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

Kritikos, Minos; Diminich, Erica D.; Meliker, Jaymie R.; Mielke, Michelle M.; Bennett, David A.; Finch, Caleb E.; Gandy, Sam; Carr, Melissa; Yang, Xiaohua; Kotov, Roman; Kuan, Pei‐Fen; Bromet, Evelyn J.; Clouston, Sean; Luft, Benjamin J.

doi:10.1002/dad2.12409

Cited by 4 publications

(5 citation statements)

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“…These results have been replicated in serological studies of humans, which report that cognitively impaired WTC responders have an upregulated macrophagic reaction in pathways indicating neuroimmunologic response, while neuroimaging studies have found evidence of glial activation and hippocampal inflammation in heavily exposed responders . Seeking potential linkages between neuroinflammation and cognitive outcomes, prior work suggests a potential role for phosphorylated tau and accompanying neurodegeneration . Further work identifying a mechanism for this process may provide useful treatment targets for WTC responders and other persons with inhaled neurotoxicants.…”

Section: Discussionmentioning

confidence: 76%

“… 32 , 33 Seeking potential linkages between neuroinflammation and cognitive outcomes, prior work suggests a potential role for phosphorylated tau and accompanying neurodegeneration. 34 Further work identifying a mechanism for this process may provide useful treatment targets for WTC responders and other persons with inhaled neurotoxicants.…”

Section: Discussionmentioning

confidence: 99%

“…Second, recall bias can emerge from exposure reports from this large and uncontrolled disaster, and there is no biomarker that measures exposure severity to neurotoxic substances at the WTC. Neuroimaging studies have identified significant differences in neuroinflammation 32 , 33 and increased phosphorylated tau 181 34 in dust-exposed WTC responders who worked for longer durations. Yet the dust that was expelled from the collapse of the Twin Towers was composed of a wide variety of hazardous material, including pulverized glass, lead, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and dioxins, and may differ from other sources of air pollution.…”

Section: Discussionmentioning

confidence: 99%

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Incidence of Dementia Before Age 65 Years Among World Trade Center Attack Responders

Clouston,

Mann,

Meliker

et al. 2024

JAMA Netw Open

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ImportanceReports suggest that the individuals who served in rescue operations following the terrorist attacks on the World Trade Center (WTC) have poorer brain health than expected.ObjectiveTo assess the incidence of dementia before age 65 years in a prospective study of WTC responders and to compare incidence among responders with severe exposures to debris vs responders not exposed to building debris or who wore personalized protective equipment (PPE).Design, Setting, and ParticipantsThis prospective cohort study was conducted from November 1, 2014, to January 1, 2023, in an academic medical monitoring program available to verified WTC responders residing on Long Island, New York. Responders 60 years of age or younger without dementia at the time of their first cognitive assessment were followed up every 18 months, on average, for up to 5 years.ExposuresExposure severity was based on responses to a detailed questionnaire of WTC exposures and exposure-related activities that included exposures to fine particulate dust and potentially neurotoxic debris, duration of work, and the use of PPE. Exposure level was divided into 5 categories ranging from low to severe.Main Outcomes and MeasuresIncidence of all-cause dementia before age 65 years was the primary outcome. Dementia was diagnosed following standard guidelines relying on repeated measures of cognition.ResultsOf 9891 responders, 5010 were eligible for inclusion in this study of cognitive function (median [IQR] age, 53 [48-57] years; 4573 [91.3%] male). There were 228 cases of dementia identified during 15 913.1 person-years of follow-up. Increasing WTC exposure severity was associated with incremental increases in the incidence rate of dementia per 1000 person-years (low, 2.95 [95% CI, 1.07-11.18]; mild, 12.16 [95% CI, 10.09-14.79]; moderate, 16.53 [95% CI, 13.30-20.81]; high, 30.09 [95% CI, 21.35-43.79]; and severe, 42.37 [95% CI, 24.86-78.24]). Adjusting for social, demographic, and relevant medical factors, each unit increase in exposure severity was associated with increased incidence of dementia (adjusted hazard ratio, 1.42 [95% CI, 1.18-1.71]; P &lt; .001; mean risk difference, 9.74 [95% CI, 2.94-32.32] per 1000 person-years; P &lt; .001).Conclusions and RelevanceIn this cohort study of WTC responders who survived these unique exposures and participated in a longitudinal follow-up study of cognition from 2014 through 2022, when compared with responders with the lowest exposure levels or responders who used PPE, more severe exposure to dust or debris was significantly associated with a higher risk of dementia before 65 years of age. This study suggests that the reliable use of PPE might help prevent the onset of dementia before age 65 years among individuals exposed to an uncontrolled building collapse. Future research is warranted to determine cerebral biomarkers for individuals with exposure-associated dementia.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Incidence of Dementia Before Age 65 Years Among World Trade Center Attack Responders

