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Accurate assessment of post-stroke deficits is crucial in translational research. Recent advances in machine learning offer precise quantification of rodent motor behavior post-stroke, yet detecting lesion-specific upper extremity deficits remains unclear. Employing proximal middle cerebral artery occlusion (MCAO) and cortical photothrombosis (PT) in mice, we assessed post-stroke impairments via the Staircase test. Lesion locations were identified using 7 T-MRI. Machine learning was applied to reconstruct forepaw kinematic trajectories and feature analysis was achieved with MouseReach, a new data-processing toolbox. Lesion reconstructions pinpointed ischemic centers in the striatum (MCAO) and sensorimotor cortex (PT). Pellet retrieval alterations were observed, but were unrelated to overall stroke volume. Instead, forepaw slips and relative reaching success correlated with increasing cortical lesion size in both models. Striatal lesion size after MCAO was associated with prolonged reach durations that occurred with delayed symptom onset. Further analysis on the impact of selective serotonin reuptake inhibitors in the PT model revealed no clear treatment effects but replicated strong effect sizes of slips for post-stroke deficit detection. In summary, refined movement analysis unveiled specific deficits in two widely-used mouse stroke models, emphasizing the value of deep behavioral profiling in preclinical stroke research to enhance model validity for clinical translation.

Asunto(s)

Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media , Accidente Cerebrovascular , Animales , Ratones , Masculino , Infarto de la Arteria Cerebral Media/diagnóstico por imagen , Infarto de la Arteria Cerebral Media/fisiopatología , Infarto de la Arteria Cerebral Media/complicaciones , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/complicaciones , Ratones Endogámicos C57BL , Imagen por Resonancia Magnética/métodos , Aprendizaje Automático , Movimiento/fisiología

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BACKGROUND: Diabetes mellitus (DM), prediabetes, and insulin resistance are highly prevalent in patients with ischemic stroke (IS). DM is associated with higher risk for poor outcomes after IS. OBJECTIVE: Investigate the risk of recurrent vascular events and mortality associated with impaired glucose metabolism compared to normoglycemia in patients with IS and transient ischemic attack (TIA). METHODS: Systematic literature search was performed in PubMed, Embase, Cochrane Library on 21st March 2024 and via citation searching. Studies that comprised IS or TIA patients and exposures of impaired glucose metabolism were eligible. Study Quality Assessment Tool was used for risk of bias assessment. Covariate adjusted outcomes were pooled using random-effects meta-analysis. MAIN OUTCOMES: Recurrent stroke, cardiac events, cardiovascular and all-cause mortality and composite of vascular outcomes. RESULTS: Of 10,974 identified studies 159 were eligible. 67% had low risk of bias. DM was associated with an increased risk for composite events (pooled HR (pHR) including 445,808 patients: 1.58, 95% CI 1.34-1.85, I2 = 88%), recurrent stroke (pHR including 1.161.527 patients: 1.42 (1.29-1.56, I2 = 92%), cardiac events (pHR including 443,863 patients: 1.55, 1.50-1.61, I2 = 0%), and all-cause mortality (pHR including 1.031.472 patients: 1.56, 1.34-1.82, I2 = 99%). Prediabetes was associated with an increased risk for composite events (pHR including 8,262 patients: 1.50, 1.15-1.96, I2 = 0%) and recurrent stroke (pHR including 10,429 patients: 1.50, 1.18-1.91, I2 = 0), however, not with mortality (pHR including 9,378 patients, 1.82, 0.73-4.57, I2 = 78%). Insulin resistance was associated with recurrent stroke (pHR including 21,363 patients: 1.56, 1.19-2.05, I2 = 55%), but not with mortality (pHR including 21,363 patients: 1.31, 0.66-2.59, I2 = 85%). DISCUSSION: DM is associated with a 56% increased relative risk of death after IS and TIA. Risk estimates regarding recurrent events are similarly high between prediabetes and DM, indicating high cardiovascular risk burden already in precursor stages of DM. There was a high heterogeneity across most outcomes.

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Glucemia , Accidente Cerebrovascular Isquémico , Recurrencia , Humanos , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular Isquémico/mortalidad , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/epidemiología , Glucemia/metabolismo , Pronóstico , Masculino , Femenino , Anciano , Persona de Mediana Edad , Diabetes Mellitus/mortalidad , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Ataque Isquémico Transitorio/mortalidad , Ataque Isquémico Transitorio/diagnóstico , Biomarcadores/sangre , Factores de Tiempo , Anciano de 80 o más Años , Estado Prediabético/mortalidad , Estado Prediabético/diagnóstico , Estado Prediabético/sangre , Estado Prediabético/epidemiología , Resistencia a la Insulina

