key: cord-0828844-d0w60yt2 authors: Yesilkaya, Umit Haluk; Sen, Meltem; Balcioglu, Yasin Hasan title: COVID-19-related cognitive dysfunction may be associated with transient disruption in the DLPFC glutamatergic pathway date: 2021-03-14 journal: J Clin Neurosci DOI: 10.1016/j.jocn.2021.03.007 sha: 5ad780cdf8129ac96a222f4a55333290d5da04e9 doc_id: 828844 cord_uid: d0w60yt2 Cognitive impairment has recently attracted researchers as one of the possible neuropsychiatric manifestations of COVID-19, although how the infection perpetuates impairment of cognitive functions is still obscure. We presented a 29-year-old male patient with COVID-19 who developed new-onset transient attention deficit and memory problems following a SARS-CoV-2 infection. Structural neuroimaging was normal. MR-spectroscopy (MRS) of the bilateral DLPFC revealed significant for decreased levels of N-acetylaspartate (NAA), glutamate, and glutamate/glutamine ratio. After a follow-up without any medical treatment but with suggestions of memory exercises for three months a control MRS screening of DLPFC showed improved levels of NAA, glutamate, and glutamate/glutamine ratio. This report may suggest that cognitive deficits in SARS-CoV-2 infection can result from glutamatergic dysfunction with decreased NAA and glutamate levels in bilateral DLPFC. It has been suggested that SARS-CoV-2 is a potential neurotrophic virus and several central nervous system (CNS) presentations associated with COVID-19 have been reported (1, 2) . Recent studies suggest that unbridled inflammation caused by either the virus itself or immunoreactivity led by the infection might be associated with neuropsychiatric outcomes in COVID-19 (2, 3) . Cognitive impairment has piqued interest as one of the possible neuropsychiatric manifestations of COVID-19, although how the infection perpetuates impairment of cognitive functions is still obscure (1) . Here, we presented a patient with COVID-19 who developed transient attention deficit and memory problems, which may be related to glutamatergic dysfunction in the dorsolateral prefrontal cortex (DLPFC), with the aim of contributing to the literature for understanding the etiopathogenesis of COVID-19's neuropsychiatric manifestations. A 29-year-old post-graduate male patient was confirmed to be SARS-CoV-2 positive by RT-PCR upon his admission to the emergency department with symptoms of cough, fatigue and myalgia. After the patient was treated according to the national COVID-19 treatment protocol with favipravir and azithromycin, his symptoms improved within a week, and a negative RT-PCR result for SARS-CoV-2 was confirmed. Two weeks after the completion of treatment of COVID-19, the patient was admitted to the psychiatry outpatient unit with complaints of difficulty of remembering past experiences, inattention and carelessness. The patient reported no previous background of neurological nor psychiatric diagnosis including an alcohol or substance abuse. Physical and neurological examinations revealed nothing significant. In psychiatric examination, concentration difficulties were noted, and he seemed to hardly find the appropriate words to speak without any articulation problems. Impaired memory-retrieval was evident when testing free recall. Abnormal findings in perception, thought or mood/affection were not identified. The patient was further evaluated with neuropsychological test which was modified according to findings and the test battery was performed by a trained and experienced neuropsychologist. He was subjected to Frontal Assessment Battery (FAB) to assess frontal lobe dysfunction, Global Deterioration Scale In animal studies, it has been shown that coronaviruses cause neurodegeneration in the hippocampal CA1 and CA3 areas, leading to a decrease in short-term learning and impairment in spatial memory (6) . Corroborating these data, Lu et al. showed hippocampal changes in brain images of SARS-CoV-2 infected patients, which correlated with a loss of memory (7) . Considering previous findings, impairment of cognitive functions that regulated by the DLPFC may be attributed to SARS-CoV-2 infection in our patient. Glutamate is the main neurotransmitter involved in cognitive functions in the frontal cortex and hippocampus. In previous research, the levels of glutamate were found to be decreased with other viral infections of the CNS, such as HIV-related dementia (8) which has been associated with metabolic derangement (9) . Congruently, Crunfli et al. have suggested that the redeployment of metabolism in SARS-CoV-2-infected astrocytes may be associated with a disruption within the glutamatergic pathway. (10) . In the index patient, the altered glutamate/glutamine ratio may further support a dysregulated glutamatergic pathway possibly associated with the CNS involvement of SARS-CoV-2. In addition, NAA is known to be involved in cognitive functions (11) , and the patient initially showed low levels of NAA, which was spontaneously rebalanced at the follow-up that overlaps the recovery phase of the SARS-CoV-2 infection. This finding also lends credence our hypothesis that cognitive dysfunction might be associated with COVID-19. Overall, our findings suggest that cognitive deficits in SARS-CoV-2 infection can result from glutamatergic dysfunction with decreased glutamate and NAA levels in the DLPFC confirmed by MRS. Of note, this dysfunction seemed to be reversible. In fact, current evidence is not encouraging that favipravir and azithromycin are likely to lead such a cognitive impairment. Moreover, cognitive impairment in COVID-19 resulting from disrupted glutamatergic pathway may be alleviated with the use of therapeutics that increase glutamate levels such as Nacetylcysteine (11, 12) and glutathione (13) . However, further research is warranted to validate the authenticity of this suggestive etiopathogenesis of neuropsychiatric outcomes of COVID-19 along with the proposed treatment strategy. -Decreased brain metabolism demonstrated through MR-spectroscopy (MRS) of the bilateral DLPFC may be related to inflammatory processes led by SARS-CoV-2. -COVID-19-related reduced brain metabolism may be associated with transient cognitive deficits including memory and attention problems. Lifting the mask on neurological manifestations of COVID-19 Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? 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Cerebral Micro-Structural Changes in COVID-19 Patients -An MRI-based 3-month Follow-up Study: A brief title: Cerebral Changes in COVID-19 7T brain MRS in HIV infection: Correlation with cognitive impairment and performance on neuropsychological tests The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs SARS-CoV-2 infects brain astrocytes of COVID-19 patients and impairs neuronal viability Moderate relationships between NAA and cognitive ability in healthy adults: Implications for cognitive spectroscopy Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19 The role of glutathione in protecting against the severe inflammatory response triggered by covid-19 The authors declared no known competing financial interests or potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Informed consent was obtained from the patient following an explanation provided on the need to request permission for use of his clinical information in a scientific work.