Is cerebrospinal fluid amyloid-β42 a promising biomarker of response to nusinersen in adult spinal muscular atrophy patients?

Introduction: Nusinersen was approved as the first treatment for all types of spinal muscular atrophy (SMA), including adults with SMA types 2 and 3. Robust biomarkers of treatment response in SMA adults are lacking. Our aim was to examine cerebrospinal fluid (CSF) amyloid-β40 (Aβ40) and amyloid-β42 (Aβ42) peptides as biomarkers of treatment response. Methods: Eight patients with SMA types 2 and 3 were recruited consecutively in a single-center study. CSF was sampled at baseline, after a loading dose, and after three maintenance doses. Levels of Aβ42 and Aβ40 were evaluated for each CSF sampling. Wilcoxon matched-pairs signed-rank test was used to detect longitudinal changes. Results: CSF levels of Aβ42 increased from baseline to day 420 (95% confidence interval, P =.018), with a significant increase at days 180 and 420 compared with days 0 and 300, respectively (95% confidence interval, P =.012 and P =.018). Discussion: The maintenance and promotion of wellness of residual motor neurons mediated by the restored level of SMN protein due to nusinersen could result in an increased level of amyloid peptides

Non-Destructive Assessment of the Adhesion at the Interface Between FRCM Reinforcements and Masonry Substrates by Non-Linear Ultrasonic Technique

The strong diffusion of Fiber Reinforced Cementitious Matrix (FRCM) composites for the reinforcement of historic masonry constructions requires suitable experimental techniques for assessing possible defects in the adhesion between FRCM and masonry, and between FRCM layers. To this aim, in this paper, an innovative nonlinear ultrasonic approach based on the Side-band Peak Count (SPC) technique is proposed. This approach is discussed and validated through experimental tests made on tuff substrates reinforced with FRCM mortars embedding a basalt fibers grid and having known artificial defects at the adhesion between tuff and FRCM as well as in the fiber gri

Motor-evoked potentials in amyotrophic lateral sclerosis: potential implications in detecting subclinical UMN involvement in lower motor neuron phenotype

Background: In amyotrophic lateral sclerosis (ALS), the involvement of lower motor neuron is well defined by electromyography, whereas a reliable marker of upper motor neuron (UMN) damage still lacks. Aim of the study was to estimate the role of transcranial magnetic stimulation (TMS)-induced motor-evoked potentials (MEPs) as marker of subclinical UMN involvement. Methods: Clinical evidence of UMN damage was prospectively compared to MEPs in 176 ALS patients diagnosed between 2011 and 2014, and classified according to existing diagnostic criteria. Finally, we evaluated the appearance of clinical UMN signs and the level of diagnostic certainty in ALS after 1 year of follow-up. Results: At presentation, abnormal MEPs were found in 80% of patients with clinical evidence of UMN damage and in 72% of patients without clinical involvement of UMN. Among these latter, 61% showed appearance of UMN clinical signs after 1 year. Approximately 70% of patients with clinical lower motor neuron (LMN) phenotype showed MEP abnormalities, while they were considered not classifiable ALS according to Airlie house or Awaji criteria. Furthermore, abnormal MEPs in absence of clinical UMN signs at baseline were found in 80% of spinal ALS that after 1-year developed UMN signs at limbs, compared to 50% of bulbar ALS. Conclusions: TMS is a reliable marker of subclinical UMN damage particularly among LMN phenotype and ensure an early ALS diagnosis in ~ 70% of such cases

Experimental and Numerical Analysis of a FRCM Reinforced Parabolic Tuff Barrel Vault

An experimental and numerical analysis of the structural behaviour of a barrel tuff masonry vault strengthened by a Fiber Reinforced Cementitious Matrix (FRCM) reinforcement system it is proposed. The geometry and the materials of the vault are representative of some historical constructions in Apulia (Italy). The vault, under the action of the self-weight and of a distributed load representative of the infill, has been first damaged by differential settlement of abutments, and then repaired and strengthened by FRCM composites. Finally the structure has been subjected to a increasing concentrated load on the extrados. A 3D heterogeneous FE Abaqus numerical model describing the above mentioned experimental conditions is carried out in order to reproduce the response of the FRCM reinforced vault. The obtained experimental and numerical results allows for discussing the structural behaviour of the reinforced vault, and then the effectiveness of the employed reinforcement

Experimental Data for the Calibration of a Non-Linear Numerical Model for Describing the Response of Masonry Constructions under Cyclic Loading

