Assessing movement changes in degenerative ataxias: from the pre-ataxic disease stage to the effects of a bio-feedback intervention

Degenerative ataxias are a heterogenous group of movement disorders defined by progressive ataxia due to a degeneration of the cerebellum and its associated tracts, often of genetic origin. Disease-modifying drugs are still lacking for degenerative ataxias, thus highlighting the need for paving the way for both interventional drug trials and for innovative neurorehabilitation approaches. Detailed quantitative movement analysis might hereby help to detect and grade cerebellar dysfunction, possibly even at the preataxic stages of the disease, thus helping to chart a promising window for early treatment interventions before clinical disease onset. Moreover, it might help to gain new insights into the functional role of the cerebellum in motor control and related sensory integration mechanisms, which might be used to inform future neurorehabilitation strategies. Correspondingly, we here hypothesized (1) that quantitative movement analysis allows to reveal early movement changes when clinical signs are still absent and to capture motor progression in subjects at the preataxic stage of spinocerebellar ataxia (SCA) (study #1). Moreover, we hypothesized (2) that quantitative movement analysis allows to identify the effects of a biofeedback intervention in patients with degenerative ataxia, where they might be able to exploit real-time acoustic bio-feedback signals (ABF) of trunk acceleration to compensate for impaired postural control (study #2). Study 1: 46 participants (14 preataxic SCA mutation carriers [SCAs 1,2,3,6], 9 SCA patients at an early symptomatic stage; and 23 healthy controls) were analysed by quantitative movement analysis during stance and walking tasks of increasing complexity. We identified motor features that (i) differentiated between preataxic mutation carriers and healthy controls, even in absence of clinical signs and (ii) correlated with repeat expansion-based estimated time to disease onset. These results demonstrate that quantitative movement analysis in combination with tasks of rising difficulty levels allows to detect subclinical motor changes in spinocerebellar ataxia before clinical manifestation, which may enable the quantification of disease progression in the preclinical phase. Study 2: Quantitative movement analysis was used to investigate the effects on postural sway during stance in a short-term ABF intervention group versus a no-ABF disease control group (23 and 17 cerebellar patients, respectively). Postural sway under the conditions ‘eyes open’ and ‘eyes closed’ was measured prior to ABF, under ABF, and post ABF. Our analysis revealed a significant reduction of body sway under ABF in the ‘eyes closed’ condition. Patients who had the largest extent of postural sway at baseline even improved their stability in the ‘eyes open’ condition under ABF. Correlations were found between the degree of postural sway at baseline and the benefits of both ABF and vision, and moreover, between the benefits of both sensory modalities (i.e. ABF and vision). The no-ABF control group did not exhibit any changes in sway across stance trials. These results provide proof-of-principle evidence that despite cerebellar degeneration, patients are still able to improve dysfunctional postural control by integrating augmented sensory cues: In absence of vision, the reliance on added auditory cues can be exploited to a similar extent as vision. In case of strong postural sway, augmented auditory information can be exploited also in combination with vision. These findings indicate promising compensatory strategies of cerebellar patients to maintain balance and might inform future assistive approaches

Real-time use of audio-biofeedback can improve postural sway in patients with degenerative ataxia

Abstract Objective Cerebellar ataxia essentially includes deficient postural control. It remains unclear whether augmented sensory information might help cerebellar patients, as the cerebellum underlies processing of various sensory modalities for postural control. Here, we hypothesized that patients with cerebellar degeneration can still exploit audio‐biofeedback (ABF) of trunk acceleration as a real‐time assistive signal to compensate for deficient postural control. Methods Effects on postural sway during stance were assessed in an ABF intervention group versus a no‐ABF disease control group (23 vs. 17 cerebellar patients) in a clinico‐experimental study. A single‐session ABF paradigm of standing plus short exergaming under ABF was applied. Postural sway with eyes open and eyes closed was quantified prior to ABF, under ABF, and post ABF. Results Postural sway in the eyes closed condition was significantly reduced under ABF. Both benefit of ABF and benefit of vision correlated with the extent of postural sway at baseline, and both types of sensory benefits correlated with each other. Patients with strongest postural sway exhibited reduced postural sway also with eyes open, thus benefitting from both vision and ABF. No changes were observed in the no‐ABF control group. Interpretation Our findings provide proof‐of‐principle evidence that subjects with cerebellar degeneration are still able to integrate additional sensory modalities to compensate for deficient postural control: They can use auditory cues functionally similar to vision in the absence of vision, and additive to vision in the presence of vision (in case of pronounced postural sway). These findings might inform future assistive strategies for cerebellar ataxia

GAD antibodies in neurological disease: a critical evaluation of the utility and treatment implications of GAD antibodies in clinical practice

