White matter mapping is needed.

Neurobiology of Aging 25 (2004) 37–39 Commentary White matter mapping is needed T.L. Jernigan ∗ , Christine Fennema-Notestine University of California, San Diego and the VASDHS, 9500 Gilman Drive, La Jolla, CA 92093-0949, USA Received 23 May 2003; accepted 3 June 2003 1. Modern brain maps lack information about oligodendrocyte structure and function An intriguing hypothesis has been advanced regarding the role of ongoing processes of myelination in the patho- genesis of Alzheimers Disease (Bartzokis, this issue). The protracted course of myelin deposition in dorsal forebrain regions was described over three decades ago in the elegant studies by Yakovlev and Lecours [12]. However, modern imaging methods permit detailed investigation of these processes in living people for the first time, and studies with these techniques have served to emphasize the degree to which ongoing events formerly deemed “maturation” merge with alterations previously associated with involu- tion. For example, recent MRI studies of brain morphology in late childhood and early adulthood [5,7–9] confirm the earlier pathological evidence for continued “whitening” of the substance of the brain long past the point at which total cranial volume is at its peak. It is now clear that exuberant brain growth in the earliest stages of neurodevelopment gives way gradually to a more dynamic interplay between progressive changes, primarily proliferation of oligodendro- cytes and myelination (but also in limited cases associated with neurogenesis and neuritic branching), offset by regres- sive changes (i.e. apoptosis and loss of neuronal processes) that are also occurring from the very beginning of brain development. Thus, the years of life between the end of adolescence and extending through middle age are probably more accurately viewed, not as years of “stability” in brain development (as they have been previously), but as a period during which progressive and regressive changes happen to be in relative balance. The neurobiological implications of ongoing dynamics of brain development during this period are likely to be no less for that coincidence, and the trea- tise by Bartzokis should provide increased impetus for the needed work of defining these implications. It is particularly relevant for this discussion that most recent work in neuroimaging has focused on the brain’s Corresponding author. Tel.: +1-858-622-5882; fax: +1-858-622-5890. E-mail address: tjernigan@ucsd.edu (T.L. Jernigan). 0197-4580/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2003.06.002 gray matter structures, and, by implication, on neuronal cell populations. Relatively few studies have focused on white matter, and most of these have examined high-signal abnormalities that are well visualized with structural imag- ing methods. In Fig. 1A, data from our laboratory taken from separate previously published studies of brain devel- opment and aging [1,4,9] are presented together. These data were generated concurrently using standardized MR mor- phometric techniques. Volumes of the total white matter compartment of the cerebrum are plotted against the ages of normal volunteers of different ages ranging from 7 to 99 years. The volumes are expressed as proportions of vol- ume of the supratentorial cranial vault, the average value of which has been reported to change negligibly, if at all, over this age range. Thus, the function is likely to reflect primarily the volume of myelinated white matter. The data from adults 20 to 70 years of age are too sparse to define with any precision the shape of the underlying function, but they are certainly consistent with evidence reviewed by Bartzokis indicating substantial ongoing myelination in adults. Developmental studies have emphasized late myeli- nation in frontal and parietal lobe regions, but the function we observe in the temporal lobe, possibly more relevant to the pathology of early AD, shows a similar (if less striking) pattern, as shown in Fig. 1B. Surprisingly, the pattern is also present within a deep subcortical white matter region which includes the internal and external capsules and surrounds the diencephalon and basal ganglia (Fig. 1C). The model presented by Bartzokis relies upon evidence for what he refers to as “heterochronologic” development of human white matter. That the process of myelination has differing time courses in different regions is not in doubt; however, a map across the brain revealing the status of myeli- nation at each point during the lifespan does not exist, and, arguably, what does exist is inadequate to provide definitive evidence regarding the hypothesis. If myelination in some deep subcortical regions (as shown in Fig. 1C) continues as long as that in “cortico-cortical” association areas, how then does this relate to the distribution of lesions in AD? The point is not that the known “heterochronicity” of myelina- tion is inconsistent with the model presented by Bartzokis,