Investigation of Behavior and Molecular Biomarkers Associated with Neurological and Psychiatric Disorders

Abstract

Cognitive decline (CD) is driven by a combination of molecular, environmental, and intrinsic factors within the pathophysiology of neurodegenerative and psychiatric disorders. The overlapping mechanisms among these diseases present significant challenges for modern medicine, requiring collaborative diagnostic efforts to investigate onset, assess severity, and monitor progression. This thesis aimed to identify behavioral and molecular markers associated with CD, uncover new pharmacological targets, and enhance the characterization of related neurodegenerative and psychiatric conditions. For this sake, two distinct behavioral assessment methods were employed: neuropsychological evaluations and video-based eye-tracking. Additionally, cerebrospinal fluid (CSF) markers were profiled to evaluate factors contributing to disease development.

Chapters 2 and 3 evaluated CSF analytes concerning metabolic and psychiatric risk factors within an older Brazilian adult cohort. In a dataset containing 31 CSF analytes, potential CD-associated therapeutical targets were identified through embedded feature selection methods, highlighting the ratio of the anti-inflammatory mediator lipoxin A4 to the inflammatory mediator cysteinyl leukotriene as significant in CD and generalized anxiety disorder. These findings supported the role of neuroinflammation in disease development. Furthermore, it was found, somewhat unexpectedly, that obesity was negatively associated with CD, suggesting protective effects. Although CSF leptin changes were related to obesity, leptin did not directly impact CD, indicating that obesity’s influence on CD was not dependent on leptin. In this context, considering that sedentarism significantly contributed to CD in Brazil, Chapter 4 reviewed the neuroprotective mechanisms induced by physical exercise, demonstrating its potential to prevent and reduce CD progression. Moreover, pharmacological alternatives were explored for individuals unable to engage in physical activity due to mobility constraints.

Recognizing that external factors such as viral infections could exacerbate inflammatory processes associated with CD, Chapter 5 assessed oculomotor behavior parameters in a previously hospitalized Brazilian COVID-19 cohort. By utilizing inhibitory control paradigms and video-based free viewing, impairments were observed in inhibitory control signals originating from the frontal cortex and basal ganglia to the superior colliculus. These results suggested that COVID-19-related inflammation had lasting neurological impacts.

Collectively, these findings may guide the development of comprehensive diagnostic tools and therapeutic strategies aimed at mitigating the progression of neurodegenerative and psychiatric disorders.