BACKGROUND: It remains unclear whether subjective and objective measures of cognitive function in Post COVID-19 Condition (PCC) are correlated. The extent of correlation has mechanistic and clinical implications.
METHODS: This post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial contains baseline data of subjective and objective measures of cognition in a rigorously characterized cohort living with PCC. Herein, we evaluated the association between subjective and objective condition function, as measured by the Perceived Deficits Questionnaire, 20-item (PDQ-20) and the Digit Symbol Substitution Test (DSST) and Trails Making Test (TMT)-A/B, respectively.
RESULTS: A total of 152 participants comprised the baseline sample. Due to missing data, our statistical analyses included 150 for self-reported PDQ-20, 147 individuals for combined DSST-measured cognitive function (composite z-score of the Pen/Paper plus Online CogState Version, NcombinedDSST), 71 for in-person DSST-measured cognitive function (Pen/Paper Version), 70 for TMT-A-measured cognitive function, and 70 for TMT-B-measured cognitive function. After adjusting for age, sex, and education, PDQ-20 was significantly correlated with pen-and-paper DSST (β = -0.003, p = 0.002) and TMT-B (β = 0.003, p = 0.008) scores, but not with TMT-A scores (β = -0.001, p = 0.751).
CONCLUSIONS: Overall, a statistically significant correlation was observed between subjective and objective cognitive functions. Clinicians providing care for individuals with PCC who have subjective cognitive function complaints may consider taking a measurement-based approach to cognition at the point of care that focuses exclusively on patient-reported measures.

BACKGROUND: Anticholinergic and sedative medications affect cognition among older adults. The Drug Burden Index (DBI) is a validated measure of exposure to these medications, with higher DBI scores indicating higher drug burden. This ancillary analysis investigated the association between DBI and cognition assessed by the Modified Mini-Mental State Examination (3MS) and the Digit Symbol Substitution Test (DSST).
METHODS: The Health, Aging, and Body Composition Study was a prospective study of community-dwelling adults aged 70-79 years at enrollment. Using data from years 1, 5, and 10, DBI was calculated using medication data per participant. Linear mixed modeling was used to assess cross-sectional and longitudinal effects of DBI on 3MS and DSST. Adjusted models included biological sex, race, education level, APOE status, and death. Sensitivity analyses included testing the strength of the associations for each year and testing attrition due to death as a possible confounding factor via Cox-Proportional Hazard models.
RESULTS: After adjustment, DBI was inversely associated with 3MS and DSST scores. These associations became stronger in each subsequent year. Neither DBI at year 1 nor within-person change in DBI were predictive of longitudinal declines in either cognitive measure. Sensitivity analyses indicated that DBI, 3MS, and DSST were associated with a greater risk of attrition due to death.
CONCLUSIONS: Results suggest that in years when older adults had a higher DBI scores, they had significantly lower global cognition and slower processing speed. These findings further substantiate the DBI as a useful pharmacological tool for assessing the effect of medication exposure.

BACKGROUND: Post-COVID-19 Condition (PCC), as defined by the World Health Organization (WHO), currently lacks any regulatory-approved treatments and is characterized by persistent and debilitating cognitive impairment and mood symptoms. Additionally, metabolic dysfunction, chronic inflammation and the associated risks of elevated body mass index (BMI) have been reported. In this study, we aim to investigate the efficacy of vortioxetine in improving cognitive deficits in individuals with PCC, accounting for the interaction of metabolic dysfunction, elevated inflammation and BMI.
METHODS: This is a post-hoc analysis of an 8-week randomized, double-blind, placebo-controlled trial that was conducted among adults aged 18 years and older living in Canada who were experiencing WHO-defined PCC symptoms. The recruitment of participants began in November 2021 and concluded in January 2023. A total of 200 individuals were enrolled, where 147 were randomized in a 1:1 ratio to receive either vortioxetine (5-20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change in the Digit Symbol Substitution Test (DSST) score from baseline to endpoint.
RESULTS: Our findings showed significant effects for time (χ2 = 7.771, p = 0.005), treatment (χ2 = 7.583, p = 0.006) and the treatment x time x CRP x TG-HDL x BMI interaction (χ2 = 11.967, p = 0.018) on cognitive function. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint (mean difference = 0.621, SEM = 0.313, p = 0.047).
CONCLUSIONS: Overall, vortioxetine demonstrated significant improvements in cognitive deficits among individuals with baseline markers of metabolic dysfunction, elevated inflammation and higher BMI at endpoint as compared to placebo.
BACKGROUND: NCT05047952 (ClinicalTrials.gov; Registration Date: September 17, 2021).

