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Adult-onset ataxias are a genetically and clinically heterogeneous group of movement disorders. In addition to nuclear gene mutations, sequence changes have also been described in the mitochondrial genome. Here, we present findings of mutation analysis of the mitochondrial gene MT-ATP6. We analyzed 94 patients with adult-onset spinocerebellar ataxia (SCA), including 34 sporadic cases. In all patients, common sequence changes found in SCAs such as repeat expansions and point mutations had been excluded previously. We found pathogenic MT-ATP variants in five of these patients (5.32%), two of whom were sporadic. Four of the five mutations have not previously been described in ataxias. All but one of these mutations affect transmembrane helices of subunit-α of ATP synthase. Two mutations (p.G16S, and p.P18S) disrupt transmembrane helix 1 (TMH1), one mutation (p.G167D) affects TMH5, and another one (p.L217P) TMH6. The fifth mutation (p.T96A) describes an amino acid change in close proximity to transmembrane helix 3 (TMH3). The level of heteroplasmy was either complete or very high ranging from 87 to 99%. The high prevalence of pathogenic MT-ATP6 variants suggests that analysis of this gene should be included in the routine workup of both hereditary and sporadic ataxias.

Background Parkinson's disease (PD) causes chronic pain in two-thirds of patients, in part originating from sensory neuropathies. The aim of the present study was to describe the phenotype of PD-associated sensory neuropathy and to evaluate its associations with lipid allostasis, the latter motivated by recent genetic studies associating mutations of glucocerebrosidase with PD onset and severity. Glucocerebrosidase catalyzes the metabolism of glucosylceramides. Methods We used quantitative sensory tests, pain ratings, and questionnaires and analyzed plasma levels of multiple bioactive lipid species using targeted lipidomic analyses. The study comprised 2 sets of patients and healthy controls: the first 128 Israeli PD patients and 224 young German healthy controls for exploration, the second 50/50 German PD patients and matched healthy controls for deeper analyses. Results The data showed a 70% prevalence of PD pain and sensory neuropathies with a predominant phenotype of thermal sensory loss plus mechanical hypersensitivity. Multivariate analyses of lipids revealed major differences between PD patients and healthy controls, mainly originating from glucosylceramides and endocannabinoids. Glucosylceramides were increased, whereas anandamide and lysophosphatidic acid 20:4 were reduced, stronger in patients with ongoing pain and with a linear relationship with pain intensity and sensory losses, particularly for glucosylceramide 18:1 and glucosylceramide 24:1. Conclusions Our data suggest that PD-associated sensory neuropathies and PD pain are in part caused by accumulations of glucosylceramides, raising the intriguing possibility of reducing PD pain and sensory loss by glucocerebrosidase substituting or refolding approaches. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep brain stimulation (DBS) is a safe and effective treatment option for patients with movement disorders as Parkinson's disease, essential tremor and dystonia[1]. For many of these patients the need for imaging may arise in the following years after implantation. The study's aim was to get an overview of the amount of patients with a DBS system who needed an MRI after successful implantation, and if they did, whether the imaging led to a surgical consequence.In this retrospective descriptive work patients were included if they had their DBS implantation for at least 12 months at the time of analysis. Data were collected by retrospective analysis of the electronic patient files as well as a telephone interview. The reason of each imaging performed was assessed, if patients got MRI after the implantation, it was additionally recorded whether imaging led to a consequence (conservative treatment or surgery). An independent neurologist assessed if an MRI would have been better than a CT for the particular indication.From 54 included patients, 28 patients received imaging after implantation, either CT or MRI. 7 patients underwent MRIs, of whom 3 patients received cranial MRIs and 4 patients received lumbar spine MRIs. All cranial MRIs led to conservative therapy, in 2 lumbar MRIs the diagnosis led to surgery. Nearly 13 % of the imaging performed in our study population occurred because of fall events, 9 of the included patients developed or have had a tumor diagnosis.Safety of MRI for patients with implanted DBS-systems is and remains an important consideration. Since it can be assumed that patients at a younger age are more likely to get an MRI in the course of their disease, we suggest paying particular attention to the MRI's suitability of the DBS device by patients age. In the end it remains always an individual decision for the surgeon or the consulting physician, which system to use.

Mild cognitive impairment (MCI) often precedes Alzheimer’s Dementia (AD), and in a high proportion of individuals affected by MCI, there are already neuropathological processes ongoing that become more evident when patients progress to AD. Accordingly, there is a need for reliable biomarkers to distinguish between normal aging and incipient AD. Recent research suggests that, in addition to established biomarkers such as CSF Aß42, total tau and hyperphosphorylated tau, resting state connectivity established by functional magnetic resonance imaging might also be a feasible biomarker for prodromal stages of AD. In order to explore this possibility, we investigated resting state functional connectivity as well as cerebrospinal fluid (CSF) biomarker profiles in patients with MCI (n = 30; age 66.43 ± 7.06 years) and cognitively healthy controls (n = 38; age 66.89 ± 7.12 years). CSF Aß42, total tau and hyperphosphorylated tau concentrations were correlated with measures of cognitive performance (immediate and delayed recall, global cognition, processing speed). Moreover, MCI-related alterations in intrinsic functional connectivity within the default mode network were investigated using functional resting state MRI. As expected, MCI patients showed decreased CSF Aß42 and increased total tau concentrations. These alterations were associated with cognitive performance. However, there were no differences between MCI patients and cognitively healthy controls regarding intrinsic functional connectivity. In conclusion, our results indicate that CSF protein profiles seem to be more closely related to cognitive decline than alterations in resting state activity. Thus, resting state connectivity might not be a reliable biomarker for early stages of AD.

