28 Jan 2020

Thousands of first responders who cleaned up the wreckage of the World Trade Center site developed long-term health problems such as post-traumatic stress disorder, respiratory diseases, and cancer. Now, emerging evidence suggests their work may have taken an even greater toll on their brains than previously thought. Researchers led by Sean Clouston at Stony Brook University, Long Island, New York, report evidence of cognitive decline in WTC responders in their 50s, two decades before such problems typically show up in the general population. As might be expected, their cognitive impairment correlated with PTSD symptoms and with the amount of their exposure to toxic dust. However, preliminary plasma analysis and PET scans also suggest accumulation of amyloid and tau pathology in the brain, although not necessarily distributed in a typical Alzheimer’s regional pattern.

People who cleaned up the World Trade Center site are developing cognitive impairment in their 50s.
These may be caused by inhalation of toxic dust, or be secondary to PTSD.
Biomarkers suggest plaque and tangle accumulation, though perhaps not in an Alzheimer’s pattern.

What do these findings mean? Clouston acknowledged that so far there are more questions than answers. “We need to figure out if the cognitive impairment progresses, and whether it fits a known disease profile or is its own condition,” he told Alzforum.

Alzheimer’s researchers are just starting to get a look at these data, with a handful of papers published, and talks scheduled at upcoming conferences. The few who have seen the data to date say there is reason for concern. Ranjan Duara at Mount Sinai Medical Center in Miami Beach, Florida, wrote to Alzforum, “Clearly we have enough signal to warrant exploration of these preliminary findings in a larger group, with a more systematic evaluation of biomarkers of cognition, amyloid and tau deposition, and inflammation.”

David Bennett at Rush University, Chicago, is interested in doing just that. He is in discussions with Stony Brook researchers on how to set up a formal cohort study to follow cognitive aging in WTC responders. “[Clouston and colleagues] have made a compelling case that these questions should be addressed,” Bennett told Alzforum.

The answers could have wide repercussions. After the twin towers fell on September 11, 2001, more than 60,000 people recovered human remains and cleaned up debris, many of them working at the site for months. More than 33,000 of these responders take part in the WTC Health Program set up by the Centers for Disease Control and Prevention at five clinical centers. Participants come in for regular checkups that focus on known health issues such as respiratory problems. Besides Stony Brook, the centers are at Icahn School of Medicine at Mount Sinai, New York University School of Medicine, Northwell Health in Rego Park, New York, and Rutgers University in Piscataway, New Jersey.

A New York City firefighter calls for 10 more rescue workers to make their way into the rubble of the World Trade Center. (U.S. Navy Photo by Journalist 1st Class Preston Keres.)

The Stony Brook program follows more than 8,000 responders who live on Long Island. The majority of them are men working in law enforcement, who have at least some college education and were on average 38 years old when the towers fell. About 20 percent of this cohort has PTSD. They come in for assessments every 12 to 18 months.

Clouston and colleagues began collecting cognitive data on this group in 2014, when they entered their 50s. At every visit, participants take the Montreal Cognitive Assessment (MoCA), which assesses multiple cognitive domains. Scores on this screen range from zero to 30, with healthy controls averaging 27, and a cutoff of 23 identifying cognitive impairment with 95 percent sensitivity and specificity (Luis et al., 2009). In an initial screen of 818 WTC responders, 13 percent had scores below this cutoff. Participants with PTSD symptoms were almost three times as likely to score below the cutoff as those without, suggesting this disorder might contribute to cognitive impairment. Direct traumatic brain injury itself was not a factor, as the handful of responders with head injuries were excluded (Clouston et al., 2016). The researchers did not compare these responder findings to normative data from the general population.

To gather more data, the researchers administered the Cogstate computerized cognitive battery to 1,193 WTC responders. This cohort was highly educated, with 75 percent having at least some college experience. They were relatively healthy overall: 30 percent had hypertension, 11 percent diabetes, 7 percent heart disease. Again, people with a history of head injury were excluded. The Cogstate battery uses three tasks with digital playing cards to assess reaction time, processing speed, and memory. On each task, WTC responders performed below the norm for their age group. In addition, there was a trend for responders with PTSD to perform worse than those without PTSD, though the trend did not reach statistical significance. Overall, 15 percent of the responders had results consistent with cognitive impairment, defined as scoring one standard deviation or more below the mean. Clouston noted that there are no definitive data on what would be expected in this age group, but some estimates he found suggested that 15 percent is two to three times the norm.

