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Background: Neurofilament light chain (NfL) is a validated biofluid marker of neuroaxonal damage with great potential for monitoring patients with neurodegenerative diseases. We aimed to further validate the clinical utility of plasma (p) vs. CSF (c) NfL for distinguishing patients with Amyotrophic Lateral Sclerosis (ALS) from ALS mimics. We also assessed the association of biomarker values with clinical variables and survival and established the longitudinal changes of pNfL during the disease course. Methods: We studied 231 prospectively enrolled patients with suspected ALS who underwent a standardized protocol including neurological examination, electromyography, brain MRI, and lumbar puncture. Patients who received an alternative clinical diagnosis were considered ALS mimics. We classified the patients based on the disease progression rate (DPR) into fast (DPR > 1), intermediate (DPR 0.5–1), and slow progressors (DPR < 0.5). All patients were screened for the most frequent ALS-associated genes. Plasma and CSF samples were retrospectively analyzed; NfL concentrations were measured with the SIMOA platform using a commercial kit. Results: ALS patients ( n = 171) showed significantly higher pNfL ( p < 0.0001) and cNfL ( p < 0.0001) values compared to ALS mimics ( n = 60). Both cNfL and pNfL demonstrated a good diagnostic value in discriminating the two groups, although cNfL performed slightly better (cNfL: AUC 0.924 ± 0.022, sensitivity 86.8%, specificity 92.4; pNfL: AUC 0.873 ± 0.036, sensitivity 84.7%, specificity 83.3%). Fast progressors showed higher cNfL and pNfL as compared to intermediate ( p = 0.026 and p = 0.001) and slow progressors (both p < 0.001). Accordingly, ALS patients with higher baseline cNfL and pNfL levels had a shorter survival (highest tertile of cNfL vs. lowest tertile, HR 4.58, p = 0.005; highest tertile of pNfL vs. lowest tertile, HR 2.59, p = 0.015). Moreover, there were positive associations between cNfL and pNfL levels and the number of body regions displaying UMN signs (rho = 0.325, p < 0.0001; rho = 0.308, p = 0.001). Finally, longitudinal analyses in 57 patients showed stable levels of pNfL during the disease course. Conclusion: Both cNfL and pNfL have excellent diagnostic and prognostic performance for symptomatic patients with ALS. The stable longitudinal trajectory of pNfL supports its use as a marker of drug effect in clinical trials.

Functional Magnetic Resonance Imaging (fMRI) is based on the Blood Oxygenation Level Dependent contrast and has been exploited for the indirect study of the neuronal activity within both the brain and the spinal cord. However, the interpretation of spinal cord fMRI (scfMRI) is still controversial and its adoption is rather restricted because of technical limitations. Overcoming these limitations would have a beneficial effect for the assessment and follow-up of spinal injuries and neurodegenerative diseases. This study was aimed at systematically verifying whether sagittal scanning in scfMRI using EPI readout is a viable alternative to the more common axial scanning, and at optimizing a pipeline for EPI-based scfMRI data analysis, based on Spinal Cord Toolbox (SCT). Forty-five healthy subjects underwent MRI acquisition in a Philips Achieva 3T MRI scanner. T2*-weighted fMRI data were acquired using a GE-EPI sequence along sagittal and axial planes during an isometric motor task. Differences on benchmarks were assessed via paired two-sample t-test at p < 0.05. We investigated the impact of the acquisition strategy by means of various metrics such as Temporal Signal to Noise Ratio (tSNR), Dice Coefficient to assess geometric distortions, Reproducibility and BOLD signal sensitivity to the stimulus. tSNR was higher in axial than in sagittal scans, as well as reproducibility within the whole cord mask (t = 7.4, p < 0.01) and within the GM mask (t = 4.2, p < 0.01). The other benchmarks, associated with distortion and functional response, showed no difference between images obtained along the axial and sagittal planes. Quantitative metrics of data quality suggest that axial scanning would be the optimal choice. We conclude that axial acquisition is advantageous specially to mitigate the effects of physiological noise and to minimize inter-subject variance.

BackgroundAssessing the safety of SARS-CoV-2 mRNA vaccines and the effect of immunotherapies on the seroconversion rate in patients with autoimmune neurological conditions (ANC) is relevant to clinical practice. Our aim was to assess the antibody response to and safety of SARS-CoV-2 mRNA vaccines in ANC.MethodsThis longitudinal study included ANC patients vaccinated with two doses of BNT162b2 or mRNA-1273 between March and August 2021. Side effects were assessed 2–10 days after each dose. Neurological status and anti-spike receptor binding domain antibody levels were evaluated before vaccination and 4 weeks after the second dose. Healthcare-workers served as controls for antibody levels.ResultsWe included 300 ANC patients (median age 52, IQR 40–65), and 347 healthcare-workers (median age 45, IQR 34–54). mRNA-1273 vaccine was associated with an increased risk of both local (OR 2.52 95% CI 1.45–4.39, p = 0.001) and systemic reactions (OR 2.51% CI 1.49–4.23, p = 0.001). The incidence of relapse was not different before and after vaccine (Incidence rate ratio 0.72, 95% CI 0.29–1.83). Anti-SARS-CoV-2 IgG were detected in 268 (89.9%) patients and in all controls (p < 0.0001). BNT162b2 vaccine (OR 8.84 95% CI 2.32–33.65, p = 0.001), anti-CD20 mAb (OR 0.004 95% CI 0.0007–0.026, p < 0.0001) and fingolimod (OR 0.036 95% CI 0.002–0.628, p = 0·023) were associated with an increased risk of not developing anti-SARS-CoV-2 IgG.ConclusionSARS-CoV-2 mRNA vaccines were safe in a large group of ANC patients. Anti-CD20 and fingolimod treatment, as well as vaccination with the BNT162b2 vaccine, led to a reduced humoral response. These findings could inform vaccine policies in ANC patients undergoing immunotherapy.

