Lower cholinergic basal forebrain volumes link with cognitive difficulties in schizophrenia

Abstract

A potential pathophysiological mechanism of cognitive difficulties in schizophrenia is a dysregulated cholinergic system. Particularly, the cholinergic basal forebrain nuclei (BFCN), the source of cortical cholinergic innervation, support multiple cognitive functions, ranging from attention to decision-making. We hypothesized that BFCN structural integrity is altered in schizophrenia and associated with patients’ attentional deficits. We assessed gray matter (GM) integrity of cytoarchitectonically defined BFCN region-of-interest in 72 patients with schizophrenia and 73 healthy controls, matched for age and gender, from the COBRE open-source database, via structural magnetic resonance imaging (MRI)–based volumetry. MRI-derived measures of GM integrity (i.e., volumes) were linked with performance on a symbol coding task (SCT), a paper-pencil-based metric that assesses attention, by correlation and mediation analysis. To assess the replicability of findings, we repeated the analyses in an independent dataset comprising 26 patients with schizophrenia and 24 matched healthy controls. BFCN volumes were lower in patients (t(139)=2.51, p = 0.01) and significantly associated with impaired SCT performance (r = 0.31, p = 0.01). Furthermore, lower BFCN volumes mediated the group difference in SCT performance. When including global GM volumes, which were lower in patients, as covariates-of-no-interest, these findings disappeared, indicating that schizophrenia did not have a specific effect on BFCN relative to other regional volume changes. We replicated these findings in the independent cohort, e.g., BFCN volumes were lower in patients and mediated patients’ impaired SCT performance. Results demonstrate lower BFCN volumes in schizophrenia, which link with patients’ attentional deficits. Data suggest that a dysregulated cholinergic system might contribute to cognitive difficulties in schizophrenia via impaired BFCN.

Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration

“…For example, the tests within the NTB most responsive to treatment with neflamapimod measure visual attention, while in a recent report mapping changes in cholinergic networks in DLB using PET imaging with an acetylcholinesterase transporter ligand, functional networks related to alertness and visual attention were most prominently disrupted 50 . In addition basal forebrain pathology (volume by MRI) has been linked to attention and attentional deficits 51 , 52 . The results in the TUG test, showing gait improvement relative to placebo, may be particularly relevant with regard to a potential effect on the cholinergic system because recent clinical translational publications have connected basal forebrain pathology (assessed as NBM atrophy by MRI) to gait impairment in PD 8 – 10 .…”

Magnetic resonance imaging of the dopamine system in schizophrenia – A scoping review

“…Although probabilistic anatomical atlases for the substantia nigra and ventral tegmental area exist, region of interest-based analysis cannot be performed, as midbrain and brainstem are classified as white matter structure by common morphometry toolboxes, which also makes whole-brain analysis results in these areas questionable. Furthermore, post-mortem-based definitions of the human dopaminergic VTA/SN and their delineation in standard spaces such as MNI are not available at the moment – in contrast to the cholinergic basal forebrain, enabling VBM-based volumetric approaches ( 63 , 64 ). FSL currently released a beta version of a toolbox called MIST, which is planned to provide tools to segment brainstem nuclei based on T1-weighted images in an upcoming release ( 65 ).…”

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