Cognitive impairment in spinocerebellar ataxia type 12.

INTRODUCTION: Cognitive impairment has now been recognised to be present in patients with several of spinocerebellar ataxias (SCAs). Cognitive impairment in patients with spinocerebellar ataxia type 12 has not been evaluated. OBJECTIVE: To evaluate the cognitive impairment in patients diagnosed with spinocerebellar ataxia type 12 (SCA12). METHODS: We conducted a cross sectional study and enrolled 30 (20 male and 10 female) genetically confirmed SCA12 patients and 30 healthy, age, gender and education matched individuals as controls. Cognitive domains were tested using a battery of validated neurocognitive tests. RESULT: Mean age of patients was 51.6 ± 8.0 years and mean disease duration was 5.3 ± 3.0 years. Mean International Cooperative Ataxia Rating Scale (ICARS) score was 29.8 ± 12.5. SCA 12 patients scored significantly lower than controls in executive function and new learning ability. Other tested cognitive domains were also affected but did not reach statistical significance. Age, age at onset, severity of ataxia, disease duration and CAG repeat length did not correlate with cognitive impairment. CONCLUSION: Cognitive impairment is a part of the spectrum of SCA12 and is characterized by dysfunction in executive function and new learning ability even early in the course of disease.

Applicability of quantitative oculomotor and SARA assessment in children.

BACKGROUND: In clinical practice, eye movements can provide an early diagnostic marker for early onset ataxia (EOA). However, quantitative oculomotor assessment is not included in the most frequently used and age-validated ataxia rating scale in children, the Scale for the Assessment and Rating of Ataxia (SARA). We aimed to investigate the applicability of semi-quantitative eye movement assessment by the International Cooperative Ataxia Rating Scale (ICARSOCM) and Ocular Motion Score (OMS7-10) complementary to SARA measurements in children. METHODS: In 52 typically developing children (aged 4-16 years; n = 4 per year of age), three independent assessors scored saccadic eye movements and ocular pursuit according to the ICARSOCM and matching parameters from the OMS7-10. For ICARSOCM, we determined 1) construct validity for coordinated eye movements by correlation with OMS7-10, ICARSEYE-HAND-COORDINATION and SARA subscale scores, 2) agreement percentage and inter-rater agreement (Fleiss Kappa) and 3) age-dependency. RESULTS: Spearman's rank correlations of ICARSOCM with OMS7-10 and ICARS- and SARA subscales were moderate to fair (all p < .001). Inter-rater agreement of ICARS-OCM was 80.8%; (Fleiss Kappa: 0.411). ICARSOCM scores revealed a similar exponentially decreasing association with age as the other SARA (sub)scores, reaching a plateau at 10 years of age. INTERPRETATION: ICARSOCM has a valid construct for the measurement of coordinated eye movement performance and is reliably assessable in children. ICARSOCM reveals a similar age-dependent relationship as the other ataxia subscales, reflecting the physiological maturation of the cerebellum. In children, these data may implicate that ICARSOCM can reliably contribute to coordination assessment, complementary to the SARA subscales.

Age is an important independent modifier of SCA3 phenotype severity.

OBJECTIVE: This study aimed to investigate factors modulating spinocerebellar ataxia type 3 (SCA3) phenotype severity besides the expanded CAG repeats (ExpCAG) of ATXN3. METHODS: Data regarding CAG trinucleotide repeats, age at onset (AO), duration, age, sex, transmitting parent, and scale scores of SCA3 patients were collected. Multiple linear regression analysis was performed to identify influential independent variables. Age, AO, ExpCAG, and duration were considered control variables to analyze the correlation between independent variables and scale scores. RESULTS: Duration, age, and ExpCAG were screened as influential independent variables (P = 0.000). Age had the greatest impact on multiple linear regression models (P<5E-8). ExpCAG and SARA/ICARS/INAS/Barthel index were not correlated (P > 0.05); considering only age as the control, ExpCAG was slightly-to-moderately correlated with all aforementioned scores except INAS (P < 0.05). Age and all scores, except INAS, were positively correlated (P < 0.05); considering duration, AO, or ExpCAG as controls, their correlations did not change significantly. On controlling age, AO was negatively correlated with all scores (P < 0.05), except for the Barthel index (P > 0.05). Furthermore, the interaction model revealed that the interaction between age, duration, and ExpCAG was significantly associated with SCA3 disease severity (P < 0.05). CONCLUSION: Age is a potentially important modifier of SCA3 phenotype severity, through the interaction between ExpCAG and aging factors.