Hitherto no therapeutic has received regulatory approval for the treatment of post-COVID-19 condition (PCC). Cognitive deficits, mood symptoms and significant reduction in health-related quality of life (HRQoL) are highly replicated and debilitating aspects of PCC. We sought to determine the impact of vortioxetine on the foregoing symptoms and HRQoL in persons living with PCC. An 8-week randomized, double-blind, placebo-controlled study of adults ≥ 18 years of age residing in Canada and who are experiencing symptoms of World Health Organization (WHO)-defined PCC, with a history of confirmed SARS-CoV-2 infection, was conducted. Recruitment began November 2021 and ended January 2023. Of the 200 participants enrolled (487 invited: 121 ineligible and 59 eligible but declined participation; 307 cleared pre-screening stage), a total of 149 participants were randomized (1:1) to receive either vortioxetine (5-20 mg, n = 75) or placebo (n = 74) daily for 8 weeks of double-blind treatment (i.e. end point). The primary outcome was the change from baseline-to-end point in the Digit Symbol Substitution Test. Secondary outcomes included the effect on depressive symptoms and HRQoL, as measured by changes from baseline-to-end point on the Quick Inventory of Depressive Symptomatology 16-item and WHO Wellbeing Scale 5-item, respectively. A total of 68 (90.7%) participants randomized to vortioxetine and 73 (98.6%) participants randomized to placebo completed all 8 weeks. Between-group analysis did not show a significant difference in the overall change in cognitive function [P = 0.361, 95% confidence interval (CI) (-0.179, 0.492)]. However, in the fully adjusted model, a significant treatment × time interaction was observed in favour of vortioxetine treatment with baseline c-reactive protein (CRP) as a moderator (P = 0.012). In addition, a significant improvement in Digit Symbol Substitution Test scores were observed in vortioxetine versus placebo treated participants in those whose baseline CRP was above the mean (P = 0.045). Moreover, significant improvement was obtained in measures of depressive symptoms [P < 0.001, 95% CI (-4.378, -2.323)] and HRQoL [P < 0.001, 95% CI (2.297, 4.647)] in vortioxetine-treated participants and between the treatment groups [depressive symptoms: P = 0.026, 95% CI (-2.847, -0.185); HRQoL: P = 0.004, 95% CI (0.774, 3.938)]. Although vortioxetine did not improve cognitive function in the unadjusted model, when adjusting for CRP, a significant pro-cognitive effect was observed; antidepressant effects and improvement in HRQoL in this debilitating disorder were also noted.

