Morphological, Cellular, and Molecular Basis of Brain Infection in COVID-19 Patients and Its Association to Psychiatric Symptoms

Background: Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. Method(s): We performed a broad translational investigation, employing brain imaging and cognitive tests in 81 living COVID-19 patients (mildly infected individuals) as well as flow cytometry, respirometry, microscopy, proteomics, and metabolomics in postmortem brain samples, and in preclinical in vitro and ex vivo models. Result(s): We observed orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms in living individuals. Postmortem brain tissue from 26 individuals who died of COVID-19 revealed histopathological signs of brain damage. Five individuals out of the 26 exhibited foci of SARS- CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a non-canonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that significantly reduces neuronal viability. Conclusion(s): Our data support the model in which COVID-19 alter cortical thickness, promoting psychiatric symptoms. In addition, SARS-CoV-2 is able to reach the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients. Funding Source: Sao Paulo Research Foundation (FAPESP) Keywords: COVID-19, Anxiety, Astrocytes, Multi-omics, Brain Magnetic Resonance Imaging (MRI)Copyright © 2023

FDG-PET Brain Imaging in the Evaluation and Follow-up of COVID-19

Aim/Introduction: The novel coronavirus disease (COVID-19) is caused by the respiratory infection of SARS-CoV-2 virus and is characterized by a multisystemic inflammation, presenting with a wide spectrum of symptoms. 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) is a promising imaging method in the evaluation of acute-phase and late changes in the central nervous system. Material(s) and Method(s): A single-centre, prospective clinical study (COMPOSIT study) was initiated where FDG-PET/CT was performed in adult COVID-19 patients during acute, infective state and 3 months later. Brain FDG-PET images were evaluated with a software utilizing a built-in, age-matched normal database and the degree of the differences (Z-scores) were investigated at the two imaging timepoints. Result(s): We present the data of 36 patients (14 women, 22 men), with a mean age of 52 years (42-75 years). In the acute, infective state, the majority of the patients presented with diffuse, significant cortical hypometabolism whereas at 3 months followup, the involved regions showed a marked and often complete metabolic normalization. The most common regions with residual hypometabolism at 3 monts were the medial prefrontal and medial temporal regions and the anterior cingulate. Also, these regions showed the proportionally lowest rates of normalization. Hypometabolism was the least frequent in the cerebellum at the acute, infective state and its FDG-uptake showed a nomalization in all but one case. Conclusion(s): Residual hypometabolism is common in the areas encompassing the orbitofrontal cortex and the limbic system while the cerebellar cortex was relatively spared. However, our study is limited by the corticosteroid-effect in the scans performed at the acute, infective state and furthermore, the fact that no metabolic data is available of the patients before SARS-CoV-2 infection.

