Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics

Abstract

The development of long-term symptoms of coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed "long COVID" or post-acute sequela of COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as fatigue, "brain fog", headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, and peripheral neuropathy. Pathogenic mechanisms of these symptoms of long COVID remain largely unclear; however, several hypotheses implicate both nervous system and systemic pathogenic mechanisms such as SARS-CoV2 viral persistence and neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, and endotheliopathy. Outside of the CNS, SARS-CoV-2 can invade the support and stem cells of the olfactory epithelium leading to persistent alterations to olfactory function. SARS-CoV-2 infection may induce abnormalities in innate and adaptive immunity including monocyte expansion, T-cell exhaustion, and prolonged cytokine release, which may cause neuroinflammatory responses and microglia activation, white matter abnormalities, and microvascular changes. Additionally, microvascular clot formation can occlude capillaries and endotheliopathy, due to SARS-CoV-2 protease activity and complement activation, can contribute to hypoxic neuronal injury and blood-brain barrier dysfunction, respectively. Current therapeutics target pathological mechanisms by employing antivirals, decreasing inflammation, and promoting olfactory epithelium regeneration. Thus, from laboratory evidence and clinical trials in the literature, we sought to synthesize the pathophysiological pathways underlying neurological symptoms of long COVID and potential therapeutics.

Keywords: COVID-19; SARS-CoV-2; brain fog; long COVID; neurological complication; neurological manifestations; outcome.

Figure 1

Neuroinvasion and persistent viral shedding. SARS-CoV-2 employs the ACE2 receptor to invade the stem cells, perivascular cells, sustentacular cells, and Bowman’s gland cells in the olfactory epithelium; this leads to chronic thinning of filia and loss of olfactory bulb volume. Additionally, there is an association between areas of hypometabolism in the cortex, cerebellum, and brainstem with the spatial distribution of ACE2 receptors, though there is little evidence for direct neuroinvasion in these areas. Rather, it is hypothesized that these regions experience elevated levels of microglial activation, cytotoxic T lymphocyte infiltration, oxidative stress, and neurodegeneration and demyelination secondary to neuroinvasion. These mechanisms likely persist due to the chronic presence of viral shedding specifically in the gastrointestinal tract where there exists ACE2 co-regulation of DDC and involvement of the dopamine metabolic pathway. Figure was created with the BioRender software.

Figure 2

Systemic and neurological immune response. The systemic immune and inflammatory response to SARS-CoV-2 infection can continue for months after the acute recovery phase, inducing a state of persistent systemic inflammation with upregulated cytokines, such as IFN-β, IFN-λ1, IFN-γ, IL-2, IL-6, IL-17, CXCL8, CXCL9, and CXCL10. This prolonged cytokine release has been linked to activation of specific immune cell populations, such as non-classical and intermediate monocytes, as well as other cell types, such as fibroblasts and myeloid cells. From an aberrant Th2 cytokine pool, production of CCL11 is induced and leads to neuroinflammation with activation of resting microglia, which can further release increased levels of CCL11. This microglial reactivity can in turn cause reduced hippocampal neurogenesis, loss of myelinating oligodendrocytes and oligodendrocyte precursors, and ensuing subcortical white matter demyelination. These systemic and neurological mechanisms have been strongly associated with a range of cognitive impairments and neuropsychiatric symptoms. Figure was created with the BioRender software.

Figure 3

Blood–brain barrier disruption and microclot formation. SARS-CoV-2 can cause increased microclot formation through spike protein interactions with fibrinogen and serum protein A that promote fibril formation and resist fibrinolysis. Antiphospholipid antibodies are also present in long COVID and can precipitate microclot formation through IL-6, IL-8, VEGF, nitric oxide synthase, and NET release. These microclots also contain α2AP which inhibit plasmin and thus prevent the degradation of fibrin, further contributing to their fibrinolysis-resistant nature. Additionally, SARS-CoV-2 can induce BBB disruption through Mpro cleavage of NEMO in endothelial cells leading to cell death and string vessel formation. Figure was created with the BioRender software.