Ataxia Rating Research Articles

Neurologic outcomes in Friedreich ataxia: Study of a single-site cohort.

ObjectiveTo investigate the pattern of progression of neurologic impairment in Friedreich ataxia (FRDA) and identify patients with fast disease progression as detected by clinical rating scales.MethodsClinical, demographic, and genetic data were analyzed from 54 patients with FRDA included at the Brussels site of the European Friedreich's Ataxia Consortium for Translational Studies, with an average prospective follow-up of 4 years.ResultsAfferent ataxia predated other features of FRDA, followed by cerebellar ataxia and pyramidal weakness. The Scale for the Assessment and Rating of Ataxia (SARA) best detected progression in ambulatory patients and in the first 20 years of disease duration but did not effectively capture progression in advanced disease. Dysarthria, sitting, and upper limb coordination items kept worsening after loss of ambulation. Eighty percent of patients needing support to walk lost ambulation within 2 years. Age at onset had a strong influence on progression of neurologic and functional deficits, which was maximal in patients with symptom onset before age 8 years. All these patients became unable to walk by 15 years after onset, significantly earlier than patients with later onset. Progression in the previous 1 or 2 years was not predictive of progression in the subsequent year.ConclusionsThe SARA is a sensitive outcome measure in ambulatory patients with FRDA and has an excellent correlation with functional capabilities. Ambulatory patients with onset before age 8 years showed the fastest measurable worsening. Loss of ambulation in high-risk patients is a disease milestone that should be considered as an end point in clinical trials.

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.

Entropy-based analysis of rhythmic tapping for the quantitative assessment of cerebellar ataxia

The severity of appendicular ataxia is currently assessed by neurological specialists observing the motor deficits during the performance of bedside tests. These tests are traditionally restricted to discrete subjective scales and prescribed by constraints that may in turn affect the subject's performance. To overcome these limitations and facilitate uniform monitoring of cerebellar ataxia, an instrumented assessment system using a wearable sensor has been developed for the rhythmic finger and foot tapping tasks. Departing from the conventional obligation to spatiotemporal parameters that are described clinically, the proposed approach investigates features based on information theory to evaluate the variability of the tapping dynamics. From a clinical trial of 24 healthy subjects and 34 patients diagnosed with cerebellar ataxia (CA), the findings revealed not only are there more variations in movement patterns and timing of tapping events in CA but that movement complexity was also degraded across multiple entropy scales. The system using combined models of different features was able to achieve an average classification accuracy of 81% and 79% in finger and foot tapping respectively. The outcomes strongly agreed with the clinical scale widely-used for the assessment and rating of ataxia (SARA) to a correlation level of 0.71 (p < 0.001) in finger tapping and 0.59 (p < 0.001) in foot tapping.

Evolution of the vestibular function during head impulses in spinocerebellar ataxia type 6.

Evolution of vestibular function requires further elucidation in spinocerebellar ataxia (SCA). This study aimed to determine temporal evolution in the findings of head impulse tests (HITs) in SCA type 6 (SCA6). We serially evaluated HITs in 12 patients with SCA6 using video-oculography for 3months to 5years [median = 12months, interquartile range (IQR) = 9-50] at two university hospitals in South Korea. Patients (8/12, 67%) usually showed abnormal responses at least for one semicircular canal during video-HITs. The gains of the vestibulo-ocular reflex (VOR) for the anterior canals (ACs) were larger than those for the posterior canals (PCs, p = 0.005) at initial presentation. During the follow-up, the VOR gains decreased for the horizontal canals (HCs, p = 0.008) and ACs (p = 0.021), but those for the PCs remained unchanged (p = 0.212). Perverted HITs were observed in seven patients (7/12, 58%). The differences in the head impulse VOR gains were larger between the ACs and PCs (ΔACs - PCs) in those with perverted HITs than in those without (p = 0.003). The gains for each semicircular canal showed a negative correlation with the Scale for the Assessment and Rating of Ataxia (HCs, Spearman's coefficient = - 0.675, p = 0.003; ACs, - 0.637, p = 0.006; PCs, - 0.605, p = 0.010). The head impulse gain of the VOR may serve a marker for clinical decline in SCA6. The dissociation in the temporal evolution of the VOR gain indicates dissimilar cerebellar modulation of the vestibular signals from each semicircular canal.

