Dysregulated Cerebrospinal Fluid Proteome of Spinocerebellar Ataxia Type 2 and its Clinical Implications.

BACKGROUND: Abnormalities in ataxin-2 associated with spinocerebellar ataxia type 2 (SCA2) may lead to widespread disruptions in the proteome. This study was performed to identify dysregulated proteome in SCA2 and to explore its clinical-radiological correlations. METHODS: Cerebrospinal fluid (CSF) samples from 21 genetically confirmed SCA2 were subjected to shotgun proteome analysis using mass spectrometry (MS) and tandem mass tag (TMT)-based multiplexing. Proteins with at least 1.5-fold change in abundance were identified. Their relative abundance was measured using parallel reaction monitoring (PRM) and correlated against disease-related factors. RESULTS: Eleven proteins were significantly upregulated in SCA2. They belonged to the family of cell adhesion molecules and granins. Their fold changes showed significant clinical, genetic, and radiological correlations. CONCLUSIONS: Significant dysregulation of CSF proteome is seen in SCA2. The dysregulated protein may have potential use in clinical evaluation of patients with SCA2. © 2024 International Parkinson and Movement Disorder Society.

Structural Brain Correlates of Sleep Microstructure in Spinocerebellar Ataxia Type 2 and its Role on Clinical Phenotype.

The influence of brain atrophy on sleep microstructure in Spinocerebellar Ataxias (SCAs) has not been extensively explored limiting the use of these sleep traits as surrogate biomarkers of neurodegeneration and clinical phenotype. The objective of the study is to explore the relationship between sleep microstructure and brain atrophy in SCA2 and its role in the clinical phenotype. Fourteen SCA2 mutation carriers (7 pre-manifest and 7 manifest subjects) underwent polysomnographic, structural MRI, and clinical assessments. Particularly, markers of REM and non-REM sleep microstructure, measures of cerebellar and brainstem atrophy, and clinical scores were analyzed through correlation and mediation analyses. The sleep spindle activity exhibited a negative correlation with the number of trials required to complete the verbal memory test (VMT), and a positive correlation with the cerebellar volume, but the significance of the latter correlation did not survive multiple testing corrections. However, the causal mediation analyses unveiled that sleep spindle activity significantly mediates the association between cerebellar atrophy and VMT performance. Regarding REM sleep, both phasic EMG activity and REM sleep without atonia exhibited significant associations with pontine atrophy and disease severity measures. However, they did not demonstrate a causal mediation effect between the atrophy measures and disease severity. Our study provides evidence about the association of the pontocerebellar atrophy with sleep microstructure in SCA2 offering insights into the cerebellar involvement in cognition via the control of the sleep spindle activity. Therefore, our findings may help to understand the disease pathogenesis and to better characterize sleep microstructure parameters as disease biomarkers.Clinical trial registration number (TRN): No applicable.

Serum S100ß Levels Are Linked with Cognitive Decline and Peripheral Inflammation in Spinocerebellar Ataxia Type 2.

Experimental and clinical studies have indicated a potential role of the protein S100ß in the pathogenesis and phenotype of neurodegenerative diseases. However, its impact on spinocerebellar ataxia type 2 (SCA2) remains to be elucidated. The objective of the study is to determine the serum levels of S100ß in SCA2 and its relationship with molecular, clinical, cognitive, and peripheral inflammatory markers of the disease. Serum concentrations of S100ß were measured by enzyme-linked immunosorbent assay in 39 SCA2 subjects and 36 age- and gender-matched controls. Clinical scores of ataxia, non-ataxia symptoms, cognitive dysfunction, and some blood cell count-derived inflammatory indices were assessed. The SCA2 individuals manifested S100ß levels similar to the control group, at low nanomolar concentrations. However, the S100ß levels were directly associated with a better performance of cognitive evaluation within the SCA2 cohort. Moreover, the S100ß levels were inversely correlated with most peripheral inflammatory indices. Indeed, the neutrophil-to-lymphocyte ratio significantly mediated the effect of serum S100ß on cognitive performance, even after controlling for the ataxia severity in the causal mediation analysis. Our findings suggested that, within physiologic concentrations, the protein S100ß exerts a neuroprotective role against cognitive dysfunction in SCA2, likely via the suppression of pro-inflammatory mechanisms.

