Mediterranean diet intervention among World Trade Center responders with post-traumatic stress disorder: Feasibility and outcomes of a pilot randomized controlled trial.

Objective: Responders of the World Trade Center (WTC) disaster suffer from co-morbidities. A Mediterranean Diet (MedDiet) nutrition intervention with physical activity was implemented among WTC responders with overweight/obesity and post-traumatic stress disorder (PTSD). Methods: WTC Health Program members (N = 62), 45-65 years, males 87%, body mass index (BMI) 27-45 kg/m2 randomized to MedDiet (n = 31) or usual nutrition counseling (n = 31). The 10-week intervention included online nutrition education, text messages, and group experiential cooking; both groups had three in-person individual nutrition counseling. Anthropometrics, serum biomarkers, psychosocial factors, MedDiet score, and PTSD symptoms were assessed at baseline, post-intervention, and 3-months (follow-up). The primary outcome was intervention feasibility and secondary outcomes were within- and between-group changes of all measures at post-intervention and follow-up. Nonparametric Wilcoxon rank sum tests for between-group comparisons and Wilcoxon signed rank tests for pre-post within-group comparisons. Results: A total of 58(94%) and 46(74%) participants completed the post-intervention and follow-up measurements, respectively. Both groups experienced significant improvements in anthropometrics, MedDiet score, oxidized low-density lipoprotein, and PTSD symptoms. Baseline median (range) were weight 100.42 (73.66-135.17) kg, BMI 33.20 (27.50-41.75) kg/m2, and Waist circumference (WC) 109.22 (90.17-150.62) cm. Median % weight loss at post-intervention was MedDiet: -3% (-11%-7%), p = 0.0002; Control: -1% (-13%-4%), p = 0.008 and at follow-up MedDiet: -2% (-14%-12%), p = 0.07; Control: -2% (-20%-3%), p = 0.006. The overall BMI was reduced by -0.68 kg/m2 (-4.61-2.09) kg/m2 p < 0.0001 at post-intervention and by -0.60 kg/m2 (-6.91-3.39) kg/m2, p < 0.0009 at follow-up. Overall, median WC was reduced (p < 0.0001); post-intervention -3.81 cm (-33.00-3.30)cm and follow-up -4.45(-38.10-4.57)cm. There were group differences in HbA1c (p = 0.019) and serum ω6/ω3 (p = 0.029) at post-intervention. Conclusion: Online intervention with personal counseling was feasible in this population. Improvements in anthropometrics, MedDiet score, selected serum biomarkers and PTSD symptoms were found in both groups; group differences in HbA1c and serum ω6/ω3. A larger study with a delayed control is needed to better assess intervention effects.

Behavioral Impairments and Increased Risk of Cortical Atrophy Risk Scores Among World Trade Center Responders.

Objective: World Trade Center (WTC) responders are susceptible to both cognitive and neuropsychiatric impairments, particularly chronic posttraumatic stress disorder. The present study examined self-reported behavioral impairments in a sample of 732 WTC responders, 199 of whom were determined to have high risk of WTC-related cortical atrophy by an artificial neural network. Results: We found that responders at increased risk of cortical atrophy showed behavioral impairment across five domains: motivation, mood, disinhibition, empathy, and psychosis (14.6% vs 3.9% in the low-risk group; P = 3.90 × 10-7). Factor analysis models revealed that responders at high risk of cortical atrophy tended to have deficits generalized across all aspects of behavioral impairment with focal dysfunction in sensory psychosis. We additionally describe how relationships are modulated by exposure severity and pharmacological treatments. Discussion: Our findings suggest a potential link between sensory deficits and the development of cortical atrophy in WTC responders and may indicate symptoms consistent with a clinical portrait of parietal dominant Alzheimer's disease or a related dementia (ADRD). Results underscore the importance of investigating neuropsychiatric symptomatology in clinical evaluations of possible ADRD.

Age of onset and cumulative risk of mental disorders: a cross-national analysis of population surveys from 29 countries.

