International study of the Complex Stress Reaction Syndrome: Implications for transdiagnostic clinical practice.

BACKGROUND: The debate regarding diagnostic classification systems in psychiatry (categorial vs dimensional systems) has essential implications for the diagnosis, prevention and treatment of stress reactions. We previously found a unique pattern of stress reaction in a study executed during the coronavirus disease 2019 pandemic using large representative samples in two countries, and termed it the Complex Stress Reaction Syndrome (CSRS). AIM: To investigate CSRS, Type A (psychiatric symptoms, spanning anxiety, depression, stress symptoms, and post-traumatic stress disorder (PTSD)), with or without long-coronavirus disease (COVID) residuals (CSRS, Type B, neuropsychiatric symptoms spanning cognitive deficits and fatigue, excluding systemic symptoms). Our two-tailed hypothesis was that CSRS is a condition related to an unrecognized type of stress reaction in daily life in the general population (Type A) or that it is related to the severe acute respiratory syndrome coronavirus 2 infection and its long-COVID residuals (Type B). METHODS: 977 individuals in four continents (North America, Europe, Australia and the Middle East) completed the online study questionnaire in six languages using the Qualtrics platform. The study was managed by six teams in six countries that promoted the study on social media. The questionnaire assessed anxiety, depression, stress symptoms and PTSD (CSRS, Type A), cognitive deficits and fatigue (CSRS, Type B). The data were analyzed using Proportion Analyses, Multivariate Analysis of Co-Variance (MANCOVA), linear regression analyses and validated clinical cutoff points. RESULTS: The results of the Proportion Analyses showed that the prevalence of 4 symptoms spanning anxiety, depression, stress symptoms, and PTSD was significantly higher than the most prevalent combinations of fewer symptoms across 4 continents, age groups, and gender. This supports the transdiagnostic argument embedded in the CSRS (Type A). The same pattern of results was found in infected/recovered individuals. The prevalence of the 4 psychiatric symptoms combination was significantly greater than that of 5 and 6 symptoms, when adding cognitive deficits and fatigue, respectively. MANCOVA showed a significant three-way interaction (age × gender × continent). Further analyses showed that the sources of this three-way interaction were threefold relating to two sub-populations at-risk: (1) Individuals that self-identified as non-binary gender scored significantly higher on all 4 psychiatric symptoms of the CSRS, Type A at young age groups (< 50 years old) in North America compared to (self-identified) women and men located in the 4 continents studied, and to other ages across the adult life span; and (2) This pattern of results (CSRS, Type A) was found also in women at young ages (< 40 years old) in North America who scored higher compared to men and women in other continents and other ages. Linear regression analyses confirmed the MANCOVA results. CONCLUSION: These results show a combined mental health risk factor related to stress reactivity, suggesting that the CSRS is sensitive to populations at risk and may be applied to future identification of other vulnerable sub-populations. It also supports the transdiagnostic approach for more accurate prevention and treatment. Time will tell if such transdiagnostic syndromes will be part of the discussions on the next revisions of the traditional classification systems or whether the crisis in psychiatry further evolves.

Evaluation of Post-COVID-19 Cognitive Dysfunction: Recommendations for Researchers.

This Viewpoint provides recommendations for assessment of post­COVID-19 cognitive dysfunction to improve understanding of the pathophysiology of the condition and develop appropriate interventions.

Characterizing Symptoms and Identifying Biomarkers of Long COVID in People With and Without HIV: Protocol for a Remotely Conducted Prospective Observational Cohort Study.