Background: Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity. Objective: The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease. Methods: We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels. Results: The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume. Conclusion: Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society Funding agencies: This publication is an outcome of ESMI, an EU Joint Programme - Neurodegenerative Disease Research (JPND) Project (see www.jpnd.eu). The project is supported under the aegis of JPND through the following funding organizations: Germany, Federal Ministry of Education and Research (BMBF; funding codes 01ED1602A/B); Netherlands, The Netherlands Organisation for Health Research and Development; Portugal, Foundation for Science and Technology and Regional Fund for Science and Technology of the Azores; United Kingdom, Medical Research Council. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement 643417. At the US sites this work was in part supported y the National Ataxia Foundation and the National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS080816. The Center for Magnetic Resonance Research is supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) grant P41 EB027061, and the Institutional Center Cores for Advanced Neuroimaging award P30 NS076408 and S10 OD017974 grant.

Summary Background Spinocerebellar ataxias (SCAs) are autosomal dominant neurodegenerative diseases. Our aim was to study the conversion to manifest ataxia among apparently healthy carriers of mutations associated with the most common SCAs (SCA1, SCA2, SCA3, and SCA6), and the sensitivity of clinical and functional measures to detect change in these individuals. Methods In this prospective, longitudinal, observational cohort study, based at 14 referral centres in seven European countries, we enrolled children or siblings of patients with SCA1, SCA2, SCA3, or SCA6. Eligible individuals were those without ataxia, defined by a score on the Scale for the Assessment and Rating of Ataxia (SARA) of less than 3; participants had to be aged 18–50 years for children or siblings of patients with SCA1, SCA2, or SCA3, and 35–70 years for children or siblings of patients with SCA6. Study visits took place at recruitment and after 2, 4, and 6 years (plus or minus 3 months). We did genetic testing to identify mutation carriers, with results concealed to the participant and clinical investigator. We assessed patients with clinical scales, questionnaires of patient-reported outcome measures, a rating of the examiner's confidence of presence of ataxia, and performance-based coordination tests. Conversion to ataxia was defined by an SARA score of 3 or higher. We analysed the association of factors at baseline with conversion to ataxia and the evolution of outcome parameters on temporal scales (time from inclusion and time to predicted age at ataxia onset) in the context of mutation status and conversion status. This study is registered with ClinicalTrials.gov , NCT01037777 . Findings Between Sept 13, 2008, and Oct 28, 2015, 302 participants were enrolled. We analysed data for 252 participants with at least one follow-up visit. 83 (33%) participants were from families affected by SCA1, 99 (39%) by SCA2, 46 (18%) by SCA3, and 24 (10%) by SCA6. In participants who carried SCA mutations, 26 (52%) of 50 SCA1 carriers, 22 (59%) of 37 SCA2 carriers, 11 (42%) of 26 SCA3 carriers, and two (13%) of 15 SCA6 carriers converted to ataxia. One (3%) of 33 SCA1 non-carriers and one (2%) of 62 SCA2 non-carriers converted to ataxia. Owing to the small number of people who met our criteria for ataxia, subsequent analyses could not be done in carriers of the SCA6 mutation. Baseline factors associated with conversion were age (hazard ratio 1·13 [95% CI 1·03–1·24]; p=0·011), CAG repeat length (1·25 [1·11–1·41]; p=0·0002), and ataxia confidence rating (1·72 [1·23–2·41]; p=0·0015) for SCA1; age (1·08 [1·02–1·14]; p=0·0077) and CAG repeat length (1·65 [1·27–2·13]; p=0·0001) for SCA2; and age (1·27 [1·09–1·50]; p=0·0031), confidence rating (2·60 [1·23–5·47]; p=0·012), and double vision (14·83 [2·15–102·44]; p=0·0063) for SCA3. From the time of inclusion, the SARA scores of SCA1, SCA2, and SCA3 mutation carriers increased, whereas they remained stable in non-carriers. On a timescale defined by the predicted time of ataxia onset, SARA progression in SCA1, SCA2, and SCA3 mutation carriers was non-linear, with marginal progression before ataxia and increasing progression after ataxia onset. Interpretation Our study provides quantitative data on the conversion of non-ataxic SCA1, SCA2, and SCA3 mutation carriers to manifest ataxia. Our data could prove useful for the design of preventive trials aimed at delaying the onset of ataxia by aiding sample size calculations and stratification of study participants. Funding European Research Area Network for Research Programmes on Rare Diseases, Polish Ministry of Science and Higher Education, Italian Ministry of Health, European Community's Seventh Framework Programme.

