Physical Functional Impairment and the Risk of Incident Mild Cognitive Impairment in an Observational Study of World Trade Center Responders

Abstract

Background and Objectives

Posttraumatic stress disorder (PTSD) has been linked to increased risk of cognitive dysfunction and physical functional impairment (PFI). The objective of this prospective cohort study was to examine whether PFI was associated with increased risk of incident mild cognitive impairment (MCI) among World Trade Center (WTC) responders with PTSD. We hypothesized that responders with PTSD would have an elevated risk of incident MCI and that PFI would mediate this increase.

Methods

We examined responder participants in the WTC Aging Study whose baseline physical assessments were completed by May 2016–April 2017 and were followed up at least once before December 2019. Those without complete demographic, medical, or behavioral data were excluded. PFI was assessed using measures of upper body strength (maximal handgrip strength [HGS]) and lower extremity physical functioning (Short Physical Performance Battery). PTSD was rated using a diagnostic interview and symptom checklist; MCI and dementia were assessed using the Montreal Cognitive Assessment and diagnosed using the National Institute on Aging–Alzheimer's Association criteria. Group differences and longitudinal comparisons were examined. Cox proportional hazards models were evaluated from time to incident MCI and conversion to dementia. A mediation analysis examined whether PFI mediated associations between PTSD and MCI.

Results

Within the sample of 2,687 WTC responders, 324 (12.06%, 95% CI = [10.83–13.29]) had lower extremity PFI. Responders with lower extremity PFI were older, had lower education and higher body mass, and were at a higher risk of pulmonary embolisms and PTSD. Responders with lower extremity PFI demonstrated lower baseline cognition and had increased hazards of MCI (multivariable-adjusted hazards ratio [aHR] = 1.55 [95% CI 1.21–1.98]); those with MCI converted to dementia more rapidly than those without PFI (2.73 [1.38–5.39] p = 0.004). In addition, each standard deviation decrease in HGS was associated with increased hazards of developing MCI (aHR = 1.35 [95% CI 1.10–1.66]). A mediation model suggested PFI played an intermediary role in the relationship between PTSD and MCI.

Discussion

WTC responders with PFI demonstrated worse cognitive and behavioral outcomes, and PFI played an intermediary role in the relationship between PTSD and incident MCI, suggesting that PFI may be an early indicator of MCI in responders with PTSD. Regular monitoring of PFI should be considered among PTSD populations.

Alzheimer disease and related dementias (ADRD) are debilitating conditions of aging and the seventh most common cause of death in the United States.¹ Mild cognitive impairment (MCI) indicates a prodromal stage in the ADRD process that is characterized by a noticeable decline in cognitive functioning, but one that is too mild to functionally interrupt everyday life.² Although MCI can be a lasting condition that does not always progress to dementia, it can nevertheless portend the presence of neuropathologic changes that are severe enough to disrupt cognition and is therefore a phenotype under intense research.³

Physical functional impairments (PFI) and frailty can comorbidly arise with other age-related conditions such as cognitive decline,^4,5 difficulties with driving,⁶ and risk of disability.⁷ In addition, some researchers have noted that upper extremity PFI, as measured by maximal handgrip strength (HGS), can be predictive of lower extremity PFI⁸ and may even act as an independent biomarker for accelerated aging.⁹

Incidence of MCI and PFI among responders to the terrorist attacks on the World Trade Center (WTC) on September 11th, 2001, is higher than expected 2 decades later.¹⁰ Now at midlife, this population has experienced severe physical (i.e., neurotoxic particulate matter [PM] inhalations) and emotional (i.e., psychological trauma) exposures,¹⁰ causing approximately 23% to develop chronic posttraumatic stress disorder (PTSD).^11,12 PTSD is a psychiatric condition often characterized by the presence of trauma-related memories, which can cause heightened physiologic stress responses sporadically throughout the day and acutely in response to triggering stimuli.¹³ Recent work has reported that PFI may be one distal outcome of chronic PTSD among the WTC responder population,^14,15 with one study speculating that PFI may be a prodromal symptom of MCI in individuals with PTSD.¹⁶ Although researchers have long reported chronic PTSD to be a risk factor for cognitive dysfunction,¹⁷ incidence of MCI,^10,18 and onset of dementia,¹⁹ the connection with PFI is yet to be examined longitudinally in a trauma-exposed population.

