Recent advances in cholinergic imaging and cognitive decline-Revisiting the cholinergic hypothesis of dementia

Abstract

Purpose of review: Although the cholinergic hypothesis of dementia provided a successful paradigm for the development of new drugs for dementia, this hypothesis has waned in popularity. Cholinergic brain imaging may provide novel insights into the viability of this hypothesis.

Recent findings: Cholinergic receptor and forebrain volumetric studies suggest an important role of the cholinergic system in maintaining brain network integrity that may deteriorate with cognitive decline in Alzheimer disease (AD) and Lewy body disorders (LBD). Bidirectional changes in regional receptor expression may suggest the presence of compensatory responses to neurodegenerative injury. Cholinergic system changes are more complex in LBD because of additional subcortical degenerations compared to AD. Cholinergic-dopaminergic interactions affect attentional, verbal learning and executive functions, and impairments in these two transmitter systems may jointly increase the risk of dementia in Parkinson disease.

Summary: The cholinergic hypothesis is evolving from a primary focus on memory toward expanded cognitive functions modulated by regionally more complex and interactive brain networks. Cholinergic network adaptation may serve as a novel research target in neurodegeneration.

Keywords: Acetylcholine; Alzheimer disease; Parkinson disease; brain network; cognition; dementia with Lewy bodies.

Figure 1

There are multiple layers of pathobiological mechanisms underlying dementia and a single layer of this multifactorial system cannot account for the complete dementia syndrome. As such, the cholinergic system is one among others that when it fails it may exacerbate cognitive deficits and worsens the severity of dementia. Although cholinergic neurotransmitter changes occur at the neuronal level, degeneration of the long axonal projections will affect regional cerebral circuits and network functions.