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Amyotrophic Lateral Sclerosis (ALS) patients express significant clinical heterogeneity that often hinders a correct diagnostic definition. Intracellular deposition of TDP-43, a protein involved in RNA metabolism characterizes the pathology. Interestingly, this protein can be detected in serum, wherein cognate naturally-occurring auto-antibodies (anti-TDP-43 NAb) might be also present, albeit they have never been documented before. In this exploratory study, we quantified the levels of both anti-TDP-43 NAb and TDP-43 protein as putative accessible markers for improving the ALS diagnostic process by using ELISA in N  = 70 ALS patients ( N  = 4 carrying TARDBP mutations), N  = 40 age-comparable healthy controls (CTRL), N  = 20 motor neuron disease mimics (MN-m), N  = 20 Alzheimer’s disease (AD) and N  = 15 frontotemporal lobar degeneration (FTLD) patients. Anti-TDP-43 NAb were found to be significantly increased in ALS patients compared to all the other groups ( p  < 0.001). On the other hand, the distribution of serum levels of TDP-43 protein was highly variable among the various groups. Levels were increased in ALS patients, albeit the highest values were detected in MN-m patients. NAb and protein serum levels failed to correlate. For the first time, we report that serum anti-TDP-43 NAb are detectable in human serum of both healthy controls and patients affected by a variety of neurodegenerative disorders; furthermore, their levels are increased in ALS patients, representing a potentially interesting trait core marker of this disease. Further studies are needed to clarify the exact role of the NAb. This information might be extremely useful for paving the way toward targeting TDP-43 by immunotherapy in ALS.

Whether and how SARS-CoV-2 outbreak affected in-hospital acute stroke care system is still matter of debate. In the setting of the STROKOVID network, a collaborative project between the ten centers designed as hubs for the treatment of acute stroke during SARS-CoV-2 outbreak in Lombardy, Italy, we retrospectively compared clinical features and process measures of patients with confirmed infection (COVID-19) and non-infected patients (non-COVID-19) who underwent reperfusion therapies for acute ischemic stroke. Between March 8 and April 30, 2020, 296 consecutive patients [median age, 74 years (interquartile range (IQR), 62–80.75); males, 154 (52.0%); 34 (11.5%) COVID-19] qualified for the analysis. Time from symptoms onset to treatment was longer in the COVID-19 group [230 (IQR 200.5–270) minutes vs. 190 (IQR 150–245) minutes; p = 0.007], especially in the first half of the study period. Patients with COVID-19 who underwent endovascular thrombectomy had more frequently absent collaterals or collaterals filling ≤ 50% of the occluded territory (50.0% vs. 16.6%; OR 5.05; 95% CI 1.82–13.80) and a lower rate of good/complete recanalization of the primary arterial occlusive lesion (55.6% vs. 81.0%; OR 0.29; 95% CI 0.10–0.80). Post-procedural intracranial hemorrhages were more frequent (35.3% vs. 19.5%; OR 2.24; 95% CI 1.04–4.83) and outcome was worse among COVID-19 patients (in-hospital death, 38.2% vs. 8.8%; OR 6.43; 95% CI 2.85–14.50). Our findings showed longer delays in the intra-hospital management of acute ischemic stroke in COVID-19 patients, especially in the early phase of the outbreak, that likely impacted patients outcome and should be the target of future interventions.

Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic events. Ischemic stroke in COVID-19 patients entails high severity and mortality rates. Here we aimed to analyze cerebral thrombi of COVID-19 patients with large vessel occlusion (LVO) acute ischemic stroke to expose molecular evidence for SARS-CoV-2 in the thrombus and to unravel any peculiar immune-thrombotic features. We conducted a systematic pathological analysis of cerebral thrombi retrieved by endovascular thrombectomy in patients with LVO stroke infected with COVID-19 ( n  = 7 patients) and non-covid LVO controls ( n  = 23). In thrombi of COVID-19 patients, the SARS-CoV-2 docking receptor ACE2 was mainly expressed in monocytes/macrophages and showed higher expression levels compared to controls. Using polymerase chain reaction and sequencing, we detected SARS-CoV-2 Clade20A, in the thrombus of one COVID-19 patient. Comparing thrombus composition of COVID-19 and control patients, we noted no overt differences in terms of red blood cells, fibrin, neutrophil extracellular traps (NETs), von Willebrand Factor (vWF), platelets and complement complex C5b-9. However, thrombi of COVID-19 patients showed increased neutrophil density (MPO + cells) and a three-fold higher Neutrophil-to-Lymphocyte Ratio (tNLR). In the ROC analysis both neutrophils and tNLR had a good discriminative ability to differentiate thrombi of COVID-19 patients from controls. In summary, cerebral thrombi of COVID-19 patients can harbor SARS-CoV2 and are characterized by an increased neutrophil number and tNLR and higher ACE2 expression. These findings suggest neutrophils as the possible culprit in COVID-19-related thrombosis. Graphical Abstract

