Restoration of the striatal circuitry: from developmental aspects toward clinical applications

In the basal ganglia circuitry, the striatum is a highly complex structure coordinating motor and cognitive functions and it is severely affected in Huntington's disease (HD) patients. Transplantation of fetal ganglionic eminence (GE) derived precursor cells aims to restore neural circuitry in the degenerated striatum of HD patients. Pre-clinical transplantation in genetic and lesion HD animal models has increased our knowledge of graft vs. host interactions, and clinical studies have been shown to successfully reduce motor and cognitive effects caused by the disease. Investigating the molecular mechanisms of striatal neurogenesis is a key research target, since novel strategies aim on generating striatal neurons by differentiating embryonic stem cells or by reprogramming somatic cells as alternative cell source for neural transplantation

The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson’s disease

Acknowledgements The authors thank Benjamin Rahm (University of Freiburg) and Michael Fox (Harvard Medical School) for valuable comments on a previous version of this manuscript. This work was supported by a grant of the BrainLinks-BrainTools Cluster of Excellence funded by the German Research Foundation (DFG, grant number EXC 1086) to C.P.K., F.A., T.P., B.O.S., C.W, and V.A.C.; A.H. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, Emmy Noether Stipend 410169619 and 424778381 – TRR 295) as well as Deutsches Zentrum für Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND). Funding Open Access funding enabled and organized by Projekt DEAL.Peer reviewedPublisher PD

BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors

<p>Abstract</p> <p>Background</p> <p>The prognosis for patients with recurrent glioblastoma is still poor with a median survival between 3 and 6 months. Reports about the application of carmustine (BCNU), one of the standard chemotherapeutic drugs in the treatment of newly diagnosed glioblastoma, in the recurrent situation are rare.</p> <p>Methods</p> <p>We performed a retrospective analysis of 35 patients with recurrent or progressive glioblastoma treated with 80 mg/m²BCNU on days 1 on 3 intravenously at our department for efficacy, toxicity and prognostic factors. Progression free survival and overall survival were estimated by the Kaplan-Meier method. The influence of age, Karnofsky performance status (KPS), tumor burden, pretreatment with temozolomide (TMZ), type of surgery for initial diagnosis and number of previous relapses on outcome was analyzed in a proportional hazards regression model.</p> <p>Results</p> <p>The median age of the group was 53 years, median KPS was 70. Median progression free survival was 11 weeks (95% confidence interval [CI]: 8-15), median overall survival 22 weeks (95% CI: 18-27). The rate of adverse events, especially hematological toxicity, is relatively high, and in 3 patients treatment had to be terminated due to adverse events (one pulmonary embolism, one pulmonary fibrosis, and one severe bone marrow suppression). No influence of age, KPS, tumor burden, pre-treatment with TMZ and number of previous relapses on outcome could be demonstrated, while gross total resection prior to recurrence showed a borderline statistically significant negative impact on PFS and OS. These data compare well with historical survival figures. However prospective randomized studies are needed to evaluate BCNU efficacy against newer drugs like bevacizumab or the intensified temozolomide regime (one week on/one week off).</p> <p>Conclusion</p> <p>In summary, BCNU treatment appears to be a valuable therapeutic option for recurrent glioblastomas, where no other validated radio- and/or chemotherapy are available.</p

Review: Neurorehabilitation With Neural Transplantation

Cell replacement therapy has been tested clinically in Parkinson’s disease (PD) and Huntington’s disease (HD), epilepsy, spinal cord injury, and stroke. The clinical outcomes have been variable, perhaps partly because of the differing levels of preclinical, basic experimental evidence that was available prior to the trials. The most promising results have been seen in PD trials, with encouraging ones in HD. A common feature of most trials is that they have concentrated on the biological and technical aspects of transplantation without presupposing that the outcomes might be influenced by events after the surgery. The growing evidence of plasticity demonstrated by the brain and grafts in response to environmental and training stimuli such as rehabilitation interventions has been mostly neglected throughout the clinical application of cell therapy. This review suggests that a different approach may be required to maximize recovery: postoperative experiences, including rehabilitation with explicit behavioral retraining, could have marked direct as well as positive secondary effects on the integration and function of grafted cells in the host neural system. The knowledge gained about brain plasticity following brain damage needs to be linked with what we know about promoting intrinsic recovery processes and how this can boost neurobiological and surgical strategies for repair at the clinical level. With proof of principle now established, a rich area for innovative research with profound therapeutic application is open for investigation

The dentato-rubro-thalamic tract as the potential common deep brain stimulation target for tremor of various origin: an observational case series

