Blood Markers Show Neural Consequences of LongCOVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system. To search for neurological markers of LongC, we investigated the soluble biomolecules present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected between 2020 and 2022, not hospitalized, and were vaccinated or unvaccinated before infection. IL-1β was significantly increased in both nLongC and Cov and IL-8 was elevated in only nLongC. Both brain-derived neurotrophic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43. This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.

Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer’s Disease

“…Conversely, there were six common proteins associated with LongC and AD. This adds to the common nEV DE proteins of Aβ and pTau181 previously reported [20]. It appears that these six DE proteins are mostly related to extracellular exosome-and immunesystem-enriched functional terms (Table S4).…”

“…In contrast, decreased BST1 in LongC may entail decreased neurogenesis in the hippocampus, which controls emotions, such as anxiety and depression, in addition to memory and learning. Supporting this hypothesis are studies showing that stress and increased glucocorticoids can decrease hippocampal neurogenesis [42,43], and we recently found increased cortisol in LongC individuals [20]. Since the LongC subjects in this study did not undergo rigorous neurological clinical assessment, it is possible that a more stringent assessment may reveal neurological features that differ between HIV and LongC.…”

“…In this study of several hundred neurological proteins, there was no overlap of nEV proteins, making it easier to differentiate HIV and AD. In contrast, we previously reported that nEVs from people with LongC and neurological symptoms had proteins associated with AD markers [14,15,32,33], including increased Aβ and pTau181 [20]. The proteomic panel used in this study had new, unreported proteins and did not include Aβ and pTau181.…”

“…Reports of elevated neurotoxic proteins in nEVs, such as amyloid beta (Aβ), neurofilament light and tau phosphorylated at threonine-181 (pTau181), have been shown in AD [14,15], traumatic brain injury [16][17][18] and HIV cognitive impairment [19]. We previously reported that nEVs from LongC had some of the same elevated toxic proteins as nEVs from individuals with AD [20]. Recently, neuropathologic findings suggest that SARS-CoV-2 and AD have similar neuroinflammatory pathways [21][22][23].…”

Organ-Dysfunction Markers in Mild-to-Moderate COVID-19 Convalescents

“…Despite a statistically significant difference in S100 between convalescents and never-infected subjects, we cannot clearly conclude, based on our results, that past COVID-19 infection may influence functioning of the nervous system. However, according to many reports suggesting a negative impact of SARS-CoV-2 infection on the CNS [50], convalescents should pay attention to any neurological symptoms that may appear after the disease.…”