Cortical abnormalities in youth at clinical high-risk for psychosis: Findings from the NAPLS2 cohort

Abstract

In a recent machine learning study classifying “brain age” based on cross-sectional neuroanatomical data, clinical high-risk (CHR) individuals were observed to show deviation from the normal neuromaturational pattern, which in turn was predictive of greater risk of conversion to psychosis and a pattern of stably poor functional outcome. These effects were unique to cases who were between 12 and 17 years of age when their prodromal and psychotic symptoms began, suggesting that neuroanatomical deviance observable at the point of ascertainment of a CHR syndrome marks risk for an early onset form of psychosis. In the present study, we sought to clarify the pattern of neuroanatomical deviance linked to this “early onset” form of psychosis and whether this deviance is associated with poorer premorbid functioning. T 1 MRI scans from 378 CHR individuals and 190 healthy controls (HC) from the North American Prodrome Longitudinal Study (NAPLS2) were analyzed. Widespread smaller cortical volume was observed among CHR individuals compared with HC at baseline evaluation, particularly among the younger group (i.e., those who were 12 to 17 years of age). Moreover, the younger CHR individuals who converted or presented worsened clinical symptoms at follow-up (within 2 years) exhibited smaller surface area in rostral anterior cingulate, lateral and medial prefrontal regions, and parahippocampal gyrus relative to the younger CHR individuals who remitted or presented a stable pattern of prodromal symptoms at follow-up. In turn, poorer premorbid functioning in childhood was associated with smaller surface area in medial orbitofrontal, lateral frontal, rostral anterior cingulate, precuneus, and temporal regions. Together with our prior report, these results are consistent with the view that neuroanatomical deviance manifesting in early adolescence marks vulnerability to a form of psychosis presenting with poor premorbid adjustment, an earlier age of onset (generally prior to the age of 18 years), and poor long-term outcome.

ENIGMA MDD: Seven Years of Global Neuroimaging Studies of Major Depression through Worldwide Data Sharing

“…This might be explained by (1) normalization of cortical surface area when transitioning into adulthood; (2) cortical surface area alterations being only present in a specific subgroup (subtype) of adult patients with adolescent-onset MDD, which we were unable to detect; or (3) those with cortical surface area alterations in early adolescence may be at higher risk for transitioning from MDD to other mental disorders over time. This latter possibility is consistent with reports of lower cortical surface area in adolescents and adults with psychosis or schizophrenia 82,83 , and in individuals at high risk for and/or transitioning to psychosis 84,85 . Longitudinal studies are required to test the hypothesis that cortical surface area alteration is a pre-existing risk factor for the development of MDD, and to investigate the subsequent clinical course of these young people with MDD and global surface area reductions.…”

Structural and functional imaging markers for susceptibility to psychosis

“…Two recent studies showcase the complex interactions of age with neuroanatomy and transition prediction. As detailed above, a larger gap between “brain age” and chronological age and was predictive of greater risk of transition to psychosis, was observed in the NAPLS 2 study; however, this effect was found only in patients diagnosed with CHR status at a young age (i.e., 12–17 years), while it was not present in patients diagnosed at a later age [ 86 ]. Another long-term follow-up study [ 186 ] reported that surface area decreases in the prefrontal, cingulate, and parahippocampal areas predicted poor symptomatic outcomes in younger, but not in older CHR adolescents.…”

“…Other implementations of machine-learning models include their use to investigate age-related maturation of brain structure, which has been reported to follow deviant patterns in CHR patients. The North American Prodrome Longitudinal study (NAPLS 2) used structural MRI scans [ 86 ] of healthy individuals ( n = 190) to develop age prediction models, and subsequently calculated the gap between model-predicted age and chronological age in CHR patients ( n = 380); the Personalized Prognostic Tools for Early Psychosis Management study (PRONIA) implemented a similar approach on neurocognitive performance data of 36 healthy individuals and 48 CHR patients [ 87 ]. A larger “brain-age” gap in CHR patients, which was predictive of greater risk of transition to psychosis, was observed in the NAPLS 2 study [ 86 ].…”

“…The North American Prodrome Longitudinal study (NAPLS 2) used structural MRI scans [ 86 ] of healthy individuals ( n = 190) to develop age prediction models, and subsequently calculated the gap between model-predicted age and chronological age in CHR patients ( n = 380); the Personalized Prognostic Tools for Early Psychosis Management study (PRONIA) implemented a similar approach on neurocognitive performance data of 36 healthy individuals and 48 CHR patients [ 87 ]. A larger “brain-age” gap in CHR patients, which was predictive of greater risk of transition to psychosis, was observed in the NAPLS 2 study [ 86 ]. The neurocognitive age gap (“CogAGE”) in the PRONIA study was also significantly higher in CHR patients than healthy controls [ 87 ], and was associated with increased gray matter volume in frontotemporal areas and diffuse white matter reductions.…”

Selective Review of Neuroimaging Findings in Youth at Clinical High Risk for Psychosis: On the Path to Biomarkers for Conversion

“…Very interestingly, the degree and timing of grey matter loss may depend on age of symptom onset. In a recent report, Chung et al evaluated baseline MRI parameters of converters and non-converters and observed that younger CHR subjects (12–17 years old) that converted to psychosis exhibited decreased grey matter volume at baseline and a less steep grey matter decline at first episode psychosis ( 134 ). However, older CHR subjects (> 18yrs old) that converted to psychosis did not have decreased grey matter volume at baseline, but exhibited a much steeper rate of volume loss as illness progressed.…”