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.

Caregiving for Foreign-Born Older Adults With Dementia.

OBJECTIVES: This study examines how nativity, dementia classification, and age of migration (AOM) of older foreign-born (FB) adults are associated with caregiver psychological well-being and care burden. METHODS: We used linked data from Round 1 and Round 5 of the National Health and Aging Trends Study and Round 5 of the National Study of Caregiving for a sample of nondementia caregivers (n = 941), dementia caregivers (n = 533), and matched care recipients. Ordinary least squares regression models were estimated, adjusting for caregiver characteristics. RESULTS: Relative to nondementia caregivers, dementia caregivers were more likely to provide care for an older FB adult (8.69% vs. 26.70%), reported more assistance with caregiving activities, worse quality of relationship with care recipients, and higher care burden than nondementia caregivers. In adjusted models, interactions of nativity status × dementia and AOM × dementia revealed that overall, caregivers of older FB adults with dementia who migrated in late life (50+) reported lower psychological well-being than those caring for older FB older adults who migrated at (20-49 years) and (0-19 years). Moderating effects of AOM on the link between dementia caregiving and care burden were not observed. DISCUSSION: Age of migration of older FB adults with probable dementia may have unique effects on the caregiver's psychological well-being. Our results underscore the importance of considering sociocultural factors of FB adults beyond nativity and the need for research to develop culturally appropriate interventions to enhance psychological well-being and reduce the care burden among dementia caregivers.

Addressing the disparities in dementia risk, early detection and care in Latino populations: Highlights from the second Latinos & Alzheimer's Symposium.

The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD.

Cognitive impairment and World Trade Centre-related exposures.

On 11 September 2001 the World Trade Center (WTC) in New York was attacked by terrorists, causing the collapse of multiple buildings including the iconic 110-story 'Twin Towers'. Thousands of people died that day from the collapse of the buildings, fires, falling from the buildings, falling debris, or other related accidents. Survivors of the attacks, those who worked in search and rescue during and after the buildings collapsed, and those working in recovery and clean-up operations were exposed to severe psychological stressors. Concurrently, these 'WTC-affected' individuals breathed and ingested a mixture of organic and particulate neurotoxins and pro-inflammogens generated as a result of the attack and building collapse. Twenty years later, researchers have documented neurocognitive and motor dysfunctions that resemble the typical features of neurodegenerative disease in some WTC responders at midlife. Cortical atrophy, which usually manifests later in life, has also been observed in this population. Evidence indicates that neurocognitive symptoms and corresponding brain atrophy are associated with both physical exposures at the WTC and chronic post-traumatic stress disorder, including regularly re-experiencing traumatic memories of the events while awake or during sleep. Despite these findings, little is understood about the long-term effects of these physical and mental exposures on the brain health of WTC-affected individuals, and the potential for neurocognitive disorders. Here, we review the existing evidence concerning neurological outcomes in WTC-affected individuals, with the aim of contextualizing this research for policymakers, researchers and clinicians and educating WTC-affected individuals and their friends and families. We conclude by providing a rationale and recommendations for monitoring the neurological health of WTC-affected individuals.

Effect of citalopram on hippocampal volume in first-episode schizophrenia: Structural MRI results from the DECIFER trial.

Hippocampal volume loss is prominent in first episode schizophrenia (FES) and has been associated with poor clinical outcomes and with BDNF genotype; antidepressants are believed to reverse hippocampal volume loss via release of BDNF. In a 12-month, placebo-controlled add-on trial of the antidepressant, citalopram, during the maintenance phase of FES, negative symptoms were improved with citalopram. We now report results of structural brain imaging at baseline and 6 months in 63 FES patients (34 in citalopram group) from the trial to assess whether protection against hippocampal volume loss contributed to improved negative symptoms with citalopram. Hippocampal volumetric integrity (HVI) did not change significantly in the citalopram or placebo group and did not differ between treatment groups, whereas citalopram was associated with greater volume loss of the right CA1 subfield. Change in cortical thickness was associated with SANS change in 4 regions (left rostral anterior cingulate, right frontal pole, right cuneus, and right transverse temporal) but none differed between treatment groups. Our findings suggest that minimal hippocampal volume loss occurs after stabilization on antipsychotic treatment and that citalopram's potential benefit for negative symptoms is unlikely to result from protection against hippocampal volume loss or cortical thinning.

Association of Aripiprazole With Reduced Hippocampal Atrophy During Maintenance Treatment of First-Episode Schizophrenia.

