Diagnosing primary lateral sclerosis: a clinico-pathological study.

Background:  Primary lateral sclerosis (PLS) is a rare motor neuron disease characterized by upper motor neuron degeneration, diagnosed clinically due to the absence of a (neuropathological) gold standard. Post-mortem studies, particularly TDP-43 pathology analysis, are limited.

Methods: This study reports on 5 cases in which the diagnostic criteria for PLS were met, but in which neuropathology findings showed (partially) conflicting results.

CACNA1A haploinsufficiency leads to reduced synaptic function and increased intrinsic excitability.

Haploinsufficiency of the CACNA1A gene, encoding the pore-forming α1 subunit of P/Q-type voltage-gated calcium channels, is associated with a clinically variable phenotype ranging from cerebellar ataxia, to neurodevelopmental syndromes with epilepsy and intellectual disability. To understand the pathological mechanisms of CACNA1A loss-of-function variants, we characterized a human neuronal model for CACNA1A haploinsufficiency, by differentiating isogenic induced pluripotent stem cell lines into glutamatergic neurons, and investigated the effect of CACNA1A haploinsufficiency on mature neuronal networks through a combination of electrophysiology, gene expression analysis, and in silico modeling. We observed an altered network synchronization in CACNA1A+/- networks alongside synaptic deficits, notably marked by an augmented contribution of GluA2-lacking AMPA receptors.

Are clinical tests and biomechanical measures of gait stability able to differentiate fallers from non-fallers in hereditary spastic paraplegia?

Introduction: Balance and gait impairments are common in people with hereditary spastic paraplegia (HSP) and often result in falls. Measures that identify patients at risk of falling are clinically relevant, but relatively unexplored in HSP. Here, we evaluated the potential of different balance and gait constructs to (1) identify differences between healthy controls and people with HSP and (2) discriminate between fallers and non-fallers with HSP.

The parkin V380L variant is a genetic modifier of Machado-Joseph disease with impact on mitophagy.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia caused by a polyglutamine-coding CAG repeat expansion in the ATXN3 gene. While the CAG length correlates negatively with the age at onset, it accounts for approximately 50% of its variability only. Despite larger efforts in identifying contributing genetic factors, candidate genes with a robust and plausible impact on the molecular pathogenesis of MJD are scarce.

Cognitive impairment in young adults following cerebellar stroke: Prevalence and longitudinal course.

Introduction: Cognitive impairment is a well-known result of a stroke, but for cerebellar stroke in young patients detailed knowledge on the nature and extent of cognitive deficits is limited. This study examined the prevalence and course of cognitive impairment in a large cohort of patients with cerebellar stroke.

Methods: Sixty young (18-49 years) cerebellar stroke patients completed extensive neuropsychological assessments in the subacute (<9 months post-stroke) and/or chronic phase (≥9 months post-stroke).

A New Case Series Suggests That SCA48 (ATX/STUB1) Is Primarily a Monogenic Disorder.

Background: Monoallelic, pathogenic STUB1 variants cause autosomal dominant cerebellar ataxia (ATX-STUB1/SCA48). Recently, a genetic interaction between STUB1 variants and intermediate or high-normal CAG/CAA repeats in TBP was suggested, indicating digenic inheritance or a disease-modifying role for TBP expansions.

Objective: To determine the presence and impact of intermediate or high-normal TBP expansions in ataxic patients with heterozygous STUB1 variants.

Genetic Interventions for Spinocerebellar Ataxia and Huntington's Disease: A Qualitative Study of the Patient Perspective.

Background: For various genetic disorders characterized by expanded cytosine-adenine-guanine (CAG) repeats, such as spinocerebellar ataxia (SCA) subtypes and Huntington's disease (HD), genetic interventions are currently being tested in different clinical trial phases. The patient's perspective on such interventions should be included in the further development and implementation of these new treatments.

Objective: To obtain insight into the thoughts and perspectives of individuals with SCA and HD on genetic interventions.