BACKGROUND: Information on the frequency and timing of mental disorder onsets across the lifespan is of fundamental importance for public health planning. Broad, cross-national estimates of this information from coordinated general population surveys were last updated in 2007. We aimed to provide updated and improved estimates of age-of-onset distributions, lifetime prevalence, and morbid risk. METHODS: In this cross-national analysis, we analysed data from respondents aged 18 years or older to the World Mental Health surveys, a coordinated series of cross-sectional, face-to-face community epidemiological surveys administered between 2001 and 2022. In the surveys, the WHO Composite International Diagnostic Interview, a fully structured psychiatric diagnostic interview, was used to assess age of onset, lifetime prevalence, and morbid risk of 13 DSM-IV mental disorders until age 75 years across surveys by sex. We did not assess ethnicity. The surveys were geographically clustered and weighted to adjust for selection probability, and standard errors of incidence rates and cumulative incidence curves were calculated using the jackknife repeated replications simulation method, taking weighting and geographical clustering of data into account. FINDINGS: We included 156 331 respondents from 32 surveys in 29 countries, including 12 low-income and middle-income countries and 17 high-income countries, and including 85 308 (54·5%) female respondents and 71 023 (45·4%) male respondents. The lifetime prevalence of any mental disorder was 28·6% (95% CI 27·9-29·2) for male respondents and 29·8% (29·2-30·3) for female respondents. Morbid risk of any mental disorder by age 75 years was 46·4% (44·9-47·8) for male respondents and 53·1% (51·9-54·3) for female respondents. Conditional probabilities of first onset peaked at approximately age 15 years, with a median age of onset of 19 years (IQR 14-32) for male respondents and 20 years (12-36) for female respondents. The two most prevalent disorders were alcohol use disorder and major depressive disorder for male respondents and major depressive disorder and specific phobia for female respondents. INTERPRETATION: By age 75 years, approximately half the population can expect to develop one or more of the 13 mental disorders considered in this Article. These disorders typically first emerge in childhood, adolescence, or young adulthood. Services should have the capacity to detect and treat common mental disorders promptly and to optimise care that suits people at these crucial parts of the life course. FUNDING: None.

Functional changes in neural mechanisms underlying post-traumatic stress disorder in World Trade Center responders.

World Trade Center (WTC) responders exposed to traumatic and environmental stressors during rescue and recovery efforts have a high prevalence of chronic WTC-related post-traumatic stress disorder (WTC-PTSD). We investigated neural mechanisms underlying WTC-PTSD by applying eigenvector centrality (EC) metrics and data-driven methods on resting state functional magnetic resonance (fMRI). We identified how EC differences relate to WTC-exposure and behavioral symptoms. We found that connectivity differentiated significantly between WTC-PTSD and non-PTSD responders in nine brain regions, as these differences allowed an effective discrimination of PTSD and non-PTSD responders based solely on analysis of resting state data. Further, we found that WTC exposure duration (months on site) moderates the association between PTSD and EC values in two of the nine brain regions; the right anterior parahippocampal gyrus and the left amygdala (p = 0.010; p = 0.005, respectively, adjusted for multiple comparisons). Within WTC-PTSD, a dimensional measure of symptom severity was positively associated with EC values in the right anterior parahippocampal gyrus and brainstem. Functional neuroimaging can provide effective tools to identify neural correlates of diagnostic and dimensional indicators of PTSD.

Glial suppression and post-traumatic stress disorder: A cross-sectional study of 1,520 world trade center responders.

Background: Chronically re-experiencing the memory of a traumatic event might cause a glial response. This study examined whether glial activation would be associated with PTSD in a study of responders present after the 9/11 World Trade Center attacks without comorbid cerebrovascular disease. Methods: Plasma was retrieved from 1,520 WTC responders and stored for a cross-sectional sample of responders of varying levels of exposure and PTSD. Plasma levels (pg/ml) of glial fibrillary acidic protein (GFAP) were assayed. Because stroke and other cerebrovascular diseases cause distributional shifts in GFAP levels, multivariable-adjusted finite mixture models analyzed GFAP distributions in responders with and without possible cerebrovascular disease. Results: Responders were aged 56.3 years and primarily male; 11.07% (n = 154) had chronic PTSD. Older age was associated with increased GFAP, whereas higher body mass was associated with decreased GFAP. Multivariable-adjusted finite mixture models revealed that severe re-experiencing trauma from 9/11 was associated with lower GFAP (B = -0.558, p = 0.003). Conclusion: This study presents evidence of reduced plasma GFAP levels among WTC responders with PTSD. Results suggest re-experiencing traumatic events might cause glial suppression.