Relationship between ataxia and inferior cerebellar peduncle injury in patients with cerebral infarct.

Introduction:The inferior cerebellar peduncle (ICP) is a major neural tract in the cerebellum and is involved in coordination of movement and proprioceptive; therefore, ICP injury can be accompanied by poor coordination of movement, including ataxia. In this study, using diffusion tensor tractography (DTT), we investigated the relationship between ataxia and ICP injury in patients with cerebral infarct.Methods:We recruited 14 stroke patients with ataxia after the onset of stroke and 12 normal subjects. The Score of Assessment and Rating of Ataxia (SARA) was used to evaluate ataxia. The values of fractional anisotropy (FA), apparent diffusion coefficient, and fiber number (FN) of the ICP were measured for the diffusion tensor imaging parameters.Results:Significant differences were observed in the FA and FN values of the ICP in the affected hemisphere between the patient and control groups (P < .05). In addition, the FN value of the ICP in the affected hemisphere showed a negative correlation with SARA (r = −0.538, P < .05). However, parameters of the ICP in the unaffected hemisphere or the FN value in the unaffected hemisphere showed no correlation with SARA (P > .05).Conclusion:We found that the ataxia severity was closely related to the severity of ICP injury in patients with cerebral infarct. Our results suggest that evaluation of the ICP using DTT would be useful for patients with ataxia after cerebral infarct.

Ocular Involvement in Friedreich Ataxia Patients and its Relationship with Neurological Disability, a Follow-up Study.

Background: This study compared functional and structural visual changes in Friedreich ataxia (FRDA) patients with healthy controls (HC) and correlated these changes with neurological disability. Methods: Eight FRDA Spanish patients and eight HC were selected from 2014 to 2018. Best corrected visual acuity (BCVA), visual field (VF), optic coherence tomography (OCT), and neurological disability measured by “scale for the assessment and rating of ataxia” (SARA) were taken in a basal exploration and repeated after 6 months. A linear mixed analysis and Bonferroni p-value correction were performed. Results: FRDA baseline and follow-up patients showed statistically significant decreases in BCVA, VF, and OCT parameters compared with the HC. Some of the VF measurements and most of the OCT parameters had an inverse mild-to-strong correlation with SARA. Moreover, the analysis of the ROC curve demonstrated that the peripapillary retinal nerve fiber layer (pRNFL) average thickness was the best parameter to discriminate between FRDA patients and HC. Conclusions: The follow-up study showed a progression in OCT parameters. Findings showed a sequential effect in pRNFL, ganglion cell complex (GCC), and macula. The VF and the OCT could be useful biomarkers in FRDA, both for their correlation with neurological disease as well as for their ability to evaluate disease progression.

Developing an objective evaluating system to quantify the degree of upper limb movement impairment in patients with severe Friedreich's ataxia.

The use of standardized tools and objective measurements is essential to test the effectiveness of new drugs or rehabilitative protocols. Friedreich's ataxia (FRDA) patients with severe disease are often unable to perform the quantitative measurement tests currently used. The purpose of our study was to develop an easy-to-use application, for touchscreen devices, able to quantify the degree of upper limb movement impairment in patients with severe Friedreich's ataxia. The APP, which we named "Twelve-Red-Squares App-Coo-Test" (12-RSACT), assesses the upper limb ataxia by measuring the test execution time. All patients were clinically evaluated using the Composite Cerebellar Functional Severity (CCFS) and the Scale for the Assessment and Rating of Ataxia (SARA). We recruited 92 healthy subjects and 36 FRDA patients with a SARA mean value of 28.8.1 ± 8.2. All participants in our study underwent upper limb movement assessment using the new 12-RSACT, the Click Test, and a well-established system, i.e., the Nine-Hole Peg Test (9HPT). We observed a strong linear correlation between the measurements obtained with the 12-RSACT and those obtained with 9HPT, Click Test, CCFS, and SARA. The 12-RSACT was characterized by excellent internal consistency and intra-rater and test-retest reliability. The minimal detectable change (MDC%) was excellent too. Additionally, the 12-RSACT turned out to be faster and easier to perform compared with the 9HPT. The 12-RSACT is an inexpensive test and is easy to use, which can be administered quickly. Therefore, 12-RSACT is a promising tool to assess the upper limb ataxia in FRDA patients and even those with severe diseases.