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BACKGROUND: Central nervous system (CNS) injury following brain-directed radiotherapy remains a major challenge. Proton radiotherapy (PRT) minimizes radiation to healthy brain, potentially limiting sequelae. We characterized CNS radiotoxicity, including radiation-induced leukoencephalopathy (RIL), brain tissue necrosis (TN), and cerebral microbleeds (CMB), in glioma patients treated with PRT or photons (XRT). PATIENTS AND METHODS: Thirty-four patients (19 male; median age 39.6 years) with WHO grade 2-3 gliomas treated with partial cranial radiotherapy (XRT [n = 17] vs PRT[n = 17]) were identified and matched by demographic/clinical criteria. Radiotoxicity was assessed longitudinally for 3 years post-radiotherapy via serial analysis of T2/FLAIR- (for RIL), contrast-enhanced T1- (for TN), and susceptibility (for CMB)-weighted MRI sequences. RIL was rated at whole-brain and hemispheric levels using a novel Fazekas scale-informed scoring system. RESULTS: The scoring system proved reliable (ICC > 0.85). Both groups developed moderate-to-severe RIL (62%[XRT]; 71%[PRT]) within 3 years; however, XRT was associated with persistent RIL increases in the contralesional hemisphere, whereas contralesional hemispheric RIL plateaued with PRT at 1-year post-radiotherapy (t = 2.180; P = .037). TN rates were greater with PRT (6%[XRT] vs 18%[PRT]; P = ns). CMB prevalence (76%[XRT]; 71%[PRT]) and burden (mean #CMB: 4.0[XRT]; 4.2[PRT]) were similar; however, XRT correlated with greater contralesional hemispheric CMB burden (27%[XRT]; 17%[PRT]; X2 = 4.986; P = .026), whereas PRT-specific CMB clustered at the radiation field margin (X2 = 14.7; P = .002). CONCLUSIONS: CNS radiotoxicity is common and progressive in glioma patients. Injury patterns suggest radiation modality-specificity as RIL, TN, and CMB exhibit unique spatiotemporal differences following XRT vs PRT, likely reflecting underlying dosimetric and radiobiological differences. Familiarity with such injury patterns is essential to improve patient management. Prospective studies are needed to validate these findings and assess their impacts on neurocognitive function.

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The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies1. Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events1,2. However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET-DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events.

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Aterosclerosis , Ácidos Nucleicos Libres de Células , Proteínas de Unión al ADN , Modelos Animales de Enfermedad , Inflamasomas , Placa Aterosclerótica , Recurrencia , Accidente Cerebrovascular , Animales , Inflamasomas/metabolismo , Ratones , Masculino , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/inmunología , Humanos , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/complicaciones , Ácidos Nucleicos Libres de Células/sangre , Ácidos Nucleicos Libres de Células/metabolismo , Ácidos Nucleicos Libres de Células/genética , Femenino , Trampas Extracelulares/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Inflamación/patología , Ratones Endogámicos C57BL

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BACKGROUND: Health-related quality of life (HRQL) has become an important outcome parameter in cardiology. The MOS 36-ltem Short-Form Health Survey (SF-36) and the PROMIS-29 are two widely used generic measures providing composite HRQL scores. The domains of the SF-36, a well-established instrument utilized for several decades, can be aggregated to physical (PCS) and mental (MCS) component summary scores. Alternative scoring algorithms for correlated component scores (PCSc and MCSc) have also been suggested. The PROMIS-29 is a newer but increasingly used HRQL measure. Analogous to the SF-36, physical and mental health summary scores can be derived from PROMIS-29 domain scores, based on a correlated factor solution. So far, scores from the PROMIS-29 are not directly comparable to SF-36 results, complicating the aggregation of research findings. Thus, our aim was to provide algorithms to convert PROMIS-29 data to well-established SF-36 component summary scores. METHODS: Data from n = 662 participants of the Berlin Long-term Observation of Vascular Events (BeLOVE) study were used to estimate linear regression models with either PROMIS-29 domain scores or aggregated PROMIS-29 physical/mental health summary scores as predictors and SF-36 physical/mental component summary scores as outcomes. Data from a subsequent assessment point (n = 259) were used to evaluate the agreement between empirical and predicted SF-36 scores. RESULTS: PROMIS-29 domain scores as well as PROMIS-29 health summary scores showed high predictive value for PCS, PCSc, and MCSc (R2 ≥ 70%), and moderate predictive value for MCS (R2 = 57% and R2 = 40%, respectively). After applying the regression coefficients to new data, empirical and predicted SF-36 component summary scores were highly correlated (r > 0.8) for most models. Mean differences between empirical and predicted scores were negligible (|SMD|<0.1). CONCLUSIONS: This study provides easy-to-apply algorithms to convert PROMIS-29 data to well-established SF-36 physical and mental component summary scores in a cardiovascular population. Applied to new data, the agreement between empirical and predicted SF-36 scores was high. However, for SF-36 mental component summary scores, considerably better predictions were found under the correlated (MCSc) than under the original factor model (MCS). Additionally, as a pertinent byproduct, our study confirmed construct validity of the relatively new PROMIS-29 health summary scores in cardiology patients.