Effects of disaster-related traumatic events on worry about radiation and COVID-19: A decade after the Fukushima nuclear power plant accident.

Community residents exposed to nuclear power plant (NPP) accidents have long-term worry about the effects of radiation. After the 2011 Fukushima NPP accident, those who experienced traumatic events during the Great East Japan Earthquake (GEJE) tended to have greater worry about radiation. Along with the prolonged worry about radiation, there may also be cognitive changes caused by the traumatic events. We hypothesized that if there were cognitive changes underlying the prolonged worry about radiation, those who experienced the traumatic events would tend to have greater worry about other issues unrelated to radiation. We examined the effects of the traumatic events during the GEJE on community residents' worry about radiation and COVID-19 a decade after the Fukushima NPP accident. Using the data of a longitudinal questionnaire survey following a random sample of 4900 community residents outside the evacuation zone in Fukushima, this study analyzed 774 responses (15.8%). The traumatic events consisted of (1) injury, (2) injury or death of a family member, and (3) the loss of a house or other property. We developed a mediation model drawing paths from the traumatic events to worry about radiation and COVID-19, including posttraumatic stress symptoms (PTSS) as a mediator, using structural equation modeling. The traumatic events directly affected worry about radiation. Although it did not directly affect worry about COVID-19, it did so indirectly through worry about radiation and PTSS. Traumatic events can increase trauma-related worry independently of PTSS and increase trauma-unrelated worry indirectly through trauma-related worry and PTSS.

Plasma amyloid beta 40/42, phosphorylated tau 181, and neurofilament light are associated with cognitive impairment and neuropathological changes among World Trade Center responders: A prospective cohort study of exposures and cognitive aging at midlife.

Introduction: World Trade Center (WTC) responders are experiencing a high risk of mild cognitive impairment (MCI) and dementia, though the etiology remains inadequately characterized. This study investigated whether WTC exposures and chronic post-traumatic stress disorder (PTSD) were correlated with plasma biomarkers characteristic of Alzheimer's disease (AD) neuropathology. Methods: Eligible participants included WTC-exposed individuals with a baseline cognitive assessment and available plasma sample. We examined levels of the amyloid beta (Aß)40/42 ratio, phosphorylated tau 181 (p-tau181), and neurofilament light chain (NfL) and associations with a WTC exposures (duration on site ≥15 weeks, dust cloud), the PTSD Symptom Checklist for Diagnostic and Statistical Manual of Mental Disorders, 4th edition PTSD, and classification of amyloid/tau/neurodegeneration (AT[N]) profiles. Multinomial logistic regressions assessed whether biomarkers predicted increased risk of MCI or dementia. Results: Of 1179 eligible responders, 93.0% were male, mean (standard deviation) age 56.6 years (7.8). Aß40/42, p-tau181, and NfL intercorrelated and increased with age. In subgroup analyses of responders with available neuroimaging data (n = 75), Aß40/42 and p-tau181 were further associated with decreased hippocampal volume (Spearman's ρ = -0.3). Overall, 58.08% of responders with dementia had ≥1 elevated biomarker, and 3.45% had elevations across all biomarkers. In total, 248 (21.05%) had MCI and 70 (5.94%) had dementia. Increased risk of dementia was associated with plasma AT(N) profile T+ or A+N+. Exposure on site ≥15 weeks was independently associated with T+ (adjusted risk ratio [aRR] = 1.03 [1.01-1.05], P = 0.009), and T+N+ profile (aRR = 2.34 [1.12-4.87]). The presence of PTSD was independently associated with risk of A+ (aRR = 1.77 [1.11-2.82]). Discussion: WTC exposures and chronic PTSD are associated with plasma biomarkers consistent with neurodegenerative disease.

World Trade Center responders in their own words: predicting PTSD symptom trajectories with AI-based language analyses of interviews.