A Random Forest Approach for Quantifying Gait Ataxia With Truncal and Peripheral Measurements Using Multiple Wearable Sensors

Gait disturbance is one of the most pronounced and disabling symptoms of cerebellar disease (CD). Generally, gait studies quantify human gait characteristics under natural walking speeds while mainly considering upper body movements. Therefore, the primary goal of this study was to investigate the influence of different walking speeds on different gait parameters of both the upper and lower body, as a result of disabilities caused by Cerebellar Ataxia (CA). We employed wearable sensor technology to identify the kinematic characteristics which best identify the gait abnormalities seen in CA. Measurements were made at self-selected slow, preferred and fast walking speeds. Velocity irregularity and resonant frequency characteristics were identified as key features of truncal and lower limb movements respectively. Subsequently, the differentiating features for both trunk and lower limb movements were combined to produce an even greater separation between the patients and the normal subjects, as well as better correlation with the expert clinical assessment (ECA) (0.86) and the Scale for the Assessment and Rating of Ataxia (SARA) (0.62). The different speed of walking conditions resulted in varying degrees of the separation and the correlation. Moreover, the contribution of the extracted features was examined using the random forest algorithm. Clinically observable truncal medio-lateral movements express the disability at relatively slow gait speeds while the anterior-posterior movements captured by the sensory mechanisms characterises the disability across all walking speeds. The importance of selected dominant features from the trunk and lower limb suggest that overall clinical assessments are predominantly influenced by the lower body peripheral movements, particularly at higher cadences.

Effect of rovatirelin in patients with cerebellar ataxia: two randomised double-blind placebo-controlled phase 3 trials

ObjectiveTo investigate the efficacy of rovatirelin, a thyrotropin-releasing hormone analogue, for ataxias in patients with spinocerebellar degeneration (SCD).MethodsTwo multicentre, randomised, double-blind, placebo-controlled phase 3 studies (KPS1301, KPS1305) enrolled patients with...

Gait characteristics and clinical relevance of hereditary spinocerebellar ataxia on deep learning.

Deep learning has always been at the forefront of scientific research. It has also been applied to medical research. Hereditary spinocerebellar ataxia (SCA) is characterized by gait abnormalities and is usually evaluated semi-quantitatively by scales. However, more detailed gait characteristics of SCA and related objective methods have not yet been established. Therefore, the purpose of this study was to evaluate the gait characteristics of SCA patients, as well as to analyze the correlation between gait parameters, clinical scales, and imaging on deep learning. Twenty SCA patients diagnosed by genetic detection were included in the study. Ten patients who were tested via functional magnetic resonance imaging (fMRI) were included in the SCA imaging subgroup. All SCA patients were evaluated with the International Cooperative Ataxia Rating Scale (ICARS) and Scale for the Assessment and Rating of Ataxia (SARA) clinical scales. The gait control group included 16 healthy subjects, and the imaging control group included seven healthy subjects. Gait data consisting of 10 m of free walking of each individual in the SCA group and the gait control group were detected by wearable gait-detection equipment. Stride length, stride time, velocity, supporting-phase percentage, and swinging-phase percentage were extracted as gait parameters. Cerebellar volume and the midsagittal cerebellar proportion in the posterior fossa (MRVD) were calculated according to MR. There were significant differences in stride length, velocity, supporting-phase percentage, and swinging-phase percentage between the SCA group and the gait control group. The stride length and stride velocity of SCA groups were lower while supporting phase was longer than those of the gait control group. SCA group's velocity was negatively correlated with both the ICARS and SARA scores. The cerebellar volume and MRVD of the SCA imaging subgroup were significantly smaller than those of the imaging control group. MRVD was significantly correlated with ICARS and SARA scores, as well as stride velocity variability. SCA gait parameters were characterized by a reduced stride length, slower walking velocity, and longer supporting phase. Additionally, a smaller cerebellar volume correlated with an increased irregularity in gait. Gait characteristics exhibited considerable clinical relevance to hereditary SCA. We conclude that a combination of gait parameters, ataxia scales, and MRVD may represent more objective markers for clinical evaluations of SCA.

