Aging of cerebral white matter

Abstract

White matter (WM) occupies a large volume of the human cerebrum and is mainly composed of myelinated axons and myelin-producing glial cells. The myelinated axons within WM are the structural foundation for efficient neurotransmission between cortical and subcortical areas. Similar to neuron-enriched gray matter areas, WM undergoes a series of changes during the process of aging. WM malfunction can induce serious neurobehavioral and cognitive impairments. Thus, age-related changes in WM may contribute to the functional decline observed in the elderly. In addition, aged WM becomes more susceptible to neurological disorders, such as stroke, traumatic brain injury (TBI), and neurodegeneration. In this review, we summarize the structural and functional alterations of WM in natural aging and speculate on the underlying mechanisms. We also discuss how age-related WM changes influence the progression of various brain disorders, including ischemic and hemorrhagic stroke, TBI, Alzheimer's disease, and Parkinson's disease. Although the physiology of WM is still poorly understood relative to gray matter, WM is a rational therapeutic target for a number of neurological and psychiatric conditions.

Keywords: Aging; Axon; Myelin; Neurodegeneration; Stroke; Traumatic brain injury; White matter.

Figure 1. Differences between young adult (YA) and old adult (OA) in fractional anisotropy (FA) overlaid on representative sagittal (left), coronal (middle), and axial (right) DTI images

Regions depicted in red–yellow indicate areas where FA was lower in OA compared to YA; regions depicted in blue indicate areas where FA was higher in OA compared to YA. Reprinted from Cognition in healthy aging is related to regional white matter integrity, but not cortical thickness. Ziegler DA1, Piguet O, Salat DH, Prince K, Connally E, Corkin S. Neurobiol Aging. 2010 Nov;31(11):1912–26 (Ziegler et al., 2010). Copyright (2010), with permission from Elsevier.

Figure 2. Molecular mechanisms underlying age-related deterioration of WM after stroke

Ischemic injury leads to ATP depletion and reversal of the Na⁺/Ca²⁺ exchanger. This is followed by increased intracellular Na⁺ and subsequent reversal of the Na⁺ dependent glutamate transporter (GLT1). The resulting glutamate overload overactivates AMPA/kainate receptors. 1) In aged WM, the expression of GLT-1 greatly increases in multiple cellular components, resulting in more rapid and robust glutamate release and severe excitotoxicity during ischemia. Excessive oxidative stress is also likely to aggravate WM injury in the aged brain. Mitochondria are the main source of reactive oxygen species (ROS) after ischemia. 2) Age-related mitochondrial dysfunction results in reduced ATP production and excessive oxidative stress. 3) The functions of endogenous antioxidant systems decline with aging in parallel with the increase in mitochondrial impairments. All these changes converge to increase axonal and oligodendrocyte vulnerability in aged brains and exacerbate WM injury upon ischemia.