RECOVER-NEURO: study protocol for a multi-center, multi-arm, phase 2, randomized, active comparator trial evaluating three interventions for cognitive dysfunction in post-acute sequelae of SARS-CoV-2 infection (PASC).

BACKGROUND: Post-acute sequelae of SARS-CoV-2 infection (PASC) symptoms have broad impact, and may affect individuals regardless of COVID-19 severity, socioeconomic status, race, ethnicity, or age. A prominent PASC symptom is cognitive dysfunction, colloquially referred to as "brain fog" and characterized by declines in short-term memory, attention, and concentration. Cognitive dysfunction can severely impair quality of life by impairing daily functional skills and preventing timely return to work. METHODS: RECOVER-NEURO is a prospective, multi-center, multi-arm, phase 2, randomized, active-comparator design investigating 3 interventions: (1) BrainHQ is an interactive, online cognitive training program; (2) PASC-Cognitive Recovery is a cognitive rehabilitation program specifically designed to target frequently reported challenges among individuals with brain fog; (3) transcranial direct current stimulation (tDCS) is a noninvasive form of mild electrical brain stimulation. The interventions will be combined to establish 5 arms: (1) BrainHQ; (2) BrainHQ + PASC-Cognitive Recovery; (3) BrainHQ + tDCS-active; (4) BrainHQ + tDCS-sham; and (5) Active Comparator. The interventions will occur for 10 weeks. Assessments will be completed at baseline and at the end of intervention and will include cognitive testing and patient-reported surveys. All study activities can be delivered in Spanish and English. DISCUSSION: This study is designed to test whether cognitive dysfunction symptoms can be alleviated by the use of pragmatic and established interventions with different mechanisms of action and with prior evidence of improving cognitive function in patients with neurocognitive disorder. If successful, results will provide beneficial treatments for PASC-related cognitive dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov NCT05965739. Registered on July 25, 2023.

Greater executive dysfunction in patients post-COVID-19 compared to those not infected.

BACKGROUND: A number of patients post-coronavirus disease-19 (COVID-19) report cognitive impairment (CI), even months after acute infection. We aimed to assess if COVID-19 is associated with increased incidence of CI in comparison to controls. METHODS: We analyzed data from the Mount Sinai Health System Post-COVID-19 Registry in New York City, a prospective cohort of patients post-COVID-19 ≥18 years of age and non-infected controls. CI was defined by scores ≥ 1.0 standard deviation below population norms, and was assessed using well-validated measures of attention, working memory, processing speed, executive functioning/cognitive flexibility, language, learning, and memory. Logistic regression models assessed odds for CI in each domain in patients post-COVID-19 vs. controls after adjusting for potential confounders. In exploratory analyses, we assessed odds for CI by site of acute COVID-19 care as a proxy for disease severity. FINDINGS: 417 patients post-COVID-19 and 151 controls (mean age 49 years, 63% female, 21% Black, 17% Latinx) were included. In adjusted analyses, patients were significantly more likely than controls to have CI in executive functioning (odds ratio [OR]: 2.19; 95% confidence interval [CI]: 1.03 to 4.67), particularly those treated in outpatient (OR: 2.22; 95% CI: 1.02 to 4.82) and inpatient hospital (OR: 3.59; 95% CI: 1.27 to 10.16) settings. There were no significant associations between CI in other domains and history of COVID-19 or site of acute care. INTERPRETATION: Patients post-COVID-19 have greater odds of executive dysfunction, suggesting that focused cognitive screening may be prudent, even in those with mild to moderate disease. Studies should explore the pathophysiology and potential treatments for CI in this population. FUNDING: This work was funded by the Icahn School of Medicine at Mount Sinai.

Rates of Undiagnosed Cognitive Impairment and Performance on the Montreal Cognitive Assessment Among Older Adults in Primary Care.

