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

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

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

Quasiparticle approach to the transport in infinite-layer nickelates

The normal-state transport properties of superconducting infinite-layer nickelates are investigated within an interacting three-orbital model. It includes effective Ni-$d_{z^2}$, Ni-$d_{x^2-y^2}$ bands as well as the self-doping band degree of freedom. Thermopower, Hall coefficient and optical conductivity are modelled within a quasiparticle approximation to the electronic states. Qualitative agreement in comparison to experimentally available Hall data is achieved, with notably a temperature-dependent sign change of the Hall coefficient for larger hole doping $x$. The Seebeck coefficient changes from negative to positive in a non-trivial way with $x$, but generally shows only modest temperature dependence. The optical conductivity shows a pronounced Drude response and a prominent peak structure at higher frequencies due to interband transitions. While the quasiparticle picture is surely approximative to low-valence nickelates, it provides enlightening insights into the multiorbital nature of these challenging systems.Comment: 7 pages, 3 figure

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'

Electronic correlations and superconducting instability in La3_3Ni2_2O7_7 under high pressure

Motivated by the report of superconductivity in bilayer La$_3$Ni$_2$O$_7$ at high pressure, we examine the interacting electrons in this system. First-principles many-body theory is utilized to study the normal-state electronic properties. Below 100\,K, a multi-orbital non-Fermi liquid state resulting from loss of Ni-ligand coherence within a flat-band dominated low-energy landscape is uncovered. The incoherent low-temperature Fermi surface displays strong mixing between Ni-$d_{z^2}$ and Ni-$d_{x^2-y^2}$ orbital character. In a model-Hamiltonian picture, spin fluctuations originating mostly from the Ni-$d_{z^2}$ orbital give rise to strong tendencies towards a superconducting instability with $d_{x^2-y^2}$ order parameter. The dramatic enhancement of $T_{\rm c}$ in pressurized La$_3$Ni$_2$O$_7$ is due to stronger Ni-$d_{z^2}$ correlations compared to those in the infinite-layer nickelates.Comment: 5 pages, 4 figure