Progressive white matter degeneration in patients with spinocerebellar ataxia type 2.

PURPOSE: Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder characterized by cerebellar atrophy. However, studies to elucidate the longitudinal progression of the neuropathology are limited. We sought to identify brain macrostructural and microstructural alterations in patients with SCA2 using fixel-based analysis (FBA) to better understand its distribution patterns and progression. METHODS: We enrolled 9 patients with SCA2 and 16 age- and gender-matched controls. Longitudinal clinical and imaging data were collected at baseline, and 3.5 years later. Fiber density (FD), fiber-bundle cross-section (FC), and a combination of FD and FC (FDC) were calculated. The paired t-test was used to examine longitudinal differences. The associations between fixel-based metrics and clinical variables were explored in SCA2 patients. RESULTS: At baseline, patients with SCA2 displayed multiple white matter tracts with significantly decreased FD, FC, and FDC in the corticospinal tract, cerebellar peduncles, brainstem, corpus callosum, thalamus, striatum, and prefrontal cortex, compared to controls. Over time, many of these macrostructural and microstructural alterations progressed, manifesting lower FD, FC, and FDC in corticospinal tract, middle cerebellar peduncle, brainstem, striatum, fornix, and cingulum. No significant brain white matter alterations were found in the healthy controls over time. There was no association between the FBA-derived metrics and clinical variables in SCA2. CONCLUSION: This study provides evidence of brain macrostructural and microstructural alterations and of progression over time in SCA2. The FBA-derived metrics may serve as potential biomarkers of SCA2 progression.

Optic Disc and Retinal Architecture Changes in Patients with Spinocerebellar Ataxia Type 2.

BACKGROUND: ATXN2 is the causative gene of spinocerebellar ataxia type 2 (SCA2) and has been implicated in glaucoma pathogenesis. Therefore, studying ocular changes in SCA2 could uncover clinically relevant changes. OBJECTIVE: The aim was to investigate optic disc and retinal architecture in SCA2. METHODS: We evaluated 14 patients with SCA2 and 26 controls who underwent intraocular pressure measurement, fundoscopy, and macular and peripapillary spectral domain optical coherence tomography (SD-OCT). We compared SD-OCT measurements in SCA2 and controls, and the frequency of glaucomatous changes among SCA2, controls, and 76 patients with other SCAs (types 1, 3, 6, and 7). RESULTS: The macula, peripapillary retinal nerve fiber and inner plexiform layers were thinner in SCA2 than in controls. Increased cup-to-disc ratio was more frequent in SCA2 than in controls and other SCAs. CONCLUSIONS: Ocular changes are part of SCA2 phenotype. Future studies should further investigate retinal and optic nerve architecture in this disorder.

A model for the dynamics of expanded CAG repeat alleles: ATXN2 and ATXN3 as prototypes.

Background: Spinocerebellar ataxia types 2 (SCA2) and 3 (SCA3/MJD) are diseases due to dominant unstable expansions of CAG repeats (CAGexp). Age of onset of symptoms (AO) correlates with the CAGexp length. Repeat instability leads to increases in the expanded repeats, to important AO anticipations and to the eventual extinction of lineages. Because of that, compensatory forces are expected to act on the maintenance of expanded alleles, but they are poorly understood. Objectives: we described the CAGexp dynamics, adapting a classical equation and aiming to estimate for how many generations will the descendants of a de novo expansion last. Methods: A mathematical model was adapted to encompass anticipation, fitness, and allelic segregation; and empirical data fed the model. The arbitrated ancestral mutations included in the model had the lowest CAGexp and the highest AO described in the literature. One thousand generations were simulated until the alleles were eliminated, fixed, or 650 generations had passed. Results: All SCA2 lineages were eliminated in a median of 10 generations. In SCA3/MJD lineages, 593 were eliminated in a median of 29 generations. The other ones were eliminated due to anticipation after the 650th generation or remained indefinitely with CAG repeats transitioning between expanded and unexpanded ranges. Discussion: the model predicted outcomes compatible with empirical data - the very old ancestral SCA3/MJD haplotype, and the de novo SCA2 expansions -, which previously seemed to be contradictory. This model accommodates these data into understandable dynamics and might be useful for other CAGexp disorders.

