William P. Milberg

Background: Identifying biomarkers of Alzheimer's disease (AD) is critical for early diagnosis and AD risk assessment. Objective: We examined the hypothesis that the plasma amyloid-β 42 and 40 (Aβ _42:40 ) ratio has a curvilinear relationship with age among individuals who are at higher genetic risk for AD. Methods: This study investigated the relationship between plasma amyloid-β 42 and 40 (Aβ _42:40 ) ratio and age in 315 men and women Veterans, including those at genetic risk for AD. Hierarchical regression models investigated linear and nonlinear relationships between age, genetic risk, and Aβ _42:40 . Results: We observed a curvilinear relationship between age and Aβ _42:40 in individuals with higher genetic risk, characterized by an increase in the Aβ _42:40 during midlife followed by a decrease in older age. Conclusions: These findings highlight distinct patterns in Aβ metabolism among genetically predisposed individuals, suggesting that early metabolic shifts may play a role in the progression of AD. Understanding these nuanced changes is essential for refining the use of Aβ _42:40 ratio as a biomarker, potentially leading to more accurate risk stratification and earlier intervention strategies in AD.

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is common among Veterans but overlapping symptoms with other prevalent psychiatric disorders (e.g., posttraumatic stress disorder [PTSD]) complicate diagnosis. This study aims to (1) assess the prevalence of ADHD, (2) evaluate the correspondence between ADHD self-report measures, and (3) examine the association between ADHD and PTSD in a sample of combat-deployed post-9/11 Veterans. Materials and Methods: A total of 332 combat-deployed post-9/11 Veterans from VA Boston Healthcare System completed the Clinician-Administered PTSD Rating Scale, 2 ADHD self-report questionnaires (Wender Utah Rating Scale–25 and the Adult ADHD Self-Report Scale v1.1), and report of the presence/absence of a historical ADHD diagnosis. Attention-deficit/hyperactivity disorder status via Wender Utah Rating Scale ([WURS-25] criterion standard) was compared to historical ADHD diagnosis and the ASRSv.1.1 screener. Log-binomial regression models assessed the relationship between ADHD and PTSD. This study was reviewed and approved by the VA Boston Institutional Review Board. Results: In all, 12.7% of the sample met criteria for ADHD per the WURS-25. The WURS-25 demonstrated poor sensitivity with historical ADHD diagnosis (27.7%) but adequate specificity (90.3%). Poor sensitivity (60.7%) and specificity (60.8%) were observed between the WURS-25 and the ASRS-v.1.1. The prevalence of ADHD was 2.5 times as high for Veterans with a history of PTSD (Prevalence Ratio [PR] = 2.53, 95% CI: 1.11, 7.28) and over twice as high for those with current PTSD (PR = 2.19, 95% CI: 1.17, 4.38). Conclusions: Attention-deficit/hyperactivity disorder is prevalent in this sample of Veterans and is associated with an increased risk of current and lifetime PTSD. The low correspondence across self-report ADHD measures illustrates the complexity of assessing ADHD in this highly comorbid population. When evaluating ADHD in Veterans, clinicians should carefully consider alternative and contributory symptom etiologies, such as PTSD, to ensure accurate diagnosis and treatment.