ObjectiveTo characterize patients with acute ischemic stroke related to SARS-CoV-2 infection and assess the classification performance of clinical and laboratory parameters in predicting in-hospital outcome of these patients.MethodsIn the setting of the STROKOVID study including patients with acute ischemic stroke consecutively admitted to the ten hub hospitals in Lombardy, Italy, between March 8 and April 30, 2020, we compared clinical features of patients with confirmed infection and non-infected patients by logistic regression models and survival analysis. Then, we trained and tested a random forest (RF) binary classifier for the prediction of in-hospital death among patients with COVID-19.ResultsAmong 1013 patients, 160 (15.8%) had SARS-CoV-2 infection. Male sex (OR 1.53; 95% CI 1.06–2.27) and atrial fibrillation (OR 1.60; 95% CI 1.05–2.43) were independently associated with COVID-19 status. Patients with COVID-19 had increased stroke severity at admission [median NIHSS score, 9 (25th to75th percentile, 13) vs 6 (25th to75th percentile, 9)] and increased risk of in-hospital death (38.1% deaths vs 7.2%; HR 3.30; 95% CI 2.17–5.02). The RF model based on six clinical and laboratory parameters exhibited high cross-validated classification accuracy (0.86) and precision (0.87), good recall (0.72) and F1-score (0.79) in predicting in-hospital death.ConclusionsIschemic strokes in COVID-19 patients have distinctive risk factor profile and etiology, increased clinical severity and higher in-hospital mortality rate compared to non-COVID-19 patients. A simple model based on clinical and routine laboratory parameters may be useful in identifying ischemic stroke patients with SARS-CoV-2 infection who are unlikely to survive the acute phase.

Amyotrophic lateral sclerosis (ALS) patients often express cognitive and behavioral dysfunctions within the so-called “frontotemporal spectrum disorders.” Guidelines recommend screening of such dysfunctions, albeit only ALS dedicated tools are eventually suitable, due to the profound motor limitations induced by the disease. ALS Cognitive Behavioral Screen (ALS-CBS) is such a screening tool but normative data are not available, limiting its widespread implementation. Our aim consisted in producing normative data for the Italian version of the ALS-CBS. The scale was administered to n = 458 healthy controls with different age and education. Following translation and back translation of the original version of the test, normative data and correction scores for the ALS-CBS cognitive subtest (ALS-CBSci) were generated. Furthermore, n = 100 ALS consecutive outpatients with a wide range of cognitive and motor severity underwent to the ALS-CBS, besides FAB and Weigl sorting test (WST), in order to check its usability. Completion rate was 100% for ALS-CBS and WST, and 68% for the FAB. Corrected ALS-CBS scores showed 12% detection rate of significant cognitive dysfunction with a moderate kappa with FAB and WST. For the ALS-CBS behavioral subtest (ALS-CBSbi), a caregiver was available for n = 81 ALS patients and asked to complete the subset. The detection rate for behavioral dysfunction was 55.5%, and a mild correlation between with the Caregiver Burden Inventory was present (r = − 0.26, p = 0.04). In conclusion, we offer here normative data for the ALS-CBS, a handy tool for screening frontotemporal spectrum dysfunctions in ALS patients, and confirm its usability and validity in an outpatient setting.

Background Epileptiform activity, including status epilepticus (SE), occurs in up to one‐third of comatose survivors of cardiac arrest and may predict poor outcome. The relationship between SE and hypoxic–ischemic brain injury (HIBI) is not established. Methods This is a single‐center retrospective study on consecutive patients with post‐anoxic super‐refractory SE. HIBI was graded as non‐widespread (group 1) or widespread (group 2) by qualitative analysis of DWI/ADC and T2w‐FLAIR. Between‐group differences in the rate of poor neurological outcome at 6 months (primary outcome), SE resolution and consciousness recovery before discharge, and mortality at 6 months (secondary outcomes) were investigated. Results From January 2011 to February 2023, 40 patients were included. HIBI was widespread in 45% of patients and non‐widespread in 55%. The rate of poor neurological outcome at 6 months was 27% in group 1 and 83% in group 2 (OR 12.8, CI 95% [2.5–64.3], p = 0.002). The rate of consciousness recovery before discharge was 73% in group 1 versus 22% in group 2 (OR 8.8, CI 95% [1.9–40.3], p = 0.005). SE resolved in 95% of patients in group 1 versus 67% in group 2 (OR 10.5, CI 95% [1.1–97.9], p = 0.039). Mortality rate at 6 months was 27% in group 1 versus 50% in group 2 (OR 0.4, CI 95% [0.1–1.9], p = 0.303). Conclusion Patients with widespread HIBI had higher odds of poor outcome at 6 months, lower probability of SE resolution and of consciousness recovery before discharge compared to those with non‐widespread HIBI. Mortality at 6 months did not differ significantly between the two groups.

