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

Economic analyses to support decisions about HPV vaccination in low- and middle-income countries: a consensus report and guide for analysts.

Low- and middle-income countries need to consider economic issues such as cost-effectiveness, affordability and sustainability before introducing a program for human papillomavirus (HPV) vaccination. However, many such countries lack the technical capacity and data to conduct their own analyses. Analysts informing policy decisions should address the following questions: 1) Is an economic analysis needed? 2) Should analyses address costs, epidemiological outcomes, or both? 3) If costs are considered, what sort of analysis is needed? 4) If outcomes are considered, what sort of model should be used? 5) How complex should the analysis be? 6) How should uncertainty be captured? 7) How should model results be communicated? Selecting the appropriate analysis is essential to ensure that all the important features of the decision problem are correctly represented, but that the analyses are not more complex than necessary. This report describes the consensus of an expert group convened by the World Health Organization, prioritizing key issues to be addressed when considering economic analyses to support HPV vaccine introduction in these countries

Synergistic influence of phosphorylation and metal ions on tau oligomer formation and coaggregation with alpha-synuclein at the single molecule level

Background: Fibrillar amyloid-like deposits and co-deposits of tau and alpha-synuclein are found in several common neurodegenerative diseases. Recent evidence indicates that small oligomers are the most relevant toxic aggregate species. While tau fibril formation is well-characterized, factors influencing tau oligomerization and molecular interactions of tau and alpha-synuclein are not well understood. Results: We used a novel approach applying confocal single-particle fluorescence to investigate the influence of tau phosphorylation and metal ions on tau oligomer formation and its coaggregation with alpha-synuclein at the level of individual oligomers. We show that Al3+ at physiologically relevant concentrations and tau phosphorylation by GSK-3 beta exert synergistic effects on the formation of a distinct SDS-resistant tau oligomer species even at nanomolar protein concentration. Moreover, tau phosphorylation and Al3+ as well as Fe3+ enhanced both formation of mixed oligomers and recruitment of alpha-synuclein in pre-formed tau oligomers. Conclusions: Our findings provide a new perspective on interactions of tau phosphorylation, metal ions, and the formation of potentially toxic oligomer species, and elucidate molecular crosstalks between different aggregation pathways involved in neurodegeneration

Clinical outcome after surgical management of spontaneous spinal epidural hematoma.

PURPOSE Spontaneous spinal epidural hematoma (SSEH) is a rare pathology characterized by a hemorrhage in the spinal epidural space without prior surgical or interventional procedure. Recent literature reported contradictory findings regarding the clinical, radiological and surgical factors determining the outcome, hence the objective of this retrospective analysis was to re-assess these outcome-determining factors. METHODS Patients surgically treated for SSEH at our institution from 2010 - 2022 were screened and retrospectively assessed regarding management including the time-to-treatment, the pre-and post-treatment clinical status, the radiological findings as well as other patient-specific parameters. The outcome was assessed using the modified McCormick Scale. Statistical analyses included binary logistic regression and Fisher's exact test. RESULTS In total, 26 patients (17 men [65%], 9 women [35%], median age 70 years [interquartile range 26.5]) were included for analysis. The SSEHs were located cervically in 31%, cervicothoracically in 42% and thoracically in 27%. Twenty-four patients (92%) improved after surgery. Fifteen patients (58%) had a postoperative modified McCormick Scale grade of I (no residual symptoms) and 8 patients (31%) had a grade of II (mild symptoms). Only 3 (12%) patients remained with a modified McCormick Scale grade of IV or V (severe motor deficits / paraplegic). Neither time-to-treatment, craniocaudal hematoma expansion, axial hematoma occupation of the spinal canal, anticoagulation or antiplatelet drugs, nor the preoperative clinical status were significantly associated with the patients' outcomes. CONCLUSION Early surgical evacuation of SSEH generally leads to favorable clinical outcomes. Surgical hematoma evacuation should be indicated in all patients with symptomatic SSEH

Anti-amyloid antibody therapies in Alzheimer's disease

After years of failed attempts to develop a disease-modifying therapy for Alzheimer's disease, consistent evidence in support of clinical efficacy was finally presented for a monoclonal antibody targeting the amyloid-beta protofibrils. In addition to meeting the primary outcome of slowing clinical disease progression over 18 months, secondary clinical outcomes and amyloid-beta lowering on PET also underpin the positive results of the trial. In this opinion piece, we highlight the key characteristics of the previous unsuccessful trials and analyse the potential reasons why those attempts to develop a treatment for early Alzheimer's disease failed. We compare the safety profiles of the different antibodies and highlight cautionary measures for their routine clinical use. Last, we discuss the role of blood-based biomarkers in transforming the clinical care pathway to facilitate the uptake of antibody treatments, proposing an integrated case-finding and treatment model crossing the different healthcare sectors. Taken together, a real breakthrough may have been achieved by proving that amyloid-beta reduction results in clinical benefits, rather than just biomarker changes. At the same time, routine use of the new generation of drugs will show if statistical efficacy translates into clinically meaningful change. This may just be the beginning of a new era of Alzheimer's disease drug development. Perneczky et al. examine why previous trials of disease-modifying treatments for Alzheimer's disease failed and why lecanemab fared differently. They discuss what the results may mean for patients, and argue that healthcare systems must adapt to facilitate rapid and safe uptake of anti-amyloid antibody treatment