Metacognition is disrupted in several clinical populations. One aspect of metacognition, global metacognitive bias (difference between objective and self-reported abilities), has shown to be particularly relevant to clinical functioning. However, previous studies of global metacognitive biases in populations with elevated depressive/posttraumatic stress disorder (PTSD) symptoms have not measured objective and self-reported abilities relative to normative samples, limiting the quantification of biases. Additionally, few studies have examined whether cognitive interventions can improve metacognitive biases or how this relates to depressive/PTSD symptom severity. A total of 84 participants with mild traumatic brain injury (77% veterans) performed PTSD and depression assessments along with self-reported and objective measures of global cognition. Age-adjusted norm-based z scores were used for self-reported and objective cognition, and bias was calculated by subtracting objective minus self-report scores. Participants then received 13 weeks of targeted cognitive training or entertainment games training (both providing performance feedback). Participants were assessed at baseline, immediately posttraining, and 3 months posttraining. We found large negative metacognitive biases in those with clinically significant severity of depressive symptoms (z score difference = -1.77), PTSD symptoms (-1.47), and depressive + PTSD symptoms (-2.29). Metacognitive biases improved after both targeted and entertainment training and was associated with reductions in depressive/PTSD symptom severity (r = -.41/-.42, respectively), led by the entertainment training group (r = -.54/-.46, respectively). These findings show that clinically significant severity of depressive/PTSD symptoms is associated with substantial negative global metacognitive biases and preliminarily suggests that cognitive training may improve these biases and depressive/PTSD symptom severity. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Posttraumatic stress disorder (PTSD) is associated with significant disability and can become chronic. Predictors of PTSD symptom changes over time, especially in those with a PTSD diagnosis, remain incompletely characterized. In the present study, we examined 187 post-9/11 veterans (M_age = 32.8 years, 87% male) diagnosed with PTSD who performed two extensive clinical and cognitive evaluations approximately 2 years apart. We found that greater PTSD symptom reductions over time were related to lower lifetime drinking history and better baseline inhibitory control ability (Color-Word Inhibition and Inhibition/Switching), though not performance on other executive function tasks. Further, groups with reliably Improved, Worsened, or Chronic PTSD symptoms demonstrated significant differences in baseline inhibitory control and lifetime drinking history, with marked drinking differences starting in the early-to-mid 20s. We also found that PTSD symptom changes showed little-to-no associations with changes in inhibitory control or alcohol consumption. Together, these findings suggest that, in those diagnosed with PTSD, inhibitory control and alcohol use history reflect relatively stable risk/resiliency factors predictive of PTSD chronicity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Are semantic impairments in Alzheimer's disease (AD) partially due to deficits in spatial attention?In a target detection task, both older adults (OAs) and AD individuals were facilitated by valid ...

Metacognitive awareness, insight into one’s abilities, is thought to be disrupted in depression and posttraumatic stress disorder (PTSD), with more negative metacognitive biases and reduced awareness, respectively. However, studies have rarely examined global aspects of metacognitive awareness in depression and PTSD, instead using task-specific measures. In 467 trauma-exposed post-9/11 veterans, we administered assessments of PTSD and depression, self-report and objective measures of cognitive functioning (neuropsychological battery of memory, attention, and executive function measures), and self-report and objective measures of general health (index of five cardiometabolic factors). We used self-report/objective correlations to measure metacognitive sensitivity and 'self-report minus objective' scores to measure bias. We also examined associations between changes in metacognitive awareness and changes in PTSD and depression over time. Metacognitive sensitivity was comparable between individuals with and without PTSD and depression. However, metacognitive bias was significantly more negative in those with greater depressive symptoms (i.e., underconfidence) across cognition and health, independent of PTSD symptoms. Notably, metacognitive bias changes covaried with depressive and PTSD symptom changes two years later. This shows that, in trauma-exposed veterans, negative metacognitive biases are specifically related to depressive symptoms and these biases may be relatively domain general. Further, our longitudinal results suggest that, rather than being a stable trait, metacognitive biases change with PTSD/depressive symptoms over time.

Post-9/11 Veterans endorse greater self-reported functional disability than 80% of the adult population. Previous studies of trauma-exposed populations have shown that increased post-traumatic stress disorder (PTSD) and depressive symptoms are consistently associated with greater disability. Additionally, poorer cognitive performance in the domain of executive functions, particularly inhibitory control, has been associated with disability, though it is unclear if this effect is independent of and/or interacts with PTSD and depression. Three overlapping samples of n = 582, 297, and 183 combat-deployed post-9/11 Veterans completed comprehensive assessments of executive functions, PTSD and depressive symptoms, and self-reported World Health Organization Disability Assessment Schedule-II (WHODAS II). Poorer performance on measures of inhibitory control (Delis-Kaplan Executive Functioning System Color-Word Interference-CWI Test and gradual-onset Continuous Performance Test-gradCPT), but not other executive functions, were significantly associated with greater disability on the WHODAS II (ρ’s = −.13 and −.13, p = .002 and .026, respectively). CWI inhibitory control measures accounted for unique variance in disability after controlling for PTSD and depressive symptoms (R² change = 0.02, p < .001). Further, CWI significantly moderated the effect of depressive symptoms on disability, such that better inhibitory control weakened the relationship between depression and disability. Inhibitory control deficits are uniquely associated with increased disability in combat-deployed post-9/11 Veterans, and better inhibitory control abilities may serve as a protective factor for depressive symptoms leading to increased disability. In a trauma-exposed Veteran population, does inhibitory control predict functional disability above and beyond PTSD and depressive symptoms? After controlling for PTSD and depressive symptoms, inhibitory control explained unique variance in self-reported disability. Inhibitory control also showed a moderation effect on depression where greater inhibitory control on the color-word interference test reduced the association between depression and disability symptoms. Inhibitory control represents an important mechanism in understanding and improving daily life functioning in trauma-exposed Veteran populations. Future research should further characterize the different aspects of inhibitory control deficits in trauma-exposed populations and focus on enhancing inhibitory control paired with more standard psychological distress treatments.

