Maria Rakowicz

The aim of this study was to determine the time between the first detection of postural control impairments and the evident manifestation of ataxia in preclinical SCA1 individuals. Twenty five preclinical SCA1 mutation carriers: 13 with estimated disease onset ≤ 6 years (SCA1 +) aged 27.8 ± 8.1 years; 12 with expected disease onset > 6 years (SCA1-) aged 26.6 ± 3.1 years and 26 age and sex matched healthy controls (HCs) underwent static posturography during 5 years of observation. The movements of the centre of feet pressure (COP) during quiet standing with eyes open (EO) and closed (EC) were quantified by calculating the mean radius (R), developed surface area (A) and mean COP movement velocity (V). Ataxia was evaluated by use of the Scale for Assessment and Rating of Ataxia (SARA). SCA1 + exhibited significantly worse quality of stance with EC vs. SCA1- (p < 0.05 for V) and HCs (p < 0.001) even 5 to 6 years before estimated disease onset. There were no statistically significant differences between SCA1- and HCs. A slow increase in Cohen’s d effect size was observed for V_EO up to the clinical manifestation of ataxia. V_EO and A_EC recorded in preclinical SCA1 individuals correlated slightly but statistically significantly with SARA (r = 0.47). The study confirms that static posturography detects COP sway changes in SCA1 preclinical gene carriers even 5 to 6 years before estimated disease onset. The quantitative evaluation of stance in preclinical SCA is a sensitive biomarker for the monitoring of the disease progression and may be useful in clinical trials.

Spinocerebellar ataxia type 3 (SCA3) is a devastating multisystemic neurodegenerative disease for which targeted molecular therapies are coming into reach (e.g. antisense oligonucleotides). To pave the way for upcoming translational trials, easily accessible biomarkers in SCA3 are needed, particularly for subjects at the preataxic stage and cross-validated also in animal models. We hypothesised that serum neurofilaments might serve as blood biomarkers of disease progression in both human SCA3 and mouse models, expecting increased concentrations already at the preataxic stage. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) levels were determined by ultra-sensitive single molecule array (Simoa) in cross-sectional samples of ataxic and preataxic SCA3 subjects and controls in two independent cohorts (ESMI cohort = cohort #1: n=160, EuroSCA/RiSCA cohort = cohort #2: n=89). Serum NfL and pNfH were also assessed in a 304Q SCA3 knock-in mouse model across presymptomatic and symptomatic disease stages (n=147). Ataxic SCA3 subjects showed increased serum NfL (p<0.001) and pNfH (p<0.001) levels in cohort #1, with NfL levels already increased in preataxic subjects (p<0.001). All these results were replicated in cohort #2 (all p<0.001). Cross-sectional NfL levels correlated with clinical disease severity (Scale for the Assessment and Rating of Ataxia [SARA]; r=0.43, p<0.001) and with longitudinal disease progression (annual SARA score change, ϱ=0.42, p=0.012). CAG count and age were significant predictors of individual NfL concentrations (each p<0.001). NfL levels in preataxic subjects increased with proximity to individual expected onset of ataxia (p<0.001), with significant elevations already 7.5 years before onset. Serum NfL and pNfH increases in SCA3 subjects were paralleled by similar changes in SCA3 knock-in mice, here also already starting at the presymptomatic stage and close to the onset of ataxin-3 protein increase. Serum concentrations of neurofilaments, particularly NfL, might provide easily accessible biomarkers of disease severity in both ataxic and preataxic SCA3 subjects and mice prior to conversion. Neurofilaments thus entail potential applications as progression, onset/proximity and treatment-response markers in both human and murine SCA3 trials.

