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Ataxien des Erwachsenenalters sind klinisch und atiologisch heterogene Erkrankungen, die das Kleinhirn und seine afferenten und efferenten Verbindungen betreffen. Initial besteht meist eine progrediente Stand- und Gangataxie, gefolgt von einer Extremitatenataxie, zerebellarer Dysarthrie und Okulomotorikstorung. Verschiedenste neurologische und nichtneurologische Zusatzsymptome sind moglich. Man unterscheidet hereditare, erworbene und sporadisch-degenerative Ataxien. Diagnostisch ist eine detaillierte Anamnese und klinische Untersuchung sowie eine kraniale Magnetresonanztomographie essenziell. Oft sind gezielte biochemische und molekulargenetische Tests zur Diagnosestellung erforderlich. Neben rehabilitativen Therapien sind fur einige Ataxien auch spezifische medikamentose Therapien verfugbar. Eine fruhzeitige und prazise Diagnose ist wichtig, um unnotige Diagnostik zu vermeiden sowie Patienten und Angehorige zu beraten.

Autosomal-dominant spinocerebellar ataxias (SCA) are neurodegenerative diseases characterized by progressive ataxia. Here, we report on neurometabolic alterations in spinocerebellar ataxia type 1 (SCA1; SCA-ATXN1) and 14 (SCA14; SCA-PRKCG) assessed by non-invasive 1H magnetic resonance spectroscopy. Three Tesla 1H magnetic resonance spectroscopy was performed in 17 SCA14, 14 SCA1 patients, and in 31 healthy volunteers. We assessed metabolites in the cerebellar vermis, right cerebellar hemisphere, pons, prefrontal, and motor cortex. Additionally, clinical characteristics were obtained for each patient to correlate them with metabolites. In SCA14, metabolic changes were restricted to the cerebellar vermis compared with widespread neurochemical alterations in SCA1. In SCA14, total N-acetylaspartate (tNAA) was reduced in the vermis by 34%. In SCA1, tNAA was reduced in the vermis (24%), cerebellar hemisphere (26%), and pons (25%). SCA14 patients showed 24% lower glutamate+glutamine (Glx) and 46% lower γ-aminobutyric acid (GABA) in the vermis, while SCA1 patients showed no alterations in Glx and GABA. SCA1 revealed a decrease of aspartate (Asp) in the vermis (62%) and an elevation in the prefrontal cortex (130%) as well as an elevation of myo-inositol (Ins) in the cerebellar hemisphere (51%) and pons (46%). No changes of Asp and Ins were detected in SCA14. Beyond, glucose (Glc) was increased in the vermis of both SCA14 (155%) and SCA1 (247%). 1H magnetic resonance spectroscopy revealed differing neurochemical profiles in SCA1 and SCA14 and confirmed metabolic changes that may be indicative for neuronal loss and dysfunctional energy metabolism. Therefore, 1H magnetic resonance spectroscopy represents a helpful tool for in-vivo tracking of disease-specific pathophysiology. Electronic supplementary material The online version of this article (10.1007/s12311-020-01201-y) contains supplementary material, which is available to authorized users.

Spinocerebellar ataxia type 14 (SCA-PRKCG, formerly SCA14) is a rare, slowly progressive disorder caused by conventional mutations in protein kinase Cγ (PKCγ). The disease usually manifests with ataxia, but previous reports suggested PRKCG variants in retinal pathology. To systematically investigate for the first time visual function and retinal morphology in patients with SCA-PRKCG. Seventeen patients with PRKCG variants and 17 healthy controls were prospectively recruited, of which 12 genetically confirmed SCA-PRKCG patients and 14 matched controls were analyzed. We enquired a structured history for visual symptoms. Vision-related quality of life was obtained with the National Eye Institute Visual Function Questionnaire (NEI-VFQ) including the Neuro-Ophthalmic Supplement (NOS). Participants underwent testing of visual acuity, contrast sensitivity, visual fields, and retinal morphology with optical coherence tomography (OCT). Measurements of the SCA-PRKCG group were analyzed for their association with clinical parameters (ataxia rating and disease duration). SCA-PRKCG patients rate their vision-related quality of life in NEI-VFQ significantly worse than controls. Furthermore, binocular visual acuity and contrast sensitivity were worse in SCA-PRKCG patients compared with controls. Despite this, none of the OCT measurements differed between groups. NEI-VFQ and NOS composite scores were related to ataxia severity. Additionally, we describe one patient with a genetic variant of uncertain significance in the catalytic domain of PKCγ who, unlike all confirmed SCA-PRKCG, presented with a clinically silent epitheliopathy. SCA-PRKCG patients had reduced binocular vision and vision-related quality of life. Since no structural retinal damage was found, the pathomechanism of these findings remains unclear. Electronic supplementary material The online version of this article (10.1007/s12311-020-01130-w) contains supplementary material, which is available to authorized users.

