Neurodegeneration Biomarkers in Adult Spinal Muscular Atrophy (SMA) Patients Treated with Nusinersen.

The objective of this study is to evaluate biomarkers for neurodegenerative disorders in adult SMA patients and their potential for monitoring the response to nusinersen. Biomarkers for neurodegenerative disorders were assessed in plasma and CSF samples obtained from a total of 30 healthy older adult controls and 31 patients with adult SMA type 2 and 3. The samples were collected before and during nusinersen treatment at various time points, approximately at 2, 6, 10, and 22 months. Using ELISA technology, the levels of total tau, pNF-H, NF-L, sAPPß, Aß40, Aß42, and YKL-40 were evaluated in CSF samples. Additionally, plasma samples were used to measure NF-L and total tau levels using SIMOA technology. SMA patients showed improvements in clinical outcomes after nusinersen treatment, which were statistically significant only in walkers, in RULM (p = 0.04) and HFMSE (p = 0.05) at 24 months. A reduction in sAPPß levels was found after nusinersen treatment, but these levels did not correlate with clinical outcomes. Other neurodegeneration biomarkers (NF-L, pNF-H, total tau, YKL-40, Aß40, and Aß42) were not found consistently changed with nusinersen treatment. The slow progression rate and mild treatment response of adult SMA types 2 and 3 may not lead to detectable changes in common markers of axonal degradation, inflammation, or neurodegeneration, since it does not involve large pools of damaged neurons as observed in pediatric forms. However, changes in biomarkers associated with the APP processing pathway might be linked to treatment administration. Further studies are warranted to better understand these findings.

Geographical distribution of clinical trials in amyotrophic lateral sclerosis: a scoping review.

Introduction: Clinical trials location is determined by many factors, including the availability of patient populations, regulatory environment, scientific expertise, and cost considerations. In clinical drug development of amyotrophic lateral sclerosis (ALS), where genetic differences have been described and may be related to geographic setting, this could have implications for the clinical interpretation of results in underrepresented geographic settings. Objective: The aim of this study was to review country participation in ALS clinical research based on available data from clinical trial registries and databases. Methods: We performed a scoping review with available information about clinical trials on ALS in ClinicalTrials.gov (CT), EU clinical trials register (EudraCT), WHO International Clinical Trials Registry Platform (ICTRP) and Web of Science (WOS). Inclusion criteria were clinical trials in phase 2 and 3 to treat ALS, recruiting or active not recruiting, from 23/06/2018 to 23/06/2023. Results: The total number of clinical trials identified were 188; 54 studies in CT, 38 in EudraCT, 47 in ICTRP and 49 in WOS. We identified 77 clinical trials after deleting duplicates and applying exclusion criteria. The countries with most studies conducted were the US with 35 studies (10.9%), followed by the United Kingdom, Belgium, France and Germany with 21 studies each one of them (6.5%). Conclusion: The data obtained in our review showed a non-homogeneous distribution in clinical trials at the international level, which may influence the interpretation of the results obtained.

Design and Validation of a Clinical Outcome Measure for Adolescents and Adult Patients with Spinal Muscular Atrophy: SMA Life Study Protocol.

INTRODUCTION: The objective of this study is to develop a clinical tool for the evaluation and follow-up of adolescent and adult patients with 5q spinal muscular atrophy (SMA) and to design its validation. METHODS: This prospective, non-interventional study will be carried out at five centres in Spain and will include patients aged 16 years or older with a confirmed diagnosis of 5q SMA (biallelic mutation of the survival motor neuron 1 [SMN1] gene). A panel of experts made up of neurologists, physiatrists and Spanish patients' association (FundAME), participated in the design of the clinical tool. Physicians will administer the tool at three time points (baseline, 12 months and 24 months). Additionally, data from other questionnaires and scales will be collected. Once recruitment is achieved, an interim statistical analysis will be performed to assess its psychometric properties by applying Rasch analysis and classical statistical tests. RESULTS: The tool will consist of up to 53 items to assess functional status from a clinical perspective in seven key dimensions (bulbar, respiratory, axial, lower, upper, fatigability and other symptoms), which will be collected together with objective clinical measures (body mass index, forced vital capacity, pinch strength and 6-minute walk test). CONCLUSIONS: The validation of this tool will facilitate the clinical evaluation of adult and adolescent patients with SMA and the quantification of their response to new treatments in both clinical practice and research.

Clinicopathological correlates in the frontotemporal lobar degeneration-motor neuron disease spectrum.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology.

