Pathology of the insular cortex in Alzheimer disease depends on cortical architecture

The insular cortex plays important roles in a variety of regulatory mechanisms ranging from visceral control and sensation to covert judgments regarding inner well-being. The dementia of Alzheimer disease (AD) often includes behavioral dyscontrol and visceral dysfunction not observed in other diseases affecting cognition. This could be related to autonomic instability and to loss of the sense of self, and pathologic changes within the insula may play essential roles. The pattern of insular pathology of 17 patients with AD was examined and the severity of pathology was compared with that of the entorhinal cortex (EC), a region involved early in AD with reciprocal connections to the insula. Thioflavin S staining and Alz-50 immunostaining revealed that the insula carries a heavy burden of pathology in AD. Neurofibrillary tangles (NFTs) were largely confined to the deep layers of the cortex, whereas neuritic plaques (NPs) were distributed throughout the cellular layers and subcortical white matter. The density of NFTs, but not NPs, was highly correlated with the degree of EC pathology. However, NFTs were not seen in the insula until EC pathology reached a relatively advanced level. The density of insular NFTs varied according to architectonic type, with agranular cortex most affected, dysgranular cortex less affected, and granular cortex least affected. Thus, the insula is often involved in AD, and some of the behavioral abnormalities in AD may reflect insular pathology.