Background Spinocerebellar ataxias are rare dominantly inherited neurodegenerative diseases that lead to severe disability and premature death. Objective To quantify the impact of disease progression measured by the Scale for the Assessment and Rating of Ataxia on survival, and to identify different profiles of disease progression and survival. Methods Four hundred sixty‐two spinocerebellar ataxia patients from the EUROSCA prospective cohort study, suffering from spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6, and who had at least two measurements of Scale for the Assessment and Rating of Ataxia score, were analyzed. Outcomes were change over time in Scale for the Assessment and Rating of Ataxia score and time to death. Joint model was used to analyze disease progression and survival. Results Disease progression was the strongest predictor for death in all genotypes: An increase of 1 standard deviation in total Scale for the Assessment and Rating of Ataxia score increased the risk of death by 1.28 times (95% confidence interval: 1.18–1.38) for patients with spinocerebellar ataxia type 1; 1.19 times (1.12–1.26) for spinocerebellar ataxia type 2; 1.30 times (1.19–1.42) for spinocerebellar ataxia type 3; and 1.26 times (1.11–1.43) for spinocerebellar ataxia type 6. Three subgroups of disease progression and survival were identified for patients with spinocerebellar ataxia type 1: “severe” (n = 13; 12%), “intermediate” (n = 31; 29%), and “moderate” (n = 62; 58%). Patients in the severe group were more severely affected at baseline with higher Scale for the Assessment and Rating of Ataxia scores and frequency of nonataxia signs compared to those in the other groups. Conclusion Rapid ataxia progression is associated with poor survival of the most common spinocerebellar ataxia. Theses current results have implications for the design of future interventional studies of spinocerebellar ataxia. © 2019 International Parkinson and Movement Disorder Society

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders. Numerous genes linked to HSPs, overlapping phenotypes between HSP subtypes and other neurodegenerative disorders and the HSPs’ dual mode of inheritance (both dominant and recessive) make the genetic diagnosis of HSPs complex and difficult. Out of the original HSP cohort comprising 306 index cases (familial and isolated) who had been tested according to “traditional workflow/guidelines” by Multiplex Ligation-dependent Probe Amplification (MLPA) and Sanger sequencing, 30 unrelated patients (all familial cases) with unsolved genetic diagnoses were tested using next-generation sequencing (NGS). One hundred thirty-two genes associated with spastic paraplegias, hereditary ataxias and related movement disorders were analysed using the Illumina TruSight™ One Sequencing Panel. The targeted NGS data showed pathogenic variants, likely pathogenic variants and those of uncertain significance (VUS) in the following genes: SPAST (spastin, SPG4), ATL1 (atlastin 1, SPG3), WASHC5 (SPG8), KIF5A (SPG10), KIF1A (SPG30), SPG11 (spatacsin), CYP27A1, SETX and ITPR1. Out of the nine genes mentioned above, three have not been directly associated with the HSP phenotype to date. Considering the phenotypic overlap and joint cellular pathways of the HSP, spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis (ALS) genes, our findings provide further evidence that common genetic testing may improve the diagnostics of movement disorders with a spectrum of ataxia-spasticity signs.

Introduction: Myotonic dystrophies (DMs) type 1 (DM1) and type 2 (DM2) are autosomal dominant, multisystem disorders, considered the most common dystrophies in adults. DM1 and DM2 are caused by dynamic mutations in the DMPK and CNBP genes, respectively. Methods: Molecular analyses were performed by PCR and the modified RP-PCR in patients, in their at-risk relatives and prenatal cases. Results: The analysis of Polish controls revealed the range of 5-31 CTG repeats for DM1 and 110-228 bp alleles for DM2. Among 318 confirmed probands - 196 (62%) were DM1 and 122 (38%) - DM2. Within DM1families, 10 subjects carried a low expanded CTG tract (< 100 repeats), which resulted in a full mutation in subsequent generations. Two related individuals had unstable alleles-188 bp and 196 bp without common interruptions. Conclusion: The relative frequencies of DM1/DM2 among Polish patients were 68% and 32%, respectively, with a relatively high proportion of DM2 mutations (1.6:1). (C) 2018 Polish Neurological Society. Published by Elsevier Sp. z o.o. All rights reserved.