The data suggested that PTSD alone does not explain the responder’s cognitive problems. Low scores on the Cogstate battery independently correlated with spending more than five weeks on the site, which would have increased exposure to the fine-particulate toxins that filled the air there (Clouston et al., 2017).

These initial studies offered no way to quantify how much higher the rate of cognitive decline might be than in the general population, or among people who do other types of clean-up work. To determine a rate, Clouston and colleagues next analyzed longitudinal data from 1,800 WTC responders who at baseline were cognitively healthy and whose average age was 53. Over an average of 1.5 years, 14 percent of them fell from above 23 to 23 or below on the MoCA (Clouston et al., 2019). There are few published studies of cognitive decline in this young age range, therefore Clouston found it difficult to compare the responders’ rate to population norms. However, their incidence of MCI was three times higher than that seen among people in their 70s in the general population, a group that is two decades older (Roberts et al., 2012). The data hint at skyrocketing rates of cognitive decline among WTC responders.

In discussion with other researchers, Clouston has encountered resistance to the idea that cognitive impairment could start at ages this young in a relatively healthy cohort. “When we’ve told some collaborators the statistics, they said we must be wrong,” Clouston told Alzforum. While he insists that his numbers are correct, he cautions that at this point, it is unclear if this cognitive impairment is a stable condition, or if it will worsen into dementia. Unlike Alzheimer’s disease, MCI is a heterogeneous, clinically defined syndrome. It has many causes and sometimes improves on its own.

Mary Sano at Mount Sinai School of Medicine in New York, who is a co-author on these papers, was unsurprised at finding cognitive impairment among WTC responders. “What’s important is to determine what the underlying biology of the impairment is,” she wrote to Alzforum (full comment below).

Three days after the September 11 terrorist attacks, a "bucket brigade" works to clear rubble and debris at the World Trade Center, hoping to find survivors. (U.S. Navy photo by Photographer’s Mate 2nd Class Jim Watson.)

Then what is the cause? One factor is PTSD, Clouston believes. In the longitudinal analysis of 1,800 responders, PTSD correlated with low cognitive scores. Moreover, gene expression changes in blood cells of WTC responders with PTSD hint at a chronic stress response (Kuan et al., 2017; Kuan et al., 2019). “PTSD is potentially a lasting condition that causes systemic changes,” Clouston said. Prior research links PTSD to accelerated cognitive decline and an elevated risk of dementia, although the etiology is unknown (Schuitevoerder et al., 2013; Sumner et al., 2017; Flatt et al., 2017).

Pollution might be a risk factor for cognitive impairment in responders, as well. Among the 1,800, longer exposure to the WTC site correlated with worse impairment among ApoE4 carriers, though not noncarriers. Some previous research reported that the E4 allele makes carriers more susceptible to air pollution by increasing permeability of their blood-brain barriers (Methia et al., 2001; Kulick et al., 2020). In animal studies, inhalation of nanosized particles triggered neuroinflammation and Aβ amyloidosis (Woodward et al., 2017; Babadjouni et al., 2018; Cacciottolo et al., 2020). Recent epidemiological studies link exposure to airborne pollutants with a higher risk for dementia (Jan 2017 news; Cacciotollo et al., 2017, Tsai et al., 2019; Zhang et al., 2020; Younan et al., 2020, Kulick 2020).

Sam Gandy at Mount Sinai in New York is a co-author on Clouston’s papers. He suspects inhaled neurotoxins are the culprit behind early cognitive decline in this population. Gandy wrote to Alzforum that Lung-Chi Chen at New York University Langone Medical Center injected dust from the WTC site into the nasal passages of mice and subsequently observed intense neuroinflammation and elevated Aβ in these animals. The data are unpublished.