Generation of human induced pluripotent stem cell lines (LUMCi051-A,B and LUMCi052-A,B,C) of two patients with Spinocerebellar ataxia type 7.

Spinocerebellar Ataxia Type 7 (SCA7) is an autosomal dominantly inherited disorder, primarily characterized by cerebellar ataxia and visual loss. SCA7 is caused by a CAG repeat expansion in exon 3 of the ATXN7 gene. We generated human induced pluripotent stem cells (hiPSCs) from peripheral blood-derived erythroblasts from two SCA7 patients (LUMCi051-A,B and LUMCi052-A,B,C) using integration-free episomal vectors.

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.

Smartphone applications for Movement Disorders: Towards collaboration and re-use.

Background: Numerous smartphone and tablet applications (apps) are available to monitor movement disorders, but an overview of their purpose and stage of development is missing.

Objectives: To systematically review published literature and classify smartphone and tablet apps with objective measurement capabilities for the diagnosis, monitoring, assessment, or treatment of movement disorders.

Methods: We systematically searched for publications covering smartphone or tablet apps to monitor movement disorders until November 22nd 2023.

Cognitive Complaints and Their Impact on Daily Life in Patients with Degenerative Cerebellar Disorders.

Cognitive and affective sequelae of cerebellar disease are receiving increased attention, but their actual rate of occurrence remains unclear. Complaints may have a significant impact on patients, affecting social behavior and psychological well-being. This study aims to explore the extent of subjective cognitive and affective symptoms in patients with degenerative ataxias in the Netherlands.

Interindividual differences in posterior fossa morphometry affect cerebellar tDCS-induced electric field strength.

Objective: Clinical, behavioural, and neurophysiological effects of cerebellar transcranial direct current stimulation (tDCS) are highly variable and difficult to predict. We aimed to examine associations between cerebellar tDCS-induced electric field strength, morphometric posterior fossa parameters, and skin-cerebellum distance. As a secondary objective, field characteristics were compared between cephalic and extracephalic electrode configurations.

Therapeutic Strategies for Spinocerebellar Ataxia Type 1.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000. The disease is caused by an extended CAG repeat in exon 8 of the gene and is characterized mostly by a profound loss of cerebellar Purkinje cells, leading to disturbances in coordination, balance, and gait. At present, no curative treatment is available for SCA1.

A standardised protocol for blood and cerebrospinal fluid collection and processing for biomarker research in ataxia.

The European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI) is a consortium established with the ambition to set up the largest European longitudinal trial-ready cohort of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD), the most common autosomal dominantly inherited ataxia worldwide. A major focus of ESMI has been the identification of SCA3/MJD biomarkers to enable future interventional studies. As biosample collection and processing variables significantly impact the outcomes of biomarkers studies, biosampling procedures standardisation was done previously to study visit initiation.

Therapeutic Misestimation in Patients with Degenerative Ataxia: Lessons from a Randomized Controlled Trial.

Background: The absence of effective treatments may render patients with degenerative cerebellar ataxias susceptible to a placebo response, which could affect the outcome of clinical trials.

Objective: To retrospectively examine expectations of benefit in participants of an ataxia trial and identify determinants of possible therapeutic misestimation.

Methods: Individuals with spinocerebellar ataxia type 3 who participated in a randomized, double-blind, sham-controlled trial received a custom-designed questionnaire about short-term and long-term treatment expectations, allocation preferences, and interpretation of treatment arm assignment based on the presence or absence of clinical improvement.

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.

Cerebellar transcranial direct current stimulation modulates timing but not acquisition of conditioned eyeblink responses in SCA3 patients.

Background: Delay eyeblink conditioning is an extensively studied motor learning paradigm that critically depends on the integrity of the cerebellum. In healthy individuals, modulation of cerebellar excitability using transcranial direct current stimulation (tDCS) has been reported to alter the acquisition and/or timing of conditioned eyeblink responses (CRs). It remains unknown whether such effects can also be elicited in patients with cerebellar disorders.