PURPOSE/BACKGROUND: Hippocampal volume loss in early schizophrenia has been linked with markers of inflammation and oxidative stress, and with less response of negative symptoms. Aripiprazole has been reported to preserve hippocampal volume and to reduce inflammation. METHODS/PROCEDURES: Study 1 was a 12-month multicenter randomized placebo-controlled trial of citalopram added to clinician-determined second-generation antipsychotic medication in 95 patients with first-episode schizophrenia (FES), 19 of whom received aripiprazole. We compared participants taking aripiprazole with those on other antipsychotics to determine whether those on aripiprazole had less hippocampal volume loss. We also examined peripheral biomarker data from medication-naive patients with schizophrenia receiving 8 weeks of antipsychotic treatment (n = 24) to see whether markers of inflammation and oxidative stress that previously predicted hippocampal volume differed between aripiprazole (n = 9) and other antipsychotics (study 2). FINDINGS/RESULTS: Aripiprazole was associated with a mean increase in hippocampal volume of 0.35% (SD, 0.80%) compared with a 0.53% decrease (SD, 1.2%) with other antipsychotics during the first year of maintenance treatment in patients with FES. This difference was significant after adjusting for age, sex, citalopram treatment, and baseline Brief Psychiatric Rating Scale score (B = 0.0079, P = 0.03). Aripiprazole was also associated with reduced concentrations of the inflammatory cytokines interleukin-8 and tumor necrosis factor (P < 0.01) during the first 8 weeks of treatment in medication-naive patients with FES. IMPLICATIONS/CONCLUSIONS: These results suggest that aripiprazole may protect against hippocampal atrophy via an anti-inflammatory mechanism, but these results require replication in larger, randomized trials, and the clinical relevance of hippocampal volume loss is not established.

A Workshop on Cognitive Aging and Impairment in the 9/11-Exposed Population.

The terrorist attacks on 11 September 2001 potentially exposed more than 400,000 responders, workers, and residents to psychological and physical stressors, and numerous hazardous pollutants. In 2011, the World Trade Center Health Program (WTCHP) was mandated to monitor and treat persons with 9/11-related adverse health conditions and conduct research on physical and mental health conditions related to the attacks. Emerging evidence suggests that persons exposed to 9/11 may be at increased risk of developing mild cognitive impairment. To investigate further, the WTCHP convened a scientific workshop that examined the natural history of cognitive aging and impairment, biomarkers in the pathway of neurodegenerative diseases, the neuropathological changes associated with hazardous exposures, and the evidence of cognitive decline and impairment in the 9/11-exposed population. Invited participants included scientists actively involved in health-effects research of 9/11-exposed persons and other at-risk populations. Attendees shared relevant research results from their respective programs and discussed several options for enhancements to research and surveillance activities, including the development of a multi-institutional collaborative research network. The goal of this report is to outline the meeting's agenda and provide an overview of the presentation materials and group discussion.

Chronic Posttraumatic Stress Disorder and Comorbid Cognitive and Physical Impairments in World Trade Center Responders.

Posttraumatic stress disorder (PTSD) has been linked to increased prevalence and incidence of cognitive and physical impairment. When comorbid, these conditions may be associated with poor long-term outcomes. We examined associations between chronic PTSD and symptom domains with cognitive and physical functioning in World Trade Center (WTC) responders nearly 20 years after the September 11, 2001, terrorist attacks. Participants included a cross-sectional sample of 4,815 responders who attended a monitoring program in 2015-2018. Montreal Cognitive Assessment scores less than 23 indicated cognitive impairment (CogI); Short Physical Performance Battery scores 9 or lower on a hand-grip test indicated physical impairment (PhysI). Comorbid cognitive/physical impairment (Cog/PhysI) was defined as having cognitive impairment with at least one objective PhysI indicator. Clinical chart review provided PTSD diagnoses; symptom domains were assessed using the PTSD Checklist. Participants were on average 53.05 years (SD = 8.01); 13.44% had PTSD, 7.8% had CogI, 24.8% had PhysI, and 5.92% had comorbid Cog/PhysI. Multivariable-adjusted multinomial logistic regression demonstrated that Responders with PTSD have more than three times the risk of Cog/PhysI (adjusted RR = 3.29, 95% CI 2.44- 4.44). Domain-specific analyses revealed that emotional numbing symptoms predicted an increased risk of PhysI (adjusted RR = 1.57, 95% CI 1.08-2.28), whereas reexperiencing symptoms were associated with comorbid Cog/PhysI (adjusted RR = 3.96, 95% CI, 2.33-6.74). These results suggest that responders with chronic PTSD may have increased risk of deficits beyond age-expected impairment characterized by the emergence of comorbid Cog/PhysI at midlife.