Elaine Peskind at the VA Northwest Network Mental Illness Research, Education, and Clinical Center in Seattle also thinks exposure to pollutants may be the major factor. Peskind noted that the types of chemicals in the air at the WTC site were similar to what soldiers are exposed to in war zones. Many of these pollutants are known risk factors for Alzheimer’s disease. In studies of Iraq and Afghanistan veterans with an average age of 34, she has found Alzheimer’s-like changes in biomarkers of Aβ and tau in their cerebrospinal fluid, although not yet cognitive decline. “Exposure to toxicants alone could cause cognitive problems, and PTSD adds another factor,” she told Alzforum. PTSD may contribute indirectly, she speculated. PTSD is associated with poor health behaviors such as alcohol abuse, lack of exercise, and disrupted sleep, all of which are known to increase AD risk.

To investigate the underlying pathology, Clouston and colleagues have started to collect biomarker data. In a pilot study of 34 WTC responders, they measured plasma levels of total Aβ, the Aβ42/Aβ40 ratio, total tau, and NfL using Quanterix Simoa technology. The responders had lower Aβ42/Aβ40, and higher total tau and NfL than would be the norm for their age group. Notably, the 17 responders who had current symptoms of PTSD had lower levels of total Aβ in blood than did the 17 without PTSD (Clouston et al., 2019). Clouston is now examining whether those biomarkers correlate with cognitive impairment.

The researchers have scanned six WTC responders with Aβ PET and six with tau PET. Clouston told Alzforum that those with cognitive impairment appear to have elevated uptake of both tracers, with the tau PET signal perhaps stronger than amyloid. So far, the regional pattern does not resemble Alzheimer’s, with tracer retention occurring in distinct brain regions, Clouston said. They are submitting the data for publication.

Caleb (Tuck) Finch at the University of Southern California, Los Angeles, saw some of the scans at a recent workshop. “Most discussants agreed that the findings are not yet definitive for any specific neuropathologic processes,” he wrote to Alzforum (full comment below). The DoD-ADNI of Vietnam War veterans has linked PTSD to both amyloid and tangle accumulation (Mohamed et al., 2018; Mohamed et al., 2019).

Gandy speculated that WTC responders who develop amyloidosis might have genetic risk factors that predispose them, such as ApoE4 or other risk variants. He noted that researchers will eventually need neuropathology data to learn what is going on (full comment below).

Currently, Stony Brook is the only center in the WTC Health Program that monitors cognition. Clouston is sharing his data with other centers, and some have expressed interest in adding cognitive testing, he said. He will present more data at the upcoming Tau 2020 Global Conference, to be held Feb 12–13 in Washington, D.C.—Madolyn Bowman Rogers

Comments

- Caleb (Tuck) Finch
  University of Southern California
- Posted: 28 Jan 2020
Last October, I attended a workshop on WTC and brain injury Sean Clouston organized. Clouston showed some preliminary brain imaging, and most discussants agreed that findings are not yet definitive for any specific neuropathologic processes.

Besides the three clinical-cognitive studies that suggest higher risk of cognitive decline, two WTC responder studies show increased risk of peripheral neuropathy (Colbeth et al., 2019) and CVD (Cohen et al., 2019).

There are individual differences in exposure to the WTC dust by levels inhaled and adsorbed; the dust chemistry may also vary with time and distance from the event. Everyone at the workshop agreed that the WTC emergency workers need long-term follow-up for all aspects of their health, from head to heart to toe.

References:

Colbeth HL, Zeig-Owens R, Webber MP, Goldfarb DG, Schwartz TM, Hall CB, Prezant DJ. Post-9/11 Peripheral Neuropathy Symptoms among World Trade Center-Exposed Firefighters and Emergency Medical Service Workers. Int J Environ Res Public Health. 2019 May 16;16(10) PubMed.

Cohen HW, Zeig-Owens R, Joe C, Hall CB, Webber MP, Weiden MD, Cleven KL, Jaber N, Skerker M, Yip J, Schwartz T, Prezant DJ. Long-term Cardiovascular Disease Risk Among Firefighters After the World Trade Center Disaster. JAMA Netw Open. 2019 Sep 4;2(9):e199775. PubMed.