ObjectivesAim of this study was to investigate the reliability and validity of 2D linear measures of ventricular enlargement as indirect markers of brain atrophy and possible predictors of clinical disability.MethodsIn this retrospective longitudinal analysis of relapsing-remitting MS patients, brain volumes were computed at baseline and after 2 years. Frontal horn width (FHW), intercaudate distance (ICD), third ventricle width (TVW), and 4th ventricle width were obtained. Two-dimensional measures associated with brain volume at correlation analyses were entered in linear and logistic regression models testing the relationship with baseline clinical disability and 10-year confirmed disability progression (CDP), respectively. Possible cutoff values for clinically relevant atrophy were estimated via receiver operating characteristic (ROC) analyses and probed as 10-year CDP predictors using hierarchical logistic regression.ResultsEighty-seven patients were available (61/26 = F/M; 34.1 ± 8.5 years). Moderate negative correlations emerged between ICD and TVW and normalized brain volume (NBV; p < 0.001) and percentage brain volume change per year (PBVC/y) and FHW, ICD, and TVW annual changes (p ≤ 0.005). Baseline disability was moderately associated with NBV, ICD, and TVW (p < 0.001), while PBVC/y predicted 10-year CDP (p = 0.01). A cutoff percentage ICD change per year (PICDC/y) value of 4.38%, corresponding to − 0.91% PBVC/y, correlated with 10-year CDP (p = 0.04). These estimated cutoff values provided extra value for predicting 10-year CDP (PBVC/y: p = 0.001; PICDC/y: p = 0.03).ConclusionsTwo-dimensional measures of ventricular enlargement are reproducible and clinically relevant markers of brain atrophy, with ICD and its increase over time showing the best association with clinical disability. Specifically, a cutoff PICDC/y value of 4.38% could serve as a potential surrogate marker of long-term disability progression.Key Points• Assessment of ventricular enlargement as a rapidly accessible indirect marker of brain atrophy may prove useful in cases in which brain volume quantification is not practicable.• Two-dimensional linear measures of ventricular enlargement represent reliable, valid, and clinically relevant markers of brain atrophy.• A cutoff annualized percentage brain volume change of − 0.91% and the corresponding annualized percentage increase of 4.38% for intercaudate distance are able to discriminate patients who will develop long-term disability progression.

3C-SiC is a promising material for low-voltage power electronic devices but its growth is still challenging. Heteroepitaxy of 3C-SiC on Si micrometer-sized pillars is regarded as a viable method to achieve high crystalline quality, minimizing the effects of lattice and thermal expansion mismatch. Three-dimensional micro-crystals with sharply-faceted profiles are obtained, eventually touching with each other to form a continuous layer, suspended on the underlying pillars. By comparing experimental data and simulation results obtained by a phase-field growth model, here we demonstrate that the evolution of the crystal morphology occurs in a kinetic regime, dominated by the different incorporation times on the crystal facets. These microscopic parameters, effective to characterize the out-of-equilibrium growth process, are estimated by a best-fitting procedure, matching simulation profiles to the experimental one at different deposition stages. Then, simulations are exploited to inspect the role of a different pillar geometry and template effects are recognized. Finally, coalescence of closely spaced crystals ordered into an hexagonal array is investigated. Two possible alignments of the pattern are compared and the most convenient arrangement is evaluated.

La coartazione aortica può associarsi frequentemente con la bicuspidia e, molto più raramente, con la presenza di aneurismi del circolo arterioso cerebrale. Tale associazione sembra essere determinata da un comune substrato patogenetico non ancora dimostrato in maniera inequivocabile.Presentiamo il caso di una paziente di 32 anni con unico precedente anamnestico di soffio cardiaco “funzionale” che, in pieno benessere, ha presentato un quadro di ictus emorragico con dimostrazione angiografica di aneurisma dell’arteria silviana, trattato chirurgicamente. L’angiografia ha evidenziato anche un quadro misconosciuto di coartazione istmica dell’aorta. All’ecocardiogramma era rilevata anche la presenza di una valvola aortica bicuspide. Dopo il recupero clinico-funzionale la paziente è stata sottoposta con successo ad angioplastica dell’aorta con stenting a livello della coartazione.Il caso clinico riportato rientra a pieno titolo in una più ampia sindrome caratterizzata dall’associazione delle tre anomalie sopra descritte, con alcune peculiarità da evidenziare: la diagnosi è stata compiuta in età adulta in seguito ad una grave complicanza; la particolarità del caso clinico consiste, a nostro avviso, nella mancanza in anamnesi di sintomatologia riferibile a cardiopatia e nell’assenza di ipertensione arteriosa nonostante la coartazione, verosimilmente per la coesistenza di un ampio circolo collaterale.Si conferma l’importanza di eseguire sempre uno studio ecocardiografico allargato all’aorta toracica in caso di ictus nel giovane, specie se di tipo emorragico, e si ravvisa l’opportunità di studiare con angiografia cerebrale tutti i pazienti con coartazione aortica.

