Severity Of Ataxia Research Articles

ATXN7-Related Cone-Rod Dystrophy

Reliable biomarkers with diagnostic and prognostic values are needed for upcoming gene therapy trials for spinocerebellar ataxias. To identify ophthalmological biomarkers in a sample of spinocerebellar ataxia type 7 (SCA7) carriers. This article presents baseline data from a cross-sectional natural history study conducted in Paris, France, reference centers for rare diseases from May 2020 to April 2021. Data were analyzed from September to December 2022. Fifteen adult ATXN7 pathogenic expansion carriers (9 with preataxia and 6 with ataxia) were included, all with a Scale for the Assessment and Rating of Ataxia (SARA) score of 15 of 40 or lower. Patients were recruited at the Paris Brain Institute, and all contacted patients accepted to participate in the study. Three visits (baseline, 6 months, and 12 months) were planned, including neurological examination (SARA and Composite Cerebellar Functional Severity Score), ophthalmological examination (best-corrected visual acuity, microperimetry, full-field electroretinogram, optical coherence tomography, and fundus autofluorescence imaging), and neurofilament light chain (NfL) measurements. Here we report the baseline ophthalmic data from the cohort and determine whether there is a correlation between disease scores and ophthalmic results. Among the 15 included SCA7 carriers (median [range] age, 38 [18-60] years; 8 women and 7 men), 12 displayed cone or cone-rod dystrophy, with the number of CAG repeats correlating with disease severity (ρ, 0.73, 95% CI, 0.34 to 0.90; P < .001). Two patients with cone-rod dystrophy exhibited higher repeat numbers and greater ataxia scores (median [range] SARA score, 9 [7-15]) compared to those with only cone dystrophy (median [range] SARA score, 2 [0-5]). A correlation emerged for outer nuclear layer thickness with SARA score (ρ, -0.88; 95% CI, -0.96 to -0.59; P < .001) and NfL levels (ρ, -0.87; 95% CI, -0.86 to 0.96; P < .001). Moreover, ataxia severity was correlated with visual acuity (ρ: 0.89; 95% CI, 0.68 to 0.96; P < .001) and retinal sensitivity (ρ, -0.88; 95% CI, -0.96 to 0.59; P < .001). In this cross-sectional study, retinal abnormalities were found at preataxic stages of the disease. Most of the carriers presented with cone dystrophy and preserved rod function. The outer nuclear layer thickness correlated with SARA score and plasma NfL levels suggesting nuclear layer thickness to be a biomarker of disease severity. These findings contribute to understanding the dynamics of SCA7-related retinal dystrophy and may help lay the groundwork for future therapeutic intervention monitoring and clinical trials. ClinicalTrials.gov Identifier: NCT04288128.

Fatigue Impacts Quality of Life in People with Spinocerebellar Ataxias.

Fatigue is a prevalent and debilitating symptom in neurological disorders, including spinocerebellar ataxias (SCAs). However, the risk factors of fatigue in the SCAs as well as its impact have not been well investigated. To study the prevalence of fatigue in SCAs, the factors contributing to fatigue, and the influence of fatigue on quality of life. Fatigue was assessed in 418 participants with SCA1, SCA2, SCA3, and SCA6 from the Clinical Research Consortium for the Study of Cerebellar Ataxia using the Fatigue Severity Scale. We conducted multi-variable linear regression models to examine the factors contributing to fatigue as well as the association between fatigue and quality of life. Fatigue was most prevalent in SCA3 (52.6%), followed by SCA1 (36.7%), SCA6 (35.7%), and SCA2 (35.6%). SCA cases with fatigue had more severe ataxia and worse depressive symptoms. In SCA3, those with fatigue had a longer disease duration and longer pathological CAG repeat numbers. In multi-variable models, depressive symptoms, but not ataxia severity, were associated with more severe fatigue. Fatigue, independent of ataxia and depression, contributed to worse quality of life in SCA3 and SCA6 at baseline, and fatigue continued affecting quality of life throughout the disease course in all types of SCA. Fatigue is a common symptom in SCAs and is closely related to depression. Fatigue significantly impacts patients' quality of life. Therefore, screening for fatigue should be considered a part of standard clinical care for SCAs.

