Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3.

OBJECTIVE: This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. METHODS: SCA1 or SCA3 mutation carriers and controls (n = 107) underwent MR scanning in the US-European READISCA study to obtain structural, diffusion MRI, and MR spectroscopy data using an advanced protocol at 3T. Morphometric, microstructural, and neurochemical metrics were analyzed blinded to diagnosis and compared between preataxic SCA (n = 11 SCA1, n = 28 SCA3), ataxic SCA (n = 14 SCA1, n = 37 SCA3), and control (n = 17) groups using nonparametric testing accounting for multiple comparisons. MR metrics that were most sensitive to preataxic abnormalities were identified using receiver operating characteristic (ROC) analyses. RESULTS: Atrophy and microstructural damage in the brainstem and cerebellar peduncles and neurochemical abnormalities in the pons were prominent in both preataxic groups, when patients did not differ from controls clinically. MR metrics were strongly associated with ataxia symptoms, activities of daily living, and estimated ataxia duration. A neurochemical measure was the most sensitive metric to preataxic changes in SCA1 (ROC area under the curve [AUC] = 0.95), and a microstructural metric was the most sensitive metric to preataxic changes in SCA3 (AUC = 0.92). INTERPRETATION: Changes in cerebellar afferent and efferent pathways underlie the earliest symptoms of both SCAs. MR metrics collected with a harmonized advanced protocol in the multisite trial setting allow detection of disease effects in individuals before ataxia onset with potential clinical trial utility for subject stratification. ANN NEUROL 2022.

Short and Mid Term Outcomes of Cryopreserved Abdominal Aortic Allografts Used as a Substitute for Infected Prosthetic Grafts in 200 Patients.

OBJECTIVE: To investigate the use of cryopreserved arterial allografts (CAA) as a substitute for infected infrarenal aortic prostheses, and its outcomes. METHODS: A single centre retrospective study of consecutive patients receiving an abdominal aortic CAA after removal of an infected graft was conducted between January 1997 and December 2013. The primary outcome was the rate of allograft related revision surgery. Secondary outcomes were the 30 day mortality rate, survival, primary patency, limb salvage, and infection recurrence. Allograft ruptures secondary to infection and risk factors for allograft failure were also investigated. RESULTS: Two hundred patients (mean age 64.2 ± 9.4 years) were included. In 56 (28%) cases, infection was related to an enteric fistula. The mean follow up duration was 4.1 years. The 30 day mortality rate was 11%. Early revision surgery was needed in 59 patients (29.5%). Among them, 15 (7.5%) were allograft related and led to the death of three patients (1.5%), corresponding to a 7.5% 30 day allograft related revision surgery rate. During the first six months, 17 (8.5%) patients experienced 21 events with complete or partial rupture (pseudo-aneurysm) of the allograft responsible for five (2.5%) deaths, corresponding to a re-infection rate of 8.5%. The multivariable analysis showed that diabetes and pseudo-aneurysm of the native aorta on presentation were predictive factors for short term allograft rupture. After six months, 25 (12.5%) patients experienced long term allograft complications (rupture, n = 2, 1%; pseudo-aneurysm, n = 6, 3%; aneurysm, n = 2, 1%; thrombosis, n = 11, 5.5%; stenosis, n = 4, 2%;) requiring revision surgery resulting in one death. The five year rates of survival, allograft related revision surgery, limb salvage, primary patency, and infection recurrence were 56%, 30%, 89%, 80%, and 12%, respectively. CONCLUSION: CAAs provide acceptable results to treat aortic graft infection with few early graft related fatal complications. Long term allograft related complications are quite common but are associated with low mortality and amputation rates.

Conversion of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 to manifest ataxia (RISCA): a longitudinal cohort study.

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.

Modeling the Cognitive Trajectory in CADASIL.

