Age-related reduction in microcolumnar structure in area 46 of the rhesus monkey correlates with behavioral decline

doi:10.1073/pnas.0407002101

Age-related reduction in microcolumnar structure in area 46 of the rhesus monkey correlates with behavioral decline

^*Center for Polymer Studies and Department of Physics, Boston University, Boston, MA 02215; ^‡Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118; ^¶Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322; and ^§Department of Biostatistics, Boston University School of Public Health, 715 Albany Street, T4E, Boston, MA 02118

Contributed by H. E. Stanley, September 21, 2004

Abstract

Many age-related declines in cognitive function are attributed to the prefrontal cortex, area 46 being especially critical. Yet in normal aging, studies indicate that neurons are not lost in area 46, suggesting that impairments result from more subtle processes. One cortical feature that is functionally important, but that has not been examined in normal aging because of a lack of efficient quantitative methods, is the vertical arrangement of neurons into microcolumns, a fundamental computational unit of the cortex. By using a density-map method derived from condensed-matter physics, we quantified microcolumns in area 46 of seven young and seven aged rhesus monkeys that had been cognitively tested. This analysis demonstrated that there is no age-related reduction in total neuronal density or in microcolumn width, length, or periodicity. There was, however, a statistically significant decrease in the strength of microcolumns, indicating microcolumnar disorganization. This reduction in strength was significantly correlated with age-related cognitive decline on tests of spatial working memory and recognition memory independent of the effect of age. Modeling demonstrated that random neuron displacements of ≈30% of a neuronal diameter (<3 μm) produced the observed reduction in strength. Hence, it is possible that, with changes in dendrites and myelinated axons, subtle displacements of neurons occur that alter microcolumnar structure and correlate with age-induced dysfunction. Therefore, quantitative measurement of microcolumnar structure may provide a sensitive morphological method to assay microcolumnar function in aging and other conditions.

Footnotes

↵ † To whom correspondence should be addressed at: Center for Polymer Studies, Department of Physics, Boston University, 590 Commonwealth Avenue, Boston, MA 02215. E-mail: ccruz{at}bu.edu.
Author contributions: L.C., H.E.S., and D.L. Rosene designed research; L.C., D.L. Roe, and B.U. performed research; L.C., H.C., and D.L. Rosene analyzed data; and L.C., D.L. Roe, B.U., and D.L. Rosene wrote the paper.
Abbreviations: AD, Alzheimer's disease; LBD, Lewy body dementia; DNMS, delayed non-match to sample test; DRST, delayed recognition span task; CII, cognitive impairment index; W, microcolumnar width; P, distance between microcolumns; L, length (vertical span) of microcolumns; S, strength of microcolumns; T, degree of microcolumnar periodicity.
↵ ∥ Casanova, M. F., Buxhoeveden, D., Roy, E. & Switala, A. (2003) Biol. Psychiatry 53, Suppl. S, 169 (abstr.).
↵ ** Buxhoeveden, D. & Casanova, M. F. (2003) Am. J. Phys. Anthropol. 36, 73 (abstr.).