The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study

Abstract

Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [11C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [11C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.

Meta-Analysis of Neurochemical Changes Estimated via Magnetic Resonance Spectroscopy in Mild Cognitive Impairment and Alzheimer's Disease

“…In addition, its concentration in white matter can reflect the development of axons. Due to NAA being located at the synaptic terminal, dendrites, and neuronal somata, its concentration may reflect the level of synapses and the ratio of NAA/Cr reflects the integrity of synapses (Onwordi et al, 2021). Our meta-analysis showed that during the pathological development from MCI to AD, the ratio of NAA/Cr in the hippocampus and PC, and the concentration of NAA in PC decreased dramatically.…”

Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer’s disease

“…Indirect measures of synaptic loss as changes in brain functional MRI network topology have previously been associated with major disease symptoms ( 46 ). In vivo human PET imaging studies evaluating SV2A density ( 47 – 49 ) show reduced tissue SV2A binding and indicate that measures of cortical volume reduction ( 50 ) underestimate the extent of synaptic loss in AD. Although we observed some volume loss over the short 12- to 18-month longitudinal follow-up, we could not measure reductions of SV2A binding in the remaining brain tissue.…”

Synaptic Vesicle Glycoprotein 2A: Features and Functions

“…Glutamatergic dysfunction is an important factor in schizophrenia onset, and SV2A density and glutamate levels in anterior cingulate cortex and hippocampus have been measured in patients with schizophrenia compared to healthy volunteers with [ 11 C]UCB-J PET. Interestingly, no significant relationship was reported between [ 11 C]UCB-J binding and glutamate levels in the patients, while a positive correlation was detected in healthy control subjects ( Onwordi et al, 2021 ).…”