Background Hypertrophic olivary degeneration (HOD) occurs as a result of a lesion in the anatomical functional loop of the Guillain-Mollaret triangle. Frequent causes are intracerebral hemorrhage and brain infarction. After a latent period of weeks to months after the index event a hyperintensity can initially be observed in magnetic resonance imaging T2/FLAIR-weighting and finally an enlargement of the affected olive. Characteristic symptoms are a rhythmic palatal tremor, a primarily vertical pendular nystagmus as well as Holmes' tremor of the upper limbs. Aim of the study The goal of this study was to illustrate the course of the disease and its clinical presentation in order to provide an improved understanding of the pathophysiology of HOD after stroke. Material and methods The neuroradiological database of the Goethe University Hospital was screened for HOD and related keywords (in German). Between 2010 and 2017 a total of 27 cases of HOD were identified, of which 12 patients had suffered a stroke in their medical history. Results The mean age of the 12 patients was 51.4 years (±13.6 years) and one third of the patients were women. Of the patients eight had an intracerebral hemorrhage, three an ischemic stroke and one had a subarachnoid hemorrhage as the causative event. The lesions were located in the pons (n = 7), cerebellum (n = 4) and pontomesencephalon (n = 1). The median latent period from the causative index event to radiological diagnosis was 24 months (min. 4 months, max. 115 months). The leading symptoms of HOD were palatal tremor (55%), Holmes' tremor (18%), pendular nystagmus (18%) and dysarthria (73%). A logopedic examination with flexible endoscopic evaluation of swallowing (FEES) could determine a palatal tremor in five out of nine cases. The diagnosis of HOD was named in the medical report in only 50% of the cases. Conclusion Analysis of the dataset provided confirmation of the results in the literature that lesions within the Guillain-Mollaret triangle more often lead to HOD. Patients with corresponding symptoms should be closely observed over time with respect to the occurrence of corresponding clinical and imaging leading symptoms. Even though the named clinical symptoms are characteristic for HOD, in many cases the diagnosis is hampered and delayed by imprecise examination and misinterpretation of the symptoms. A logopedic examination using FEES in this collective often provided indicative information. Currently, no reliable data are available on the incidence of HOD after brainstem lesions or on potential preventive and treatment options. Future epidemiological and translational studies could perspectively enable valuable insights to be gained.

Zervikale Dystonien sind die häufigsten fokalen Dystonien. Der apparativen Diagnostik müssen eine gründliche allgemeine klinische neurologische Untersuchung und eine exakte phänomenologische Bewertung voran gestellt werden. Bei der Detektion der dystonen Muskeln hilft das Collum-Caput Concept, da nahezu alle Halsmuskeln entweder am Kopf oder an der HWS wirken. Die Behandlung mit Botulinumtoxin ist das therapeutische Mittel der Wahl.

Hypertrophic olivary degeneration (HOD) occurs as a result of a lesion in the anatomical functional loop of the Guillain-Mollaret triangle. Frequent causes are intracerebral hemorrhage and brain infarction. After a latent period of weeks to months after the index event a hyperintensity can initially be observed in magnetic resonance imaging T2/FLAIR-weighting and finally an enlargement of the affected olive. Characteristic symptoms are a rhythmic palatal tremor, a primarily vertical pendular nystagmus as well as Holmes' tremor of the upper limbs.The goal of this study was to illustrate the course of the disease and its clinical presentation in order to provide an improved understanding of the pathophysiology of HOD after stroke.The neuroradiological database of the Goethe University Hospital was screened for HOD and related keywords (in German). Between 2010 and 2017 a total of 27 cases of HOD were identified, of which 12 patients had suffered a stroke in their medical history.The mean age of the 12 patients was 51.4 years (±13.6 years) and one third of the patients were women. Of the patients eight had an intracerebral hemorrhage, three an ischemic stroke and one had a subarachnoid hemorrhage as the causative event. The lesions were located in the pons (n = 7), cerebellum (n = 4) and pontomesencephalon (n = 1). The median latent period from the causative index event to radiological diagnosis was 24 months (min. 4 months, max. 115 months). The leading symptoms of HOD were palatal tremor (55%), Holmes' tremor (18%), pendular nystagmus (18%) and dysarthria (73%). A logopedic examination with flexible endoscopic evaluation of swallowing (FEES) could determine a palatal tremor in five out of nine cases. The diagnosis of HOD was named in the medical report in only 50% of the cases.Analysis of the dataset provided confirmation of the results in the literature that lesions within the Guillain-Mollaret triangle more often lead to HOD. Patients with corresponding symptoms should be closely observed over time with respect to the occurrence of corresponding clinical and imaging leading symptoms. Even though the named clinical symptoms are characteristic for HOD, in many cases the diagnosis is hampered and delayed by imprecise examination and misinterpretation of the symptoms. A logopedic examination using FEES in this collective often provided indicative information. Currently, no reliable data are available on the incidence of HOD after brainstem lesions or on potential preventive and treatment options. Future epidemiological and translational studies could perspectively enable valuable insights to be gained.