Automated Topographic Prominence based quantitative assessment of speech timing in Cerebellar Ataxia

Clinical assessment of speech abnormalities in Cerebellar Ataxia (CA) is subjective and prone to intra- and inter-clinician inconsistencies. This paper presents an automated objective method based on a single syllable repetition task to detect and quantify speech-timing anomalies in ataxic speech. Such a technique is non-invasive, reliable, fast, cost-effective and can be used in the comfort of home without any professional assistance. A mathematically inclined topographic prominence-based algorithm with an extensive outlier detection mechanism is designed for the automatic detection of syllables in the captured speech data. Six acoustic features and eleven corresponding speech timing and vocal stability measurements were extracted during the topographical prominence analysis. These features are used to classify CA from normal speakers and objectively identify the CA speakers based on their severity. The effectiveness of the proposed algorithm is experimentally evaluated through a clinical study involving 63 patients diagnosed with CA (to varying degrees of dysarthria) and 28 age-matched normal speakers. In syllable detection, our proposed automated algorithm achieved an accuracy of 95.6% and 99.1% for ataxic and normal speech respectively. These speech samples were clinically rated using the Scale for the Assessment and Rating of Ataxia (SARA). SVM classifier achieved a classification accuracy of 84.7% (area under ROC=0.91) in healthy-CA discrimination and 74.7% (average area under ROC=0.82) in the modified 4-level CA severity estimation based on SARA ratings. The strong classification ability of selected features and the SVM model supports suitability of this scheme to monitor speech motor abnormalities in persons suffering from CA.

Development of SaraHome: A novel, well-accepted, technology-based assessment tool for patients with ataxia

Background and objectiveEarly onset ataxias (EOAs) are a heterogeneous group of neurological conditions, responsible for severe motor disability in paediatric age, which still lack reliable outcome measures. Available scales to assess ataxia, such as the Scale for Assessment and Rating of Ataxia (SARA), are based on subjective assessment of specific motor and language tasks by an examiner, and therefore is age dependent and lacks accuracy in detecting small variations in disease severity.In last years, novel technologies, including computer interfaces and videogames, have emerged for clinical applications and the advent of Internet of Medical Things and of Information Communication Technology have allowed the remote control of such technologies. This pilot study describes a newly developed tool (SaraHome) for the assessment at home of EOA evaluating its feasibility and acceptability on a small sample of children. MethodsTen EOA children and ten caregivers have been enrolled for a preliminary outpatient evaluation. The Microsoft Kinect 2.0 and Leap Motion Controller (LMC) connected to a personal computer with an ad hoc software have been set-up, for the acquisition of standardized motor tasks performed by the patients with the caregivers’ assistance. Acceptance and practicability have been tested by QUEST 2.0 and IMI questionnaires in caregivers and patients respectively. ResultsThe SaraHome software was developed, based on a collection of services provided by a complex architecture that consists of a Restful interface, which enables to access a series of plugins for the execution of different tasks. A graphical user interface allows the acquisition of the patient movements while performing a motor task. A protocol of standard tasks inspired by SARA was established, and a system of video-assisted instruction provided. The set-up for the optimal acquisition of such protocol by Kinect and LMC has been defined. Both patients and caregivers accomplished the SaraHome assessment with good feedback at the technology acceptance questionnaires. ConclusionsSaraHome represents a newly developed tool for the assessment of ataxia in patients, resulting from the integration of low-cost and easy-accessible technologies. This pilot application highlighted the feasibility and the acceptability of the system, suggesting the potential use in clinical practice.