Assessment and Rating of Motor Cerebellar Ataxias With the Kinect v2 Depth Sensor: Extending Our Appraisal.

Current assessment of patients with cerebellar disorders is based on conventional neurological examination that is dependent on subjective judgements. Quantitative measurement of cerebellar ataxias (CAs) is essential for assessment of evidence-based treatments and the monitoring of the progress or recovery of diseases. It may provide us a useful tool to navigate future treatments for ataxia. We developed a Kinect v2. sensor system with a novel algorithm to measure and evaluate movements for two tests of Scale for the Assessment and Rating of Ataxia (SARA): the nose-finger test and gait. For the nose-finger test, we evaluated and compared accuracy, regularities and smoothness in the movements of the index finger and the proximal limbs between cerebellar patients and control subjects. For the task of walking, we evaluated and compared stability between the two groups. The precision of the system for evaluation of movements was smaller than 2 mm. For the nose-finger test, the mildly affected patients tended to show more instability than the control subjects. For a severely affected patient, our system quantified the instability of movements of the index finger using kinematic parameters, such as fluctuations and average speed. The average speed appears to be the most sensitive parameter that contrasts between patients with CAs and control subjects. Furthermore, our system also detected the adventitious movements of more proximal body parts, such as the elbow, shoulder and head. Assessment of walking was possible only in patients with mild CAs. They demonstrated large sways and compensatory wide stances. These parameters appeared to show higher accuracy than SARA. This examiner-independent device measures movements of the points of interest of SARA more accurately than eye and further provides additional information about the ataxic movements (e.g., the adventitious movements of the elbow, shoulder and head in the nose-finger test and the wide-based walking with large oscillation in the gait task), which is out of the scope of SARA. Our new system enables more accurate scoring of SARA and further provides additional information that is not currently evaluated with SARA. Therefore, it provides an easier, more accurate and more systematic description of CAs.

Carboxyl Terminus of Hsp70-Interacting Protein Is Increased in Serum and Cerebrospinal Fluid of Patients With Spinocerebellar Ataxia Type 3.

Background: Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is the most common type of autosomal dominant ataxia. Like other neurodegenerative diseases, is characterized by the dysfunction of the protein quality control (PQC) system. The carboxyl terminus of the Hsp70-interacting protein (CHIP), an important component of PQC, participates in the clearance of misfolded proteins to maintain cellular homeostasis. While no cure for SCA3 exists, the disease progresses slowly. Thus, the identification of biomarkers that indicate the severity and prognosis of this disease would be valuable. Methods: In this exploratory case-control study, we quantitatively evaluated the concentrations of CHIP in the sera of 80 patients with SCA3 and 80 age and sex-matched controls, using the enzyme-linked immunosorbent assay (ELISA). CHIP levels in the cerebrospinal fluid (CSF) donated by six patients and six healthy volunteers, who were matched for sex and age were also measured. All the baseline data were collected, and the patients underwent clinical evaluation. The correlations between CHIP levels and several clinical measurements were analyzed. Results: The serum CHIP level in the SCA3 group was (80.93 ± 28.68) ng/mL, which was significantly higher than those in the control group [(40.37 ± 18.55) ng/mL]. Similar results were observed for the CSF [(164.59 ± 42.99) ng/mL and (37.47 ± 7.85) ng/mL, respectively]. CSF CHIP levels were significantly higher than the serum CHIP levels in the SCA3 group but not in the control group. The Dunn-Bonferroni post-hoc for Kruskal-Wallis test revealed no significant difference between the serum and CSF of the patients and the control group. Multivariate linear regression showed that serum CHIP levels correlated positively with disease severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). Moreover, we found that serum CHIP levels were moderately correlated with age in healthy controls. Conclusion: The present study determined that CHIP levels increased significantly in the serum and CSF of patients with SCA3 and that serum CHIP levels were corelated with disease severity. Thus, CHIP is a promising biomarker for SCA3.

Scales for the clinical evaluation of cerebellar disorders.

