Quadratic trajectories of brain myelin content: unifying construct for neuropsychiatric disorders

Abstract Myelin plays an essential but largely underappreciated role in human brain structure and function. The central challenge raised by the six commentaries is whether the developmental model of age-related cognitive decline and Alzheimer’s disease (AD) (Bartzokis, 2003, this issue) is applicable to a wider range of neurodegenerative and neuropsychiatric disorders. The model’s premise that the trajectory of myelin development and breakdown is essential to our very uniqueness as a species, directly addresses this issue. In its widest perspective, the model primarily delineates a myelin hypothesis of human brain evolution and normal development and is “secondarily” useful in conceptualizing a wide range of age-related neuropsychiatric diseases. The unique vulnerabilities of oligodendrocytes and the highly protracted and extensive developmental process of human brain myelination delineated in the model are directly pertinent to many uniquely human brain functions and neuropsychiatric diseases including late-life neurodegenerative disorders. This lifelong perspective classifies AD as a disorder likely to arise in old age after a normal trajectory of myelin development. Genetic and environmental factors causing deviations in the myelination trajectory at any point in the lifespan will contribute to differences in the manifestations of later-life degenerative diseases and/or be detected in epidemiologic studies as risk factors or risk mitigators (age, cholesterol, iron, gender, education, brain, trauma, etc.). Ultimately, these perturbations of the myelination process could result in divergent-appearing disorders, such as frontotemporal dementia, dementia pugilistica, AD, dementia with Lewy bodies, and Parkinson’s disease, that nonetheless have overlapping neuropathologic and/or clinical manifestations. Furthermore, the model’s developmental perspective suggests that dysregulation in the uniquely vulnerable myelination process also contributes to highly prevalent early-life psychiatric disorders such as autism, attention deficit, schizophrenia, addiction, as well as their striking male predominance. Eventually, the dysregulated myelination associated with such disorders may have a direct and predictable impact on the appearance and manifestations of the later-life dementias. By increasing the scientific focus on the process of myelination, this model may facilitate our understanding of the pathophysiology of multiple disorders and pathophysiologic processes that cut across our current classification of diseases. Ultimately, the model provides a rational framework for the development of novel, myelin-centered treatments that may have widespread efficacy across multiple disease states and could potentially be used in delaying or even preventing some of the most devastating of human disorders.