View all comments by Caleb (Tuck) Finch

- Mary Sano
  Mount Sinai School of Medicine
- Posted: 28 Jan 2020
I do not think it is surprising that these individuals, who have a range of post-WTC problems, also have cognitive impairment. What is important is to determine the underlying biology of the impairment. Also, it will be important in future studies to know if it is persistent and progressing.

The study has important implications for understanding the potential of long-term consequences of trauma occurring in early life. This basic knowledge is needed to find a path for intervention and treatment.

View all comments by Mary Sano

- Ranjan Duara
  Mount Sinai Medical Center
- Posted: 28 Jan 2020
So far, the data are very preliminary. Some responders/survivors are cognitively impaired. There are subjects who appear to be amyloid-positive or tau-positive, but it is not clear what the overlap is between them. The number of tau and amyloid scans done are small and, apparently, not necessarily on the same people.

We also do not know the levels of cognitive impairment and how the results would compare to age-matched controls at approximately the same level of cognitive impairment. So at this time it’s difficult to know whether the number of cases who are cognitively impaired and amyloid- or tau-positive in this cohort is unusual for the population to which they belong.

However, clearly we have enough signal to warrant further exploration of these preliminary findings in a larger group, and with a more systematic evaluation of biomarkers of cognition as well as amyloid and tau deposition, and perhaps indices of inflammation. We also need to know more about their lifestyle, e.g., diet, exercise, social habits.

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- Sam Gandy
  Icahn School of Medicine at Mount Sinai
- Posted: 29 Jan 2020
Sean Clouston, Ben Luft, Evie Bromet, and Roberto Lucchini discovered this WTC-related cognitive impairment and began reporting the clinical picture as early as 2016. Roberto recruited Mary Sano, Cheuk Tang, and me to join the group to advise on clinical, neuropsychological, and biomarker characterization of the cognitive decline.

Tuck Finch and I share (with Clouston et al.) the suspicion that this WTCFR-PTSD-dementia complex is due to one or more inhaled neurotoxins. Relevant to this story is a study by Lung Chi Chen and his graduate student Michelle Hernandez, who acquired dust from the WTC site and introduced it intranasally into mice. They noted that the mice developed intense neuroinflammation and elevated Aβ levels. To my knowledge, no one has yet established a pathway where an inciting event acts first through inflammation and only later leads to accumulation of secondary plaques and tangles, but this is the sort of thing we have been pondering.

Among the WTC first responders, the syndrome appears to include both dementia and a PTSD-like neurobehavioral phenotype. In fact, those who develop dementia are among those who suffered the most severe PTSD-like symptoms. There is a literature on increased dementia risk from chronic stress in Holocaust survivors. Also in animal models of excess corticotrophin-releasing hormone, Bruce McEwen has reported neurobehavioral-neurodegenerative syndrome with proteinopathy. I see the question with the WTCRs as whether some toxin(s) caused both PTSD and neurodegeneration directly, or whether the toxin mostly caused the PTSD and then neurodegeneration was mostly secondary and caused by stress rather than by the toxin. These are not mutually exclusive, and there could be interindividual variation in which pathways were more responsible.

Allan Levey and colleagues identified elevated levels of pesticides in some sporadic AD brains (Richardson et al., 2014), and the role of pesticides in parkinsonism is established. The WTCR story sounds somewhat similar. What makes it different is the early age at onset, suggesting that the magnitude of the toxin, the stress, or the genetic susceptibility was also unusually "large."

By genetic susceptibility, I refer to the possibility that the affected responders were a genetically destined subgroup. I don’t mean dominant APP or presenilin mutations, but rather, individuals who harbor APOE epsilon 4 alleles and/or some of the two dozen high-risk variants found in GWAS. I guesstimated that this EOAD risk genotype is 10- to 20-fold over-represented among WTCFRs affected with cognitive decline and amyloid/tau biomarkers, though this calculation is not straightforward, and these guesstimates could be wrong. In any event, to learn more, we really need state-of-the-art molecular neuropathology but, as in CTE, the WTC responders are young and largely otherwise healthy.