Digital Gait Measures Capture 1-Year Progression in Early-Stage Spinocerebellar Ataxia Type 2.

With disease-modifying drugs in reach for cerebellar ataxias, fine-grained digital health measures are highly warranted to complement clinical and patient-reported outcome measures in upcoming treatment trials and treatment monitoring. These measures need to demonstrate sensitivity to capture change, in particular in the early stages of the disease. Our aim is to unravel gait measures sensitive to longitudinal change in the-particularly trial-relevant-early stage of spinocerebellar ataxia type 2 (SCA2). We performed a multicenter longitudinal study with combined cross-sectional and 1-year interval longitudinal analysis in early-stage SCA2 participants (n = 23, including nine pre-ataxic expansion carriers; median, ATXN2 CAG repeat expansion 38 ± 2; median, Scale for the Assessment and Rating of Ataxia [SARA] score 4.8 ± 4.3). Gait was assessed using three wearable motion sensors during a 2-minute walk, with analyses focused on gait measures of spatio-temporal variability that have shown sensitivity to ataxia severity (eg, lateral step deviation). We found significant changes for gait measures between baseline and 1-year follow-up with large effect sizes (lateral step deviation P = 0.0001, effect size rprb = 0.78), whereas the SARA score showed no change (P = 0.67). Sample size estimation indicates a required cohort size of n = 43 to detect a 50% reduction in natural progression. Test-retest reliability and minimal detectable change analysis confirm the accuracy of detecting 50% of the identified 1-year change. Gait measures assessed by wearable sensors can capture natural progression in early-stage SCA2 within just 1 year-in contrast to a clinical ataxia outcome. Lateral step deviation represents a promising outcome measure for upcoming multicenter interventional trials, particularly in the early stages of cerebellar ataxia. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cerebellar Volumetry in Ataxias: Relation to Ataxia Severity and Duration.

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

Retinal ganglion cell and microvascular density loss in hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is characterized by progressive degeneration of distal axons in the long corticospinal tracts. Loss of retinal cells and microvascular networks has neither been suspected nor investigated. We concurrently examined the retinal microvasculature and retinal layer morphology in patients with HSP to assess whether retinal features may portray disease and its progression. Fifteen patients with HSP and 30 healthy controls were included in this cross-sectional case-control study. Disease severity was assessed with the Spastic Paraplegia Rating Scale (SPRS). Severity of ataxia was determined by the Scale for the Assessment and Rating of Ataxia (SARA). Retinal microvasculature was measured by means of optical coherence tomography angiography (OCT-A) and morphology of retinal layers using structural OCT. Mixed-effects models were applied for data analysis. HSP patients showed significantly reduced vessel density of the superficial vascular plexus (SVP), reduced ganglion cell layer (GCL) volume, reduced inner plexiform layer (IPL) volume and reduced temporal-inferior peripapillary retinal nerve fiber layer (pRNFL) thickness versus healthy controls. GCL volume reduction correlated significantly with the worsening of visual acuity and higher SARA scores. These findings demonstrate that, in HSP both cells and vascular networks of the retina are compromised. Assessment of the retinal GCL, IPL and SVP may aid in diagnosis and monitoring of disease progression as well as provide novel structural outcome measures for clinical trials.

Videoocular assessment of eye movement activity in an ataxia-telangiectasia: a case study.

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by progressive neurological deficits, including prominent oculomotor dysfunction. We report 5 cases of eye movement assessment in children 9-15years old with A-T. Three different oculomotor tasks (gaze holding, visually guided saccades and visual search) were used, and video-oculography was performed. Additionally, the scale for the assessment and rating of ataxia(SARA) score was used to assess severity of the cerebellar ataxia. Unstable gaze holding, nystagmus and saccadic intrusions were found. In addition to psychophysiological assessment results, we provide quantitative analysis of oculomotor activity, revealing a specific abnormal oculomotor pattern, consisting of (i) marked saccade hypermetria, (ii) unstable gaze holding, and (iii) gaze-evoked nystagmus. Our study opens the prospect to evaluate efficacy and safety of alternative methods for supporting the patient and improving his/her life quality.

