6.Pardiñas AF, Holmans P, Pocklington AJ, et al; GERAD1 Consortium; CRESTAR Consortium. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.

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Introduction Traumatic brain injury (TBI) may alter the course of neuropsychiatric symptom (NPS) onset during dementia development. The connection among TBI, NPS, and dementia progression is of increasing interest to researchers and clinicians. Methods Incidence of NPS was examined in participants with normal cognition who progressed to all‐cause dementia based on whether TBI history was present (n = 130) or absent (n = 849). Survival analyses were used to examine NPS incidence across 7.6 ± 3.0 years of follow‐up. Results Participants with TBI history had increased prevalence and incidence of apathy (44.7% vs 29.9%, P = .0062; HRadj. = 1.708, P = .0018) and motor disturbances (17.2% vs 9.5%, P = .0458; HRadj. = 2.023, P = .0168), controlling for demographics and type of dementia diagnosis. Earlier anxiety onset was associated with TBI (692 days prior to dementia diagnosis vs 161 days, P = .0265). Discussion History of TBI is associated with increased risk for and earlier onset of NPS in the trajectory of dementia development.

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Psychosis is a rare, but particularly serious sequela of traumatic brain injury. However, little is known as to the neurobiological processes that may contribute to its onset. Early evidence suggests that psychotic symptom development after traumatic brain injury may co-occur with hippocampal degeneration, invoking the possibility of a relationship. Particularly regarding the hippocampal head, these degenerative changes may lead to dysregulation in dopaminergic circuits, as is reported in psychoses due to schizophrenia, resulting in the positive symptom profile typically seen in post-injury psychosis. The objective of this study was to examine change in hippocampal volume and psychotic symptoms across time in a sample of moderate-to-severe traumatic brain injury patients. We hypothesized that hippocampal volume loss would be associated with increased psychotic symptom severity. From a database of n = 137 adult patients with prospectively collected, longitudinal imaging and neuropsychiatric outcomes, n = 24 had complete data at time points of interest (5- and 12-months post-traumatic brain injury) and showed increasing psychotic symptom severity on the Personality Assessment Inventory psychotic experiences subscale of the schizophrenia clinical scale across time. Secondary analysis employing stepwise regression with hippocampal volume change (independent variable) and Personality Assessment Inventory psychotic symptom change (dependent variable) from 5 to 12 months post-injury was conducted including age, sex, marijuana use, family history of schizophrenia, years of education, and injury severity as control variables. Total right hippocampal volume loss predicted an increase on the Personality Assessment Inventory psychotic experiences subscale (F(1, 22)=5.396, adj.R2=0.161, p=0.030; β =-0.017, 95%CI=-0.018,-0.016) as did volume of the right hippocampal head (F(1, 22)=5.764, adj.R2=0.172, p=0.025; β=-0.019, 95% CI=-0.021,-0.017). Final model goodness of fit was confirmed using k-fold (k = 5) cross validation. Consistent with our hypotheses, the current findings suggest that hippocampal degeneration in the chronic stages of moderate-to-severe traumatic brain injury may play a role in the delayed onset of psychotic symptoms after traumatic brain injury. These findings localized to the right hippocampal head are supportive of a proposed etiological mechanism whereby atrophy of the hippocampal head may lead to dysregulation of dopaminergic networks following traumatic brain injury; possibly accounting for observed clinical features of psychotic disorder after traumatic brain injury (including prolonged latency period to symptom onset and predominance of positive symptoms). If further validated, these findings may bear important clinical implications for neurorehabilitative therapies following traumatic brain injury.

Background: Traumatic brain injury (TBI) and Alzheimer's disease (AD) bear a complex relationship, potentially increasing risk of one another reciprocally. However, recent evidence suggests post-TBI dementia exists as a distinct neurodegenerative syndrome, confounding AD diagnostic accuracy in clinical settings. This investigation sought to evaluate TBI's impact on the accuracy of clinician-diagnosed AD using gold standard neuropathological criteria. Methods:In this preliminary analysis, data was acquired from the National Alzheimer's Coordinating Center (NACC), which aggregates clinical and neuropathologic information from Alzheimer's Disease Centers across the United States. Modified National Institute on Aging-Reagan criteria were applied to confirm AD by neuropathology.Results: Among participants with clinician-diagnosed AD, TBI history was associated with misdiagnosis (false positives) (OR = 1.351 (95% CI: 1.091 -1.674), p = 0.006). Among participants without clinician-diagnosed AD, TBI history was not associated with false negatives.Discussion: TBI moderates AD diagnostic accuracy. Possible AD misdiagnosis can mislead patients, influence treatment decisions, and confound research study designs. Further work examining the influence of TBI on dementia diagnosis is warranted.