Clinical scales represent an important tool not only for the initial grading/scoring of disease and assessment of progression, but also for the quantification of therapeutic effects in clinical trials. There are several scales available for the clinical evaluation of cerebellar symptoms. While some scales have been developed and evaluated for specific cerebellar disorders such as Friedreich ataxia, others reliably capture cerebellar symptoms with no respect to the underlying etiology. Each scale has its strengths and weaknesses. Extensive scales are certainly useful for thorough documentation of specific features of certain phenotypes, but this gain of information is not always essential for the purpose of a study. Therefore, compact and manageable scales like the Scale for the Assessment and Rating of Ataxia (SARA) or Brief Ataxia Rating Scale (BARS) are often preferred compared to more complex scales in observational and therapeutic studies.

A quantitative assessment of the evolution of cerebellar syndrome in children with phosphomannomutase-deficiency (PMM2-CDG).

BACKGROUND: We aim to delineate the progression of cerebellar syndrome in children with phosphomannomutase-deficiency (PMM2-CDG) using the International Cooperative Ataxia Rating Scale (ICARS). We sought correlation between cerebellar volumetry and clinical situation. We prospectively evaluated PMM2-CDG patients aged from 5 to 18 years through ICARS at two different time points set apart by at least 20 months. We reviewed available MRIs and performed volumetric analysis when it was possible. RESULTS: From the eligible 24, four patients were excluded due to severe mental disability (n = 2) and supratentorial lesions (n = 2). Two different ICARS evaluations separated by more than 20 months were available for 14 patients showing an improvement in the cerebellar syndrome: ICARS1: 35.71 versus ICARS2: 30.07 (p < 0.001). When we considered time, we saw an improvement of 2.64 points in the ICARS per year with an SD of 1.97 points (p < 0.001). The ICARS subscales results improved with time, reaching statistical significance in "Posture and gait" (p < 0.001), "Kinetic functions" (p = 0.04) and "Speech abnormalities" (p = 0.045). We found a negative correlation between the ICARS results and total cerebellar volume (r = -0.9, p = 0.037) in a group of five patients with available volumetric study, meaning that the higher the ICARS score, the more severe was the cerebellar atrophy. CONCLUSIONS: Our study shows a stabilization or mild improvement in the cerebellar functions of paediatric PMM2-CDG patients despite cerebellar volume loss. ICARS is a valid scale to quantify the evolution of cerebellar syndrome in PMM2-CDG patients. The availability of ICARS and other reliable and sensitive follow-up tools may prove essential for the evaluation of potential therapies.

Validity and reliability of the International Cooperative Ataxia Rating Scale (ICARS) and the Scale for the Assessment and Rating of Ataxia (SARA) in multiple sclerosis patients with ataxia.

BACKGROUND: Ataxia is an extremely common problem in multiple sclerosis (MS) patients. Thus, appropriate scales are required for detailed assessment of this issue. The aim of our study was to investigate the reliability and validity of the Turkish version of the International Cooperative Ataxia Rating Scale (ICARS) and Scale for the Assessment and Rating of Ataxia (SARA), which are widely used in ataxia evaluation in the context of other cerebellar diseases. METHOD: This cross-sectional study included 80 MS patients with Kurtzke cerebellar functional system score (C-FSS) greater than zero and slight pyramidal involvement. The Expanded Disability Status Scale (EDSS), C-FSS, and Berg Balance Scale (BBS) were administered. SARA and ICARS were assessed on first admission by two physical therapists. Seven days later, second assessments were repeated in same way for reliability. RESULTS: Intra-rater and inter-rater reliability were found to be high for both ICARS and SARA (p< 0.001) The Cronbach's α coefficients were 0.922 and 0.921 for SARA (reviewer 1 and reviewer 2 respectively) and 0.952 and 0.952 for ICARS (reviewer 1 and reviewer 2, respectively). There were no floor or ceiling effects determined for either scale except for item 17 of ICARS (p= 0.055). The EDSS total score had significant correlations with both SARA and ICARS (rho: 0.557 and 0.707, respectively). C-FSS had moderate correlation with SARA and high correlation with ICARS (rho: 0.469 and 0.653, respectively). BBS had no significant correlation with SARA and ICARS. (rho: -0.048 and -0.008 respectively). According to the area under the curve (AUC) value, ICARS is the best scale to discriminate mild and moderate ataxia. (AUC: 0.875). Factor analyses of ICARS showed that the rating results were determined by five different factors that did not coincide with the ICARS sub-scales. CONCLUSION: Our study demonstrated that ICARS and SARA are both reliable in MS patients with ataxia. Although ICARS has some structural problems, it seems to be more valid given its high correlations with EDSS and C-FSS. SARA also can be preferred as a brief assessment.

