The pathophysiology underlying PCS remains unclear. Hypotheses on pathogenic mechanisms implicate both systemic effects and sequelae from acute SARS-CoV-2 organ injury. Hyperinflammation (Proal and VanElzakker, 2021), abnormal immunological response and autoimmunity (Leng et al., 2023), viral persistence (Sherif et al., 2023), reactivation of latent Epstein-Barr virus (Su et al., 2022), microvascular dysfunction (Navis, 2023), as well as coagulopathies and endotheliopathy (Leng et al., 2023) have been suggested in the etiopathogenesis of PCS.

Specific pathogenic mechanisms involved in COVID-19-associated cognitive impairment are also not fully understood. The three main factors identified by recent literature reviews (Yang et al., 2021; Monje and Iwasaki, 2022), i.e., neuroinflammation, neurovascular dysfunction, and disruption of cellular energy metabolism, are summarized below. Several other mechanisms are currently being researched, e.g., microbial dysbiosis (Gang et al., 2022), adverse effects of the viral spike protein on the angiotensin-converting enzyme two receptor, or inhibition of the gamma-aminobutyric acid (GABA) receptors (Manganotti et al., 2023).

As shown by viral detection in the cerebrospinal fluid in some patients, SARS-CoV-2 is neuroinvasive and may spread through various pathways into the central nervous system (Song et al., 2021). This has been suggested to trigger neuroinflammation (Castanares-Zapatero et al., 2022), which may account for neurotoxicity and neuronal damage. Microglia, the resident mononuclear immune cells of the central nervous system (CNS), play an essential role in the response to neuroinflammation. Activated microglia cells in the white matter of the brain further amplify neuroinflammation and can be associated with brain tissue damage (Fernandez-Castaneda et al., 2022). Furthermore, the generation of autoantibodies has a negative impact on neurogenesis and neuronal repair (Elizalde-Diaz et al., 2022).

Microvascular injury and endothelial damage can trigger excessive thrombin production and inhibit fibrinolysis that leads to formation of microthrombi. These pathogenetic factors may cause hypoperfusion and oxidative stress (Ostergaard, 2021). In a prospective observational cohort study, prolonged endothelial dysfunction with impairments of the microcirculation was observed and may explain ongoing symptoms in PCS (Kuchler et al., 2023).

Mitochondrial dysfunction, possibly caused by oxidative stress, leads to systemic reduction of metabolic activity and cellular bioenergetics within the CNS structures, which adversely affects neuronal function (Astin et al., 2023; Davis et al., 2023).

To date, no clear diagnostic criteria or biological markers for PCS have been established. Unless there are warning signs, diagnostics should be handled within the primary care setting. The steps described below have been recommended in a guideline (Koczulla et al., 2022) and are based on clinical experience. An algorithm for pragmatic management of individuals with cognitive impairment associated with post-COVID syndrome in primary care is also depicted in Figure 2.

Firstly, the preceding SARS-CoV-2 infection should be confirmed in patients’ medical history, ideally by polymerase chain reaction (PCR) or by a positive antigen test, even if asymptomatic. In primary care, this should be documented in the relevant patient files. The severity of the preceding infection has relevance for the individual prognosis and can be classified by means of WHO criteria. If patients report cognitive complaints, they should be asked about the onset of symptoms and whether complaints are related to PCS or may have another cause.

Physical examinations should be tailored to the specific concerns of patients, but should also include assessment of the cardiovascular system and a neurological examination. To assess functional status, the 1-min sit-to-stand test can be used, with the patient sitting down and standing up as often as possible within 1 minute. Depending on their age group, women can perform an average of 27–40 repeats per minute and men 30–45 repeats per minute. Lower values may indicate a reduced physical performance, which then should be examined further. Handgrip strength was shown to be a good indicator for fatigue. It requires a dynamometer and an accurate and standardized conduct.

Blood tests should be performed routinely and include heart, liver, and kidney function parameters. Furthermore, inflammatory markers, i.e., primarily C-reactive protein, immunological parameters, and blood coagulation parameters, should be determined. Testing for COVID-infection markers must be decided case by case, e.g., to exclude an acute infection. In PCS, tests for SARS-CoV-2 have often turned negative when the patient presents.