BACKGROUND: Living with HIV is a risk factor for severe acute COVID-19, but it is unknown whether it is a risk factor for long COVID. OBJECTIVE: This study aims to characterize symptoms, sequelae, and cognition formally and prospectively 12 months following SARS-CoV-2 infection in people living with HIV compared with people without HIV. People with no history of SARS-CoV-2 infection, both with and without HIV, are enrolled as controls. The study also aims to identify blood-based biomarkers or patterns of immune dysregulation associated with long COVID. METHODS: This prospective observational cohort study enrolled participants into 1 of the following 4 study arms: people living with HIV who had SARS-CoV-2 infection for the first time <4 weeks before enrollment (HIV+COVID+ arm), people without HIV who had SARS-CoV-2 infection for the first time within 4 weeks of enrollment (HIV-COVID+ arm), people living with HIV who believed they never had SARS-CoV-2 infection (HIV+COVID- arm), and people without HIV who believed they never had SARS-CoV-2 infection (HIV-COVID- arm). At enrollment, participants in the COVID+ arms recalled their symptoms, mental health status, and quality of life in the month before having SARS-CoV-2 infection via a comprehensive survey administered by telephone or on the web. All participants completed the same comprehensive survey 1, 2, 4, 6, and 12 months after post-acute COVID-19 symptom onset or diagnosis, if asymptomatic, (COVID+ arms) or after enrollment (COVID- arms) on the web or by telephone. In total, 11 cognitive assessments were administered by telephone at 1 and 4 months after symptom onset (COVID+ arms) or after enrollment (COVID- arms). A mobile phlebotomist met the participants at a location of their choice for height and weight measurements, orthostatic vital signs, and a blood draw. Participants in the COVID+ arms donated blood 1 and 4 months after COVID-19, and participants in the COVID- arms donated blood once or none. Blood was then shipped overnight to the receiving study laboratory, processed, and stored. RESULTS: This project was funded in early 2021, and recruitment began in June 2021. Data analyses will be completed by summer 2023. As of February 2023, a total of 387 participants were enrolled in this study, with 345 participants having completed enrollment or baseline surveys together with at least one other completed study event. The 345 participants includes 76 (22%) HIV+COVID+, 121 (35.1%) HIV-COVID+, 78 (22.6%) HIV+COVID-, and 70 (20.3%) HIV-COVID- participants. CONCLUSIONS: This study will provide longitudinal data to characterize COVID-19 recovery over 12 months in people living with and without HIV. Additionally, this study will determine whether biomarkers or patterns of immune dsyregulation associate with decreased cognitive function or symptoms of long COVID. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47079.

Depressive Symptoms at Kidney Transplant Evaluation and Access to the Kidney Transplant Waitlist.

Introduction: Depressive symptoms, even without a clinical diagnosis of depression, are common in kidney failure patients and may be a barrier to completing the complex process of kidney transplant (KT) evaluation. We assessed depressive symptom burden and association between depressive symptoms and access to KT waitlist by age. Methods: In a prospective cohort of 3728 KT patients (aged 18-88 years), the Center for Epidemiologic Studies-Depression (CES-D) scale was used to measure depressive symptoms at evaluation. Depressive symptom severity was defined as follows: none: 0; minimal: 1 to 15; mild: 16 to 20; moderate: 21 to 25; severe: 26 to 60. Hazard ratios (HRs) of active listing within 1 year after evaluation were estimated using Cox proportional hazards models, adjusted for clinical and social factors. Results: At evaluation, 85.8% of the patients reported at least minimal depressive symptoms; the proportion was lower among older patients: 18 to 29 years = 92.0%; 30 to 39 years = 88.3%; 40 to 49 years = 87.2%; 50 to 59 years = 87.0%; 60 to 69 years = 83.4%; and ≥70 years = 82.0%. Chance of active listing decreased with more severe depressive symptoms (log-rank, P < 0.001). After adjustment, every 5-point higher CES-D score (more depressive symptoms) was associated with a 13% lower chance of listing (HR = 0.87, 95% CI: 0.85-0.90); the strongest association was found among patients aged ≥70 years (adjusted HR [aHR] = 0.73, 95% CI: 0.62-0.86). Furthermore, minimal (HR = 0.69, 95% CI: 0.60-0.79), mild (HR = 0.57, 95% CI: 0.44-0.72), moderate (HR = 0.53, 95% CI: 0.39-0.71), and severe (HR = 0.44, 95% CI: 0.34-0.57) depressive symptoms were all associated with a lower chance of listing. Conclusion: Older candidates were less likely to report depressive symptoms at KT evaluation. Regardless of age, candidates who did report depressive symptoms, and even minimal symptoms, had a lower chance of listing. Transplant centers should routinely screen patients for depressive symptoms and refer the affected patients to mental health services to improve access to KT.

Cognitive Dysfunction, Psychiatric Distress, and Functional Decline After COVID-19.

