IntroductionThis study examined whether World Trade Center (WTC)-related exposures and posttraumatic stress disorder (PTSD) were associated with cognitive function and whether WTC responders' cognition differed from normative data.MethodsA computer-assisted neuropsychological battery was administered to a prospective cohort study of 1193 WTC responders with no history of stroke or WTC-related head injuries. Data were linked to information collected prospectively since 2002. Sample averages were compared to published norms.ResultsApproximately 14.8% of sampled responders had cognitive dysfunction. WTC responders had worse cognitive function compared to normative data. PTSD symptom severity and working >5 weeks on-site was associated with lower cognition.DiscussionResults from this sample highlight the potential for WTC responders to be experiencing an increased burden of cognitive dysfunction and linked lowered cognitive functioning to physical exposures and to PTSD. Future research is warranted to understand the extent to which cognitive dysfunction is evident in neural dysfunction.

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.

Introduction Chronic posttraumatic stress disorder (PTSD) is associated with poor memory and increased burden of various degenerative cerebral neuropathologies. The goal of this pilot study was to determine whether PTSD was associated with changes in plasma-based neuropathological biomarkers of neurodegeneration among World Trade Center (WTC) responders. Methods Thirty-four WTC responders had blood drawn and flash-frozen within 15 minutes of retrieval. PTSD symptoms were assessed at that time. Age, sex, and WTC exposure duration were obtained from medical records. Plasma was assayed in duplicate using an ultra-sensitive single-molecule enzyme-linked immunosorbent assay to examine the distribution of amyloid-β (Aβ) 42/40 ratios, total Aβ, total tau, and neurofilament light (NfL). The comparison group was drawn from a bank of healthy controls collected and assayed at the same facility. Results The average age of WTC responders at blood draw was 53 years. Half were PTSD positive (PTSD+) as indicated by symptom severity. WTC responders had lower Aβ42/Aβ40 ratios but higher total tau and NfL levels in the plasma than healthy controls. PTSD+ status was associated with lower plasma Aβ load and higher Aβ42/Aβ40 ratios. Discussion Findings suggest that PTSD may be associated with alterations in plasma markers related to Aβ, tau, and NfL, highlighting the potential association between PTSD status and neurodegenerative neuropathology in WTC responders.

Background Recent reports suggest that World Trade Center (WTC) responders are at increased risk for cognitive impairment (CI). The current study utilized neuroimaging to determine whether WTC responders with CI have reduced cortical thickness (CTX). Method WTC responders (N=99) with and without CI, recruited from an epidemiologic study of cognitive aging among WTC responders, participated in a neuroimaging study that included a T1‐MPRAGE protocol. CTX was computed in 34 Desikan‐Killiany atlas regions of interest (ROIs). Regional CTX between CI and non‐CI responders were compared using t‐tests and reported using Cohen’s D, and whole‐brain surface‐based morphometry using threshold‐free cluster analysis. Sensitivity analyses were used to examine possible associations of CTX with symptoms of PTSD and/or severity of WTC exposure. Analyses were adjusted for multiple comparisons using the false discovery rate (FDR = 0.05). Results Participants were aged 55.84 years on average, and 47 had CI as determined by clinical mental status examination using the Montreal Cognitive Assessment (MoCA≤20). When compared to unimpaired responders, responders with CI had reduced mean whole‐brain CTX (P = 0.002). Region‐based analyses identified reduced CTX in 21/34 bilateral ROIs (D = ‐0.60) with the largest effects centered in the precentral gyrus (D = ‐0.74, P = 0.007). Surface‐based morphometry revealed that CTX was reduced across large parts of the frontal, temporal, and occipital lobes, all of which remained significant following adjustment for multiple comparisons. While more regions were identified as reduced in responders with both PTSD and CI (18 versus 9 ROIs in responders with PTSD and CI versus CI alone respectively), sensitivity analyses were not able to distinguish CI with PTSD as compared to CI alone. Conclusions Results from structural imaging revealed that WTC responders with CI had reduced cortical thickness across multiple brain regions including but not limited to those commonly affected by Alzheimer’s disease. This study represents the first neuroimaging study investigating CTX as an indicator of CI in WTC responders at midlife.

Vaccine adjuvants and vaccines may induce autoimmune and inflammatory manifestations in susceptible individuals. To date most human vaccine trials utilize aluminum (Al) adjuvants as placebos despite much evidence showing that Al in vaccine-relevant exposures can be toxic to humans and animals. We sought to evaluate the effects of Al adjuvant and the HPV vaccine Gardasil versus the true placebo on behavioral and inflammatory parameters in female mice. Six-week-old C57BL/6 female mice were injected with either, Gardasil, Gardasil + pertussis toxin (Pt), Al hydroxide, or, vehicle control in amounts equivalent to human exposure. At 7.5 months of age, Gardasil and Al-injected mice spent significantly more time floating in the forced swimming test (FST) in comparison with vehicle-injected mice (Al, p = 0.009; Gardasil, p = 0.025; Gardasil + Pt, p = 0.005). The increase in floating time was already highly significant at 4.5 months of age for the Gardasil and Gardasil + Pt group (p ≤ 0.0001). No significant differences were observed in the number of stairs climbed in the staircase test which measures locomotor activity. These results indicate that differences observed in the FST were unlikely due to locomotor dysfunction, but rather due to depression. Moreover, anti-HPV antibodies from the sera of Gardasil and Gardasil + Pt-injected mice showed cross-reactivity with the mouse brain protein extract. Immunohistochemistry analysis revealed microglial activation in the CA1 area of the hippocampus of Gardasil-injected mice. It appears that Gardasil via its Al adjuvant and HPV antigens has the ability to trigger neuroinflammation and autoimmune reactions, further leading to behavioral changes.

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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 earlyonset 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 bamyloid 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 Ab 40 subtype in A is not well understood. This study examined plasma-based neuropathological markers of Ab 42 and Ab 40 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 b-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 Ab 40 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 Digital Features To view digital features for this article go to

Introduction The objective of this study was to investigate associations between dementia in World Trade Center (WTC) responders and in vivo volumetric measures of hippocampal subfield volumes in WTC responders at midlife. Methods A sample of 99 WTC responders was divided into dementia and unimpaired groups. Participants underwent structural T1‐weighted magnetic resonance imaging. Volumetric measures included the overall hippocampus and eight subfields. Regression models examined volumetric measure of interest adjusting for confounders including intracranial volume. Results Dementia was associated with smaller hippocampal volume and with reductions across hippocampal subfields. Smaller hippocampal subfield volumes were associated with longer cumulative time worked at the WTC. Domain‐specific cognitive performance was associated with lower volumetric measures across hippocampal subregions. Conclusions This is the first study to investigate hippocampal subfield volumes in a sample of WTC responders at midlife. Selective hippocampal subfield volume reductions suggested abnormal cognition that were associated with WTC exposure duration.