BACKGROUND: Oral histories from 9/11 responders to the World Trade Center (WTC) attacks provide rich narratives about distress and resilience. Artificial Intelligence (AI) models promise to detect psychopathology in natural language, but they have been evaluated primarily in non-clinical settings using social media. This study sought to test the ability of AI-based language assessments to predict PTSD symptom trajectories among responders. METHODS: Participants were 124 responders whose health was monitored at the Stony Brook WTC Health and Wellness Program who completed oral history interviews about their initial WTC experiences. PTSD symptom severity was measured longitudinally using the PTSD Checklist (PCL) for up to 7 years post-interview. AI-based indicators were computed for depression, anxiety, neuroticism, and extraversion along with dictionary-based measures of linguistic and interpersonal style. Linear regression and multilevel models estimated associations of AI indicators with concurrent and subsequent PTSD symptom severity (significance adjusted by false discovery rate). RESULTS: Cross-sectionally, greater depressive language (ß = 0.32; p = 0.049) and first-person singular usage (ß = 0.31; p = 0.049) were associated with increased symptom severity. Longitudinally, anxious language predicted future worsening in PCL scores (ß = 0.30; p = 0.049), whereas first-person plural usage (ß = -0.36; p = 0.014) and longer words usage (ß = -0.35; p = 0.014) predicted improvement. CONCLUSIONS: This is the first study to demonstrate the value of AI in understanding PTSD in a vulnerable population. Future studies should extend this application to other trauma exposures and to other demographic groups, especially under-represented minorities.

World Trade Center Site Exposure Duration Is Associated with Hippocampal and Cerebral White Matter Neuroinflammation.

Responders to the World Trade Center (WTC) attacks on 9/11/2001 inhaled toxic dust and experienced severe trauma for a prolonged period. Studies report that WTC site exposure duration is associated with peripheral inflammation and risk for developing early-onset dementia (EOD). Free Water Fraction (FWF) can serve as a biomarker for neuroinflammation by measuring in vivo movement of free water across neurons. The present case-controlled study aimed to examine associations between WTC site exposure duration as well as EOD status with increased hippocampal and cerebral neuroinflammation. Ninety-nine WTC responders (mean age of 56) were recruited between 2017 and 2019 (N = 48 with EOD and 51 cognitively unimpaired). Participants were matched on age, sex, occupation, race, education, and post-traumatic stress disorder (PTSD) status. Participants underwent neuroimaging using diffusion tensor imaging protocols for FWF extraction. Region of interest (ROI) analysis and correlational tractography explored topographical distributions of FWF associations. Apolipoprotein-e4 allele (APOEε4) status was available for most responders (N = 91). Hippocampal FWF was significantly associated with WTC site exposure duration (r = 0.30, p = 0.003), as was cerebral white matter FWF (r = 0.20, p = 0.044). ROI analysis and correlational tractography identified regions within the limbic, frontal, and temporal lobes. Hippocampal FWF and its association with WTC exposure duration were highest when the APOEε4 allele was present (r = 0.48, p = 0.039). Our findings demonstrate that prolonged WTC site exposure is associated with increased hippocampal and cerebral white matter neuroinflammation in WTC responders, possibly exacerbated by possession of the APOEε4 allele.

Worry about Radiation and Its Risk Factors Five to Ten Years after the Fukushima Nuclear Power Plant Disaster.

Worry about radiation persists long after nuclear power plant accidents. Young age, low socioeconomic status, being married, and disaster-related experiences are known to be associated with greater worry about radiation. This study explored the duration of the effects of these risk factors on worry about radiation after the 2011 Fukushima nuclear power plant accident, using the longitudinal data of randomly sampled non-evacuee community residents who were followed five to ten years after the accident. Questionnaire surveys were conducted five times with 1825 respondents (37.2% of the 4900 initial targets). We examined the interaction of time and risk factors of worry about radiation using a mixed model. Fear or anxiety immediately after the accident had effects on worry about radiation that continued even after 10 years, though it slightly attenuated with time. Family problems stemming from the disaster retained their effects. While direct damage and evacuation experience were significantly associated with worry about radiation in the early phase, their effects diminished and became non-significant during the study period. Being under the age of 65, having low educational attainment, and being married were significantly associated with worry about radiation, although the association with age weakened over time. Individuals who experience intense fear or anxiety post-nuclear power plant accidents or disaster-related family problems may need continuous monitoring for their worry about radiation even 10 years after such accidents.

