Elevated Levels of Methylmalonate and Homocysteine in Parkinson's Disease, Progressive Supranuclear Palsy and Amyotrophic Lateral Sclerosis

Background/Aims: Increasing evidence suggests that elevated levels of homocysteine (Hcy) and methylmalonate (MMA) may be involved in the pathogenesis of neurodegenerative diseases. Methods: The urine levels of MMA and serum levels of Hcy as well as folic acid and vitamin B 12 were measured in patients suffering from the distinct neurodegenerative diseases progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD), and compared to age-and gender-matched control subjects. Results: We found significantly elevated concentrations of Hcy (PD 15.1, PSP 15.8, ALS 13.9, control 11.2 mu mol/l) and MMA (PD 3.7, PSP 3.1, ALS 3.7, control 1.8 mg/g) in all patient groups in comparison with controls. Levels of Hcy and MMA did not differ significantly between the neurodegenerative diseases. Conclusion: Our findings might imply that Hcy and MMA are released as a consequence of neurodegeneration regardless of the underlying cause and serve as surrogate markers of neurodegeneration. Alternatively they might be directly implicated in the pathogenesis of these diseases. Since elevated levels of both Hcy and MMA are neurotoxic, further studies might investigate the effect of vitamin therapy on disease progression. Copyright (C) 2010 S. Karger AG, Base

Single-channel electrophysiology reveals a distinct and uniform pore complex formed by α-synuclein oligomers in lipid membranes.

Synucleinopathies such as Parkinson's disease, multiple system atrophy and dementia with Lewy bodies are characterized by deposition of aggregated α-synuclein. Recent findings indicate that pathological oligomers rather than fibrillar aggregates may represent the main toxic protein species. It has been shown that α-synuclein oligomers can increase the conductance of lipid bilayers and, in cell-culture, lead to calcium dyshomeostasis and cell death. In this study, employing a setup for single-channel electrophysiology, we found that addition of iron-induced α-synuclein oligomers resulted in quantized and stepwise increases in bilayer conductance indicating insertion of distinct transmembrane pores. These pores switched between open and closed states depending on clamped voltage revealing a single-pore conductance comparable to that of bacterial porins. Pore conductance was dependent on transmembrane potential and the available cation. The pores stably inserted into the bilayer and could not be removed by buffer exchange. Pore formation could be inhibited by co-incubation with the aggregation inhibitor baicalein. Our findings indicate that iron-induced α-synuclein oligomers can form a uniform and distinct pore species with characteristic electrophysiological properties. Pore formation could be a critical event in the pathogenesis of synucleinopathies and provide a novel structural target for disease-modifying therapy

Bilateral double beta peaks in a PD patient with STN electrodes

Subthalamic local field potentials in the beta band are considered as potential biomarkers for closed-loop deep brain stimulation. To investigate the subthalamic beta band peak amplitudes in a Parkinson's disease patient over an extended period of time by using a novel and commercially available neurostimulator with permanent sensing capability. We recorded local field potentials of the subthalamic nucleus using the Medtronic Percept™ implantable neurostimulator at rest and during physical activity (gait) with and in response to deep brain stimulation. We found a double-peaked beta activity on both sides. Increasing stimulation and physical activity resulted in a decreased beta band amplitude, but was accompanied by the appearance of a second, and previously unrecognized peak at 13~Hz in the right hemisphere. Our results will support the investigation of distinct different peaks in the beta band and their relevance and usefulness as closed-loop biomarkers

Long-Term Efficacy and Safety of Chronic Globus Pallidus Internus Stimulation in Different Types of Primary Dystonia

Background: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) offers a very promising therapy for medically intractable dystonia. However, little is known about the long-term benefit and safety of this procedure. We therefore performed a retrospective long-term analysis of 18 patients (age 12-78 years) suffering from primary generalized (9), segmental (6) or focal (3) dystonia (minimum follow-up: 36 months). Methods: Outcome was assessed using the Burke-Fahn-Marsden (BFM) scores (generalized dystonia) and the Tsui score (focal/segmental dystonia). Follow-up ranged between 37 and 90 months (mean 60 months). Results: Patients with generalized dystonia showed a mean improvement in the BFM movement score of 39.4% (range 0 68.8%), 42.5% (range -16.0 to 81.3%) and 46.8% (range-2.7 to 83.1%) at the 3- and 12-month, and long-term follow-up, respectively. In focal/ segmental dystonia, the mean reduction in the Tsui score was 36.8% (range 0-100%), 65.1% (range 16.7-100%) and 59.8% (range 16.7-100%) at the 3- and 12-month, and long-term follow-up, respectively. Local infections were noted in 2 patients and hardware problems (electrode dislocation and breakage of the extension cable) in 1 patient. Conclusion: Our data showed Gpi-DBS to offer a very effective and safe therapy for different kinds of primary dystonia, with a significant long-term benefit in the majority of cases. Copyright (c) 2008 S. Karger AG, Base

Early Globus Pallidus Internus Stimulation in Pediatric Patients With Generalized Primary Dystonia: Long-Term Efficacy and Safety

