Altered corticostriatal connectivity in long-COVID patients

Still bad news on the evidence that SARS-CoV-2 clearly leads to neurocognitive problems through objective pathophysiological events. Whether this may be treated remain a mistery, but, if I have to be honest, some of the events demonstrated in this new paper seems very difficult to be treated. Not by chance, I confess that the neurocognitive problems in long covid are those most difficult to be managed in my experience.

The authors of this study investigated functional connectivity (FC) changes in patients with long-COVID and their associations with cognitive impairment. Resting-state functional MRI data from 60 long-COVID patients and 52 age- and sex-matched healthy controls were analyzed using seed-based functional connectivity analysis.

They found increased FC between the right caudate nucleus and both the left and right precentral gyri in long-COVID patients compared with healthy controls. In addition, elevated FC was observed between the right anterior globus pallidus and posterior cingulate cortex as well as the right temporal pole in long-COVID patients. Importantly, the magnitude of FC between the caudate and the left precentral gyrus showed a significant negative correlation with Montreal Cognitive Assessment (MoCA) scores and a negative correlation with Trail Making Test B performance in the patient group.

In summary, these data suggest that patients with long-COVID present enhanced FC between the caudate and the left precentral gyrus. Furthermore, those FC alterations are related to the severity of cognitive impairment, particularly in the domain of executive functions.

If you follow my blog, you know that brain involvement in Covid-19 is real, and this means that the mechanisms behind cognitive impairment in long-COVID can be multifactorial, but starting with the infection. As summarized in the paper, evidence suggests that cellular damage resulting from viral invasion is linked to a dysregulated immune response and mitochondrial dysfunction, both of which contribute to increased oxidative stress (Parry, Wani, & Yaseen, 2020; Pierce, Shen, Cintron, & Hiebert, Reference Pierce, Shen, Cintron and Hiebert2022). The integrity of neural circuits and cognitive function is disturbed by this oxidative stress, and the invasion of cytokines, chemokines, and reactive microglia causes imbalances in myelin maintenance (Quan et al., Reference Quan, Wang, Gong, Wang, Li and Jia2023). Additionally, COVID-19 can compromise the blood–brain barrier, permitting the infiltration of fibrinogen and other proinflammatory agents, which causes neural inflammation (Quan et al., Reference Quan, Wang, Gong, Wang, Li and Jia2023). This inflammation has already been found to be concentrated within the BG (Rudroff, Reference Rudroff2024). The ACE-2 receptor serves as an entry point for SARS-CoV-2, as the spike protein on the surface of the virus binds to those receptors, allowing the virus to enter and infect the cell (Montani et al., Reference Montani, Savale, Noel, Meyrignac, Colle, Gasnier and Monnet2022; Pierce et al., Reference Pierce, Shen, Cintron and Hiebert2022). SARS-CoV-2 has the potential to directly infect neurons, glial cells, and the capillary endothelium by binding its spike protein to ACE-2 receptors, leading to neural tissue invasion and subsequently triggering neuroinflammation and the activation of microglia (Montani et al., Reference Montani, Savale, Noel, Meyrignac, Colle, Gasnier and Monnet2022; Quan et al., Reference Quan, Wang, Gong, Wang, Li and Jia2023; Xu & Lazartigues, Reference Xu and Lazartigues2022).

Histological samples of the caudate show expression of ACE2, which puts the caudate at risk for neuronal damage (Chen et al., Reference Chen, Wang, Yu, Howard, French, Chen and Xu2020). Moreover, the overexpression of ACE-2 receptors is associated with the development of cognitive deficits in long-COVID patients (Quan et al., Reference Quan, Wang, Gong, Wang, Li and Jia2023). Moreover, an autopsy study revealed SARS-CoV-2 RNA and protein in the BG (Stein et al., Reference Stein, Ramelli, Grazioli, Chung, Singh, Yinda and Consortium2022), and the same group consistently reported structural changes within the BG in patients with long-COVID (Besteher et al., Reference Besteher, Machnik, Troll, Toepffer, Zerekidze, Rocktäschel and Walter2022). Furthermore, another systematic review reported that cerebrovascular damage in the acute phase of COVID-19 causes hyperintensities and microhemorrhages of white matter, especially within the BG (Manca, De Marco, Ince, & Venneri, Reference Manca, De Marco, Ince and Venneri2021).

In summary, the BG shows overlapping structural and functional abnormalities, emphasizing its vulnerability to COVID-19-related damage. Due to cerebrovascular damage caused by the invasion and transmission of SARS-CoV-2, along with inflammation and disrupted neuronal integrity within the central nervous system, the resulting functional alterations are likely to impair cognitive efficiency (Swain et al., Reference Swain, Romano, Miryala, Tsai, Parikh and Umanah2021).

Given the mentioned events, although we don’t have a treatment for these neurocognitive problems I try to tackle all of them to help my patients (IVIG, PEA and rapamicyn for chronic inflammation, enoxaparin for endothelial dysfunction and inflammation, antivirals for viral persistence).

Will we find a single effective treatment for such problems?