Asunto(s)

Enfermedades Cardiovasculares , Calidad de Vida , Humanos , Masculino , Femenino , Enfermedades Cardiovasculares/psicología , Persona de Mediana Edad , Anciano , Encuestas y Cuestionarios/normas , Algoritmos , Salud Mental , Psicometría , Encuestas Epidemiológicas

RESUMEN

Background: Patients suffering from neurological symptoms after COVID-19 vaccination (post-COVID-19 vaccination syndrome (PCVS)) have imposed an increasing challenge on medical practice, as diagnostic precision and therapeutic options are lacking. Underlying autoimmune dysfunctions, including autoantibodies, have been discussed in neurological disorders after SARS-CoV-2 infection and vaccination. Here, we describe the frequency and targets of autoantibodies against peripheral nervous system tissues in PCVS. Methods: Sera from 50 PCVS patients with peripheral neurological symptoms after COVID-19 vaccination and 35 vaccinated healthy controls were used in this study. IgG autoreactivity was measured via indirect immunofluorescence assays on mouse sciatic nerve teased fibers. The frequencies of autoantibodies were compared between groups using Fisher's exact test. Serum anti-ganglioside antibodies were measured in ganglioside blots. Autoantibody target identification was performed using immunoprecipitation coupled to mass spectrometry. Subsequent target confirmation was conducted via cell-based assays and ELISA. Results: Compared with controls, PCVS patients had a significantly greater frequency of autoantibodies against peripheral nervous system structures (9/50(18%) vs 1/35(3%); p=0.04). Autoantibodies bound to paranodes (n=5), axons (n=4), Schmidt-Lanterman incisures (n=2) and Schwann cell nuclei (n=1). Conversely, antibodies against gangliosides were absent in PCVS patients. Target identification and subsequent confirmation revealed various subunits of neurofilaments as well as DFS-70 as autoantibody epitopes. Conclusion: Our data suggest that autoantibodies against nervous system tissue could be relevant in PCVS patients. Autoantibodies against neurofilaments and cell nuclei with so far non-established links to this disease spectrum should be further elucidated to determine their biomarker potential.

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Autoanticuerpos , Vacunas contra la COVID-19 , COVID-19 , Inmunoglobulina G , SARS-CoV-2 , Humanos , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Masculino , Femenino , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Persona de Mediana Edad , COVID-19/inmunología , SARS-CoV-2/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Anciano , Ratones , Animales , Adulto , Vacunación , Gangliósidos/inmunología , Nervios Periféricos/inmunología

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Accidente Cerebrovascular , Animales , Humanos , Modelos Animales de Enfermedad , Resultado del Tratamiento

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BACKGROUND: Since the antisense oligonucleotide tofersen has recently become available for the treatment of amyotrophic lateral sclerosis (ALS) caused by mutations in SOD1, determining the causality of the over 230 SOD1 variants has become even more important. The most common SOD1 variant worldwide is p.D91A (c.272A > C), whose causality for ALS is contested when in a heterozygous state. The reason is the high allele frequency of SOD1D91A in Europe, exceeding 1% in Finno-Scandinavia. METHODS: We present the clinical disease course and serum neurofilament light chain (NfL) results of treating 11 patients either homo- or heterozygous for the SOD1D91A allele for up to 16 months with tofersen. RESULTS: Tofersen decreases serum neurofilament levels (sNFL), which are associated with the ALS progression rate, in the 6 ALS patients homozygous for SOD1D91A. We observe significantly lower sNfL levels in the 5 patients heterozygous for SOD1D91A. The results indicate that both mono- and bi-allelic SOD1D91A are causally relevant targets, with a possibly reduced effect size of SOD1D91Ahet. CONCLUSIONS: The finding is relevant for decision making regarding tofersen treatment, patient counseling and inclusion of SOD1D91A patients in drug trials. As far as we are aware, the approach is conceptually new since it provides evidence for the causality of an ALS variant based on a biomarker response to gene-specific treatment.

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Amyotrophic lateral sclerosis (ALS) is a disease that can be inherited which affects nerve cells in the brain and spinal cord. Changes within a gene called SOD1 that result in a mutation named p.D91A can lead to the development of ALS. People have two copies of the SOD1 gene. It has been unclear whether the presence of only one copy of p.D91A can cause ALS. We treated ALS patients with the p.D91A variant of SOD1 with a drug called tofersen. We found that a marker of disease progression was reduced in patients with one or two copies of the p.D91A mutation. This suggests that the presence of just one p.D91A variant of SOD1 contributes to disease development. This information could be used to improve treatment decisions for people with ALS.