BACKGROUND: The number of adults in the USA with cognitive impairment is increasing; however, few studies report prevalence rates of undiagnosed cognitive impairment among older adults in primary care. OBJECTIVE: To determine the prevalence of undiagnosed cognitive impairment among adults ages 55 years and older in primary care settings and provide normative data for the Montreal Cognitive Assessment in this context. DESIGN: Single interview, observational study. PARTICIPANTS: English-speaking adults ages 55 years and older without diagnoses of cognitive impairment recruited from primary care practices in New York City, NY, and Chicago, IL (n = 872). MAIN MEASURES: Montreal Cognitive Assessment (MoCA). Undiagnosed cognitive impairment was defined by age and education adjusted z-scores more than 1.0 and 1.5 standard deviations below published norms, corresponding to mild or moderate to severe cognitive impairment, respectively. KEY RESULTS: The mean age was 66.8 (8.0) years, 44.7% were male, 32.9% were Black or African-American, and 29.1% were Latinx. Undiagnosed cognitive impairment was identified in 20.8% of subjects (mild impairment, 10.5%; moderate-severe impairment, 10.3%). Impairment at any level of severity was associated in bivariate analyses with several patient characteristics, most notably for race and ethnicity (White, non-Latinx, 6.9% vs. Black, non-Latinx, 26.8%, Latinx, 28.2%, other race, 21.9%; p < 0.0001), place of birth (US 17.5% vs. non-US 30.7%, p < 0.0001), depression (33.1% vs. no depression, 18.1%; p < 0.0001), and impairment in activities of daily living (≥ 1 ADL impairment, 34.0% vs. no ADL impairment, 18.2%; p < 0.0001). CONCLUSIONS: Undiagnosed cognitive impairment is common among urban dwelling older adults attending primary care practices, and was associated with several patient characteristics, including non-White race and ethnicity and depression. Normative data for the MoCA from this study may serve as a useful resource for studies of similar patient populations.

Semi-automated Segmentation and Quantification of Perivascular Spaces at 7 Tesla in COVID-19.

While COVID-19 is primarily considered a respiratory disease, it has been shown to affect the central nervous system. Mounting evidence shows that COVID-19 is associated with neurological complications as well as effects thought to be related to neuroinflammatory processes. Due to the novelty of COVID-19, there is a need to better understand the possible long-term effects it may have on patients, particularly linkage to neuroinflammatory processes. Perivascular spaces (PVS) are small fluid-filled spaces in the brain that appear on MRI scans near blood vessels and are believed to play a role in modulation of the immune response, leukocyte trafficking, and glymphatic drainage. Some studies have suggested that increased number or presence of PVS could be considered a marker of increased blood-brain barrier permeability or dysfunction and may be involved in or precede cascades leading to neuroinflammatory processes. Due to their size, PVS are better detected on MRI at ultrahigh magnetic field strengths such as 7 Tesla, with improved sensitivity and resolution to quantify both concentration and size. As such, the objective of this prospective study was to leverage a semi-automated detection tool to identify and quantify differences in perivascular spaces between a group of 10 COVID-19 patients and a similar subset of controls to determine whether PVS might be biomarkers of COVID-19-mediated neuroinflammation. Results demonstrate a detectable difference in neuroinflammatory measures in the patient group compared to controls. PVS count and white matter volume were significantly different in the patient group compared to controls, yet there was no significant association between PVS count and symptom measures. Our findings suggest that the PVS count may be a viable marker for neuroinflammation in COVID-19, and other diseases which may be linked to neuroinflammatory processes.

Cognition, symptom perception, and medication non-adherence in older adults with asthma.

BACKGROUND: Cognitive impairment (CI) is highly prevalent in elderly asthmatics and is associated with worse asthma self-management (SM) and outcomes. CI may also explain why older adults may under-perceive asthma symptoms. We hypothesized that CI would be associated with low medication adherence and asthma symptom under-perception (ASP). We also hypothesized that ASP would mediate the relationship between CI and medication adherence. METHODS: Participants of this longitudinal cohort study were asthmatics (N = 334) ≥60 years (51% Hispanic, 25% Black). Cognitive measures assessed general cognition, attention, processing speed, executive functioning, memory, and language. Measures of SM were self-reported and electronically measured adherence to controller medications. ASP was assessed for 6 weeks by participants entering estimates of peak expiratory flow (PEF) into a programmable peak flow meter, followed by PEF blows. Participants were blinded to actual PEF values. Percentage of time that participants were in the over-perception zone was calculated as an average. RESULTS: In regression analyses, those with impairments in memory and general cognition had lower odds ratios (OR) for self-reported non-adherence (OR: 0.96, 95% CI 0.93 - 0.98 & OR: 0.90, 95% CI 0.83 - 0.96, respectively). CI was not associated with electronically measured non-adherence or ASP. In structural equation modeling, while CI was associated with adherence (ß = 0.04, SE = 0.021, p = 0.04), ASP did not mediate this relationship. CONCLUSIONS: While results confirmed the importance of cognition in asthma SM, these findings were not linked to ASP. Future analyses are needed to understand the role of confounding factors.

The Relationship Between Post-Traumatic Stress Disorder and Self-Management Behaviors in World Trade Center Workers with Asthma.

