The AP-2 complex interacts with γ-TuRC and regulates the proliferative capacity of neural progenitors.

Centrosomes are organelles that nucleate microtubules via the activity of gamma-tubulin ring complexes (γ-TuRC). In the developing brain, centrosome integrity is central to the progression of the neural progenitor cell cycle, and its loss leads to microcephaly. We show that NPCs maintain centrosome integrity via the endocytic adaptor protein complex-2 (AP-2). NPCs lacking AP-2 exhibit defects in centrosome formation and mitotic progression, accompanied by DNA damage and accumulation of p53. This function of AP-2 in regulating the proliferative capacity of NPCs is independent of its role in clathrin-mediated endocytosis and is coupled to its association with the GCP2, GCP3, and GCP4 components of γ-TuRC. We find that AP-2 maintains γ-TuRC organization and regulates centrosome function at the level of MT nucleation. Taken together, our data reveal a novel, noncanonical function of AP-2 in regulating the proliferative capacity of NPCs and open new avenues for the identification of novel therapeutic strategies for the treatment of neurodevelopmental and neurodegenerative disorders with AP-2 complex dysfunction.

Improvements in Walking Distance during Nusinersen Treatment - A Prospective 3-year SMArtCARE Registry Study.

BACKGROUND AND OBJECTIVES: Disease progression in patients with spinal muscular atrophy (SMA) has changed dramatically within the past years due to the approval of three different disease-modifying treatments. Nusinersen was the first drug to be approved for the treatment of SMA patients. Clinical trials provided data from infants with SMA type 1 and children with SMA type 2, but there is still insufficient evidence and only scarcely reported long-term experience for nusinersen treatment in ambulant patients. Here, we report data from the SMArtCARE registry of ambulant patients under nusinersen treatment with a follow-up period of up to 38 months. METHODS: SMArtCARE is a disease-specific registry in Germany, Austria and Switzerland. Data are collected as real-world data during routine patient visits. Our analysis included all patients under treatment with nusinersen able to walk independently before start of treatment with focus on changes in motor function. RESULTS: Data from 231 ambulant patients were included in the analysis. During the observation period, 31 pediatric walkers (27.2%) and 31 adult walkers (26.5%) experienced a clinically meaningful improvement of≥30 m in the 6-Minute-Walk-Test. In contrast, only five adult walkers (7.7%) showed a decline in walking distance≥30 m, and two pediatric walkers (1.8%) lost the ability to walk unassisted under treatment with nusinersen. HFMSE and RULM scores improved in pediatric and remained stable in adult patients. CONCLUSION: Our data demonstrate a positive effect of nusinersen treatment in most ambulant pediatric and adult SMA patients. We not only observed a stabilization of disease progression or lack of deterioration, but clinically meaningful improvements in walking distance.

Normative Observational Nerve Ultrasound Values in School-Age Children and Adolescents and Their Application to Hereditary Neuropathies.

Backgrounds: We have aimed to establish nerve ultrasound reference data in 8 to 17-year-old children and adolescents and to compare those data to younger children, adults, and age-matched children with polyneuropathies. Methods: High-resolution ultrasounds of the nerves were performed in 117 healthy children and adolescents at 20 predefined landmarks in the neck and the extremities of both sides. Mean values, side-to-side differences and intraneural ratios, as well as upper limits have been calculated. In a second step, a comparison between 25 children and adolescents of the same age range with proven hereditary and acquired neuropathies and lysosomal storage diseases has been carried out. Results: Nerve growth correlates significantly with age and reaches adult values at the age of around 15 years. The influence of body mass index and gender is negligible at most segments. By the use of age-specific upper limits, nerve enlargement could be seen in distinct types of neuropathies, particularly in demyelinating hereditary and inflammatory types, which is comparable to findings in adults, but also in rare lysosomal storage diseases. Conclusion: Nerve size correlates with age during childhood and reaches a climax in younger adults. Age-matched reference data are inevitable to differ between hypertrophic and non-hypertrophic nerve damage, e.g., in neuropathies.

Nerve ultrasound reference data in children from two to seven years.

OBJECTIVE: We examined selected peripheral and spinal nerves of children aged between two and seven years. METHOD: High resolution ultrasound was performed in 116 children (2-7 years of age) at 19 predefined landmarks of median, ulnar, tibial, fibular, sural and radial nerves, the vagus as well as cervical spinal nerve 5 and 6. Further, side-to-side measuring and grey-scale analysis was done at selected nerve sites. RESULTS: Nerves of children were on average smaller than those of adults. Nerve growth correlates significantly with age in all nerves, the mean values were similar in the age of two to four years and five to seven years. Body mass index (BMI) and gender showed moderate effect at some nerve sites, however not uniformly in all. A side-to-side difference of up to 30% in median, and up to 20% in tibial nerve can occur in healthy individuals. Grey-scale analysis for echointensity has been performed in median, ulnar and tibial nerves. CONCLUSION: Nerve size increases with age, BMI and gender have moderate effect. A side-to-side-difference of up to 30% can exist. SIGNIFICANCE: Reference values of nerve cross-sectional area, side-to-side-difference and echo intensity are necessary to detect nerve pathology in children as well as in adults.

The time window for successful right-hemispheric language reorganization in children.