BACKGROUND: There is a limited understanding of the cognitive and psychiatric sequelae of COVID-19 during the post-acute phase, particularly among racially and ethnically diverse patients. OBJECTIVE: We sought to prospectively characterize cognition, mental health symptoms, and functioning approximately four months after an initial diagnosis of COVID-19 in a racially and ethnically diverse group of patients. METHODS: Approximately four months after COVID-19 diagnosis, patients in the Johns Hopkins Post-Acute COVID-19 Team Pulmonary Clinic underwent a clinical telephone-based assessment of cognition, depression, anxiety, trauma, and function. RESULTS: Most Johns Hopkins Post-Acute COVID-19 Team patients assessed were women (59%) and members of racial/ethnic minority groups (65%). Of 82 patients, 67% demonstrated ≥1 abnormally low cognitive score. Patients requiring intensive care unit (ICU) stays displayed greater breadth and severity of impairment than those requiring less intensive treatment. Processing speed (35%), verbal fluency (26%-32%), learning (27%), and memory (27%) were most commonly impaired. Among all patients, 35% had moderate symptoms of depression (23%), anxiety (15%), or functional decline (15%); 25% of ICU patients reported trauma-related distress. Neuropsychiatric symptoms and functional decline did not differ by post-ICU versus non-ICU status and were unrelated to global cognitive composite scores. CONCLUSIONS: At approximately 4 months after acute illness, cognitive dysfunction, emotional distress, and functional decline were common among a diverse clinical sample of COVID-19 survivors varying in acute illness severity. Patients requiring ICU stays demonstrated greater breadth and severity of cognitive impairment than those requiring less intensive treatment. Findings help extend our understanding of the nature, severity, and potential duration of neuropsychiatric morbidity after COVID-19 and point to the need for longitudinal assessment of cognitive and mental health outcomes among COVID-19 survivors of different demographic backgrounds and illness characteristics.

Microstructural white matter abnormalities in Lesch-Nyhan disease.

Lesch-Nyhan disease is a rare, sex-linked, genetic neurodevelopmental disorder that is characterized by hyperuricemia, dystonia, cognitive impairment and recurrent self-injury. We previously found reduced brain white matter volume in patients with Lesch-Nyhan disease compared with healthy adults using voxel-based morphometry. Here, we address the structural integrity of white matter via diffusion tensor imaging. We hypothesized that white matter integrity would be decreased in men with Lesch-Nyhan disease and to a lesser extent in men with a milder variant of the disease (Lesch-Nyhan variant) relative to healthy men. After acquiring diffusion-weighted brain images from Lesch-Nyhan disease (n = 5), Lesch-Nyhan variant (n = 6) and healthy participants (n = 10), we used both tract-based spatial statistics and a regions of interest approach to analyse between-group fractional anisotropy differences. We first replicated earlier findings of reduced intracranial, grey matter and white matter volumes in patients. We then discovered marked reductions of fractional anisotropy relative to the healthy control group. The Lesch-Nyhan disease group showed more pronounced reductions in white matter integrity than the Lesch-Nyhan variant group. In addition to whole brain fractional anisotropy group differences, reductions in white matter integrity were observed in the corpus callosum, corona radiata, cingulum, internal capsule and superior longitudinal fasciculus. Moreover, the variant group had attenuated dystonia severity symptoms and cognitive deficits. These findings highlight the need to better understand the role of white matter in Lesch-Nyhan disease.

Crossword Puzzles for Brain Training in Mild Cognitive Impairment.

Given the increasing prevalence and public health impact of dementia, it is imperative that we identify prevention strategies. One approach, broadly termed brain training, can be defined as guided drill-and-practice mental exercises targeting cognitive domains. We have evidence suggesting that brain training may prevent dementia in cognitively intact adults, including the well-validated protective effect of education early in life and the results of the ACTIVE (Advanced Cognitive Training for Independent and Vital Elderly) trial,1 which showed not only a long-term cognitive benefit of training in processing speed, but also a possible decrease in dementia incidence and transfer of cognitive benefits to performance in everyday functioning (as measured by performance on instrumental activities of daily living).

Interventions for multidimensional aspects of breast cancer-related fatigue: a meta-analytic review.

PURPOSE: This meta-analysis sought to determine whether exercise, psychological, or alternative forms of interventions differentially improve cognitive, physical, and general dimensions of cancer-related fatigue (CRF) in women with a history of breast cancer. METHODS: Databases (PubMed, PsychINFO, EMBASE, and Cochrane Library) were systematically reviewed from inception through March 2019, with data extracted from randomized controlled trials of fatigue interventions using multidimensional CRF outcome measures. Two authors independently assessed methodological quality using the Cochrane Collaboration's risk of bias tool. Analyses were performed with Comprehensive Meta-Analysis (v.3). RESULTS: A total of 471 studies were assessed, of which 11 studies with 12 sets of data involving 1067 patients were included. Across intervention types, small to moderate improvements were observed for cognitive (g = - 0.38), physical (g = - 0.46), and general (g = - 0.45) CRF (p values < 0.01). Exercise produced moderate benefit for cognitive (g = - 0.44), physical (g = - 0.48), and general (g = - 0.49) CRF (p values < 0.01) whereas psychotherapy and disparate forms of alterative interventions were not effective (p values > 0.45). However, a large effect size was observed for a single trial of acupressure across all three CRF dimensions (p < 0.05). CONCLUSIONS: Exercise improved both cognitive and physical aspects of CRF. Further studies should determine the most effective forms, duration, intensity, and methods of supporting exercise in breast cancer patients. Further investigation of acupressure as an intervention for CRF should also be considered.

