Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution...Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of α-synuclein both between different patients and between different brain regions. Methods: The reliable detection of α-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA. Results: Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of α-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived α-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in α-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of α-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders. Conclusions: We have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.展开更多
Purpose:The median time from the event leading to the spinal cord injury(SCI)to the time of decompressive surgery is estimated to be 6.9 days in Iran,which is much longer than the proposed ideal time(less than 24 h)in...Purpose:The median time from the event leading to the spinal cord injury(SCI)to the time of decompressive surgery is estimated to be 6.9 days in Iran,which is much longer than the proposed ideal time(less than 24 h)in published guidelines.The current qualitative study aimed to determine the reasons for the observed decompression surgery delay in Iran from the perspective of neurosurgeons.Methods:This qualitative study is designed to perform content analysis on the gathered data from face-to-face semi-structured interviews with 12 Iranian neurosurgeons.Results:The findings of the current study suggest that patient-related factors constitute more than half of the codes extracted from the interviews.Overall,the type of injury,presence of polytrauma,and surgeons’’wrong attitude are the main factors causing delayed spinal cord decompression in Iranian patients from the perspective of neurosurgeons.Other notable factors include delay in transferring patients to the trauma center,delay in availability of necessary equipment,and scarce medical personnel.Conclusion:In the perspective of neurosurgeons,the type of injury,presence of polytrauma,and surgeons’’wrong attitude are the leading reasons for delayed decompressive surgery of individuals with SCI in Iran.展开更多
基金the Edmond J Safra Philanthropic Foundation,the Krembil Foundation,and the Rossy FoundationThe funding bodies did not take part in design of the study,in collection,analysis,or interpretation of data,or in writing the manuscript.
文摘Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of α-synuclein both between different patients and between different brain regions. Methods: The reliable detection of α-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA. Results: Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of α-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived α-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in α-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of α-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders. Conclusions: We have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.
基金funded by Sina Trauma and Surgery Research Center,Tehran University of Medical Sciences(grant number 98-01-38-41413)。
文摘Purpose:The median time from the event leading to the spinal cord injury(SCI)to the time of decompressive surgery is estimated to be 6.9 days in Iran,which is much longer than the proposed ideal time(less than 24 h)in published guidelines.The current qualitative study aimed to determine the reasons for the observed decompression surgery delay in Iran from the perspective of neurosurgeons.Methods:This qualitative study is designed to perform content analysis on the gathered data from face-to-face semi-structured interviews with 12 Iranian neurosurgeons.Results:The findings of the current study suggest that patient-related factors constitute more than half of the codes extracted from the interviews.Overall,the type of injury,presence of polytrauma,and surgeons’’wrong attitude are the main factors causing delayed spinal cord decompression in Iranian patients from the perspective of neurosurgeons.Other notable factors include delay in transferring patients to the trauma center,delay in availability of necessary equipment,and scarce medical personnel.Conclusion:In the perspective of neurosurgeons,the type of injury,presence of polytrauma,and surgeons’’wrong attitude are the leading reasons for delayed decompressive surgery of individuals with SCI in Iran.
