Complexity

The retina has long been considered a window into the brain, generating significant interest in identifying potential ocular biomarkers for brain disorders. Functional changes in the retina can be detected using electroretinography (ERG). In fact, recent research has revealed alterations in the characteristics of the ERG in patients with Alzheimer’s disease (AD). However, the effects of aging and neurodegeneration on retinal electrophysiology remain unclear, as do the most effective tools to detect these changes. Furthermore, recently proposed protective mechanisms against brain cell senescence, such as the overexpression of the transcription factor XBP1s, may be reflected in retinal electrophysiology. In this study we used entropy tools to explore the complexity of retinal dynamics in two age stages: young (2-5 months) and adult (5-8 months) in four mouse models: wild-type (WT) (n= 8 young, 9 adult), AD 5xFAD transgenic model (n = 9, 10), Tg XBP1s mice (n = 7, 6), and a crossbreed Tg XBP1s / 5xFAD (n = 6, 7). We applied a chirp light stimulus—a flashlight followed by sinusoidal light of increasing frequency and then increasing amplitude light—to retinas ex vivo while recording μERG responses from a multielectrode recording array (MEA). We calculated the multiscale entropy (MSE) of the μERG signals and estimated a complexity index as the slope of the linear regression of the MSE curves. The median complexity index (upper: lower quartile) of all young groups was positive: WT young 4.6 (6:1.4), 5xFAD young 2.4 (3.5: -1.7), Tg XBP1s young 1.7 (2.4: 0.18) and Tg XBP1s / 5xFAD young 0.94 (1.7: -1.4), which was higher than those of the respective older groups: WT adult -2.2 (0.98:-11.4), 5xFAD adult -5.3 (-3:-8.9), Tg XBP1s adult 0.09 (3.4:-2.1) and Tg XBP1s / 5xFAD adult 0.89 (1.7:-1.4). This reduction in complexity among older groups supports the theory of loss of complexity with age. Furthermore, the 5xFAD groups exhibited lower complexity compared to their respective WT groups, consistent with a theory of loss of complexity in the disease. Tg XBP1s overexpression appeared to confer protection against aging, a benefit that extended to Tg XBP1s / 5xFAD animals, suggesting that Tg XBP1s may counteract aging and neurodegenerative mechanisms in the retina. These findings not only advance our understanding of retinal electrophysiology with aging but also have significant implications for the identification of new AD biomarkers and the development of novel therapeutic strategies.

Neurodegenerative diseases (NDs) are one of our most significant public health challenges. In these diseases, neurons in specific brain areas progressively and irreversibly deteriorate until they die. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are two of the major NDs and among the leading causes of death in the elderly population. For NDs, early detection is fundamental because therapeutic interventions can be more successful if initiated at pre-clinical stages before neuronal loss. However, early and accurate diagnosis remains challenging because of the lack of noninvasive and inexpensive reliable diagnostic tests. Moreover, NDs often share pathological and clinical features, making it difficult to differentiate between diseases, especially in early stages. The retina, i.e., where light is converted to nerve impulses, has long been considered a window into the brain. Not surprisingly, there has been great interest in understanding common eye-brain pathophysiological mechanisms and finding potential eye biomarkers for brain disorders. Retinal morphology and function appear to be affected in AD and PD patients, and the critical pathological molecules of AD and PD have been detected in patients’ retinas postmortem. Collectively, these findings show great promise in the search of biomarkers for NDs in the retina. Functional changes in the retina can be detected using the electroretinogram (ERG), in which electrodes placed on the cornea or the skin beneath the eye are used to record the bio-electrical activity of the retina. Recent research has revealed alterations in some ERG characteristics of AD patients, opening the door for further investigation using innovative signal analysis approaches. We recently showed that complexity-based metrics can be used to detect AD in the retina of animals, bringing up new opportunities for the investigation of potential retinal biomarker of NDs. To translate these findings into clinical benefits, in this work we will introduce a new paradigm for ND diagnosis based on 1) a noninvasive ERG device and 2) mathematical tools from complexity theory. Here, complexity refers to the nonlinear interactions and collective behavior of different structural units acting at diverse temporal and spatial scales. Our approach is inspired by the theory of complexity-loss, which postulates that biological complexity decays with aging and disease, an idea supported by mounting evidence in various physiological systems.