A Prospective Cohort Study of Neural Progenitor Cell-Sparing Radiation Therapy Plus Temozolomide for Newly Diagnosed Patients With Glioblastoma.

BACKGROUND: In treating glioblastoma, irradiation of the neural progenitor cell (NPC) niches is controversial. Lower hippocampal doses may limit neurocognitive toxicity, but higher doses to the subventricular zones (SVZ) may improve survival. OBJECTIVE: To prospectively evaluate the impact of limiting radiation dose to the NPC niches on tumor progression, survival, and cognition in patients with glioblastoma. METHODS: Patients with glioblastoma received resection followed by standard chemoradiation. Radiation dose to the NPC niches, including the bilateral hippocampi and SVZ, was minimized without compromising tumor coverage. The primary outcome was tumor progression in the spared NPC niches. Follow-up magnetic resonance imaging was obtained bimonthly. Neurocognitive testing was performed before treatment and at 6- and 12-mo follow-up. Cox regression evaluated predictors of overall and progression-free survival. Linear regression evaluated predictors of neurocognitive decline. RESULTS: A total of 30 patients enrolled prospectively. The median age was 58 yr. Median mean doses to the hippocampi and SVZ were 49.1 and 41.8 gray (Gy) ipsilaterally, and 16.5 and 19.9 Gy contralaterally. Median times to death and tumor progression were 16.0 and 7.6 mo, and were not significantly different compared to a matched historical control. No patients experienced tumor progression in the spared NPC-containing regions. Overall survival was associated with neurocognitive function (P ≤ .03) but not dose to the NPC niches. Higher doses to the hippocampi and SVZ predicted greater decline in verbal memory (P ≤ .01). CONCLUSION: In treating glioblastoma, limiting dose to the NPC niches may reduce cognitive toxicity while maintaining clinical outcomes. Further studies are needed to confirm these results.

Cognitive Changes Related to Cancer Therapy.

A growing population of cancer survivors is at risk for acute and long-term consequences resulting from cancer and its treatment. Cancer-related cognitive impairment (CRCI) typically manifests as modest deficits in attention, processing speed, executive functioning, and memory, which may persist for decades after treatment. Although some risk factors for CRCI are largely immutable (eg, genetics and demographic factors), there are many other contributors to CRCI that when appropriately addressed can result in improved cognitive functioning and quality of life. Neuropsychological assessment can help identify patient cognitive strengths and weaknesses, target psychological and behavioral contributors to CRCI, and guide treatment interventions.

Balanced bifrontal transcranial direct current stimulation enhances working memory in adults with high-functioning autism: a sham-controlled crossover study.

