. The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. Brain. 2018 Jul 1;141(7):1917-1933. PubMed.

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  1. Cholinergic Highlight: A comment by the Cholinergic System Working Group

    Co-authors and members of the CWG: H .Hampel, M. Mesulam, P. Snyder, A. Vergallo, G. Grossberg, M. Farlow, E. Giacobini, A. Levey, A. Nordberg, A. Khachaturian, and Z. Khachaturian.

    The discovery, testing, and validation of a broad spectrum of interventions to delay and eventually prevent neurodegeneration underlying chronic brain diseases such as dementia syndromes and Alzheimer’s disease remain vital global goals. Strategies to improve the productivity of drug development and to accelerate the discovery of cures have been extensively deliberated at meetings, which have examined potential solutions and the challenges they face.

    One critical factor that may contribute to the lack of success may be the inadequacy of current concepts on the core pathogenic mechanisms and their role in the progression of neurodegeneration. A formal and comprehensive reassessment of existing theories appears indicated.

    The Cholinergic System Working Group [CWG] was convened to address this need by reassessing the role of the cholinergic system in the pathogenesis of AD in light of emerging new data.

    Cholinergic pharmacology has for decades been at the center of symptomatic therapy for clinically diagnosed AD. In this condition, cholinesterase inhibitors have been shown to confer transient relief from cognitive decline in a large number of cases. As such, along with memantine, they remain the only drugs approved by the FDA for AD.

    The historical roots of such therapeutic approaches are based on solid scientific evidence that inhibiting CNS muscarinic receptors results in memory loss in humans, in nonhuman primates, and in rodents. Conversely, improving “cholinergic tone” by sparing acetylcholine from degradation by cholinesterases has shown, in many experimental models, the ability to improve memory and cognitive skills.

    The above studies coincided with the realization that the basal forebrain cholinergic system—a system of neurons that in humans provides the sole source of acetylcholine to the cerebral cortex and hippocampus—is most vulnerable to the pathology of AD.

    These developments generated the “Cholinergic Hypothesis of AD.” In addition to helping to introduce efficacious cholinesterase inhibitors, this concept also unleashed the false expectation that this approach could cure the disease. As cholinergic failure is not the initiating cause of AD, the cholinergic approach to understanding or treating the disease fell into disrepute. We suggest, however, that we should not abandon a fuller understanding of the neurobiology of this important system in brain health and disease. This recent publication of the CWG (Hampel et al., 2018) articulates why the forebrain cholinergic system remains relevant in the search for mechanisms to ameliorate the devastating effects of AD.

    Below, we highlight aspects of this publication that could guide future preclinical and clinical research:

    • Despite the pathological brain “devastation” at clinical stages, cholinergic drugs are able to render tangible cognitive improvements.
    • Cholinergic therapy has been shown to significantly diminish the annual rate of hippocampal and basal forebrain cholinergic nuclei atrophy, as well as the loss of regional cortical thickness in mildly cognitively impaired individuals suspected of having AD.
    • Long-term use of drugs with secondary anti-muscarinic effects increases the incidence of dementia and AD.
    • Low doses of the muscarinic antagonist scopolamine provoke poor cognitive performance in individuals revealing a posterior positive brain amyloid.
    • Muscarinic stimulation favors an APP non-amyloidogenic pathway.
    • Novel MRI studies reveal early shrinkage of the nucleus basalis of Meynert in the progression of Alzheimer’s pathology.
    • Tau accumulates at early AD stages in cholinergic neurons of the nucleus basalis.
    • Alterations of nerve growth factor metabolism, essential for the integrity of basal forebrain cholinergic neurons, correlate with cognitive state in Down’s syndrome individuals with preclinical AD pathology.
    • Current acetylcholinesterase drugs are likely not reaching optimal therapeutic levels due to poor tolerability and peripheral side effects (i.e., nausea and emesis) at high doses. Hence, the potential benefit of such interventions will not be properly tested until the initiation of appropriate trials with newer, highly specific cholinergic agonists that lack adverse peripheral effects or are applied concurrently with specific peripheral blockers of muscarinic receptors.

    The second publication by the CWG, which is in press, offers an integrated account based on our reassessment of the Cholinergic Hypothesis in light of emerging evidence. We intend this paper to be part of an ongoing effort to reformulate the hypothesis. We expect revisions of this initial report and enlargement of the CWG membership in response to commentaries from the wider scientific community.

    References:

    . WITHDRAWN: Revisiting the cholinergic hypothesis in Alzheimer's disease: Emerging evidence from translational and clinical research. Alzheimers Dement. 2017 Oct 10; PubMed.

    . Optimal use of cholinergic drugs in Alzheimer's disease. Brain. 2018 Sep 1;141(9):e68. PubMed.

    . Reply: Optimal use of cholinergic drugs in Alzheimer's disease. Brain. 2018 Sep 1;141(9):e69. PubMed.

    . An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation. Alzheimers Dement. 2016 Nov;12(11):1132-1148. Epub 2016 Jul 21 PubMed.

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