Journal of neurology 269(8), 4363-4374 (2022). doi:10.1007/s00415-022-11071-5, Published by Steinkopff, [Darmstadt]

Background Variants in genes of the nucleotide excision repair (NER) pathway have been associated with heterogeneous clinical presentations ranging from xeroderma pigmentosum to Cockayne syndrome and trichothiodystrophy. NER deficiencies manifest with photosensitivity and skin cancer, but also developmental delay and early‐onset neurological degeneration. Adult‐onset neurological features have been reported in only a few xeroderma pigmentosum cases, all showing at least mild skin manifestations. Objective The aim of this multicenter study was to investigate the frequency and clinical features of patients with biallelic variants in NER genes who are predominantly presenting with neurological signs. Methods In‐house exome and genome datasets of 14,303 patients, including 3543 neurological cases, were screened for deleterious variants in NER‐related genes. Clinical workup included in‐depth neurological and dermatological assessments. Results We identified 13 patients with variants in ERCC4 (n = 8), ERCC2 (n = 4), or XPA (n = 1), mostly proven biallelic, including five different recurrent and six novel variants. All individuals had adult‐onset progressive neurological deterioration with ataxia, dementia, and frequently chorea, neuropathy, and spasticity. Brain magnetic resonance imaging showed profound global brain atrophy in all patients. Dermatological examination did not show any skin cancer or pronounced ultraviolet damage. Conclusions We introduce NERDND as adult‐onset neurodegeneration (ND) within the spectrum of autosomal recessive NER disorders (NERD). Our study demonstrates that NERDND is probably an underdiagnosed cause of neurodegeneration in adulthood and should be considered in patients with overlapping cognitive and movement abnormalities. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The cerebellar nuclei are a brain region with high iron content. Surprisingly, little is known about iron content in the cerebellar nuclei and its possible contribution to pathology in cerebellar ataxias, with the only exception of Friedreich’s ataxia. In the present exploratory cross-sectional study, quantitative susceptibility mapping was used to investigate volume, iron concentration and total iron content of the dentate nuclei in common types of hereditary and non-hereditary degenerative ataxias. Seventy-nine patients with spinocerebellar ataxias of types 1, 2, 3 and 6; 15 patients with Friedreich’s ataxia; 18 patients with multiple system atrophy, cerebellar type and 111 healthy controls were also included. All underwent 3 T MRI and clinical assessments. For each specific ataxia subtype, voxel-based and volumes-of-interest-based group analyses were performed in comparison with a corresponding age- and sex-matched control group, both for volume, magnetic susceptiblity (indicating iron concentration) and susceptibility mass (indicating total iron content) of the dentate nuclei. Spinocerebellar ataxia of type 1 and multiple system atrophy, cerebellar type patients showed higher susceptibilities in large parts of the dentate nucleus but unaltered susceptibility masses compared with controls. Friedreich’s ataxia patients and, only on a trend level, spinocerebellar ataxia of type 2 patients showed higher susceptibilities in more circumscribed parts of the dentate. In contrast, spinocerebellar ataxia of type 6 patients revealed lower susceptibilities and susceptibility masses compared with controls throughout the dentate nucleus. Spinocerebellar ataxia of type 3 patients showed no significant changes in susceptibility and susceptibility mass. Lower volume of the dentate nuclei was found to varying degrees in all ataxia types. It was most pronounced in spinocerebellar ataxia of type 6 patients and least prominent in spinocerebellar ataxia of type 3 patients. The findings show that alterations in susceptibility revealed by quantitative susceptibility mapping are common in the dentate nuclei in different types of cerebellar ataxias. The most striking changes in susceptibility were found in spinocerebellar ataxia of type 1, multiple system atrophy, cerebellar type and spinocerebellar ataxia of type 6. Because iron content is known to be high in glial cells but not in neurons of the cerebellar nuclei, the higher susceptibility in spinocerebellar ataxia of type 1 and multiple system atrophy, cerebellar type may be explained by a reduction of neurons (increase in iron concentration) and/or an increase in iron-rich glial cells, e.g. microgliosis. Hypomyelination also leads to higher susceptibility and could also contribute. The lower susceptibility in SCA6 suggests a loss of iron-rich glial cells. Quantitative susceptibility maps warrant future studies of iron content and iron-rich cells in ataxias to gain a more comprehensive understanding of the pathogenesis of these diseases.