Physical Functional Impairment and the Risk of Incident Mild Cognitive Impairment in an Observational Study of World Trade Center Responders.

Background and Objectives: Posttraumatic stress disorder (PTSD) has been linked to increased risk of cognitive dysfunction and physical functional impairment (PFI). The objective of this prospective cohort study was to examine whether PFI was associated with increased risk of incident mild cognitive impairment (MCI) among World Trade Center (WTC) responders with PTSD. We hypothesized that responders with PTSD would have an elevated risk of incident MCI and that PFI would mediate this increase. Methods: We examined responder participants in the WTC Aging Study whose baseline physical assessments were completed by May 2016-April 2017 and were followed up at least once before December 2019. Those without complete demographic, medical, or behavioral data were excluded. PFI was assessed using measures of upper body strength (maximal handgrip strength [HGS]) and lower extremity physical functioning (Short Physical Performance Battery). PTSD was rated using a diagnostic interview and symptom checklist; MCI and dementia were assessed using the Montreal Cognitive Assessment and diagnosed using the National Institute on Aging-Alzheimer's Association criteria. Group differences and longitudinal comparisons were examined. Cox proportional hazards models were evaluated from time to incident MCI and conversion to dementia. A mediation analysis examined whether PFI mediated associations between PTSD and MCI. Results: Within the sample of 2,687 WTC responders, 324 (12.06%, 95% CI = [10.83-13.29]) had lower extremity PFI. Responders with lower extremity PFI were older, had lower education and higher body mass, and were at a higher risk of pulmonary embolisms and PTSD. Responders with lower extremity PFI demonstrated lower baseline cognition and had increased hazards of MCI (multivariable-adjusted hazards ratio [aHR] = 1.55 [95% CI 1.21-1.98]); those with MCI converted to dementia more rapidly than those without PFI (2.73 [1.38-5.39] p = 0.004). In addition, each standard deviation decrease in HGS was associated with increased hazards of developing MCI (aHR = 1.35 [95% CI 1.10-1.66]). A mediation model suggested PFI played an intermediary role in the relationship between PTSD and MCI. Discussion: WTC responders with PFI demonstrated worse cognitive and behavioral outcomes, and PFI played an intermediary role in the relationship between PTSD and incident MCI, suggesting that PFI may be an early indicator of MCI in responders with PTSD. Regular monitoring of PFI should be considered among PTSD populations.

The Role of Personality in the Mental and Physical Health of World Trade Center Responders: Self- versus Informant-Reports.

Personality is linked to important health outcomes, but most prior studies have relied on self-reports, making it possible that shared-method variance explains the associations. The present study examined self- versus informant-reports of personality and multi-method outcomes. World Trade Center (WTC) responders and informants, 283 pairs, completed five-factor model personality measures and multi-method assessments of stressful events, functioning, mental disorders, 9/11-related treatment costs, BMI, and daily activity across three years. Self-reports were uniquely related to stressful events and functioning. Both self-reports and informant-reports showed incremental validity over one another for mental disorder diagnoses and treatment costs. For objective outcomes daily activity and BMI, informant-reports showed incremental validity over self-reports, accounting for all self-report variance and more. The findings suggest that informant-reports of personality provide better validity for objective health outcomes, which has implications for understanding personality and its role in mental and physical health.

Assessment of Alzheimer's Disease Imaging Biomarkers in World Trade Center Responders with Cognitive Impairment at Midlife.