COVID-19 Impacts the Mental Health and Speech Function in Spinocerebellar Ataxia Type 2: Evidences from a Follow-Up Study.

Limited evidence suggests that the SARS-CoV-2 infection can accelerate the progression of neurodegenerative diseases, but this has been not verified in the spinocerebellar ataxias (SCA). The objective of this study is to assess the impact of COVID-19 on the mental health and motor features of SCA2. A follow-up study was carried out in 170 Cuban SCA2 subjects and 87 community controls between 2020 and 2021. All subjects underwent a structured questionnaire to assess the risks of exposure to COVID-19, the confirmation of COVID-19 diagnosis, and the Hospital Anxiety and Depression Scale (HADS). Moreover, 36 subjects underwent the Scale for the Assessment and Rating of ataxia (SARA). The risk of exposure to SARS-CoV-2 and the frequency of COVID-19 were similar between the ataxia cohort and the community controls. Within the ataxia group, significantly increased HADS scores existed at the 2nd visit in both groups, but this increase was more evident for the infected group regarding the depression score. Moreover, a significant within-group increase of SARA score was observed in the infected group but not the non-infected group, which was mainly mediated by the significant increase of the speech item score in the infected group. Similar results were observed within the subgroup of preclinical carriers. Our study identified no selective vulnerability nor protection to COVID-19 in SCA2, but once infected, the patients experienced a deterioration of mental health and speech function, even at preclinical disease stage. These findings set rationales for tele-health approaches that minimize the detrimental effect of COVID-19 on SCA2 progression and identify SCA2 individuals as clinical model to elucidate the link between SARS-CoV-2 infection and neurodegeneration.

Signo de la cruz en una paciente peruana con ataxia espinocerebelosa tipo 2: reporte de un caso / Hot cross bun sign in a Peruvian patient with spinocerebellar ataxia type 2: A case report

RESUMEN La ataxia espinocerebelosa tipo 2 (SCA2) es una enfermedad neurodegenerativa hereditaria autosómica dominante, causada por una expansión anormal del trinucleótido CAG en el gen ATXN2. La SCA2 se presenta habitualmente en la edad adulta, con ataxia progresiva asociada a neuropatía periférica, alteración de movimientos oculares, parkinsonismo, entre otros síntomas. Exámenes auxiliares aplicables incluyen pruebas bioquímicas, neuroimágenes, como resonancia magnética cerebral, y estudio genético molecular. Describimos, por primera vez en la población peruana, el caso de una mujer de mediana edad con diagnóstico confirmado de SCA2, cuya resonancia magnética cerebral muestra el signo de la cruz (o hot cross bun sign).

ABSTRACT Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant inherited neurodegenerative disease, caused by an abnormal CAG trinucleotide expansion in the ATXN2 gene. SCA2 usually occurs in adulthood, with progressive ataxia associated with peripheral neuropathy, impaired eye movements, parkinsonism, and other symptoms. Auxiliary exams include biochemical tests, neuroimaging such as brain MRI, and a molecular genetic study. We describe, for the first time in the Peruvian population, the case of a middle-aged woman with a confirmed diagnosis of SCA2, whose brain MRI shows the "Hot Cross Bun Sign".