Adult-onset ataxias are clinically and etiologically heterogeneous disorders affecting the cerebellum and its afferent and efferent connections. Early symptoms are usually a progressive ataxia of gait and stance, followed by limb ataxia, cerebellar dysarthria and oculomotor disturbances. In addition, various neurological and non-neurological symptoms may occur. Hereditary, acquired, and sporadic degenerative ataxias are distinguished. A detailed medical history and clinical examination as well as cranial magnetic resonance imaging are essential for the diagnostic work-up; however, specific biochemical or genetic tests are often required to make a definitive diagnosis. Besides rehabilitative therapies, specific drugs or dietary recommendations are available for some types of ataxia. An early and precise diagnosis is important to avoid redundant diagnostics and for counselling of patients and their relatives.Ataxien des Erwachsenenalters sind klinisch und ätiologisch heterogene Erkrankungen, die das Kleinhirn und seine afferenten und efferenten Verbindungen betreffen. Initial besteht meist eine progrediente Stand- und Gangataxie, gefolgt von einer Extremitätenataxie, zerebellärer Dysarthrie und Okulomotorikstörung. Verschiedenste neurologische und nichtneurologische Zusatzsymptome sind möglich. Man unterscheidet hereditäre, erworbene und sporadisch-degenerative Ataxien. Diagnostisch ist eine detaillierte Anamnese und klinische Untersuchung sowie eine kraniale Magnetresonanztomographie essenziell. Oft sind gezielte biochemische und molekulargenetische Tests zur Diagnosestellung erforderlich. Neben rehabilitativen Therapien sind für einige Ataxien auch spezifische medikamentöse Therapien verfügbar. Eine frühzeitige und präzise Diagnose ist wichtig, um unnötige Diagnostik zu vermeiden sowie Patienten und Angehörige zu beraten.

During recent decades, many studies have yielded evidence for cerebellar involvement in cognitive, emotional and affective processes besides the well-known cerebellar contribution to motor performance and learning (Koziol et al., 2014; Marien et al., 2014; Van Overwalle et al., 2014; Strata, 2015; Adamaszek et al., 2017; Kansal et al., 2017; Guell et al., 2018; King et al., 2019). Cerebellar diseases can result in executive, linguistic and visuospatial dysfunctions as well as problems with the regulation of emotion and affect. This combination of non-motor symptoms has been named cerebellar cognitive affective/Schmahmann syndrome (CCAS) (Schmahmann and Sherman, 1998). For many years, diagnosis has relied on non-standardized bedside cognitive examination and, if available, detailed neuropsychological test batteries. A short and easily applicable bedside test (CCAS Scale), published by Hoche et al. (2018) in Brain, was developed to screen for CCAS and is already in widespread use. We therefore believe that it is important to share our recent findings that the reference values published by Hoche and colleagues may apply only within a limited age and education range, while their more universal application may lead to a substantial number of false-positive test results.

Background 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 Cerebellar Cognitive Affective/ Schmahmann Syndrome (CCAS). 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. Methods 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. Perspective 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. Study registration The study is registered at the German Clinical Study Register (DRKS-ID: DRKS00016854).

DYT-THAP1 dystonia is known to present a variety of clinical symptoms. To the best of our knowledge, this is the first case with DYT-THAP 1 dystonia and clinical signs of cerebellar involvement studied with transcranial magnetic stimulation in vivo. We report a case of a 51-year-old male DYT-THAP1 mutation carrier with dystonia, who additionally developed ataxia 1.5 years ago. To study cerebellar involvement in our patient, we used a TMS protocol called cerebellar inhibition (CBI). The lack of CBI in our patient strongly suggests cerebellar involvement. According to our findings, cerebellar syndrome may be part of the phenotypical spectrum of DYT-THAP1 mutations.

Instrumental gait analysis is increasingly recognized as a useful tool for the evaluation of movement disorders. The various assessment devices available to date have mostly been evaluated in healthy populations only. We aimed to explore whether reliability and validity seen in healthy subjects can also be assumed in subjects with cerebellar ataxic gait. Gait was recorded simultaneously with two devices - a sensor-embedded walkway and an inertial sensor based system - to explore test accuracy in two groups of subjects: one with mild to moderate cerebellar ataxia due to a subtype of autosomal-dominantly inherited neurodegenerative disorder (SCA14), the other were healthy subjects matched for age and height (CTR). Test precision was assessed by retest within session for each device. In conclusion, accuracy and repeatability of gait measurements were not compromised by ataxic gait disorder. The accuracy of spatial measures was speed-dependent and a direct comparison of stride length from both devices will be most reliably made at comfortable speed. Measures of stride variability had low agreement between methods in CTR and at retest in both groups. However, the marked increase of stride variability in ataxia outweighs the observed amount of imprecision.

