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

Abstract

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 left anterior cingulate, superior temporal, inferior parietal, occipital, and hippocampal cortices for quantification of neurofibrillary tangles (NFTs) and diffuse and neuritic plaques. Sections from frontal, cingulate, and hippocampal cortices were reviewed for the presence of Lewy bodies (LBs). Hypothesis-driven correlational analyses were performed by the bootstrap method. Subgroup analyses contrasted a group with high scores of one specific behavior to a group with low scores after equating groups for other behaviors. NFT burden in the left orbitofrontal cortex across all 31 patients significantly correlated with agitation scores (r = 0.41, p < 0.015) and NFTs correlated significantly (r = 0.66, p = 0.004) with higher agitation scores in the subgroup analysis. Left anterior cingulate NFTs, although not within our hypotheses, also showed a significant relationship to agitation within the subgroups (r = 0.76, p = 0.0003; Bonferroni p = 0.02). Seven patients, including three in the agitation subgroup, had cortical LBs. Aberrant motor behavior and NFT density in the left orbitofrontal cortex showed a significant relationship for the entire group (r = 0.38, p < 0.03) and for subgroups (r = 0.49, p = 0.04), whereas apathy and left anterior cingulate NFTs showed a significant relationship only for the entire group (r = 0.25, p < or = 0.01). These observations suggest that agitation and aberrant motor behavior are correlates of greater NFT pathology in the orbitofrontal cortex in AD, whereas increasing apathy may relate to greater NFT burden in the anterior cingulate.

Metabolic correlates of behavioral and affective disturbances in frontal lobe pathologies

“…In respect to behavioral disturbances, they support an association between hypometabolism in the orbitofrontal cortex and "impaired behavioral control" in frontal lobe pathologies [9,31,41]. They also indicate a strong relationship between left amygdala hypometabolism and "impaired emotional control" symptoms such as impulsiveness, personality changes (including irritability, increased anger, and frequent loss of patience) and loss of emotional control.…”

Neuropathologic Correlates of Activities of Daily Living in Alzheimer Disease

“…The reliability of this approach was demonstrated previously. 8,9 Neuropathologic Data Mean post-mortem interval was 20.2 6 11.2 hours. Neuritic plaque (NP) and neurofibrillary tangle (NFT) counts were performed on all brain autopsy specimens by two investigators.…”

“…9 Five randomly selected linear fields, spanning the whole cortical thickness, were counted for each brain region. The mean of the five fields was calculated and counts were reported as lesion density per mm 2 of tissue.…”

Loss of [3H]4-DAMP binding to muscarinic receptors in the orbitofrontal cortex of Alzheimer’s disease patients with psychosis

“…To date, BPSD is widely considered to be a direct consequence of neuronal degeneration and perturbed neurotransmission, and much research effort has been expanded on uncovering the neuropathologic and neurochemical substrates of BPSD. For example, psychosis, apathy and agitation have been associated with higher neurofibrillary tangle loads in the orbitofrontal cortex and anterior cingulate gyrus (Farber et al 2000;Marshall et al 2006;Tekin et al 2001). With regards to the neurochemical correlates of BPSD, one research focus has been on cholinergic changes.…”