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      The cerebral network of COVID-19-related encephalopathy: a longitudinal voxel-based 18F-FDG-PET study

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          Abstract

          Purpose

          Little is known about the neuronal substrates of neuropsychiatric symptoms associated with COVID-19 and their evolution during the course of the disease. We aimed at describing the longitudinal brain metabolic pattern in COVID-19-related encephalopathy using 18F-FDG-PET/CT.

          Methods

          Seven patients with variable clinical presentations of COVID-19-related encephalopathy were explored thrice with brain 18F-FDG-PET/CT, once in the acute phase, 1 month later and 6 months after COVID-19 onset. PET images were analysed with voxel-wise and regions-of-interest approaches in comparison with 32 healthy controls.

          Results

          Patients’ neurological manifestations during acute encephalopathy were heterogeneous. However, all of them presented with predominant cognitive and behavioural frontal disorders. SARS-CoV-2 RT-PCR in the CSF was negative for all patients. MRI revealed no specific abnormalities for most of the subjects. All patients had a consistent pattern of hypometabolism in a widespread cerebral network including the frontal cortex, anterior cingulate, insula and caudate nucleus. Six months after COVID-19 onset, the majority of patients clinically had improved but cognitive and emotional disorders of varying severity remained with attention/executive disabilities and anxio-depressive symptoms, and lasting prefrontal, insular and subcortical 18F-FDG-PET/CT abnormalities.

          Conclusion

          The implication of this widespread network could be the neural substrate of clinical features observed in patients with COVID-19, such as frontal lobe syndrome, emotional disturbances and deregulation of respiratory failure perception. This study suggests that this network remains mildly to severely impaired 6 months after disease onset.

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          Most cited references4

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          Neurological associations of COVID-19

          Summary Background The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. On the basis of knowledge of other coronaviruses, especially those that caused the severe acute respiratory syndrome and Middle East respiratory syndrome epidemics, cases of CNS and peripheral nervous system disease caused by SARS-CoV-2 might be expected to be rare. Recent developments A growing number of case reports and series describe a wide array of neurological manifestations in 901 patients, but many have insufficient detail, reflecting the challenge of studying such patients. Encephalopathy has been reported for 93 patients in total, including 16 (7%) of 214 hospitalised patients with COVID-19 in Wuhan, China, and 40 (69%) of 58 patients in intensive care with COVID-19 in France. Encephalitis has been described in eight patients to date, and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the CSF of some patients. Anosmia and ageusia are common, and can occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease is also emerging as an important complication, with cohort studies reporting stroke in 2–6% of patients hospitalised with COVID-19. So far, 96 patients with stroke have been described, who frequently had vascular events in the context of a pro-inflammatory hypercoagulable state with elevated C-reactive protein, D-dimer, and ferritin. Where next? Careful clinical, diagnostic, and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-2. Precise case definitions must be used to distinguish non-specific complications of severe disease (eg, hypoxic encephalopathy and critical care neuropathy) from those caused directly or indirectly by the virus, including infectious, para-infectious, and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barré syndrome. Recognition of neurological disease associated with SARS-CoV-2 in patients whose respiratory infection is mild or asymptomatic might prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will probably remain small. However, these patients might be left with severe neurological sequelae. With so many people infected, the overall number of neurological patients, and their associated health burden and social and economic costs might be large. Health-care planners and policy makers must prepare for this eventuality, while the many ongoing studies investigating neurological associations increase our knowledge base.
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            Is Open Access

            Imaging the Role of Inflammation in Mood and Anxiety-related Disorders

            Background Studies investigating the impact of a variety of inflammatory stimuli on the brain and behavior have reported evidence that inflammation and release of inflammatory cytokines affect circuitry relevant to both reward and threat sensitivity to contribute to behavioral change. Of relevance to mood and anxiety-related disorders, biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins are reliably elevated in a significant proportion of patients with major depressive disorder (MDD), bipolar disorder, anxiety disorders and post-traumatic stress disorder (PTSD). Methods This review summarized clinical and translational work demonstrating the impact of peripheral inflammation on brain regions and neurotransmitter systems relevant to both reward and threat sensitivity, with a focus on neuroimaging studies involving administration of inflammatory stimuli. Recent translation of these findings to further understand the role of inflammation in mood and anxiety-related disorders is also discussed. Results Inflammation was consistently found to affect basal ganglia and cortical reward and motor circuits to drive reduced motivation and motor activity, as well as anxiety-related brain regions including amygdala, insula and anterior cingulate cortex, which may result from cytokine effects on monoamines and glutamate. Similar relationships between inflammation and altered neurocircuitry have been observed in MDD patients with increased peripheral inflammatory markers, and such work is on the horizon for anxiety disorders and PTSD. Conclusion Neuroimaging effects of inflammation on reward and threat circuitry may be used as biomarkers of inflammation for future development of novel therapeutic strategies to better treat mood and anxiety-related disorders in patients with high inflammation.
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              Uncovering the role of the insula in non-motor symptoms of Parkinson's disease.

              Patients with Parkinson's disease experience a range of non-motor symptoms, including cognitive impairment, behavioural changes, somatosensory and autonomic disturbances. The insula, which was once thought to be primarily a limbic cortical structure, is now known to be highly involved in integrating somatosensory, autonomic and cognitive-affective information to guide behaviour. Thus, it acts as a central hub for processing relevant information related to the state of the body as well as cognitive and mood states. Despite these crucial functions, the insula has been largely overlooked as a potential key region in contributing to non-motor symptoms of Parkinson's disease. The insula is affected in Parkinson's disease by alpha-synuclein deposition, disruptions in normal neurotransmitter function, alterations in connectivity as well as metabolic and structural changes. Although research focusing on the role of the insula in Parkinson's disease is scarce, there is evidence from neuroimaging studies linking the insula to cognitive decline, behavioural abnormalities and somatosensory disturbances. Here, we review imaging studies that provide insight into the potential role of the insula in Parkinson's disease non-motor symptoms. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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                Author and article information

                Contributors
                aurelie.kas@aphp.fr
                Journal
                Eur J Nucl Med Mol Imaging
                Eur J Nucl Med Mol Imaging
                European Journal of Nuclear Medicine and Molecular Imaging
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1619-7070
                1619-7089
                15 January 2021
                : 1-15
                Affiliations
                [1 ]Sorbonne Université, AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, Service de Médecine Nucléaire and LIB, INSERM U1146, 75013 Paris, France
                [2 ]Département de Neuroradiologie, Sorbonne Université, AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, 75013 Paris, France
                [3 ]Département de Neurologie, Sorbonne Université, AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, 75013 Paris, France
                [4 ]Service de Maladies infectieuses et Tropicales, Sorbonne Université, AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, 75013 Paris, France
                [5 ]GRID grid.411439.a, ISNI 0000 0001 2150 9058, Sorbonne Université, AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, , Institut de la Mémoire et de la Maladie d’Alzheimer, ; 75013 Paris, France
                Author information
                http://orcid.org/0000-0001-9463-3658
                Article
                5178
                10.1007/s00259-020-05178-y
                7810428
                33452633
                4314edfb-552e-48c7-9f57-8cc9de0a5374
                © The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 24 September 2020
                : 22 December 2020
                Categories
                Short Communication

                Radiology & Imaging
                glucose metabolism,18f-fdg-pet,sars-cov-2,prefrontal impairment,covid-19
                Radiology & Imaging
                glucose metabolism, 18f-fdg-pet, sars-cov-2, prefrontal impairment, covid-19

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