We thank Gauquelin et al. (2017) for their interesting letter regarding our recent publication ‘Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia’ (Minnerop et al., 2017). The authors of the letter question the pathogenic relevance of the novel hypomorphic intronic POLR3A variant, which we observed in a total of 19 independent families. Gauquelin et al. suspected undetected mutations in other HSP and ataxia genes in at least a subset of our families, while at the same time arguing that the phenotype we reported in those very same families falls well within the spectrum of POLR3-related disease and should rather be classified as atypical POLR3-related disease. They put forth clinical as well as genetic arguments to support...

Autosomal dominant ataxia type 14 (SCA14) is a rare usually adult-onset progressive disorder with cerebellar neurodegeneration caused by mutations in protein kinase C gamma. We set out to examine cerebellar and extracerebellar neurochemical changes in SCA14 by MR spectroscopy. In 13 SCA14 patients and 13 healthy sex- and age-matched controls, 3-T single-voxel brain proton MR spectroscopy was performed in a cerebellar voxel of interest (VOI) at TE = 30 ms to obtain a neurochemical profile of metabolites with short relaxation times. In the cerebellum and in additional VOIs in the prefrontal cortex, motor cortex, and somatosensory cortex, a second measurement was performed at TE = 144 ms to mainly extract the total N-acetyl-aspartate (tNAA) signal besides the signals for total creatine (tCr) and total choline (tCho). The cerebellar neurochemical profile revealed a decrease in glutathione (6.12E−06 ± 2.50E−06 versus 8.91E−06 ± 3.03E−06; p = 0028) and tNAA (3.78E−05 ± 5.67E−06 versus 4.25E−05 ± 5.15E−06; p = 0023) and a trend for reduced glutamate (2.63E−05 ± 6.48E−06 versus 3.15E−05 ± 7.61E−06; p = 0062) in SCA14 compared to controls. In the tNAA-focused measurement, cerebellar tNAA (296.6 ± 42.6 versus 351.7 ± 16.5; p = 0004) and tCr (272.1 ± 25.2 versus 303.2 ± 31.4; p = 0004) were reduced, while the prefrontal, somatosensory and motor cortex remained unaffected compared to controls. Neuronal pathology in SCA14 detected by MR spectroscopy was restricted to the cerebellum and did not comprise cortical regions. In the cerebellum, we found in addition to signs of neurodegeneration a glutathione reduction, which has been associated with cellular damage by oxidative stress in other neurodegenerative diseases such as Parkinson’s disease and Friedreich’s ataxia.

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10−4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

Background Although it is well established that there is cognitive dysfunction in spinocerebellar ataxia type 3 (SCA3), it is unknown whether cognition deteriorates with disease progression. We therefore prospectively studied cognitive function in patients with SCA3. Methods Eleven patients with SCA3 were assessed using an extensive neuropsychological test battery and retested after 3.5 ± 0.4 years. Results In addition to ataxia and motor control, verbal learning and verbal and figural memory deteriorated significantly during the follow-up period. An increase in depressive symptoms was not observed. Conclusions The observation that memory and learning abilities deteriorated with disease progression suggests that cognitive dysfunction is an integral part of SCA3. Because the applied tests for memory function did not require motor responses, cognitive decline cannot be attributed to progressive cerebellar ataxia. The deterioration of verbal and figural memory can be explained either by extracerebellar pathology or by disruption of cerebellar-cerebral circuitries. © 2013 International Parkinson and Movement Disorder Society

Background Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder which causes early sustained disability and quality of life impairment. Recently, a self-reported questionnaire focusing on MSA-specific symptoms (Multiple System Atrophy Quality of Life questionnaire, MSA-QoL) was developed in the English language. This article reports the validation of the German translation of the MSA-QoL. Methods Translation of the MSA-QoL was implemented in a 3-tiered approach including a forward translation, a back translation and an independent review. For the validation study 38 consecutive patients with MSA according to the consensus criteria were recruited by the participating centers in a German-Austrian cohort. Data were analyzed using standard psychometric procedures. Results As determined by the independent review, the German translation of the MSA-QoL was classified as fully equivalent to the English version. The validation study confirmed good psychometric properties of the rating scale. Conclusion The German translation of the MSA-QoL was shown to be a reliable patient-reported rating scale to determine health-related quality of life in MSA patients.

Both single photon emission computed tomography (SPECT) and positron emission tomography (PET) are tomographic imaging procedures using tracers to facilitate the evaluation of disease processes. Numerous PET and SPECT studies have been performed in disorders or conditions involving the cerebellum, focussing on changes of regional glucose metabolism, cerebral blood flow or receptor binding. While these methods allow studying specific functional and metabolic changes in detail, their spatial resolution is lower than that of MRI; anatomical localisation of the observed cerebellar changes using these methods often lacks precision. Their value for differential diagnosis of cerebellar disorders mainly depends on characterizing disease-specific patterns of involved extracerebellar brain structures. However, next to the investigation of disease-related functional changes, SPECT and in particular PET studies support detecting target structures for potential therapeutic interventions and visualising therapeutic effects.

