Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing.

Hereditary adult-onset ataxias are a heterogeneous group of phenotypically overlapping conditions, often caused by pathogenic expansions of short tandem repeats. Currently, 18 repeat disorders with a core phenotype of adult-onset ataxia are known. Diagnosis typically relies on sequential PCR-based methods, which are labour-intensive and lack precision.

Validation of clinical ratings of cervical dystonia using computer-generated avatars.

Introduction: The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and the Collum-Caput (Col-Cap) concept are tools for clinically assessing cervical dystonia severity. However, the accuracy of human ratings using these scales has not been systematically evaluated due to the lack of objective reference measurements. This study aims to assess and compare the accuracy of human TWSTRS and Col-Cap ratings to evaluate their robustness for clinical and research applications.

The arrow of time in Parkinson's disease.

Background: Parkinson's disease (PD) is a system-level disorder that implicates brain network dynamics across multiple scales. Detecting the 'arrow of time', or temporal reversibility of the brain's information processing flow enables quantification of equilibrium in the brain and inferences on the hierarchical organization. Therefore we aimed to explore disturbances in resting-state equilibrium levels as well as changes in the hierarchical organization due to PD.

-linked Parkinson's disease: Deep phenotyping, MDSGene literature review, and application of SynNeurGe criteria.

Background: The p.Ser71Arg variant is a novel cause of monogenic Parkinson's disease (PD), for which detailed phenotypic information is currently scarce.

Objectives: To clinically and biologically characterize individuals with PARK- to gain insights into genotype-phenotype relationships, disease severity, and underlying pathology.

Deep Brain Stimulation for VPS16-Related Dystonia: A Multicenter Study.

Objective: The objective was to evaluate the effects of deep brain stimulation (DBS) in an international cohort of patients with VPS16-related dystonia.

Methods: This observational study collected preoperative and postoperative demographic, clinical, stimulation, genetic, neuroimaging, and neurophysiological data of medically refractory DYT-VPS16 patients with implanted DBS in 10 international centers. Motor symptoms and disability outcomes were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale Motor (BFMDRS-M) and Disability (BFMDRS-D) scales.

Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large-Scale Exome Sequencing.

Objective: Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (~25%), the etiology in most patients remains elusive. Moreover, understanding correlations between clinical manifestations and genetic variants has become increasingly complex.

Structure-function association of the cerebellar motor network is altered in isolated cervical dystonia.

Background: Cervical dystonia (CD) has been recognized as a disorder of the brain's sensorimotor network. Within this malfunctioning network, the cerebellum plays an important role that needs to be further characterized.

Methods: To investigate the structural connectivity of the dentato-rubro-thalamic tract (DRTT), probabilistic tractography was performed in 18 CD patients and 18 matched healthy control (HC) subjects.

The mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner in mice.

Age is the greatest risk factor for many neurodegenerative diseases, yet immune system aging, a contributor to neurodegeneration, is understudied. Genetic variation in the gene affects risk for both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein is implicated in peripheral immune cell signaling, but the effects of an aging immune system on LRRK2 function remain unclear.

Increased beta synchronization underlies perception-action hyperbinding in functional movement disorders.

Functional movement disorders are amongst the most common and disabling neurological conditions, placing a significant burden on the healthcare system. Despite the frequency and importance of functional movement disorders, our understanding of the underlying pathophysiology is limited, hindering the development of causal treatment options. Traditionally, functional movement disorders were considered as a psychiatric condition, associated with involuntary movements triggered by psychological stressors.

Atrophy of cerebellar lobule VI and primary motor cortex in cervical dystonia - a region of interest-based study.

Background: Recently, a network model of cervical dystonia (CD) has been adopted that implicates nodes and pathways involving cerebellar, basal-ganglia and cortico-cortical connections. Although functional changes in the cerebello-thalamo-cortical network in dystonia have been reported in several studies, structural information of this network remain sparse.

Objective: To characterize the structural properties of the cerebellar motor network in isolated CD patients.

A multi-network model of Parkinson's disease tremor: exploring the finger-dimmer-switch theory and role of dopamine in thalamic self-inhibition.

. Tremor is a cardinal symptom of Parkinson's disease (PD) that manifests itself through complex oscillatory activity across multiple neuronal populations. According to the finger-dimmer-switch (FDS) theory, tremor is triggered by transient pathological activity in the basal ganglia-thalamo-cortical (BTC) network (the finger) and transitions into an oscillatory form within the inner circuitry of the thalamus (the switch).

Premotor cortical beta synchronization and the network neuromodulation of externally paced finger tapping in Parkinson's disease.

Parkinson's disease (PD) is characterized by the disruption of repetitive, concurrent and sequential motor actions due to compromised timing-functions principally located in cortex-basal ganglia (BG) circuits. Increasing evidence suggests that motor impairments in untreated PD patients are linked to an excessive synchronization of cortex-BG activity at beta frequencies (13-30 Hz). Levodopa and subthalamic nucleus deep brain stimulation (STN-DBS) suppress pathological beta-band reverberation and improve the motor symptoms in PD.

A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.

Despite linkage to chromosome 16q in 1996, the mutation causing spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, remained unknown. Here, using long-read single-strand whole-genome sequencing (LR-GS), we identified a heterozygous GGC-repeat expansion in a large Utah pedigree encoding polyglycine (polyG) in zinc finger homeobox protein 3 (ZFHX3), also known as AT-binding transcription factor 1 (ATBF1). We queried 6,495 genome sequencing datasets and identified the repeat expansion in seven additional pedigrees.

DYT-THAP1: exploring gene expression in fibroblasts for potential biomarker discovery.

Dystonia due to pathogenic variants in the THAP1 gene (DYT-THAP1) shows variable expressivity and reduced penetrance of ~ 50%. Since THAP1 encodes a transcription factor, modifiers influencing this variability likely operate at the gene expression level. This study aimed to assess the transferability of differentially expressed genes (DEGs) in neuronal cells related to pathogenic variants in the THAP1 gene, which were previously identified by transcriptome analyses.

Large-Scale Screening: Phenotypic and Mutational Spectrum in Isolated and Combined Dystonia Genes.

Background: Pathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson's disease (PD).

Objectives: To screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes.

The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner.

Considering age is the greatest risk factor for many neurodegenerative diseases, aging, in particular aging of the immune system, is the most underappreciated and understudied contributing factor in the neurodegeneration field. Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein has been implicated in peripheral immune signaling, however, the effects of an aging immune system on LRRK2 function have been neglected to be considered.

Cerebellar Modulation of Sensorimotor Associative Plasticity Is Impaired in Cervical Dystonia.

Background: In recent years, cervical dystonia (CD) has been recognized as a network disorder that involves not only the basal ganglia but other brain regions, such as the primary motor and somatosensory cortex, brainstem, and cerebellum. So far, the role of the cerebellum in the pathophysiology of dystonia is only poorly understood.

Objective: The objective of this study was to investigate the role of the cerebellum on sensorimotor associative plasticity in patients with CD.

Disability and persistent motor deficits are linked to structural crossed cerebellar diaschisis in chronic stroke.

Brain imaging has significantly contributed to our understanding of the cerebellum being involved in recovery after non-cerebellar stroke. Due to its connections with supratentorial brain networks, acute stroke can alter the function and structure of the contralesional cerebellum, known as crossed cerebellar diaschisis (CCD). Data on the spatially precise distribution of structural CCD and their implications for persistent deficits after stroke are notably limited.