Relationship between muscarinic M1 receptor binding and cognition in medication-free subjects with psychosis

Abstract

Background: It is still unclear which underlying mechanisms are involved in cognitive deficits of psychotic disorders. Pro-cognitive effects of muscarinic M₁ receptor agonists suggest alterations in M₁ receptor functioning may modulate these symptoms. Post mortem studies in patients with schizophrenia have shown significantly reduced M₁ receptor expression rates in the dorsolateral prefrontal cortex (DLPFC) compared to controls. To date no in-vivo examinations of M₁ receptor binding in relation to cognitive impairments have been done. As cognitive deficits have similar course and prognostic relevance across psychotic disorders, the current study assessed M₁ receptor binding in the DLPFC and hippocampus in relation to cognitive functioning.

Methods: Muscarinic M₁ receptor binding potential (BP_ND) was measured using ¹²³I-IDEX, single photon emission computed tomography (SPECT) in 30 medication-free subjects diagnosed with a psychotic disorder. A computerized neuropsychological test battery was used to assess cognition, and the positive and negative syndrome scale (PANSS) to assess severity of psychotic symptoms.

Results: Assessment of cognitive domains showed that lower M₁ BP_ND in the DLPFC was related to overall lower performance in verbal learning and memory. In addition, lower M₁ BP_ND in the DLPFC was related to greater negative symptom severity. Lastly, lower M₁ BP_ND in the hippocampus was related to worse delayed recognition of verbal memory.

Conclusion: This is the first study to show that variation in M₁ receptors in the DLPFC is related to cognitive and negative symptom outcome in psychotic disorders. The M₁ receptor may be an important biomarker in biological stratification of patients with psychotic disorders.

Fig. 1

Panel A. shows gray matter segmentation image derived from the T1 structural MRI image used for co-registration of the ¹²³I-IDEX SPECT scan. Panel B. ¹²³I-IDEX SPECT scan of the same subject showing high cortical binding with no binding in white matter and cerebrospinal fluid. Panel C. ¹²³I-IDEX SPECT scan co-registered to subject's own T1 structural MRI image; darker areas are over white matter tracts, ventricles, and cerebellum showing no ¹²³I-IDEX binding. Panel D. In blue masks created from a segmented FreeSurfer image of the dorsolateral prefrontal cortex (DLPFC) (region of interest B_s), used for the assessment of M₁ binding, and cerebellar gray matter (B_n), overlaid over the SPECT scan in pseudo colors. Panel E. In blue, masks used for the assessment of M₁ binding (B_s) in the hippocampus, caudate nucleus and putamen.

Fig. 2

Lower M₁ receptor binding potential (BP_ND) in the dorsolateral prefrontal cortex (DLPFC) was related to lower verbal learning and memory capacity. r = Pearson's correlation coefficient; R² = goodness of fit.

Fig. 3

Decreased hippocampal M₁ BP_ND was associated with worse delayed recognition of verbal information. r = Pearson's correlation coefficient, R² = goodness of fit.

Fig. 4

Low M₁ BP_ND in the DLPFC was significantly related to increased severity and presence of negative symptoms measured by the positive and negative syndrome scale (PANSS) at time of scanning. No significant correlation was found between M₁ BP_ND and positive symptoms or general psychiatry at time of scanning. r = Pearson's correlation coefficient R² = goodness of fit.