Cognitive impairment is on the rise around the world, with profound economic and social consequences. Serum globulin, a marker of liver function, may also play a role in cognitive function. Unfortunately, no consistent conclusion exists regarding the association between serum globulin and cognitive function.
Data from the 2011 to 2014 National Health and Nutrition Examination Survey were used to assess the association between serum globulin and cognitive impairment. Cognitive function was assessed by three tests: Consortium to Establish a Registry for Alzheimer\'s Disease (CERAD), Animal Fluency (AF), and Digit Symbol Substitution Test (DSST). Furthermore, the breakthrough point of cognitive impairment correlated with CERAD < 5, AF < 14, and DSST < 34. A weighted multiple logistics regression model was used to verify the association between serum globulin and cognitive impairment. Generalized additive models (GAMs) and a smooth curve fit (penalty spline method) were used to determine a non-linear relationship between serum globulin and cognitive impairment. Finally, subgroup analysis and interaction tests were conducted to further verify the association between serum globulin and cognitive impairment.
Data from 2,768 participants aged ≥60 (in accordance with the study design) were collected for the final analysis. Data suggested that serum globulin levels were associated with an elevated cognitive impairment based on the AF [full adjustment, OR = 1.05, 95% CI: 1.01-1.08] and DSST [full adjustment, OR = 1.06, 95% CI: 1.02-1.10] tests. Eventually, the GAM and smooth curve fit model was conducted to confirm that the association between serum globulin and cognitive impairment was non-linear. Moreover, the inflection point was 27 g/L serum globulin based on the CERAD test and 35 g/L serum globulin based on the AF test. Finally, the interaction term between serum globulin and cognitive impairment based on the AF test indicated no significant interactions among all variables (all p for interaction >0.05).
The association between serum globulin levels and cognitive impairment is non-linear. A threshold effect exists between serum globulin and cognitive impairment. Large-scale prospective clinical trials are needed to validate our findings.

UNASSIGNED: Exponential population aging has led to an increased prevalence of cognitive impairment worldwide. Hand grip strength, which may be associated with physical activity, could be a useful predictor of cognitive impairment. However, few studies have reported the association, if any, between hand grip strength and cognitive function.
UNASSIGNED: We used data obtained from the National Health and Nutrition Examination Survey between 2011-2012 and 2013-2014 to investigate the association between hand grip strength and cognitive impairment. Cognitive impairment was assessed using the Consortium to Establish a Registry for Alzheimer\'s Disease (CERAD), animal fluency (AF), and digit symbol substitution test (DSST) scores. Cutoff values of CERAD < 5, AF < 14, and DSST < 34 were used to define cognitive impairment. In this cross-sectional study, we used odds ratios to determine the potential usefulness of hand grip strength for the prediction of cognitive impairment.
UNASSIGNED: This study included 2,623 participants aged ≥60 years. The DSST results showed that hand grip strength was associated with a low risk of cognitive impairment and that subgroup analysis showed that male sex, 60-69 years of age, and the Non-Hispanic (NH)-White, NH Black, and Asian were associated with a significantly low risk of cognitive impairment. The CERAD test results showed that 70-79 years of age and the NH White were significantly associated with a low risk of cognitive impairment. By following full adjustment, we did not observe statistically significant differences between hand grip strength and cognitive impairment based on the CERAD test. The AF test results showed that >80 years of age, female sex, and the NH White were associated with a significantly low risk of cognitive impairment. The most important finding is that a linear association lies between grip strength and cognitive impairment, as well as a sex-based linear association. Machine learning of the XGBoost model suggests that grip strength is one of the top two most important negative predictor variables.
UNASSIGNED: We observed an inverse relationship between hand grip strength and cognitive impairment, which might suggest a shared underlying mechanism that needs to be further investigated using a large-scale prospective clinical trial to validate our findings.

The current study investigates the impact of sleep loss on neurobehavioral functioning and sleepiness in a natural setting among healthy adolescents. Fifty-nine adolescents (32 females) from grades 7 to 12 (mean age of 16.29 ± 1.86 years) participated in the study. All participants wore the actigraph for a continuous five to seven days, including school and nonschool days. Subjective sleepiness and neurobehavioral performance (using the psychomotor vigilance test and the digit symbol substitution test) were measured three times a day on two school days and one nonschool day. The results presented that sleep loss influenced subjective sleepiness reports, showing higher sleepiness scores following sleep loss than following sufficient night sleep. Neurobehavioral functioning across all measurements was also significantly worse following sleep loss. Furthermore, participants performed worse on weekday morning assessments than on assessments at other times of the day following sleep loss. These findings suggest that sleep loss in natural settings has a significant impact on neurobehavioral performance and subjective sleepiness. Our findings have essential implications for public policy on school schedules.