This study is aimed to determine whether PFI was associated with elevated incidence of MCI and conversion to dementia and to determine whether adjusting for PFI explained associations between PTSD and incident MCI among WTC responders. We hypothesized that responders with PTSD would have increased incidence of MCI and, in addition, that PFI would explain this elevated risk. We also examined the degree to which different measures of PFI including gait speed, chair-rise speed, balance difficulties, and maximal HGS were attributable for the explanatory effect.

Methods

Setting

Participants from the WTC Aging Study were eligible for this study if they completed physical and cognitive assessments between May 2016 and April 2017 and had at least one follow-up cognitive assessment completed before 2020, when in-person examinations were curtailed by the COVID-19 pandemic. Those who did not have complete demographic, medical, or behavioral data were excluded from the analysis (n = 271), leaving a sample of 2,687 WTC responders (Table 1).

Table 1.

Baseline Demographic Characteristics, Provided as Mean (SD) or Percentages, for WTC Responders Stratified by Lower Extremity Physical Functional Impairment Status as Operationalized Using the Short Physical Performance Battery

Measures

MCI

MCI and dementia were diagnosed algorithmically following the National Institute on Aging–Alzheimer's Association diagnostic guidelines,² in a manner that has been determined to be more reliable than the criteria using self-reported symptomatology.¹⁰ Cognition was assessed using the Montreal Cognitive Assessment (MoCA) using recommended scoring standards.²⁰ The MoCA is a validated measure of mental status developed to objectively and reliably identify multidomain MCI.²⁰ Total and individual subdomain scores were used to rate cognitive status at a level consistent with MCI (MoCA total = 21–23) and dementia (MoCA total ≤20). Those without a diagnosis of MCI or dementia were classified as cognitively unimpaired (CU; MoCA total ≥24).

PFI

PFI was operationalized in 2 different ways for this study. Lower extremity physical function was derived from performance on the Short Physical Performance Battery (SPPB).²¹ This assessment consists of 3 components: balance (side-by-side, semitandem, and tandem positions held for 10 seconds unassisted), gait speed (amount of time to walk a four-meter course at a typical pace), and repetitive chair stand (amount of time to rise from a chair unassisted 5 consecutive times). Each component is rated on a 4-point scale based on the ability and amount of time necessary to complete each task.²¹ SPPB ≥10 indicated scores in the normal range (n = 2,363), whereas a score of ≤9 indicated PFI (n = 324).²² PFI was further stratified into mild (7–9; n = 274) vs moderate (4–6; n = 41) to severe (≤3; n = 9) (n = 50).

Upper extremity strength was derived from HGS and was evaluated for both hands if responders did not indicate any issues with the hands, shoulders, or wrists, or concerns with gripping the hand dynamometer (Vernier Software & Technology, Beaverton, OR). Trained research staff administered the HGS test and recorded data in a computer with Logger Pro software (Vernier Software & Technology). Responders were instructed to complete the assessment while sitting upright in a chair, with their elbow fixed at a right angle as they squeezed the dynamometer as tightly as possible for 10 seconds with minimal extraneous movement. All responders completed 4 trials in total, beginning with the left hand and alternating so 2 trials were completed for each hand. HGS data were entered by administrators into a Qualtrics survey, and maximum HGS for each responder was used for this study. Owing to the unique nature of the responder population, including a previous study which suggests this population may have lower HGS compared with norms,¹⁵ we derived Z-scores within this sample that varied across sexes and by hand dominance; upper extremity impairment was defined as 1.5 standard deviations or more below the mean.

