Relationships between Inflammation and Age-Related Neurocognitive Changes

Abstract

The relationship between inflammation and age-related neurocognitive changes is significant, which may relate to the age-related immune dysfunctions characterized by the senescence of immune cells and elevated inflammatory markers in the peripheral circulation and the central nervous system. In this review, we discuss the potential mechanisms, including the development of vascular inflammation, neuroinflammation, organelle dysfunctions, abnormal cholesterol metabolism, and glymphatic dysfunctions as well as the role that the key molecules play in the immune-cognition interplay. We propose potential therapeutic pharmacological and behavioral strategies for ameliorating age-related neurocognitive changes associated with inflammation. Further research to decipher the multidimensional roles of chronic inflammation in normal and pathological aging processes will help unfold the pathophysiological mechanisms underpinning neurocognitive disorders. The insight gained will lay the path for developing cost-effective preventative measures and the buffering or delaying of age-related neurocognitive decline.

Keywords: aging; brain; cognition; inflammation; neurodegeneration.

Figure 1

The proposed mechanisms underpinning the relationship between chronic inflammation and neurocognitive decline. Panel (A) shows the factors initiating or precipitating neuroinflammation and cognitive decline, including genetic susceptibility, vascular inflammation and blood-brain barrier (BBB) breakdown, the emergence of toxic proteins, glymphatic dysfunctions, and chronic inflammation in the aging process. Panel (B) presents degenerative changes in the brain due to inflammation and elevated cytokines. Microglial activation with morphological and functional changes is a key event in neuroinflammation. Elevated cytokines affect neural activities and mediate environmental homeostasis. With the accelerated production and deposition of neuropathological proteins, neurons gradually lose their vitality due to the loss of synaptic plasticity, reduced neurogenesis, and demyelination. Finally, researchers have detected microstructural changes in white matter and brain atrophy. Older people generally show behavioral changes, including slower processing speed, memory loss, and declines in executive functions. We created this figure using BioRender.com, accessed on 19 July 2022.

Figure 2

The glymphatic system. Structurally, the glymphatic space is a composite of the periarterial and perivenous space, surrounded by the blood vessel walls and vascular end-feet of astrocytes (in purple). Within the glymphatic spaces, arterial pulsations drive the flow of the cerebrospinal fluid (CSF), and the fluid enters the brain parenchyma via aquaporin-4 (AQP4) water channels. Lastly, this current will converge into the perivenous space. The exchanges between CSF and interstitial fluid (ISF) are particularly important for material exchanges and waste cleaning in the brain. Panel (A) shows effective cleaning of the metabolic waste in the glymphatic system. Neurons (in pink), microglia (in yellow), and astrocytes and oligodendrocytes (in green) are in normal conditions. In panel (B), during aging and chronic inflammation, a significant reduction occurs in the CSF/ISF flow exchanges due to age-related AQP4 depolarization. Furthermore, excessive immune cells in the perivascular spaces as well as sleep disturbances adversely affect the functioning of the glymphatic system, resulting in neuronal death and altered gene expression profiles in glial cells. We created this figure using BioRender.com, accessed on 19 July 2022.