BACKGROUND: For developing future clinical trials in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), it seems crucial to study the long-term changes of cognition. OBJECTIVE: We aimed to study the global trajectory of cognition, measured by the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (MDRS), along the course of CADASIL. METHODS: Follow-up data of 185 CADASIL patients, investigated at the French National Referral center CERVCO from 2003, were considered for analysis based on strict inclusion criteria. Assuming that the MMSE and the MDRS provide imprecise measures of cognition, the trajectory of a common cognitive latent process during follow-up was delineated using a multivariate latent process mixed model. After adjustment of this model for sex and education, the sensitivities of the two scales to cognitive change were compared. RESULTS: Analysis of the cognitive trajectory over a time frame of 60 years of age showed a decrease of performances with aging, especially after age of 50 years. This decline was not altered by sex or education but patients who graduated from high school had a higher mean cognitive level at baseline. The sensitivities of MMSE and MDRS scales were similar and the two scales suffered from a ceiling effect and curvilinearity. CONCLUSION: These data support that cognitive decline is not linear and mainly occurs after the age of 50 years during the course of CADASIL. They also showed that MMSE and MDRS scales are hampered by major limitations for longitudinal studies.

Long-term evolution of patient-reported outcome measures in spinocerebellar ataxias.

INTRODUCTION: 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. METHODS: 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). RESULTS: 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]. CONCLUSIONS: 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.

Anterior pallidal deep brain stimulation for Tourette's syndrome: a randomised, double-blind, controlled trial.

BACKGROUND: Deep brain stimulation (DBS) has been proposed to treat patients with severe Tourette's syndrome, and open-label trials and two small double-blind trials have tested DBS of the posterior and the anterior internal globus pallidus (aGPi). We aimed to specifically assess the efficacy of aGPi DBS for severe Tourette's syndrome. METHODS: In this randomised, double-blind, controlled trial, we recruited patients aged 18-60 years with severe and medically refractory Tourette's syndrome from eight hospitals specialised in movement disorders in France. Enrolled patients received surgery to implant bilateral electrodes for aGPi DBS; 3 months later they were randomly assigned (1:1 ratio with a block size of eight; computer-generated pairwise randomisation according to order of enrolment) to receive either active or sham stimulation for the subsequent 3 months in a double-blind fashion. All patients then received open-label active stimulation for the subsequent 6 months. Patients and clinicians assessing outcomes were masked to treatment allocation; an unmasked clinician was responsible for stimulation parameter programming, with intensity set below the side-effect threshold. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) score between the beginning and end of the 3 month double-blind period, as assessed with a Mann-Whitney-Wilcoxon test in all randomly allocated patients who received active or sham stimulation during the double-blind period. We assessed safety in all patients who were enrolled and received surgery for aGPi DBS. This trial is registered with ClinicalTrials.gov, number NCT00478842. FINDINGS: Between Dec 6, 2007, and Dec 13, 2012, we enrolled 19 patients. We randomly assigned 17 (89%) patients, with 16 completing blinded assessments (seven [44%] in the active stimulation group and nine [56%] in the sham stimulation group). We noted no significant difference in YGTSS score change between the beginning and the end of the 3 month double-blind period between groups (active group median YGTSS score 68·5 [IQR 34·0 to 83·5] at the beginning and 62·5 [51·5 to 72·0] at the end, median change 1·1% [IQR -23·9 to 38·1]; sham group 73·0 [69·0 to 79·0] and 79·0 [59·0 to 81·5], median change 0·0% [-10·6 to 4·8]; p=0·39). 15 serious adverse events (three in patients who withdrew before stimulation and six each in the active and sham stimulation groups) occurred in 13 patients (three who withdrew before randomisation, four in the active group, and six in the sham group), with infections in DBS hardware in four patients (two who withdrew before randomisation, one in the sham stimulation group, and one in the active stimulation group). Other serious adverse events included one electrode misplacement (active stimulation group), one episode of depressive signs (active stimulation group), and three episodes of increased tic severity and anxiety (two in the sham stimulation group and one in the active stimulation group). INTERPRETATION: 3 months of aGPi DBS is insufficient to decrease tic severity for patients with Tourette's syndrome. Future research is needed to investigate the efficacy of aGPi DBS for patients over longer periods with optimal stimulation parameters and to identify potential predictors of the therapeutic response. FUNDING: French Ministry of Health.