Zervikale Dystonien sind die häufigsten fokalen Dystonien. Der apparativen Diagnostik müssen eine gründliche allgemeine klinische neurologische Untersuchung und eine exakte phänomenologische Bewertung voran gestellt werden. Bei der Detektion der dystonen Muskeln hilft das Collum-Caput Concept, da nahezu alle Halsmuskeln entweder am Kopf oder an der HWS wirken. Die Behandlung mit Botulinumtoxin ist das therapeutische Mittel der Wahl.

Summary Background Spinocerebellar ataxias are dominantly inherited progressive ataxia disorders that can lead to premature death. We aimed to study the overall survival of patients with the most common spinocerebellar ataxias (SCA1, SCA2, SCA3, and SCA6) and to identify the strongest contributing predictors that affect survival. Methods In this longitudinal cohort study (EUROSCA), we enrolled men and women, aged 18 years or older, from 17 ataxia referral centres in ten European countries; participants had positive genetic test results for SCA1, SCA2, SCA3, or SCA6 and progressive, otherwise unexplained, ataxias. Survival was defined as the time from enrolment to death for any reason. We used the Cox regression model adjusted for age at baseline to analyse survival. We used prognostic factors with a p value less than 0·05 from a multivariate model to build nomograms and assessed their performance based on discrimination and calibration. The EUROSCA study is registered with ClinicalTrials.gov, number NCT02440763. Findings Between July 1, 2005, and Aug 31, 2006, 525 patients with SCA1 (n=117), SCA2 (n=162), SCA3 (n=139), or SCA6 (n=107) were enrolled and followed up. The 10-year survival rate was 57% (95% CI 47–69) for SCA1, 74% (67–81) for SCA2, 73% (65–82) for SCA3, and 87% (80–94) for SCA6. Factors associated with shorter survival were: dysphagia (hazard ratio 4·52, 95% CI 1·83–11·15) and a higher value for the Scale for the Assessment and Rating of Ataxia (SARA) score (1·26, 1·19–1·33) for patients with SCA1; older age at inclusion (1·04, 1·01–1·08), longer CAG repeat length (1·16, 1·03–1·31), and higher SARA score (1·15, 1·10–1·20) for patients with SCA2; older age at inclusion (1·44, 1·20–1·74), dystonia (2·65, 1·21–5·53), higher SARA score (1·26, 1·17–1·35), and negative interaction between CAG and age at inclusion (0·994, 0·991–0·997) for patients with SCA3; and higher SARA score (1·17, 1·08–1·27) for patients with SCA6. The nomogram-predicted probability of 10-year survival showed good discrimination ( c index 0·905 [SD 0·027] for SCA1, 0·822 [0·032] for SCA2, 0·891 [0·021] for SCA3, and 0·825 [0·054] for SCA6). Interpretation Our study provides quantitative data on the survival of patients with the most common spinocerebellar ataxias, based on a long follow-up period. These results have implications for the design of future interventional studies of spinocerebellar ataxias; for example, the prognostic survival nomogram could be useful for selection and stratification of patients. Our findings need validation in an external population before they can be used to counsel patients and their families. Funding European Union 6th Framework programme, German Ministry of Education and Research, Polish Ministry of Scientific Research and Information Technology, European Union 7th Framework programme, and Fondation pour la Recherche Medicale.

To study the long-term evolution of patient-reported outcome measures (PROMs) in the most common spinocerebellar ataxias (SCAs), we analyzed 8 years follow-up data of the EUROSCA Natural History Study, a cohort study of 526 patients with SCA1, SCA2, SCA3 and SCA6. To assess the functional capacity in daily living, we used the functional assessment (part IV) of the Unified Huntington’s Disease Rating Scale (UHDRS-IV), for health-related quality of life the visual analogue scale of the EuroQol Five Dimensions Questionnaire (EQ-5D VAS), and for depressive symptoms the Patient Health Questionnaire (PHQ-9). Severity of ataxia was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and neurological symptoms other than ataxia with the Inventory of Non-Ataxia Signs (INAS). UHDRS-IV [SCA1: − 1.35 (0.12); SCA2: − 1.15 (0.11); SCA3: − 1.16 (0.11); SCA6: − 0.99 (0.12)] and EQ-5D [SCA1: − 2.88 (0.72); SCA2: − 1.97 (0.49); SCA3: − 2.06 (0.55); SCA6: − 1.03 (0.57)] decreased linearly, whereas PHQ-9 increased [SCA1: 0.15 (0.04); SCA2: 0.09 (0.03); SCA3: 0.06 (0.04); SCA6: 0.07 (0.04)] during the observational period. Standard response means (SRMs) of UHDRS-IV (0.473–0.707) and EQ-5D VAS (0.053–0.184) were lower than that of SARA (0.404–0.979). In SCA1, higher SARA scores [− 0.0288 (0.01), p = 0.0251], longer repeat expansions [− 0.0622 (0.02), p = 0.0002] and the presence of cognitive impairment at baseline [− 0.5381 (0.25), p = 0.0365] were associated with faster UHDRS-IV decline. In SCA3, higher INAS counts were associated with a faster UHDRS-IV decline [− 0.05 (0.02), p = 0.0212]. In SCA1, PHQ-9 progression was faster in patients with cognitive impairment [0.14 (0.07); p = 0.0396]. In the common SCAs, PROMs give complementary information to the information provided by neurological scales. This underlines the importance of PROMs as additional outcome measures in future interventional trials.