Age of Migration and Cognitive Function Among Older Latinos in the United States.

BACKGROUND: Age of migration has been shown to have a robust association with Latino immigrant health outcomes; however, the relationship between timing of migration and cognition is less understood. OBJECTIVE: To examine associations between race/ethnicity, nativity, age of migration, and cognitive aging among US-born (USB) non-Latino Whites (NLW) and USB and foreign-born Latinos 50 years and older. METHODS: We used longitudinal biennial data from the Health and Retirement Study (HRS; 2006-2014) to fit generalized linear and linear latent growth curve models for: 1) global cognition (Modified Telephone Interview for Cognitive Status; TICS-M); 2) memory and attention subdomains of TICS-M; and 3) cognitive dysfunction. We also tested for sex modifications. RESULTS: In age and sex adjusted models, all Latino subgroups, independent of nativity and age of migration, had lower global and domain-specific cognitive scores and higher propensity of cognitive impairment classification compared to USB-NLWs. Differences between USB Latinos, but not other Latino subgroups, and USB-NLWs remained after full covariate adjustment. Latinas, independent of nativity or age of migration, had poorer cognitive scores relative to NLW females. Differences between all Latinos and USB-NLWs were principally expressed at baseline. Racial/ethnic, nativity, and age of migration grouping was not associated with slope (nor explained variance) of cognitive decline. CONCLUSION: Older US-born Latinos, regardless of sex exhibit poorer cognitive function than older USB-NLWs and foreign-born Latinos. Social determinants that differentially affect cognitive function, particularly those that compensate for education and sex differences among US-born Latinos and foreign-born Latinos, require further exploration.

D-cycloserine augmentation of cognitive behavioral therapy for delusions: A randomized clinical trial.

OBJECTIVE: D-cycloserine (DCS) promotes consolidation of extinction learning. This study extends earlier work by examining whether DCS can enhance cognitive behavioral therapy (CBT) for delusions. METHODS: Adults reporting moderate or greater delusions were randomly assigned to receive 50 mg of DCS or placebo prior to 10 weekly CBT sessions. The primary outcome was change in severity of delusions measured with the Psychotic Symptom Rating Scale delusion subscale (PSYRATS-D). Secondary outcomes included persistence of response at 3 and 6 month follow-up and the effects of DCS on memory consolidation and cognitive flexibility. Fifty-eight participants were randomized and 44 completed the trial. RESULTS: The DCS and placebo groups did not differ in change from baseline to end of CBT on PSYRATS-D, nor did DCS improve memory consolidation or cognitive flexibility compared to placebo. However, at the 3 month follow-up visit (week 24), 47% of participants who completed treatment with DCS reported a 20% or greater decrease on PSYRATS-D compared to 15% in the placebo group (p = .04). Change in distress across CBT sessions interacted with treatment group to predict change from baseline to week 24 in PSYRATS-D total score (p = .03) such that response at week 24 was greatest in DCS-treated participants who experienced a decrease in distress during CBT sessions. CONCLUSIONS: DCS augmentation of CBT did not improve delusions compared to placebo during treatment; however, DCS was associated with a higher response rate at 3-month follow-up. DCS may produce a delayed therapeutic effect, associated with successful CBT sessions, but this finding requires replication.

Pathway Analysis for Plasma ß-Amyloid, Tau and Neurofilament Light (ATN) in World Trade Center Responders at Midlife.