Purpose Incidence of early onset neurocognitive dysfunction has been reported in World Trade Center (WTC) responders. Ongoing studies are investigating the underlying etiology, as we are concerned that an underlying risk of neurodegenerative dementia may be occurring because of their stressful and neurotoxic exposures to particulate matter when they responded to the search and rescue efforts on September 11, 2001. The purpose of this study is to report preliminary results from two ongoing positron emission tomography (PET)/magnetic resonance imaging (MRI) imaging studies investigating the presence of Alzheimer's disease (AD) biomarkers, such as ß-amyloid, tau, and neurodegeneration, and compare our findings to published norms. Methods We present findings on 12 WTC responders diagnosed with either cognitive impairment (CI) or mild cognitive impairment (MCI), now at midlife, who underwent PET/MRI brain imaging as part of ongoing studies. Six responders with CI received [ 18 F] florbetaben (FBB) to detect ß-amyloidosis and six separate responders with MCI received [ 18 F] flortaucipir (FTP) to detect tauopathy. All 12 responders underwent concomitant MRI scans for gray matter volume analysis of neurodegeneration. Results PET analysis revealed 50% FBB and 50% of FTP scans were clinically read as positive and that 50% of FTP scans identified as consistent with Braak's stage I or II. Furthermore, one responder identified as centiloid positive for AD. Gray matter volumes from MRI analyses were compared with age/sex-matched norms (Neuroquant), identifying abnormally low cortical volumes in the occipital and temporal lobes, as well as the inferior temporal gyri and the entorhinal cortex. Conclusion These preliminary results suggest that WTC responders with neurocognitive dysfunction may be at increased risk for a neurodegenerative dementia process as a result of their exposures at September 11, 2001.

Pleasant and unpleasant odor identification ability is associated with distinct dimensions of negative symptoms transdiagnostically in psychotic disorders.

Negative symptoms are among the greatest sources of functional impairment for individuals with schizophrenia, yet their mechanisms remain poorly understood. Olfactory impairment is associated with negative symptoms. The processing of pleasant olfactory stimuli is subserved by reward-related neural circuitry while unpleasant olfactory processing is subserved by emotion-related neural circuitry, suggesting that these two odor dimensions may offer a window into differential mechanisms of negative symptoms. We examined whether pleasant and unpleasant odor identification bears differential relationships with avolition and inexpressivity dimensions of negative symptoms, whether these relationships are transdiagnostic, and whether pleasant and unpleasant odor processing also relate differently to other domains of functioning in a sample of individuals diagnosed with schizophrenia (N = 54), other psychotic disorders (N = 65), and never-psychotic adults (N = 160). Hierarchical regressions showed that pleasant odor identification was uniquely associated with avolition, while unpleasant odor identification was uniquely associated with inexpressivity. These relationships were largely transdiagnostic across groups. Additionally, pleasant and unpleasant odor identification displayed signs of specificity with other functional and cognitive measures. These results align with past work suggesting dissociable pathomechanisms of negative symptoms and provide a potential avenue for future work using valence-specific olfactory dysfunction as a semi-objective and low-cost marker for understanding and predicting the severity of specific negative symptom profiles.

The associations between traumatic experiences and subsequent onset of a substance use disorder: Findings from the World Health Organization World Mental Health surveys.

AIM: Exposure to traumatic events (TEs) is associated with substance use disorders (SUDs). However, most studies focus on a single TE, and are limited to single countries, rather than across countries with variation in economic, social and cultural characteristics. We used cross-national data to examine associations of diverse TEs with SUD onset, and variation in associations over time. METHODS: Data come from World Mental Health surveys across 22 countries. Adults (n = 65,165) retrospectively reported exposure to 29 TEs in six categories: "exposure to organised violence"; "participation in organised violence"; "interpersonal violence"; "sexual-relationship violence"; "other life-threatening events"; and those involving loved ones ("network traumas"). Discrete-time survival analyses were used to examine associations with subsequent first SUD onset. RESULTS: Most (71.0%) reported experiencing at least one TE, with network traumas (38.8%) most common and exposure to organised violence (9.5%) least. One in five (20.3%) had been exposed to sexual-relationship violence and 26.6% to interpersonal violence. Among the TE exposed, lifetime SUD prevalence was 14.5% compared to 5.1% with no trauma exposure. Most TE categories (except organised violence) were associated with increased odds of SUD. Increased odds of SUD were also found following interpersonal violence exposure across all age ranges (ORs from 1.56 to 1.78), and sexual-relationship violence exposure during adulthood (ORs from 1.33 to 1.44), with associations persisting even after >11 years. CONCLUSION: Sexual and interpersonal violence have the most consistent associations with progression to SUD; increased risk remains for many years post-exposure. These need to be considered when working with people exposed to such traumas.

