Neuropil Pruning in Early-Course Schizophrenia: Immunological, Clinical, and Neurocognitive Correlates

Abstract

Introduction Neuropathological studies suggest neuropil reduction in schizophrenia. Altered synaptic pruning is proposed to underlie neuropil reduction. Underlying factors and clinical correlates of synaptic pruning are poorly understood. Using phosphorus magnetic resonance spectroscopy (31P MRS), it is feasible to assess membrane phospholipid (MPL) metabolites in the brain that specifically and sensitively reflect neuropil expansion (elevated MPL precursors) or contraction (elevated MPL catabolites). Methods We examined MPL metabolites and their cognitive, clinical and immunologic correlates among 28 early-course schizophrenia individuals (illness duration 1.99±1.33 years; antipsychotic-naïve=18) and 21 controls. We acquired whole-brain multi-voxel 31P MRS data from 12 unique brain regions. Interleukin-6 and C-reactive protein (CRP) were assayed in the serum. Generalized linear mixed models examined case-control differences in MPL metabolites in these regions correcting for multiple testing. Partial correlations accounting for multiple tests examined the relationship of Interleukin-6 and CRP levels with MPL metabolite levels. Results MPL catabolite levels were increased in the thalamus in schizophrenia compared to controls. Interleukin-6 and CRP levels did not show case-control differences. Interleukin-6 levels positively correlated with MPL catabolite levels in the thalamus after correcting for multiple tests. The left thalamus MPL catabolite levels correlated negatively with sustained attention (corrected p=0.039). Discussion Elevated MPL catabolites in the thalamus suggest increased neuropil contraction that may be related to excessive synaptic pruning. The thalamic neuropil contraction is associated with Interleukin-6 levels suggesting central pathogenic mechanisms for the inflammatory mediators. Correlation of increased thalamic MPL catabolite levels with cognitive impairments suggests clinical correlates of neuropil contraction.

Neuropil contraction in relation to Complement C4 gene copy numbers in independent cohorts of adolescent-onset and young adult-onset schizophrenia patients–a pilot study

“…C4A (Fisher’s exact test, p = 0.69) and C4B (Fisher’s exact test, p = 0.23) GCN did not show schizophrenia-HC differences (Table 1 ). We recapitulated our earlier published results on differences in MPL metabolites in a larger YASZ and HC cohort 11 .…”

“…Details of 31 P MRS data acquisition and processing are published 11 . Briefly, whole-brain, multi-voxel, in vivo 31 P MRS data in 3-dimensions was collected on a 3 T Siemens Tim Trio system using a dual-tuned ¹H-³¹P volume head coil and a conventional chemical shift imaging (CSI) sequence.…”

“…Separate regression models were built for GPC + GPE and PC + PE levels for AOSZ and YASZ by including these metabolite levels for all hypothesized regions, diagnosis, age, sex and education as covariates. Since antipsychotic dose did not significantly contribute to MPL metabolite alterations 11 , we did not covary for medications. To test primary hypothesis on the association of GPC + GPE levels with C4A GCNs, we built two separate forward stepwise regression models with Akaike Information Criterion (AIC) for the YASZ and the AOSZ cohorts.…”

“…One of the neurodevelopmental models that propose excessive loss of synapses 6 may be one such mechanism. Convergent animal 7 , 8 , human developmental 9 , neuroimaging 10 , 11 , postmortem 12 , 13 , and computational modeling 14 , 15 data suggest that increased neuropil loss predates 16 – 23 and continues after the onset of psychosis 24 , 25 , and may predict short-term outcome 26 . The genetic underpinnings of excessive synaptic pruning are poorly understood in humans.…”

“…The rationale for the superiority of 31 P MRS has been described in prior publications 9 , 11 , 62 . Briefly, synapse/dendritic spine formation and dendritic branching requires expansion of dendritic/axonal membranes.…”