Item does not contain fulltext BACKGROUND: Spinocerebellar ataxias are dominantly inherited neurodegenerative diseases. As potential treatments for these diseases are being developed, precise knowledge of their natural history is needed. We aimed to study the long-term disease progression of the most common spinocerebellar ataxias: SCA1, SCA2, SCA3, and SCA6. Furthermore, we aimed to establish the order and occurrence of non-ataxia symptoms, and identify predictors of disease progression. METHODS: In this longitudinal cohort study (EUROSCA), we enrolled men and women with positive genetic testing for SCA1, SCA2, SCA3, or SCA6 and with progressive, otherwise unexplained ataxia who were aged 18 years or older from 17 ataxia referral centres in ten European countries. Patients were seen every year for 3 years, and at irregular intervals thereafter. The primary outcome was the scale for the assessment and rating of ataxia (SARA), and the inventory of non-ataxia signs (INAS). We used linear mixed models to analyse progression. To account for dropouts, we applied a pattern-mixture model. This study is registered with ClinicalTrials.gov, number NCT02440763. FINDINGS: Between July 1, 2005, and Aug 31, 2006, 526 patients with SCA1, SCA2, SCA3, or SCA6 were enrolled. We analysed data for 462 patients with at least one follow-up visit. Median observation time was 49 months (IQR 35-72). SARA progression data were best fitted with a linear model in all genotypes. Annual SARA score increase was 2.11 (SE 0.12) in patients with SCA1, 1.49 (0.07) in patients with SCA2, 1.56 (0.08) in patients with SCA3, and 0.80 (0.09) in patients with SCA6. The increase of the number of non-ataxia signs reached a plateau in SCA1, SCA2, and SCA3. In patients with SCA6, the number of non-ataxia symptoms increased linearly, but more slowly than in patients with SCA1, SCA2, and SCA3 (p

Deep brain stimulation (DBS) is a highly efficient, evidence-based therapy for a set of neurological and psychiatric conditions and especially movement disorders such as Parkinson's disease, essential tremor and dystonia. Recent developments have improved the DBS technology. However, no unequivocal algorithms for an optimized postoperative care exist so far. The aim of this review is to provide a synopsis of the current clinical practice and to propose guidelines for postoperative and rehabilitative care of patients who undergo DBS. A standardized work-up in the DBS centers adapted to each patient's clinical state and needs is important, including a meticulous evaluation of clinical improvement and residual symptoms with a definition of goals for neurorehabilitation. Efficient and complete information transfer to subsequent caregivers is essential. A coordinated therapy within a multidisciplinary team (trained in movement disorders and DBS) is needed to achieve the long-range maximal efficiency. An optimized postoperative framework might ultimately lead to more effective results of DBS.

Objective:To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations.Methods:The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing.Results:The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74, p < 0.0001) and disease duration (0.22 ± 0.06 per additional year, p = 0.0007) were associated with a higher SARA score. Forty-eight participants who did not fulfill MSA-C criteria and had a disease duration of >10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8, p = 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2, p = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made.Conclusions:Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort.ClinicalTrials.gov registration:NCT02701036.

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

Carriers of a single heterozygous PINK1 (PTEN-induced putative kinase 1) gene mutation provide an ideal opportunity to study the development of parkinsonian motor signs from the very beginning. Measuring tools that reliably represent mild motor symptoms could also facilitate the assessment of future neuroprotective therapies and early diagnosis of Parkinson's disease (PD). We investigated nine family members carrying a heterozygous PINK1 mutation in comparison with 25 age-matched healthy controls. Arm kinematics were quantified during treadmill walking at four different speeds using ultrasound-based motion analysis. Heterozygous PINK1 mutation carriers showed a bilateral reduction of arm swing amplitudes (P = 0.003) and arm anteversion (P = 0.001), which was more pronounced on the predominantly affected body side but also was present, albeit to a lesser degree, contralaterally (amplitude P = 0.01, anteversion P = 0.002, repeated measures analysis of covariance [rmANCOVA]). Single post-hoc comparisons revealed similar results for all speeds on both body sides (P

SCA28 is caused by mutations in the AFG3L2 gene. This gene encodes a subunit of the mitochondrial metalloprotease AFG3L2 (AFG3-like protein 2). Clinical features of SCA28 include slow to moderate progressive ataxia, dysarthria, and additional symptoms such as nystagmus, slow saccades, and increased deep tendon reflexes. Here, we report on a novel AFG3L2 mutation in a patient with slowly progressive ataxia and a positive family history. The nucleotide change results in the substitution of an evolutionarily highly conserved tyrosine by histidine (p.Y689H) in the M41 peptidase domain of AFG3L2.

Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem. White matter pathology is generally less severe and thought to occur in the brainstem, spinal cord, and cerebellar white matter. Here, we investigated both grey and white matter pathology in a group of 12 SCA3 patients and matched controls. We used voxel-based morphometry for analysis of tissue loss, and tract-based spatial statistics (TBSS) on diffusion magnetic resonance imaging to investigate microstructural pathology. We analysed correlations between microstructural properties of the brain and ataxia severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) score. SCA3 patients exhibited significant loss of both grey and white matter in the cerebellar hemispheres, brainstem including pons and in lateral thalamus. On between-group analysis, TBSS detected widespread microstructural white matter pathology in the cerebellum, brainstem, and bilaterally in thalamus and the cerebral hemispheres. Furthermore, fractional anisotropy in a white matter network comprising frontal, thalamic, brainstem and left cerebellar white matter strongly and negatively correlated with SARA ataxia scores. Tractography identified the thalamic white matter thus implicated as belonging to ventrolateral thalamus. Disruption of white matter integrity in patients suffering from SCA3 is more widespread than previously thought. Moreover, our data provide evidence that microstructural white matter changes in SCA3 are strongly related to the clinical severity of ataxia symptoms.

International contractors must consider the substantial risks related to unexpected foreign exchange fluctuation when conducting their business and using foreign currencies in foreign countries. Most international contractors attempt to minimize foreign exchange exposure within a manageable range because it may influence the company's fundamental financial structure, reduce market value or profit margins, or disrupt ongoing and future projects. This research provides a qualitative study of existing foreign exchange exposure (transaction, operation, and translation exposure) and current and effective foreign exchange risk management in American and Korean international contractors, as they represent both new and long-time members of the global construction market. Finally, recommendations of strategies for new and existing international contractors to minimize and better manage foreign exchange risk will be offered.

Multi-Core processors have become main-stream microprocessors in recent years. Servers based on these multi-core processors are widely adopted in High Performance Computing (HPC) and commercial business applications as well. These servers provide increased level of parallelism, thus can potentially boost the performance for applications. However, the shared resources among multiple cores on the same chip can become hot spots and act as performance bottlenecks. Therefore it is essential to optimize the use of shared resources for high performance and scalability for the multi-core servers. In this paper, we conduct experimental studies to analyze the positive and negative effects of the resource sharing on the performance of HPC applications. Through the analyses we also characterize the performance of multi-core servers.

BACKGROUND Tractography based on diffusion tensor imaging has become a popular tool for delineating white matter tracts for neurosurgical procedures. OBJECTIVE To explore whether navigated transcranial magnetic stimulation (nTMS) might increase the accuracy of fiber tracking. METHODS Tractography was performed according to both anatomic delineation of the motor cortex (n = 14) and nTMS results (n = 9). After implantation of the definitive electrode, stimulation via the electrode was performed, defining a stimulation threshold for eliciting motor evoked potentials recorded during deep brain stimulation surgery. Others have shown that of arm and leg muscles. This threshold was correlated with the shortest distance between the active electrode contact and both fiber tracks. Results were evaluated by correlation to motor evoked potential monitoring during deep brain stimulation, a surgical procedure causing hardly any brain shift. RESULTS Distances to fiber tracks clearly correlated with motor evoked potential thresholds. Tracks based on nTMS had a higher predictive value than tracks based on anatomic motor cortex definition (P < .001 and P = .005, respectively). However, target site, hemisphere, and active electrode contact did not influence this correlation. CONCLUSION The implementation of tractography based on nTMS increases the accuracy of fiber tracking. Moreover, this combination of methods has the potential to become a supplemental tool for guiding electrode implantation.

Item does not contain fulltext Although ataxia is by definition the prominent symptom of ataxia disorders, there are various neurological signs that may accompany ataxia in affected patients. Reliable and quantitative assessment of these signs is important because they contribute to disability, but may also interfere with ataxia. Therefore we devised the Inventory of Non-Ataxia Signs (INAS), a list of neurological signs that allows determining the presence and severity of non-ataxia signs in a standardized way. INAS underwent a rigorous validation procedure that involved a trial of 140 patients with spinocerebellar ataxia (SCA) for testing of inter-rater reliability and another trial of 28 SCA patients to assess short-term intra-rater reliability. In addition, data of the ongoing EUROSCA natural history study were used to determine the reproducibility, responsiveness and validity of INAS. Inter-rater reliability and short-term test-retest reliability was high, both for the total count and for most of the items. However, measures of responsiveness, such as the smallest detectable change and the clinically important change were not satisfactory. In addition, INAS did not differentiate between subjects that were subjectively stable and those that worsened in the 2-year observation period. In summary, INAS and INAS count showed good reproducibility, but unsatisfactory responsiveness. The present analysis and published data from the EUROSCA natural history study suggest that INAS is a valid measure of extracerebellar involvement in progressive ataxia disorders. As such, it is useful as a supplement to the measures of ataxia, but not as a primary outcome measure in future interventional trials.

