Research from JAMA Psychiatry — Long-term Follow-up of a Group at Ultra High Risk (“Prodromal”) for Psychosis — The PACE 400 Study

Objective: It is likely that cognitive deficits are vulnerability markers for developing schizophrenia, as these deficits are already well‐established findings in first‐episode psychosis. Studies at‐risk adolescents and young adults are likely to provide information about cognitive deficits that predate the onset of the illness.Method: We conducted meta‐analyses of studies comparing familial‐high risk (FHR) or ultra‐high risk (UHR; n = 2113) and healthy controls (n = 1748) in youth studies in which the mean age was between 15 and 29.Results: Compared with controls, high risk subjects were impaired in each domain in both UHR (d = 0.34–0.71) and FHR (d = 0.24–0.81). Heterogeneity of effect sizes across studies was modest, increasing confidence to the findings of the current meta‐analysis (I² = 0–0.18%). In both risk paradigms, co‐occurrence of genetic risk with attenuated symptoms was associated with more severe cognitive dysfunction. In UHR, later transition to psychosis was associated with more severe cognitive deficits in all domains (d = 0.31–0.49) except sustained attention. However, cognitive impairment has a limited capacity to predict the outcome of high‐risk patients.Conclusion: Cognitive deficits are already evident in adolescents and young adults who have familial or clinical risk for psychosis. Longitudinal developmental studies are important to reveal timing and trajectory of emergence of such deficits.

OBJECTIVE—In this study, we used neurocognitive assessment and neuroimaging to examine brain function in youth with type 1 diabetes studied prospectively from diagnosis. RESEARCH DESIGN AND METHODS—We studied type 1 diabetic (n = 106) and control subjects (n = 75) with no significant group difference on IQ at baseline 12 years previously by using the Wechsler Abbreviated Scale of General Intelligence, magnetic resonance spectroscopy and imaging, and metabolic control data from diagnosis. RESULTS—Type 1 diabetic subjects had lower verbal and full scale IQs than control subjects (both P < 0.05). Type 1 diabetic subjects had lower N-acetylaspartate in frontal lobes and basal ganglia and higher myoinositol and choline in frontal and temporal lobes and basal ganglia than control subjects (all P < 0.05). Type 1 diabetic subjects, relative to control subjects, had decreased gray matter in bilateral thalami and right parahippocampal gyrus and insular cortex. White matter was decreased in bilateral parahippocampi, left temporal lobe, and middle frontal area (all P < 0.0005 uncorrected). T2 in type 1 diabetic subjects was increased in left superior temporal gyrus and decreased in bilateral lentiform nuclei, caudate nuclei and thalami, and right insular area (all P < 0.0005 uncorrected). Early-onset disease predicted lower performance IQ, and hypoglycemia was associated with lower verbal IQ and volume reduction in thalamus; poor metabolic control predicted elevated myoinositol and decreased T2 in thalamus; and older age predicted volume loss and T2 change in basal ganglia. CONCLUSIONS—This study documents brain effects 12 years after diagnosis in a type 1 diabetic sample whose IQ at diagnosis matched that of control subjects. Findings suggest several neuropathological processes including gliosis, demyelination, and altered osmolarity.