RESUMEN

Importance: Elevated values of high-sensitivity cardiac troponin (hs-cTn) are common in patients with acute ischemic stroke and are associated with poor prognosis. However, diagnostic and therapeutic implications in patients with ischemic stroke remain unclear. Objective: To identify factors indicative of myocardial infarction (MI) in patients with acute ischemic stroke and hs-cTn elevation. The primary hypothesis was that a dynamic change of hs-cTn values (>50% change) in patients with acute ischemic stroke indicates MI. Design, Setting, and Participants: This cross-sectional study was a prospective, observational study with blinded end-point assessment conducted across 26 sites in Germany. Patients were included if they had acute ischemic stroke within 72 hours and either (1) highly elevated hs-cTn values on admission (>52 ng/L) or (2) hs-cTn levels above the upper limit of normal and a greater than 20% change at repeated measurements. Patients were enrolled between August 2018 and October 2020 and had 1 year of follow-up. Statistical analysis was performed between April 2022 and August 2023. Exposure: Standardized electrocardiography, echocardiography, and coronary angiography. Main Outcome and Measures: Diagnosis of MI as adjudicated by an independent end-point committee based on the findings of electrocardiography, echocardiography, and coronary angiography. Results: In total, 254 patients were included. End points were adjudicated in 247 patients (median [IQR] age, 75 [66-82] years; 117 were female [47%] and 130 male [53%]). MI was present in 126 of 247 patients (51%) and classified as type 1 MI in 50 patients (20%). Dynamic change in hs-cTn value was not associated with MI in univariable (32% vs 38%; χ2 P = .30) or adjusted comparison (odds ratio, 1.05; 95% CI, 0.31-3.33). The baseline absolute hs-cTn value was independently associated with type 1 MI. The best cutoffs for predicting type 1 MI were at hs-cTn values 5 to 10 times the upper limit normal. Conclusions and Relevance: This study found that in patients with acute ischemic stroke, a dynamic change in hs-cTn values did not identify MI, underscoring that dynamic changes do not identify the underlying pathophysiological mechanism. In exploratory analyses, very high absolute hs-cTn values were associated with a diagnosis of type 1 MI. Further studies are needed how to best identify patients with stroke who should undergo coronary angiography.

Asunto(s)

Accidente Cerebrovascular Isquémico , Infarto del Miocardio , Humanos , Masculino , Femenino , Anciano , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/complicaciones , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/sangre , Estudios Transversales , Persona de Mediana Edad , Anciano de 80 o más Años , Estudios Prospectivos , Electrocardiografía , Ecocardiografía

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Thalamic aphasia results from focal thalamic lesions that cause dysfunction of remote but functionally connected cortical areas due to language network perturbation. However, specific local and network-level neural substrates of thalamic aphasia remain incompletely understood. Using lesion symptom mapping, we demonstrate that lesions in the left ventrolateral and ventral anterior thalamic nucleus are most strongly associated with aphasia in general and with impaired semantic and phonemic fluency and complex comprehension in particular. Lesion network mapping (using a normative connectome based on fMRI data from 1000 healthy individuals) reveals a Thalamic aphasia network encompassing widespread left-hemispheric cerebral connections, with Broca's area showing the strongest associations, followed by the superior and middle frontal gyri, precentral and paracingulate gyri, and globus pallidus. Our results imply the critical involvement of the left ventrolateral and left ventral anterior thalamic nuclei in engaging left frontal cortical areas, especially Broca's area, during language processing.

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Afasia , Imagen por Resonancia Magnética , Accidente Cerebrovascular , Tálamo , Núcleos Talámicos Ventrales , Humanos , Masculino , Persona de Mediana Edad , Femenino , Núcleos Talámicos Ventrales/fisiopatología , Núcleos Talámicos Ventrales/diagnóstico por imagen , Afasia/fisiopatología , Afasia/etiología , Afasia/diagnóstico por imagen , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/fisiopatología , Tálamo/fisiopatología , Tálamo/diagnóstico por imagen , Anciano , Adulto , Conectoma , Lóbulo Frontal/fisiopatología , Lóbulo Frontal/diagnóstico por imagen , Red Nerviosa/fisiopatología , Red Nerviosa/diagnóstico por imagen , Vías Nerviosas/fisiopatología

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Excessive stride variability is a characteristic feature of cerebellar ataxias, even in pre-ataxic or prodromal disease stages. This study explores the relation of variability of arm swing and trunk deflection in relationship to stride length and gait speed in previously described cohorts of cerebellar disease and healthy elderly: we examined 10 patients with spinocerebellar ataxia type 14 (SCA), 12 patients with essential tremor (ET), and 67 healthy elderly (HE). Using inertial sensors, recordings of gait performance were conducted at different subjective walking speeds to delineate gait parameters and respective coefficients of variability (CoV). Comparisons across cohorts and walking speed categories revealed slower stride velocities in SCA and ET patients compared to HE, which was paralleled by reduced arm swing range of motion (RoM), peak velocity, and increased CoV of stride length, while no group differences were found for trunk deflections and their variability. Larger arm swing RoM, peak velocity, and stride length were predicted by higher gait velocity in all cohorts. Lower gait velocity predicted higher CoV values of trunk sagittal and horizontal deflections, as well as arm swing and stride length in ET and SCA patients, but not in HE. These findings highlight the role of arm movements in ataxic gait and the impact of gait velocity on variability, which are essential for defining disease manifestation and disease-related changes in longitudinal observations.

