ABSTRACT
Background: Nervous system post-acute sequelae of COVID-19 (NS-PASC) include cognitive and mental health symptoms. To further define these, we applied a Research Domain Criteria (RDoC) approach to examine motor, positive valence (PV) and negative valence (NV) systems, and social processing data in The COVID Mind Study of NS-PASC. Method(s): NS-PASC participants (>3 months after COVID-19) referred from a NeuroCOVID Clinic and non-COVID controls from New Haven, CT and Baltimore, MD completed an RDoC test battery for cognition (language, declarative and working memory, cognitive control, perception), motor, PV, NV, and social processes. To date, 3T MRI with diffusion tensor imaging was performed in 11 NS-PASC to assess white matter integrity (global white matter fractional anisotropy [FA]) as a contributor to alterations identified on the RDoC tests. Analysis of Covariance examined group differences after adjusting for sex, race, ethnicity, age, and years of education. Result(s): 25 NS-PASC participants (age 43.4+/-11.3 yrs, 76% female, 402 days after COVID-19 symptom onset) and 29 controls (age 46.2.6+/-13.1 yrs, 66% female) completed the battery. Controls were more racially diverse and less educated than NS-PASC (43% vs. 12% Black, p=0.005;14.5 vs. 16.1 yrs of education, p< 0.05). Means and statistics for RDoC between NS-PASC and controls are shown in Table. NS-PASC performed worse in language, verbal working and declarative memory, and perception and reported greater cognitive control difficulties (e.g., behavioral inhibition, set shifting) without issues on performance-based metrics (Stroop, Trail Making Test-Part B), and had slower motor function. NS-PASC reported more NV issues including greater symptoms of depression, rumination in response to depressive mood, apathy, childhood trauma, anxiety, and perceived stress. There were no differences in PV and social processing. In a subset of NS-PASC participants who underwent MRI, there was a dynamic range of FA values with a mean of 0.509 (IQR 0.481 - 0.536). Conclusion(s): Our findings extend previous PASC studies characterizing cognitive and mental health alterations, indicating that additional RDoC assessments warrant focus, including alterations in motor and the negative valence system. In future analyses, we will examine white matter integrity as a pathophysiologic contributor to these RDoC systems.
ABSTRACT
Background: It is unknown whether individuals with neurological post-acute sequelae of COVID-19 (NeuroPASC) display altered levels of neuroimmune activity or neuronal injury. Method(s): Participants with new or worsened neurologic symptoms at least 3 months after laboratory-confirmed COVID-19 were enrolled in The COVID Mind Study at Yale. Never COVID controls (no history of COVID-19;nucleocapsid (N) antibody negative) were pre-pandemic or prospectively enrolled volunteers. CSF and plasma were assessed for neopterin and for IL-1beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, MCP-1, TNFalpha by bead-based multiplex assay;and for anti-SARS-CoV-2 N antibodies by Luminex-based multiplex assay in technical replicate, normalized against bovine serum albumin conjugated beads. Plasma concentrations of D-dimer, C-reactive protein, neurofilament light chain (NFL), and glial fibrillary acid protein (GFAP) were measured using high-sensitivity immunoassays. Group comparisons used non-parametric tests. Result(s): NeuroPASC participants (n=38) were studied 329 (median) days (range 81-742) after first positive test for acute COVID-19. Cognitive impairment (84%) and fatigue (82%) were the most frequent post-COVID symptoms. NeuroPASC and controls (n=22) were median 49 vs 52 yrs old (p=0.9), 74% vs 32% female (p< 0.001), 76% vs 23% white race (p< 0.001), and 6% vs 57% smokers (p< 0.001). CSF white blood cells/mL, CSF protein, and serum:CSF albumin ratio were normal in both groups. CSF TNFalpha (0.66 vs 0.55 pg/ul) and plasma IL12p40 were higher (103.3 vs 42.7);and MCP-1 (503 vs 697 pg/ul) and IL-6 (1.32 vs 1.84 pg/ul;p < 0.05 for IL-6) were lower in NeuroPASC vs controls (p< 0.05);but none of these differences were significant after adjusting for multiple comparisons. Plasma GFAP was elevated in NeuroPASC vs controls (54.4 vs 42.3 pg/ml;adjusted p< 0.03). There were no differences in the other biomarkers tested. 10/31 and 7/31 NeuroPASC had anti-N antibodies in CSF and plasma, respectively. Conclusion(s): When comparing NeuroPASC to never COVID controls, we found no evidence of neuroinflammation (normal CSF cell count, inflammatory cytokines) or blood-brain barrier dysfunction (normal albumin ratio), and no support for ongoing neuronal damage (normal plasma NFL). Future studies should include better gender and race matched controls and should explore the significance of a persistent CNS humoral immune response to SARS-CoV-2 and elevated plasma GFAP after COVID-19. (Figure Presented).
