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