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Handb Clin Neurol ; 187: 407-427, 2022.
Article in English | MEDLINE | ID: covidwho-1990833


Neuropathological examination of the temporal lobe provides a better understanding and management of a wide spectrum of diseases. We focused on inflammatory diseases, epilepsy, and neurodegenerative diseases, and highlighted how the temporal lobe is particularly involved in those conditions. Although all these diseases are not specific or restricted to the temporal lobe, the temporal lobe is a key structure to understand their pathophysiology. The main histological lesions, immunohistochemical markers, and molecular alterations relevant for the neuropathological diagnostic reasoning are presented in relation to epidemiology, clinical presentation, and radiological findings. The inflammatory diseases section addressed infectious encephalitides and auto-immune encephalitides. The epilepsy section addressed (i) susceptibility of the temporal lobe to epileptogenesis, (ii) epilepsy-associated hippocampal sclerosis, (iii) malformations of cortical development, (iv) changes secondary to epilepsy, (v) long-term epilepsy-associated tumors, (vi) vascular malformations, and (vii) the absence of histological lesion in some epilepsy surgery samples. The neurodegenerative diseases section addressed (i) Alzheimer's disease, (ii) the spectrum of frontotemporal lobar degeneration, (iii) limbic-predominant age-related TDP-43 encephalopathy, and (iv) α-synucleinopathies. Finally, inflammatory diseases, epilepsy, and neurodegenerative diseases are considered as interdependent as some pathophysiological processes cross the boundaries of this classification.

Epilepsy, Temporal Lobe , Epilepsy , Neurodegenerative Diseases , Epilepsy/epidemiology , Epilepsy/pathology , Epilepsy, Temporal Lobe/diagnosis , Epilepsy, Temporal Lobe/pathology , Hippocampus/pathology , Humans , Temporal Lobe/pathology
Am J Respir Cell Mol Biol ; 65(4): 403-412, 2021 10.
Article in English | MEDLINE | ID: covidwho-1237350


Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model, VILI was simulated in anesthetized adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. CC3 (cleaved caspase-3), a neuronal apoptosis marker, was significantly increased in the frontal (P < 0.001) and hippocampal (P < 0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice (P < 0.001). These findings were not related to cerebral hypoxia, and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (P < 0.01 and P < 0.0001, respectively) and anti-IL-6 receptor antibody (P < 0.05 and P < 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.

Antibodies/pharmacology , Apoptosis/drug effects , Delirium/metabolism , Interleukin-6/antagonists & inhibitors , Neurons/metabolism , Ventilator-Induced Lung Injury/metabolism , Animals , Delirium/drug therapy , Delirium/pathology , Disease Models, Animal , Female , Frontal Lobe/injuries , Frontal Lobe/metabolism , Frontal Lobe/pathology , HSP90 Heat-Shock Proteins/metabolism , Hippocampus/injuries , Hippocampus/metabolism , Hippocampus/pathology , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Interleukin-6/metabolism , Mice , Neurons/pathology , Proto-Oncogene Proteins c-fos/metabolism , Repressor Proteins/metabolism , Tumor Suppressor Proteins/metabolism , Ventilator-Induced Lung Injury/drug therapy , Ventilator-Induced Lung Injury/pathology
Int J Mol Sci ; 22(4)2021 Feb 08.
Article in English | MEDLINE | ID: covidwho-1069829


Alzheimer's disease is a chronic neurodegenerative disorder and represents the main cause of dementia globally. Currently, the world is suffering from the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of patients with Alzheimer's disease. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer's disease and ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease, and brains with the disease examined in this study also exhibited higher carbonylated proteins, as well as an increased thiol oxidation state of peroxiredoxin 6 (Prx6). A moderate positive correlation was found between the increased ACE2 protein expression and oxidative stress in brains with Alzheimer's disease. In summary, the present study reveals the relationships between Alzheimer's disease and ACE2, the receptor for SARS-CoV-2. These results suggest the importance of carefully monitoring patients with both Alzheimer's disease and COVID-19 in order to identify higher viral loads in the brain and long-term adverse neurological consequences.

Alzheimer Disease/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , COVID-19/metabolism , Hippocampus/metabolism , Pandemics , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Up-Regulation , Alzheimer Disease/complications , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Autopsy , COVID-19/complications , COVID-19/virology , Hippocampus/pathology , Humans , Oxidation-Reduction , Oxidative Stress , Peroxiredoxin VI/metabolism , Plaque, Amyloid/metabolism , Protein Carbonylation , Severity of Illness Index , Virus Internalization