Most of the objective cognitive tests applied in clinical studies of PCS were developed in the context of dementia research. As can be seen from the literature found, the domains of cognition that are most frequently impaired in the case of PCS are executive functioning (Calabria et al., 2022; Garcia-Sanchez et al., 2022; Hadad et al., 2022; Serrano-Castro et al., 2022; Shanley et al., 2022; Diez-Cirarda et al., 2023; Ferrucci et al., 2023; Ludwig et al., 2023; Manganotti et al., 2023; Matias-Guiu et al., 2023; Taruffi et al., 2023), attention (Calabria et al., 2022; Garcia-Sanchez et al., 2022; Hadad et al., 2022; Serrano-Castro et al., 2022; Diez-Cirarda et al., 2023; Ferrucci et al., 2023; Ludwig et al., 2023; Matias-Guiu et al., 2023), and delayed recall (Calabria et al., 2022; Crivelli et al., 2022; Garcia-Sanchez et al., 2022; Serrano-Castro et al., 2022; Shanley et al., 2022). Notably, up to two-thirds of patients with subjective cognitive impairment due to PCS still pass these tests successfully, either in the total scores or in single domains (Lauria et al., 2022), which shows the limitations of using these cognitive tests in this patient group. Nevertheless, reliable, short, and easy-to-perform cognitive tests such as the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), or the Demenz-Detektion (DemTect) are useful in primary care, especially if their conduct can be delegated to the nursing staff.

Since there is no specific test for PCS-associated cognitive impairment, the MoCA or the MMSE are recommended as global screening tools (Frontera et al., 2023). In 19 of the 44 included studies, the MoCA was applied as an outcome criterion (Nasreddine et al., 2005). Twelve of the studies applied the MMSE. In studies where both tests were applied, the MMSE tended to be less sensitive than the MoCA (Aiello et al., 2022; Schild et al., 2023). Overall, although there are concerns that it may not be sensitive enough to reliably detect mild impairment or impairment in single domains of cognition, MoCA appears to be the most used tool (Lynch et al., 2022). Noteworthy, a positive screening result may indicate a severe course or a comorbid condition requiring special attention while a negative result does not exclude mild cognitive deficits.

Patient self-assessment tools can be used both to identify cognitive impairment and for follow-up (Koczulla et al., 2022). The German S1 guideline on long/post-COVID (Rabady et al., 2023) recommends the abbreviated Measurement of Everyday Cognition (ECog12), which is an assessment tool for self-reported cognitive decline. Another self-assessment tool is the Clinical Global Impression Scale which offers an alternative in terms of a robust measure assessing the global improvement of a patient’s condition. It can be applied to cognition and memory by asking the patient to score from 1 = ‘very much improved’ to 7 = ‘very much worse’. Finally, the five-item version of the Perceived Deficits Questionnaire may be used (Walker et al., 2023), which contains five simple cognition-related questions related to the previous week that are answered by the patients by means of a scale ranging from ‘never’ to ‘almost always’.

In eight studies relating to diagnosis of PCS, imaging procedures such as magnetic resonance imaging (MRI) or computed tomography (CT) were most frequently reported. In a retrospective analysis of case files from 243 patients, 37% were referred for neuroradiological examinations, 31% for electroencephalogram (EEG), and 28% for color Doppler of blood vessels of the head and neck. The results of the tests were not stated (Hegna et al., 2023).

In five studies with patient numbers ranging from 12 to 156, MRI scans of the brain (Franke et al., 2023; Ludwig et al., 2023; Mina et al., 2023; Taruffi et al., 2023), or MRI or CT (Hadad et al., 2022) did not reveal specific pathological findings correlating with cognitive impairment.

From another study including 86 patients with subjective PCS and 36 healthy controls, persistent structural and functional brain abnormalities following MRI examination 11 months after the acute infection were reported (Diez-Cirarda et al., 2023). Bilateral hypometabolism of regions of cerebrum and cerebellum associated with cognitive impairment was detected by positron emission tomography (PET) scan (Guedj et al., 2021) even 1 year after COVID-19 infection (Ferrucci et al., 2023).

Differential diagnosis is of utmost importance to ensure that cognitive impairment has not been present before the acute phase of COVID-19. The patient, or a caregiver, should be asked since when cognitive problems have existed. Primary care physicians usually have an advantage of knowing the patient’s medical history and thus do not have to rely solely on the patient’s own assessment.

Results from a qualitative study conducted in Germany in primary care provided some insights into how GPs managed patients with PCS (Bachmeier et al., 2023). The exclusion of other underlying conditions, such as hypothyroidism, and other neurologic-psychiatric conditions such as depression, dementia, stroke, or encephalopathy was the most common diagnostic approach.

