The cholinergic hypothesis of cognitive aging revisited again: Cholinergic functional compensation

doi:10.1016/j.pbb.2011.02.022

Pharmacology Biochemistry and Behavior

Volume 99, Issue 2, August 2011, Pages 254-261

https://doi.org/10.1016/j.pbb.2011.02.022 Get rights and content

Abstract

It is now possible to reevaluate the cholinergic hypothesis of age-related cognitive dysfunction based on a synthesis of new evidence from cholinergic stimulation studies and cognitive models. We propose that a change of functional circuitry that can be observed through a combination of pharmacologic challenge and functional neuroimaging is associated with age-related changes in cholinergic system functioning. Psychopharmacological manipulations using cholinergic agonists and antagonists have been consistent in replicating patterns of aging seen in functional imaging studies. In addition, studies of anticholinesterase drugs in patients with Alzheimer's disease and mild cognitive impairment show support for the proposal that cholinergic compensation causes alterations in task-related brain activity. Thus, the cholinergic hypothesis of age-related cognitive dysfunction deserves further consideration as new methodologies for evaluating its validity are increasingly being used. Future directions for testing hypotheses generated from this model are presented.

Research Highlights

► The cholinergic hypothesis of age-related cognitive dysfunction is reevaluated. ► The compensation response during fMRI in aging is related to cholinergic function. ► Synaptic loss, cholinergic stimulation, and cognitive performance presented in a model.

Section snippets

Cholinergic influences on human cognitive performance

Initial support for the cholinergic hypothesis came from four areas of research. First, studies by Drachman and colleagues (Drachman and Leavitt, 1974, Drachman, 1977) showed that temporary blockade of muscarinic cholinergic receptors produced impairments of learning and memory that resembled changes associated with normal aging (Ghoneim and Mewaldt, 1977, Peterson, 1977). Second, Whitehouse et al. (1982) showed that there is a loss of cholinergic neurons in the basal forebrain in Alzheimer's

Evidence for cholinergic modulation of task-related brain activity

The effects of cholinergic modulation on cognitive processing and related brain circuitry have also been revealed by neuroimaging studies (see Thiel, 2003 for a review). To preview, procholinergic and anticholinergic drugs show opposite patterns of brain activation across a range of cognitive tasks. While there are some task-specific effects of cholinergic stimulation and blockade studies, there are also task-general patterns that may be related to attentional processes that involve cholinergic

Cholinergic functional compensation model of age-related cognitive dysfunction

Our model proposes that it is age-related alterations in the activity of the cholinergic system that are responsible for the PASA pattern. Early in the aging process, increases in cholinergic system activity act to compensate for age-related changes in sensory and/or executive control processes by increasing the engagement of frontal-mediated top-down processes (as represented by the middle panel in Fig. 1). Functional compensation will require the recruitment of additional frontal regions to

Potential mechanisms for the cholinergic role in functional compensation

There is a significant body of evidence that supports the role of the cholinergic system in directing and modulating cognitive operations (see Hasselmo and Sarter, 2010, Sarter et al., 2005 for reviews). What remains to be fully elucidated is how these biological processes relate the activity of the cholinergic system to patterns of brain activation in functional imaging studies and patterns of performance on tests of attention and memory. Below we make a preliminary attempt to link the

Tests of the cholinergic functional compensation model of cholinergic functioning using cognitive enhancers in AD and MCI

A number of clinical trials have examined the ability of acetylcholinesterase inhibitors to modify cognitive performance in AD and MCI and these studies have been reviewed elsewhere (e.g., Diniz et al., 2009, Hansen et al., 2008, Wilkins and Newhouse, 2010). Briefly, most clinical trials have shown that chronic administration of acetylcholinesterase inhibitors improves scores on cognitive subscales of the Alzheimer's Disease Assessment Scale, the Mini-Mental State examination, and global scales

Are there inconsistencies with the functional compensation hypothesis?

