Association between brain similarity to severe mental illnesses and comorbid cerebral, physical, and cognitive impairments

Severe mental illnesses (SMIs) are often associated with compromised brain health, physical comorbidities, and cognitive deficits, but it is incompletely understood whether these comorbidities are intrinsic to SMI patho-physiology or secondary to having SMIs. We tested the hypothesis that cerebral, cardiometabolic, and cognitive impairments commonly observed in SMIs can be observed in non-psychiatric individuals with SMI-like brain pat-terns of deviation as seen on magnetic resonance imaging. 22,883 participants free of common neuropsychiatric conditions from the UK Biobank (age = 63.4 +/- 7.5 years, range = 45-82 years, 50.9% female) were split into discovery and replication samples. The regional vulnerability index (RVI) was used to quantify each participant's respective brain similarity to meta-analytical patterns of schizophrenia spectrum disorder, bipolar disorder, and major depressive disorder in gray matter thickness, subcortical gray matter volume, and white matter integrity. Cluster analysis revealed five clusters with distinct RVI profiles. Compared with a cluster with no RVI elevation, a cluster with RVI elevation across all SMIs and brain structures showed significantly higher volume of white matter hyperintensities (Cohen's d = 0.59, pFDR < 10 - 16), poorer cardiovascular (Cohen's d = 0.30, pFDR < 10 - 16) and metabolic (Cohen's d = 0.12, pFDR = 1.3 x 10 - 4) health, and slower speed of information processing (|Cohen's d | = 0.11-0.17, pFDR = 1.6 x 10 - 3-4.6 x 10 - 8). This cluster also had significantly higher level of C-reactive protein and alcohol use (Cohen's d = 0.11 and 0.28, pFDR = 4.1 x 10 - 3 and 1.1 x 10 - 11). Three other clusters with respec-tive RVI elevation in gray matter thickness, subcortical gray matter volume, and white matter integrity showed intermediate level of white matter hyperintensities, cardiometabolic health, and alcohol use. Our results suggest that cerebral, physical, and cognitive impairments in SMIs may be partly intrinsic via shared pathophysiological pathways with SMI-related brain anatomical changes.