TR-FRET-Based Immunoassay to Measure Ataxin-2 as a Target Engagement Marker in Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease, which belongs to the trinucleotide repeat disease group with a CAG repeat expansion in exon 1 of the ATXN2 gene resulting in an ataxin-2 protein with an expanded polyglutamine (polyQ)-stretch. The disease is late manifesting leading to early death. Today, therapeutic interventions to cure the disease or even to decelerate disease progression are not available yet. Furthermore, primary readout parameter for disease progression and therapeutic intervention studies are limited. Thus, there is an urgent need for quantifiable molecular biomarkers such as ataxin-2 becoming even more important due to numerous potential protein-lowering therapeutic intervention strategies. The aim of this study was to establish a sensitive technique to measure the amount of soluble polyQ-expanded ataxin-2 in human biofluids to evaluate ataxin-2 protein levels as prognostic and/or therapeutic biomarker in SCA2. Time-resolved fluorescence energy transfer (TR-FRET) was used to establish a polyQ-expanded ataxin-2-specific immunoassay. Two different ataxin-2 antibodies and two different polyQ-binding antibodies were validated in three different concentrations and tested in cellular and animal tissue as well as in human cell lines, comparing different buffer conditions to evaluate the best assay conditions. We established a TR-FRET-based immunoassay for soluble polyQ-expanded ataxin-2 and validated measurements in human cell lines including iPSC-derived cortical neurons. Additionally, our immunoassay was sensitive enough to monitor small ataxin-2 expression changes by siRNA or starvation treatment. We successfully established the first sensitive ataxin-2 immunoassay to measure specifically soluble polyQ-expanded ataxin-2 in human biomaterials.

Peripheral Inflammation Links with the Severity of Clinical Phenotype in Spinocerebellar Ataxia 2.

BACKGROUND: The role of peripheral inflammation in spinocerebellar ataxia type 2 (SCA2) is unknown. OBJECTIVE: The objective of this study was to identify peripheral inflammation biomarkers and their relationship with the clinical and molecular features. METHODS: Blood cell count-derived inflammatory indices were measured in 39 SCA2 subjects and their matched controls. Clinical scores of ataxia, nonataxia, and cognitive dysfunction were assessed. RESULTS: The neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the Systemic Inflammation Index (SII), and the Aggregate Index of Systemic Inflammation (AISI) were significantly increased in SCA2 subjects compared with controls. The increases in PLR, SII, and AISI were even observed in preclinical carriers. NLR, PLR, and SII were correlated with the Scale for the Assessment and Rating of Ataxia speech item score rather than with the total score. The NLR and SII were correlated with the nonataxia and the cognitive scores. CONCLUSIONS: Peripheral inflammatory indices are biomarkers in SCA2, which may help to design future immunomodulatory trials and advance our understanding of the disease. © 2023 International Parkinson and Movement Disorder Society.

The "Hot Cross Bun Sign" in Spinocerebellar Ataxia Types 2 and 7-Case Reports and Review of Literature.

Background: The "hot cross bun" sign is a cruciform hyperintensity is seen on T2 weighted imaging within the pons. The sign is considered to be pathognomic for Multiple system atrophy type C. The clinical and radiological features of Multiple system atrophy type C overlap with the autosomal dominant inherited ataxias. We present a case series of 3 African patients with genetically proven Spinocerebellar Ataxia presenting with the Hot cross bun sign and a scoping review of similar studies. Cases: We described the phenotypic and radiological presentation of genetically confirmed SCA-2 in two, and SCA-7 in one patient, with the "hot cross bun" sign. Literature Review: We performed a scoping review on the Hot Cross Bun Sign.A total of 66 articles were retrieved. We describe the diverse aetiologies of the sign and associated phenotypic and radiological features. We review the Spinocerebellar Ataxias described with a Hot cross bun sign and make comparisons to Multiple System Atrophy Type C [Ref. 1,2]. Conclusions: To our knowledge this is the first description of an African cohort presenting with the Hot Cross Bun Sign. We expand the differential diagnosis of the Hot Cross Bun Sign.