Conversion of Stuporous Catatonia to Excited Catatonia from Lorazepam Challenge

Background: Catatonia, a motor dysregulation syndrome with behavioral components, has undergone many conceptual changes since its inception as a syndrome by Kahlbaum in 1874. Prevalence of catatonia in consultation-liaison services is approximately 5.5 percent in patients aged 65 and older.1 Stuporous catatonia is most common, but catatonia may present in excited or malignant subtypes. Together, the subtypes have over 40 documented signs and symptoms, making catatonia difficult to diagnose and appropriately treat.2 Catatonia involves hyperactivation of the orbitofrontal cortex (OFC) and ventromedial prefrontal cortex. GABA, NMDA, and dopamine have been implicated. GABA-A agonism by benzodiazepines improve catatonia by normalizing OFC activity.3 Case: A 66-year-old male with schizophrenia was admitted to a medical unit for failure to thrive after not eating for three days. He had not taken his medications for 2 weeks including chlorpromazine, quetiapine, oxcarbazepine, and clonazepam. Upon psychiatric consult, the patient exhibited staring, grimacing, echopraxia, and negativism. He was diagnosed with stuporous catatonia. 30 minutes after lorazepam challenge (2 milligram intravenous lorazepam), the patient was moving, conversing, and eating. After second dose of lorazepam, the patient became difficult to redirect, displaying stereotypy, verbigeration, and hitting. Additional doses of lorazepam were unsuccessful in breaking excited catatonia. History revealed previous catatonic episodes, including nine months prior when the patient was admitted to a gero-psychiatric unit. He initially presented in stuporous state, normalized with lorazepam, then transitioned to excited state. He received 16 milligrams of lorazepam in 24 hours without successful termination of excited catatonia. Lorazepam in combination with carbamazepine, clozapine, or valproic acid was unsuccessful. Catatonia was successfully treated with 10 sessions of electroconvulsive therapy (ECT) with lorazepam, clozapine, and valproic acid. Maintenance ECT was not continued because of the COVID pandemic, and the patient was admitted to a state facility after regression. Discussion: Catatonia is often encountered on consultation-liaison services in general hospital settings. We observed conversion of stuporous catatonia to excited catatonia after administration of lorazepam. This treatment-resistant catatonia ultimately required ECT. No reported cases of stuporous catatonia transitioning to excited catatonia were found on thorough literature review. Recognition of this conversion may be difficult and may require development of a catatonia scale that clearly identifies the presenting subtype. This is a challenge;clinical signs are not mutually exclusive among subtypes. This patient’s clinical course may provide insight into the identification of treatment-resistant catatonia, and accurate identification is necessary to allow for timely escalation of treatment. References: 1. Solmi M, et al. Prevalence of catatonia and its moderators in clinical samples: Results from a meta-analysis and meta-regression analysis. Schizophrenia Bulletin. 2017;44(5):1133–50. 2. Fink M, Taylor MA. The catatonia syndrome. Archives of General Psychiatry. 009;66(11):1173. 3. Ellul P, Choucha W. Neurobiological approach of Catatonia and Treatment Perspectives. Frontiers in Psychiatry. 2015;6.

18fluorodeoxyglucose (FDG) brain PET/CT as the only diagnostic tool able to identify early cognitive impairment in a covid-19 patient: a case-report

Background-Aim: Cognitive impairment may represent a long lasting symptom after COVID-19 resolution and FDG brain PET is useful to evaluate if brain metabolic changes are transient or long lasting. Hypometabolism was shown in many brain areas, i.e. cingulate cortex, bilateral gyrus rectus, prefrontal and orbitofrontal cortex and cerebellar vermis. Methods: We report the case of a 62 years old man with type 2 diabetes, affected by COVID-19 infection in October 2020. After resolution, the patient had short-term memory loss and speech deficit affecting daily living and working activities and referred to the Gerontology and Geriatrics Institute (Univ. of Perugia). Neurological examination and neuropsychological tests were carried out and no alterations were found. In October 2021, the neurological examination was still normal, as well as neuropsychological tests. Brain MRI showed only two small chronic ischemic foci without bi-hemispheric white matter clinically significant abnormalities. In November 2021, the patient underwent FDG brain PET/CT (discovery ST, G.E.) according to standard protocols and images were evaluated both qualitatively and semiquantitatively. Results: An area of moderate significant hypometabolism was identified in the precuneus (predominant on the right side) and others multiple small and mild hypometabolic regions were localized in bilateral pre-frontal cortex, sensorimotor and parietal cortex both on left hemisphere. PET and MRI fusion images (Syngo.via VB10B image processing software, Siemens) showed that hypometabolic areas corresponded to structurally intact parenchyma at MRI. In January 2022 clinical and neuropsychological follow up did not evidence cognitive impairment, although the patient still felt depressed and impaired in memory, attention and daily living activities. Conclusions: In this case, FDG brain PET/CT was the only diagnostic procedure showing findings consistent with patient symptoms. In particular, precuneus hypometabolism may represent in this patient an early hallmark of dementia (i.e. Alzheimer's disease-AD), although other characteristic brain areas are not significantly impaired (i.e. cingulate cortex). In this case, FDG brain PET use, during follow up, could be crucial to evaluate if the metabolic changes may evolve into a chronic state, thus supporting mild cognitive impairment clinical suspect due to AD or confirming a stable COVID related neuronal damage. Furthermore, a second normal FDG brain PET/CT scan may suggest a post-acute infection transient phase, preluding to normal functional status. In conclusion, FDG brain PET/CT may represent an important diagnostic tool in modifying subsequent diagnostic assessment suggesting or routinely clinical follow up or other investigations for dementia (i.e. amyloid PET, amyloid and Tau protein liquor measurement). In our study, fused PET and MRI images were used, although hybrid PET/MRI system could be the choice option if available.