Asunto(s)

Brazo , Marcha , Velocidad al Caminar , Humanos , Masculino , Marcha/fisiología , Femenino , Anciano , Brazo/fisiopatología , Brazo/fisiología , Velocidad al Caminar/fisiología , Persona de Mediana Edad , Torso/fisiopatología , Torso/fisiología , Movimiento/fisiología , Enfermedades Cerebelosas/fisiopatología , Caminata/fisiología , Fenómenos Biomecánicos/fisiología , Rango del Movimiento Articular/fisiología , Temblor Esencial/fisiopatología

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Heart failure (HF) is associated with poor outcome after stroke, but data from large prospective trials are sparse.We assessed the impact of HF on clinical endpoints in patients hospitalized with acute ischemic stroke or transient ischemic attack (TIA) enrolled in the prospective, multicenter Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke (MonDAFIS) trial. HF was defined as left ventricular ejection fraction (LVEF) < 55% or a history of HF on admission. The composite of recurrent stroke, major bleeding, myocardial infarction, and all-cause death, and its components during the subsequent 24 months were assessed. We used estimated hazard ratios in confounder-adjusted models. Overall, 410/2562 (16.0%) stroke patients fulfilled the HF criteria (i.e. 381 [14.9%] with LVEF < 55% and 29 [1.9%] based on medical history). Patients with HF had more often diabetes, coronary and peripheral arterial disease and presented with more severe strokes on admission. HF at baseline correlated with myocardial infarction (HR 2.21; 95% CI 1.02-4.79), and all-cause death (HR 1.67; 95% CI 1.12-2.50), but not with major bleed (HR 1.93; 95% CI 0.73-5.06) or recurrent stroke/TIA (HR 1.08; 95% CI 0.75-1.57). The data were adjusted for age, stroke severity, cardiovascular risk factors, and randomization. Patients with ischemic stroke or TIA and comorbid HF have a higher risk of myocardial infarction and death compared with non-HF patients whereas the risk of recurrent stroke or major hemorrhage was similar. Trial registration number Clinicaltrials.gov NCT02204267.

Asunto(s)

Insuficiencia Cardíaca , Accidente Cerebrovascular Isquémico , Humanos , Masculino , Femenino , Anciano , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/fisiopatología , Estudios Prospectivos , Accidente Cerebrovascular Isquémico/mortalidad , Accidente Cerebrovascular Isquémico/complicaciones , Persona de Mediana Edad , Factores de Riesgo , Recurrencia , Anciano de 80 o más Años

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INTRODUCTION: Lacunar stroke represents around a quarter of all ischemic strokes; however, their identification with computed tomography in the hyperacute setting is challenging. We aimed to validate a clinical score to identify lacunar stroke in the acute setting, independently, with data from the WAKE-UP trial using magnetic resonance imaging. METHODS: We analyzed data from the WAKE-UP trial and extracted Oxfordshire Community Stroke Project (OCSP) classification. Lacunar score was defined by National Institutes of Health Stroke Scale (NIHSS) < 7 and OCSP lacunar syndrome. Assessment of lacunar infarct by two independent investigators was blinded to clinical data. We calculated sensitivity, specificity, negative and positive predictive value (NPV and PPV, respectively) of lacunar score. RESULTS: We included 503 patients in the analysis, mean (±SD) age 65.2 (±11.6) years, 325 (65%) males, median (IQR) NIHSS = 6 (4-9); 108 (22%) lacunar infarcts were identified on magnetic resonance (MR), patients fulfilling lacunar score criteria were 120 (24%), of which 47 (44%) had a lacunar infarct. Lacunar score was negative in 322 (82%) of patients without lacunar infarct. Patients with lacunar score had lower NIHSS (4 vs 7, p < 0.001), higher systolic (157 vs 151 mmHg, p = 0.001) and diastolic (86 vs 83 mmHg, p = 0.013) blood pressure and smaller infarct volume (2.4 vs 9.5 mL, p < 0.001). Performance of lacunar score was as follows: sensitivity 0.44; specificity 0.82; PPV 0.39; NPV 0.84; and accuracy 0.73. Assuming a prevalence of lacunar stroke of 13%, PPV lowered to 0.30 but NPV was 0.90. Lacunar score performed better for supratentorial lacunar infarcts. CONCLUSION: Lacunar score had a very good specificity and NPV for screening of lacunar stroke. Implementation of this simple tool into clinical practice may help hyperacute management and guide patient selection in clinical trials. DATA ACCESS STATEMENT: Data supporting the results of this paper are available upon reasonable request to the corresponding author.