To delineate possibly distinct cognitive impairment in patients with multiple system atrophy (MSA) of cerebellar (MSA-C) and striatonigral (MSA-P) predominance, we employed two experimental tasks sensitive to striatal lesions: the Weather-Prediction Task (WPT) and the Object Alternation Task (OAT). Only MSA-P ( n = 10) patients showed reduced learning in the WPT and were impaired at maintaining the alternation rule in the OAT, compared to MSA-C ( n = 10) and matched controls ( n = 26). Both MSA-groups were impaired regarding digit span and verbal fluency. This distinct pattern of cognitive impairment reflects the prevailing involvement of striato-thalamo-cortical circuits in MSA-P patients and of cerebellar-prefrontal circuits in MSA-C patients. The specific cognitive impairments correspond to the type of motor predominance in MSA.

Primary progressive aphasia (PPA) is a rare clinical dementia syndrome affecting predominantly language abilities. Word-finding difficulties and comprehension deficits despite relatively preserved cognitive functions are characteristic symptoms during the first two years, and distinguish PPA from other dementia types like Alzheimer's disease. However, the dynamics of changes in language and non-linguistic abilities are not well understood. Most studies on progression used cross-sectional designs, which provide only limited insight into the course of the disease. Here we report the results of a longitudinal study in three cases of logopenic PPA over a period of 18 months, with exemplary longitudinal data from one patient even over 46 months. A comprehensive battery of neurolinguistic and neuropsychological tests was applied four times at intervals of six months. Over this period, deterioration of verbal abilities such as picture naming, story retelling, and semantic word recall was found, and the individual decline was quantified and compared between the three patients. Furthermore, decrease in non-verbal skills such as divided attention and increasing apraxia was observed in all three patients. In addition, inter-subject variability in the progression with different focuses was observed, with one patient developing a non-fluent PPA variant. The longitudinal, multivariate investigation of logopenic PPA thus provides novel insights into the progressive deterioration of verbal as well as non-verbal abilities. These deficits may further interact and thus form a multi-causal basis for the patients' problems in every-day life which need to be considered when planning individually targeted intervention in PPA.

Background Alexithymia is a personality construct predominately associated with an impaired ability to identify and communicate emotions. Functional imaging studies showed that an altered function of the anterior cingulate cortex (ACC) may be relevant in alexithymia. In this study we investigated if the altered functional anatomy is related to structural changes (A) in the whole brain and (B) specifically in the ACC by applying a region-of-interest analysis. Methods 33 high- and 31 low-alexithymic right-handed young male subjects (selected by the 20-item Toronto Alexithymia Scale, TAS-20) were investigated using voxel-based morphometry (VBM) on high-resolution 3D magnetic resonance images. The group differences were analyzed by applying voxel-wise comparisons using two-sample t -tests. Moreover regression analyses with regard to the individual TAS-20 sum scores were calculated. Results Neither the subtraction analyses nor the correlation analyses revealed significant differences between high- and low-alexithymic subjects. Thus, according to our results, the null hypothesis of no structural difference between the groups could not be rejected. Limitations The findings cannot be generalized to female subjects. Conclusions Our results did not reveal morphological differences between high- and low-alexithymic subjects. The functional differences known from imaging studies could not be attributed to underlying anatomical changes. Thus, the personality trait of alexithymia might be associated with fewer morphological abnormalities than previously assumed.

Objective: To test the effects of stochastic whole body vibration (WBV) we performed a double-blind randomized controlled study. Methods: Patientswereallocatedeithertotheexperimental orsham group. Theexperimental groupreceived 5cyclesof stochastic WBV on three days, each cycle consisting of 5 stimulus trains of 60 seconds duration (frequency 6.5 Hz) and 60 seconds resting time between stimuli. Patients allocated to the control group received a sham treatment with 1 Hz. Unified Parkinson's Disease Rating Scale, part III (UPDRSIII) was performed after treatment at baseline, after the first series on day 1 and on day 5. Results: The reduction of subscores included in UPDRS III relative to baseline served as primary outcome measure. After the five-day course bradykinesia was improved in 14 of 18 patients (77.8%) and postural stability in 8 of 18 (44.4%). Speech and facial expression remained unchanged in both groups. Tremor (p = 0,027) and postural stability (p = 0,048) showed a reduction also, but did not reached level of significance ( p< 0,01); UPDRSIII sum score was improved by 26,7%. Conclusion: Stochastic whole body vibration may offer a supplementation to canonical physical treatments of PD motor symptoms.