Since most patients present with moderate or mild symptoms in primary care, a conservative approach including non-pharmacological and pharmacological measures is suitable (Figure 2). According to a practice-based recommendation based on experiences at the COVID-rehabilitation ambulance (Teixido et al., 2023), this includes counseling or coaching of patients and addressing their individual concerns. Besides the restitution of health and capabilities to carry out daily activities, maintaining or regaining the ability to work is of major importance for many patients. They should therefore be informed that complaints due to PCS are mostly reversible within several weeks or months, and usually disappear without any sequelae. It is important for patients to accept that they have to give themselves time for recovery (Bachmeier et al., 2023). Granting sufficiently long sick leave is therefore reasonable in most cases. In a recent study, guided qualitative interviews were conducted with 25 people with PCS (Schmachtenberg et al., 2023). Results showed that many interviewees reached their stress limit during routine household activities or childcare. Of the 25 participants, 19 experienced limitations in pursuing leisure activities, and 10 of those 23 interviewees with jobs reported being on sick leave for several months. Returning to work is possible if daily activities are manageable and 500 m can be walked symptom-free. Work intensity should be discussed with the employer and other restrictions may apply, e.g., avoiding night shifts (Magnavita et al., 2023). Moreover, physicians should discuss with their patients if their cognitive impairment may be a safety issue for professional or leisure activities, particularly for driving or operating machinery.

Follow-up visits at 4- to 8-week intervals are considered appropriate. If patients present with serious, unclear, suddenly evolving symptoms, poor general condition, or other warning signs such as disorientation and confusion, referrals to specialized care are indicated. However, sometimes there are waiting times, particularly for psychotherapy or inpatient rehabilitation.

General recommendations for patients with cognitive impairment associated with PCS include counseling on lifestyle factors such as improving sleep, reducing stress, adopting a healthy diet, and stopping smoking. A healthy diet consists of ample portions of fruits and salad, prioritizing freshly cooked meals, and reducing meat consumption (Bachmeier et al., 2023). Physical activity plays a crucial role in reducing the impact of PCS and engagement in exercise two to three times a week is recommended (Bachmeier et al., 2023). However, setting realistic and achievable goals and avoiding overexertion is of great importance.

Excessive body weight has been identified as a prognostic factor for poor outcomes of COVID-19. Obesity is likely to impair immune response to viral infections, leading to the development of a chronic low-grade inflammatory state and an elevated level of oxidative stress. Hence, body weight reduction may potentially have a positive effect in obese patients with PCS. In this context, there is ongoing discussion regarding the use of ketogenic diets, which are high-fat diets characterized by a marked carbohydrate restriction. It is important to note that particularly very low-calorie ketogenic diets should be supervised by professionals (Barrea et al., 2022). Implementation of weight reduction training aligns with the goal of strengthening muscles by exercise to improve PCS symptoms and has been found beneficial (Bachmeier et al., 2023; Jimeno-Almazan et al., 2023).

Behavioral interventions mentioned by Müller and Di Benedetto (Muller and Di Benedetto, 2023) comprise mind-body interventions, musical therapy, and meditation. These interventions, which are of low to moderate cost, can be conducted as self-practice at home and can alleviate symptoms of PCS. On a biochemical level, meditation is associated with a release of anti-inflammatory cytokines, modulation of neuroimmune responses, and decrease in C-reactive protein levels.

A practical guideline on PCS including cognitive impairment recommends various non-pharmacological therapeutic measures including digital solutions for cognition or memory training (Teixido et al., 2023). Some of them are freely available on the internet (e.g., for German-speaking patients: https://www.mental-aktiv.de/uebungen-klassisch/) or as YouTube videos with brain training exercises. Others can be prescribed by physicians, e.g., the App NeuroNation MED as digital health application (Digitale Gesundheitsanwendung, DiGA) in Germany. A currently ongoing study is evaluating the efficacy of computer-aided cognitive training in adult patients with PCS (ClinicalTrials.gov ID NCT05338749). Despite the pending results, this study presents an interesting approach to use game-based computer-delivered cognitive training to address mental symptoms such as attention, memory, or deficits in executive functions.

Further elements of outpatient rehabilitation may be physiotherapy, physical rehabilitation, or special fitness measures (Teixido et al., 2023). The RECOVE trial evaluated the effectiveness of exercise and respiratory muscle training administered in outpatient settings for patients with PCS. The authors found that exercises based on concurrent training (including supervised resistance and endurance exercises of low-to-moderate intensity) and concurrent training combined with inspiratory muscle training significantly alleviated dyspnea and fatigue, as well as enhanced overall health status (Jimeno-Almazan et al., 2023).

In specific circumstances, ergotherapy and speech therapy may be recommended. The latter may be necessary if given cognitive communication problems lead to the impairment of language fluency.

Micronutrients, including selenium, iron, zinc, and magnesium, are also critical for proper functioning of the immune system. Although there is no evidence for a general benefit in PCS patients, daily supplementation with 35–40 µg selenium, 15 mg iron, 15 mg zinc, or 350 mg magnesium daily can be considered in cases where a deficiency of these nutrients is present (Tosato et al., 2022; Pavlidou et al., 2024).

