Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease

Few studies evaluate neuropathological correlates of behavioral changes in Alzheimer disease (AD). We identified 31 autopsy patients with a diagnosis of definite AD. Behavioral changes were assessed with the Neuropsychiatric Inventory. Brain sections were collected from bilateral orbitofrontal and l eft anterior cingulate, superior temporal, inferior parietal, occipital, an d hippocampal cortices for quantification of neurofibrillary tangles (NFTs) and diffuse and neuritic plaques. Sections from frontal, cingulate, and hi ppocampal cortices were reviewed for the presence of Lewy bodies (LBs), Hyp othesis-driven correlational analyses were performed by the bootstrap metho d. Subgroup analyses contrasted a group with high scores of one specific be havior to a group with low scores after equating groups for other behaviors . NFT burden in the left orbitofrontal cortex across all 31 patients signif icantly correlated with agitation scores (r = 0.41, p < 0.015) and NFTs cor related significantly (r = 0.66, p = 0.004) with higher agitation scores in the subgroup analysis. Left anterior cingulate NFTs, although not within o ur hypotheses, also showed a significant relationship to agitation within t he subgroups (r = 0.76, p = 0.0003; Bonferroni p = 0.02). Seven patients, i ncluding three in the agitation subgroup, had cortical LBs. Aberrant motor behavior and NFT density in the left orbitofrontal cortex showed a signific ant relationship for the entire group (r = 0.38, p < 0.03) and for subgroup s (r = 0.49, p = 0.04), whereas apathy and left anterior cingulate NFTs sho wed a significant relationship only for the entire group (r = 0.25, p less than or equal to 0.01). These observations suggest that agitation and aberr ant motor behavior are correlates of greater NFT pathology in the orbitofro ntal cortex in AD, whereas increasing apathy may relate to greater NFT burd en in the anterior cingulate.