Mutant Ataxin-2 Expression in Aged Animals Aggravates Neuropathological Features Associated with Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is a rare autosomal, dominantly inherited disease, in which the affected individuals have a disease onset around their third life decade. The molecular mechanisms underlying SCA2 are not yet completely understood, for which we hypothesize that aging plays a role in SCA2 molecular pathogenesis. In this study, we performed a striatal injection of mutant ataxin-2 mediated by lentiviral vectors, in young and aged animals. Twelve weeks post-injection, we analyzed the striatum for SCA2 neuropathological features and specific aging hallmarks. Our results show that aged animals had a higher number of mutant ataxin-2 aggregates and more neuronal marker loss, compared to young animals. Apoptosis markers, cleaved caspase-3, and cresyl violet staining also indicated increased neuronal death in the aged animal group. Additionally, mRNA levels of microtubule-associated protein 1 light-chain 3B (LC3) and sequestosome-1 (SQSTM1/p62) were altered in the aged animal group, suggesting autophagic pathway dysfunction. This work provides evidence that aged animals injected with expanded ataxin-2 had aggravated SCA2 disease phenotype, suggesting that aging plays an important role in SCA2 disease onset and disease progression.

Curso optativo sobre ataxia espinocerebelosa tipo 2 en la Universidad de Ciencias Médicas de Holguín

Introducción: Recientemente inició la formación de profesionales en una nueva modalidad de Programas Técnico Superior de Ciclo Corto en la especialidad Neurofisiología Clínica, en la Universidad de Ciencias Médicas de Holguín, atendiendo a la alta incidencia de enfermedades neurológicas, como la ataxia espinocerebelosa tipo 2, que constituye un serio problema de salud en Cuba. Un programa de curso optativo que aborde esta temática, contribuye al conocimiento de esta enfermedad para su investigación y posibles tratamientos. Objetivo: Diseñar un programa de curso optativo sobre diagnóstico e intervención físico-terapéutica en la fase prodrómica de la ataxia espinocerebelosa tipo 2 para estudiantes de Neurofisiología Clínica Primer Año en la Facultad de Enfermería ¨Arides Estévez Sánchez¨ de Holguín. Método: Se realizó una investigación didáctica metodológica utilizando los métodos empíricos: observación; teóricos: histórico-lógico, estudio documental, dialéctico; análisis-síntesis e inducción-deducción. Resultados: Se propuso un programa para curso optativo basado en la búsqueda de información científica y métodos empíricos, el cual fue estructurado en cuatro temas, con carácter presencial y duración de 24 horas. Se presentaron los contenidos por temas, objetivos, conocimientos esenciales a adquirir, habilidades principales a dominar y sistema de evaluación. Conclusiones: La aplicación de este programa contribuye a desarrollar habilidades en los profesionales en formación, en el conocimiento de la fase prodrómica de esta enfermedad.

Introduction: It recently began the training of professionals in a new modality of Programas Técnico Superior de Ciclo Corto (Short Cycle Superior Technical Programs) in the Clinical Neurophysiology specialty, at the Universidad de Ciencias Médicas de Holguín, attending to the high incidence of neurological diseases, such as spinocerebellar ataxia type 2, which constitutes a serious health problem in Cuba. This is an elective course program that addresses this topic and contributes to the knowledge of this disease, in order to improve research and possible treatments. Objective: To design an elective course program on diagnosis and physical-therapeutic intervention in the prodromal phase of spinocerebellar ataxia type 2 for first year Clinical Neurophysiology students at the ¨Arides Estévez Sánchez¨ School of Nursing in Holguín. Method: A methodological didactic research was carried out using the empirical methods: observation; theoretical: historical-logical, documentary study, dialectical; analysis-synthesis and induction-deduction. Results: A program was proposed for an optional course, based on the search for scientific information and empirical methods, which was structured in four themes, in face-to-face modality and with a duration of 24 hours. The contents were presented by themes, objectives, essential knowledge to acquire, main skills to master and evaluation system. Conclusions: The application of this program contributes to developing skills in training professionals, in the knowledge of the prodromal phase of this disease.