Objective To comprehensively assess whether neopterin in urine could be a candidate biomarker for determining the neuroinflammatory status in ALS. Methods We performed an observational, cross-sectional study in 81 pALS, 68 age- and sex-comparable healthy controls (HC), 14 patients affected by MS and 24 OND patients. ALS patients underwent a neurological evaluation to assess the global functional status evaluated by Amyotrophic Lateral Sclerosis Functional Rating Scale—Revised (ALSFRS-R) and the disease progression rate. Urinary neopterin concentrations were determined by high-performance liquid chromatography method and were recorded at the time of first examination to assess their effect on disease severity and survival. Results Urinary neopterin was significantly higher in pALS (263.90 [198.71–474.90]) compared to MS (155.28 [131.74–190.38], p  =  < .001), OND patients (205.60 [158.96–299.41], p  = 0.04) and HC (169.55 [134.91–226.10], p  < .001). Moreover, a significant negative correlation was found between neopterin level and the severity of symptoms evaluated by ALSFRS-R total score ( r  = − 0.46, p  < .001) and its subscores (bulbar r  = − 0.34, p  = 0.002; motor r  = − 0.33, p  = 0.003; respiratory r  = − 0.53, p  < .001), also adjusting for the effect of sex, site of onset, age at evaluation and time from onset to evaluation. Conclusions Our finding indicates that urine neopterin is elevated in ALS, emphasizing the role of the cell-mediated inflammation in the disease. Moreover, whether confirmed in further studies, our results will underline the neopterin’s potential use as non-invasive clinical biomarker of ALS, to discriminate patients possibly candidates to clinical interventions aimed to interfere the neuroinflammatory processes.

Abstract BackgroundThe infectious disease phenotype of acute stroke associated with COVID-19 has been poorly characterized.ObjectiveWe investigated the neurovascular and infectious disease phenotype of stroke patients with and without COVID-19 infection, and their effect on in-hospital mortality.MethodsThis is a retrospective cohort study of consecutive patients with acute stroke, admitted to any ward of a hub hospital for stroke in Lombardy, Italy, during the first wave of COVID-19. Demographic, neurovascular, infectious disease, and respiratory characteristics were collected. The effect of clinical variables on survival was evaluated using logistic regression models.ResultsOne hundred thirty-seven patients with acute stroke were recruited; 30 (21.9%) patients had COVID-19 and represented 2.5% of the 1218 COVID-19 patients hospitalized in the study period. Demographics, comorbidities, stroke type, stroke severity, and etiology did not differ between COVID + stroke patients and non-COVID stroke patients, except for an excess of multi-embolic ischemic stroke in the COVID + group. Most COVID + stroke patients had symptomatic infection (60%) and interstitial pneumonia (70%). COVID + stroke patients required more frequently respiratory support (77% versus 29%; p < 0.0001) and had higher in-hospital mortality (40% versus 12%; p = 0.0005) than non-COVID stroke patients. Mortality was independently associated with symptomatic interstitial pneumonia (aOR 6.7; 95% CI 2.0–22.5; p = 0.002) and, to a lesser extent, with NIHSS on admission (aOR 1.1; 95% CI 1.03–1.2; p = 0.007) and recanalization therapies (aOR 0.2; 95% CI 0.04–0.98; p = 0.046).ConclusionSymptomatic interstitial pneumonia was the major driver of in-hospital mortality in COVID + stroke patients.

Hypothermia is a promising therapeutic strategy for severe vasospasm and other types of non-thrombotic cerebral ischemia, but its clinical application is limited by significant systemic side effects. We aimed to develop an intraventricular device for the controlled cooling of the cerebrospinal fluid, to produce a targeted hypothermia in the affected cerebral hemisphere with a minimal effect on systemic temperature. An intraventricular cooling device (acronym: V-COOL) was developed by in silico modelling, in vitro testing, and in vivo proof-of-concept application in healthy Wistar rats (n = 42). Cerebral cortical temperature, rectal temperature, and intracranial pressure were monitored at increasing flow rate (0.2 to 0.8 mL/min) and duration of application (10 to 60 min). Survival, neurological outcome, and MRI volumetric analysis of the ventricular system were assessed during the first 24 h. The V-COOL prototyping was designed to minimize extra-cranial heat transfer and intra-cranial pressure load. In vivo application of the V-COOL device produced a flow rate-dependent decrease in cerebral cortical temperature, without affecting systemic temperature. The target degree of cerebral cooling (− 3.0 °C) was obtained in 4.48 min at the flow rate of 0.4 mL/min, without significant changes in intracranial pressure. Survival and neurological outcome at 24 h showed no significant difference compared to sham-treated rats. MRI study showed a transient dilation of the ventricular system (+ 38%) in a subset of animals. The V-COOL technology provides an effective, rapid, selective, and safe cerebral cooling to a clinically relevant degree of − 3.0 °C.