Abstract
Methamphetamine-associated psychosis (MAP) involves widespread neurocognitive and molecular deficits, however accurate diagnosis remains challenging. Integrating relationships between biological markers, brain imaging and clinical parameters may provide an improved mechanistic understanding of MAP, that could in turn drive the development of better diagnostics and treatment approaches. We applied selected reaction monitoring (SRM)-based proteomics, profiling 43 proteins in serum previously implicated in the etiology of major psychiatric disorders, and integrated these data with diffusion tensor imaging (DTI) and psychometric measurements from patients diagnosed with MAP (N = 12), methamphetamine dependence without psychosis (MA; N = 14) and healthy controls (N = 16). Protein analysis identified changes in APOC2 and APOH, which differed significantly in MAP compared to MA and controls. DTI analysis indicated widespread increases in mean diffusivity and radial diffusivity delineating extensive loss of white matter integrity and axon demyelination in MAP. Upon integration, several co-linear relationships between serum proteins and DTI measures reported in healthy controls were disrupted in MA and MAP groups; these involved areas of the brain critical for memory and social emotional processing. These findings suggest that serum proteomics and DTI are sensitive measures for detecting pathophysiological changes in MAP and describe a potential diagnostic fingerprint of the disorder.
Highlights
Research using neuroimaging techniques has shown METH abuse is associated with abnormalities of brain function[6], structure[7] and receptor pharmacology[1,8]
We applied a highly sensitive selected reaction monitoring (SRM)-based proteomics assay to assess changes in 43 proteins in serum previously implicated in the pathophysiology of major psychiatric disorders, and those related to candidate inflammatory and lipid metabolism pathways
We explored the hypothesis that serum proteins previously implicated in the pathophysiology of major psychiatric disorders, and those related to candidate inflammatory and metabolic pathways, mediate susceptibility for psychosis with METH abuse, and that these differences occur in parallel with white matter
Summary
Research using neuroimaging techniques has shown METH abuse is associated with abnormalities of brain function[6], structure[7] and receptor pharmacology[1,8]. While no studies have directly assessed protein levels in either blood serum or post-mortem brain of MAP patients, several reports from human and murine models indicate METH use impacts protein abundance in both compartments.
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