Introdução: Iniciou-se recentemente a formação de profissionais em uma nova modalidade de Programas Técnicos Superiores de Ciclo Curto na especialidade de Neurofisiologia Clínica, na Universidad de Ciencias Médicas de Holguín, atendendo à alta incidência de doenças neurológicas, como a ataxia espinocerebelar tipo 2, que constitui um grave problema de saúde em Cuba. Um programa de disciplina eletiva que aborde esse tema contribui para o conhecimento dessa doença para sua investigação e possíveis tratamentos. Objetivo: Elaborar um programa de disciplina eletiva sobre diagnóstico e intervenção fisioterapêutica na fase prodrômica da ataxia espinocerebelar tipo 2 para alunos do primeiro ano de Neurofisiologia Clínica da Escola de Enfermagem ¨Arides Estévez Sánchez¨ de Holguín. Método: Foi realizada uma pesquisa didática metodológica utilizando os métodos empíricos: observação; teórico: histórico-lógico, estudo documental, dialético; análise-síntese e indução-dedução. Resultados: Foi proposto um programa para um curso opcional baseado na busca de informações científicas e métodos empíricos, o qual foi estruturado em quatro temas, com caráter presencial e duração de 24 horas. Os conteúdos foram apresentados por temas, objetivos, conhecimentos essenciais a adquirir, principais competências a dominar e sistema de avaliação. Conclusões: A aplicação deste programa contribui para o desenvolvimento de competências nos profissionais em formação, no conhecimento da fase prodrómica desta doença.

"Mens Sana in Corpore Sano": The Emerging Link of Motor Reserve with Motor and Cognitive Abilities and Compensatory Brain Networks in SCA2 Patients.

The ability to resiliently cope with neuropathological lesions is a key scientific concern. Accordingly, this study aims to investigate whether motor reserve (MR), likely to be boosted by exercise engagement in a lifetime, affects motor symptom severity, cognitive functioning, and functional brain networks in spinocerebellar ataxia type 2 (SCA2)-a cerebellar neurodegenerative disease. The MR of 12 SCA2 patients was assessed using the Motor Reserve Index Questionnaire (MRIq), developed ad hoc for estimating lifespan MR. The International Cooperative Ataxia Rating Scale was used to assess clinical motor features, and neuropsychological tests were used to evaluate cognitive functioning. Patients underwent an MRI examination, and network-based statistics (NBS) analysis was carried out to detect patterns of functional connectivity (FC). Significant correlations were found between MRIq measures and the severity of motor symptoms, educational and intellectual levels, executive function, and processing speed. NBS analysis revealed a higher FC within subnetworks consisting of specific cerebellar and cerebral areas. FC patterns were positively correlated with MRIq measures, likely indicating the identification of an MR network. The identified network might reflect a biomarker likely to underlie MR, influenced by education and cognitive functioning, and impacting the severity of motor symptoms.

A quantitative high-throughput screen identifies compounds that lower expression of the SCA2-and ALS-associated gene ATXN2.

CAG repeat expansions in the ATXN2 (ataxin-2) gene can cause the autosomal dominant disorder spinocerebellar ataxia type 2 (SCA2) as well as increase the risk of ALS. Abnormal molecular, motor, and neurophysiological phenotypes in SCA2 mouse models are normalized by lowering ATXN2 transcription, and reduction of nonmutant Atxn2 expression has been shown to increase the life span of mice overexpressing the TDP-43 (transactive response DNA-binding protein 43 kDa) ALS protein, demonstrating the potential benefits of targeting ATXN2 transcription in humans. Here, we describe a quantitative high-throughput screen to identify compounds that lower ATXN2 transcription. We screened 428,759 compounds in a multiplexed assay using an ATXN2-luciferase reporter in human embryonic kidney 293 (HEK-293) cells and identified a diverse set of compounds capable of lowering ATXN2 transcription. We observed dose-dependent reductions of endogenous ATXN2 in HEK-293 cells treated with procillaridin A, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), and heat shock protein 990 (HSP990), known inhibitors of HSP90 and Na+/K+-ATPases. Furthermore, HEK-293 cells expressing polyglutamine-expanded ATXN2-Q58 treated with 17-DMAG had minimally detectable ATXN2, as well as normalized markers of autophagy and endoplasmic reticulum stress, including STAU1 (Staufen 1), molecular target of rapamycin, p62, LC3-II (microtubule-associated protein 1A/1B-light chain 3II), CHOP (C/EBP homologous protein), and phospho-eIF2α (eukaryotic initiation factor 2α). Finally, bacterial artificial chromosome ATXN2-Q22 mice treated with 17-DMAG or HSP990 exhibited highly reduced ATXN2 protein abundance in the cerebellum. Taken together, our study demonstrates inhibition of HSP90 or Na+/K+-ATPases as potentially effective therapeutic strategies for treating SCA2 and ALS.

