Matthis Synofzik

Intensive coordinative training improves motor performance in degenerative cerebellar disease

Objectives: The cerebellum is known to play a strong functional role in both motor control and motor learning. Hence, the benefit of physiotherapeutic training remains controversial for patients with cerebellar degeneration. In this study, we examined the effectiveness of a 4-week intensive coordinative training for 16 patients with progressive ataxia due to cerebellar degeneration (n = 10) or degeneration of afferent pathways (n = 6). Methods: Effects were assessed by clinical ataxia rating scales, individual goal attainment scores, and quantitative movement analysis. Four assessments were performed: 8 weeks before, immediately before, directly after, and 8 weeks after training. To control for variability in disease progression, we used an intraindividual control design, where performance changes with and without training were compared. Results: Significant improvements in motor performance and reduction of ataxia symptoms were observed in clinical scores after training and were sustained at follow-up assessment. Patients with predominant cerebellar ataxia revealed more distinct improvement than patients with afferent ataxia in several aspects of gait like velocity, lateral sway, and intralimb coordination. Consistently, in patients with cerebellar but without afferent ataxia, the regulation of balance in static and dynamic balance tasks improved significantly. Conclusion: In patients with cerebellar ataxia, coordinative training improves motor performance and reduces ataxia symptoms, enabling them to achieve personally meaningful goals in everyday life. Training effects were more distinct for patients whose afferent pathways were not affected. For both groups, continuous training seems crucial for stabilizing improvements and should become standard of care. Level of evidence: This study provides Class III evidence that coordinative training improves motor performance and reduces ataxia symptoms in patients with progressive cerebellar ataxia.

A Pan-European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats

We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan‐European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early‐Onset Dementia (EOD) consortium. Next, we performed a meta‐analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7–24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss‐of‐function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC‐rich low complexity sequence adjacent to the G4C2 repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G4C2 repeat, which is likely more prone to replication slippage and pathological expansion.

Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.

Stimulating personality: Ethical criteria for deep brain stimulation in psychiatric patients and for enhancement purposes

Within the recent development of brain‐machine‐interfaces deep brain stimulation (DBS) has become one of the most promising approaches for neuromodulation. After its introduction more than 20 years ago, it has in clinical routine become a successful tool for treating neurological disorders like Parkinsons disease, essential tremor and dystonia. Recent evidence also demonstrates efficacy in improving emotional and cognitive processing in obsessive‐compulsive disorder and major depression, thus allowing new treatment options for treatment refractory psychiatric diseases, and even indicating future potential to enhance functioning in healthy subjects. We demonstrate here that DBS is neither intrinsically unethical for psychiatric indications nor for enhancement purposes. To gain normative orientation, the concept of “personality” is not useful – even if a naturalistic notion is employed. As an alternative, the common and widely accepted bioethical criteria of beneficence, non‐maleficence, and autonomy allow a clinically applicable, highly differentiated context‐ and case‐sensitive approach. Based on these criteria, an ethical analysis of empirical evidence from both DBS in movement disorders and DBS in psychiatric disease reveals that wide‐spread use of DBS for psychiatric indications is currently not legitimated and that the basis for enhancement purposes is even more questionable. Nevertheless, both applications might serve as ethically legitimate, promising purposes in the future.

The cerebellum updates predictions about the visual consequences of one's behavior.

Each action has sensory consequences that need to be distinguished from sensations arising from the environment. This is accomplished by the comparing of internal predictions about these consequences with the actual afference, thereby isolating the afferent component that is self-produced. Because the sensory consequences of actions vary as a result of changes of the effectors efficacy, internal predictions need to be updated continuously and on a short time scale. Here, we tested the hypothesis that this updating of predictions about the sensory consequences of actions is mediated by the cerebellum, a notion that parallels the cerebellums role in motor learning. Patients with cerebellar lesions and their matched controls were equally able to detect experimental modifications of visual feedback about their pointing movements. When such feedback was constantly rotated, both groups instantly attributed the visual feedback to their own actions. However, in interleaved trials without actual feedback, patients did no longer account for this feedback rotation--neither perceptually nor with respect to motor performance. Both deficits can be explained by an impaired updating of internal predictions about the sensory consequences of actions caused by cerebellar pathology. Thus, the cerebellum guarantees both precise performance and veridical perceptual interpretation of actions.

The experience of agency: an interplay between prediction and postdiction

The experience of agency, i.e., the registration that I am the initiator of my actions, is a basic and constant underpinning of our interaction with the world. Whereas several accounts have underlined predictive processes as the central mechanism (e.g., the comparator model by C. Frith), others emphasized postdictive inferences (e.g., post-hoc inference account by D. Wegner). Based on increasing evidence that both predictive and postdictive processes contribute to the experience of agency, we here present a unifying but at the same time parsimonious approach that reconciles these accounts: predictive and postdictive processes are both integrated by the brain according to the principles of optimal cue integration. According to this framework, predictive and postdictive processes each serve as authorship cues that are continuously integrated and weighted depending on their availability and reliability in a given situation. Both sensorimotor and cognitive signals can serve as predictive cues (e.g., internal predictions based on an efferency copy of the motor command or cognitive anticipations based on priming). Similarly, other sensorimotor and cognitive cues can each serve as post-hoc cues (e.g., visual feedback of the action or the affective valence of the action outcome). Integration and weighting of these cues might not only differ between contexts and individuals, but also between different subject and disease groups. For example, schizophrenia patients with delusions of influence seem to rely less on (probably imprecise) predictive motor signals of the action and more on post-hoc action cues like e.g., visual feedback and, possibly, the affective valence of the action outcome. Thus, the framework of optimal cue integration offers a promising approach that directly stimulates a wide range of experimentally testable hypotheses on agency processing in different subject groups.