For WTCFRs and their families and caregivers, it will be important to add this debilitating post-WTCFR neurocognitive/neurobehavioral syndrome to the list of recognized illnesses that are covered by federal 9/11 healthcare funding.

References:

Richardson JR, Roy A, Shalat SL, von Stein RT, Hossain MM, Buckley B, Gearing M, Levey AI, German DC. Elevated serum pesticide levels and risk for Alzheimer disease. JAMA Neurol. 2014 Mar;71(3):284-90. PubMed.

View all comments by Sam Gandy

- Sjors Scheres
  MRC Laboratory of Molecular Biology
- Posted: 29 Jan 2020
CryoEM structures of tau filaments isolated from brain could lead to insights whether this disease is similar to Alzheimer's at the molecular level or not.

View all comments by Sjors Scheres

- Marcia Ratner
  Boston University Chobanian & Avedisian School of Medicine
- Posted: 03 Feb 2020
That these subjects are younger than expected points to a possible interaction between environmental exposure and age at onset of latent idiopathic disease, which may be unmasked by the specific exposure circumstances in this population. As Gandy speculated, WTC responders who develop amyloidosis might have genetic risk factors that predispose them, such as ApoE4 or other risk variants. It is certainly prudent to look at the interactions between predisposing genetic factors and familial history as this relates to exposure history and age at onset of disease.

Parsing out the effects of the neurotoxic soup these first responders encountered will be a daunting task given the lack of biological markers of exposure, which is further complicated because the effects of individual chemicals may be additive and/or synergistic.

This work should therefore begin by characterizing compounds known have been present by their shared mechanisms of action, such as increasing oxidative stress versus increasing neuroinflammation.

Subjects will then need to be stratified by duration of exposure based on hours worked to assess for dose-response relationships. Data on use of respirators will need to be obtained.

Work records will need to be reviewed for employment in previous occupations that involved exposure to toxic chemicals, such as working as a painter.

Subjects who received chemotherapy for cancer will need to be stratified into different subgroups, or excluded.

A time-exposure symptoms line should be created for each subject. It well be important to correlate the cognitive deficits with symptoms of peripheral neuropathy and paresthesias, which have been associated with WTC-exposure intensity (Colbeth et al., 2019).

The last piece of this complex puzzle will be to explore the interactions of these toxicants with stress hormones and neuroactive steroids, such as allopregnanolone, in subjects stratified by gender, as men and women are likely to respond differently.

References:

Colbeth HL, Zeig-Owens R, Webber MP, Goldfarb DG, Schwartz TM, Hall CB, Prezant DJ. Post-9/11 Peripheral Neuropathy Symptoms among World Trade Center-Exposed Firefighters and Emergency Medical Service Workers. Int J Environ Res Public Health. 2019 May 16;16(10) PubMed.

Ratner MH, Kumaresan V, Farb DH. Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders. Front Endocrinol (Lausanne). 2019;10:169. Epub 2019 Apr 9 PubMed.

Farb DH, Ratner MH. Targeting the modulation of neural circuitry for the treatment of anxiety disorders. Pharmacol Rev. 2014 Oct;66(4):1002-32. PubMed.

Ratner MH, Jabre JF. Neurobehavioral Toxicology. In Reference Module in Neuroscience and Biobehavioral Psychology, Elsevier, 2016

Ratner MH. A critical review of the interrelationships between genetics, neurotoxicant exposure, and age at onset of neurodegenerative diseases. Current Topics in Toxicology. 2016; (12):1-10. Embase PUI: L616391802

Hayes TB, Case P, Chui S, Chung D, Haeffele C, Haston K, Lee M, Mai VP, Marjuoa Y, Parker J, Tsui M. Pesticide mixtures, endocrine disruption, and amphibian declines: are we underestimating the impact?. Environ Health Perspect. 2006 Apr;114 Suppl 1:40-50. PubMed.

Feldman RG, Ratner MH, Ptak T. Chronic toxic encephalopathy in a painter exposed to mixed solvents. Environ Health Perspect. 1999 May;107(5):417-22. PubMed.

View all comments by Marcia Ratner