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SUMMARY There is comparatively little information about premorbid maturational brain abnormalities in schizophrenia. We investigated whether a history of childhood enuresis, a well-established marker of neurodevelopmental delay, is associated with schizophrenia and with measures of brain abnormalities also associated with schizophrenia. A DSM-IV based history of enuresis, volumetric brain MRI scans, and neuropsychological testing were obtained in patients with schizophrenia, their non-psychotic siblings, and non-psychiatric controls. The subjects were 211 patients (79.6% male), 234 of their siblings (43.2% male), and 355 controls (39.2% male). Frequency of enuresis was compared across groups and correlated with cognitive measures. Total and regional brain volumes were determined using VBM on matched subsets of probands (n=82) with or without enuresis (n=16, n=66, respectively) and controls (n=102) with or without enuresis (n=11, n=91, respectively). Patients with schizophrenia had higher rates of childhood enuresis (21%) compared with siblings (11%; χ2=6.42, p=0.01) or controls (7%; χ2=23.65, p<0.0001) and relative risk for enuresis was increased in siblings (λS=2.62). Patients with enuresis performed worse on two frontal lobe cognitive tests [Letter Fluency (t=1.97, p=0.05, df=200) and Category Fluency (t=2.15, p=0.03, df=200)] as compared with non-enuretic patients. VBM analysis revealed gray matter volume reductions in several frontal regions (right BA 9, right BA 10, and bilateral BA 45), and right superior parietal cortex (BA 7) in patients with a history of enuresis as compared with non-enuretic patients (all t>3.57, all p<0.001). The high frequency of childhood enuresis associated with schizophrenia, and abnormalities in prefrontal function and structure in patients with a childhood history of enuresis suggest that childhood enuresis may be a premorbid marker for neurodevelopmental abnormalities related to schizophrenia. These findings add to the evidence implicating prefrontal dysmaturation in this disorder, potentially related to genetic risk factors.

Objectives-Postmortem human brain is a valuable resource for studying the neuropathology, neurochemistry, and molecular pathways of genes associated with bipolar disorder (BPD), yet available well-characterized BPD brain tissue appears scarce. We set out to evaluate BPD postmortem brain collections in order to identify both successful methods as well as barriers to collection.Methods-We conducted a literature review of postmortem studies of BPD over the past 30 years, compared and contrasted characteristics of established BPD collections, and identified possible barriers specific to BPD brain collection based on our experience at the NIMH Brain Collection.Results-Currently, 80% of postmortem BPD studies were derived from just two brain repositories worldwide: the Stanley Brain Collection (69%) and Harvard Brain Tissue Resource Center (HBTRC) (11%) (Combined subjects n=72). The NIMH Brain Collection collected BPD cases four times less frequently than cases with schizophrenia, despite similar prevalence rates for these disorders. Only 53% of cases referred to the NIMH collection as BPD met DSM-IV criteria, with inadequate documentation and comorbid substance abuse as primary confounds for diagnosis in the remaining 47% of cases.Conclusions-Accurate identification and diagnosis of BPD is a central obstacle to BPD brain collection. Comorbid substance abuse and manner of death are two of many critical factors to consider in BPD postmortem studies. Difficulties in BPD brain collection, coupled with the cessation of brain collection by the Stanley Brain Collection, make the need for alternative BPD brain sources imperative. Recommendations for future BPD tissue collection are offered.

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