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Imagen por Resonancia Magnética , Accidente Vascular Cerebral Lacunar , Humanos , Accidente Vascular Cerebral Lacunar/diagnóstico por imagen , Accidente Vascular Cerebral Lacunar/diagnóstico , Masculino , Femenino , Anciano , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Valor Predictivo de las Pruebas

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Introduction: Subgroups of autoantibodies directed against voltage-gated potassium channel (Kv) complex components have been associated with immunotherapy-responsive clinical syndromes. The high prevalence and the role of autoantibodies directly binding Kv remain, however, controversial. Our objective was to determine Kv autoantibody binding requirements and to clarify their contribution to the observed immune response. Methods: Binding epitopes were studied in sera (n = 36) and cerebrospinal fluid (CSF) (n = 12) from a patient cohort positive for Kv1.2 but negative for 32 common neurological autoantigens and controls (sera n = 18 and CSF n = 5) by phospho and deep mutational scans. Autoantibody specificity and contribution to the observed immune response were resolved on recombinant cells, cerebellum slices, and nerve fibers. Results: 83% of the patients (30/36) within the studied cohort shared one out of the two major binding epitopes with Kv1.2-3 reactivity. Eleven percent (4/36) of the serum samples showed no binding. Fingerprinting resolved close to identical sequence requirements for both shared epitopes. Kv autoantibody response is directed against juxtaparanodal regions in peripheral nerves and the axon initial segment in central nervous system neurons and exclusively mediated by the shared epitopes. Discussion: Systematic mapping revealed two shared autoimmune responses, with one dominant Kv1.2-3 autoantibody epitope being unexpectedly prevalent. The conservation of the molecular binding requirements among these patients indicates a uniform autoantibody repertoire with monospecific reactivity. The enhanced sensitivity of the epitope-based (10/12) compared with that of the cell-based detection (7/12) highlights its use for detection. The determined immunodominant epitope is also the primary immune response visible in tissue, suggesting a diagnostic significance and a specific value for routine screening.

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Autoanticuerpos , Autoinmunidad , Epítopos Inmunodominantes , Canal de Potasio Kv.1.2 , Humanos , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Canal de Potasio Kv.1.2/inmunología , Epítopos Inmunodominantes/inmunología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Autoantígenos/inmunología , Mapeo Epitopo , Animales

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OBJECTIVE: In neurocritical care, data from multiple biosensors are continuously measured, but only sporadically acknowledged by the attending physicians. In contrast, machine learning (ML) tools can analyze large amounts of data continuously, taking advantage of underlying information. However, the performance of such ML-based solutions is limited by different factors, for example, by patient motion, manipulation, or, as in the case of external ventricular drains (EVDs), the drainage of CSF to control intracranial pressure (ICP). The authors aimed to develop an ML-based algorithm that automatically classifies normal signals, artifacts, and drainages in high-resolution ICP monitoring data from EVDs, making the data suitable for real-time artifact removal and for future ML applications. METHODS: In their 2-center retrospective cohort study, the authors used labeled ICP data from 40 patients in the first neurocritical care unit (University Hospital Zurich) for model development. The authors created 94 descriptive features that were used to train the model. They compared histogram-based gradient boosting with extremely randomized trees after building pipelines with principal component analysis, hyperparameter optimization via grid search, and sequential feature selection. Performance was measured with nested 5-fold cross-validation and multiclass area under the receiver operating characteristic curve (AUROC). Data from 20 patients in a second, independent neurocritical care unit (Charité - Universitätsmedizin Berlin) were used for external validation with bootstrapping technique and AUROC. RESULTS: In cross-validation, the best-performing model achieved a mean AUROC of 0.945 (95% CI 0.92-0.969) on the development dataset. On the external validation dataset, the model performed with a mean AUROC of 0.928 (95% CI 0.908-0.946) in 100 bootstrapping validation cycles to classify normal signals, artifacts, and drainages. CONCLUSIONS: Here, the authors developed a well-performing supervised model with external validation that can detect normal signals, artifacts, and drainages in ICP signals from patients in neurocritical care units. For future analyses, this is a powerful tool to discard artifacts or to detect drainage events in ICP monitoring signals.

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Artefactos , Presión Intracraneal , Humanos , Presión Intracraneal/fisiología , Estudios Retrospectivos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Monitoreo Fisiológico/métodos , Aprendizaje Automático Supervisado , Anciano , Drenaje/métodos , Algoritmos , Estudios de Cohortes , Aprendizaje Automático