To study the long-term evolution of patient-reported outcome measures (PROMs) in the most common spinocerebellar ataxias (SCAs), we analyzed 8 years follow-up data of the EUROSCA Natural History Study, a cohort study of 526 patients with SCA1, SCA2, SCA3 and SCA6.

Cel pracy: Przezczaszkowa stymulacja magnetyczna serią bodźców (ang. repetitive transcranial magnetic stiumlation – rTMS) poprawia nastrój u chorych na depresję. Obecne badanie miało odpowiedzieć na pytanie czy rTMS wpływa także na bezsenność towarzyszącą depresji.Metoda: Zbadano 13 chorych (średni wiek 50,6 ±13,9; 11 kobiet) z rozpoznaniem zaburzeń depresyjnych nawracających i zaburzeń afektywnych dwubiegunowych. Chorzy zostali poddani dwudziestu, codziennym sesjom rTMS nad okolicą kory przedczołowej grzbietowo-bocznej po stronie lewej (ang. dorsolateral prefrontal cortex – DLPFC) o częstotliwości 10Hz. Efekt stymulacji mierzono za pomocą Skali Ogólnej Oceny Klinicznej (ang. Clinical Global Impression – CGI), 21-punktowej Skali Depresji Hamiltona (ang. 21-item Hamilton Depression Rating Scale - HDRS), Ateńskiej Skali Bezsenności (ang. Athens Insomnia Scale AIS) oraz za pomocą dzienniczka snu i badania aktygraficznego.Wyniki: Po rTMS obserwowano istotny spadek punktacji w CGI, w generalnej punktacji HDRS oraz w punktach HDRS dotyczących jakości snu. AIS wykazała trend w kierunku redukcji liczby punktów. Nie obserwowano zmian w zakresie dzienniczka snu i aktygrafii.Wnioski: Badanie potwierdziło korzystny wpływ rTMS na nastrój w depresji. Pozostałe wyniki sugerują, że rTMS o wysokiej częstotliwości nad lewą DLPFC nie wykazuje znacznego wpływu na jakość snu u chorych na depresję. Dodatkowe metody terapeutyczne lub modyfikacja protokołu rTMS powinny zostać rozważone celem poprawy bezsenności u chorych z depresją.

Background: Spinocerebellar ataxias (SCAs) are dominantly inherited, progressive ataxia disorders. Disease progression could be preceded by weight loss.Objectives: We aimed to study the course of weight loss in patients who had the most common SCAs (SCA1, SCA2 SCA3, and SCA6). Additional objectives were to identify subgroups of weight evolution, to determine the factors influencing these evolutions, and to assess the impact of these evolutions on disease progression.Methods: In total, 384 patients from the EUROSCA prospective cohort study were analyzed who had SCA1, SCA2, SCA3, or SCA6 and at least 3 measurements of weight. Age was used as a time scale. Clinical outcomes were body mass index (BMI) and the Scale for the Assessment and Rating Ataxia (SARA), with scores ranging from 0 to 40. We used a linear mixed model to analyze the course of BMI and a latent class mixed model to identify subgroup BMI evolution.Results: Overall, BMI declined over time (−0.11 ± 0.03 kg/m² per decade; P = 0.0009). Three subgroups of BMI evolution were identified: “decreasing BMI” (n = 88; 23%), “increasing BMI” (n = 70; 18%) and “stable BMI” (n = 226; 59%). Patients in the decreasing BMI group were more severely affected at baseline with higher SARA scores and a higher frequency of non‐ataxia signs (especially motor symptoms) compared with those in the other groups. Weight loss was associated with faster disease progression (5.7 ± 0.7 SARA points per decade; P = 0.036).Conclusions: The current data have substantial implications for the design of future interventional studies in SCA, as they provide a basis for patient stratification and emphasize the usefulness of BMI as a biomarker for monitoring disease progression.