Summary Background Spinocerebellar ataxias (SCAs) are autosomal, dominantly inherited, fully penetrant neurodegenerative diseases. Our aim was to study the preclinical stage of the most common SCAs: SCA1, SCA2, SCA3, and SCA6. Methods Between Sept 13, 2008, and Dec 1, 2011, offspring or siblings of patients with SCA1, SCA2, SCA3, or SCA6 were enrolled into a prospective, longitudinal observational study at 14 European centres. To be eligible for inclusion in our study, individuals had to have no ataxia and be aged 18–50 years if directly related to individuals with SCA1, SCA2, or SCA3, or 35–70 years if directly related to individuals with SCA6. We did anonymous genetic testing to identify mutation carriers. We assessed participants with clinical scales, questionnaires, and performance-based coordination tests. In eight of the 14 centres, participants underwent MRI. We analysed relations between outcome variables and time from onset (defined as the difference between present age and estimated age at ataxia onset). This study is registered with ClinicalTrials.gov, number NCT01037777. Findings 276 participants met inclusion criteria and agreed to participate, of whom 12 (4%) were excluded from final analysis because DNA samples were missing or genotyping failed. Estimated time from onset was −9 years (IQR −13 to −6) in 50 carriers of the SCA1 mutation, −12 years (–15 to −9) in 31 SCA2 mutation carriers, −8 years (–11 to −6) in 26 SCA3 mutation carriers, and −18 years (–22 to −16) in 16 SCA6 mutation carriers. Compared with non-carriers of each mutation, SCA1 mutation carriers had higher median scores on the scale for the assessment and rating of ataxia (SARA; 0·5 [IQR 0–1·0] vs 0 [0–0]; p=0·0052), as did SCA2 mutation carriers (0·5 [0–2·0] vs 0 [0–0·5]; p=0·0037). SCA2 mutation carriers had lower SCA functional index scores than did non-carriers (–0·43 [–0·91 to −0·07] vs 0·09 [–0·30 to 0·56]; p=0·0007). SCA2 mutation carriers had worse composite cerebellar functional scores than did their non-carrier counterparts (0·915 [0·861–0·959] vs 0·849 [0·764–0·886]; p=0·0039). All other differences between carriers and non-carriers were non-significant. In SCA1 and SCA2 mutation carriers, SARA scores were increased in participants who were closer to the estimated age at onset (SCA1: r =0·36, p=0·0112; SCA2: r =0·50, p=0·0038). 83 individuals (30%) underwent MRI. Voxel-based morphometry showed grey-matter loss in the brainstem and cerebellum in SCA1 and SCA2 mutation carriers, and normalised brainstem volume was lower in SCA2 mutation carriers (median 0·015, range 0·012–0·016) than in non-carriers (0·019, 0·017–0·021; p=0·0107). Interpretation Preclinical SCA1 and SCA2 mutation carriers seem to have mild coordination deficits and abnormalities in the brain that are more common in carriers who are closer to the estimated onset of ataxia. Individuals in this early disease stage could be targeted in future preventive trials. Funding ERA-Net E-Rare and Polish Ministry of Science and Higher Education.

Background Recently, a link between resting motor threshold (RMT) and local tissue microstructure, as indexed by fractional anisotropy (FA), was demonstrated in large parts of white matter. However, regions showing such correlations were generally found outside of the corticospinal tract (CST). Therefore, the question arises whether other electrophysiologic measurements could be more locally related to microstructural properties of the CST. In this study, we explored the relationship between such measurements and regional FA in a group of healthy volunteers. Objective/Hypothesis We hypothesized that RMT might be more related to an overall susceptibility of white matter to TMS, whereas other electrophysiologic markers might be more specifically related to properties of the CST only. Methods Thirty-seven subjects were included. We studied RMT, active motor threshold (AMT), intensity to evoke a motor-evoked potential (MEP) of 1 mV (S1mV), MEP input-output curve (IO-curve), and central motor conduction time (CMCT) using transcranial magnetic stimulation, and FA of the corticospinal tract using diffusion tensor magnetic resonance imaging. We performed voxel-wise and TBSS correlation analysis between these electrophysiologic measurements and FA. In addition, we tested for significant correlation between these parameters and mean diffusivity (MD). Results On voxel-wise analysis, we did not detect significant correlations between any electrophysiologic parameter (RMT, AMT, S1mV, IO curve slope, CMCT) and FA. With TBSS, we detected correlations between FA and bilateral AMT, as well as left-hemispheric S1mV, but these correlations were found in locations unlikely to contribute to motor pathways. Conclusions Although a relationship between structure and function has been shown in many other regions of the brain, it seems to be much more challenging to demonstrate such a relationship in the CST of healthy subjects.