Hypocalcemia after thyroidectomy in patients with a history of bariatric surgery.

BACKGROUND: Hypocalcemia is a common complication after total thyroidectomy. Previous bariatric surgery could be a higher factor risk for hypocalcemia due to alterations in calcium absorption and vitamin D deficiency. OBJECTIVES: To evaluate incidence and factors involved in the risk of hypocalcemia (transient and permanent) and the postoperative outcomes of these patients after total thyroidectomy. SETTING: University hospital in Paris, France. METHODS: All patients who had previously undergone obesity surgery (i.e., Roux-en-Y gastric bypass, sleeve gastrectomy, or adjustable gastric band) who had a total thyroidectomy from 2006 to 2015 were included. No patient was lost to follow-up. Each patient was matched 1:1 with a patient who had no previous bariatric surgery for age, gender, body mass index, and year of surgery. RESULTS: Forty-eight patients were identified (43 female; mean age 48.9±9.2 yr). Nineteen patients (40%) had a postoperative hypocalcemia: transient in 14 patients (29.2%) and permanent in 5 patients (10.4%). No significant predictive clinical or biochemical factors were found for hypocalcemia risk, except for the type of bariatric procedure: Bypass surgery had a 2-fold increased risk of hypocalcemia compared to others procedures (60% versus 30%, P = .05). In the matched pair analysis, the risk of hypocalcemia was significantly higher in patients with previous bariatric surgery than in the matched cohort (40% versus 15%, P = .006). CONCLUSION: Patients with previous bariatric surgery have an increased risk for hypocalcemia after total thyroidectomy, especially after Roux-en-Y gastric bypass. Careful and prolonged follow-up of calcium, vitamin D, and parathyroid hormone levels should be suggested for these patients.

Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma Is Associated With Aggressive Histopathological Features and a Poor Outcome: Results of a Large Multicentric Study.

CONTEXT: Diffuse sclerosing variant (DSV) is a rare and aggressive subtype of papillary thyroid carcinoma (PTC). OBJECTIVE: The objective of the study was to investigate the clinicopathological features and prognosis of DSV patients and compare these findings with all other PTCs and high-risk PTCs. DESIGN AND SETTING: The data of patients who underwent surgery for DSV and PTC between 2003 and 2014 in seven surgical departments specialized in endocrine surgery were reviewed. PATIENTS: Fifty-six DSV patients were included (mean age 32.6 ± 12.5 y; 46 [82%] female) and were compared with 2945 non-DSV PTCs and 48 high-risk PTCs. RESULTS: Forty-six DSV patients (82%) were pT3, 43 (77%) had an extrathyroidal extension, and 54 (96%) had lymph node metastasis, including 48 patients with involvement in the lateral compartment (86%). During the follow-up period of 4.3 ±2.3 years, 19 patients (34%) had a recurrence, including 18 patients with an ipsilateral lateral compartment recurrence. The only prognostic factor for recurrence in the multivariate analysis was extranodal extension (odds ratio 3.4 [1.1; 10.8]). The 7-year recurrence-free survival (RFS) was 63%. The RFS was significantly worse in patients with DSV than in other PTC patients (hazard risk 8.5 [5.2; 13.9], P < .0001) and were similar to the RFS of high-risk PTCs (hazard risk 1.1 [0.6; 2.2], P = .5). CONCLUSION: DSV patients share the same recurrence rate as high-risk PTC patients. Despite aggressive surgical approaches, the recurrence rate within the first 5 years requires a careful ongoing surveillance, similar to the follow-up of high-risk PTC patients.

Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study.

