Determinants of Schizophrenia Endophenotypes Based on Neuroimaging and Biochemical Parameters

Abstract

Despite extensive research, there is no convincing evidence of a reliable diagnostic biomarker for schizophrenia beyond clinical observation. Disorders of glutamatergic neurotransmission associated with N-methyl-D-aspartate (NMDA) receptor insufficiency, neuroinflammation, and redox dysregulation are the principal common mechanism linking changes in the periphery with the brain, ultimately contributing to the emergence of negative symptoms of schizophrenia that underlie differential diagnosis. The aim of the study was to evaluate the influence of these systems via peripheral and cerebral biochemical indices in relation to the patient's clinical condition. Using neuroimaging diagnostics, we were able to define endophenotypes of schizophrenia based on objective laboratory data that form the basis of a personalized approach to diagnosis and treatment. The two distinguished endophenotypes differed in terms of the quality of life, specific schizophrenia symptoms, and glutamatergic neurotransmission metabolites in the anterior cingulate gyrus. Our results, as well as further studies of the excitatory or inhibitory balance of microcircuits, relating the redox systems on the periphery with the distant regions of the brain might allow for predicting potential biomarkers of neuropsychiatric diseases, including schizophrenia. To the best of our knowledge, our study is the first to identify an objective molecular biomarker of schizophrenia outcome.

Keywords: anterior cingulate gyrus; endophenotypes; glutamatergic metabolites; magnetic resonance spectroscopy; schizophrenia.

Figure 1

Potential mechanism explaining the occurrence of negative symptoms, and the developing resistance to classical neuroleptics due to the glutamatergic hypothesis and the NMDA receptor hypofunction. In addition to the glutamate projection pathway in the cortical brain stem, which is associated with the primary GLU neuron, the GABA interneuron, and the secondary GLU neuron, additional synapses in the midbrain with another GABA interneuron that targets neuronal DA projections that return to the frontal cortex, are involved in the projection of negative symptoms in schizophrenia. During normal psychiatric functioning, this circuit is balanced and sufficient DA reaches the frontal cortex without negative symptoms. However, when the pathway is modified with the formation of an additional GABA interneuron (originally: GLU-GABA-GLU-D; after modification: GLU-GABA-GLU-GABA-DA), this change might be associated with the appearance of negative symptoms. In the case of generating positive symptoms, glutamate from the primary GLU neuron reaches hypofunctional NMDA receptors located on the primary GABA interneuron, whose tone disappears in the absence of GLU stimulation and the secondary GLU neuron becomes hyperactive again. In contrast to the mechanism associated with the generation of positive symptoms, the main issue concerns the secondary GLU neuron, which hits another GABA interneuron, which, through a higher than normal GLU signal, releases much higher concentrations of GABA. This results in the inhibition of the final pathway of DA neurons derived from the midbrain and their lower release. This mesocortical DA pathway is now active and does not provide adequate amounts of DA in the frontal cortex, which causes hypofrontality and negative symptoms.

Figure 2

Separated clusters of subjects based on the GLU 2.1 (ACC) level, i.e., differing to the greatest possible extent in terms of the quality of life.

Figure 3

Scoring of the scales concerning the quality of life in selected clusters of patients.

Figure 4

Predicting the membership of the second cluster on the basis of the T-scale scores. An ROC curve can be considered as the average value of the sensitivity for a test over all possible values of specificity or vice versa. A more general interpretation is that given the test results, the probability that for a randomly selected pair of patients with and without the disease/condition, the patient with the disease/condition has a result indicating greater suspicion. The area under the ROC (AUC) curve is bounded by the blue line and red baseline. The value of the AUC index is in the interval (0.1) delimited by two marked color lines. AUC, a high area under curve value limited by a blue line; ROC, a Receiver Operating Characteristic curve that includes all the possible decision thresholds from a diagnostic test result.

Figure 5

(A) On the MR spectrum, the yellow line is at the level of glutamatergic neurotransmission metabolites Glu, Gln (2.1–2.5 ppm) peak in endophenotype I, and the yellow line is at the level of Glu, Gln (2.1–2.5 ppm) peak in endophenotype II. (B) T2 weighted axial image, with the location of VOI in the ACC region.