Monitoring disease progression in spinocerebellar ataxias: implications for treatment and clinical research.

INTRODUCTION: Spinocerebellar ataxias (SCAs) are autosomal dominant diseases characterized by progressive gait and limb incoordination, disequilibrium, dysarthria, and eye movement disturbances. Approximately 40 genetic subtypes of SCAs are known and classified according to the causative disease gene/locus. With the possibility of the specific genetic diagnosis in patients and at-risk family members, several clinical scales and functional tests have been validated and used in ataxic patients with the purposes of measuring the entity of disease progression in natural history studies and the possible slowing of neurological impairment in therapeutic trials. Areas covered: This paper reviews the most widely used clinical scales and quantitative tests that contributed in monitoring disease progression of the most common forms of SCAs. Expert commentary: The currently available and validated clinical scales and quantitative performance scores are adequate to measure disease severity, but may require a considerable number of subjects and a long period of treatment to allow the recognition of beneficial effect of interventional therapies. Advanced MRI techniques are a consistent biomarker and maybe useful to track disease progression from the preclinical to the manifest ataxic phase in association with appropriate clinical or paraclinical investigations.

Development of global rating instruments for pediatric patients with ataxia telangiectasia.

INTRODUCTION: Ataxia telangiectasia (AT) is a neurodegenerative disorder with cerebellar and extrapyramidal features. Interventional and epidemiological studies in AT should rely on specific scales which encompass the specific neurological features, as well the early progressive course and the subsequent plateau. The aim of this study was to build a scale of the CGI type (Clinical Global Impression) which is disease specific, as well as to check the feasibility of the ICARS scale for ataxia in this population. METHODS: We recruited 63 patients with ataxia, aged 10.76 ± 3.2 years, followed at 6 international AT centers, 49 of them (77.8%) with classical AT. All patients were evaluated for ataxia with ICARS scale. In patients with AT, two CGI scales were scored, unstructured as structured for which separate anchors were provided. RESULTS: Mean ICARS score was 44.7 ± 20.52, and it's severity positively correlated with age (Spearman correlation, r = 0.46, p < 0.01). Mean CGI score was 2 (moderately involved). There was a high correlation between the structured and unstructured CGIs (Spearman correlation, r = 0.87, p < 0.01). Both CGI scales showed positive correlation between severity and increasing age (Spearman correlation r = 0.59, p < 0.01 for structured CGI and r = 0.61, p < 0.01 for unstructured). DISCUSSION: We succeeded to build two CGI scales: structured and unstructured, which are disease specific for AT. The unstructured scale showed better connection to disease course; the sensitivity of the unstructured scale could be improved by adding anchors related to extrapyramidal features. In addition we showed that ataxia can be reliably measured in children with AT by using ICARS.

The gait variability index: a new way to quantify fluctuation magnitude of spatiotemporal parameters during gait.

This article describes a conglomerate measure of gait variability based on nine spatiotemporal parameters: the Gait Variability Index (GVI). Concurrent validity, inter-session reliability and minimum detectable change (MDC) were evaluated in 31 patients with Friedreich's Ataxia (FRDA), through comparisons with classically used evaluation tools such as the International Cooperative Ataxia Rating Scale (ICARS). GVI scores for the healthy population were 100.3±8.6 and were significantly reduced in FRDA patients (70.4±7.9). The GVI was correlated with the global ICARS score and was sensitive enough to differentiate between groups of FRDA patients categorized by the Posture and Gait Disturbances sub-score. The GVI was found to have a high inter-session reliability with an intraclass correlation coefficient of 0.91. A MDC of 8.6 points was found necessary to ensure that a change in GVI reflects a true change rather than measurement error. The GVI provides a quantitative measure of variability which behaves well statistically in both HP and patients with FRDA. It can be easily implemented using the supplemental data provided with this article. Complementary work is necessary to strengthen the GVI validation.