DTI Connectometry Analysis Reveals White Matter Changes in Cognitively Impaired World Trade Center Responders at Midlife.

BACKGROUND: More than 8% of responders who participated in the search and rescue efforts at the World Trade Center (WTC) following 9/11 developed early-onset cognitive impairment (CI). Approximately 23% were also diagnosed with chronic post-traumatic stress disorder (PTSD). OBJECTIVE: To shed light on the pathophysiology of these WTC-related conditions, we examined diffusion connectometry to identify altered white matter tracts in WTC responders with CI and/or PTSD compared to unaffected responders. METHODS: 99 WTC responders (mean age 56 years) consisting of CI-/PTSD- (n = 27), CI+/PTSD- (n = 25), CI-/PTSD+ (n = 24), and CI+/PTSD+ (n = 23) were matched on age, sex, occupation, race, and education. Cognitive status was determined using the Montreal Cognitive Assessment and PTSD status was determined using the DSM-IV SCID. Diffusion tensor imaging was acquired on a 3T Siemens Biograph mMR scanner. Connectometry analysis was used to examine whole-brain tract-level differences in white matter integrity as reflected by fractional anisotropy (FA) values after adjusting for confounders. RESULTS: Analyses identified that FA was negatively correlated with CI and PTSD status in the fornix, cingulum, forceps minor of the corpus callosum and the right uncinate fasciculus. Furthermore, FA was negatively correlated with PTSD status, regardless of CI status in the superior thalamic radiation and the cerebellum. CONCLUSION: This is the first connectometry study to examine altered white matter tracts in a sample of WTC responders with CI and/or PTSD. Results from this study suggest that WTC responders with early-onset CI may be experiencing an early neurodegenerative process characterized by decreased FA in white matter tracts.

The Course of General Cognitive Ability in Individuals With Psychotic Disorders.

Importance: Schizophrenia is associated with major cognitive deficits and has been conceptualized as both a neurodevelopmental and a neurodegenerative disorder. However, when deficits develop and how they change over the course of illness is uncertain. Objective: To trace cognition from elementary school to old age to test neurodevelopmental and neurodegenerative theories of psychotic disorders. Design, Setting, and Participants: Data were taken from the Suffolk County Mental Health Project, a first-admission longitudinal cohort study of individuals with psychotic disorders. Participants were recruited from all 12 inpatient psychiatric facilities in Suffolk County, New York. This analysis concerns the 428 participants with at least 2 estimates of general cognitive ability. Data were collected between September 1989 and October 2019, and data were analyzed from January 2020 to October 2021. Exposures: Psychiatric hospitalization for psychosis. Main Outcomes and Measures: Preadmission cognitive scores were extracted from school and medical records. Postonset cognitive scores were based on neuropsychological testing at 6-month, 24-month, 20-year, and 25-year follow-ups. Results: Of the 428 included individuals (212 with schizophrenia and 216 with other psychotic disorders), 254 (59.6%) were male, and the mean (SD) age at psychosis onset was 27 (9) years. Three phases of cognitive change were observed: normative, declining, and deteriorating. In the first phase, cognition was stable. Fourteen years before psychosis onset, those with schizophrenia began to experience cognitive decline at a rate of 0.35 intelligence quotient (IQ) points per year (95% CI, 0.29-0.42; P < .001), a significantly faster decline than those with other psychotic disorders (0.15 IQ points per year; 95% CI, 0.08-0.22, P < .001). At 22 years after onset, both groups declined at a rate of 0.59 IQ points per year (95% CI, 0.25-0.94; P < .001). Conclusions and Relevance: In this cohort study, cognitive trajectories in schizophrenia were consistent with both a neurodevelopmental and neurodegenerative pattern, resulting in a loss of 16 IQ points over the period of observation. Cognitive decline began long prior to psychosis onset, suggesting the window for primary prevention is earlier than previously thought. A window for secondary prevention emerges in the third decade of illness, when cognitive declines accelerate in individuals with schizophrenia and other psychotic disorders.

Rare coding variants in ten genes confer substantial risk for schizophrenia.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.