One of the crucial issues in the still open problem of seismic analyses of masonry constructions is the study of the structural capacity for cyclic loadings; the difficulties are even more pronounced when constructions embedding curved elements like arches, vaults and domes have to be studied. In order to develop effective nonlinear numerical models, the latter have to be capable of representing the relevant aspects of the experimental behavior, and the mechanical parameters of the model have to be carefully calibrated with reference to suitable experimental test results. In this paper the outcomes of experimental tests on a tuff masonry arch under cyclic loading are proposed and discussed, along with the results of experimental tests on the masonry materials (blocks and mortar) aimed at determining the compressive, flexural and shear behavior

Geometric numerical integrators based on the Magnus expansion in bifurcation problems for non-linear elastic solids

We illustrate a procedure based on the Magnus expansion for studying mechanical problems which lead to non-autonomous systems of linear ODE’s. The effectiveness of the Magnus method is enlighten by the analysis of a bifurcation problem in the framework of three-dimensional non-linear elasticity. In particular, for an isotropic compressible elastic tube subject to an azimuthal shear primary deformation we study the possibility of axially periodic twist-like bifurcations. The approximate matricant of the resulting differential problem and the first singular value of the bifurcating load corresponding to a non-trivial bifurcation are determined by employing a simplified version of the Magnus method, characterized by a truncation of the Magnus series after the second term

Cerebrospinal Fluid and Clinical Profiles in Adult Type 2–3 Spinal Muscular Atrophy Patients Treated with Nusinersen: An 18-Month Single-Centre Experience

Background and Objectives: Nusinersen was approved as the first disease-modifying therapy in spinal muscular atrophy (SMA). Our aim was to analyse therapy-related changes in cerebrospinal fluid (CSF) and serum parameters of adult type 2–3 SMA and to correlate biochemical data with motor functional status. Methods: Nine adult SMA type 2–3 patients and ten control subjects without neurodegenerative diseases were included in our single-centre study. Cross-sectional analysis of CSF routine parameters, CSF neurofilament light chain, CSF Tau, CSF phospho-Tau and serum creatinine was performed between SMA patients at baseline (T0) and control subjects. The above-mentioned fluid parameters were longitudinally analysed in the SMA cohort after loading dose (T1) and after four maintenance doses (T2, T3, T4, T5). Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) and the 6-minute walking test (6MWT) were used to evaluate motor outcomes. Results: Improvements in HFMSE, RULM and 6MWT were observed only after the loading dose of nusinersen. No significant differences in routine CSF parameters and CSF markers of neurodegeneration were found between SMA patients and control subjects. Serum creatinine levels were significantly lower in SMA patients than in control subjects. CSF/serum albumin ratio (Qalb) significantly increased from T0 to each time point, without any further increase after the maintenance doses. Persistent systemic oligoclonal bands (OCBs) were found in five patients from baseline. Three more patients developed persistent systemic OCBs from T1; one patient showed intrathecal OCBSs from baseline to T5. Markers of neurodegeneration did not change during the follow-up and did not correlate with motor scores at baseline and at each timepoint. Serum creatinine levels significantly correlated with HFMSE and RULM at each time point. Conclusions: The increase of the Qalb values and the development of systemic OCBs in some SMA patients could be due to repeated lumbar puncture and to the immunogenic effect of nusinersen. On the other hand, the presence of OCBs in serum and/or CSF at baseline should be further investigated. Furthermore, biomarkers of neurodegeneration did not play a prognostic role in our cohort of adult SMA patients

Dynamic Identification of the Damage for a Parabolic Tuff Barrel Vault with Differential Settlements of the Supports

The dynamic identification of structural damage for masonry constructions could play a crucial role for the preservation of architectural heritage. The interest is this experimental technique is motivated both by its non-destructive nature and by the possibility of assessing the damage at an early stage. In this context, this paper studies the damage identification of a full-scale parabolic tuff barrel vault subjected to differential settlements of the supports starting from vibration measurements. The geometry of the vault (polycentric near parabolic shape) and the masonry material (Apulian tuff) have been chosen in order to be representative of some masonry vaults common in rural constructions of Apulia region

Full-scale Dynamic Tests on Unreinforced and GFRCM-reinforced Apulian Tuff Masonry Arches

The study of the dynamic behavior of masonry arches and vaults is of paramount importance for several reasons: the evaluation of the seismic capacity; the determination of failure modes; the determination of the ductility and of behavior factors; the design of effective strengthening interventions, like for example by employing Fiber Reinforced Cementitious Matrix (FRCM) composites. Despite this, the literature still lacks a sufficiently large number of contributions on this subject, especially for what concerns either experimental study or reinforced arches. In this context, this paper, starting from the data of full-scale dynamic tests performed on unreinforced and Glass-FRCM reinforced Apulian tuff masonry arches, proposes some interesting observations on the dynamic behavior of masonry arches