INTRODUCTION: World Trade Center (WTC) responders who aided in the search and rescue efforts are now at midlife, and evidence has demonstrated that many are experiencing early-onset cognitive impairment and are at risk of developing dementia, such as Alzheimer's disease (AD). According to the recent NIA-AA framework, AD is characterized by a neuropathological cascade commencing with ß-amyloid deposition (A), followed by tauopathy (T) and neurodegeneration (N). However, the ATN model has not been replicated utilizing recently validated plasma-based biomarkers, and the role of the Aß40 subtype in A is not well understood. This study examined plasma-based neuropathological markers of Aß42 and Aß40 for A, total tau for T, and NfL for N in a cohort of World Trade Center responders at midlife in order to determine the role for the two ß-amyloid subtypes in the ATN model. METHODS: Ultrasensitive Simoa technology was utilized to measure neuropathology in plasma collected from a consecutive clinical sample (n =398). Generalized structural equation modeling was utilized for modeling linkages between pathological markers. Model fit was utilized to determine proposed directions of association. RESULTS: Our findings support the ATN neuropathological cascade model of AD and further identify an associative role for Aß40 in A as playing a central role linking T to N. A strong correlation was found between CI and age, and it was found that women may be at increased risk of elevated T levels, with plasma NfL levels higher in responders with CI. Notably, our model reported associations between: Aß42, CI and N; Aß40, T and N; T and CI; Aß42 and Aß40. CONCLUSIONS: The current ATN model of AD does not specify the subtype of ß-amyloid to be considered, which may be overlooking the differential roles that these two subtypes serve in the pathogenesis of AD.

Glycosylated hemoglobin level, race/ethnicity, and cognition in midlife and early old age.

Empirical evidence linking racial/ethnic differences in glycosylated hemoglobin levels (HbA1c) to cognitive function in midlife and early old age is limited. We use biomarker data from the Health and Retirement Study (HRS, 2006-2014), on adults 50-64 years at baseline (57-73 years by 2014), and fit multinomial logistic regression models to assess the association between baseline HbA1c, cognitive function (using Langa-Weir classifications) and mortality across 8-years. Additionally, we test for modification effects by race/ethnicity. In age- and sex-adjusted models high HbA1c level was associated with lower baseline cognition and higher relative risk ratios (RRR; vs. normal cognition) for cognitive impairment no dementia (CIND; RRR= 2.3; 95%CI=[1.38;3.84]; p<0.01), and dementia (RRR= 4.00; 95%CI=[1.76;9.10]; p<0.01). Adjusting for sociodemographic, behavioral risk factors, and other health conditions explained the higher RRR for CIND and attenuated the RRR for dementia by approximately 30%. HbA1c levels were not linked to the slope of cognitive decline, and we found no evidence of modification effects for HbA1c by race/ethnicity. Targeting interventions for glycemic control in the critical midlife period can protect baseline cognition and buffer against downstream development of cognitive impairment. This can yield important public health benefits and reductions in burdens associated with cognitive impairment, particularly among race/ethnic minorities who are at higher risk for metabolic diseases.

Incidence of mild cognitive impairment in World Trade Center responders: Long-term consequences of re-experiencing the events on 9/11/2001.

OBJECTIVE: This study examined whether World Trade Center (WTC) exposures and chronic posttraumatic stress disorder (PTSD) were associated with incidence of mild cognitive impairment (MCI) in a longitudinal analysis of a prospective cohort study of WTC responders. METHODS: Incidence of MCI was assessed in a clinical sample of WTC responders (N = 1800) who were cognitively intact at baseline assessment. Crude incidence rates were calculated and compared to population estimates using standardized incidence ratios. Multivariable analyses used Cox proportional-hazards regression. RESULTS: Responders were 53.1 years old (SD = 7.9) at baseline. Among eligible cognitively intact responders, 255 (14.2%) developed MCI at follow-up. Incidence of MCI was higher than expected based on expectations from prior published research. Incidence was higher among those with increased PTSD symptom severity, and prolonged exposure was a risk factor in apolipoprotein-ε4 carriers. CONCLUSIONS: PTSD and prolonged WTC exposures were associated with increased incidence of MCI in WTC responders, results that may portend future high rates of dementia in WTC-exposed responders.

Association of Hippocampal Atrophy With Duration of Untreated Psychosis and Molecular Biomarkers During Initial Antipsychotic Treatment of First-Episode Psychosis.