BACKGROUND: Working memory (WM) often is impaired in autism spectrum disorder (ASD). Such impairment may underlie core deficits in cognition and social functioning. Transcranial direct current stimulation (tDCS) has been shown to enhance WM in both healthy adults and clinical populations, but its efficacy in ASD is unknown. We predicted that bifrontal tDCS would improve WM performances of adults with high-functioning autism during active stimulation compared to sham stimulation and that such enhancement would generalize to an untrained task. METHODS: Twelve adults with high-functioning ASD engaged in a battery of WM tasks that included backward spatial span, backward digit span, spatial n-back and letter n-back. While engaged, 40 min of 1.5 mA bifrontal stimulation was applied over the left and the right dorsolateral prefrontal cortices (DLPFC). Using a single-blind crossover design, each participant received left anodal/right cathodal stimulation, right anodal/left cathodal stimulation, or sham stimulation, in randomized counterbalanced order on three separate days. Following tDCS, participants again engaged in letter and spatial n-back tasks before taking the Brief Test of Attention (BTA). We used repeated-measures ANOVA to compare overall performance on the WM battery as measured by a composite of z-scores for all five measures. Post hoc ANOVAs, t tests, Friedman's tests, and Wilcoxon signed-rank tests were used to measure the online and offline effects of tDCS and to assess performances on individual measures. RESULTS: Compared to sham stimulation, both left DLPFC anodal stimulation (t11 = 5.4, p = 0.0002) and right DLPFC anodal stimulation (t11 = 3.57, p = 0.004) improved overall WM performance. Left anodal stimulation (t11 = 3.9, p = 0.003) and right anodal stimulation (t11 = 2.7, p = 0.019) enhanced performances during stimulation. Enhancement transferred to an untrained task 50 min after right anodal stimulation (z11 = 2.263, p = 0.024). The tasks that showed the largest effects of active stimulation were spatial span backward (z11 = 2.39, p = 0.017) and BTA (z11 = 2.263, p = 0.024). CONCLUSIONS: In adults with high-functioning ASD, active bifrontal tDCS given during WM tasks appears to improve performance. TDCS benefits also transferred to an untrained task completed shortly after stimulation. These results suggest that tDCS can improve WM task performance and could reduce some core deficits of autism. TRIAL REGISTRATION: NCT01602263.

The link between childhood adversity and late-life mental health: evidence for the influence of early-life experiences or illusory correlations?

Adverse childhood experiences (ACEs) reflect stressful or traumatic early life events such as abuse, neglect, and significant household challenges. These experiences are increasingly appreciated as factors that exert influence on physical and mental functioning throughout the lifespan. Numerous studies have demonstrated dose-response relationships between the number of ACEs reported and negative health outcomes in adulthood (Anda et al., 2006). At the same time, evidence points to the role of ACEs in the development of heightened biological reactivity to stress that may serve to increase vulnerability to the development of mental and substance use disorders (e.g., Heim et al., 2010). Furthermore, the existence of sex differences in both stress reactivity and the prevalence of various forms of psychopathology in adulthood (Doom et al., 2013) raises the question of whether men and women are differentially vulnerable to the health risks posed by ACEs. Much of the work concerning ACEs has focused on outcomes as they present in middle adulthood, which may not generalize to later life, as there may be cohort effects in the prevalence of (or likelihood of reporting) ACEs. Studies finding that the newly old report greater numbers of ACEs than their more senior counterparts imply that rates of ACEs are increasing over time and may be contributing to the development of mental and substance abuse disorders (MSUDs) in the growing population of aging adults, and make a case for better understanding these associations in later life.

Can Transcranial Direct Current Stimulation Improve Cognitive Functioning in Adults with Schizophrenia?

Cognitive impairment is nearly ubiquitous in schizophrenia. First-degree relatives of persons with schizophrenia often show similar but milder deficits. Current methods for the treatment of schizophrenia are often ineffective in cognitive remediation. Since transcranial direct current stimulation (tDCS) can enhance cognitive functioning in healthy adults, it might provide a viable option to enhance cognition in schizophrenia. We sought to explore whether tDCS can be tolerated by persons with schizophrenia and potentially improve their cognitive functioning. We examined the effects of anodal versus cathodal tDCS on working memory and other cognitive tasks in five outpatients with schizophrenia and six first-degree relatives of persons with schizophrenia. Each participant completed tasks thought to be mediated by the prefrontal cortex during two 30-minute sessions of tDCS to the left and right dorsolateral prefrontal cortex (DLPFC). Anodal stimulation over the left DLPFC improved performance relative to cathodal stimulation on measures of working memory and aspects of verbal fluency relevant to word retrieval. The patient group showed differential changes in novel design production without alteration of overall productivity, suggesting that tDCS might be capable of altering self-monitoring and executive control. All participants tolerated tDCS well. None withdrew from the study or experienced any adverse reaction. We conclude that adults with schizophrenia can tolerate tDCS while engaging in cognitive tasks and that tDCS can alter their performance.