ABSTRACT
Background: The pathogenesis of neuropsychiatric symptoms persisting months after acute SARS-CoV-2 infection is poorly understood. We examined clinical and laboratory parameters in participants with post-acute COVID-19 neuropsychiatric symptom to assess for systemic and nervous system immune perturbations. Methods: Participants with a history of laboratory confirmed COVID-19 and ongoing neurologic symptoms were enrolled in an observational study that collected medical history;detailed post-COVID symptom survey;and paired cerebrospinal fluid (CSF) and blood. In addition to standard clinical labs, neopterin and anti-SARS-CoV-2 antibodies (anti-spike, RBD, and nucleocapsid) were measured by ELISA. Non-parametric tests were used to compare CSF and blood findings between the post-COVID participants and pre-COVID-19 era healthy controls. Results: Post-COVID participants (n=27) and controls (n=21) were similar in age (median 51 and 46 years), but there was a greater proportion of females (67% vs 24%;p=0.004) and white participants in the post-COVID cohort (63% vs 24%;p=0.04). The post-COVID study visit was a median of 264 days (IQR 59-332) after acute COVID-19 symptom onset. 35% were hospitalized during their acute illness;12% required intensive care. 33% had previously been treated with medications for mental health conditions. The most frequent neuropsychiatric symptoms were cognitive impairment (67%), mood symptoms (67%), headache (56%), and neuropathy (41%). Blood c-reactive protein, T cell count, and T cell subset frequency (CD4% and CD8%) were similar between groups, while D-dimer was higher in the post-COVID cohort (median 0.48 vs 0.27 mg/L;p = 0.019) (Figure). CSF WBC, protein, neopterin, and CSF/blood albumin ratio were similar between the groups;the frequency of CSF lymphocytes was lower in the post-COVID cohort (p = 0.05) (Figure 1). Antibodies against at least one SARS-CoV-2 antigen were detected in 7/10 CSF and 8/9 blood samples in the post-COVID CSF (antibody reactivity range 1.5 to 55-fold greater than to control antigens). Conclusion: In this small cohort of post-COVID participants with neurologic symptoms, we found limited differences in CSF and blood markers when compared to pre-pandemic healthy controls. Deeper immunophenotyping in a larger number of participants may provide greater insight into subtle differences. The presence of anti-SARS-CoV-2 antibodies in CSF months after acute infection warrants further investigation.
ABSTRACT
Background: Public health emergencies increase stress, anxiety, and fear, and older adults and those with pre-existing conditions may be especially vulnerable. We used a survey-based pilot study to explore the psychosocial impact of COVID-19 on older PLWH and correlate the level of COVID-19 related distress with baseline HIV disease metrics. Methods: Participants were PLWH > age 50 who had previously (2017-2020) enrolled in the HARC HIV biorepository study at Yale. 48 PLWH were contacted and 22 participated in this study, conducted Aug-Sep 2020. An 8-part survey was administered to inquire about COVID-19 exposure, financial distress, medication adherence/medical follow-up, social support, substance use, and mood symptoms (Table 1). Cross-sectional analysis was performed on results at the time of survey administration, and longitudinal analysis was performed to compare anxiety (GAD-7), alcohol/drug use (ASSIST), and depression (CES-D) to baseline values obtained pre-pandemic (median 1.3 years prior). Results: Participant demographics are reported in Table 1. 2 participants reported having been diagnosed with COVID-19, 1 of whom had a known COVID-19 positive contact. 68% of participants were retired and reported no changes to their work due to COVID-19, and most reported moderate (4.1 on scale of 0-7) financial distress. Most reported excellent medication adherence, with 77% reporting no missed doses. 95% stated they felt “very well supported” by their primary HIV care providers, with 18% saying their care was improved during COVID-19. Only 18% felt their care was “somewhat worse.” Most participants also scored highly on the social support scale, with an average score of 11 out of 14. There were no significant differences between pre-pandemic and current scores for anxiety, alcohol/drug use, and depression, and there was no correlation between baseline HIV metrics and current level of distress. However, there was an association between COVID-19-associated worsening in GAD-7 score and a history of substance use disorder (p = 0.02). Conclusion: These results suggest that overall, most participants were doing well with excellent medication adherence and no significant changes in scores for anxiety, depression, and substance use, but that older PLWH with a history of substance use disorder had a greater risk for increased anxiety during COVID- 19. These findings can help identify groups who may be the most at-risk to experience distress from a second wave of COVID-19 and put support measures in place.