Importance: Duration of untreated psychosis (DUP) has been associated with poor outcomes in schizophrenia, but the mechanism responsible for this association is not known. Objectives: To determine whether hippocampal volume loss occurs during the initial 8 weeks of antipsychotic treatment and whether it is associated with DUP, and to examine molecular biomarkers in association with hippocampal volume loss and DUP. Design, Setting, and Participants: A naturalistic longitudinal study with matched healthy controls was conducted at Shanghai Mental Health Center. Between March 5, 2013, and October 8, 2014, 71 medication-naive individuals with nonaffective first-episode psychosis (FEP) and 73 age- and sex-matched healthy controls were recruited. After approximately 8 weeks, 31 participants with FEP and 32 controls were reassessed. Exposures: The participants with FEP were treated according to standard clinical practice with second-generation antipsychotics. Main Outcomes and Measures: Hippocampal volumetric integrity (HVI) (an automated estimate of the parenchymal fraction in a standardized hippocampal volume of interest), DUP, 13 peripheral molecular biomarkers, and 14 single-nucleotide polymorphisms from 12 candidate genes were determined. Results: The full sample consisted of 71 individuals with FEP (39 women and 32 men; mean [SD] age, 25.2 [7.7] years) and 73 healthy controls (40 women and 33 men; mean [SD] age, 23.9 [6.4] years). Baseline median left HVI was lower in the FEP group (n = 57) compared with the controls (n = 54) (0.9275 vs 0.9512; difference in point estimate, -0.020 [95% CI, -0.029 to -0.010]; P = .001). During approximately 8 weeks of antipsychotic treatment, left HVI decreased in 24 participants with FEP at a median annualized rate of -.03791 (-4.1% annualized change from baseline) compared with an increase of 0.00115 (0.13% annualized change from baseline) in 31 controls (difference in point estimate, -0.0424 [95% CI, -0.0707 to -0.0164]; P = .001). The change in left HVI was inversely associated with DUP (r = -0.61; P = .002). Similar results were found for right HVI, although the association between change in right HVI and DUP did not achieve statistical significance (r = -0.35; P = .10). Exploratory analyses restricted to the left HVI revealed an association between left HVI and markers of inflammation, oxidative stress, brain-derived neurotrophic factor, glial injury, and markers reflecting dopaminergic and glutamatergic transmission. Conclusions and Relevance: An association between longer DUP and accelerated hippocampal atrophy during initial treatment suggests that psychosis may have persistent, possibly deleterious, effects on brain structure. Additional studies are needed to replicate these exploratory findings of molecular mechanisms by which untreated psychosis may affect hippocampal volume and to determine whether these effects account for the known association between longer DUP and poor outcome.

Faces, feelings, words: divergence across channels of emotional responding in complicated grief.

Recent evidence suggests that the inability to respond in a context appropriate manner earlier in bereavement is predictive of a protracted grief course with poorer adjustment following the loss (Coifman & Bonanno, 2010). However, little is known about the emotional behavior of adults later in bereavement and whether emotional responding becomes dsyregulated across other channels. An impressive body of evidence in the schizophrenia literature demonstrates a marked disconnection between observable displays of emotion and experienced affect within individuals diagnosed with schizophrenia (e.g., Kring & Moran, 2008). On the basis of this influential work, we examined the emotional responses of a sample of bereaved adults who lost a spouse 1.5-3 years previously. One bereaved group had complicated grief (CG) and the other was relatively asymptomatic. We used an idiographic task where participants discussed their relationships with their spouse and current attachment figure in contexts of conflict and intimacy. We measured emotional responses across 3 channels: self-reported affect, facial expressions, and emotional word use. Individuals within the CG group were less facially expressive across contexts than the asymptomatic group but in some contexts reported experiencing greater affect and used more negative emotion words. These findings suggest that complicated grief in later bereavement is characterized by a disassociation between emotional responding across channels, with context insensitive responding, restricted to facial displays of emotion.

Annual Research Review: Positive adjustment to adversity--trajectories of minimal-impact resilience and emergent resilience.

BACKGROUND: Research on resilience in the aftermath of potentially traumatic life events (PTE) is still evolving. For decades, researchers have documented resilience in children exposed to corrosive early environments, such as poverty or chronic maltreatment. Relatively more recently, the study of resilience has migrated to the investigation of isolated PTE in adults. METHODS: In this article, we first consider some of the key differences in the conceptualization of resilience following chronic adversity versus resilience following single-incident traumas, and then describe some of the misunderstandings that have developed about these constructs. To organize our discussion, we introduce the terms emergent resilience and minimal-impact resilience to represent trajectories of positive adjustment in these two domains, respectively. RESULTS: We focused in particular on minimal-impact resilience, and reviewed recent advances in statistical modeling of latent trajectories that have informed the most recent research on minimal-impact resilience in both children and adults and the variables that predict it, including demographic variables, exposure, past and current stressors, resources, personality, positive emotion, coping and appraisal, and flexibility in coping and emotion regulation. CONCLUSIONS: The research on minimal-impact resilience is nascent. Further research is warranted with implications for a multiple levels of analysis approach to elucidate the processes that may mitigate or modify the impact of a PTE at different developmental stages.