Primary generalized dystonia presents mainly at a young age and commonly is severely disabling. The authors report the long-term follow-up (mean, 73 months; range, 50-101 months) of 5 pediatric patients (mean age at surgery 13 years; range, 8-16 years) undergoing globus pallidus internus deep brain stimulation. Mean improvement in the Burke-Fahn-Marsden movement score was 67.4% (range, 47.0%-87.5%), 75.4% (range, 61.5%-91.7%), and 83.5% (range, 72.0%-93.3%) at 3 months, 12 months, and long-term follow-up (>36 months), respectively. Hardware problems (electrode dislocation/breakage of extension cable, and imminent perforation of extension cable) were observed in 2 patients (operative revision without sequelae). Except for mild dysarthria in 2 patients, no other therapy-related morbidity was observed. The authors found globus pallidus internus stimulation to offer a very effective and safe therapy in pediatric patients with primary dystonia. Early neurosurgical intervention seems to be crucial to prevent irreversible impairment of motor function

Movement kinematic after deep brain stimulation associated microlesions

Deep brain stimulation is widely used for the treatment of movement disorders such as Parkinson's disease and dystonia. After the implantation of electrodes an immediate improvement of clinical symptoms has been described. It is unclear, whether movement kinematics are also changed by this 'microlesion effect'

Establishment of a Visual Analog Scale for DBS Programming (VISUAL-STIM Trial)

Background: Deep brain stimulation (DBS) has become a standard treatment for advanced stages of Parkinson's disease, essential tremor, and dystonia. In addition to the correct surgical device implantation, effective programming is regarded to be the most important factor for clinical outcome. Despite established strategies for adjusting neurostimulation, DBS programming remains time- and resource-consuming. Although kinematic and neuronal biosignals have recently been examined as potential feedback for closed-loop DBS (CL-DBS), there is an ongoing need for programming strategies to adapt the stimulation parameters and electrode configurations accurately and effectively. Methods: Here, we tested the usefulness of a patient-rated visual analog scale (VAS) for real-time adjustment of DBS parameters. The stimulation parameters (contact and amplitude) in Parkinson's patients with STN-DBS (n = 17) were optimized based on the patient's subjective VAS rating. A Minkowski distance (Md) was calculated to compare the individual combination of contact selection and amplitude to the stimulation parameters that resulted from classical programming based on clinical signs and symptoms. Results: We found no statistically significant difference between VAS-based and classical programming in regard to the specific contact or amplitude used or in regard to the clinical disease severity (UPDRS). Conclusions: Our data suggest that VAS-based and classical programming strategies both lead to similar short-term results. Although further research will be required to assess the validity of VAS-based DBS programming, our results support the investigation of the patient's subjective rating as an additional and valid feedback signal for individualized DBS adjustment

Intermediate Latency-Evoked Potentials of Multimodal Cortical Vestibular Areas: Galvanic Stimulation

Introduction: Human multimodal vestibular cortical regions are bilaterally anterior insulae and posterior opercula, where characteristic vestibular-related cortical potentials were previously reported under acoustic otolith stimulation. Galvanic vestibular stimulation likely influences semicircular canals preferentially. Galvanic stimulation was compared to previously established data under acoustic stimulation. Methods: 14 healthy right-handed subjects, who were also included in the previous acoustic potential study, showed normal acoustic and galvanic vestibular-evoked myogenic potentials. They received 2,000 galvanic binaural bipolar stimuli for each side during EEG recording. Results: Vestibular cortical potentials were found in all 14 subjects and in the pooled data of all subjects ("grand average") bilaterally. Anterior insula and posterior operculum were activated exclusively under galvanic stimulation at 25, 35, 50, and 80 ms;frontal regions at 30 and 45 ms. Potentials at 70 ms in frontal regions and at 110 ms at all of the involved regions could also be recorded;these events were also found using acoustic stimulation in our previous study. Conclusion: Galvanic semicircular canal stimulation evokes specific potentials in addition to those also found with acoustic otolith stimulation in identically located regions of the vestibular cortex. Vestibular cortical regions activate differently by galvanic and acoustic input at the peripheral sensory level

Visual cues combined with treadmill training to improve gait performance in Parkinson's disease: a pilot randomized controlled trial

Objective: To evaluate the effects of visual cues combined with treadmill training on gait performance in patients with Parkinson's disease and to compare the strategy with pure treadmill training. Design: Pilot, exploratory, non-blinded, randomized controlled trial. Setting: University Hospital of Munich, Germany. Subjects: Twenty-three outpatients with Parkinson's disease (Hoehn and Yahr stage II-IV). Interventions: Patients received 12 training sessions within five weeks of either visual cues combined with treadmill training (n = 12) or pure treadmill training (n = 11). Main measures: Outcome measures were gait speed, stride length and cadence recorded on the treadmill. Functional tests included the Timed Up and Go Test, the Unified Parkinson's Disease Rating Scale and the Freezing of gait-questionnaire. Assessments were conducted at baseline, after the training period and at two months follow-up. Results: After the training period (n = 20), gait speed and stride length had increased in both groups (p <= 0.05). Patients receiving the combined training scored better in the Timed Up and Go Test compared with the patients receiving pure treadmill training (p <= 0.05). At two months follow-up (n = 13), patients who underwent the combined training sustained better results in gait speed and stride length (p <= 0.05) and sustained the improvement in the Timed Up and Go Test (p <= 0.05). Conclusions: This pilot study suggests that visual cues combined with treadmill training have more beneficial effects on gait than pure treadmill training in patients with a moderate stage of Parkinson's disease. A large-scale study with longer follow-up is required