Differential epigenetic profiles can be present in patient-derived central and peripheral tissues. Indeed, a rapidly increasing number of studies have identified differential levels of DNA methylation, histone and chromatin modifications, and ncRNA expression in a spectrum of neurological disorders using patient-derived central and peripheral tissues and animal models. Although the contribution of these aberrant epigenetic profiles to disease processes is sometimes unclear, deregulation of these multilayered epigenetic processes is likely to be responsible, either directly or indirectly, for disease pathophysiology by mediating cross talk between genetic susceptibilities and sex, environment, nutritional states, and aging. These seemingly ubiquitously abnormal signatures may, therefore, have clinical applications as indicators of disease risk, onset, progression, and responsiveness to treatment. For example, the DNA methylation status of genomic repetitive elements in blood correlates with Alzheimer disease and Mini-Mental State Examination scores, stroke and total mortality, and other clinical phenotypes. Moreover, in multiple sclerosis, miRNA expression profiles have been measured in white matter lesions, where they can discriminate between active and inactive lesions, and blood, where they can discriminate between relapsing-remitting and other forms of the disease and patients treated with different therapies (glatiramer acetate and natalizumab) and those who are untreated.23 The secretion of microvesicles, including exosomes, is one interesting mechanism that might explain why peripheral levels of ncRNAs reflect central disease processes. Microvesicles are secreted by donor cells (neural, immune, and other cell types) into cerebrospinal fluid, lymphatics, and blood.24 Microvesicles transfer DNA, RNA, and proteins and can actively “reprogram” recipient cells. For example, transferred miRNAs can silence target mRNAs in recipient cells. The majority of miRNAs found in the peripheral circulation are derived from microvesicles, suggesting that these factors are not simply bystanders but key effectors of dynamic central-peripheral signaling. Long ncRNAs are similarly found in microvesicles and their expression patterns are also deregulated in a range of neurological diseases,25 suggesting that interrogating central and peripheral lncRNA profiles may have diagnostic and prognostic value.