Cerebral perfusion alterations are associated with clinical phenotypes and biotypes across the psychosis spectrum

Abstract

Abstract Background Cerebral perfusion abnormalities may contribute to the pathophysiology of psychosis spectrum disorders (PSD), including schizophrenia (SZ), schizoaffective disorder (SAD), and bipolar disorder with psychotic features (BP), yet large-scale investigations remain limited. Methods Pseudo-continuous arterial spin labeling scans were acquired from 2412 SZ, 2278 SAD, 158 BP, 401 neurotypical controls (NC) and processed using ExploreASL and FreeSurfer to quantify resting-state cerebral blood flow (CBF) across total gray matter and 60 brain regions. General linear regression compared CBF between NC and diagnostic groups or biologically informed biotypes derived from neurophysiological clustering. Within patient groups, Spearman correlations assessed associations between cognitive/clinical measures and CBF. Analyses were corrected for multiple comparisons. Results Compared to NC, patient groups showed significantly lower total gray matter CBF (PSD: Cohen’s d=-0.124, p-adjusted=0.037; BP: d=-0.259, p-adjusted=0.004; the most severe biotype, Biotype 1: d=-0.222, p-adjusted=0.006). BP and Biotype 1 exhibited significant hypoperfusion in 25 regions spanning bilateral temporal, occipital, inferior frontal cortices, and subcortical structures (BP d= -0.21 to -0.33; Biotype 1 d=-0.19 to -0.26). No significant CBF-cognition associations were observed. Within PSD, higher total gray matter CBF correlated with greater psychotic symptom severity, while right superior temporal sulcus hyperperfusion was associated with greater psychotic, manic, and depressive symptoms. Conclusions Distinct perfusion patterns exist in PSD, with widespread hypoperfusion in BP and Biotype 1 and hyperperfusion associated with greater symptom severity, supporting perfusion as a potential biomarker to stratify PSD subtypes.