Introduction!#!Deep brain stimulation alleviates tremor of various origins. The dentato-rubro-thalamic tract (DRT) has been suspected as a common tremor-reducing structure. Statistical evidence has not been obtained. We here report the results of an uncontrolled case series of patients with refractory tremor who underwent deep brain stimulation under tractographic assistance.!##!Methods!#!A total of 36 patients were enrolled (essential tremor (17), Parkinson's tremor (8), multiple sclerosis (7), dystonic head tremor (3), tardive dystonia (1)) and received 62 DBS electrodes (26 bilateral; 10 unilateral). Preoperatively, diffusion tensor magnetic resonance imaging sequences were acquired together with high-resolution anatomical T1W and T2W sequences. The DRT was individually tracked and used as a direct thalamic or subthalamic target. Intraoperative tremor reduction was graded on a 4-point scale (0 = no tremor reduction to 3 = full tremor control) and recorded together with the current amplitude, respectively. Stimulation point coordinates were recorded and compared to DRT. The relation of the current amplitude needed to reduce tremor was expressed as TiCR (tremor improvement per current ratio).!##!Results!#!Stimulation points of 241 were available for analysis. A total of 68 trajectories were tested (62 dB leads, 1.1 trajectories tested per implanted lead). Tremor improvement was significantly decreasing (p &amp;lt; 0.01) if the distance to both the border and the center of the DRT was increasing. On the initial trajectory, 56 leads (90.3%) were finally placed. Long-term outcomes were not part of this analysis.!##!Discussion!#!Tremor of various origins was acutely alleviated at different points along the DRT fiber tract (above and below the MCP plane) despite different tremor diseases. DRT is potentially a common tremor-reducing structure. Individual targeting helps to reduce brain penetrating tracts. TiCR characterizes stimulation efficacy and might help to identify an optimal stimulation point

Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult

Niemann–Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty

Consensus Statement on High-Intensity Focused Ultrasound for Functional Neurosurgery in Switzerland.

Background: Magnetic resonance-guided high-intensity focused ultrasound (MRgHiFUS) has evolved into a viable ablative treatment option for functional neurosurgery. However, it is not clear yet, how this new technology should be integrated into current and established clinical practice and a consensus should be found about recommended indications, stereotactic targets, patient selection, and outcome measurements. Objective: To sum up and unify current knowledge and clinical experience of Swiss neurological and neurosurgical communities regarding MRgHiFUS interventions for brain disorders to be published as a national consensus paper. Methods: Eighteen experienced neurosurgeons and neurologists practicing in Switzerland in the field of movement disorders and one health physicist representing 15 departments of 12 Swiss clinical centers and 5 medical societies participated in the workshop and contributed to the consensus paper. All experts have experience with current treatment modalities or with MRgHiFUS. They were invited to participate in two workshops and consensus meetings and one online meeting. As part of workshop preparations, a thorough literature review was undertaken and distributed among participants together with a list of relevant discussion topics. Special emphasis was put on current experience and practice, and areas of controversy regarding clinical application of MRgHiFUS for functional neurosurgery. Results: The recommendations addressed lesioning for treatment of brain disorders in general, and with respect to MRgHiFUS indications, stereotactic targets, treatment alternatives, patient selection and management, standardization of reporting and follow-up, and initialization of a national registry for interventional therapies of movement disorders. Good clinical evidence is presently only available for unilateral thalamic lesioning in treating essential tremor or tremor-dominant Parkinson's disease and, to a minor extent, for unilateral subthalamotomy for Parkinson's disease motor features. However, the workgroup unequivocally recommends further exploration and adaptation of MRgHiFUS-based functional lesioning interventions and confirms the need for outcome-based evaluation of these approaches based on a unified registry. MRgHiFUS and DBS should be evaluated by experts familiar with both methods, as they are mutually complementing therapy options to be appreciated for their distinct advantages and potential. Conclusion: This multidisciplinary consensus paper is a representative current recommendation for safe implementation and standardized practice of MRgHiFUS treatments for functional neurosurgery in Switzerland

Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease

Clinical studies of Parkinson’s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO (NCT01898390), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials

Parkinson’s disease laterality : a 11C-PE2I PET imaging study

Asymmetry of striatal dopaminergic deficits and motor symptoms is a typical characteristic of idiopathic Parkinson’s disease (PD). This study aims to characterise the trend of asymmetry in moderate-stage PD. We performed a 19-month longitudinal study in 27 patients with PET-CT imaging and appropriate clinical assessments. 11C-PE2I non-displaceable binding potential (BPND) was calculated bilaterally for the striatum at baseline and follow-up to estimate the in vivo density of striatal dopamine transporters (DAT). Changes in striatal 11C-PE2I BPND over time were more prominent in the ipsilateral as compared to contralateral side. Changes in MDS-UPDRS-III (motor component of the Movement Disorders Society Unified PD Rating Scale) were not different between the clinically most and least affected body sides. Our data support that the asymmetry in striatal dopaminergic degeneration becomes less prominent in moderate-stage PD. In contrast, during the above period, the asymmetry of motor symptoms was maintained between the clinically most and least affected body sides