A persisting reduction in the richness of normal composition of gut microbiota can be found even 6 months after recovering from COVID-19 infection. Although controlled clinical trials focusing on patients with PCS are currently lacking, the use of probiotics and prebiotics may be considered as a supportive measure (Catalano et al., 2022). Additionally, immunomodulatory effects of probiotics may help in restoring the gut microbiome altered during viral infections (Muller and Di Benedetto, 2023).

To date, the pathologic mechanisms of cognitive impairment associated with PCS are unclear and no evidence-based treatments are available (Bonilla et al., 2023). Thus, management is currently focused on symptomatic treatment including anti-inflammatory drugs such as corticosteroids, anticoagulants, or analgesics, if indicated. The following treatment option specific for cognitive impairment was selected from the literature search based on empirical pharmacological plausibility. Due to the lack of rigorously controlled clinical trials, a favorable safety profile is of high importance.

Most published nonclinical and clinical studies investigating Ginkgo biloba extract were done using the proprietary Ginkgo biloba leaves extract EGb 761^®. EGb 761^® was shown to display multimodal effects on a variety of pathogenetic processes which may be involved in PCS (Mueller and Muller, 2024). Flavonoids, terpenoids, and anthocyanidins exhibit neuroprotective effects by modulating signaling pathways known to be impacted by COVID-19 (Zaa et al., 2023). They have been shown to inhibit neuroinflammation by reducing inflammatory activation in microglia cells (Gargouri et al., 2018). Importantly, it protects the function of endothelial cells (Pierre et al., 2008; Zhang et al., 2017) and improves brain and sensory organ perfusion by reducing blood viscosity (Erdinҫler et al., 1996). Randomized controlled trials demonstrated the efficacy of Ginkgo extract at the dose of 240 mg daily in mild cognitive impairment (Grass-Kapanke et al., 2011; Gavrilova et al., 2014). A meta-analysis of seven randomized, placebo-controlled trials in patients with dementia showed that treatment-associated risks (relative risk of adverse events, rates of premature withdrawal) in patients taking EGb 761^® did not differ noticeably compared to the placebo group and confirmed the safety and tolerability of this extract (Gauthier and Schlaefke, 2014). However, even if these pharmacological and clinical results are promising, the available data are still preliminary and require additional proof by further studies (Mueller and Muller, 2024).

In patients with cognitive impairment, treatment with Ginkgo extract can be started immediately at first consultation. Follow-up is recommended after 8 weeks of treatment. In a small case series with five patients aged 26–59 years and suffering from concentration and attention deficits, cognitive deficiencies, and/or fatigue, cognitive deficits and other symptoms, such as fatigue and hyposmia, were substantially improved or completely restored by treatment with EGb 761^® within 6 months (Zifko et al., 2022). The authors therefore recommended randomized controlled clinical trials to be conducted in order to confirm efficacy in this indication.

Our literature search revealed nine publications on experimental studies investigating therapeutic approaches. Table 1 presents an overview of study methodologies and main outcomes Table 2. Out of the studies found, only three were small scale randomized controlled studies. Each one was a controlled study on the efficacy of the H2 antagonist famotidine (Momtazmanesh et al., 2023) or donezepil hydrochloride (Pooladgar et al., 2023), and one investigated the effectiveness of a neuro-meditation program (Hausswirth et al., 2023). A case control study evaluated the efficacy of cognitive remediation therapy (Palladini et al., 2023), a feasibility pilot study was carried out on a personalized computerized cognitive training (Dunabeitia et al., 2023), and one observational pilot study evaluated a multimodal therapy concept with behavioral therapy-oriented, disorder-specific psychotherapy and exercise therapy (Kupferschmitt et al., 2023). Moreover, a retrospective analysis was performed with data from 64 patients suffering from PCS who were treated with a day-by-day individualized psychological intervention of cognitive stimulation in addition to a standard in-hospital rehabilitation program (Rabaiotti et al., 2023). A case series with 23 outpatients investigated the effect of transcranial magnetic stimulation (Noda et al., 2023) and another case series reported on five patients treated with EGb 761^® following presentation with concentration and attention deficits, cognitive deficiencies, and/or fatigue 9–35 weeks after COVID-19 infection (Zifko et al., 2022).

In August 2023, the US National Library of Medicine of the National Institutes of Health (NIH) clinical research registry (www.clinicaltrials.gov) reported 28 clinical trials investigating treatments of cognitive impairment associated with PCS. Of these, 18 clinical trials investigated various non-pharmacological interventions (ranging from Tai Chi, psychoeducation to computer-based cognitive trainings) and 10 investigated pharmacological treatments (atorvastatin, the NMDA receptor antagonist DAOIB, the antidepressant vortioxetine, an amniotic fluid product VIX001 for intravenous injection, ketamine (CI-581a and b) as glutamatergic modulator, as well as medium chain triglycerides, safflower oil, or nicotinamide riboside as dietary supplements).