18F-FDG brain PET hypometabolism in post-SARS-CoV-2 infection: substrate for persistent/delayed disorders?

Abstract

Purpose Several brain complications of SARS-CoV-2 infection have been reported. It has been moreover speculated that this neurotropism could potentially cause a delayed outbreak of neuropsychiatric and neurodegenerative diseases of neuroinflammatory origin. A propagation mechanism has been proposed across the cribriform plate of the ethmoid bone, from the nose to the olfactory epithelium, and possibly afterward to other limbic structures, and deeper parts of the brain including the brainstem. Methods Review of clinical examination, and whole-brain voxel-based analysis of 18 F-FDG PET metabolism in comparison with healthy subjects ( p voxel < 0.001, p -cluster < 0.05, uncorrected), of two patients with confirmed diagnosis of SARS-CoV-2 explored at the post-viral stage of the disease. Results Hypometabolism of the olfactory/rectus gyrus was found on the two patients, especially one with 4-week prolonged anosmia. Additional hypometabolisms were found within amygdala, hippocampus, parahippocampus, cingulate cortex, pre-/post-central gyrus, thalamus/hypothalamus, cerebellum, pons, and medulla in the other patient who complained of delayed onset of a painful syndrome. Conclusion These preliminary findings reinforce the hypotheses of SARS-CoV-2 neurotropism through the olfactory bulb and the possible extension of this impairment to other brain structures. 18 F-FDG PET hypometabolism could constitute a cerebral quantitative biomarker of this involvement. Post-viral cohort studies are required to specify the exact relationship between such hypometabolisms and the possible persistent disorders, especially involving cognitive or emotion disturbances, residual respiratory symptoms, or painful complaints.

Cardiovascular protective properties of oxytocin against COVID-19

“…Since AT II is increased due to the reduction of ACE2, which can also reduce OXT secretion in COVID-19 patients. Decreases in these hypothalamus- and pituitary-associated hormones are in agreement with the hypometabolism found in the hypothalamus and pathological manifestations in COVID-19 patients [ 16 , 81 ], and they together indicate suppression of the hypothalamic neuroendocrine activity including the OXT-secreting system.…”

“…Factors that are associated with mortality include male sex, advanced age, cytokine storm, ARDS, acute cardiac injury, acute kidney injury and the presence of comorbidities including hypertension, diabetes mellitus, CV diseases, and cerebrovascular diseases [ 11 , 12 ]. Patients often exhibit ground-glass opacity on chest computed tomography [ 13 ], troponinemia [ 14 ], increased cytokines, and lymphocytopenia [ 15 ] as well as hypometabolism in many brain regions including the hypothalamus [ 16 ]. All of these findings indicate the involvement of multiple organ systems.…”

“…Since the mammillary bodies function as the upstream center of OXT neuronal activity, particularly its release in a pulsatile pattern [ 72 ], viral infection of the mammillary bodies unavoidably changes the downstream OXT neuronal activity and OXT secretion. In COVID-19 patients, many brain areas innervated by olfactory bulbs including the hypothalamus showed hypometabolism in 18 F-FDG positron emission tomography scans [ 16 ], suggesting low activity of olfaction-associated hypothalamic neuroendocrine processes. It is also reported that activation of ACE2 in the PVN increases neuronal NO synthase and NO production, which can increase sympatho-inhibitory GABA activity and decrease sympatho-excitatory AT II signaling and glutamate activity [ 73 ].…”

“…This can result from the malfunction of sex glands as well as hypothalamic gonadotropin-releasing hormone. Levels of thyroid stimulating hormone and serum total triiodothyronine of COVID-19 patients are significantly lower than those of the healthy control group and non-COVID-19 pneumonia patients [ 78 ], which likely worsens the hypometabolism of the hypothalamus [ 16 ]. COVID-19 patients also have lower circulating levels of natriuretic peptides [ 79 ].…”

“…It is likely that SARS-CoV-2 enters the brain from the nose to the olfactory bulbs, and then infects neurons in the hypothalamus via the olfactory nerve [ 16 ]. The olfactory bulb involvement is supported by the high rates of anosmia or hyposmia in patients with COVID-19 [ 81 ] and by neural connections between the olfactory bulb and SON [ 82 ].…”