Parallel Appearance of Polyglutamine and Transactivation-Responsive DNA-Binding Protein 43 and Their Complementary Subcellular Localization in Brains of Patients With Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is caused by mutations in the ATXN2 gene in which toxic effects are triggered by expanded polyglutamine repeats within ataxin-2. SCA2 is accompanied by motor neuron degeneration as occurs in amyotrophic lateral sclerosis (ALS). We investigated the distribution patterns of ataxin-2 and transactivation-responsive DNA-binding protein 43 (TDP-43), a major disease-related protein in ALS, in the CNS of 3 SCA2 patients. Phosphorylated TDP-43 (pTDP-43)-positive lesions were widely distributed throughout the CNS and generally overlapped with 1C2 (expanded polyglutamine)-immunoreactive lesions. This distribution pattern is different from the pattern in limbic-predominant age-related TDP-43 encephalopathy. In SCA2, double immunostaining of TDP-43 and 1C2 in motor neurons revealed 3 staining patterns: cytoplasmic 1C2 and nuclear TDP-43, nucleocytoplasmic 1C2 and nuclear TDP-43, and nuclear 1C2 and cytoplasmic TDP-43, which reflect the early, active, and final stages of pathological change, respectively. The translocation of TDP-43 from the nucleus to the cytoplasm along with the translocation of 1C2 in the opposite direction indicates that nuclear accumulation of the disease-specific protein ataxin-2 affects the intracellular dynamics of TDP-43. Such a close interrelationship between mutant ataxin-2 and TDP-43 in the cell might account for the similarity of their distribution in the CNS of patients with SCA2.

Erythropoietin in Spinocerebellar Ataxia Type 2: Feasibility and Proof-of-Principle Issues from a Randomized Controlled Study.

BACKGROUND: Several pieces of evidence have shown the neurotrophic effect of erythropoietin (EPO) and its introduction in the therapeutic practice of neurological diseases. However, its usefulness in the treatment of spinocerebellar ataxia type 2 (SCA2) has not been proven despite the fact that it is endogenously reduced in these patients. OBJECTIVE: The study aims to investigate the safety, tolerability, and clinical effects of a nasally administered recombinant EPO in SCA2 patients. METHODS: Thirty-four patients were enrolled in this double-blind, randomized, placebo-controlled, phase I-II clinical trial of the nasally administered human-recombinant EPO (NeuroEPO) for 6 months. The primary outcome was the change in the spinocerebellar ataxia functional index (SCAFI), while other motor, neuropsychological, and oculomotor measures were assessed. RESULTS: The 6-month changes in SCAFI score were slightly higher in the patients allocated to NeuroEPO treatment than placebo in spite of the important placebo effect observed for this parameter. However, saccade latency was significantly decreased in the NeuroEPO group but not in placebo. The frequency and severity of adverse events were similar between both groups, without evidences of hematopoietic activity of the drug. CONCLUSIONS: This study demonstrated the safety and tolerability of NeuroEPO in SCA2 patients after 6 months of treatments and suggested a small clinical effect of this drug on motor and cognitive abnormalities, but confirmatory studies are warranted. © 2022 International Parkinson and Movement Disorder Society.

Neurophysiological features in spinocerebellar ataxia type 2: Prospects for novel biomarkers.