Serum S100β 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 S100β 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 S100β in SCA2 and its relationship with molecular, clinical, cognitive, and peripheral inflammatory markers of the disease. Serum concentrations of S100β 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 S100β levels similar to the control group, at low nanomolar concentrations. However, the S100β levels were directly associated with a better performance of cognitive evaluation within the SCA2 cohort. Moreover, the S100β levels were inversely correlated with most peripheral inflammatory indices. Indeed, the neutrophil-to-lymphocyte ratio significantly mediated the effect of serum S100β on cognitive performance, even after controlling for the ataxia severity in the causal mediation analysis. Our findings suggested that, within physiologic concentrations, the protein S100β exerts a neuroprotective role against cognitive dysfunction in SCA2, likely via the suppression of pro-inflammatory mechanisms.

Factors Influencing Health-Related Quality of Life of Patients with Spinocerebellar Ataxia

BackgroundLittle is known about the progression of health-related quality of life (HRQoL) and predicting factors in spinocerebellar ataxia (SCA). Such knowledge is crucial to identify modifiable factors promoting everyday life with SCA and attenuating HRQoL decline.ObjectivesThis study is to assess HRQoL progression and identify factors affecting SCA patients’ HRQoL.MethodsLongitudinal data (three-year follow-up) of 310 SCA patients of the European SCA3/Machado-Joseph-Disease Initiative (ESMI) (2016-2022) and 525 SCA patients (SCA1, SCA2, SCA3 or SCA6) of the EUROSCA natural history study cohort (2006–2015) were assessed. Both large cohort studies share standardized assessments of clinical measures, SARA, INAS, PHQ-9, and HRQoL (EQ-5D-3L). The association between HRQoL and clinical measures was assessed by Spearman Correlation (rs). Multivariable panel regression models were performed to evaluate the impact of patients’ socio-demographics, age of onset, SCA type and body mass index (BMI), and clinical measures on HRQoL progression.ResultsHRQoL significantly decreased over one (− 0.014, p = 0.095), two (− 0.028, p = 0.003), and three years (− 0.032, p = 0.002). Ataxia severity and mental health strongly correlated with HRQoL (rsSARA = − 0.589; rsPHQ-9 = − 0.507). HRQoL more intensively declined in male (ß = − 0.024, p = 0.038) patients with an earlier age of onset (ß = 0.002, p = 0.058). Higher progression of ataxia severity (ß = − 0.010, p ≤ 0.001), mental health problems (ß = − 0.012, p < 0.001), and higher BMI (ß = − 0.003, p = 0.029) caused more severe decline of patients’ HRQoL over time.DiscussionIn absence of curative treatments, stronger focus on mental health and weight influence could help clinical evaluation and accompany treatment improving SCA patients’ HRQoL, especially in male patients with early disease onset.

Dietary Supplementation with 23-Hydroxy Ursolic Acid Reduces the Severity and Incidence of Acute Experimental Autoimmune Encephalomyelitis (EAE) in a Murine Model of Multiple Sclerosis.

23-Hydroxy ursolic acid (23-OH UA) is a potent atheroprotective and anti-obesogenic phytochemical, with anti-inflammatory and inflammation-resolving properties. In this study, we examined whether dietary 23-OH UA protects mice against the acute onset and progression of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). Female C57BL/6 mice were fed either a defined low-calorie maintenance diet (MD) or an MD supplemented with 0.2% wgt/wgt 23-OH UA for 5 weeks prior to actively inducing EAE and during the 30 days post-immunization. We observed no difference in the onset of EAE between the groups of mice, but ataxia and EAE disease severity were suppressed by 52% and 48%, respectively, and disease incidence was reduced by over 49% in mice that received 23-OH UA in their diet. Furthermore, disease-associated weight loss was strikingly ameliorated in 23-OH UA-fed mice. ELISPOT analysis showed no significant differences in frequencies of T cells producing IL-17 or IFN-γ between 23-OH UA-fed mice and control mice, suggesting that 23-OH UA does not appear to regulate peripheral T cell responses. In summary, our findings in EAE mice strongly suggest that dietary 23-OH UA may represent an effective oral adjunct therapy for the prevention and treatment of relapsing-remitting MS.