PNPLA6 mutations cause Boucher-Neuhäuser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum

Boucher-Neuhäuser and Gordon Holmes syndromes are clinical syndromes defined by early-onset ataxia and hypogonadism plus chorioretinal dystrophy (Boucher-Neuhäuser syndrome) or brisk reflexes (Gordon Holmes syndrome). Here we uncover the genetic basis of these two syndromes, demonstrating that both clinically distinct entities are allelic for recessive mutations in the gene PNPLA6. In five of seven Boucher-Neuhäuser syndrome/Gordon Holmes syndrome families, we identified nine rare conserved and damaging mutations by applying whole exome sequencing. Further, by dissecting the complex clinical presentation of Boucher-Neuhäuser syndrome and Gordon Holmes syndrome into its neurological system components, we set out to analyse an additional 538 exomes from families with ataxia (with and without hypogonadism), pure and complex hereditary spastic paraplegia, and Charcot-Marie-Tooth disease type 2. We identified four additional PNPLA6 mutations in spastic ataxia and hereditary spastic paraplegia families, revealing that Boucher-Neuhäuser and Gordon Holmes syndromes in fact represent phenotypic clusters on a spectrum of neurodegenerative diseases caused by mutations in PNPLA6. Structural analysis indicates that the majority of mutations falls in the C-terminal phospholipid esterase domain and likely inhibits the catalytic activity of PNPLA6, which provides the precursor for biosynthesis of the neurotransmitter acetylcholine. Our findings show that PNPLA6 influences a manifold of neuronal systems, from the retina to the cerebellum, upper and lower motor neurons and the neuroendocrine system, with damage of this protein causing an extraordinarily broad continuous spectrum of associated neurodegenerative disease.

Long-term effects of coordinative training in degenerative cerebellar disease†

Few clinical studies have evaluated physiotherapeutic interventions for patients with degenerative cerebellar disease. In particular, evidence for long‐term effects and transfer to activities of daily life is rare. We have recently shown that coordinative training leads to short‐term improvements in motor performance. To evaluate long‐term benefits and translation to real world function, we here assessed motor performance and achievements in activities of daily life 1 year after a 4 week intensive coordinative training, which was followed by a home training program. Effects were assessed by clinical rating scales, a goal attainment score and quantitative movement analysis. Despite gradual decline of motor performance and gradual increase of ataxia symptoms due to progression of disease after 1 year, improvements in motor performance and achievements in activities of daily life persisted. Thus, also in patients with degenerative cerebellar disease, continuous coordinative training leads to long‐term improvements, which translate to real world function.

Video game–based coordinative training improves ataxia in children with degenerative ataxia

ABSTRACT Objective: Degenerative ataxias in children present a rare condition where effective treatments are lacking. Intensive coordinative training based on physiotherapeutic exercises improves degenerative ataxia in adults, but such exercises have drawbacks for children, often including a lack of motivation for high-frequent physiotherapy. Recently developed whole-body controlled video game technology might present a novel treatment strategy for highly interactive and motivational coordinative training for children with degenerative ataxias. Methods: We examined the effectiveness of an 8-week coordinative training for 10 children with progressive spinocerebellar ataxia. Training was based on 3 Microsoft Xbox Kinect video games particularly suitable to exercise whole-body coordination and dynamic balance. Training was started with a laboratory-based 2-week training phase and followed by 6 weeks training in children’s home environment. Rater-blinded assessments were performed 2 weeks before laboratory-based training, immediately prior to and after the laboratory-based training period, as well as after home training. These assessments allowed for an intraindividual control design, where performance changes with and without training were compared. Results: Ataxia symptoms were significantly reduced (decrease in Scale for the Assessment and Rating of Ataxia score, p = 0.0078) and balance capacities improved (dynamic gait index, p = 0.04) after intervention. Quantitative movement analysis revealed improvements in gait (lateral sway: p = 0.01; step length variability: p = 0.01) and in goal-directed leg placement (p = 0.03). Conclusions: Despite progressive cerebellar degeneration, children are able to improve motor performance by intensive coordination training. Directed training of whole-body controlled video games might present a highly motivational, cost-efficient, and home-based rehabilitation strategy to train dynamic balance and interaction with dynamic environments in a large variety of young-onset neurologic conditions. Classification of evidence: This study provides Class III evidence that directed training with Xbox Kinect video games can improve several signs of ataxia in adolescents with progressive ataxia as measured by SARA score, Dynamic Gait Index, and Activity-specific Balance Confidence Scale at 8 weeks of training.

S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-α pathway

Parkinson’s disease is a neurodegenerative disorder that can, at least partly, be mimicked by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. S100B is a calcium-binding protein expressed in, and secreted by, astrocytes. There is increasing evidence that S100B acts as a cytokine or damage-associated molecular pattern protein not only in inflammatory but also in neurodegenerative diseases. In this study, we show that S100B protein levels were higher in post-mortem substantia nigra of patients with Parkinson’s disease compared with control tissue, and cerebrospinal fluid S100B levels were higher in a large cohort of patients with Parkinson’s disease compared with controls. Correspondingly, mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine showed upregulated S100B messenger RNA and protein levels. In turn, ablation of S100B resulted in neuroprotection, reduced microgliosis and reduced expression of both the receptor for advanced glycation endproducts and tumour necrosis factor-α. Our results demonstrate a role of S100B in the pathophysiology of Parkinson’s disease. Targeting S100B may emerge as a potential treatment strategy in this disorder.