OBJECTIVE: The aim of the current study was to estimate the discriminant potential and validity of the Digit Symbol Substitution Test (DSST) of the WAIS-R in the Greek elderly population meeting criteria for subjective cognitive decline (SCD), mild cognitive impairment (aMCI; amnestic subtype), or Alzheimer\'s disease dementia (ADD).
METHODS: Four hundred eighty-eight community-dwelling older adults, visitors of the Day Center of Alzheimer Hellas, participated in the study. Two hundred forty-three of them met the criteria for ADD, one hundred eighty-two for aMCI and sixty-three for SCD.
RESULTS: Path analysis indicated that the DSST score is affected by age group, educational level, and diagnostic category, but is not affected by gender. The ROC curve analysis showed that the DSST sum score could perfectly differentiate SCD from ADD patients, whereas test\'s discriminant potential between aMCI and dementia ADD\'s subtype was satisfactory. However, DSST was unable to separate the SCD from the aMCI group.
CONCLUSIONS: It appears that the DSST is unable to separate the SCD from aMCI population. Therefore, the test in question may be insensitive to incipient cognitive decline. On the contrary, the discriminant potential of the DSST as regards SCD and ADD is excellent, while discrimination between aMCI and ADD is good.

To obtain new insights into research questions on how executive function and social interaction would be observed to change after the introduction of hearing aids (HAs) in older people with hearing impairment.
Multi-institutional prospective single-arm observational study.
Outpatients with complaints of hearing difficulty who visited HA clinics between October 18, 2017, and June 30, 2019, in 7 different university hospitals in Japan.
The inclusion criteria of the study named Hearing-Aid Introduction for Hearing-Impaired Seniors to Realize a Productive Aging Society-A Study Focusing on Executive Function and Social Activities Study (HA-ProA study) were age ≥60 years and no history of HA use. A series of multi-institution common evaluations including audiometric measurements, the digit symbol substitution test to assess executive functions, convoy model as an index of social relations, and hearing handicap inventory for the elderly (HHIE) were performed before (pre-HA) and after 6 months of the HA introduction (post-HA).
Out of 127 enrollments, 94 participants completed a 6-month follow-up, with a mean age of 76.9 years. The digit symbol substitution test score improved significantly from 44.7 at baseline to 46.1 at 6 months (P = .0106). In the convoy model, the social network size indicated by the number of persons in each and whole circles were not significantly different between pre- and post-HA; however, the total count for kin was significantly increased (P = .0344). In the analyses of HHIE, the items regarding the family and relatives showed significant improvement.
HA use could benefit older individuals beginning to use HAs in executive function and social interaction, though the results should be interpreted cautiously given methodological limitations such as a single-arm short 6 months observation. Reduction in daily hearing impairment would have a favorable effect on relationships with the family.

A cognitive throughput task known as the Digit Symbol Substitution Test (DSST) (or Symbol Digit Modalities Test) has been used as an assay of general cognitive slowing during sleep deprivation. Here, the effects of total sleep deprivation (TSD) on specific cognitive processes involved in DSST performance, including visual search, spatial memory, paired-associate learning, and motor response, were investigated through targeted task manipulations.
A total of 12 DSST variants, designed to manipulate the use of specific cognitive processes, were implemented in two laboratory-based TSD studies with N = 59 and N = 26 subjects, respectively. In each study, the Psychomotor Vigilance Test (PVT) was administered alongside the DSST variants.
TSD reduced cognitive throughput on all DSST variants, with response time distributions exhibiting rightward skewing. All DSST variants showed practice effects, which were however minimized by inclusion of a pause between trials. Importantly, TSD-induced impairment on the DSST variants was not uniform, with a principal component analysis revealing three factors. Diffusion model decomposition of cognitive processes revealed that inter-individual differences during TSD on a two-alternative forced choice DSST variant were different from those on the PVT.
While reduced cognitive throughput has been interpreted to reflect general cognitive slowing, such TSD-induced impairment appears to reflect cognitive instability, like on the PVT, rather than general slowing. Further, comparisons between task variants revealed not one, but three distinct underlying processes impacted by sleep deprivation. Moreover, the practice effect on the task was found to be independent of the TSD effect and minimized by a task pacing manipulation.