Abnormal cortical excitability in patients with spinocerebellar ataxia type 12

BackgroundSpinocerebellar ataxia type 12 (SCA-12) is an uncommon autosomal dominant cerebellar ataxia characterized by action tremors in the upper limbs, dysarthria, head tremor, and gait ataxia. We aimed to evaluate the motor cortical excitability in patients with SCA-12 using transcranial magnetic stimulation (TMS). MethodsThe study was done in the department of Neurology at the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore. Nine patients with SCA-12 (2 females) and 10 healthy controls (2 females) were included in the study. TMS was performed in all the subjects and various parameters such as resting motor threshold (RMT), central motor conduction time (CMCT) and contralateral silent period (cSP) were recorded. The left motor cortex was stimulated and the recording was done from right first dorsal interossei muscle. The severity of ataxia was assessed using the scale for assessment and rating in ataxia (SARA). ResultsThe mean age of the patients was 58.11 ± 7.56 years mean age at onset: 51.67 ± 4.18 years. The mean duration of illness was 9.44 ± 4.88 years. The mean SARA score was 13.83 ± 3.60. Patients with SCA-12 had significantly increased RMT (88.80 ± 12.78 %) compared to HC (44.90 ± 9.40 %, p < 0.05). A significantly prolonged CMCT was observed in patients (13.70 ± 2.52 msec) compared to HC (7.31 ± 1.21 msec, p < 0.05). In addition, cSP was significantly increased in SCA-12 patients (144.43 ± 25.79 msec) compared to HC (82.14 ± 28.90 msec, p < 0.05). ConclusionsPatients with SCA-12 demonstrate a reduced cortical excitability and increased cortical inhibition suggesting an increase in the GABAergic neurotransmission.

Differential diagnosis of chronic acquired demyelinating polyneuropathies

Introduction. The rarity of chronic acquired polyneuropathies (PNP) with the demyelinating nature of peripheral nerve damage causes the difficulties of their differential diagnosis that persist in our country and abroad. Objective: to identify significant clinical, neurophysiological and sonographic differential diagnostic markers in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and non-IgM paraproteinemic demyelinating polyneuropathies (PDP).Material and methods: 80 patients were included in the study: 30 with CIDP, 30 with non-IgM-PDP associated with monoclonal gammapathy of unclear significance (PDP-MGUS), and 20 with non-IgM-PDP associated with lymphoproliferative disease (PDP-LPD). The patients included in the study underwent clinical evaluation of neurological disorders according to the MRC, NIS, VAS, INCAT, IRODS, SARA scales; ENMG and ultrasound studies of peripheral nerves.Results. The predominance of men in all groups was noted (p &gt; 0.05). Compared with patients with CIDP, patients with PDP were significantly older, they were more likely to have neuropathic pain syndrome and trophic disorders (p &lt; 0.05). In patients with PDP-LPD, in contrast to CIDP and PDP-MGUS, there was a predominance of the distal pattern of muscle weakness distribution and a greater severity of sensitive ataxia (p &lt; 0.05). During NCV studies in patients with CIDP, compared with patients with PDP, blocks of conduction and dispersion of M-waves were signifi -cantly more often recorded in the study of motor fibers of the nerves of the hands (p &lt; 0.05); and in the study of motor nerves of the legs, non-excitability of motor fibers was significantly less often noted (p &lt; 0.05). Ultrasound examination of peripheral nerves showed no significant differences between patients (p &gt; 0.05).Conclusion. Clinical phenotype, neurophysiological and sonographic changes in patients with CIDP and PDP do not have highly specific differences. Electrophoresis of serum proteins with immunofixation makes it possible to differentiate CIDP and PDP, and further examination by an oncohematologist with paraproteinemia makes it possible to distinguish MGUS from LPD.