PTSD

PTSD diagnosis was based on a standard diagnostic interview schedule for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, (DSM-IV),²³ a validated research-focused interview that can be reliably used to diagnose PTSD.²⁴ PTSD symptom severity was also assessed using the PTSD Checklist (PCL) tailored to the WTC disaster.²⁵ The PCL has good internal consistency and convergent validity²⁶ and can differentiate between individuals with/without diagnoses with a high degree of accuracy in this sample (AUC = 0.91 [0.90–0.93]). At study baseline, responders rated the extent to which they were bothered by 17 DSM-IV WTC-related PTSD symptoms during the past month on a scale from 1 (not at all) to 5 (extremely). Previous work has identified re-experiencing symptom severity, a cluster of PTSD symptom defined by recurrence of stressful memories, as the most consistent indicator of aging and that these symptoms are insensitive to reverse causation¹⁰ with similar results evident for physical functioning.¹⁵ Replicating this work, this study found that the re-experiencing symptom cluster measured at study enrollment, nearly a decade before physical functioning assessment, was more indicative of risk of MCI at baseline (AUC = 0.57 vs 0.52) even among those without diagnosed PTSD (AUC = 0.58), supporting the use of re-experiencing symptoms in this study.

Health-Related Covariates

Clinician-reported medical conditions at study baseline were extracted from electronic medical records (EMR) for each participant, and the following was coded: hypertension, cancer, cardiovascular disease, diabetes, neuropathy, respiratory conditions, and pulmonary embolism. Body mass index (BMI, kg/m²) was collected during the study baseline visit. In addition, an EMR extraction was performed on medications to evaluate whether any significant differences in medication usage may affect the results of this study. Medications were included if they were used by at least 20 responders (approximately 0.7% of the population) to ensure statistical power; a pharmacist then categorized the drugs into classes that affect cognition or behavioral disorders, including antihistamines, antivertigo, atypical antidepressants, benzodiazepines, beta-blockers, h2-receptor antagonists, opioids, proton pump inhibitors, serotonin and norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, second-generation antipsychotics, spinal muscle relaxants, statins, and tricyclic antidepressants. Utilization of all other drugs were combined into a residual category.

WTC Exposure Severity

In this study, WTC exposure severity was measured using an interviewer-administered exposure assessment questionnaire upon enrollment to record psychological and physical exposures that occurred during their WTC response efforts. Exposure severity was operationalized in several ways. “Early arrival” indicated whether the responder arrived to the site on September 11, 2001, “duration” indicated the time spent (in days) on the site during the search and rescue efforts,²⁷ “ergonomic exposure” indicated whether the responder had occupation-based physical exposures (e.g., repetitive motions, manual or heavy lifting, or vibrations), and “occupation” indicated the responders' occupation at the time of their response efforts (law enforcement vs other).

Demographic Characteristics

Age in years, sex (male vs female), race/ethnicity (White, Black, Hispanic, and other), and education level (less than high school, high school, some college/technical school, and college or more) were collected and were included as covariates.

Statistical Analyses

Cross-sectional analyses, including descriptive statistics, were performed using mean and standard deviations, or frequencies and percentages as noted. Data distribution and normality were evaluated using a Shapiro-Wilk test. Cross-sectional and longitudinal pairwise comparisons were conducted using the Welch t-test, Mann-Whitney U-test, and Kruskal-Wallis test with post hoc analyses, and χ² tests as denoted.

To test the association between lower extremity PFI, low HGS, and incident MCI we used proportional hazards models. All models were adjusted for demographics, WTC exposure severity measures, and medical history. Longitudinal analyses relied on proportional hazards regression to estimate the time until onset of MCI.²⁸ The time scale used was measured in days since initial evaluation, scaled to reflect yearly change. Because the outcome for this study was new onset of MCI or conversion to dementia, responders were censored from follow-up when they had evidence of MCI or dementia. Those with evidence of dementia at baseline (n = 78) were excluded from longitudinal analyses; those with MCI at baseline (n = 439) were only included in analyses of conversion to dementia. The marginal exact method was used to handle ties, and the proportional hazards assumption was tested using Schoenfeld residuals. Mediation analyses relied on generalized structural equation modeling to test direct and indirect pathways linking PTSD at enrollment with physical impairment at initial assessment preceding the onset of MCI. A Weibull survival distribution was used, bootstrapping with 100 replicates was used to calculate Huber-White robust standard errors.