There are some studies in the prior literature described above that may not be entirely consistent with the cholinergic functional compensation hypothesis as proposed here. First, not all studies of older and younger adults show the expected PASA pattern (Grady et al., 1995, Iidaka et al., 2001, Milham et al., 2002, Stebbins et al., 2002). These studies do not demonstrate increased frontal activation for older adults and this discrepancy may have to do with specifics related to the tasks used

Recommendations for future studies

Future studies may be able to capitalize on the use of cholinergic-related brain activity as a biomarker of treatment response. The effects of cholinergic stimulation and blockade in younger and older adults as well as in MCI and AD patients need further study to more fully understand the relationship between synaptic integrity, cholinergic function, and brain circuitry involved in memory and attention processes. Other neuroimaging modalities such as PET may be utilized to examine the effects

Summary

Research on cholinergic modulation of cognition in aging and dementia has flourished in recent years. There have been a number of neuroimaging studies utilizing psychopharmacological manipulations to examine the effects of aging and dementia on brain circuitry. However, there has been no neurobiological model proposed to integrate the effects of age on cognitive performance and the imaging data thus far. We propose that the cholinergic changes that occur with aging may be one explanation for

Acknowledgements

The authors are supported by grants NIA K01 AG030380 to JD and NIA R01 AG021476 to PN. The authors thank Christopher Newhouse for help with creating Fig. 2 and Jason Arndt and Jenny Rusted for providing helpful comments on an earlier version of this manuscript.

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ReviewThe cholinergic hypothesis of cognitive aging revisited again: Cholinergic functional compensation

Abstract

Research Highlights

Section snippets

Cholinergic influences on human cognitive performance

Evidence for cholinergic modulation of task-related brain activity

Cholinergic functional compensation model of age-related cognitive dysfunction

Potential mechanisms for the cholinergic role in functional compensation

Tests of the cholinergic functional compensation model of cholinergic functioning using cognitive enhancers in AD and MCI

Are there inconsistencies with the functional compensation hypothesis?

Recommendations for future studies

Summary

Acknowledgements

Neurosci Biobehav Rev

Behav Neural Biol

Neuron

Eur J Pharmacol

Neurosci Biobehav Rev

Horm Behav

Am J Geriatr Psychiatry

Neuroscience

Neuroimage

Cogn Brain Res

Neuron

Neurosci Lett

Brain Cogn

Curr Opin Pharmacol

Brain Res Rev

Brain Res Rev

Biochem Pharmacol

Magn Reson Imaging

Neuron

Prog Neuropsychopharmacol Biol Psychiatry

Neurobiol Learn Mem

Neural Netw

Neuron

Age-related cognitive deficits mediated by changes in the striatal dopamine system

Am J Psychiatry

Emergence of a powerful connection between sensory and cognitive functions across the adult life span: a new window to the study of cognitive aging

Psychol Aging

The cholinergic hypothesis of geriatric memory dysfunction

Science

Cholinesterase inhibition modulates visual and attentional brain responses in Alzheimer's disease and health

Brain

Donepezil for mild cognitive impairment

Cochrane Database Syst Rev

Task-independent and task-specific age effects on brain activity during working memory, visual attention and episodic memory retrieval

Cereb Cortex

Evolving conceptions of memory storage, selective attention, and their mutual constraints within the human information processing system

Psychol Bull

Que PASA? The posterior anterior shift in aging

Cereb Cortex

A double-blind, placebo-controlled multicenter study of tactine for Alzheimer's disease

The New England Journal of Medicine

Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment

Ann Neurol

To treat or not to treat? A meta-analysis of the use of cholinesterase inhibitors in mild cognitive impairment for delaying progression to Alzheimer's disease

Eur Arch Psychiatry Clin Neurosci

Memory and cognitive function in man: does the cholinergic system have a specific role?

Neurology

Review
The cholinergic hypothesis of cognitive aging revisited again: Cholinergic functional compensation