[Discontinuation of psychotropic medication: a critical review of the evidence].

Background: Pharmacotherapy is an effective treatment strategy for psychiatric disorders. Nevertheless, many patients discontinue their medication at some point. Evidence-based practices for patients, clinicians, and policymakers to discontinue psychotropic medication properly are therefore important.

Regional distribution of polymorphisms associated to the disease-causing gene of spinocerebellar ataxia type 3.

Introduction: Knowledge about the distribution and frequency of the respective haplotypes on the wildtype and mutant allele is highly relevant in the context of future gene therapy clinical studies in Spinocerebellar Ataxia Type 3, the most common autosomal dominantly inherited ataxia. Single nucleotide polymorphisms associated to the disease-causing gene, ATXN3, have been determined. We wanted to investigate the frequency and regional distribution of two intragenic single nucleotide polymorphisms (SNPs) in a large European SCA3 cohort and their relation to the clinical phenotype.

From Critical Raw Materials to Circular Raw Materials.

This perspective addresses the key challenge of advancing the use of Critical Raw Materials (CRMs) and proposes a transition towards circular raw material management. In the context of our current economy, the unsustainable consumption, environmental degradation, geopolitical risks, and economic vulnerabilities associated with CRMs highlight the limitations in ensuring long-term CRM availability, emphasizing the environmental, social, and economic implications. In response, this perspective underlines a multifaceted technological approach to mitigate CRM criticality, focusing on reducing CRM use, substituting CRMs with less critical materials, and enhancing recovery and recycling processes, with Design for Circularity as the most impactful solution.

Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy.

Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers.

Mechanistic studies on single-electron transfer in frustrated Lewis pairs and its application to main-group chemistry.

Advances in the field of frustrated Lewis pair (FLP) chemistry have led to the discovery of radical pairs, obtained by a single-electron transfer (SET) from the Lewis base to the Lewis acid. Radical pairs are intriguing for their potential to enable cooperative activation of challenging substrates (, CH, N) in a homolytic fashion, as well as the exploration of novel radical reactions. In this review, we will cover the two known mechanisms of SET in FLPs-thermal and photoinduced-along with methods (, CV, DFT, UV-vis) to predict the mechanism and to characterise the involved electron donors and acceptors.

Discontinuation of psychotropic medication: a synthesis of evidence across medication classes.

Pharmacotherapy is an effective treatment modality across psychiatric disorders. Nevertheless, many patients discontinue their medication at some point. Evidence-based guidance for patients, clinicians, and policymakers on rational discontinuation strategies is vital to enable the best, personalized treatment for any given patient.

Genotype-specific spinal cord damage in spinocerebellar ataxias: an ENIGMA-Ataxia study.

Background: Spinal cord damage is a feature of many spinocerebellar ataxias (SCAs), but well-powered in vivo studies are lacking and links with disease severity and progression remain unclear. Here we characterise cervical spinal cord morphometric abnormalities in SCA1, SCA2, SCA3 and SCA6 using a large multisite MRI dataset.

Methods: Upper spinal cord (vertebrae C1-C4) cross-sectional area (CSA) and eccentricity (flattening) were assessed using MRI data from nine sites within the ENIGMA-Ataxia consortium, including 364 people with ataxic SCA, 56 individuals with preataxic SCA and 394 nonataxic controls.

Cerebellar Volumetry in Ataxias: Relation to Ataxia Severity and Duration.

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C).

Cerebellar volumetry in ataxias: Relation to ataxia severity and duration.

Background: Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C).

Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3/Machado-Joseph disease is the most common autosomal dominant ataxia. In view of the development of targeted therapies, knowledge of early biomarker changes is needed. We analyzed cross-sectional data of 292 spinocerebellar ataxia type 3/Machado-Joseph disease mutation carriers.

Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.

Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34).

Stage-dependent biomarker changes in spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3) is the most common autosomal dominant ataxia. In view of the development of targeted therapies for SCA3, precise knowledge of stage-dependent fluid and MRI biomarker changes is needed. We analyzed cross-sectional data of 292 SCA3 mutation carriers including 57 pre-ataxic individuals, and 108 healthy controls from the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) cohort.