BACKGROUND: Comorbid posttraumatic stress disorder (PTSD) is highly prevalent and associated with increased morbidity among World Trade Center (WTC) rescue and recovery workers with asthma. However, the potential behavioral pathways underlying this relationship remain unclear. OBJECTIVE: To evaluate whether PTSD is associated with lower adherence to asthma self-management behaviors among WTC workers with asthma. METHODS: We used data from a prospective cohort of WTC workers with a physician diagnosis of asthma who were prescribed controller medications. Presence of comorbid PTSD was determined based on structured clinical interviews. Asthma self-management behaviors included medication adherence, inhaler technique, use of action plans, and trigger avoidance. We conducted unadjusted and multiple regression analyses to evaluate the association of PTSD with asthma self-management. RESULTS: Overall, 30% of 276 WTC workers with asthma had comorbid PTSD. Posttraumatic stress disorder was associated with worse asthma control and poorer quality of life. However, PTSD was not significantly associated with medication adherence (odds ratio [OR] -0.15; 95% confidence interval [CI] -0.5 to 0.2), inhaler technique (OR -0.12; 95% CI -0.7 to 0.5), use of action plans (OR 0.8; 95% CI 0.4 to 1.8), or trigger avoidance (OR 0.9; 95% CI 0.4 to 1.8). CONCLUSIONS: We did not find significant differences in key asthma self-management behaviors between WTC workers with and without PTSD. These results suggest that other mechanisms, such as differences in symptom perception or inflammatory pathways, may explain the association between PTSD and increased asthma morbidity.

The impact of cognitive impairment on self-regulatory styles in breast cancer survivors.

OBJECTIVE: Cognitive impairment (CI) is highly prevalent in breast cancer survivors (BCS), and can be a barrier to health-promoting behaviours. However, the ways in which CI may affect self-regulation or motivation to perform such behaviours have not been explored. We assessed if BCS with CI report greater extrinsic self-regulation compared to those without CI and if this relationship persists after controlling for depression. METHODS: We recruited BCS with diabetes and assessed cognition and motivation to perform healthy diabetes management behaviours (e.g., diet and exercise). Participants completed a cognitive battery evaluating attention, working memory, executive functioning (EF), processing speed (PS), language and memory. The Treatment Self-Regulation Questionnaire (TSRQ) assessed intrinsic versus extrinsic motivation. Depression was determined by a score ≥16 on the Center for Epidemiological Studies Depression Scale. Wilcoxon rank-sum test compared associations between CI and TSRQ scores. RESULTS: Participants were 118 older adults (mean age 65 years). Participants with CI in the following domains had higher extrinsic self-regulation scores compared to those without CI: attention (p < 0.01), PS (p = 0.01), EF (p < 0.01), language (p = 0.02; p = 0.04) and memory (p = 0.04; p = 0.03). After adjusting for depression, the relationship between CI and higher extrinsic self-regulation scores remained significant. CONCLUSIONS: BCS with CI appear to rely more on external sources of motivation to perform health behaviours, regardless of depression. Future studies and interventions to improve health behaviours should consider screening for CI and involving caregivers for those with CI to improve outcomes.

The Utility of a Pre-Transplant Psychosocial Evaluation in Predicting Post-Liver Transplant Outcomes.

BACKGROUND: There is insufficient evidence about the ability of pretransplant psychosocial evaluations to predict posttransplant outcomes. While standardized assessments were developed to increase predictive validity, it is unclear whether the risk scores they yield predict outcomes. We investigated if the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT), a scaling approach to those assessments, would have been a superior predictor than the standard psychosocial evaluation. METHODS: In this retrospective study, medical records of 182 adult liver transplant recipients who were at least 1 year posttransplant and prescribed tacrolimus for immunosuppression were analyzed. Regression analyses predicted outcomes of interest, including immunosuppressant nonadherence and biopsy-proven rejection, obtained 1-year posttransplant to time of data collection. Nonadherence was determined using the medication level variability index (MLVI). RESULTS: Approximately 49% of patients had MLVI > 2.5, suggestive of nonadherence, and 15% experienced rejection. SIPAT total score did not predict adherence either using the continuous (P = .70), or dichotimized score, above or below > 2.5 (P = .14), or rejection (P = 0.87). Using a SIPAT threshold (total score > 69) did not predict adherence (p = .16) nor was a superior predictor of the continuous adherence score (P = .45), MLVI > 2.5 (P = .42), or rejection (P = 0.49), than the standard evaluation. CONCLUSION: Our findings suggest that the SIPAT is unable to predict 2 of the most important outcomes in this population, immunosuppressant adherence and rejection. Research efforts should attempt to evaluate the best manner to use psychosocial evaluations.