Expectativas e percepções da mãe quanto ao seu recém-nascido: aplicação do inventário de percepção neonatal de Broussard / Mother's perceptions and expectations regarding their newborn infants: the use of Broussard's neonatal perception inventory

OBJETIVOS: Analisar o Inventário de Percepção Neonatal de Broussard, um instrumento que detecta as percepções e expectativas maternas com respeito aos filhos logo após o parto (Tempo 1) e com um mês de vida (Tempo 2), em puérperas multíparas e primíparas. MÉTODOS: Coorte prospectiva com 27 multíparas e 29 primíparas mães de neonatos a termo saudáveis. Inquiriu-se à mãe no segundo dia pós-parto quanta dificuldade ela esperava que a maioria dos bebês tivesse em relação a chorar, alimentar, regurgitar ou vomitar, evacuar, dormir e ter uma rotina. As respostas foram marcadas em uma escala de 5 pontos. A seguir, repetiam-se as perguntas em relação ao seu filho recém-nascido. Após 30 dias, perguntava-se à mãe quanta dificuldade ela achava que a maioria dos bebês e seu próprio filho apresentavam em relação aos mesmos quesitos. A análise estatística utilizou ANOVA para medidas repe-tidas, considerando os seguintes efeitos principais: tempo, grupo (primíparas e multíparas) e categoria (seu bebê e a maioria dos bebês). RESULTADOS: Logo após o parto, as mães esperavam que seus filhos tivessem menos dificuldade nas atividades avalia-das do que a maioria dos bebês. Essa expectativa se confirmou com 30 dias de vida para todos os comportamentos. Não houve diferenças entre primíparas e multíparas. CONCLUSÕES: O Inventário de Percepção Neonatal de Broussard foi bem entendido e aceito pelas mães, mostrando resultados consistentes neste estudo. O instrumento pode ser útil para triar pares mãe-bebê com dificuldades no estabelecimento de vínculo.

OBJECTIVES: To evaluate Broussard's Neonatal Perception Inventory (BPNI), an instrument to measure the mother's perception and expectations regarding her newborn infant at immediate postpartum and one month afterwards in primiparous and multiparous women. METHODS: Prospective cohort of 27 multiparous and 29 primiparous mothers of healthy newborn infants. In the second day postpartum, mothers were asked about the difficulties they thought that babies would offer regarding specific behaviors: crying, spitting, feeding, elimination, sleeping and predictability. Answers were rated in a 5-point scale. Next, mothers were questioned about their own babies regarding the same items. After 30 days, the mothers were questioned again about her perception of most babies and their own baby regarding the same items. The results were analyzed by repeated measures ANOVA considering the following main effects: time, group (primiparous and mul-tiparous), and subjects (mother's baby and most babies). RESULTS: Following birth, mothers expected their babies to have fewer difficulties in the daily activities than the ma-jority of the babies. These expectations were confirmed one month later for all items. There were no differences between primiparous and multiparous mothers. CONCLUSIONS: The Broussard's Neonatal Perception In-ventory was well understood and accepted by mothers and showed consistent results in this study. It can be used as a screening psychological tool to assess bonding between mothers and infants.

OBJETIVOS: Analizar el Inventario de Percepción Neonatal de Broussard (BNPI - un instrumento que detecta las percepciones y expectativas maternas respecto a los hijos) enseguida al parto (T1) y con un mes de vida (T2), en puér-peras multíparas y primíparas. MÉTODOS: Coorte prospectiva con 27 multíparas y 29 primíparas madres de neonatos a término sanos. Se preguntó a la madre en T1 la dificultad que ella esperaba que la mayoría de los bebés tuviera respecto a llorar, alimentarse, regurgitar o vomitar, evacuar, dormir y tener una rutina. Las respuestas fueron marcadas en una escala de 5 puntos. Enseguida, se repitieron las preguntas respecto a su hijo recién-nacido. En T2, se preguntaba a la madre la dificultad que ella creía que la mayoría de los bebés y su propio hijo presentaban respecto a los mismos requisitos. El análisis estadístico utilizó ANOVA para medidas repetidas, teniendo en cuenta los siguientes efectos principales: tiempo (T1 y T2), grupo (primíparas y multíparas) y categoría (su bebé y la mayoría de los bebés). RESULTADOS: Enseguida al parto, las madres esperaban que sus hijos tuvieran menos dificultad en las actividades evaluadas que la mayoría de los bebés. Esta expectativa se confirmó con 30 días de vida para todos los comportamientos. No hubo diferencias entre primíparas y multíparas. CONCLUSIONES: El BNPI fue bien atendido y aceptado por las madres, mostrando resultados consistentes en este estudio. El instrumento puede ser útil para seleccionar pares madre-bebé con dificultades en el establecimiento de vínculo.