Power analyses suggested that we would need to identify at least 120 cases of new-onset MCI during the follow-up period to detect a two-fold increase in the hazards ratio while adjusting for 2 confounders, leading us to focus specifically on MCI in this study. Incidence rates for dementia were too low for survival analyses to have sufficient power, so these analyses were reported as exploratory and relied on fewer covariables that included only those factors that were thought to be most predictive for MCI.

Standard Protocol Approvals, Registrations, and Patient Consents

The Institutional Review Board at Stony Brook University (ID# 604113) approved study procedures, and all participants provided written informed consent.

Data Availability

Medical information is protected, so only processed de-identified data will be made available upon receipt of a reasonable request to the corresponding author.

Results

Sample Characteristics

At study baseline, the 2,687 WTC responders who participated in this study were an average of 53 (SD = 8) years old. The sample is mostly comprised of White (79.4%) men (91.8%) who were law enforcement officials (72.7%) during the 9/11 response and recovery efforts. Responders had an average BMI of 31, and respiratory conditions (6.7%), cancer (5.5%), and cardiovascular disease (3.6%) were the most commonly reported comorbid health conditions. 11.8% had PTSD, and 19.2% had impaired cognition.

Three hundred twenty-four responders (12.06%, 95% CI = [10.83–13.29]) in this sample had lower extremity PFI. Participants with lower extremity PFI were approximately 3 years older, had higher BMI, lower educational attainment, were more likely to report a pulmonary embolism and worse PTSD symptoms, and were more likely to be nontraditional responders. Sample characteristics are shown in Table 1 for the total sample and stratified by PFI status.

Physical Functional Performance by Cognitive Status

A series of Kruskal-Wallis tests with standard post hoc analyses were used to examine lower extremity performance and upper extremity strength. Differences in lower extremity physical functioning were assessed between responders who were stratified by their baseline cognitive status (Figures 1). Significant differences across groups were identified when examining the SPPB total score (χ²(2, N = 2051) = 35.17, p < 0.001), with post hoc analyses indicating significant differences between CU and MCI (p < 0.001), CU and dementia (p < 0.001), and between MCI and dementia (p < 0.05).

Figure 1. A Kruskal-Wallis Test Was Conducted to Examine the Differences on SPPB Total Score and Balance, Gait, and Chair Rise Performance in WTC Responders According to Baseline Cognitive Status.

Note: (A) Significant differences in SPPB total score were found across groups (χ²(2, N = 2051) = 35.17, p < 0.001). A post hoc analysis using the Dunn test with Holm correction showed significant differences between CU and MCI, p < 0.001, CU and dementia, p < 0.001, and between MCI and dementia, p < 0.05. (B) Significant differences in balance score were found across groups (χ²(2, N = 2051) = 25.04, p < 0.001). A post hoc analysis using the Dunn test with Holm correction showed significant differences between CU and MCI, p < 0.05, CU and dementia, p < 0.001, and between MCI and dementia, p < 0.001. (C) Significant differences in gait score were found across groups (χ²(2, N = 2051) = 27.28, p < 0.001). A post hoc analysis using the Dunn test with Holm correction showed significant differences between CU and MCI, p < 0.001, CU and dementia, p < 0.001, and between MCI and dementia, p < 0.01. (D) Significant differences in chair score were found across groups (χ²(2, N = 2051) = 24.99, p < 0.001). A post hoc analysis using the Dunn test with Holm correction showed significant differences between CU and MCI, p < 0.001, and between CU and dementia, p < 0.001. Note: Figure depicts means and standard error bars; CU = cognitively unimpaired; MCI = mild cognitive impairment; D = dementia; SPBB = Short Physical Performance Battery.