Feasibility of a randomized, sham-controlled pilot study for accelerated rTMS-treatment of the cerebellum plus physiotherapy in CANVAS patients.

Cerebellar ataxia, neuropathy and bilateral vestibular areflexia (CANVAS) is a rare neurodegenerative disease affecting the cerebellum, the peripheral nervous system and the vestibular system. Due to the lack of approved drugs, therapy comprises physiotherapy and speech therapy. Transcranial magnetic stimulation is a promising non-invasive therapeutic option to complement classical symptomatic therapies. To test feasibility of the combination of transcranial magnetic stimulation using an accelerated protocol and standard symptomatic therapy in patients with CANVAS. Eight patients with genetically confirmed CANVAS were assigned to either verum or sham cerebellar transcranial magnetic stimulation using an accelerated protocol. Treatment duration was limited to 5 days. Additionally, patients in both groups received symptomatic therapy (speech and physiotherapy) for the duration of the study. All patients completed the stimulation protocol. Adverse events were rare. Ataxia severity improved in the verum group only. The combination of transcranial magnetic stimulation and classic symptomatic therapy is feasible in a neuro-rehabilitation setting and potentially ameliorates ataxia severity.

Rates of change of pons and middle cerebellar peduncle diameters are diagnostic of multiple system atrophy of the cerebellar type.

Definitive diagnosis of multiple system atrophy of the cerebellar type (MSA-C) is challenging. We hypothesized that rates of change of pons and middle cerebellar peduncle diameters on MRI would be unique to MSA-C and serve as diagnostic biomarkers. We defined the normative data for anterior-posterior pons and transverse middle cerebellar peduncle diameters on brain MRI in healthy controls, performed diameter-volume correlations and measured intra- and inter-rater reliability. We studied an Exploratory cohort (2002-2014) of 88 MSA-C and 78 other cerebellar ataxia patients, and a Validation cohort (2015-2021) of 49 MSA-C, 13 multiple system atrophy of the parkinsonian type (MSA-P), 99 other cerebellar ataxia patients and 314 non-ataxia patients. We measured anterior-posterior pons and middle cerebellar peduncle diameters on baseline and subsequent MRIs, and correlated results with Brief Ataxia Rating Scale scores. We assessed midbrain:pons and middle cerebellar peduncle:pons ratios over time. The normative anterior-posterior pons diameter was 23.6 ± 1.6 mm, and middle cerebellar peduncle diameter 16.4 ± 1.4 mm. Pons diameter correlated with volume, r = 0.94, P < 0.0001. The anterior-posterior pons and middle cerebellar peduncle measures were smaller at first scan in MSA-C compared to all other ataxias; anterior-posterior pons diameter: Exploratory, 19.3 ± 2.6 mm versus 20.7 ± 2.6 mm, Validation, 19.9 ± 2.1 mm versus 21.1 ± 2.1 mm; middle cerebellar peduncle transverse diameter, Exploratory, 12.0 ± 2.6 mm versus 14.3 ±2.1 mm, Validation, 13.6 ± 2.1 mm versus 15.1 ± 1.8 mm, all P < 0.001. The anterior-posterior pons and middle cerebellar peduncle rates of change were faster in MSA-C than in all other ataxias; anterior-posterior pons diameter rates of change: Exploratory, -0.87 ± 0.04 mm/year versus -0.09 ± 0.02 mm/year, Validation, -0.89 ± 0.48 mm/year versus -0.10 ± 0.21 mm/year; middle cerebellar peduncle transverse diameter rates of change: Exploratory, -0.84 ± 0.05 mm/year versus -0.08 ± 0.02 mm/year, Validation, -0.94 ± 0.64 mm/year versus -0.11 ± 0.27 mm/year, all values P < 0.0001. Anterior-posterior pons and middle cerebellar peduncle diameters were indistinguishable between Possible, Probable and Definite MSA-C. The rate of anterior-posterior pons atrophy was linear, correlating with ataxia severity. Using a lower threshold anterior-posterior pons diameter decrease of -0.4 mm/year to balance sensitivity and specificity, area under the curve analysis discriminating MSA-C from other ataxias was 0.94, yielding sensitivity 0.92 and specificity 0.87. For the middle cerebellar peduncle, with threshold decline -0.5 mm/year, area under the curve was 0.90 yielding sensitivity 0.85 and specificity 0.79. The midbrain:pons ratio increased progressively in MSA-C, whereas the middle cerebellar peduncle:pons ratio was almost unchanged. Anterior-posterior pons and middle cerebellar peduncle diameters were smaller in MSA-C than in MSA-P, P < 0.001. We conclude from this 20-year longitudinal clinical and imaging study that anterior-posterior pons and middle cerebellar peduncle diameters are phenotypic imaging biomarkers of MSA-C. In the correct clinical context, an anterior-posterior pons and transverse middle cerebellar peduncle diameter decline of ∼0.8 mm/year is sufficient for and diagnostic of MSA-C.