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<0.0001). Factors that were associated with faster progression of the SARA score were short duration of follow-up (p=0.0179), older age at inclusion (0.04 [SE 0.02] per additional year; p=0.0476), and longer repeat expansions (0.06 [SE 0.02] per additional repeat unit; p=0.0128) in SCA1, short duration of follow-up (p<0.0001), lower age at onset (-0.02 [SE 0.01] per additional year; p=0.0014), and lower baseline SARA score (-0.02 [SE 0.01] per additional SARA point; p=0.0083) in SCA2, and lower baseline SARA score (-0.03 [SE 0.01] per additional SARA point; p=0·0195) in SCA6. In SCA3, we did not identify factors that affected progression of the SARA score. INTERPRETATION: Our study provides quantitative data on the progression of the most common spinocerebellar ataxias based on a follow-up period that exceeds those of previous studies. Our data could prove useful for sample size calculation and patient stratification in interventional trials. FUNDING: EU FP6 (EUROSCA), German Ministry of Education and Research (BMBF; GeneMove), Polish Ministry of Science, EU FP7 (NEUROMICS).

Unraveling the Role of Huntingtin in Breast Cancer Metastasis.

BACKGROUND: Huntingtin (HTT) is mutated in Huntington's disease but is ubiquitously expressed, and mutant HTT influences cancer progression. We investigated wild-type HTT function during breast cancer. METHODS: We analyzed HTT and ZO1 expression as well as the HTT phosphoserine 421-activated form (S421-P-HTT) in human breast cancer tissues by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. We performed in vitro migration and invasion assays as well as in vivo tail vein injections of the metastatic 4T1 cells in BALB/c mice (n = 11 per group). We analyzed tumor progression in knock-in mice with modified S421 crossed with the MMTV-PyVT mammary cancer model (at least n = 12 per group). Data were analyzed with unpaired t tests, analysis of variance, Pearson or Spearman correlation, and Mann Whitney or Kruskal-Wallis tests. All statistical tests were two-sided. RESULTS: Levels of HTT and of S421-P-HTT are abnormally low in poorly differentiated and metastatic human breast cancers. HTT expression is downregulated in invasive compared with in situ carcinoma (P < .001). In BALB/c mice, silencing of HTT promotes lung colonization by a metastatic mammary cancer cell line (P = .005) and S421-unphosphorylatable-HTT accelerates cancer progression. HTT interacts with ZO1 and regulates both its expression and its localization to tight junctions. In human breast tumors, the patterns of HTT and ZO1 expression are similar (Pearson correlation coefficient = 0.66, P < .001). CONCLUSIONS: HTT may inhibit breast tumor dissemination through maintenance of ZO1 at tight junctions. Downregulation of HTT transcript and protein levels is a prognostic factor for poor prognosis and metastasis development.

Deep Brain Stimulation for Obsessive-Compulsive Disorder: A Meta-Analysis of Treatment Outcome and Predictors of Response.

BACKGROUND: Deep brain stimulation (DBS) has been proposed as an alternative to ablative neurosurgery for severe treatment-resistant Obsessive-Compulsive Disorder (OCD), although with partially discrepant results probably related to differences in anatomical targetting and stimulation conditions. We sought to determine the efficacy and tolerability of DBS in OCD and the existence of clinical predictors of response using meta-analysis. METHODS: We searched the literature on DBS for OCD from 1999 through January 2014 using PubMed/MEDLINE and PsycINFO. We performed fixed and random-effect meta-analysis with score changes (pre-post DBS) on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) as the primary-outcome measure, and the number of responders to treatment, quality of life and acceptability as secondary measures. FINDINGS: Thirty-one studies involving 116 subjects were identified. Eighty-three subjects were implanted in striatal areas--anterior limb of the internal capsule, ventral capsule and ventral striatum, nucleus accumbens and ventral caudate--27 in the subthalamic nucleus and six in the inferior thalamic peduncle. Global percentage of Y-BOCS reduction was estimated at 45.1% and global percentage of responders at 60.0%. Better response was associated with older age at OCD onset and presence of sexual/religious obsessions and compulsions. No significant differences were detected in efficacy between targets. Five patients dropped out, but adverse effects were generally reported as mild, transient and reversible. CONCLUSIONS: Our analysis confirms that DBS constitutes a valid alternative to lesional surgery for severe, therapy-refractory OCD patients. Well-controlled, randomized studies with larger samples are needed to establish the optimal targeting and stimulation conditions and to extend the analysis of clinical predictors of outcome.

Parkin depletion delays motor decline dose-dependently without overtly affecting neuropathology in α-synuclein transgenic mice.

BACKGROUND: Mutations of the gene encoding the major component of Lewy bodies (LB), α-synuclein (α-syn), cause autosomal dominant forms of Parkinson's disease (PD), whereas loss-of-function mutations of the gene encoding the multifunctional E3 ubiquitin-protein ligase Parkin account for autosomal recessive forms of the disease. Parkin overproduction protects against α-syn-dependent neurodegeneration in various in vitro and in vivo models, but it remains unclear whether this process is affected by Parkin deficiency. We addressed this issue, by carrying out more detailed analyses of transgenic mice overproducing the A30P variant of human α-syn (hA30Pα-syn) and with two, one or no parkin knockout alleles. RESULTS: Longitudinal behavioral follow-up of these mice indicated that Parkin depletion delayed disease-predictive sensorimotor impairment due to α-syn accumulation, in a dose-dependent fashion. At the end stage of the disease, neuronal deposits containing fibrillar α-syn species phosphorylated at S129 (PS129α-syn) were the predominant neuropathological feature in hA30Pα-syn mice, regardless of their parkin expression. Some of these deposits colocalized with the LB markers ubiquitin and α-syn truncated at D135 (α-synD135), indicating that PS129α-syn is subjected to secondary posttranslational modification (PTM); these features were not significantly affected by parkin dysfunction. CONCLUSIONS: These findings suggest that Parkin deficiency acts as a protective modifier in α-syn-dependent neurodegeneration, without overtly affecting the composition and characteristics of α-syn deposits in end-stage disease.

Online audit and feedback improve fetal second-trimester four-chamber view images: a randomised controlled trial.

OBJECTIVES: We aimed to study the impact of online audit and feedback on fetal four-chamber view image quality. METHODS: Ultrasonographers uploaded a set of four-chamber views from 10 consecutive screening examinations and a second set 3 months later. They were randomised to receive (group A) or not (group B) a feedback for their first set. The primary outcome was the difference in image mean score and in percentage of inadequate images between the first set and the second set, comparing the groups with and without feedback. RESULTS: There were 258 ultrasonographers who completed the trial (group A: 122; group B: 136), and 5160 images were audited. In both groups, the mean score increased. In group A, it rose from 17.0 to 18.5 (p < 0.0001), and in group, B from 17.6 to 18.3 (p < 0.0001). The improvement was greater in group A than in group B (1.5 vs. 0.7, p = 0.0007). The mean percentage of inadequate images decreased in both groups. In group A, it dropped from 32% to 19% (p < 0.0001), and in group B, from 26% to 21% (p = 0.012). The decrease was greater in group A than in group B (13% vs. 5%, p = 0.007). CONCLUSIONS: Image quality improved following online audit, the improvement being slightly greater with feedback.

Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data.

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.

Annual change in Friedreich's ataxia evaluated by the Scale for the Assessment and Rating of Ataxia (SARA) is independent of disease severity.

BACKGROUND: The objective of the study was to evaluate the sensitivity to change of the Scale for the Assessment and Rating of Ataxia (score, 0-40) in Friedreich's ataxia. METHODS: This was a follow-up study in adult patients with genetically confirmed Friedreich's ataxia evaluated at least twice (minimum interval, 6 months). Participants were outpatients at the Center for Neurogenetics of the Pitie-Salpêtrière Hospital in Paris. RESULTS: We included 84 patients; 60% had 3 or more evaluations. The mean score on first assessment was 22.7 ± 9, and the mean follow-up was 1.84 ± 1.10 years. The mean increase was 1.36 ± 2.3 points/year; this variation was not significantly linked to factors known to influence disease severity such as age at onset, disease duration, GAA expansion length, and wheelchair use. CONCLUSIONS: In adult Friedreich's ataxia patients the Scale for the Assessment and Rating of Ataxia can detect annual changes independently of disease severity. In future therapeutic trials no patient stratification is globally required.

Quantitative assessment of the evolution of cerebellar signs in spinocerebellar ataxias.

BACKGROUND: Responsive ataxia rating scales are essential for determining outcome measures in clinical trials. METHODS: We evaluated the responsiveness over time of the composite cerebellar functional severity score, a quantitative score measuring cerebellar ataxia in 133 patients with autosomal dominant cerebellar ataxias (ADCA), which were prospectively evaluated at inclusion and after one-year of follow-up. A more responsive tool was developed, the Cerebellar Functional Severity score writing, incorporating the writing test at dominant hand to the Cerebellar Functional Severity score. RESULTS: Within the one-year follow-up period, the Cerebellar Functional Severity score and its writing version increased significantly and the Scale for the Assessment and Rating of Ataxia decreased significantly reflecting increased severity of the cerebellar symptoms. The Cerebellar Functional Severity score writing responsiveness was best in genotypes SCA1, 2, and 3 compared with the other genotypes (effect size = 0.196, standardized response mean (SRM) = 0.624 versus effect size = -0.051, SRM = -0.150). The Cerebellar Functional Severity score writing used as an outcome measure would require only 163 SCA1, 2, or 3 patients per group in a two-arm interventional trial for a 50% reduction in progression and 80% of power. DISCUSSION: Our study demonstrates that the Cerebellar Functional Severity score and Cerebellar Functional Severity score writing are responsive quantitative scores for evaluating sensitivity to change in ADCA patients and can be used as outcome measures in clinical trials, especially when targeting genotypes SCA1, 2 and 3.

A video Clinical Global Impression (CGI) in obsessive compulsive disorder.

The Clinical Global Impression scale (CGI) is frequently used in clinical research because of its face validity and ease of use but data on its reliability are scarce. Our goal was to estimate the reliability of the scale and compare reliability between face-to-face and video scoring. We analyzed 50 different video interviews recorded during 5 visits of a crossover trial to study the effect of subthalamic nucleus stimulation. Six specialized clinicians rated the CGI using these videos, providing 300 different ratings. The intraclass correlation was lower at inclusion (0.30 [0.13-0.50]) than at later visits (0.68 [0.61-0.80]). Reliability was not influenced by the patients' stimulation status. The mean of at least two independent evaluations of the video is needed to achieve an ICC greater than 0.8. The video CGI is a valid clinical outcome measure suitable for clinical trials (ClinicalTrials.gov number, NCT00169377).

Decrease of prefrontal metabolism after subthalamic stimulation in obsessive-compulsive disorder: a positron emission tomography study.

BACKGROUND: High-frequency bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is a promising treatment in refractory obsessive-compulsive disorder (OCD). METHOD: Using the crossover, randomized, and double-blind procedure adopted by the STOC study, 10 patients treated with high-frequency bilateral STN DBS underwent am 18-fluorodeoxyglucose positron emission tomography (PET) investigation to highlight the neural substratum of this therapeutic approach. RESULTS: The median Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores for all 10 patients were 31 (minimum = 18, maximum = 36) with "Off-Stimulation" status and 19 (minimum = 0, maximum = 30) with "On-Stimulation" status (p = .05). The OCD patients in Off-Stimulation status showed a hypermetabolism in the right frontal middle and superior gyri, right parietal lobe, postcentral gyrus, and bilateral putamen compared with healthy control subjects. A significant decrease in cerebral metabolism was observed in the left cingulate gyrus and the left frontal medial gyrus in On-Stimulation conditions compared with Off-Stimulation conditions. In addition, the improvement assessed by Y-BOCS scores during the On-Stimulation conditions was positively correlated with PET signal changes at the boundary of the orbitofrontal cortex and the medial prefrontal cortex, between PET signal changes and the Y-BOCS scores modifications in On-Stimulation status. CONCLUSION: This study suggests that the therapeutic effect of STN DBS is related to a decrease in prefrontal cortex metabolism.

Self-rated health status in spinocerebellar ataxia--results from a European multicenter study.

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.