Differences in lower extremity physical functioning were also examined when evaluating performance on each of the components of the SPPB between responders who were stratified by their baseline cognitive status. For balance, significant differences were identified across groups (χ²(2, N = 2051) = 25.04, p < 0.001), with post hoc analyses indicating significant differences between CU and MCI (p < 0.05), CU and dementia (p < 0.001), and between MCI and dementia (p < 0.001). For gait speed, significant differences were identified across groups (χ²(2, N = 2051) = 27.28, p < 0.001), with post hoc analyses indicating significant differences between CU and MCI (p < 0.001), CU and dementia (p < 0.001), and between MCI and dementia (p < 0.01). For chair rise, significant differences were identified across groups (χ²(2, N = 2051) = 24.99, p < 0.001), with post hoc analyses indicating significant differences between CU and MCI (p < 0.001) and between CU and dementia (p < 0.001). Analyses of timing for the gait speed and chair rise components yielded similar results (see eFigure 1 in the Supplement, http://links.lww.com/CPJ/A377).

Differences in HGS were also examined when stratified by sex and baseline cognitive status (Figures 2). Significant differences in HGS across groups were identified for both men (χ²(2, N = 1883) = 56.75, p < 0.001) and women (χ²(2, N = 165) = 9.42, p < 0.01). For men, post hoc analyses indicated significant differences between CU and MCI (p < 0.001), between CU and dementia (p < 0.001), and between MCI and dementia (p < 0.05). For women, post hoc analyses indicated significant differences between CU and dementia (p < 0.01) and between MCI and dementia (p < 0.01).

Figure 2. A Kruskal-Wallis Test Was Conducted to Examine the Differences on Handgrip Strength Performance in Male and Female WTC Responders According to Baseline Cognitive Status.

(A) Significant differences in were found across male groups (χ²(2, N = 1883) = 56.75, p < 0.001). A post hoc analysis using the Dunn test with Holm correction showed significant differences between CU and MCI, p < 0.001, between CU and dementia, p < 0.001, and between MCI and dementia, p < 0.05. (B) Significant differences in were found across female groups (χ²(2, N = 165) = 9.42, p < 0.01). A post hoc analysis using the Dunn test with Holm correction showed significant differences between CU and dementia, p < 0.01, and between MCI and dementia, p < 0.01. Note: Figures depict means and standard error bars; CU = cognitively unimpaired; MCI = mild cognitive impairment; D = dementia.

Cross-sectional comparisons of baseline MoCA scores between responders with and without lower extremity PFI identified that responders with PFI scored significantly lower on the MoCA total score and across executive function (trails), visual reproduction, working memory, language, and episodic memory subsections. Of interest, the largest effect sizes were evident across the total MoCA score, with focal effects evident in the domains of episodic memory, executive function (trails), working memory, language, and visuospatial functioning (see eTable 1 in the Supplement, http://links.lww.com/CPJ/A377).

Baseline Physical Functioning and Cognitive Decline

We conducted multivariable-adjusted cox proportional hazards regression to determine risk factors for incident MCI (Table 2). Analyses replicated earlier work showing an association between PTSD and incident MCI in the models excluding measures of PFI. Analyses that included measures of lower and upper extremity physical functioning showed they were both associated with incident MCI. As seen in Figure 3, the results of this model suggested that lower extremity PFI and low maximal HGS were associated with a dose-response association with incident MCI. In addition, in the model adjusting for measures of PFI, the relationship between PTSD and incident MCI diminished in size and was no longer statistically significant.

Table 2.

Multivariable Adjusted Hazards Ratios Derived From Cox Proportional Hazards Regression Examining Associations Between Posttraumatic Stress Disorder and Incident Mild Cognitive Impairment

Figure 3. Cumulative Hazards of Developing Mild Cognitive Impairment at a Follow-up Based on Baseline Physical Functional Impairment Status.

We next completed analyses determining whether measures of PFI played a role in the pathway linking PTSD with incident MCI. These analyses suggested that after adjusting for all covariates (shown in Figure 4, model 1), PTSD was associated with the incidence of MCI. However, after adjusting for PFI (Model 2), no direct association remained between PTSD and incident MCI. This model indicated that lower extremity PFI and HGS fell along the pathway between PTSD and incident MCI such that each were predicted by PTSD and each in turn predicted the risk of incident MCI at follow-up.

Figure 4. Intermediary Pathway Analyses Showing Direct and Indirect Models Adjusted for All Covariates Estimated Using Generalized Structural Equation Modeling.