AIM: To identify, in a retrospective, observational study, the time window during which successful right-hemispheric language reorganization is possible after left-hemispheric brain damage. METHOD: 25 patients (10 females; age 6-41 years; ≥12 months after insult; age at insult 0;3-15;11 years) with acute, language-relevant left-hemispheric insults acquired during childhood and adolescence completed questionnaires for self-assessment of language problems. 12 patients of those reporting no (n = 8) or only moderate (n = 4) language problems participated in language fMRI. RESULTS: Language outcome of lesions occurring before 5 years of age (n = 7) was always favorable, and language was right-lateralized (2 patients: age at lesion < 2 years) or bilateral (3 patients: age at lesion 2-5 years). Following lesions occurring after 5 years of age, language outcome was often unfavorable (11/18 patients: moderate or severe problems), and of the 7 patients without problems, none showed right-hemispheric reorganization (fMRI available in 4). INTERPRETATION: The combination of normal language outcome and right-hemispheric language reorganization after a left-hemispheric lesion sustained after the neonatal period is extremely rare. Functionally sufficient right-hemispheric language was documented in only two patients with lesions acquired before two years of age.

Predicting hand function after hemidisconnection.

Hemidisconnections (i.e. hemispherectomies or hemispherotomies) invariably lead to contralateral hemiparesis. Many patients with a pre-existing hemiparesis, however, experience no deterioration in motor functions, and some can still grasp with their paretic hand after hemidisconnection. The scope of our study was to predict this phenomenon. Hypothesizing that preserved contralateral grasping ability after hemidisconnection can only occur in patients controlling their paretic hands via ipsilateral corticospinal projections already in the preoperative situation, we analysed the asymmetries of the brainstem (by manual magnetic resonance imaging volumetry) and of the structural connectivity of the corticospinal tracts within the brainstem (by magnetic resonance imaging diffusion tractography), assuming that marked hypoplasia or Wallerian degeneration on the lesioned side in patients who can grasp with their paretic hands indicate ipsilateral control. One hundred and two patients who underwent hemidisconnections between 0.8 and 36 years of age were included. Before the operation, contralateral hand function was normal in 3/102 patients, 47/102 patients showed hemiparetic grasping ability and 52/102 patients could not grasp with their paretic hands. After hemidisconnection, 20/102 patients showed a preserved grasping ability, and 5/102 patients began to grasp with their paretic hands only after the operation. All these 25 patients suffered from pre- or perinatal brain lesions. Thirty of 102 patients lost their grasping ability. This group included all seven patients with a post-neonatally acquired or progressive brain lesion who could grasp before the operation, and also all three patients with a preoperatively normal hand function. The remaining 52/102 patients were unable to grasp pre- and postoperatively. On magnetic resonance imaging, the patients with preserved grasping showed significantly more asymmetric brainstem volumes than the patients who lost their grasping ability. Similarly, these patients showed striking asymmetries in the structural connectivity of the corticospinal tracts. In summary, normal preoperative hand function and a post-neonatally acquired or progressive lesion predict a loss of grasping ability after hemidisconnection. A postoperatively preserved grasping ability is possible in hemiparetic patients with pre- or perinatal lesions, and this is highly likely when the brainstem is asymmetric and especially when the structural connectivity of the corticospinal tracts within the brainstem is asymmetric.

Comparison of different tractography algorithms and validation by intraoperative stimulation in a child with a brain tumor.

BACKGROUND: Advanced modalities such as functional magnetic resonance imaging (MRI) and diffusion MR tractography offer in vivo information about brain networks and are therefore increasingly used for neurosurgical planning in children also. AIM: This study aims to study the application of routine and advanced tractography algorithms and its comparison with intraoperative subcortical electrical stimulation. METHOD: Presurgical functional MRI and MR diffusion tractography were performed on a 6-year-old patient presenting with seizures, but no motor symptoms, due to a neuroectodermal tumor in the left central region. Three different tractography algorithms were compared: deterministic diffusion tensor imaging (DTI)-tracking, probabilistic DTI-tracking, and probabilistic constrained spherical deconvolution tracking (pCSD). RESULTS: All three tractography algorithms could localize the core of the corticospinal tract with good agreement. The pCSD-tracking algorithm was more sensitive in revealing the anatomically most realistic fiber distribution and a proportion of fibers traversing a solid part of the tumor. Intraoperative stimulation confirmed these fibers close to the tumor. As a result, only a subtotal resection was performed, preventing postoperative sensorimotor deficits. CONCLUSION: Although, all tractography algorithms successfully identified the core of the corticospinal pathway, deterministic DTI-tractography, as widely used in clinical neuronavigation software, only insufficiently visualized critical fibers here. We believe these results argue for a stronger consideration of advanced tractography approaches in neurosurgical planning.

Combining functional and anatomical connectivity reveals brain networks for auditory language comprehension.

Cognitive functions are organized in distributed, overlapping, and interacting brain networks. Investigation of those large-scale brain networks is a major task in neuroimaging research. Here, we introduce a novel combination of functional and anatomical connectivity to study the network topology subserving a cognitive function of interest. (i) In a given network, direct interactions between network nodes are identified by analyzing functional MRI time series with the multivariate method of directed partial correlation (dPC). This method provides important improvements over shortcomings that are typical for ordinary (partial) correlation techniques. (ii) For directly interacting pairs of nodes, a region-to-region probabilistic fiber tracking on diffusion tensor imaging data is performed to identify the most probable anatomical white matter fiber tracts mediating the functional interactions. This combined approach is applied to the language domain to investigate the network topology of two levels of auditory comprehension: lower-level speech perception (i.e., phonological processing) and higher-level speech recognition (i.e., semantic processing). For both processing levels, dPC analyses revealed the functional network topology and identified central network nodes by the number of direct interactions with other nodes. Tractography showed that these interactions are mediated by distinct ventral (via the extreme capsule) and dorsal (via the arcuate/superior longitudinal fascicle fiber system) long- and short-distance association tracts as well as commissural fibers. Our findings demonstrate how both processing routines are segregated in the brain on a large-scale network level. Combining dPC with probabilistic tractography is a promising approach to unveil how cognitive functions emerge through interaction of functionally interacting and anatomically interconnected brain regions.