Neuroimaging and post-mortem studies indicate that chronic alcohol use induces global changes in brain morphology, such as cortical and subcortical atrophy. Recent studies have shown that frontal lobe structures are specifically susceptible to alcohol-related brain damage and shrinkage in this area is largely due to a loss of white matter. This may explain the high incidence of cognitive dysfunction observed in alcoholics. Using a proteomics-based approach, changes in protein expression in the dorsolateral prefrontal region (BA9) white matter were identified in human alcoholic brains. Protein extracts from the BA9 white matter of 25 human brains (10 controls; eight uncomplicated alcoholics; six alcoholics complicated with hepatic cirrhosis; one reformed alcoholic) were separated using two-dimensional gel electrophoresis. Overall, changes in the relative expression of 60 proteins were identified (Po0.05, ANOVA) in the alcoholic BA9 white matter. In total, 18 protein spots have been identified using MALDI-TOF; including hNP22, a-internexin, transketolase, creatine kinase chain B, ubiquitin carboxy-terminal hydrolase L1 and glyceraldehyde-3-phosphate dehydrogenase. Several of these proteins have been previously implicated in alcohol-related disorders and brain damage. By identifying changes in protein expression in this region from alcoholics, hypotheses may draw upon more mechanistic explanations as to how chronic ethanol consumption causes white matter damage.

Improving outcomes for diffuse glioma patients requires methods that can accurately and sensitively monitor tumour activity and treatment response. Extracellular vesicles (EV) are membranous nanoparticles that can traverse the blood–brain-barrier, carrying oncogenic molecules into the circulation. Measuring clinically relevant glioma biomarkers cargoed in circulating EVs could revolutionise how glioma patients are managed. Despite their suitability for biomarker discovery, the co-isolation of highly abundant complex blood proteins has hindered comprehensive proteomic studies of circulating-EVs. Plasma-EVs isolated from pre-operative glioma grade II–IV patients (n = 41) and controls (n = 11) were sequenced by Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) and data extraction was performed by aligning against a custom 8662-protein library. Overall, 4054 proteins were measured in plasma-EVs. Differentially expressed proteins and putative circulating-EV markers were identified (adj. p-value < 0.05), including those reported in previous in-vitro and ex-vivo glioma-EV studies. Principal component analysis showed that plasma-EV protein profiles clustered according to glioma histological-subtype and grade, and plasma-EVs resampled from patients with recurrent tumour progression grouped with more aggressive glioma samples. The extensive plasma-EV proteome profiles achieved here highlight the potential for SWATH-MS to define circulating-EV biomarkers for objective blood-based measurements of glioma activity that could serve as ideal surrogate endpoints to assess tumour progression and allow more dynamic, patient-centred treatment protocols.

Alcoholic patients commonly experience cognitive decline. It is postulated that cognitive dysfunction is caused by an alcohol-induced region-selective brain damage, particularly to the prefrontal region, and grey and white matter may be affected differently. We used a proteomics-based approach to compare protein expression profiles of the dorsolateral prefrontal cortex (Brodmann area 9 (BA9)) from human alcoholic and healthy control brains. Changes in the relative expression of 110 protein 'spots' were identified in the BA9 grey matter, of which 54 were identified as 44 different proteins. In our recent article, 60 protein spots were differentially expressed in the BA9 white matter and 18 of these were identified (Alexander-Kaufman, K., James, G., Sheedy, D., Harper, C., Matsumoto, I., Mol. Psychiatry 2006, 11, 56-65). Additional BA9 white matter proteins are identified here and discussed in conjunction to our grey matter results. Thiamine-dependent enzymes transketolase and pyruvate dehydrogenase (E1β ubunit) were among the proteins identified. To our knowledge, this is the first time a disruption in thiamine-dependent enzymes has been demonstrated in the brains of 'neurologically uncomplicated' alcoholics. By identifying protein expression changes in prefrontal grey and white matter separately, hypotheses may draw upon more mechanistic explanations as to how alcoholism causes the structural alterations associated with alcohol-related brain damage and cognitive dysfunction.