Note: Models were fit using generalized structural equation modeling and therefore relied on assumptions that physical functional impairment followed a logit-binomial model, whereas the incidence of mild cognitive impairment followed a proportional hazards model. This model in addition adjusted for sex, race/ethnicity, educational attainment, occupation, early arrival, ergonomic exposures, hypertension, diabetes, pulmonary embolism, and cancer.

We concluded by exploring risk factors for conversion to dementia among those who were determined to have MCI at baseline (See eTable 2 in the Supplement, http://links.lww.com/CPJ/A377). These analyses revealed a similar overall pattern characterized by the evidence of an association between PTSD and incident dementia that was completely attenuated by the inclusion of lower extremity PFI though not HGS.

Sensitivity Analyses

There were no significant interactions between PCL score and lower extremity PFI or low maximal HGS. We examined the potential for a dose-response relationship between more severe PFI and incident MCI by stratifying our groups further into those with moderate-severe lower extremity PFI vs those with milder and no lower extremity PFI. We found that those with moderate-severe impairment had higher hazards of incident MCI than those who had milder impairment or were unimpaired (See eFigure 2 in the Supplement, http://links.lww.com/CPJ/A377). We examined the potential for pharmaceutical usage to explain associations of PTSD, PFI, and low HGS with incident MCI. The results suggested that although pharmaceutical usage was often associated with poorer physical performance, these results did not change substantive conclusions. For example, PTSD remained statistically significant upon adjusting for all pharmaceutical usage (multivariable-adjusted hazards ratio [aHR] = 1.176 [1.050–1.318], p = 0.005) but ignoring PFIs, as did PFI (aHR = 1.390 [1.129–1.712] p = −0.002) and low HGS (1.153 (1.044–1.274], p = 0.005). Nevertheless, analyses revealed that second-generation antipsychotics, antivertigo drugs, atypical antidepressants, and benzodiazepines were all associated with the risk of both PFI and incident MCI. Finally, we examined the results using logistic regression at follow-up as compared to relying on survival analysis and found that the results remained similar overall.

Discussion

WTC responders and trauma-exposed populations have evidence of physical functional limitations and of cognitive dysfunction at high rates 2 decades after 9/11. Replicating previous work, we found that the measures of PFI were associated with cognition at baseline and that PFI predicted both new onset of MCI and conversion to dementia. In addition, mediation analyses uniquely revealed that PFI acted as an intermediary condition in the relationship between PTSD and incident MCI. Although the following discussion examines the broader implications of such a finding, these results may suggest that PTSD is related to a heretofore unknown neuropathologic or neurodegenerative condition initially characterized by PFI.

A recent systematic review investigating the relationship between dementia, PFI, and sarcopenia concluded that most reviewed studies identified a positive association between PFI and dementia, which varied in severity according to dementia subtype.²⁹ Moreover, this review indicated that individuals with dementia may present an increased prevalence of PFI and features of sarcopenia and that PFI may be a predictor for the development of dementia. Neurodegenerative diseases are the most likely cause of losses in physical functioning that are accompanied or followed by cognitive impairment. The most common conditions associated with concurrent physical and cognitive decline is thought to include Lewy bodies in the cerebral cortex³⁰ and amyotrophic lateral sclerosis.³¹ Recent work has also highlighted that cerebellar cognitive affective syndrome, a neuroanatomical syndrome with physical functional and cognitive symptoms, can arise in certain chronic psychiatric disorders.³² Therefore, changes in physical functioning may reflect a neurodegenerative process resulting from chronic PTSD and could, in part, explain our results.

Because PTSD is a known proinflammatory condition,³³ and chronic inflammation can increase PFI³⁴ and sarcopenia,³⁵ we hypothesize that examining this relationship in future studies of WTC responders and other affected populations could potentially highlight a deeper mechanistic understanding of the relationship between PTSD and physical functioning. Irrespective of the etiology, however, the results in this study suggest that lower and upper extremity physical functioning is an important measure to monitor and examine in future studies considering outcomes related to chronic PTSD.

