Post COVID-19 Conditions and Neurocognitive Impairment—Current Findings and Clinical Implications

Abstract

Despite the increasing evidence of neurocognitive impairment (NCI) in patients suffering from post-COVID-19 conditions (PCC), the interplay between patient-reported symptoms and objective findings remains poorly characterized. Valid diagnostic tests and sufficient treatment strategies are lacking. We conducted a narrative perspective synthesis of current findings of NCI, standardized assessments (e.g., MoCA, PCCIS), and their association with inflammatory parameters. We highlighted findings on the discrepancy of subjective versus objectively measured neurocognitive impairment. The “subjectivity-objectivity-gap” may contribute to patient stigmatization, impair therapy adherence and be associated with a suboptimal clinical outcome. Although established multimodal interventions, such as cognitive rehabilitation, psychoeducation, group therapy, and pharmacotherapy—show preliminary efficacy, adherence may be compromised when subjective experiences of NCI are invalidated. We summarized the current state of the literature regarding demographic and clinical risk factors such as advanced age, lower education, neuropsychiatric comorbidities and evidence on the possible underlying role of persistent neuroinflammation in NCI in PCC. This perspective emphasizes the need for evidence-based diagnostic algorithms that integrate both subjective and objective NCI, explicitly addressing the risk of stigmatization. Future research should focus on addressing the neurobiological basis of NCI, discrepant NCI findings and associated stigmatization, and incorporate these findings in clinical guidelines.

Despite numerous works investigating neurocognitive impairment (NCI) in post COVID-19 conditions (PCCs), the underlying pathophysiological mechanisms are incompletely understood. Further, valid diagnostic markers and tests remain a matter of ongoing scientific discussion, as do recommendations for therapeutic approaches. NCI is a frequent symptom of patients affected by PCCs; it may persist over many months and significantly affects individuals’ quality of life and ability to work [1,2]. We follow the scientific developments in this field with great interest and wish to highlight the need for evidence-based consensus criteria regarding the diagnosis and clinical management of NCI in PCCs.

At least 65 to 70 million people worldwide may have developed PCCs according to representative estimates [3,4]. Cavaco et al. [5] demonstrated that cognitive dysfunction persisted in 18.2% and cognitive complaints in 33.3% of COVID-19 patients as long as 12 months after SARS-CoV-2 infection [5]. Common findings include impairment of executive functions, memory, concentration, and attention, cognitive slowing, or the subjective sensation of “brain fog” [2,5,6,7,8,9,10]. Patient-reported complaints often considerably diverge from objective diagnostic findings [11,12,13]. This discrepancy underscores the necessity of taking both patient-reported symptoms and objective findings into account during the diagnostic process and ensuring adequate treatment for PCC patients. This key gap has not sufficiently been addressed within the current diagnostic framework and could lead to stigmatization [14,15]. Reflecting on the psychiatric component of PCCs, stigmatization could impair therapy adherence, in addition to other general therapy factors, thereby impacting the general therapy outcome [14,15]. However, this association has not yet been investigated in patients suffering from PCCs. Follow-up studies should assess the association of the discrepancy between subjective and objective NCI during clinical assessment, stigmatization processes, and therapy adherence [14,15]. Both subjective and objective discrepant findings regarding NCI could be addressed explicitly within clinical interviews and should be clustered with regard to the different domains of NCI.

Standardized cognitive assessments can assist in the diagnosis of NCI and help monitor therapeutic progress over time. To this end, the Montreal Cognitive Assessment (MoCA) [16] and the Post-COVID Cognitive Impairment Scale [17] have been evaluated and found eligible for evaluating PCCs.

Several risk factors for the development of NCI in the context of PCCs have been identified. On a demographic level, these include a higher age [8] and a lower educational background [18]. Further, a history of neuropsychiatric comorbidities such as fatigue, mood, and anxiety disorders has been described as a risk factor [2,18]. Still, partly due to the heterogeneity of the study samples, evidence of the associated risk factors varies across different studies.

Recent studies discuss the link between neuroinflammation and cognitive impairment in PCCs with different findings [14,18]. Elevated systemic inflammatory markers and blood–brain barrier disruption were found in patients with PCCs and NCI, suggesting a possible role of persistent neuroinflammation in establishing and upholding long-term cognitive deficits [19,20]. These neuroinflammatory processes could especially affect patients of older age due to natural cognitive decline resulting in additional damage. Further, patients suffering from neuropsychiatric comorbidities, such as fatigue, mood, and anxiety disorders, might have a high vulnerability for neuroinflammatory processes and NCI. Still, due to incoherent findings in the current literature, the role of neuroinflammation in cognitive impairment in PCC patients remains elusive and needs further evidence. Taken together, further and larger studies are needed to elaborate on the hypothesis that NCI may be linked to neuroinflammation in PCC patients. Meanwhile, alternative explanatory hypotheses, for example, encompassing direct viral effects and the role of psychological factors, should be investigated as well.

On a macroscopic level, brain imaging studies of patients with NCI found no to very few radiological signs and were hesitant to attribute those that were found to PCCs [2,21,22]. Further brain imaging studies with a larger sample size and long-term follow-up assessment of patients with NCI are needed to elaborate on the hypothesis of macroscopic brain alterations in NCI in PCC patients and their potential clinical relevance.

While the exact pathophysiological basics of NCI in PCCs may not be fully understood yet, treatment must be based on a multimodal therapeutic approach to meet the demands of a multilevel cognitive condition. Neurocognitive training focused on cognitive rehabilitation plays a main role and has shown promising effects in the therapy of PCC-associated NCI [23,24]. Preliminary data indicate that psychoeducation in combination with cognitive behavioral therapy in group settings and peer-to-peer contact focused on dealing with prolonged NCI can have beneficial effects. In parts, NCI symptoms may also improve naturally over time [23,24]. A structured “watch-and-wait” strategy with basis diagnostics, repeated and standardized symptom monitoring, and extended psychoeducation could therefore be applied as a minimum intervention until specific treatment options are available. A structured “watch-and-wait” strategy should only be applied in the absence of diagnostic red flags identified according to German PCC guidelines [25]. Pharmacological interventions with antidepressants, such as serotonin-reuptake inhibitors, should be considered in specific cases, especially when treating comorbid depressive and anxiety disorders [26,27]. These treatment recommendations are based on the current German guidelines on PCCs and additional clinical evidence from relevant selected studies [24,25,26,27,28,29,30]. Large-scale studies are needed to evaluate treatment outcomes over time and the interplay of the different treatment recommendations and modalities.

Based on its global prevalence and major impact on daily functioning, quality of life, and work ability, further research on the underlying neuropsychopathology and the exploration of viable treatment options of PCC-associated NCI are urgently sought after. A deeper understanding of the interplay between neuroinflammation and NCI, as well as the role of concomitant psychiatric comorbidities, could facilitate targeted therapeutic interventions in patients affected by PCCs based on relevant risk factors. Further, future studies should address the clinical relevance of subjectivity, the lived reality of PCC patients suffering from NCI, and the possible associated stigmatization processes. Lastly, the implementation of consensus-based standardized diagnostic algorithms and, ideally, clinical checklists based on current findings, in the format of living guidelines [31], for the assessment of NCI and personalized treatment strategies are urgently needed.