Alcoholic cerebellar degeneration: A case report

Introduction Alcohol-induced cerebellar degeneration is the commonest type of acquired toxic ataxia. The onset of the cerebellar symptoms usually occurs at middle age, with a significant history of chronic alcohol abuse. Permanent cerebellar deficits are observed among alcoholics, and they persist even with alcoholic abstinence. The cerebellum is the structure that controls the stability of the gaze, chronic cerebellar diseases and acute alcohol intoxication affect cerebellar function. Ataxia and nystagmus are neurological manifestations present in this disease. To verify vestibulocochlear disorders observed in a case of alcohol-induced cerebellar ataxia. Material and method It is a clinical case study of alcohol-induced cerebellar ataxia. The patient featured troubled walking (wide-based gait, preserved tactile sensitivity, hyperesthesia of the lower limbs, nystagmus, dysmetria, mild dysdiadochokinesia, numbness in the distal phalanges of the upper limbs, and uncoordinated movement). Results The patient evidenced bilateral hearing loss from the frequency of 3 kHz and absence of ipsilateral reflexes; magnetic resonance imaging (MRI) showed atrophy of the Cerebellar Vermis; scale for the assessment and rating of ataxia (SARA) scored 15; brainstem auditory evoked potential test (BAEP) evidenced diffused dysfunction of the auditory pathways; balance testing showed labyrinthine hypofunction with presence of bidirectional nystagmus, featuring central vestibular disorder and the falls efficacy scale (FES-1-Brazil) evidenced abnormalities. Conclusion The patient started treatment using B12 vitamin, thiamine, and physical therapy. Currently, despite reported balance improvement, he needs ambulation support. He features nystagmus, bilateral dysmetria, mild dysdiadochokinesia, continuous tinnitus in his left ear, blurred vision, and neck pain while moving it.

Motor Improvement in Adolescents Affected by Ataxia Secondary to Acquired Brain Injury: A Pilot Study.

Aim To assess changes in locomotion and balance in adolescents affected by ataxia secondary to acquired brain injury after a rehabilitation treatment with physiotherapy and the Gait Real-time Analysis Interactive Lab (GRAIL), an immersive virtual reality platform. Methods 11 ataxic adolescents (16(5) years old, 4.7(6.7) years from injury) underwent 20 45-minute sessions with GRAIL plus 20 45-minute sessions of physiotherapy in one month. Patients were assessed before and after rehabilitation with functional scales and three-dimensional multiple-step gait analysis. Results Results showed significant improvements in ataxia score assessed by the Scale for the Assessment and Rating of Ataxia, in dimension D and E of Gross Motor Function Measure, in walking endurance and in balance abilities. Moreover, the training fostered significant changes at hip, knee, and ankle joints, and the decrease of gait variability, toward healthy references. Interpretation In spite of the pilot nature of the study, data suggest that training with immersive virtual reality and physiotherapy is a promising approach for ataxic gait rehabilitation, even in chronic conditions.

Changes in standing stability with balance-based torso-weighting with cerebellar ataxia: A pilot study.

ObjectivesPeople with cerebellar ataxia have few options to improve the standing stability they need for function. Strategic placement of light weights on the torso using the balance‐based torso‐weighting (BBTW) method has improved stability and reduced falls in people with multiple sclerosis, but has not been tested in cerebellar ataxia. We examined whether torso‐weighting increased standing stability and/or functional movement in people with cerebellar ataxia.MethodsTen people with cerebellar ataxia and 10 matched controls participated in this single‐session quasi‐experimental pilot study. People with ataxia performed the Scale for the Assessment and Rating of Ataxia (SARA) prior to clinical testing. All participants donned inertial sensors that recorded postural sway; stopwatches recorded duration for standing and mobility tasks. All participants stood for up to 30 s on firm and foam surfaces with eyes open then eyes closed, and performed the Timed Up and Go (TUG) test. Light weights (0.57–1.25 kg) were strategically applied to a vest‐like garment. Paired t tests compared within‐group differences with and without BBTW weights. Independent t tests assessed differences from controls. All t tests were one‐tailed with alpha set at .05.ResultsDuration of standing for people with ataxia was significantly longer with weighting (p = .004); all controls stood for the maximum time of 120 s with and without weights. More severe ataxia according to SARA was moderately correlated with greater improvement in standing duration with BBTW (Pearson r = .54). Tasks with more sensory challenges (eyes closed, standing on firm surface) showed less body sway with weighting. Duration for the TUG was unchanged by torso‐weighting in people with ataxia.ConclusionStrategic weighting improved standing stability but not movement speed in people with ataxia. BBTW has potential for improving stability and response to challenging sensory conditions in this population. Future studies should further examine gait stability measures along with movement speed.