Neurobiological approaches in chronic PTSD have often highlighted the role of dysregulated physiologic processes causing inflammation alongside structural and functional changes. For example, previous research has linked PTSD to reduced hippocampal and amygdala volume³⁶ in addition to significant structural³⁷ and neurochemical³⁸ dysregulation in regions of the brain associated with stress or trauma. Previous work using neuroimaging in the WTC population has found that cognitively impaired responders with PTSD are indistinguishable in levels of cortical,³⁹ cerebellar,⁴⁰ and hippocampal atrophy⁴¹ when compared with cognitively impaired responders without PTSD. However, one study of MCI noted that glial activation was related to PTSD symptom severity,⁴² whereas other studies noted the presence of proteins consistent with interneuronal neurodegeneration⁴³ and amyloidogenesis.⁴⁴ In a neuroimaging study of cortical complexity,⁴⁵ a measure of concurrent cortical thickness, neural density, and surface convolution previously demonstrated to be negatively associated with psychiatric disorders, we demonstrated reduced fractal dimensions in WTC responders with PTSD vs those without. In addition, and specific to our findings here, that study identified negative associations between cortical complexity in the sensorimotor precentral gyrus with symptoms of re-experiencing and hyperarousal, highlighting a potential negative neurobiological association with physical function that may be occurring in patients with PTSD.

PFI is a core component of physical frailty, which also consists of physical weakness, cognitive impairment, and behavioral changes including fatigue. Previous work has shown that PTSD is a strong predictor of reports of fatigue and of postexertional malaise.⁴⁶ Together, these results suggest that individuals with chronic PTSD may be at increased risk of physical frailty at midlife. PFI is often a distal result of chronic systemic inflammation at midlife⁴⁷ or an indicator of biological aging.⁴⁸ Previous work in this cohort has noted that chronic PTSD is associated with accelerated transcriptional⁴⁹ and epigenetic⁵⁰ aging. The results in this study confirm this previous literature and suggest that PTSD may be an indicator of increased risk of age-related physical frailty.

Strengths of this prospective study of cognitive decline in WTC responders include comprehensive measurement of physical functioning, a large sample size, and a lengthy follow-up period. In addition, by excluding data from the period after the beginning of the COVID-19 pandemic, we reduced the potential for unobserved confounding because COVID-19 infections. Nevertheless, the findings should be considered in light of the study limitations.

First, the sample excluded individuals who were unable to complete the physical functioning battery because of physical limitations. Second, although the SPPB, a standardized battery, was used to measure lower extremity physical performance, an equivalent overall measure of upper extremity physical performance was not available. Because this study suggested that upper body strength, as measured using maximal HGS, was independently associated with the risk of MCI at follow-up, the development of an overall measure of upper body physical functioning may prove helpful. Third, although being a relatively large study that is representative of the general WTC responder population, the study sample was predominantly White and men. The results differed in some measures of PFI as compared to men, potentially suggesting that greater care is taken when generalizing results to female responders as compared to men. Last, nearly all WTC responders were employed during the 9/11 response efforts. Since workers are often healthier than unemployed individuals, the results from this cohort may be more conservative than those of studies of the general population.

There is a growing interest in understanding the early predictors of MCI and the implications of MCI in traumatized individuals with PTSD. This study suggests that one early marker for the risk of MCI or dementia might be physical frailty because PFI was associated with baseline cognitive performance as well as incident MCI and conversion to dementia longitudinally. This research therefore supports the potential for actively focusing on monitoring physical functioning in individuals with chronic PTSD.

TAKE-HOME POINTS

• → WTC responders with lower extremity PFI had poorer baseline cognition and increased hazards of developing MCI.

• → Low physical functioning seems to play an intermediary role in the relationship between PTSD and incident MCI.

• → Regular monitoring of physical functioning may be warranted among those with chronic PTSD.

Appendix. Authors

Study Funding

Funding for this article was provided by the NIH (R01 AG049953) and by the Centers for Disease Control and Prevention's National Institute of Occupational Safety and Health to administer the monitoring survey and diagnose and treat World Trade Center (WTC)-related diseases (CDC-200-2011-39361).

Disclosure

The authors report no relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.