Kalbe, Elke Onur, Oezguer A Minnerop, Martina Reimann, Jens Althaus, Astrid Ahmadzadehfar, Hojjat Dodel, Richard Strach, Katharina Clemen, Christoph S Herholz, Karl Haense, Cathleen Fink, Gereon R Schroder, Rolf Letter Research Support, Non-U.S. Gov't Germany Journal of neurology J Neurol. 2011 Mar;258(3):515-8. Epub 2010 Oct 12.

Multiple system atrophy (MSA) is a neurodegenerative disease not only affecting the basal ganglia, brainstem, cerebellum, and intermediolateral cell columns of the spinal cord but also the cerebral cortex. Clinically, cerebellar (MSA-C) and parkinsonian variants of MSA (MSA-P) are distinguished. We investigated 14 MSA patients (10 MSA-C, 4 MSA-P, men: 7, women: 7; age: 61.1 ± 3.3 years) and 14 matched controls (men: 7, women: 7; age: 58.6 ± 5.1 years) with voxel-based morphometry (VBM) to analyze gray and white matter differences both at baseline and at follow-up, 1 year later. Baseline comparisons between patients and controls confirmed significantly less gray matter in MSA in the cerebellum and cerebral cortex, and significantly less white matter in the cerebellar peduncles and brainstem. Comparisons of tissue-loss profiles (i.e., baseline versus follow-up) between patients and controls, revealed white matter reduction in MSA along the middle cerebellar peduncles, reflecting degeneration of the ponto-cerebellar tract as a particularly prominent and progressive morphological alteration in MSA. Comparisons between baseline and follow-up, separately performed in patients and controls, revealed additional white matter reduction in MSA along the corpus callosum at follow-up. This was replicated through additional shape-based analyses indicating a reduced callosal thickness in the anterior and posterior midbody, extending posteriorly into the isthmus. Callosal atrophy may possibly reflect a disease-specific pattern of neurodegeneration and cortical atrophy, fitting well with the predominant impairment of motor functions in the MSA patients.

Contains fulltext : 90674.pdf (Publisher’s version ) (Closed access) A subtype-specific impairment of cognitive functions in spinocerebellar ataxia (SCA) patients is still debated. Thirty-two SCA patients (SCA1, 6; SC2, 3; SCA3, 15; SCA6, 8) and 14 matched healthy controls underwent neuropsychological evaluation testing attention, executive functions, episodic and semantic memory, and motor coordination. Severity of ataxia was assessed with the Scale for the Assessment and Rating of Ataxia (SARA), nonataxia symptoms with the Inventory of Non-Ataxia Symptoms. Depressive symptoms were evaluated with the Beck Depression Inventory. The SARA scores of our SCA patients (range 1–19.5) indicated an overall moderate ataxia, most pronounced in SCA6 and SCA1. Mean number of nonataxia symptoms (range 0–2.2) were most distinct in SCA1 and nearly absent in SCA6. SCA1 performed poorer than controls in 33% of all cognitive test parameters, followed by SCA2, SCA3, and SCA6 patients (17%). SCA 1–3 patients presented mainly attentional and executive dysfunctions while semantic and episodic memory functions were preserved. Attentional and executive functions were partly correlated with ataxia severity and fine motor coordination. All patients exhibited mildly depressed mood. Motor and dominant hand functions were more predictive for depressed mood than cognitive measures or overall ataxia. Besides motor impairments in all patients, SCA patients with extracerebellar pathology (SCA 1–3) were characterized by poor frontal attentional and executive dysfunction while mild cognitive impairments in predominantly cerebellar SCA6 patients appeared to reflect mainly cerebellar dysfunction. Regarding the everyday relevance of symptoms, (dominant) motor hand functioning emerged as a marker for the patient’s mood. 12 p.

There is insufficient evidence concerning the efficacy of antiviral treatment of Bell's palsy (BP). We therefore compared the efficacy of prednisone and famciclovir to prednisone treatment alone in BP. A total of 167 consecutive patients with untreated acute BP were included. Severity of BP was evaluated using the House-Brackmann scale (HBS) and virus antibody tests (herpes simplex virus, varicella zoster virus) were performed. Patients admitted on even dates were treated with prednisone ("P group") and patients admitted on odd dates were treated with prednisone and famciclovir ("P+F group"). 117 patients completed the follow-up after 3 months or later (67 P/51 P+F). While most patients showed at least partial recovery with both treatment types, improvement of at least 4 grades in the HBS was more common in the "P+F group" (29.4 % vs. 11.9 %), whereas smaller changes of less than 3 grades were more common in the "P group" (29.9 % vs. 17.6 %; Chi-square test, p = 0.02). Patients with complete BP (HBS grade of 5 or 6) had significantly better chances of reaching normal function if treated with famciclovir additionally instead with prednisone alone (73.7 % vs. 47.1 %; Cochran-Armitage trend test, p = 0.03). These results suggest that the combined treatment of famciclovir and prednisolone should be considered (at least) in patients with severe BP.

