Brain aging mechanisms with mechanical manifestations

Abstract

Brain aging is a complex process that affects everything from the subcellular to the organ level, begins early in life, and accelerates with age. Morphologically, brain aging is primarily characterized by brain volume loss, cortical thinning, white matter degradation, loss of gyrification, and ventricular enlargement. Pathophysiologically, brain aging is associated with neuron cell shrinking, dendritic degeneration, demyelination, small vessel disease, metabolic slowing, microglial activation, and the formation of white matter lesions. In recent years, the mechanics community has demonstrated increasing interest in modeling the brain's (bio)mechanical behavior and uses constitutive modeling to predict shape changes of anatomically accurate finite element brain models in health and disease. Here, we pursue two objectives. First, we review existing imaging-based data on white and gray matter atrophy rates and organ-level aging patterns. This data is required to calibrate and validate constitutive brain models. Second, we review the most critical cell- and tissue-level aging mechanisms that drive white and gray matter changes. We focuse on aging mechanisms that ultimately manifest as organ-level shape changes based on the idea that the integration of imaging and mechanical modeling may help identify the tipping point when normal aging ends and pathological neurodegeneration begins.

Keywords: Brain aging mechanisms; Cerebral atrophy; Gray and white matter changes; Morphological changes; Vascular changes.

Fig. 1.

Cerebral atrophy is the most prominent morphological change in the aging brain and includes white and gray matter volume loss, cortical thinning, sulcal widening, and ventricular enlargement. Cross-sectional medical imaging studies have shown that these features gradually intensify in subjects aged 50 years and older (Fjell and Walhovd, 2010; Coupé et al., 2019). Longitudinal imaging data, i.e., two or more scans of the same subject taken at least a couple months apart, are increasingly used to determine the rate of change for individual subjects with the goal to differentiate between healthy and pathological aging processes (Resnick et al., 2003).

Fig. 2.

White matter changes are a major source for brain atrophy and loss of brain function. The resulting cognitive decline is linked to neurodegeneration, but is just as impacted by the deterioration of the axonal network (Xiong and Mok, 2011; Chen et al., 2020b). White matter aging is characterized by demyelination, axon degeneration, white matter lesions, and small vessel disease which is associated with microbleeds, lacunes, and ministrokes. White matter lesions drive neuroinflammation and disturb the intricate homeostasis in the brain. Lastly, ischemia is a common driver of gradual cell death through the brain and causes the progressive degeneration of white matter tissue (Mattson and Arumugam, 2018; Liu et al., 2017).