Background: The interpretation of antibodies to glutamic acid decarboxylase 65 (GAD-Abs) in neurological practice is challenging. GAD-Abs are not considered directly pathogenic and immunotherapy guidelines are lacking. Methods: We undertook a single-center retrospective service evaluation of GAD-Abs, documenting clinical features, immunotherapy responses, and outcomes of 335 patients with positive GAD-Abs measured by indirect ELISA between 2012 and 2020. The serum:CSF ratio of GAD-Ab values was used as a surrogate for intrathecal synthesis. Results: 168 (50%) patients had diagnosed neurological disorders (GAD-ND). Ninety-six had neurological disorders often or sometimes associated with GAD-Abs, i.e., stiff person syndrome spectrum disorders (SPS-SD, n = 26), cerebellar ataxia (n = 21), epilepsy (n = 19), encephalitis (n = 18), or any combination of these (“mixed”, n = 12). Seventy-two had other neurological disorders (ONDs) not typically associated with GAD-Abs. We defined a cut-off of 10,000 IU/mL a priori and a posteriori for GAD-Ab associated NDs, but identified values > 10,000 IU/mL in 21% and 11% of patients with ONDs or diabetes respectively, and 10,000 IU/mL, intrathecal synthesis of GAD-Abs, or oligoclonal bands, were not more likely to improve with immunotherapies than those with GAD-Ab values < 10,000 IU/mL and a non-inflammatory CSF. Rather, treatment response correlated with disease group, principally SPS-SD and encephalitis. Conclusions: These results suggest caution in over-interpreting GAD-Abs values. Better biomarkers for identifying patients with immunotherapy responsive GAD-Ab disease are needed

The genetic landscape of sporadic adult-onset degenerative ataxia: a multi-modal genetic study of 377 consecutive patients from the longitudinal multi-centre SPORTAX cohort

Background: While most sporadic adult-onset neurodegenerative diseases have only a minor monogenic component, given several recently identified late adult-onset ataxia genes, the genetic burden may be substantial in sporadic adult-onset ataxias. We report systematic mapping of the genetic landscape of sporadic adult-onset ataxia in a well-characterised, multi-centre cohort, combining several multi-modal genetic screening techniques, plus longitudinal natural history data. Methods: Systematic clinico-genetic analysis of a prospective longitudinal multi-centre cohort of 377 consecutive patients with sporadic adult-onset ataxia (SPORTAX cohort), including clinically defined sporadic adult-onset ataxia of unknown aetiology (SAOA) (n = 229) and ‘clinically probable multiple system atrophy of cerebellar type’ (MSA-Ccp) (n = 148). Combined GAA-FGF14 (SCA27B) and RFC1 repeat expansion screening with next-generation sequencing (NGS) was complemented by natural history and plasma neurofilament light chain analysis in key subgroups. Findings: 85 out of 377 (22.5%) patients with sporadic adult-onset ataxia carried a pathogenic or likely pathogenic variant, thereof 67/229 (29.3%) patients with SAOA and 18/148 (12.2%) patients meeting the MSA-Ccp criteria. This included: 45/377 (11.9%) patients with GAA-FGF14≥250 repeat expansions (nine with MSA-Ccp), 17/377 (4.5%) patients with RFC1 repeat expansions (three with MSA-Ccp), and 24/377 (6.4%) patients with single nucleotide variants (SNVs) identified by NGS (six with MSA-Ccp). Five patients (1.3%) were found to have two relevant genetic variants simultaneously (dual diagnosis). Interpretation: In this cohort of sporadic adult-onset ataxia, a cohort less likely to have a monogenic cause, a substantial burden of monogenic variants was identified, particularly GAA-FGF14 and RFC1 repeat expansions. This included a substantial share of patients meeting the MSA-Ccp criteria, suggesting a reduced specificity of this clinical diagnosis and potential co-occurrence of MSA-C plus a second, independent genetic condition. These findings have important implications for the genetic work-up and counselling of patients with sporadic ataxia, even when presenting with MSA-like features. With targeted treatments for genetic ataxias now on the horizon, these findings highlight their potential utility for these patients. Funding: This work was supported by the Clinician Scientist programme “PRECISE.net” funded by the Else Kröner-Fresenius-Stiftung (to DM, AT, CW, OR, and MS), by the Deutsche Forschungsgemeinschaft (as part of the PROSPAX project), and by the Canadian Institutes of Health Research and the Fondation Groupe Monaco. Support was also provided by Humboldt Research Fellowship for Postdocs and the Hertie-Network of Excellence in Clinical Neuroscience and a Fellowship award from the Canadian Institutes of Health Research

Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset

BACKGROUND: The Scale for Assessment and Rating of Ataxia (SARA) is widely used in different types of ataxias and has been chosen as the primary outcome measure in the European natural history study for Friedreich ataxia (FA). METHODS: To assess distribution and longitudinal changes of SARA scores and its single items, we analyzed SARA scores of 502 patients with typical-onset FA (<25 years) participating in the 4-year prospective European FA Consortium for Translational Studies (EFACTS). Pattern of disease progression was determined using linear mixed-effects regression models. The chosen statistical model was re-fitted in order to estimate parameters and predict disease progression. Median time-to-change and rate of score progression were estimated using the Kaplan-Meier method and weighted linear regression models, respectively. RESULTS: SARA score at study enrollment and age at onset were the major predictive factors of total score progression during the 4-year follow-up. To a less extent, age at evaluation also influenced the speed of SARA progression, while disease duration did not improve the prediction of the statistical model. Temporal dynamics of total SARA and items showed a great variability in the speed of score increase during disease progression. Gait item had the highest annual progression rate, with median time for one-point score increase of 1 to 2 years. INTERPRETATION: Analyses of statistical properties of SARA suggest a variable sensitivity of the scale at different disease stages, and provide important information for population selection and result interpretation in future clinical trials

Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia

BACKGROUND: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia. METHODS: We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons. FINDINGS: Variants associated with chronic progressive ataxia either decreased Na + current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na + current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. INTERPRETATION: We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions. FUNDING: BMBF, DFG, the Italian Ministry of Health, University of Tuebingen