed a redistribution of ApoC-III from HDL to VLDL and a higher ApoE/ApoC-III ratio in HDL. Whether these alterations reflect a protective response or have a causative effect on the pathology requires further investigation.

Circulating AQP4 Levels in Patients with Cerebral Amyloid Angiopathy-Associated Intracerebral Hemorrhage.

Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage (ICH) in elderly patients. Growing evidence suggests a potential role of aquaporin 4 (AQP4) in amyloid-beta-associated diseases, including CAA pathology. Our aim was to investigate the circulating levels of AQP4 in a cohort of patients who had suffered a lobar ICH with a clinical diagnosis of CAA. AQP4 levels were analyzed in the serum of 60 CAA-related ICH patients and 19 non-stroke subjects by enzyme-linked immunosorbent assay (ELISA). The CAA-ICH cohort was divided according to the time point of the functional outcome evaluation: mid-term (12 ± 18.6 months) and long-term (38.5 ± 32.9 months) after the last ICH. Although no differences were found in AQP4 serum levels between cases and controls, lower levels were found in CAA patients presenting specific hemorrhagic features such as ≥2 lobar ICHs and ≥5 lobar microbleeds detected by magnetic resonance imaging (MRI). In addition, CAA-related ICH patients who presented a long-term good functional outcome had higher circulating AQP4 levels than subjects with a poor outcome or controls. Our data suggest that AQP4 could potentially predict a long-term functional outcome and may play a protective role after a lobar ICH.

Recurrent pseudotumoral relapses in multiple sclerosis: a case report.

OBJECTIVES: Multiple sclerosis (MS) is the most common chronic disabling disease of the central nervous system (CNS) in young adults. It is characterized by the presence of multiple demyelinating inflammatory lesions disseminated in the CNS. Pseudotumoral lesions (PL) are rarely observed in patients with MS. METHODS: These atypical lesions can pose a diagnostic problem, especially when they are present at disease onset. RESULTS: Most MS patients with PLs only have a single episode throughout their disease course, which reflects its low tendency of recurrence. CONCLUSIONS: We report the rare case of a 34-year-old MS patient who suffered from recurrent pseudotumoral episodes during follow-up.