Objective: The aim of the study is to identify potential rehabilitative treatment targets associated with participants’ annual cognitive status. Design: A cohort study patients with self-reported mobility limitation who completed neuropsychological, physical performance testing, and questionnaires at baseline to 2-year follow-up were categorized into three groups (persistently cognitively normal, nonpersistent mild neurocognitive disorder, and persistently mild neurocognitive disorder) based on their annual cognitive status using baseline, years 1 and 2 performance on Hopkins Verbal Learning, Trail Making, and Digit Symbol Substitution Tests. Repeated measures multinomial regression analysis was used to examine the differences between groups and associated characteristics. Results: Study included 349 participants (mean age, 76 ± 7) with 57% of participants were persistently cognitively normal, 16% persistently mild neurocognitive disorder, and 27% nonpersistent mild neurocognitive disorder over 2 yrs of follow-up. Faster gait speed (relative risk reduction, 0.64–0.89) was associated with risk reduction and increase in depressive symptoms (relative risk reduction, 1.09–1.12) was associated with greater risk of being classified into the nonpersistent or persistently mild neurocognitive disorder compared with persistently cognitively normal. Conclusions: Variability across cognitive status over time was observed. Gait speed and depressive symptoms were modifiable risk factors associated with nonpersistent and persistent mild neurocognitive disorder status. This study reinforces the potential benefit of multifaceted rehabilitation for preventing and treating older adults with mobility and/or cognitive problems.

Cross-sectional work suggests that deployment-related posttraumatic sequelae are associated with increased disability in U.S. veterans deployed following the September 11, 2001 (9/11), terrorist attacks. However, few studies have examined the psychiatric and somatic variables associated with changes in functional disability over time. A total of 237 post-9/11 veterans completed comprehensive assessments of psychiatric and cognitive functioning, as well as a disability questionnaire, at baseline and 2-year follow-up. At baseline, higher levels of PTSD, depressive, and pain-related symptoms were associated with baseline global functional disability, semipartial r² (sr²) = .036–.044. Changes in symptoms of PTSD, depression, pain, and sleep, but not anxiety or alcohol use, were independently associated with changes in functional disability sr² = .017–.068. Baseline symptoms of these conditions were unrelated to changes in disability, and cognitive performance was unrelated to disability at any assessment point. Together, this suggests that changes in psychiatric and somatic symptoms are tightly linked with changes in functional disability and should be frequently monitored, and even subclinical symptoms may be a target of intervention.

Chronic elevation of systemic inflammation is observed in a wide range of disorders including PTSD, depression, and traumatic brain injury. Although previous work has demonstrated a link between inflammation and various diagnoses separately, few studies have examined transdiagnostic symptoms and inflammation within the same model. The objective of this study was to examine relationships between psychiatric and health variables and systemic inflammation and to determine whether mild traumatic brain injury (mTBI) and/or exposure to blast munitions moderate these relationships. Confirmatory factor analysis in a large sample (N = 357) of post-9/11 Veterans demonstrated a good fit to a four-factor model reflecting traumatic stress, affective, somatic, and metabolic latent variables. Hierarchical regression models revealed that each of the latent variables were associated with higher levels of systemic inflammation. However, the strongest relationship with inflammation emerged among those who had both war-zone blast exposures and metabolic dysregulation, even after adjusting for mental health latent variables. Exploratory analyses showed that blast exposure was associated with metabolic dysregulation in a dose-response manner, with self-reported closer blast proximity associated with the greatest metabolic dysregulation. Together, these results provide a greater understanding of the types of symptoms most strongly associated with inflammation and underscore the importance of maintaining a healthy lifestyle to reduce the impact of obesity and other metabolic symptoms on future chronic disease in younger to middle-aged Veterans.