The cholinergic system in the pathophysiology and treatment of Alzheimer's disease

被引：977
|
作者：
Hampel, Harald [1 ,2 ,3 ,4 ,5 ]
Mesulam, M. -Marsel [6 ]
Cuello, A. Claudio [7 ,8 ,9 ]
Farlow, Martin R. [10 ]
Giacobini, Ezio [11 ]
Grossberg, George T. [12 ]
Khachaturian, Ara S. [13 ]
Vergallo, Andrea [1 ,2 ,3 ,4 ,5 ]
Cavedo, Enrica [1 ,2 ,3 ,4 ,5 ]
Snyder, Peter J. [14 ,15 ]
Khachaturian, Zaven S. [13 ]
机构：
[1] AXA Res Fund, Paris, France
[2] Sorbonne Univ Chair, Paris, France
[3] Sorbonne Univ, Pitie Salpetriere Hosp, AP HP, APM,GRC 21, Blvd Hop, F-75013 Paris, France
[4] Brain & Spine Inst ICM, INSERM U 1127, CNRS UMR 7225, Blvd Hop, F-75013 Paris, France
[5] Hop La Pitie Salpetriere, AP HP, Inst Memory & Alzheimers Dis IM2A, Dept Neurol, Blvd Hop, F-75013 Paris, France
[6] Northwestern Univ, Feinberg Sch Med, Cognit Neurol & Alzheimers Dis Ctr, Chicago, IL 60611 USA
[7] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada
[8] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada
[9] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada
[10] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN 46202 USA
[11] Univ Geneva Hosp, Dept Internal Med Rehabil & Geriatr, Geneva, Switzerland
[12] St Louis Univ, Sch Med, Dept Psychiat & Behav Neurosci, St Louis, MO USA
[13] Campaign Prevent Alzheimers Dis 2020 PAD2020, Potomac, MD USA
[14] Brown Univ, Alpert Med Sch, Dept Neurol, Providence, RI 02912 USA
[15] Univ Rhode Isl, Ryan Inst Neurosci, Kingston, RI 02881 USA
来源：
BRAIN | 2018年 / 141卷
基金：
加拿大健康研究院; 加拿大自然科学与工程研究理事会;
关键词：
acetylcholine; Alzheimer's disease; cholinergic system; cholinesterase inhibitors; cognition; MILD COGNITIVE IMPAIRMENT; CEREBRAL-BLOOD-FLOW; NERVE GROWTH-FACTOR; NURSING-HOME PLACEMENT; APOLIPOPROTEIN-E EPSILON-4; LONG-TERM POTENTIATION; AMYLOID-BETA LEVELS; CHOLINESTERASE-INHIBITORS; NUCLEUS BASALIS; SENILE-DEMENTIA;
D O I：
10.1093/brain/awy132
中图分类号：
R74 [神经病学与精神病学];
学科分类号：
摘要：
Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-beta proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.
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页码：1917 / 1933
页数：17
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