Anxiety, depression, and memory loss in Chagas disease: a puzzle far beyond neuroinflammation to be unpicked and solved*

Abstract

Mental disorders such as anxiety, depression, and memory loss have been described in patients with chronic Chagas disease (CD), a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. Social, psychological, and biological stressors may take part in these processes. There is a consensus on the recognition of an acute nervous form of CD. In chronic CD patients, a neurological form is associated with immunosuppression and neurobehavioural changes as sequelae of stroke. The chronic nervous form of CD has been refuted, based on the absence of histopathological lesions and neuroinflammation; however, computed tomography shows brain atrophy. Overall, in preclinical models of chronic T. cruzi infection in the absence of neuroinflammation, behavioural disorders such as anxiety and depression, and memory loss are related to brain atrophy, parasite persistence, oxidative stress, and cytokine production in the central nervous system. Interferon-gamma (IFNγ)-bearing microglial cells are colocalised with astrocytes carrying T. cruzi amastigote forms. In vitro studies suggest that IFNγ fuels astrocyte infection by T. cruzi and implicate IFNγ-stimulated infected astrocytes as sources of TNF and nitric oxide, which may also contribute to parasite persistence in the brain tissue and promote behavioural and neurocognitive changes. Preclinical trials in chronically infected mice targeting the TNF pathway or the parasite opened paths for therapeutic approaches with a beneficial impact on depression and memory loss. Despite the path taken, replicating aspects of the chronic CD and testing therapeutic schemes in preclinical models, these findings may get lost in translation as the chronic nervous form of CD does not fulfil biomedical model requirements, as the presence of neuroinflammation, to be recognised. It is hoped that brain atrophy and behavioural and neurocognitive changes are sufficient traits to bring the attention of researchers to study the biological and molecular basis of the central nervous system commitment in chronic CD.

The beneficial effect of fluoxetine on behavioral and cognitive changes in chronic experimental Chagas disease unveils the role of serotonin fueling astrocyte infection by Trypanosoma cruzi

“…The contribution of heart abnormalities to CNS impairment in CD is a matter of debate [ 11 ]. Fx therapy improves heart rate in a non-infectious condition [ 46 ].…”

“…Initially, we addressed canonical pathways that may support depressive-like behavior and memory loss [ 45 , 53 ]. Neuroinflammation, defined as the influx of blood-borne inflammatory cells into perivascular cuffs and brain parenchyma [ 24 ], and cytokines produced in the CNS are recognized for their roles in behavioral changes in infectious [ 11 , 36 ] and neurodegenerative diseases [ 24 ]. In our model of chronic CD, inflammation is absent in the cortex and hippocampus, corroborating previous studies in Colombian-infected C57BL/6 mice [ 22 ].…”

“…Although we did not detect IFNγ and TNF expression in the CNS of chronically infected mice, their elevated serum levels suggest systemic inflammatory processes. Indeed, systemically elevated levels of IFNγ and TNF have been linked to depressive behavior and memory deficits in infectious [ 11 ] and neurodegenerative [ 57 ] diseases. Interestingly, anti-TNF monoclonal antibody therapy inhibited depressive-like behavior in experimental chronic CD [ 21 ].…”

“…cruzi are detected in the CNS of patients, and parasite DNA in tissues revealed the persistence of T . cruzi in the chronic phase [ 11 ]. The antiprotozoal drug benznidazole reduces parasite burden in the CNS, in parallel with reducing oxidative stress and improving mnemonic changes [ 22 ].…”

“…These studies mainly focus on the cardiac form of CD, which afflicts approximately 30% of the patients 10–30 years after infection [ 10 ]. In chronic CD patients, a neurological form is associated with co-infections, immunosuppression, and neurobehavioral changes as sequelae of strokes [ 11 ]. Despite the importance of mental disorders and their possible impact on patient’s quality of life and clinical management, few clinical and preclinical studies have explored behavioral and cognitive aspects of CD.…”