Evidence of Neurovascular Water Exchange and Endothelial Vascular Dysfunction in Schizophrenia: An Exploratory Study

Abstract

Background and Hypothesis Mounting evidence supports cerebrovascular contributions to schizophrenia spectrum disorder (SSD) but with unknown mechanisms. The blood–brain barrier (BBB) is at the nexus of neural-vascular exchanges, tasked with regulating cerebral homeostasis. BBB abnormalities in SSD, if any, are likely more subtle compared to typical neurological insults and imaging measures that assess large molecule BBB leakage in major neurological events may not be sensitive enough to directly examine BBB abnormalities in SSD. Study Design We tested the hypothesis that neurovascular water exchange (Kw) measured by non-invasive diffusion-prepared arterial spin label MRI (n = 27 healthy controls [HC], n = 32 SSD) is impaired in SSD and associated with clinical symptoms. Peripheral vascular endothelial health was examined by brachial artery flow-mediated dilation (n = 44 HC, n = 37 SSD) to examine whether centrally measured Kw is related to endothelial functions. Study Results Whole-brain average Kw was significantly reduced in SSD (P = .007). Exploratory analyses demonstrated neurovascular water exchange reductions in the right parietal lobe, including the supramarginal gyrus (P = .002) and postcentral gyrus (P = .008). Reduced right superior corona radiata (P = .001) and right angular gyrus Kw (P = .006) was associated with negative symptoms. Peripheral endothelial function was also significantly reduced in SSD (P = .0001). Kw in 94% of brain regions in HC positively associated with peripheral endothelial function, which was not observed in SSD, where the correlation was inversed in 52% of brain regions. Conclusions This study provides initial evidence of neurovascular water exchange abnormalities, which appeared clinically associated, especially with negative symptoms, in schizophrenia.

Regional differences in the link between water exchange rate across the blood–brain barrier and cognitive performance in normal aging

“…The positive associations observed between BBB k w and cognitive performance in frontal and parietal brain regions are in keeping with the BBB k w -cognitive performance trends previously reported by our group in the same cortical brain regions, in a cohort of cognitively normal older adults [33]. Moreover, similar associations in the neocortical brain regions have been reported by other researchers exploring BBB k w in patient populations [31,32,84]. Results from the present study provide further evidence that high BBB k w in the neocortical regions is associated with high cognitive performance.…”

Age-Related Decline in Blood-Brain Barrier Function is More Pronounced in Males than Females in Parietal and Temporal Regions

“…To the best of our knowledge, the present study is the first to simultaneously investigate the spatiotemporal trajectories of CBF, ATT and BBB kw variations with age and sex in a diverse group of cognitively normal participants across the lifespan (27, 33), enabled by the innovative DP-pCASL technique. Our findings indicate a pervasive increase in ATT and decrease in CBF across brain regions (Fig.…”

“…DP-pCASL has recently been applied in a range of brain disorders and has been validated by mannitol administration to open the BBB and using an ischemia-reperfusion model to disrupt BBB in rats (23,24). As opposed to increased BBB leakage detected by DCE MRI (25), reduced BBB kw has been found in a wide range of CNS disorders including obstructive sleep apnea (26), schizophrenia (27), multiple sclerosis (4) and heredity cSVD (28,29). In particular, emerging evidence suggests a high relevance between BBB water exchange and glymphatic function.…”