In vivo 7Tesla imaging of the dentate granule cell layer in schizophrenia

Abstract

PURPOSE The hippocampus is central to the pathophysiology of schizophrenia. Histology shows abnormalities in the dentate granule cell layer (DGCL), but its small size (~100 micron thickness) has precluded in vivo human studies. We used ultra high field magnetic resonance imaging (MRI) to compare DGCL morphology of schizophrenic patients to matched controls’. METHOD Bilateral hippocampi of 16 schizophrenia patients (10 male) 40.7±10.6 years old (mean ±standard deviation) were imaged at 7 Tesla MRI with heavily T2*-weighted gradient-echo sequence at 232 micron in-plane resolution (0.08 μL image voxels). Fifteen matched controls (8 male, 35.6±9.4 years old) and one ex vivo post mortem hippocampus (that also underwent histopathology) were scanned with same protocol. Three blinded neuroradiologists rated each DGCL on a qualitative scale of 1 to 6 (from “not discernible” to “easily visible, appearing dark gray or black”) and mean left and right DGCL scores were compared using a non-parametric Mann-Whitney test. RESULTS MRI identification of the DGCL was validated with histopathology. Mean right and left DGCL ratings in patients (3.2±1.0 and 3.5±1.2) were not statistically different from controls’ (3.9±1.1 and 3.8±0.8), but patients’ had a trend for lower right DGCL score (p=0.07), which was significantly associated with patient diagnosis (p=0.05). The optimal 48% sensitivity and 80% specificity for schizophrenia was achieved with a DGCL rating of ≤2. CONCLUSION Decreased contrast in the right DGCL in schizophrenia was predictive of schizophrenia diagnosis. Better utility of this metric as a schizophrenia biomarker may be achieved in future studies of patients with homogeneous disease subtypes and progression rates.

In Vivo Hippocampal Subfield Volumes in Schizophrenia and Bipolar Disorder

“…Our findings are in line with a study using ultra-high-field MRI (7T) reporting a trend toward lower contrast of the dentate granule cell layer (a site of neuron proliferation and maturation) in the DG of patients with schizophrenia (52). This trend may reflect altered intracellular and extracellular water as a response to abnormal neuronal density, organization, and architecture (52). Postmortem studies have reported reduced neural stem cell proliferation in the DG of patients with schizophrenia (53) and decreased number of oligodendrocytes in CA4 (54); this could contribute to reduced myelination of the axon and impaired connectivity to CA3 (54).…”

“…Our findings are in line with a study using ultra-high-field MRI (7T) reporting a trend toward lower contrast of the dentate granule cell layer (a site of neuron proliferation and maturation) in the DG of patients with schizophrenia (52). This trend may reflect altered intracellular and extracellular water as a response to abnormal neuronal density, organization, and architecture (52).…”

Hippocampal granule cell pathology in epilepsy — A possible structural basis for comorbidities of epilepsy?

“…A recent 7 Tesla MRI study of 16 schizophrenic patients and 15 controls, however, was able to overcome this technological limit. The investigators found that decreased contrast in the dentate granule cell layer was predictive of diagnosis [171], supporting the conclusion that granule cell abnormalities may be a feature of the disease. Finally, Dowlatshahi and colleagues (2000) found evidence for mossy fiber sprouting in tissue from 13 patients with bipolar disorder relative to 15 controls using the zinc stain for mossy fiber axons [172].…”

Entorhinal cortex: a good biomarker of mild cognitive impairment and mild Alzheimer’s disease

“…Ultra-high field 7.0 Tesla (7T) MRI allows neuroimaging researchers to obtain high-resolution hippocampal microstructural images (Kerchner, 2011) and to isolate specific strata within the hippocampal subfields (Kerchner et al, 2010;Kirov et al, 2013). Hippocampal cross-sectional areas, EC thickness, and other subfield dimensions of the hippocampus can be determined by using an oblique coronal T2-weighted sequence (Kerchner et al, 2012).…”