Hemispheric asymmetry, modular variability and age-related changes in the human entorhinal cortex.

The verrucae areae entorhinalis (VAE) are a characteristic feature of the human brain that occupy the anterior and posterolateral parts of the parahippocampal gyri and correspond to the islands of layer II neurons. We analyzed VAE in 60 neurologically normal subjects ranging from 23 to 85 years of age using a casting method. In 10 of these subjects the total number of neurons in the entorhinal islands was estimated stereologically using the optical fractionator. The number and surface area of VAE were higher in the left hemisphere compared with the right, and this leftward asymmetry was highly significant. Regression analysis showed a negative correlation between average VAE area and age in both hemispheres, representing a rate loss of about 800 microm2 per year. The estimated number of neurons obtained with the optical fractionator showed no significant difference between the left and the right hemisphere (468,000+/-144,000 vs. 405,000+/-117,000). There was a highly significant negative correlation between neuron numbers and age in both sides. In addition, clusters of small, undifferentiated layer II neurons ('heterotopias') were frequently observed in the rostral part of the entorhinal cortex in young and elderly adults. Layer II entorhinal neurons are among the first to show neurofibrillary changes during normal aging. The present data confirm the occurrence of age-related neuron loss in the entorhinal cortex. Considering the consistent projections from ipsilateral auditory association areas that, together with Broca's motor-speech area (Brodmann areas 44 and 45), show leftward asymmetry from early infancy (such as Brodmann area 22, planum temporale, and area 52 in the long insular gyrus), we speculate that functional lateralization of the human entorhinal cortex may be associated with specialization for memory processing related to language. Due to the dependence of hippocampal formation on entorhinal projections, this finding is also consistent with the greater capacity of the left hippocampus for verbal episodic memory.