The Impact of Demographic and Clinical Factors on the Quality of Life in Patients with Neurodegenerative Cerebellar Ataxias.

In neurodegenerative cerebellar ataxias, not only ataxia but also extra-cerebellar signs have a significant impact on patients' health related to quality of life (HRQoL). The aim of this study was to evaluate the various aspects of HRQoL and predictors of QoL in patients with neurodegenerative cerebellar ataxias. We included a total of 107 patients with cerebellar degenerative ataxia. Patients filled out the validated Serbian version of the SF-36 used for the assessment of HRQoL. All patients were clinically evaluated using SARA, INAS, and neuropsychological tests to assess their global cognitive status and different psychiatric scales. The most frequent types of neurodegenerative cerebellar ataxias were autosomal dominant ataxias (38.3%) and sporadic ataxias (32.7%). Mean age at diagnosis was 35.3 ± 16.23 years, and disease duration was on average 12.1 ± 9.91 years. Mean total SF-36 score was 50.63 ± 20.50. Hierarchical regression analysis showed that in the case of the PHC score, the most significant predictors are the patient's actual age, severity of ataxia, and ACE total score. For MHC, the Hamilton depression score was the most important predictor. Our study has shown that HRQoL measured by SF-36 in patients with neurodegenerative cerebellar disorders is strongly influenced by impaired mobility and depression.

Ataxia severity classification using enhanced feature selection and ranking optimization through machine learning model

&lt;span&gt;The examination of neurological disorders and the monitoring of ataxic gait are major scientific topics that benefit from digital signal processing techniques and machine learning (ML) technologies. In this research, an ML approach is optimized with the use of Spatio-temporal data obtained from a kinect-sensor to differentiate between normal gait and ataxic. The current ML-based approaches perform very poorly because they cannot build feature-correlation among many gait characteristics. Furthermore, current ML-based techniques generate more false-positive whenever data is imbalanced in nature; especially for performing multi-label classification. This work presents a feature selection and ranking (FSR) based on extreme gradient boost (XGB) for ataxia severity classification. The FSR-XGB introduce an enhanced misclassification minimization error optimization and presents a novel feature selection and ranking to introduce feature importance using new cross-validation mechanism, both of which are aimed at solving the multi-label classification research problems. Results from experiments demonstrate that the presented FSR-XGB approach outperforms other ML-based and deep learning-based approaches.&lt;/span&gt;

Sensorimotor Cough Dysfunction in Cerebellar Ataxias.

