Pennington Kendyl R, Debs Luca, Chung Sophia, Bava Janki, Garin Clément M, Vale Fernando L, Bick Sarah K, Englot Dario J, Terry Alvin V, Constantinidis Christos, Blake David T
Dept Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA.
Dept Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA.
bioRxiv. 2024 Nov 4:2024.03.01.582925. doi: 10.1101/2024.03.01.582925.
Brain aging contributes to cognitive decline and risk of dementia. Degeneration of the basal forebrain cholinergic system parallels these changes in aging, Alzheimer's dementia, Parkinson's dementia, and Lewy body dementia, and thus is a common element linked to executive function across the lifespan and in disease states. Here, we tested the potential of one-hour daily intermittent basal forebrain stimulation to improve cognition in senescent monkeys, and its mechanisms of action. Stimulation in five animals improved working memory duration in 8-12 weeks across all animals, with peak improvements observed in the first four weeks. In an ensuing three month period without stimulation, improvements were retained. With additional stimulation, performance remained above baseline throughout the 15 months of the study. Studies with a cholinesterase inhibitor produced inconsistent improvements in behavior. One of five animals improved significantly. Manipulating the stimulation pattern demonstrated selectivity for both stimulation and recovery period duration. Brain stimulation led to acute increases in cerebrospinal levels of tissue plasminogen activator, which is an activating element for two brain neurotrophins, Nerve Growth Factor (NGF) and Brain-Derived Growth Factor (BDNF). Stimulation also led to improved glucose utilization in stimulated hemispheres relative to contralateral. Glucose utilization also consistently declines with aging and some dementias. Together, these findings suggest that intermittent stimulation of the nucleus basalis of Meynert improves executive function and reverses some aspects of brain aging.
脑老化会导致认知能力下降和患痴呆症的风险。基底前脑胆碱能系统的退化与衰老、阿尔茨海默病性痴呆、帕金森病性痴呆和路易体痴呆中的这些变化相似，因此是一个与整个生命周期和疾病状态下的执行功能相关的共同因素。在此，我们测试了每天一小时的间歇性基底前脑刺激改善衰老猴子认知能力的潜力及其作用机制。对五只动物进行刺激后，所有动物在8至12周内工作记忆持续时间均得到改善，在前四周观察到最大改善。在随后三个月无刺激期内，改善效果得以维持。在研究的15个月中，随着额外刺激，表现始终高于基线水平。使用胆碱酯酶抑制剂的研究在行为改善方面结果不一。五只动物中有一只显著改善。对刺激模式的操控显示出对刺激期和恢复期持续时间的选择性。脑刺激导致脑脊液中组织纤溶酶原激活物水平急性升高，组织纤溶酶原激活物是两种脑神经营养因子——神经生长因子（NGF）和脑源性生长因子（BDNF）的激活元件。刺激还导致受刺激半球相对于对侧半球的葡萄糖利用率提高。葡萄糖利用率也会随着衰老和一些痴呆症持续下降。总之，这些发现表明间歇性刺激迈内特基底核对改善执行功能和逆转脑老化的某些方面具有作用。
