Metabolic Abnormalities in the Hippocampus of Patients with Schizophrenia: A 3D Multivoxel MR Spectroscopic Imaging Study at 3T

Abstract

BACKGROUND AND PURPOSE Schizophrenia is well known to be associated with hippocampal structural abnormalities. We used 1H-MRS imaging to test the hypothesis that these abnormalities are accompanied by NAA deficits, reflecting neuronal dysfunction, in patients compared with healthy controls. MATERIALS AND METHODS Nineteen patients with schizophrenia (11 male, 40.6±10.1 years old, 19.5±10.5 years disease duration) and 11 matched healthy controls (5 male, 33.7±10.1 years old) underwent MRI and multi-voxel point resolved spectroscopy (TE/TR=35/1400 ms) 1H-MRS imaging at 3 T to obtain their hippocampal GM absolute NAA, Cr, Cho and mIns concentrations. Unequal variance t-tests and ANCOVA were used to compare patients with controls. Bilateral volumes from manually outlined hippocampal masks were compared using unequal variance t-test. RESULTS Patients’ average hippocampal GM Cr concentration was 19% higher than controls’, 8.7±2.2 versus 7.4±1.2 mM (p<0.05); with no differences in NAA: 8.8±1.6 vs. 8.7±1.2 mM, Cho: 2.3±0.7 vs. 2.1±0.3 mM, or mIns: 6.1±1.5 vs. 5.2±0.9 (all p>0.1). There was a positive correlation between mIns and Cr in patients (r=0.57, p=0.05) but not controls. Bilateral hippocampal volume was ~10% lower in patients: 7.5±0.9 vs. 8.4±0.7 cm3 (p<0.05). CONCLUSION These findings suggest that the hippocampal volume deficit in schizophrenia is not due to net loss of neurons, in agreement with histopathology studies but not with prior 1H-MRS reports. Elevated Cr is consistent with hippocampal hypermetabolism and its correlation with mIns may also suggest an inflammatory process affecting some cases; this may suggest treatment targets and markers to monitor them.

Hippocampal Metabolite Concentrations in A Schizophrenia Case Series Vary in Association With Rare Gene Variants For Schizophrenia Versus Autism

“…Using a novel multi-voxel, whole hippocampal 1 H-MRSI to assess metabolite concentrations in the entire bilateral 3-dimensional structure (as opposed to single voxel approaches), our prior study demonstrated only elevated Cr concentrations [Cr] signi cantly distinguish the group of cases from the control groups (11). Notably, concentrations of Cho and NAA in this study were signi cantly more variable within the group of cases than controls, consistent with heterogeneous underpinnings among schizophrenia cases.…”

“…Schizophrenia cases with rare missense coding variants in Trio Rho Guanine Nucleotide Exchange Factor (TRIO) or its interaction partner ARMS/Kidns220, had signi cantly lower [Cho] than other schizophrenia cases in this series and compared to the healthy control group in the parent study (11). TRIO is associated with autism and intellectual impairment in addition to schizophrenia (15)(16)(17), and this analysis suggests that these cases have signi cantly reduced hippocampal myelin.…”

“…The imaging and subsequent genetic study were approved by the Institutional Review Boards of NYU and Bellevue Hospital Center and all subjects provided written informed consent. Participant assessments and 1 H-MRSI procedures were previously described in 19 schizophrenia cases (11), with nine of them further agreeing to participate in genetic studies. Targeted exome sequencing of 38 CNS signaling genes was done by targeted exome capture, also previously described (3,12).…”

Glutamatergic hypo-function in the left superior and middle temporal gyri in early schizophrenia: a data-driven three-dimensional proton spectroscopic imaging study

“…Though some single-voxel studies have reported increased t-Cr [ 32 , 33 ], these have not been replicated [ 34 ]. However, an 1 H-MRSI study of the hippocampus revealed increased t-Cr in chronically-medicated schizophrenia [ 35 ]. We found increased t-Cr only in antipsychotic-treated patients.…”

The Clinical Utility of Magnetic Resonance Spectroscopy in Traumatic Brain Injury: Recommendations from the ENIGMA MRS Working Group

“…This is often done by linear regression (Hetherington et al, 1996;Tal, Kirov, Grossman, & Gonen, 2012) or spectral decomposition methods (Goryawala, Sheriff, Stoyanova, & Maudsley, 2018), which combine information from multiple voxels with knowledge of the relative tissue content in each voxel. Linear regression can be applied in any number of (n≥2) voxels to investigate small regions such as the hippocampus (<10 voxels; Meyer et al, 2016), larger areas such as 2D slabs (McLean et al, 2000;Gasparovic et al, 2011), in entire brain lobes (Maudsley et al, 2009), and/or in global brain white matter/gray matter metabolism (100s of voxels; Tal et al, 2012). It is especially useful for studying cortical gray matter, which due to its tortuous shape, always incurs voxel partial volume effects when examined with SVS.…”