CerebNet: A fast and reliable deep-learning pipeline for detailed cerebellum sub-segmentation.

Quantifying the volume of the cerebellum and its lobes is of profound interest in various neurodegenerative and acquired diseases. Especially for the most common spinocerebellar ataxias (SCA), for which the first antisense oligonculeotide-base gene silencing trial has recently started, there is an urgent need for quantitative, sensitive imaging markers at pre-symptomatic stages for stratification and treatment assessment. This work introduces CerebNet, a fully automated, extensively validated, deep learning method for the lobular segmentation of the cerebellum, including the separation of gray and white matter.

Digital Gait Biomarkers Allow to Capture 1-Year Longitudinal Change in Spinocerebellar Ataxia Type 3.

Measures of step variability and body sway during gait have shown to correlate with clinical ataxia severity in several cross-sectional studies. However, to serve as a valid progression biomarker, these gait measures have to prove their sensitivity to robustly capture longitudinal change, ideally within short time frames (eg, 1 year). We present the first multicenter longitudinal gait analysis study in spinocerebellar ataxias.

Differential Temporal Dynamics of Axial and Appendicular Ataxia in SCA3.

Background: Disease severity in spinocerebellar ataxia type 3 (SCA3) is commonly defined by the Scale for the Assessment and Rating of Ataxia (SARA) sum score, but little is known about the contributions and progression patterns of individual items.

Objectives: To investigate the temporal dynamics of SARA item scores in SCA3 patients and evaluate if clinical and demographic factors are differentially associated with evolution of axial and appendicular ataxia.

Methods: In a prospective, multinational cohort study involving 11 European and 2 US sites, SARA scores were determined longitudinally in 223 SCA3 patients with a follow-up assessment after 1 year.

Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood.

Background: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers.

Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3.

Background: Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity.

Objective: The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease.

Methods: We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls.

The Phenotypic Spectrum of PNKP-Associated Disease and the Absence of Immunodeficiency and Cancer Predisposition in a Dutch Cohort.

Background: We aimed to expand the number of currently known pathogenic PNKP mutations, to study the phenotypic spectrum, including radiological characteristics and genotype-phenotype correlations, and to assess whether immunodeficiency and increased cancer risk are part of the DNA repair disorder caused by mutations in the PNKP gene.

Methods: We evaluated nine patients with PNKP mutations. A neurological history and examination was obtained.

A hereditary spastic paraplegia predominant phenotype caused by variants in the NEFL gene.

Introduction: This study reports a large series of patients with a clinical picture dominated by spastic paraplegia in whom variants in the NEFL gene, a known cause for Charcot-Marie-Tooth disease, were identified.

Methods: Index patients referred for a suspicion of hereditary spastic paraplegia (HSP) were clinically assessed and genetic analysis by next-generation sequencing was undertaken. Additional family members were clinically examined and subjected to targeted testing.

Inclusion body myositis in patients with spinocerebellar ataxia types 3 and 6.

Objectives: To describe the combination of spinocerebellar ataxia (SCA) types 3 and 6 and sporadic inclusion body myositis (IBM).

Methods: A description of five patients with SCA type 3 and 6 who were diagnosed with IBM. We explore possible mechanisms explaining the coexistence of both diseases.

Sjögren-Larsson syndrome: The mild end of the phenotypic spectrum.

Sjögren-Larsson syndrome (SLS) is a rare inborn error of lipid metabolism. The syndrome is caused by mutations in the gene, resulting in a deficiency of fatty aldehyde dehydrogenase. Most patients have a clearly recognizable severe phenotype, with congenital ichthyosis, intellectual disability, and spastic diplegia.

Classic ataxia-telangiectasia: the phenotype of long-term survivors.

Objective: Patients with classic ataxia-telangiectasia (A-T) generally die in the second or third decade of life. Clinical descriptions of A-T tend to focus on the symptoms at presentation. However, during the course of the disease, other symptoms and complications emerge.

KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.

Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia.