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•Cerebellar nuclei are discernible on susceptibility maps (QSM) acquired at 3 Tesla in healthy subjects and patients with SCA6.•The QSM-based volume of the dentate nuclei in adults is independent of age.•Dentate nuclei are significantly atrophied in SCA6.•The amount of iron of the dentate nuclei is reduced in SCA6.•Volume and iron concentration of the dentate nuclei did not show reliable changes in SCA6 patients within one year. Understanding cerebellar alterations due to healthy aging provides a reference point against which pathological findings in late-onset disease, for example spinocerebellar ataxia type 6 (SCA6), can be contrasted. In the present study, we investigated the impact of aging on the cerebellar nuclei and cerebellar cortex in 109 healthy controls (age range: 16 – 78 years) using 3 Tesla magnetic resonance imaging (MRI). Findings were compared with 25 SCA6 patients (age range: 38 – 78 years). A subset of 16 SCA6 (included: 14) patients and 50 controls (included: 45) received an additional MRI scan at 7 Tesla and were re-scanned after one year. MRI included T1-weighted, T2-weighted FLAIR, and multi-echo T2*-weighted imaging. The T2*-weighted phase images were converted to quantitative susceptibility maps (QSM). Since the cerebellar nuclei are characterized by elevated iron content with respect to their surroundings, two independent raters manually outlined them on the susceptibility maps. T1-weighted images acquired at 3T were utilized to automatically identify the cerebellar gray matter (GM) volume. Linear correlations revealed significant atrophy of the cerebellum due to tissue loss of cerebellar cortical GM in healthy controls with increasing age. Reduction of the cerebellar GM was substantially stronger in SCA6 patients. The volume of the dentate nuclei did not exhibit a significant relationship with age, at least in the age range between 18 and 78 years, whereas mean susceptibilities of the dentate nuclei increased with age. As previously shown, the dentate nuclei volumes were smaller and magnetic susceptibilities were lower in SCA6 patients compared to age- and sex-matched controls. The significant dentate volume loss in SCA6 patients could also be confirmed with 7T MRI. Linear mixed effects models and individual paired t-tests accounting for multiple comparisons revealed no statistical significant change in volume and susceptibility of the dentate nuclei after one year in neither patients nor controls. Importantly, dentate volumes were more sensitive to differentiate between SCA6 (Cohen's d = 3.02) and matched controls than the cerebellar cortex volume (d = 2.04). In addition to age-related decline of the cerebellar cortex and atrophy in SCA6 patients, age-related increase of susceptibility of the dentate nuclei was found in controls, whereas dentate volume and susceptibility was significantly decreased in SCA6 patients. Because no significant changes of any of these parameters was found at follow-up, these measures do not allow to monitor disease progression at short intervals. [Display omitted]

BackgroundA brief bedside test has recently been introduced by Hoche et al. (Brain, 2018) to screen for the Cerebellar Cognitive Affective Syndrome (CCAS) in patients with cerebellar disease.ObjectiveThis multicenter study tested the ability of the CCAS-Scale to diagnose CCAS in individual patients with common forms of hereditary ataxia.MethodsA German version of the CCAS-Scale was applied in 30 SCA3, 14 SCA6 and 20 FRDA patients, and 64 healthy participants matched for age, sex, and level of education. Based on original cut-off values, the number of failed test items was assessed, and CCAS was considered possible (one failed item), probable (two failed items) or definite (three failed items). In addition a total sum raw score was calculated.ResultsOn a group level, failed items were significantly higher and total sum scores were significantly lower in SCA3 patients compared to matched controls. SCA6 and FRDA patients performed numerically below controls, but respective group differences failed to reach significance. The ability of the CCAS-Scale to diagnose CCAS in individual patients was limited to severe cases failing three or more items. Milder cases failing one or two items showed a great overlap with the performance of controls exhibiting a substantial number of false-positive test results. The word fluency test items differentiated best between patients and controls.ConclusionsAs a group, SCA3 patients performed below the level of SCA6 and FRDA patients, possibly reflecting additional cerebral involvement. Moreover, the application of the CCAS-Scale in its present form results in a high number of false-positive test results, that is identifying controls as patients, reducing its usefulness as a screening tool for CCAS in individual patients.

Background Sexual health is an important aspect of human well-being. In terms of sexual health and healthcare, sex workers might need more specialized care than others, given their higher risk for both discrimination and various sexually transmitted diseases. However, little is known about the quality of healthcare professionals’ training regarding sexual health and healthcare of sex workers in Germany. Methods In an online survey, 130 physicians, 63 psychotherapists, and 154 medical students reported their perceived quality of training regarding sexual health problems in all their patients and regarding sex workers’ health issues specifically. Results A substantial share of respondents reported to have experienced inadequate training regarding both sexual health problems in general and specific issues concerning sex workers. However, most respondents reported feeling rather comfortable when dealing with these topics. There was a positive correlation between feeling comfortable when treating sexual health problems/ sex workers and the perceived training on these topics. Conclusions The results of this study indicate that sexual health issues and sex workers’ specific healthcare requirements are not sufficiently addressed in the curricula of German healthcare professionals. Future adaptations of these curricula might be necessary.

BackgroundFunctional movement disorders (FMDs) are commonly classified along canonical non-ataxic movement disorder patterns, creating a potential blind spot for frequently observed ataxia-like presentations. At the same time, normal diagnostic findings and episodic symptom variability in some cerebellar ataxias predispose to an incorrect FMD diagnosis.CasesWe present three cases that illustrate pitfalls in the differential diagnosis of ataxia. First, a patient treated for presumed immune-mediated cerebellar ataxia was diagnosed with FMD based on clinical signs. Next, a patient with intermittent and inconsistent symptoms was diagnosed with FMD after extensive exclusionary workup, but was then found to have a novel type of spinocerebellar ataxia. The third patient had a genetically confirmed spinocerebellar ataxia but developed additional functional motor symptoms.ConclusionDifferentiating cerebellar ataxias from FMDs and recognising mixed presentations is essential. Enhanced clinical awareness and systematic diagnostic evaluation are crucial to avoid misdiagnosis and ensure optimal treatment.

Fear is a vital defense mechanism to potential threats, which is influenced by the cerebellum. While the cerebellum’s role in acquiring fear responses is well understood, limited knowledge exists about its involvement in fear extinction. In this study, we investigated the effects of cerebellar theta band transcranial alternating current stimulation (ctACS) administered during fear extinction training, based on previous evidence from animal studies suggesting a role of cerebellar theta oscillations in associative memory formation. To this end, thirty-seven healthy right-handed male participants were recruited for a two-day differential fear renewal paradigm. On day 1, they underwent acquisition training in context A followed by extinction training in context B. On day 2, recall was tested in contexts A and B. One group of participants received ctACS in the theta band (6 Hz) during extinction training. The other group received sham ctACS. Although both groups demonstrated the ability to recall previously learned fear and distinguish between low and high threat stimuli, no significant differences were observed between the ctACS and sham groups, indicating that ctACS at this theta frequency range did not impact extinction and recall of previously acquired fear in this study. Nevertheless, using ctACS could still be useful in future research, including brain imaging studies, to better understand how the cerebellum is involved in fear and extinction processes.

Introduction Cerebellar brain inhibition (CBI) is a way to quantify the cerebellar influence on the motor cortex in humans. Studies suggest that the orientation of the transcranial magnetic stimulation (TMS) coil influences which motor networks are activated. This study investigated the influence of cerebellar transcranial direct current stimulation (ctDCS) on CBI as a function of coil orientation (anterior–posterior [AP] vs. posterior–anterior [PA]). An interstimulus interval (ISI) of 7 ms (CBI‐AP‐7) was used for AP orientation and 5 ms (CBI‐PA‐5) for PA orientation. Methods Young and healthy participants received anodal, cathodal, or sham ctDCS treatment for 15 min on three different days. On each day, CBI was determined for both coil positions immediately after and 30, 60, and 120 min after ctDCS application. Results For CBI‐PA‐5, no significant ctDCS effect was detected. For CBI‐AP‐7, there was an increase in CBI by anodal ctDCS and a decrease in CBI by cathodal ctDCS, although the latter did not reach statistical significance. Conclusion Findings provide further support that different cerebello–cerebral motor networks may be activated in CBI‐AP‐7 and CBI‐PA‐5, with only CBI‐AP‐7 being significantly affected by ctDCS. CBI‐AP‐7 may be a more sensitive tool for investigating CBI effects than the CBI‐PA‐5 procedure, which is most commonly used. The impact of cerebellar direct current stimulation (ctDCS) on cerebellar brain inhibition (CBI) as a function of TMS coil orientation was investigated. Anodal ctDCS led to an increase in CBI for the anterior‐posterior (AP) orientation only. These results implicate, that different motor networks may be activated depending on the coil orientation and that CBI‐AP‐7 (CBI measured with AP position of the TMS coil and an interstimulus interval of 7 ms) may be a more sensitive tool for investigating CBI effects.

Traditionally, cerebellar disorders including ataxias have been associated with deficits in motor control and motor learning. Since the 1980's growing evidence has emerged that cerebellar diseases also impede cognitive and affective processes such as executive and linguistic functions, visuospatial abilities and regulation of emotion and affect. This combination of non-motor symptoms has been named . To date, diagnosis relies on non-standardized bedside cognitive examination and, if available, detailed neuropsychological test batteries. Recently, a short and easy applicable bedside test (CCAS Scale) has been developed to screen for CCAS. It has been validated in an US-American cohort of adults with cerebellar disorders and healthy controls. As yet, the CCAS Scale has only been available in American English. We present a German version of the scale and the study protocol of its ongoing validation in a German-speaking patient cohort. A preliminary German version has been created from the original CCAS Scale using a standardized translation procedure. This version has been pre-tested in cerebellar patients and healthy controls including medical experts and laypersons to ensure that instructions are well understandable, and that no information has been lost or added during translation. This preliminary German version will be validated in a minimum of 65 patients with cerebellar disease and 65 matched healthy controls. We test whether selectivity and sensitivity of the German CCAS Scale is comparable to the original CCAS Scale using the same cut-off values for each of the test items, and the same pass/ fail criteria to determine the presence of CCAS. Furthermore, internal consistency, test-retest and interrater reliability will be evaluated. In addition, construct validity will be tested in a subset of patients and controls in whom detailed neuropsychological testing will be available. Secondary aims will be examination of possible correlations between clinical features (e.g. disease duration, clinical ataxia scores) and CCAS scores. The overall aim is to deliver a validated bedside test to screen for CCAS in German-speaking patients which can also be used in future natural history and therapeutic trials. The study is registered at the German Clinical Study Register (DRKS-ID: DRKS00016854).

Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect FGF14 expansions from short-read genome data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare FGF14 expansion alleles, including interruptions and flanking regions. Uninterrupted AAG expansions are significantly enriched in patients with ataxia from a lower threshold (180–200 repeats) than previously reported based on expansion size alone. Conversely, AAGGAG hexameric expansions are equally frequent in patients and controls. Distinct 5’ flanking regions, interruptions and pre-repeat sequences correlate with repeat size. Furthermore, pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats form different secondary structures. Regardless of expansion size, SCA27B is a recognizable clinical entity characterized by frequent episodic ataxia and downbeat nystagmus, similar to the presentation observed in a family with a previously unreported nonsense variant (SCA27A). Overall, this study suggests that SCA27B is a major overlooked cause of adult-onset ataxia, accounting for 23–31% of unsolved patients. We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process. Repeat expansions in the FGF14 gene can cause late-onset cerebellar ataxia (SCA27B), however the defining features of pathogenic expansions remain uncertain. Here, the authors compare the sequence and structure of FGF14 repeat expansions in patients and controls, leading them to suggest a lower pathogenic threshold and emphasizing the importance of sequencing the full expansion for accurate interpretation.

Background Cognitive and neuropsychiatric impairment, known as cerebellar cognitive affective syndrome (CCAS), may be present in cerebellar disorders. This study identified distinct CCAS subtypes in cerebellar patients using cluster analysis. Methods The German CCAS-Scale (G-CCAS-S), a brief screening test for CCAS, was assessed in 205 cerebellar patients and 200 healthy controls. K-means cluster analysis was applied to G-CCAS-S data to identify cognitive clusters in patients. Demographic and clinical variables were used to characterize the clusters. Multiple linear regression quantified their relative contribution to cognitive performance. The ability of the G-CCAS-S to correctly distinguish between patients and controls was compared across the clusters. Results Two clusters explained the variance of cognitive performance in patients’ best. Cluster 1 (30%) exhibited severe impairment. Cluster 2 (70%) displayed milder dysfunction and overlapped substantially with that of healthy controls. Cluster 1 patients were on average older, less educated, showed more severe ataxia and more extracerebellar involvement than cluster 2 patients. The cluster assignment predicted cognitive performance even after adjusting for all other covariates. The G-CCAS-S demonstrated good discriminative ability for cluster 1, but not for cluster 2. Conclusions The variance of cognitive impairment in cerebellar disorders is best explained by one severely affected and one mildly affected cluster. Cognitive performance is not only predicted by demographic/clinical characteristics, but also by cluster assignment itself. This indicates that factors that have not been captured in this study likely have effects on cognitive cerebellar functions. Moreover, the CCAS-S appears to have a relative weakness in identifying patients with only mild cognitive deficits. Study registration The study has prospectively been registered at the German Clinical Study Register ( https://www.drks.de ; DRKS-ID: DRKS00016854).

Introduction Knowledge about the distribution and frequency of the respective haplotypes on the wildtype and mutant allele is highly relevant in the context of future gene therapy clinical studies in Spinocerebellar Ataxia Type 3, the most common autosomal dominantly inherited ataxia. Single nucleotide polymorphisms associated to the disease-causing gene, ATXN3 , have been determined. We wanted to investigate the frequency and regional distribution of two intragenic single nucleotide polymorphisms (SNPs) in a large European SCA3 cohort and their relation to the clinical phenotype. Methods The genotypes of the two polymorphisms at base pair positions 987 and 1118 of the ATXN3 were determined for their co-localization on the normal and expanded allele, respectively, in 286 SCA3 mutation carriers and 117 healthy controls from 11 European sites. Results The distribution of genotypes on the expanded allele differed from those of the wildtype allele of SCA3 mutation carriers and of healthy controls, and was mainly influenced by the regional origin. In our cohort, no particular clinical phenotype was associated with any specific haplotype. Conclusions Our results confirm distinct allocations of SNPs associated to the expanded ATXN3 , and accordingly the consideration of allele-specific therapies.