Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes

Background Synapses are fundamental components of brain circuits and are disrupted in over 100 neurological and psychiatric diseases. The synapse proteome is physically organized into multiprotein complexes and polygenic mutations converge on postsynaptic complexes in schizophrenia, autism and intellectual disability. Directly characterising human synapses and their multiprotein complexes from post-mortem tissue is essential to understanding disease mechanisms. However, multiprotein complexes have not been directly isolated from human synapses and the feasibility of their isolation from post-mortem tissue is unknown. Results Here we establish a screening assay and criteria to identify post-mortem brain samples containing well-preserved synapse proteomes, revealing that neocortex samples are best preserved. We also develop a rapid method for the isolation of synapse proteomes from human brain, allowing large numbers of post-mortem samples to be processed in a short time frame. We perform the first purification and proteomic mass spectrometry analysis of MAGUK Associated Signalling Complexes (MASC) from neurosurgical and post-mortem tissue and find genetic evidence for their involvement in over seventy human brain diseases. Conclusions We have demonstrated that synaptic proteome integrity can be rapidly assessed from human post-mortem brain samples prior to its analysis with sophisticated proteomic methods. We have also shown that proteomics of synapse multiprotein complexes from well preserved post-mortem tissue is possible, obtaining structures highly similar to those isolated from biopsy tissue. Finally we have shown that MASC from human synapses are involved with over seventy brain disorders. These findings should have wide application in understanding the synaptic basis of psychiatric and other mental disorders

Vein of Galen malformation: diagnosis and management

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Management of patients aged ≫60 years with malignant glioma: good clinical status and radiotherapy determine outcome

Many clinical trials have shown that the most important prognostic variable in patients with malignant glioma is advanced age. However, can some patients aged >60 years still have relatively good outcomes with conventional surgical and radiotherapeutic treatment? A previous audit of practice (1983-89) suggested that functional status was an impor tant prognostic variable in the elderly. We have reviewed a fur ther cohort (1989-96) to evaluate changes in practice and outcomes given advances in neuroimaging, neurosurger y and radiotherapy.The major findings in this series of 80 patients aged over 60 years with a histological diagnosis of supratentorial malignant glioma were: (i) There was a relationship between management undertaken and clinical status of the patients ( p < 0.01), i.e. patients in good grade generally had tumour debulking and radiotherapy, whilst those in poor grade generally had only biopsy. (ii) There was a significant increase in sur vival of patients in the second period who received surgical debulking and post-operative radiotherapy (from a median of 23 to 41 weeks ( p < 0.05). (iii) It is likely that case selection accounted for much of this improvement since there was a direct relationship between median survival time and good clinical grade using the WHO performance scale. (iv) A shorter radiotherapy course (30Gy in six fractions) was as efficacious as a conventional course (60Gy in 30 fractions), and those patients having radiotherapy survived significantly longer than those not having this treatment ( p = 0.001). This study has again demonstrated the importance of preoperative clinical grade and radiotherapy treatment in deter mining outcomes in patients >60 years. To put these data in a societal context a recent prospective multicentre audit of patients with malignant glioma in Scotland, and another audit from our unit, showed that between 24 and 65% of patients aged >60 years, with a CT diagnosis of malignant glioma do not undergo either surger y or radiotherapy. Advanced age per se should not be a bar to inter ventional treatment in patients aged >60 years with suspected malignant glioma

The concepts, diagnosis and management of early imaging changes after therapy for glioblastomas

Since postoperative radiotherapy plus concomitant temozolomide followed by adjuvant temozolomide has become standard treatment for glioblastoma, the phenomenon of early post-treatment enlargement of the imaged tumour volume, usually without clinical deterioration, has become widely recognised. The term pseudoprogression has been used to describe a poorly understood pathophysiological process. In this review, the pathophysiological concepts, relevance, diagnosis and management of patients with ‘pseudoprogression’ and ‘pseudoresponse’ are discussed. Guidelines are given with respect to radiological imaging modality, mode and frequency. Further biological and clinical insights into these phenomena require carefully designed prospective studies