The role of the alpha4beta2* nicotinic acetylcholine receptors (nAChR) in tobacco addiction in humans is largely unresolved. We visualized brain alpha4beta2* nicotinic acetylcholine receptors of smokers and non-smokers with positron emission tomography using 2-[(18)F]fluoro-3-(2(S)azetidinylmethoxy)pyridine, commonly known as 2-[(18)F]F-A-85380. The total brain distribution volume of 2-[(18)F]F-A-85380 was significantly increased in smokers. Statistical parametric mapping revealed that the most prominent regional differences of distribution volumes (DV) were found in cerebellum and brainstem with an increased uptake in smokers. The up-regulation of alpha4beta2* nAChR upon chronic nicotine exposure via tobacco smoking incorporates subcortical brain regions which may play an important role in nicotine addiction.

The sporadic adult onset ataxias of unknown etiology (SAOA) denote the non-hereditary degenerative adult onset ataxias that are distinct from multiple system atrophy (MSA).To define and characterize the clinical phenotype of sporadic adult onset ataxia of unknown etiology (SAOA).A survey of clinical features, nerve conduction and evoked potentials, autonomic tests, and magnetic resonance imaging (MRI)-based brain morphometry was conducted in patients with SAOA.Study subjects were a consecutive sample of 27 patients (11 male, 16 female) who met the diagnostic criteria for SAOA (age 55 +/- 13 years; age at disease onset 47 +/- 14 years; disease duration 8 +/- 7 years).All patients presented with a cerebellar syndrome. The most frequent extracerebellar symptoms were decreased vibration sense in 70% and decreased or absent ankle reflexes in 33% of the patients. Nerve conduction studies revealed a polyneuropathy in 26% of the patients. Somatosensory evoked potentials were abnormal in 44%, and central motor conduction time in 17% of patients. Autonomic testing revealed an affected autonomic nervous system in 58% of patients. Voxel-based brain morphometry showed a predominant reduction of gray matter in the cerebellum which was significantly correlated with disease stages. A loss of white matter was found in both middle cerebellar peduncles and the outer edge of the pons.The data show that SAOA is a predominantly, but not exclusively cerebellar disorder. Clinical, electrophysiological, and imaging findings showed some similarities with multiple system atrophy which raises the question of an overlap of these two disorders.

Spinocerebellar ataxia type 3, spinocerebellar ataxia type 6 and Friedreich's ataxia are common hereditary ataxias. Different patterns of atrophy of the cerebellar cortex are well known. Data on cerebellar nuclei are sparse. Whereas cerebellar nuclei have long been thought to be preserved in spinocerebellar ataxia type 6, histology shows marked atrophy of the nuclei in Friedreich's ataxia and spinocerebellar ataxia type 3. In the present study susceptibility weighted imaging was used to assess atrophy of the cerebellar nuclei in patients with spinocerebellar ataxia type 6 (n = 12, age range 41-76 years, five female), Friedreich's ataxia (n = 12, age range 21-55 years, seven female), spinocerebellar ataxia type 3 (n = 10, age range 34-67 years, three female), and age- and gender-matched controls (total n = 23, age range 22-75 years, 10 female). T1-weighted magnetic resonance images were used to calculate the volume of the cerebellum. In addition, ultra-high field functional magnetic resonance imaging was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. As expected, the volume of the cerebellum was markedly reduced in spinocerebellar ataxia type 6, preserved in Friedreich's ataxia, and mildy reduced in spinocerebellar ataxia type 3. The volume of the cerebellar nuclei was reduced in the three patient groups compared to matched controls (P-values < 0.05; two-sample t-tests). Atrophy of the cerebellar nuclei was most pronounced in spinocerebellar ataxia type 6. On a functional level, hand-movement-related cerebellar activation was altered in all three disorders. Within the cerebellar cortex, functional magnetic resonance imaging signal was significantly reduced in spinocerebellar ataxia type 6 and Friedreich's ataxia compared to matched controls (P-values < 0.001, bootstrap-corrected cluster-size threshold; two-sample t-tests). The difference missed significance in spinocerebellar ataxia type 3. Within the cerebellar nuclei, reductions were significant when comparing spinocerebellar ataxia type 6 and Friedreich's ataxia to matched controls (P < 0.01, bootstrap-corrected cluster-size threshold; two-sample t-tests). Susceptibility weighted imaging allowed depiction of atrophy of the cerebellar nuclei in patients with Friedreich's ataxia and spinocerebellar ataxia type 3. In spinocerebellar ataxia type 6, pathology was not restricted to the cerebellar cortex but also involved the cerebellar nuclei. Functional magnetic resonance imaging data, on the other hand, revealed that pathology in Friedreich's ataxia and spinocerebellar ataxia type 3 is not restricted to the cerebellar nuclei. There was functional involvement of the cerebellar cortex despite no or little structural changes.