Cerebellar ataxias are neurological conditions with a high prevalence of aspiration pneumonia and dysphagia. Recent research shows that sensorimotor cough dysfunction is associated with airway invasion and dysphagia in other neurological conditions and may increase the risk of pneumonia. Therefore, this study aimed to characterize sensorimotor cough function and its relationship with ataxia severity. Thirty-seven participants with cerebellar ataxia completed voluntary and/or reflex cough testing. Ataxia severity was assessed using the Scale for the Assessment and Rating of Ataxia (SARA). Linear multilevel models revealed voluntary cough peak expiratory flow rate (PEFR) estimates of 2.61L/s and cough expired volume (CEV) estimates of 0.52L. Reflex PEFR (1.82L/s) and CEV (0.34L) estimates were lower than voluntary PEFR and CEV estimates. Variability was higher for reflex PEFR (15.74% coefficient of variation [CoV]) than voluntary PEFR (12.13% CoV). 46% of participants generated at least two, two-cough responses following presentations of reflex cough stimuli. There was a small inverse relationship between ataxia severity and voluntary PEFR (β = -0.05, 95% CI: -0.09 - -0.01L) and ataxia severity and voluntary CEV (β = -0.01, 95% CI: -0.02 - -0.004L/s). Relationships between reflex cough motor outcomes (PEFR β = 0.03, 95% CI: -0.007-0.07L/s; CEV β = 0.007, 95% CI: -0.004-0.02L) and ataxia severity were not statistically robust. Results indicate that voluntary and reflex cough sensorimotor dysfunction is present in cerebellar ataxias and that increased severity of ataxia symptoms may impact voluntary cough function.

Reinforcement Motor Learning After Cerebellar Damage Is Related to State Estimation.

Recent work showed that individuals with cerebellar degeneration could leverage intact reinforcement learning (RL) to alter their movement. However, there was marked inter-individual variability in learning, and the factors underlying it were unclear. Cerebellum-dependent sensory prediction may contribute to RL in motor contexts by enhancing body state estimates, which are necessary to solve the credit-assignment problem. The objective of this study was to test the relationship between the predictive component of state estimation and RL in individuals with cerebellar degeneration. Individuals with cerebellar degeneration and neurotypical control participants completed two tasks: an RL task that required them to alter the angle of reaching movements and a state estimation task that tested the somatosensory perception of active and passive movement. The state estimation task permitted the calculation of the active benefit shown by each participant, which is thought to reflect the cerebellum-dependent predictive component of state estimation. We found that the cerebellar and control groups showed similar magnitudes of learning with reinforcement and active benefit on average, but there was substantial variability across individuals. Using multiple regression, we assessed potential predictors of RL. Our analysis included active benefit, somatosensory acuity, clinical ataxia severity, movement variability, movement speed, and age. We found a significant relationship in which greater active benefit predicted better learning with reinforcement in the cerebellar, but not the control group. No other variables showed significant relationships with learning. Overall, our results support the hypothesis that the integrity of sensory prediction is a strong predictor of RL after cerebellar damage.

A Versatile, Behavioral Method to Investigate Thyroid Hormone Effects on Cerebellar Function.

Thyroid hormone (TH) action is essential during the development of the central nervous system, including the cerebellum. In case of TH deficiency in early life such as congenital hypothyroidism, patients display neurological disorders such as cognitive retardation and motor deficits. There are various studies using mouse models with tissue- or cell-specific TH deficiency to investigate the role of TH in the cerebellum. Compared to generalized congenital hypothyroid mice, cerebellar cell-specific TH-deficient mice display milder and subtler ataxic features, making the assessment of motor function difficult when using conventional tests such as the rotarod test. Due to the need for an alternative tool to assess motor function in TH-related animal models, we developed a versatile behavioral method called the "ladder beam test," in which we can design the various ladder tests depending on the severity of ataxia in model mice. We utilized transgenic mice expressing a dominant-negative TH receptor specifically in the cerebellar Purkinje cell, a sole output neuron in the cerebellar cortex modulating motor performance. The newly-built ladder beam test successfully detected robust impairments in motor performance in the transgenic mice at a greater level compared to the rotarod test. Disruption of motor learning was also detected in the ladder beam test but not in the rotarod test. The protocol with this novel behavioral apparatus can be applied to other animal models that may show mild ataxic phenotype to examine subtle changes in cerebellar function.

