A multimodal approach to studying the relationship between peripheral glutathione, brain glutamate, and cognition in health and in schizophrenia.

Involvement of oxidative stress in the pathophysiology of schizophrenia (SZ) is suggested by studies of peripheral tissue. Nonetheless, it is unclear how such biological changes are linked to relevant, pathological neurochemistry, and brain function. We designed a multi-faceted study by combining biochemistry, neuroimaging, and neuropsychology to test how peripheral changes in a key marker for oxidative stress, glutathione (GSH), may associate with central neurochemicals or neuropsychological performance in health and in SZ. GSH in dorsal anterior cingulate cortex (dACC) was acquired as a secondary 3T 1H-MRS outcome using a MEGA-PRESS sequence. Fifty healthy controls and 46 patients with SZ were studied cross-sectionally, and analyses were adjusted for effects of confounding variables. We observed lower peripheral total GSH in SZ compared to controls in extracellular (plasma) and intracellular (lymphoblast) pools. Total GSH levels in plasma positively correlated with composite neuropsychological performance across the total population and within patients. Total plasma GSH levels were also positively correlated with the levels of Glx in the dACC across the total population, as well as within each individual group (controls, patients). Furthermore, the levels of dACC Glx and dACC GSH positively correlated with composite neuropsychological performance in the patient group. Exploring the relationship between systemic oxidative stress (in particular GSH), central glutamate, and cognition in SZ will benefit further from assessment of patients with more varied neuropsychological performance.

Decoupling of Brain Temperature and Glutamate in Recent Onset of Schizophrenia: A 7T Proton Magnetic Resonance Spectroscopy Study.

BACKGROUND: Converging evidence suggests that cerebral metabolic and cellular homeostasis is altered in patients with recent onset of schizophrenia. As a possible marker of metabolic changes that might link to altered neurotransmission, we used proton magnetic resonance spectroscopy to estimate brain temperature, and we evaluated its relationship to a relevant metabolite, glutamate, within this study population. METHODS: Using proton magnetic resonance spectroscopy at 7T, 20 patients with recent onset (≤24 months after first psychotic symptoms) of schizophrenia and 20 healthy control subjects were studied. We measured levels of N-acetylaspartate and glutamate and estimated brain temperature in a noninvasive manner. RESULTS: Healthy control subjects showed a significant negative correlation between glutamate and brain temperature in the anterior cingulate cortex. In contrast, the physiological correlation between glutamate and brain temperature was lost in patients with recent onset of schizophrenia. CONCLUSIONS: This study supports the hypothesized disrupted relationship between brain metabolism and neurotransmission in patients with recent onset of schizophrenia. The findings include mechanistic implications that are to be followed up in both preclinical and clinical studies.

Neuroinflammation and brain atrophy in former NFL players: An in vivo multimodal imaging pilot study.

There are growing concerns about potential delayed, neuropsychiatric consequences (e.g, cognitive decline, mood or anxiety disorders) of sports-related traumatic brain injury (TBI). Autopsy studies of brains from a limited number of former athletes have described characteristic, pathologic changes of chronic traumatic encephalopathy (CTE) leading to questions about the relationship between these pathologic and the neuropsychiatric disturbances seen in former athletes. Research in this area will depend on in vivo methods that characterize molecular changes in the brain, linking CTE and other sports-related pathologies with delayed emergence of neuropsychiatric symptoms. In this pilot project we studied former National Football League (NFL) players using new neuroimaging techniques and clinical measures of cognitive functioning. We hypothesized that former NFL players would show molecular and structural changes in medial temporal and parietal lobe structures as well as specific cognitive deficits, namely those of verbal learning and memory. We observed a significant increase in binding of [(11)C]DPA-713 to the translocator protein (TSPO), a marker of brain injury and repair, in several brain regions, such as the supramarginal gyrus and right amygdala, in 9 former NFL players compared to 9 age-matched, healthy controls. We also observed significant atrophy of the right hippocampus. Finally, we report that these same former players had varied performance on a test of verbal learning and memory, suggesting that these molecular and pathologic changes may play a role in cognitive decline. These results suggest that localized brain injury and repair, indicated by increased [(11)C]DPA-713 binding to TSPO, may be linked to history of NFL play. [(11)C]DPA-713 PET is a promising new tool that can be used in future study design to examine further the relationship between TSPO expression in brain injury and repair, selective regional brain atrophy, and the potential link to deficits in verbal learning and memory after NFL play.

Regional brain distribution of translocator protein using [(11)C]DPA-713 PET in individuals infected with HIV.

Imaging the brain distribution of translocator protein (TSPO), a putative biomarker for glial cell activation and neuroinflammation, may inform management of individuals infected with HIV by uncovering regional abnormalities related to neurocognitive deficits and enable non-invasive therapeutic monitoring. Using the second-generation TSPO-targeted radiotracer, [(11)C]DPA-713, we conducted a positron emission tomography (PET) study to compare the brains of 12 healthy human subjects to those of 23 individuals with HIV who were effectively treated with combination antiretroviral therapy (cART). Compared to PET data from age-matched healthy control subjects, [(11)C]DPA-713 PET of individuals infected with HIV demonstrated significantly higher volume-of-distribution (VT) ratios in white matter, cingulate cortex, and supramarginal gyrus, relative to overall gray matter VT, suggesting localized glial cell activation in susceptible regions. Regional TSPO abnormalities were evident within a sub-cohort of neuro-asymptomatic HIV subjects, and an increase in the VT ratio within frontal cortex was specifically linked to individuals affected with HIV-associated dementia. These findings were enabled by employing a gray matter normalization approach for PET data quantification, which improved test-retest reproducibility, intra-class correlation within the healthy control cohort, and sensitivity of uncovering abnormal regional findings.