RESUMEN

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severely debilitating condition which markedly restricts activity and function of affected people. Since the beginning of the COVID-19 pandemic ME/CFS related to post-acute COVID-19 syndrome (PACS) can be diagnosed in a subset of patients presenting with persistent fatigue 6 months after a mostly mild SARS-CoV-2 infection by fulfillment of the Canadian Consensus Criteria (CCC 2003). Induction of autoimmunity after viral infection is a mechanism under intensive investigation. In patients with ME/CFS, autoantibodies against thyreoperoxidase (TPO), beta-adrenergic receptors (ß2AR), and muscarinic acetylcholine receptors (MAR) are frequently found, and there is evidence for effectiveness of immunomodulation with B cell depleting therapy, cyclophosphamide, or intravenous immunoglobulins (IVIG). Preliminary studies on the treatment of ME/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement. However, evidence from placebo-controlled trials is currently missing. METHODS: In this double-blinded, randomized, sham-controlled, exploratory trial the therapeutic effect of five cycles of IA every other day in patients with ME/CFS, including patients with post-acute COVID-19 chronic fatigue syndrome (PACS-CFS), will be evaluated using the validated Chalder Fatigue Scale, a patient-reported outcome measurement. A total of 66 patients will be randomized at a 2:1 ratio: 44 patients will receive IA (active treatment group) and 22 patients will receive a sham apheresis (control group). Moreover, safety, tolerability, and the effect of IA on patient-reported outcome parameters, biomarker-related objectives, cognitive outcome measurements, and physical parameters will be assessed. Patients will be hospitalized at the clinical site from day 1 to day 10 to receive five IA treatments and medical visits. Four follow-up visits (including two visits at site and two visits via telephone call) at month 1 (day 30), 2 (day 60), 4 (day 120), and 6 (day 180; EOS, end of study visit) will take place. DISCUSSION: Although ME/CFS including PACS-CFS causes an immense individual, social, and economic burden, we lack efficient therapeutic options. The present study aims to investigate the efficacy of immunoadsorption and to contribute to the etiological understanding and establishment of diagnostic tools for ME/CFS. TRIAL REGISTRATION: Registration Number: NCT05710770 . Registered on 02 February 2023.

Asunto(s)

COVID-19 , Síndrome de Fatiga Crónica , Humanos , Canadá , COVID-19/terapia , Síndrome de Fatiga Crónica/diagnóstico , Síndrome de Fatiga Crónica/terapia , Pandemias , Síndrome Post Agudo de COVID-19 , Ensayos Clínicos Controlados Aleatorios como Asunto , SARS-CoV-2

RESUMEN

BACKGROUND: Subclinical myocardial injury in form of hs-cTn (high-sensitivity cardiac troponin)  levels has been associated with cognitive impairment and imaging markers of cerebral small vessel disease (SVD) in population-based and cardiovascular cohorts. Whether hs-cTn is associated with domain-specific cognitive decline and SVD burden in patients with stroke remains unknown. METHODS AND RESULTS: We analyzed patients with acute stroke without premorbid dementia from the prospective multicenter DEMDAS (DZNE [German Center for Neurodegenerative Disease]-Mechanisms of Dementia after Stroke) study. Patients underwent neuropsychological testing 6 and 12 months after the index event. Test results were classified into 5 cognitive domains (language, memory, executive function, attention, and visuospatial function). SVD markers (lacunes, cerebral microbleeds, white matter hyperintensities, and enlarged perivascular spaces) were assessed on cranial magnetic resonance imaging to constitute a global SVD score. We examined the association between hs-cTnT (hs-cTn T levels) and cognitive domains as well as the global SVD score and individual SVD markers, respectively. Measurement of cognitive and SVD-marker analyses were performed in 385 and 466 patients with available hs-cTnT levels, respectively. In analyses adjusted for demographic characteristics, cardiovascular risk factors, and cognitive status at baseline, higher hs-cTnT was negatively associated with the cognitive domains "attention" up to 12 months of follow-up (beta-coefficient, -0.273 [95% CI, -0.436 to -0.109]) and "executive function" after 12 months. Higher hs-cTnT was associated with the global SVD score (adjusted odds ratio, 1.95 [95% CI, 1.27-3.00]) and the white matter hyperintensities and lacune subscores. CONCLUSIONS: In patients with stroke, hs-cTnT is associated with a higher burden of SVD markers and cognitive function in domains linked to vascular cognitive impairment. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01334749.

Asunto(s)

Enfermedades de los Pequeños Vasos Cerebrales , Disfunción Cognitiva , Demencia , Enfermedades Neurodegenerativas , Accidente Cerebrovascular , Humanos , Troponina T , Estudios Prospectivos , Enfermedades Neurodegenerativas/complicaciones , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/complicaciones , Cognición , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Enfermedades de los Pequeños Vasos Cerebrales/epidemiología , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Imagen por Resonancia Magnética

