Elsevier

Biological Psychiatry

Volume 62, Issue 4, 15 August 2007, Pages 294-301
Biological Psychiatry

Neuroscience Perspective
Acetylcholinesterase Inhibitors May Improve Myelin Integrity

https://doi.org/10.1016/j.biopsych.2006.08.020Get rights and content

Recent clinical trials have revealed that cholinergic treatments are efficacious in a wide spectrum of neuropsychiatric disorders that span the entire human lifespan and include disorders without cholinergic deficits. Furthermore, some clinical and epidemiological data suggest that cholinergic treatments have disease modifying/preventive effects. It is proposed that these observations can be usefully understood in a myelin-centered model of the human brain. The model proposes that the human brain’s extensive myelination is the central evolutionary change that defines our uniqueness as a species and our unique vulnerability to highly prevalent neuropsychiatric disorders. Within the framework of this model the clinical, biochemical, and epidemiologic data can be reinterpreted to suggest that nonsynaptic effects of cholinergic treatments on the process of myelination and myelin repair contributes to their mechanism of action and especially to their disease modifying/preventive effects. The ability to test the model in human populations with safe and noninvasive imaging technologies makes it possible to undertake novel clinical trial efforts directed at primary prevention of some of the most prevalent and devastating of human disorders.

Section snippets

The Myelin Model of the Human Brain

The four types of data outlined above are interpreted in the context of a myelin-centered model of human brain development and degeneration (Bartzokis 2004a, Bartzokis 2004b, Bartzokis 2005) that will briefly be summarized here. The human brain is unique, even among primates (Schoenemann et al. 2005), in its extensive and pervasive myelination process that supports its high-capacity information processing (Bartzokis 2004a). The lifelong trajectory of brain myelination has a quadratic-like

The Cholinergic System and the Continual Process of Myelination and Repair

The complex cholinergic (nicotinic and muscarinic) receptor changes in brain development, aging, and associated disease states (Court et al 1997, Pimlott et al 2004, Sihver et al 1998) support the possibility that nonneuronal cholinergic targets may contribute to efficacy of cholinergic treatments. A large proportion (up to 90%) of cholinergic transmission both in the developing and adult brain is nonsynaptic, with acetylcholine being released from cholinergic varicosities into the

Nonsynaptic Effects of Cholinergic Treatments may Explain Their Wide Spectrum of Efficacy

Recent clinical trials have revealed a very wide spectrum of efficacy of cholinergic treatments that span developmental and degenerative disorders as well as the “normal” myelin breakdown process leading to dementia. AChEIs can improve cognition in patients with MCI (Salloway et al. 2004). Moreover, such treatment delayed the progression from MCI to AD especially in patients that carried the ApoE4 allele (Petersen et al. 2005), and the ApoE4 allele is known to lower the age at onset of AD (

Conclusions

It is proposed that at least part of the efficacy demonstrated by cholinergic treatments of neuropsychiatric diseases may be attributed to nonsynaptic effects on oligodendrocytes and myelin. Many details remain to be investigated in order to fully understand the role of nonsynaptic cholinergic effects on brain development-to-degeneration myelination trajectories. The hypotheses presented above are testable through in vivo imaging technologies that provide new avenues of assessing the trajectory

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