Background The cerebellum plays an important role for balance control and the coordination of voluntary movements. Beyond that there is growing evidence that the cerebellum is also involved in cognitive functions. How ataxic motor symptoms are influenced by simultaneous performance of a cognitive task, however, has rarely been assessed and some of the findings are contradictory. We assessed stance in 20 patients with adult onset degenerative almost purely cerebellar disorders and 20 healthy controls during single and dual task conditions (verbal working memory task). To objectively measure postural sway and the impact of somatosensory, visual and vestibular inputs we used static and dynamic posturography with the Sensory Organization Test (SOT). Results In both groups, cerebellar patients and controls, dual tasking reduced all sway parameters. Reduction of sway path was higher in cerebellar patients and increased with the difficulty of the postural task. The frequency of falls was higher in the patients group especially during the more challenging conditions and dual task performance in particular increased the risk of falls in cerebellar patients. Conclusion Dual task conditions had a larger impact on sway parameters in patients with chronic cerebellar disorders than in healthy controls and lead to an increased risk of falls. As performing two tasks simultaneously is common and therefore important in daily life dual task exercises should be part of physical therapy programs for cerebellar patients.

Nicotinic acetylcholine receptors (nAChR) are involved in many physiological functions and appear to be affected in neurodegenerative diseases like Alzheimer's disease and Parkinson's disease (PD). Here, we describe the in vitro evaluation of nAChRs in PD with 2-[18F]F-A85380, a ligand with high affinity to the beta2 nAChR subunit. Autoradiography with 2-[18F]F-A85380 in untreated rat brain corresponded to the known distribution of alpha4beta2 nAChRs with high uptake in the thalamus, moderate uptake in the striatum and cortex and low uptake in the cerebellum (47%, 43% and 19% of the thalamus, respectively). The localization of alpha4beta2 nAChRs in the striatum was investigated in rodents with unilateral lesion of the substantia nigra. 2-[18F]F-A85380 binding was significantly reduced in the striatum ipsilateral to the lesion side (to 64% of the contralateral side), indicating that a fraction of alpha4beta2 nAChRs is located on dopaminergic terminals, whereas another fraction resides on striatal interneurons or cortical afferents. Similarly, in human brain sections of PD patients, 2-[18F]F-A85380 uptake was significantly reduced not only in the caudate and putamen but also in the thalamus (approximately 30% of the binding of control brain in all three regions); within the striatum, nAChRs in the putamen were significantly more severely affected as in the caudate. The observed pattern of alpha4beta2* nAChR loss demonstrates the potential of 2-[18F]F-A85380 for further investigations of this positron emission tomography ligand for in vivo studies of alpha4beta2* nAChRs in PD.

Voxel-based relaxometry (VBR) is a novel morphometric method that analyses the relaxation rate R2 derived from multi-echo T2-weighted images on a voxel-by-voxel basis. We used VBR to study the brain morphology of 14 patients suffering from multiple-system atrophy of cerebellar type (MSA-C) and compared the results with those obtained by voxel-based morphometry (VBM) of T1-weighted images. VBR analysis revealed reduction of relaxation rate R2 in the cerebellum and brainstem reflecting infratentorial brain atrophy. The affected regions largely corresponded to those regions in which VBM showed reductions of grey and white matter. In addition, R2 was increased in the putamen, a region in which VBM did not show abnormalities. Our data show that the combination of VBR and VBM provided convergent and complimentary information about the brain morphology of MSA-C.

Whole body vibration (WBV) is a biomechanical treatment used widely in professional sports and rehabilitation. We examined the effect of stochastic WBV on ataxia in spinocerebellar ataxia types 1, 2, 3, and 6 (SCA 1, 2, 3 and 6) in a single-center double-blind sham-controlled study. Stochastic WBV was applied on four sequent days, each treatment consisting of five stimulus trains of 60-s duration at a frequency of 6.5 Hz and 60-s resting time between stimuli (n = 17). Patients allocated to the sham group received the same treatment with 1 Hz (n = 15). All patients were rated at baseline and after the last treatment using clinical scores (SARA, SCAFI, and INAS). After treatment, we found significant improvements of gait, posture, and speed of speech in the verum group while limb kinetics and ataxia of speech did not respond. Stochastic WBV might act on proprioceptive mechanisms and could also stimulate non-cerebellar/compensatory mechanisms. But at present, the involved cellular mechanism and the presumed neuronal loops cannot be deciphered. Thus, future work is needed to understand the mechanisms of whole body vibration. Finally, the use of stochastic WBV could provide a supplementation to treat ataxia in SCA and can be combined with physiotherapeutical motor training.