Long COVID is associated with severe cognitive slowing: a multicentre cross-sectional study.

Background: COVID-19 survivors may experience a wide range of chronic cognitive symptoms for months or years as part of post-COVID-19 conditions (PCC). To date, there is no definitive objective cognitive marker for PCC. We hypothesised that a key common deficit in people with PCC might be generalised cognitive slowing. Methods: To examine cognitive slowing, patients with PCC completed two short web-based cognitive tasks, Simple Reaction Time (SRT) and Number Vigilance Test (NVT). 270 patients diagnosed with PCC at two different clinics in UK and Germany were compared to two control groups: individuals who contracted COVID-19 before but did not experience PCC after recovery (No-PCC group) and uninfected individuals (No-COVID group). All patients with PCC completed the study between May 18, 2021 and July 4, 2023 in Jena University Hospital, Jena, Germany and Long COVID clinic, Oxford, UK. Findings: We identified pronounced cognitive slowing in patients with PCC, which distinguished them from age-matched healthy individuals who previously had symptomatic COVID-19 but did not manifest PCC. Cognitive slowing was evident even on a 30-s task measuring simple reaction time (SRT), with patients with PCC responding to stimuli ∼3 standard deviations slower than healthy controls. 53.5% of patients with PCC's response speed was slower than 2 standard deviations from the control mean, indicating a high prevalence of cognitive slowing in PCC. This finding was replicated across two clinic samples in Germany and the UK. Comorbidities such as fatigue, depression, anxiety, sleep disturbance, and post-traumatic stress disorder did not account for the extent of cognitive slowing in patients with PCC. Furthermore, cognitive slowing on the SRT was highly correlated with the poor performance of patients with PCC on the NVT measure of sustained attention. Interpretation: Together, these results robustly demonstrate pronounced cognitive slowing in people with PCC, which distinguishes them from age-matched healthy individuals who previously had symptomatic COVID-19 but did not manifest PCC. This might be an important factor contributing to some of the cognitive impairments reported in patients with PCC. Funding: Wellcome Trust (206330/Z/17/Z), NIHR Oxford Health Biomedical Research Centre, the Thüringer Aufbaubank (2021 FGI 0060), German Forschungsgemeinschaft (DFG, FI 1424/2-1) and the Horizon 2020 Framework Programme of the European Union (ITN SmartAge, H2020-MSCA-ITN-2019-859890).

Persistent cognitive slowing in post-COVID patients: longitudinal study over 6 months.

BACKGROUND: Fatigue is a frequent and one of the most debilitating symptoms in post-COVID syndrome (PCS). Recently, we proposed that fatigue is caused by hypoactivity of the brain's arousal network and reflected by a reduction of cognitive processing speed. However, it is unclear whether cognitive slowing is revealed by standard neuropsychological tests, represents a selective deficit, and how it develops over time. OBJECTIVES: This prospective study assesses whether PCS patients show deficits particularly in tests relying on processing speed and provides the first longitudinal assessment focusing on processing speed in PCS patients. METHODS: Eighty-eight PCS patients with cognitive complaints and 50 matched healthy controls underwent neuropsychological assessment. Seventy-seven patients were subsequently assessed at 6-month follow-up. The Test for Attentional Performance measured tonic alertness as primary study outcome and additional attentional functions. The Neuropsychological Assessment Battery evaluated all key cognitive domains. RESULTS: Patients showed cognitive slowing indicated by longer reaction times compared to control participants (r = 0.51, p < 0.001) in a simple-response tonic alertness task and in all more complex tasks requiring speeded performance. Reduced alertness correlated with higher fatigue (r = - 0.408, p < 0.001). Alertness dysfunction remained unchanged at 6-month follow-up (p = 0.240) and the same was true for most attention tasks and cognitive domains. CONCLUSION: Hypoarousal is a core deficit in PCS which becomes evident as a selective decrease of processing speed observed in standard neuropsychological tests. This core deficit persists without any signs of amelioration over a 6-month period of time.

Characterization of neurocognitive deficits in patients with post-COVID-19 syndrome: persistence, patients' complaints, and clinical predictors.

Introduction: Cognitive symptoms persisting beyond 3 months following COVID-19 present a considerable disease burden. We aimed to establish a domain-specific cognitive profile of post-COVID-19 syndrome (PCS). We examined the deficits' persistence, relationships with subjective cognitive complaints, and clinical variables, to identify the most relevant cognitive deficits and their predictors. Methods: This cross-sectional study examined cognitive performance and patient-reported and clinical predictors of cognitive deficits in PCS patients (n = 282) and socio-demographically comparable healthy controls (n = 52). Results: On the Oxford Cognitive Screen-Plus, the patient group scored significantly lower in delayed verbal memory, attention, and executive functioning than the healthy group. In each affected domain, 10 to 20% of patients performed more than 1.5 SD below the control mean. Delayed memory was particularly affected, with a small effect of hospitalization and age. Attention scores were predicted by hospitalization and fatigue. Discussion: Thus, PCS is associated with long-term cognitive dysfunction, particularly in delayed memory, attention, and executive functioning. Memory deficits seem to be of particular relevance to patients' experience of subjective impairment. Hospitalization, fatigue, and age seem to predict cognitive deficits, while time since infection, depression, and pre-existing conditions do not.

A hypoarousal model of neurological post-COVID syndrome: the relation between mental fatigue, the level of central nervous activation and cognitive processing speed.

BACKGROUND: Knowledge on the nature of post-COVID neurological sequelae often manifesting as cognitive dysfunction and fatigue is still unsatisfactory. OBJECTIVES: We assumed that cognitive dysfunction and fatigue in post-COVID syndrome are critically linked via hypoarousal of the brain. Thus, we assessed whether tonic alertness as a neurocognitive index of arousal is reduced in these patients and how this relates to the level of central nervous activation and subjective mental fatigue as further indices of arousal. METHODS: 40 post-COVID patients with subjective cognitive dysfunction and 40 matched healthy controls underwent a whole-report paradigm of briefly presented letter arrays. Based on report performance and computational modelling according to the theory of visual attention, the parameter visual processing speed (VPS) was quantified as a proxy of tonic alertness. Pupillary unrest was assessed as a measure of central nervous activation. The Fatigue Assessment Scale was applied to assess subjective mental fatigue using the corresponding subscale. RESULTS: VPS was reduced in post-COVID patients compared to controls (p = 0.005). In these patients, pupillary unrest (p = 0.029) and mental fatigue (p = 0.001) predicted VPS, explaining 34% of the variance and yielding a large effect with f2 = 0.51. CONCLUSION: In post-COVID patients with subjective cognitive dysfunction, hypoarousal of the brain is reflected in decreased processing speed which is explained by a reduced level of central nervous activation and a higher level of mental fatigue. In turn, reduced processing speed objectifies mental fatigue as a core subjective clinical complaint in post-COVID patients.