A comprehensive monocentric ophthalmic study with Gaucher disease type 3 patients: vitreoretinal lesions, retinal atrophy and characterization of abnormal saccades

SummaryBackgroundThe differentiation between Gaucher disease type 3 (GD3) and type 1 is challenging because pathognomonic neurologic symptoms may be subtle and develop at late stages. The ophthalmologist plays a crucial role in identifying the typical impairment of horizontal saccadic eye movements, followed by vertical ones. Little is known about further ocular involvement. The aim of this monocentric cohort study is to comprehensively describe the ophthalmological features of Gaucher disease type 3. We suggest recommendations for a set of useful ophthalmologic investigations for diagnosis and follow up and for saccadometry parameters enabling a correlation to disease severity.MethodsSixteen patients with biochemically and genetically diagnosed GD3 completed ophthalmologic examination including optical coherence tomography (OCT), clinical oculomotor assessment and saccadometry by infrared based video-oculography. Saccadic peak velocity, gain and latency were compared to 100 healthy controls, using parametric tests. Correlations between saccadic assessment and clinical parameters were calculated.ResultsPeripapillary subretinal drusen-like deposits with retinal atrophy (2/16), preretinal opacities of the vitreous (4/16) and increased retinal vessel tortuosity (3/16) were found. Oculomotor pathology with clinically slowed saccades was more frequent horizontally (15/16) than vertically (12/16). Saccadometry revealed slowed peak velocity compared to 100 controls (most evident horizontally and downwards). Saccades were delayed and hypometric. Best correlating with SARA (scale for the assessment and rating of ataxia), disease duration, mSST (modified Severity Scoring Tool) and reduced IQ was peak velocity (both up- and downwards). Motility restriction occurred in 8/16 patients affecting horizontal eye movements, while vertical motility restriction was seen less frequently. Impaired abduction presented with esophoria or esotropia, the latter in combination with reduced stereopsis.ConclusionsVitreoretinal lesions may occur in 25% of Gaucher type 3 patients, while we additionally observed subretinal lesions with retinal atrophy in advanced disease stages. Vertical saccadic peak velocity seems the most promising “biomarker” for neuropathic manifestation for future longitudinal studies, as it correlates best with other neurologic symptoms. Apart from the well documented abduction deficit in Gaucher type 3 we were able to demonstrate motility impairment in all directions of gaze.

Neurofilament light chain is a promising serum biomarker in spinocerebellar ataxia type 3