Proprioceptive and tactile processing in individuals with Friedreich ataxia: an fMRI study.

Friedreich ataxia (FA) neuropathology affects dorsal root ganglia, posterior columns in the spinal cord, the spinocerebellar tracts, and cerebellar dentate nuclei. The impact of the somatosensory system on ataxic symptoms remains debated. This study aims to better evaluate the contribution of somatosensory processing to ataxia clinical severity by simultaneously investigating passive movement and tactile pneumatic stimulation in individuals with FA. Twenty patients with FA and 20 healthy participants were included. All subjects underwent two 6 min block-design functional magnetic resonance imaging (fMRI) paradigms consisting of twelve 30 s alternating blocks (10 brain volumes per block, 120 brain volumes per paradigm) of a tactile oddball paradigm and a passive movement paradigm. Spearman rank correlation tests were used for correlations between BOLD levels and ataxia severity. The passive movement paradigm led to the lower activation of primary (cSI) and secondary somatosensory cortices (cSII) in FA compared with healthy subjects (respectively 1.1 ± 0.78 vs. 0.61 ± 1.02, p = 0.04, and 0.69 ± 0.5 vs. 0.3 ± 0.41, p = 0.005). In the tactile paradigm, there was no significant difference between cSI and cSII activation levels in healthy controls and FA (respectively 0.88 ± 0.73 vs. 1.14 ± 0.99, p = 0.33, and 0.54 ± 0.37 vs. 0.55 ± 0.54, p = 0.93). Correlation analysis showed a significant correlation between cSI activation levels in the tactile paradigm and the clinical severity (R = 0.481, p = 0.032). Our study captured the difference between tactile and proprioceptive impairments in FA using somatosensory fMRI paradigms. The lack of correlation between the proprioceptive paradigm and ataxia clinical parameters supports a low contribution of afferent ataxia to FA clinical severity.

Health-Related Quality of Life in Patients with Spinocerebellar Ataxia: a Validation Study of the EQ-5D-3L

Although health-related quality of life (HRQoL) has developed into a crucial outcome parameter in clinical research, evidence of the EQ-5D-3L validation performance is lacking in patients with spinocerebellar ataxia (SCA) types 1, 2, 3, and 6. The objective of this study is to assess the acceptability, validity, reliability, and responsiveness of the EQ-5D-3L. For n = 842 predominantly European SCA patients of two longitudinal cohort studies, the EQ-5D-3L, PHQ-9 (Patient Health Questionnaire), and ataxia-specific clinical assessments (SARA: Scale for Assessment and Rating of Ataxia; ADL: activities of daily living as part of Friedreich’s Ataxia Rating Scale; INAS: Inventory of Non-Ataxia Signs) were assessed at baseline and multiple annual follow-ups. The EQ-5D-3L was evaluated regarding acceptability, distribution properties, convergent and known-groups validity, test-retest reliability, and effect size measures to analyze health changes. The non-item response was low (EQ-5D-3L index: 0.8%; EQ-VAS: 3.4%). Ceiling effects occurred in 9.9% (EQ-5D-3L) and 3.0% (EQ-VAS) with a mean EQ-5D-3L index of 0.65 ± 0.21. In total, convergent validity showed moderate to strong Spearman’s rho (rs > 0.3) coefficients comparing EQ-5D-3L and EQ-VAS with PHQ-9, SARA, ADL, and INAS. EQ-5D-3L could discriminate between groups of age, SARA, ADL, and INAS. Intra-class correlation coefficients (EQ-5D-3LICC: 0.95/EQ-VASICC: 0.88) and Kappa statistics (range 0.44 to 0.93 for EQ-5D-3L items) indicated tolerable reliability. EQ-5D-3L shows small (effect size < 0.3) to moderate (effect size 0.3–0.59) health changes regarding ataxia severity. The analysis confirms an acceptable, reliable, valid, and responsive recommended EQ-5D-3L in SCA patients, measuring the HRQoL adequately, besides well-established clinical instruments.