Aortic coarctation is often linked to bicuspid aortic valve and only rarely to congenital aneurysm of the circle of Willis. It is possible that a common pathogenetic substrate determines this association, but it has not yet been demonstrated. In this report we describe the case of a 32-year-old woman, affected by previous anamnestic functional cardiac murmur. She has suddenly presented a hemorrhagic stroke due to the breaking of the sylvian artery, angiographically demonstrated and surgically corrected. On the same occasion aortic angiography revealed aortic coarctation. Later, an echocardiographic exam demonstrated the coexistence of bicuspid aortic valve. Afterwards the patient underwent angioplasty in order to correct aortic coarctation. Any coexisting cardiac and vascular disease may influence survival in unoperated adults with aortic coarctation, which can even be lethal. In this case the simultaneous presence of these three malformations was particularly dangerous since the patient was not enough symptomatic and so an early diagnosis was not possible. Therefore, we strongly recommend to perform echocardiography in every young patient affected by hemorrhagic stroke and to take into consideration the possibility of performing cerebral angiography in all cases of aortic coarctation.

BACKGROUND: Functional Magnetic Resonance Imaging (fMRI) is based on the Blood Oxygenation Level Dependent contrast and has been exploited for the indirect study of the neuronal activity within both the brain and the spinal cord. However, the interpretation of spinal cord fMRI (scfMRI) is still controversial and its diffusion is rather limited because of technical limitations. Overcoming these limitations would have a beneficial effect for the assessment and follow-up of spinal injuries and neurodegenerative diseases. PURPOSE: This study was aimed at systematically verify whether sagittal scanning in scfMRI using EPI readout is a viable alternative to the more common axial scanning, and at optimizing a pipeline for EPI-based scfMRI data analysis, based on Spinal Cord Toolbox (SCT). METHODS: Forty-five healthy subjects underwent MRI acquisition in a Philips Achieva 3T MRI scanner. T2*-weighted fMRI data were acquired using a GE-EPI sequence along sagittal and axial planes during an isometric motor task. Differences on benchmarks were assessed via paired two-sample t-test at p=0.05. RESULTS: We investigated the impact of the acquisition strategy by means of various metrics such as Temporal Signal to Noise Ratio (tSNR), Dice Coefficient to assess geometric distortions, Reproducibility and Sensitivity. tSNR was higher in axial than in sagittal scans, as well as reproducibility within the whole cord mask (t=7.4, p<0.01) and within the GM mask (t=4.2, p<0.01). The other benchmarks, associated with distortion and functional response, showed no difference between images obtained along the axial and sagittal planes. CONCLUSIONS: Quantitative metrics of data quality suggest that axial scanning would be the optimal choice. We conclude that axial acquisition is advantageous specially to mitigate the effects of physiological noise and to minimize inter-subject variance.

Neural organoids have the potential to improve our understanding of human brain development and neurological disorders. However, it remains to be seen whether these tissues can model circuit formation with functional neuronal output. Here we have adapted air–liquid interface culture to cerebral organoids, leading to improved neuronal survival and axon outgrowth. The resulting thick axon tracts display various morphologies, including long-range projection within and away from the organoid, growth-cone turning, and decussation. Single-cell RNA sequencing reveals various cortical neuronal identities, and retrograde tracing demonstrates tract morphologies that match proper molecular identities. These cultures exhibit active neuronal networks, and subcortical projecting tracts can innervate mouse spinal cord explants and evoke contractions of adjacent muscle in a manner dependent on intact organoid-derived innervating tracts. Overall, these results reveal a remarkable self-organization of corticofugal and callosal tracts with a functional output, providing new opportunities to examine relevant aspects of human CNS development and disease.A modified brain-organoid culture generates extensive axon outgrowth with specific tract-like patterns. Organoid tracts connect neurons across distant sites and can innervate and stimulate co-cultured mouse spinal cord tissue to elicit muscle contractions.

The ANTHEM (Advanced Technologies for Human-centered Medicine) Radio-Frequency Quadrupole (RFQ) will employ eight coaxial power couplers, which will be magnetically coupled to the device through a loop antenna. The coupler design can support up to 140 kW in continuous wave operation. This paper presents the design of the cavity used for high-power testing, with the primary objectives of both optimizing the coupling between the couplers and ensuring operations at the designated operating frequency. Furthermore, the paper encompasses thermal and structural assessments conducted through numerical simulations.