Clouston,

Mann,

Meliker

et al. 2024

JAMA Netw Open

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“…Neurofilament light (NfL), a marker of neural axonal damage, was found to be elevated in patients with a history of PTSD and mild TBI in a single study [77]. However, two other studies did not observe a significant association between PTSD and NfL levels [61,79].…”

Section: Biochemical Marker Studiesmentioning

confidence: 98%

Biomarkers of Neurodegeneration in Post-Traumatic Stress Disorder: An Integrative Review

Rajkumar

2023

Biomedicines

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Post-Traumatic Stress Disorder (PTSD) is a chronic psychiatric disorder that occurs following exposure to traumatic events. Recent evidence suggests that PTSD may be a risk factor for the development of subsequent neurodegenerative disorders, including Alzheimer’s dementia and Parkinson’s disease. Identification of biomarkers known to be associated with neurodegeneration in patients with PTSD would shed light on the pathophysiological mechanisms linking these disorders and would also help in the development of preventive strategies for neurodegenerative disorders in PTSD. With this background, the PubMed and Scopus databases were searched for studies designed to identify biomarkers that could be associated with an increased risk of neurodegenerative disorders in patients with PTSD. Out of a total of 342 citations retrieved, 29 studies were identified for inclusion in the review. The results of these studies suggest that biomarkers such as cerebral cortical thinning, disrupted white matter integrity, specific genetic polymorphisms, immune-inflammatory alterations, vitamin D deficiency, metabolic syndrome, and objectively documented parasomnias are significantly associated with PTSD and may predict an increased risk of subsequent neurodegenerative disorders. The biological mechanisms underlying these changes, and the interactions between them, are also explored. Though requiring replication, these findings highlight a number of biological pathways that plausibly link PTSD with neurodegenerative disorders and suggest potentially valuable avenues for prevention and early intervention.

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“…Neurofilament light (NfL), a marker of neural axonal damage, was found to be elevated in patients with a history of PTSD and mild TBI in a single study [66]. However, two other studies did not observe a significant association between PTSD and NfL levels [50,68].…”

Section: Biochemical Marker Studiesmentioning

confidence: 98%

Biomarkers of neurodegeneration in post-traumatic stress disorder: an integrative review

Rajkumar¹

2023

Preprint

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Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder that occurs following exposure to traumatic events. The prevalence of PTSD is estimated to be 5-10% worldwide, and it is associated with significant distress and disability. Recent evidence suggests that PTSD may be a risk factor for the development of subsequent neurodegenerative disorders, including Alzheimer’s dementia and Parkinson’s disease. Identification of biomarkers known to be associated with neurodegeneration in patients with PTSD would shed light on the pathophysiological mechanisms linking these disorders, and would also help in the development of preventive approaches aimed at reducing the risk of neurodegenerative disorders in PTSD. In the current review, the PubMed and Scopus databases were searched for studies aimed at identifying genetic, biochemical, neuroimaging or behavioral markers associated with neurodegeneration in patients with PTSD. Out of a total of 342 citations retrieved, 29 relevant studies were identified for inclusion in the review. The results of these studies suggest that several potentially relevant biological markers, including cerebral cortical thinning, disrupted white matter integrity, specific genetic polymorphisms, immune-inflammatory alterations, vitamin D deficiency, metabolic syndrome and parasomnias, may be associated with an increased risk of neurodegeneration in patients with PTSD. Though many of these results need replication, they highlight a number of biological pathways that plausibly link PTSD with neurodegenerative disorders, and suggest potentially valuable avenues for prevention and early intervention in this patient population.

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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

Cited by 4 publications

References 51 publications

Incidence of Dementia Before Age 65 Years Among World Trade Center Attack Responders

Incidence of Dementia Before Age 65 Years Among World Trade Center Attack Responders

Biomarkers of Neurodegeneration in Post-Traumatic Stress Disorder: An Integrative Review

Biomarkers of neurodegeneration in post-traumatic stress disorder: an integrative review

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