Reproducibility of tDCS Results in a Randomized Trial: Failure to Replicate Findings of tDCS-Induced Enhancement of Verbal Fluency.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been shown to enhance verbal productivity, but the finding and extent of enhancement vary across studies. Few attempts to replicate positive tDCS findings have been reported, suggesting the possibility of publication bias. OBJECTIVE: We aimed to replicate the tDCS methodology and findings of Cattaneo, Pisoni, and Papagno (2011, Neuroscience 183:64-70) in a new population sample. We hypothesized that our study of anodal tDCS would improve verbal fluency production similarly to the original study. METHODS: In our single-blind, sham-controlled crossover experiment, 14 healthy young adults were randomly assigned to receive 2 mA of anodal and sham stimulation to the Broca area in counterbalanced order before completing verbal fluency tasks. RESULTS: Participants tolerated the stimulation well. Despite closely mirroring the original study methods, we saw no main effect of stimulation condition: F1,13=0.002, P=0.97, letter fluency sham mean (standard deviation)=16.8 (2.3), letter fluency anodal=17.5 (3.8), category fluency sham=25.3 (5.4), or category fluency anodal=24.7 (5.2), η≤0.01. CONCLUSIONS: While tDCS may enhance cerebral functions in general, the lack of consistency between studies suggests either that this tDCS protocol does not affect verbal fluency or, at minimum, that tDCS may be more sensitive to experimental conditions than has been thought. Our findings also highlight the need for replication studies in brain stimulation research. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (Identifier NCT01602263).

Brain white matter volume abnormalities in Lesch-Nyhan disease and its variants.

OBJECTIVE: We sought to examine brain white matter abnormalities based on MRI in adults with Lesch-Nyhan disease (LND) or an attenuated variant (LNV) of this rare, X-linked neurodevelopmental disorder of purine metabolism. METHODS: In this observational study, we compared 21 adults with LND, 17 with LNV, and 33 age-, sex-, and race-matched healthy controls using voxel-based morphometry and analysis of covariance to identify white matter volume abnormalities in both patient groups. RESULTS: Patients with classic LND showed larger reductions of white (26%) than gray (17%) matter volume relative to healthy controls. Those with LNV showed comparable reductions of white (14%) and gray (15%) matter volume. Both patient groups demonstrated reduced volume in medial inferior white matter regions. Compared with LNV, the LND group showed larger reductions in inferior frontal white matter adjoining limbic and temporal regions and the motor cortex. These regions likely include such long association fibers as the superior longitudinal and uncinate fasciculi. CONCLUSIONS: Despite earlier reports that LND primarily involves the basal ganglia, this study reveals substantial white matter volume abnormalities. Moreover, white matter deficits are more severe than gray matter deficits in classic LND, and also characterize persons with LNV. The brain images acquired for these analyses cannot precisely localize white matter abnormalities or determine whether they involve changes in tract orientation or anisotropy. However, clusters of reduced white matter volume identified here affect regions that are consistent with the neurobehavioral phenotype.

Higher baseline serum uric acid is associated with poorer cognition but not rates of cognitive decline in women.

Serum uric acid is a powerful antioxidant that may have neuroprotective properties. While some studies have found that greater serum uric acid is associated with better cognition in older adults, it is also associated with numerous vascular risk factors that increase risk for dementia. Women may also be particularly vulnerable to the vascular effects of elevated uric acid. We previously found that mildly elevated serum uric acid is a biomarker of cognitive dysfunction in older adults, and that this likely is mediated by cerebral ischemic burden. Here we examine both cross-sectional and longitudinal associations between serum uric acid and declines in cognition and functioning in 423 cognitively healthy community-dwelling older women in the Women's Health and Aging Study (WHAS II). We hypothesized that higher serum uric acid would be associated with poorer concurrent functioning and greater declines over 9 years. In linear regression analyses, higher baseline serum uric acid was associated with poorer working memory, with a trend toward slower manual speed and dexterity before and after adjusting for baseline serum uric acid, demographic and health/cardiovascular variables. However, there were no associations for global cognitive functioning, learning/memory, sequencing, verbal fluency, or visuoconstruction. Mixed effects models also revealed no association with subsequent cognitive declines. Future research should examine changes in serum uric acid at earlier periods in the lifespan and their relationships with later cognitive declines.

Capturing additional information about the organization of entries in the lexicon from verbal fluency productions.

Troyer and colleagues [Troyer, A. K., Moscovitch, M., & Winocur, G. (1997). Clustering and switching as two components of verbal fluency: evidence from younger and older healthy adults. Neuropsychology, 11(1), 138-146] developed a seminal method to measure clustering and switching behaviors during verbal fluency (VF) productions. We sought to expand the reach of their system by modifying the scoring rules. Compared to the Troyer system, our modifications yield comparable estimates of interrater reliability and similar patterns of correlation with demographic characteristics for both clustering and switching in healthy adults. However, two objective measures of word relatedness (interword interval timing and latent semantic analysis) confirm that our revisions capture additional information about the organization of entries in the lexical network.