BackgroundSpinocerebellar ataxia type 3 (SCA3) is the most common subtype of autosomal dominantly inherited spinocerebellar ataxias (SCAs). No validated blood biomarker is available to assess either disease progression or therapeutic response. Neurofilament light chain (NfL) was recently proposed as a serum biomarker for many neurodegenerative disorders. The present study investigated whether NfL was a promising serum biomarker for SCA3.MethodsSeventeen SCA3 patients and 9 controls were enrolled in cohort A, and 116 SCA3 individuals (preclinical and patients) and 91 controls were recruited as cohort B. We assessed whether serum NfL correlated with cerebrospinal fluid (CSF) NfL in cohort A and correlations between serum NfL levels and clinical features and brain volumes were determined in cohort B. The single-molecule array method was used to measure serum NfL levels. Disease severity was determined using the scale for the assessment and rating of ataxia (SARA) and the international cooperative ataxia rating scale (ICARS). Cerebellar and brainstem volumes were assessed using MRI neuroimaging measurements.ResultsSerum/CSF NfL levels in cohort A were elevated in SCA3 patients, and serum and CSF NfL exhibited a significant positive correlation (r = 0.9179, p < 0.0001). Levels of serum NfL in cohort B were significantly higher in preclinical SCA3 (15.03 ± 7.49 vs 6.88 ± 2.72 pg/ mL, p < 0.0001) and manifest SCA3 subjects (37.56 ± 13.47 vs 9.07 ± 6.02 pg/ mL, p < 0.0001) compared to those in controls. Serum NfL concentrations increased from early disease stage to the next stage. Levels of serum NfL in ATXN3 mutation carriers were positively associated with SARA (r = 0.5458, p < 0.0001) and ICARS scores (r = 0.5522, p < 0.0001). Significant negative associations with cerebellar volumes (r = − 0.4217, p = 0.0003) and brainstem volumes (r = − 0.4263, p = 0.0003) were observed. All changes remained significant after adjustment for age and CAG repeat.ConclusionsLevels of serum NfL were significantly elevated in SCA3 individuals and correlated with disease severity. Serum NfL is a promising serum biomarker of disease onset and progression, and a potential candidate biomarker of treatment response in SCA3.

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.

Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA)

IntroductionCurrently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4 g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown.MethodsThe aim of the NICOFA study is to investigate the efficacy and safety of nicotinamide for the treatment of Friedreich ataxia over 24 months. An open-label dose adjustment wash-in period with nicotinamide (phase A: weeks 1–4) to the individually highest tolerated dose of 2–4 g nicotinamide/day will be followed by a 2 (nicotinamide group): 1 (placebo group) randomization (phase B: weeks 5–104). In the nicotinamide group, patients will continue with their individually highest tolerated dose between 2 and 4 g/d per os once daily and the placebo group patients will be receiving matching placebo. Safety assessments will consist of monitoring and recording of all adverse events and serious adverse events, regular monitoring of haematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations including cardiological signs. The primary outcome is the change in the Scale for the Assessment and Rating of Ataxia (SARA) over time as compared with placebo in patients with Friedreich ataxia based on the linear mixed effect model (LMEM) model. Secondary endpoints are measures of quality of life, functional motor and cognitive measures, clinician’s and patient’s global impression-change scales as well as the up-regulation of the frataxin protein level, safety and survival/death.PerspectiveThe NICOFA study represents one of the first attempts to assess the clinical efficacy of an epigenetic therapeutic intervention for this disease and will provide evidence of possible disease modifying effects of nicotinamide treatment in patients with Friedreich ataxia.Trial registrationEudraCT-No.: 2017-002163-17, ClinicalTrials.govNCT03761511.

Development and validation of a disease severity index for ataxia of Charlevoix-Saguenay.

To develop a disease-specific severity index for adults with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) (DSI-ARSACS) that considers the 3 components (pyramidal, cerebellar, neuropathic) of the disease, and to document its content validity, internal consistency, and construct validity. The Beta DSI-ARSACS (17 items) was developed based on literature review and expert inputs and then administered to 26 participants. Items reduction was based on Cronbach α and desirable criteria. Performance measures were administered to assess the construct validity of the final version of the DSI-ARSACS. The final DSI-ARSACS have 8 items that can be easily performed during usual medical follow-up. The mean score was 19.6 ± 8.1 (range 6.0-35.5) and the Cronbach α was 0.912. The DSI-ARSACS score increased with disease stage and age (p ≤ 0.001) and was closely correlated with other measures assessing similar construct (9-Hole Peg Test, 10-Meter Walk Test, Scale for the Assessment and Rating of Ataxia, Berg Balance Scale, Barthel Index) (r s = 0.75-0.95, p < 0.01). A moderate but not significant correlation was found with the 6-Minute Walk test (r s = -0.611, p = 0.108). The DSI-ARSACS is a valid measure of disease severity for the adult ARSACS population that is able to distinguish between patients with different clinical profiles. Further documentation of metrologic properties is necessary, but these first results are promising.