This study set out to determine whether there is white matter involvement in essential tremor (ET), the most common movement disorder. We collected diffusion MRI and analysed differences in fractional anisotropy (FA) and mean diffusivity (MD) between ET patients and control subjects as markers of white matter integrity. We used both classical ROI‐based statistics and whole‐brain analysis techniques, including voxel‐wise analysis with SPM5 and tract‐based spatial statistics (TBSS). Using region of interest (ROI) analysis, we found increased MD bilaterally in the inferior cerebellar peduncles (ICP) and reduced FA in the right‐sided ICP of ET patients. Whole‐brain analyses with TBSS detected increased MD distributed in both motor and nonmotor white matter fibers of ET patients predominantly in the left parietal white matter, while there were no significant FA differences in these areas between ET patients and controls. Voxel‐wise analysis with SPM detected significant increase of MD congruent with the highest probability of difference as detected by TBSS. VBM analysis of T1 images did not detect significant differences in either gray or white matter density between our study groups. In summary, we found evidence for changes in white matter MRI properties in ET. The circumscript pathology of the ICP corroborates the pathogenetic concept of the cerebellum and its projections as key structures for tremor generation in ET. Moreover, increased diffusivity in white matter structures of both hemispheres suggests widespread alterations of fiber integrity in motor and nonmotor networks in ET patients. The underlying cause of the DTI changes observed remains to be elucidated. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.

Contains fulltext : 89297.pdf (Publisher’s version ) (Closed access) Patient-based measures of subjective health status are increasingly used as outcome measures in interventional trials. We aimed to determine the variability and predictors of subjective health ratings in a possible target group for future interventions: the spinocerebellar ataxias (SCAs). A consecutive sample of 526 patients with otherwise unexplained progressive ataxia and genetic diagnoses of SCA1 (117), SCA2 (163), SCA3 (139), and SCA6 (107) were enrolled at 18 European referral centers. Subjective health status was assessed with a generic measure of health related quality of life, the EQ-5D (Euroqol) questionnaire. In addition, we performed a neurological examination and a screening questionnaire for affective disorders (patient health questionnaire). Patient-reported health status was compromised in patients of all genotypes (EQ-5D visual analogue scale (EQ-VAS) mean 61.45 +/- 20.8). Specifically, problems were reported in the dimensions of mobility (86.9% of patients), usual activities (68%), pain/discomfort (49.4%), depression/anxiety (46.4%), and self care (38.2%). Multivariate analysis revealed three independent predictors of subjective health status: ataxia severity, extent of noncerebellar involvement, and the presence of depressive syndrome. This model explained 30.5% of EQ-VAS variance in the whole sample and might be extrapolated to other SCA genotypes.

Contains fulltext : 87493.pdf (Publisher’s version ) (Closed access) BACKGROUND AND OBJECTIVE: Biomarkers to monitor neurological dysfunction in autosomal dominant inherited spinocerebellar ataxias (SCA) are lacking. We therefore aimed to visualize, quantify and correlate localized brain atrophy with clinical symptoms in SCA1, SCA3, and SCA6. METHODS: We compared patients suffering from SCA1 (n=48), SCA3 (n=24), and SCA6 (n=10) with 32 controls using magnetic resonance imaging (MRI) on four different scanners in eight centers followed by voxel-based morphometry (VBM) and quantitative three-dimensional (3D) volumetry. RESULTS: SCA1 and SCA3 patients presented with severe atrophy in total brainstem (consisting of midbrain, pons, and medulla), pons, medulla, total cerebellum, cerebellar hemispheres and cerebellar vermis, putamen and caudate nucleus. Atrophy in the cerebellar hemispheres was less severe in SCA3 than in SCA1 and SCA6. Atrophy in SCA6 was restricted to the grey matter of the cerebellum (VBM and volumetry), total brainstem and pons (volumetry only). Overall, we did not observe substantial atrophy in the cerebral cortex. A discriminant analysis taking into account data from pons, cerebellar hemispheres, medulla, midbrain and putamen achieved a reclassification probability of 81.7% for SCA1, SCA3, and SCA6. The repeat length of the expanded allele showed a weak negative correlation with the volume of the brainstem, pons, caudate nucleus and putamen in SCA3, and a weak correlation with the pons in SCA1, whereas no such correlation was found in SCA6. Clinical dysfunction as measured by the Scale for the Assessment and Rating of Ataxia (SARA) and the Unified Huntington's Disease Rating Scale functional assessment correlated best with the atrophy of pons in SCA1, with total brainstem atrophy in SCA3 and atrophy of total cerebellum in SCA6. CONCLUSIONS: Our data provide strong evidence that MRI is an attractive surrogate marker for clinical studies of SCA. In each SCA genotype clinical dysfunction may be caused by different patho-anatomical processes.