Electrophysiological biomarkers are useful to assess the degeneration and progression of the nervous system in pre-ataxic and ataxic stages of the Spinocerebellar Ataxia Type 2 (SCA2). These biomarkers are essentially defined by their clinical significance, discriminating patients and/or preclinical subjects from healthy controls in cross-sectional studies, their significant changes over time in longitudinal studies, and their correlation with the cytosine-guanine-adenine (CAG) repeat expansion and/or clinical ataxia scores, time of evolution and time to ataxia onset. We classified electrophysiological biomarkers into three main types: (1) preclinical, (2) disease progression and (3) genetic damage. We review the data that identify sural nerve potential amplitude, maximum saccadic velocity, sleep efficiency, rapid eye movement (REM) sleep percentage, K-complex density, REM sleep without atonia percentage, corticomuscular coherence, central motor conduction time, visual P300 latency, and antisaccadic error correction latency as reliable preclinical, progression and/or genetic damage biomarkers of SCA2. These electrophysiological biomarkers will facilitate the conduction of clinical trials that test the efficacy of emerging treatments in SCA2.

Weight loss is correlated with disease severity in Spinocerebellar ataxia type 2: a cross-sectional cohort study.

BACKGROUND: Body weight changes occur frequently during advanced stages of Spinocerebellar Ataxia type 2 (SCA2), nevertheless limited information exists on biomarkers of nutritional status of these patients. OBJECTIVE.: To assess changes in surrogate nutritional markers of SCA2 patients; to explore their associations with expanded CAG repeats and disease severity. METHODS: One-hundred-thirteen SCA2 patients and 50 healthy controls underwent a comprehensive anthropometrical and biochemical assessment protocol of the nutritional status. Neurological and genotype assessments were also performed. RESULTS: A decrease in weight, body mass index (BMI), cutaneous skinfold thickness, fat mass, arm muscle circumference, calf circumference and skeletal muscle mass was observed in SCA2 patients compared to the controls. The total/HDL cholesterol ratio was significantly reduced in patients. BMI was correlated with the age at onset. Overall, anthropometric measures were correlated with clinical markers of disease severity and were more evident in severe and moderate cases. CONCLUSIONS: Using anthropometric measures in the assessment of the nutritional status of SCA2 patients might provide hints about pathophysiological mechanisms that underlie metabolic abnormalities in SCA2. Anthropometric are close related with disease severity and progression, and trigger preventive therapies aimed to ameliorate weight loss and wasting in these patients.

Cognitive Decline Is Closely Associated with Ataxia Severity in Spinocerebellar Ataxia Type 2: a Validation Study of the Schmahmann Syndrome Scale.

The cerebellar cognitive affective syndrome scale (CCAS-S) was designed to detect specific cognitive dysfunctions in cerebellar patients but is scarcely validated in spinocerebellar ataxias (SCA). The objective of this study is to determine the usefulness of the CCAS-S in a Cuban cohort of SCA2 patients and the relationship of its scores with disease severity. The original scale underwent a forward and backward translation into Spanish language, followed by a pilot study to evaluate its comprehensibility. Reliability, discriminant, and convergent validity assessments were conducted in 64 SCA2 patients and 64 healthy controls matched for sex, age, and education. Fifty patients completed the Montreal Cognitive Assessment (MoCA) test. The CCAS-S showed an acceptable internal consistency (Cronbach's alpha = 0.74) while its total raw score and the number of failed tests showed excellent (ICC = 0.94) and good (ICC = 0.89) test-retest reliability, respectively. Based on original cut-offs, the sensitivity of CCAS-S to detect possible/probable/definite CCAS was notably high (100%/100%/91%), but specificities were low (6%/30/64%) because the decreased specificity observed in four items. CCAS-S performance was significantly influenced by ataxia severity in patients and by education in both groups. CCAS-S scores correlated with MoCA scores, but showed higher sensitivity than MoCA to detect cognitive impairments in patients. The CCAS-S is particularly useful to detect cognitive impairments in SCA2 but some transcultural and/or age and education-dependent adaptations could be necessary to improve its diagnostic properties. Furthermore, this scale confirmed the parallelism between cognitive and motor deficits in SCA2, giving better insights into the disease pathophysiology and identifying novel outcomes for clinical trials.