The Leukocentric Theory of Neurological Disorder: A Manifesto

Approximately half of the human brain is composed of white matter (WM), a specialized tissue housing the axonal projection of neurons and their necessary supporting glial cells. Axons course long distances from their parent soma, have a delicate structure, large surface area and in many cases are dependent upon a uniquely close morphological arrangement with myelinating oligodendrocyte partners; all factors that may predispose them to injury and disease. WM damage is central to a range of well-characterized disorders including multiple sclerosis and spinal cord injury and is also makes a significant contribution to disorders often considered to be largely focused in gray matter; for example, in stroke where ~49% of injury by volume is located in WM. In addition, advances in brain imaging have revealed early, often prodromal, changes in WM structure in most forms of neurodegeneration including Alzheimer's, Huntingdon's and Parkinson's diseases as well as during normal cognitive decline and a variety of behavioral conditions. The significance of the early WM changes for the etiology of these diseases is largely unknown. Subtle, early changes in synaptic function may produce the prodromal WM changes evident in imaging, or WM and gray mater structures may undergo simultaneous reactions to the underlying disease process. However, there are rational mechanisms for the transmission of pathology from WM to gray matter and this article suggests an alternative hypothesis: that WM pathology precedes and to some extent is causal of synaptic dysfunction in many common neurological disorders. Neurological disorders that have their origin or their principle lesion in WM are here defined as "leukopathologies".