Executive dyscontrol in dementia, with emphasis on subcortical pathology and the role of butyrylcholinesterase

Abstract

Executive functions describe a variety of cognitive processes responsible for structuring behaviors around goals, and developing plans to achieve those goals in relation to the environment. In addition to deficits in basal forebrain cholinergic neuronal input into the frontal cortex, impaired control of executive function has been associated with lesions to the frontal cortex and its basal ganglia-thalamic connections. In addition to executive dysfunction, features that imply fronto-subcortical pathology include profound slowing of cognition, attentional deficits, apathy and changes in mood. Fronto-subcortical systems are vulnerable to white matter change, atrophy, and certain forms of neurotransmitter depletion. The diffuse, and likely non-cholinergic, projections of acetylcholinesterase (AChE)-containing thalamic neurons innervate all cortical areas. Butyrylcholinesterase (BuChE) activity is relatively high in thalamic nuclei that project to frontal cortical structures involved in attention, executive function, and behavior. However, the largest pool of BuChE in the brain is found in the glia, particularly those in deeper cortical and subcortical structures. These findings suggest that BuChE may also be an important therapeutic target in the management of symptoms due to subcortical pathology. Whereas 'pure' Alzheimer's disease (AD) may involve significant subcortical pathology in addition to cortical pathology, AD with cerebrovascular disease, vascular dementia (VaD), Parkinson's disease dementia (PDD) and dementia due to Lewy bodies (DLB) may involve a generally greater degree of subcortical, in addition to cortical, pathology. It may be hypothesized that these dementia types, which are characterized by executive dysfunction, might derive particular benefits from cholinesterase inhibitors such as rivastigmine that inhibit BuChE in addition to AChE.