Metabolic correlates of olfactory dysfunction in covid-19 and Parkinson's disease (PD)

Background-Aim: A potential link has been investigated between hyposmia after COVID-19 and an increased risk to develop neurological long-term sequelae also in patients who experienced mild or moderate disease. Hyposmia is a common feature PD and parkinsonism has been reported after COVID-19 suggesting a potential link between SARS-CoV2 infection and PD. [18F]FDG PET may represent a suitable tool to capture potential common metabolic signature of hyposmia after COVID-19 and in PD patients. We aimed to evaluate brain metabolic correlates of isolated persistent hyposmia after mild-to-moderate COVID-19 and to compare them with metabolic signature of hyposmia in drug-naive PD patients. Methods: Forty-four patients who experienced hyposmia after SARSCOV2 infection underwent brain [18F]FDG-PET in the first 6 months after recovery. Olfaction was assessed by means of the 16-item ''Sniffin-Sticks'' test and patients were classified as with or without persistent hyposmia (COVID-hyposmia and COVID-no-hyposmia respectively). Brain [18F]FDG-PET of post-COVID subgroups were compared in SPM12. COVID-hyposmia patients were also compared with eighty-two drug-naïve PD patients with hyposmia. Multiple-regression- analysis was used to identify correlations between olfactory test-scores and brain metabolism in patients' subgroups. Results: COVID-hyposmia patients (n = 21) exhibited significant hypometabolism in bilateral gyrus rectus and orbitofrontal cortex with respect to COVID-non-hyposmia (n = 23) (p<0.002) and in middle and superior temporal gyri, medial/middle frontal gyri and right insula with respect to PD-hyposmia (p<0.012). With respect to COVIDhyposmia, PD-hyposmia patients showed hypometabolism in inferior/ middle occipital gyri and cuneus bilaterally. Olfactory test-scores were directly correlated with metabolism in bilateral rectus and medial frontal gyri and in right middle temporal and anterior-cingulate gyri in COVID-hyposmia patients (p<0.006) and with bilateral cuneus/precuneus and left lateral occipital-cortex in PD-hyposmia patients (p<0.004). Conclusions: Metabolic signature of persistent hyposmia after COVID-19 encompasses cortical regions involved in olfactory perception and does not overlap metabolic correlates of hyposmia in PD. An impairment in olfactory judgement seem to underlie hyposmia in PD patients while a more restricted perception deficit seems to explain hyposmia in COVID-19. The potential long term neurological sequelae of COVID-19 are of interest from the clinical and economical point of view. Studies targeting symptoms common to COVID-19 and chronic neurological diseases and aiming to explore potential common pathways are of interest also to avoid unjustified claims about a future high incidence of neurodegenerative diseases secondary to the SARS-CoV-2 pandemic.

Neuroimaging Recovery in Human Drug Addiction: An Eye Towards Intervention Development

Drug addiction is on the rise during these COVID-19 times that intensify the factors contributing to relapse and overdose across drugs of abuse and continents. Using a multimodal approach (neuropsychology, fMRI, ERP), human neuroimaging studies in my lab have elucidated core mechanisms underlying drug addiction, with a focus on the role of the dopaminergic mesocorticolimbic circuit, especially the prefrontal cortex, in higher-order cognitive and emotional dysfunction in this population. Our theoretical model is called iRISA (Impaired Response Inhibition and Salience Attribution), postulating that abnormalities in the orbitofrontal cortex and anterior cingulate cortex (and other cortical regions underlying higher order executive function), contribute to the core clinical symptoms in addiction. Specifically, our program of research is guided by the working hypothesis that drug addicted individuals disproportionately attribute salience and value to their drug of choice at the expense of other reinforcing stimuli, with a concomitant decrease in the ability to inhibit maladaptive drug use. Our complex and multifaceted dataset has allowed us to study the impact of abstinence on recovery in these brain-behavior compromises in treatment-seeking addicted individuals, where non-linear relationships exemplify incubation of craving while other trajectories of change, including in white matter tracks and for small subcortical regions (such as the habenula), are also explored. Novel paradigm shifts in the lab include the use of naturalistic and dynamic stimuli for enhanced generalizability and validity, in addition to development of effective neurorehabilitation strategies (including cognitive reappraisal, mindfulness, and transcranial direct current stimulation) in drug addiction. Keywords: Neuroimaging, drug addiction