Quantifying age-related myelin breakdown with MRI: novel therapeutic targets for preventing cognitive decline and Alzheimer's disease

Abstract

Myelin plays an essential role in brain structure and function and the human brain is uniquely dependent on the elaboration of this late invention of evolution. Our brain has the most extensive and protracted process of myelination that extends to approximately age 50 in cortical regions that have the highest risk for developing Alzheimer's disease (AD) pathology. This myelin-centered model of the human brain asserts that unique vulnerabilities of myelin, especially late-developed myelin, and the oligodendrocytes that produce it are directly pertinent to many uniquely human neuropsychiatric diseases including late-life neurodegenerative disorders such as AD. Magnetic resonance imaging (MRI) technology permits the in vivo assessment of the roughly quadratic (inverted U) lifelong trajectory of human myelin development and its subsequent breakdown. There is close agreement between neuropsychology, neuropathology, and imaging measures suggesting that the process of myelin breakdown begins in adulthood, accelerates as aging progresses, and underlies both age-related cognitive declines and the most powerful risk factor of dementia-causing disorders such as AD: age. This myelin-centered model together with the technology that makes it possible to measure the trajectory of myelin breakdown provide a framework for developing novel treatments, as well as assessing efficacy of currently available treatments, intended to slow or reverse the breakdown process in both clinically healthy as well as symptomatic populations. Such treatments can be expected to have a wide spectrum of efficacy and impact multiple human disease processes including potentially slowing brain aging and thus provide opportunities for primary prevention of age-related degenerative disorders such as AD.