RESUMEN

Background: Despite the high prevalence and major disability associated with fatigue and cognitive deficits after SARS-CoV-2 infection, little is known about long-term trajectories of these sequelae. We aimed to assess long-term trajectories of these conditions and to identify risk factors for non-recovery. Methods: We analyzed longitudinal data from the population-based COVIDOM/NAPKON-POP cohort in Germany. Participants with confirmed SARS-CoV-2 infection were assessed at least 6 months (baseline) and again at least 18 months (follow-up) after infection using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale (cutoff ≤ 30) and the Montreal Cognitive Assessment (MoCA, cutoff ≤ 25). Predictors of recovery from fatigue or cognitive deficits between assessments were identified through univariate and multivariable logistic regression models. The COVIDOM study is registered at the German registry for clinical studies (DRKS00023742) and at ClinicalTrials.gov (NCT04679584). Findings: Between 15 November 2020 and 9 May 2023, a total of 3038 participants were assessed at baseline (median 9 months after infection) and 83% responded to invitations for follow-up (median 26 months after infection). At baseline, 21% (95% confidence interval (CI) [20%, 23%]) had fatigue and 23% (95% CI [22%, 25%]) had cognitive deficits according to cutoff scores on the FACIT-Fatigue or MoCA. Participants with clinically relevant fatigue (at baseline) showed significant improvement in fatigue scores at follow-up (Hedges' g [95% CI] = 0.73 [0.60, 0.87]) and 46% (95% CI [41%, 50%]) had recovered from fatigue. Participants with cognitive deficits showed a significant improvement in cognitive scores (g [95% CI] = 1.12 [0.90, 1.33]) and 57% (95% CI [50%, 64%]) had recovered from cognitive deficits. Patients with fatigue exhibiting a higher depressive symptom burden and/or headache at baseline were significantly less likely to recover. Significant risk factors for cognitive non-recovery were male sex, older age and <12 years of school education. Importantly, SARS-CoV-2 reinfection had no significant impact on recovery from fatigue or cognitive deficits. Interpretation: Fatigue and cognitive deficits are common sequelae after SARS-CoV-2 infection. These syndromes improved over time and about half of the patients recovered within two years. The identified risk factors for non-recovery from fatigue and cognitive deficits could play an important role in shaping targeted strategies for treatment and prevention. Funding: Funded by the German Federal Ministry of Education and Research (BMBF; grant number 01KX2121) and German Research Foundation (DFG) Excellence Cluster "Position Medicine in Information".

RESUMEN

The rise of cancer immunotherapy has been a milestone in clinical oncology. Above all, immune checkpoint inhibitor treatment (ICI) with monoclonal antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has improved survival rates for an increasing number of malignancies. However, despite the clinical benefits, ICI-related autoimmunity has become a significant cause of non-relapse-related morbidity and mortality. Neurological immune-related adverse events (irAE-n) are particularly severe toxicities with a high risk for chronic illness, long-term steroid dependency, and early ICI treatment termination. While the clinical characteristics of irAE-n are well described, little is known about underlying immune mechanisms and potential biomarkers. Recently, high frequencies of neuronal autoantibodies in patients with irAE-n have been reported, however, their clinical relevance is unclear. Here, we present a dataset on neuronal autoantibody profiles in ICI-treated cancer patients with and without irAE-n, which was generated to investigate the potential role of neuronal autoantibodies in ICI-induced autoimmunity. Between September 2017 and January 2022 serum samples of 29 cancer patients with irAE-n post-ICI treatment) and 44 cancer control patients without high-grade immune-related adverse events (irAEs, n = 44 pre- and post-ICI treatment) were collected and tested for a large panel of brain-reactive and neuromuscular autoantibodies using indirect immunofluorescence and immunoblot assays. Prevalence of autoantibodies was compared between the groups and correlated with clinical characteristics such as outcome and irAE-n manifestation. These data represent the first systematic comparison of neuronal autoantibody profiles between ICI-treated cancer patients with and without irAE-n, providing valuable information for both researchers and clinicians. In the future, this dataset may be valuable for meta-analyses on the prevalence of neuronal autoantibodies in cancer patients.

RESUMEN

BACKGROUND: Sex differences in presentation, treatment, and prognosis of cardiovascular disorders are well recognized. Although an association between acute myocardial injury and mortality after ischemic stroke has been demonstrated, it is unclear whether prevalence and outcome of poststroke acute myocardial injury differ between women and men. METHODS AND RESULTS: We prospectively screened consecutive patients with acute ischemic stroke and serial high-sensitivity cardiac troponin T measurements admitted to our center. Acute myocardial injury was defined as at least 1 high-sensitivity cardiac troponin T value above the upper reference limit (14 ng/L) with a rise/fall of >20%. Rates of acute myocardial injury were also calculated using sex-specific high-sensitivity cardiac troponin T cutoffs (women upper reference limit, 9 ng/L; men upper reference limit, 16 ng/L). Logistic regression analyses were performed to evaluate the association between acute myocardial injury and outcomes. Of 1067 patients included, 494 were women (46%). Women were older, had a higher rate of known atrial fibrillation, were more likely to be functionally dependent before admission, had higher stroke severity, and more often had cardioembolic strokes (all P values <0.05). The crude prevalence of acute myocardial injury differed by sex (29% women versus 23% men, P=0.024). Statistically significant associations between acute myocardial injury and outcomes were observed in women (7-day in-hospital mortality: adjusted odds ratio [aOR], 3.2 [95% CI, 1.07-9.3]; in-hospital mortality: aOR, 3.3 [95% CI, 1.4-7.6]; modified Rankin Scale score at discharge: aOR, 1.6 [95% CI, 1.1-2.4]) but not in men. The implementation of sex-specific cutoffs did not increase the prognostic value of acute myocardial injury for unfavorable outcomes. CONCLUSIONS: The prevalence of acute myocardial injury after ischemic stroke and its association with mortality and greater disability might be sex-dependent. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03892226.

Asunto(s)

Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Femenino , Humanos , Masculino , Biomarcadores , Pronóstico , Caracteres Sexuales , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Troponina T