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Cortical Thickness and Plasma Proteins Correlate with Cognition in 9-11 World Trade Center Responders

Article In Brief

Workers at the site of the 9-11 World Trade Center (WTC) attacks in 2001 showed a reduction in cortical thickness among cognitively impaired responders both with and without post-traumatic stress disorder. Another investigation identified proteins in plasma that can differentiate between those with only post-traumatic stress disorder (PTSD), only with mild cognitive impairment, and those with both conditions.

Two large related studies of workers at the site of the 9-11 World Trade Center (WTC) attacks in 2001 showed distinct brain changes and levels of proteins in plasma in those who were cognitively impaired years later. Both studies were described at the Alzheimer's Association International Conference held virtually in July.

In one study, the largest neuroimaging study of the workers to date, researchers observed reduced cortical thickness. The reduction in cortical thickness was observed in cognitively impaired responders both with and without post-traumatic stress disorder, said the study author Sean Clouston, PhD, associate professor of public health at Stony Brook Medicine.

And a second related study involving proteomic analysis of WTC responders—conducted by a group led by Benjamin Luft, MD, director of the Stony Brook World Trade Center Wellness Program—identified proteins in plasma that can differentiate between those with only post-traumatic stress disorder (PTSD), those only with mild cognitive impairment, and those with both conditions.

Studies have suggested that inhalation of fine particulate matter, such as that at the WTC site, could cause neurodegeneration. No studies had used neuroimaging to assess these responders, but they are at more risk of cognitive impairment than the general population.

The Imaging Study

In the imaging study, researchers conducted T1-MPRAGE, a kind of MRI on 99 responders, 51 of whom were cognitively unimpaired and 48 who were impaired—and calculated cortical thickness in 34 regions of interest.

The gray matter volume for those who were cognitively impaired was 603 cubic centimeters, compared with 629 cubic centimeters for the cognitively unimpaired (p=0.03). Whole-brain average cortical thickness was 2.41 mm among the impaired, compared with 2.48 among the unimpaired (p=0.0003). No differences were found in average cortical thickness when researchers compared PTSD to non-PTSD groups. Significant reductions in cortical thickness were found in 23 of the 34 regions analyzed.

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“In short, the findings from these two studies are interesting, but more work is needed to fully elucidate the relationships between PTSD and CI in this population.”—DR. MARCIA RATNER

Researchers also compared cortical thickness to the norms seen in the published literature. They found significant reductions among those who were cognitively unimpaired in seven of the regions, with the greatest reductions in the entorhinal cortex. In impaired responders, significant reductions in thickness were in 14 of the 34 regions.

“Our healthy World Trade Center responders may also be in the earlier stages of disease in some cases,” Dr. Clouston said in his presentation.

The Proteomics Study

In the proteomics study, researchers analyzed plasma from 181 responders—34 with PTSD and mild cognitive impairment (MCI), 39 with only PTSD, 27 with only MCI, and 81 controls with neither one. They identified 16 proteins that were associated with PTSD and MCI together, 20 associated with PTSD alone, and 24 associated with MCI alone.

Those associated with both disorders together included Neurocan core protein, Brevican core protein, Cathepsin S, and others—“all of which have known correlates in the Alzheimer's and psychiatric—and in particular, schizophrenia—research field,” Dr. Clouston said.

The researchers also created a multi-protein composite risk score that was reasonably accurate, identifying PTSD-MCI, PTSD alone, and MCI alone. The areas under the curve for those scores were 0.84, 0.77, and 0.83, respectively.

“To our knowledge, the current study was the largest to profile a targeted set of proteins involved in the neurobiologic processes,” Dr. Clouston said. “The significant associations across these three case-group analyses suggested that shared biological mechanisms may be involved in the two disorders. If findings from the multi-protein composite score are replicated in independent samples, it has the potential to add a new tool to help classify both post-traumatic stress disorder and mild cognitive impairment.”

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“The significant associations across these three case-group analyses suggested that shared biological mechanisms may be involved in the two disorders. If findings from the multi-protein composite score are replicated in independent samples, it has the potential to add a new tool to help classify both post-traumatic stress disorder and mild cognitive impairment.”—DR. SEAN CLOUSTON

Expert Commentary

Charles Hall, PhD, professor of epidemiology and public health at Albert Einstein College of Medicine who has studied the neurologic effects of WTC responders, said the findings represent a significant step forward. Up until now, researchers had found cognitive impairment effects that were strongly associated with PTSD. Still, the question remained whether this link was an artifact of the neuropsychological instruments used to assess patients.

“These studies are important in that they show that there may be a biological substrate to this,” he said. “These are not large studies, it's going to require a lot more work, but this certainly should motivate more work.”

Much research has been done over the past several years on associations between air pollution and cognition. Still, it has tended to rely on regional ambient air quality measurements that are not very good at quantifying individual levels of exposure, Dr. Hall said. Although the World Trade Center exposure to particulate matter is a “much larger exposure than most people would ever see in a lifetime,” these findings should encourage researchers to continue that line of research.

“Here we have a huge exposure that is showing not just effect on cognition, but a biological substrate for some of the impairment,” he said. “So as far as the general population is concerned, I think this should stimulate more research in general population cohorts on the effect of particulate matter, with better exposure measures.”

Dr. Hall and colleagues recently had a paper accepted to the International Journal of Environmental Research and Public Health that found that PTSD symptoms mediated the association between WTC exposure and subjective cognitive concerns. In contrast, the Stony Brook findings on cortical thickness found reductions both in those with and without PTSD.

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“Here we have a huge exposure that is showing not just effect on cognition, but a biological substrate for some of the impairment. So as far as the general population is concerned, I think this should stimulate more research in general population cohorts on the effect of particulate matter, with better exposure measures.”—DR. CHARLES HALL

Dr. Hall said the difference might be attributable to the way PTSD was treated in the studies. In his research, PTSD symptoms were considered along a continuum, while in the Stony Brook study, participants were either considered to have PTSD or they weren't.

Marcia Ratner, PhD, a behavioral neuroscientist and toxicologist who studies the neurological effects of occupational exposures, said the studies report “interesting results which need to be replicated.”

She said there are many potential confounders that were not controlled for in the studies, including comorbid medical conditions and medications taken. She added that PTSD alters levels of neuroactive steroids that can influence memory function. Furthermore, she said, mild cognitive impairment and dementia are stressful, and elevated cortisol levels have been associated with dementia.

“A major limitation of this study is that the findings were not related to serum concentrations of cortisol,” she said. An important question, she said, is how many patients had received treatment for their symptoms and how many were naïve. After breaking groups down by disorder, the sample sizes are small, she added.

“In short,” she said, “the findings from these two studies are interesting, but more work is needed to fully elucidate the relationships between PTSD and CI in this population.”

Disclosures

Drs. Clouston, Luft, Hall, and Ratner had no relevant disclosures.