Intranasal insulin boosted cognitive function and even brain activity in patients with mild cognitive impairment and early Alzheimer’s disease in a 4-month, randomized, placebo-controlled trial.
The study, presented July 14 at the International Conference on Alzheimer’s Disease, holds tantalizing hints of an Alzheimer’s therapy that could be relatively inexpensive and easy to administer, although more research on a much larger scale is necessary before this science could move into the clinic.
Dr. Suzanne Craft of the Veterans Affairs Puget Sound Medical Center and the University of Washington, both in Seattle, said growing evidence suggests that insulin may play a key role in cognition and that patients with Alzheimer’s disease have significantly disrupted brain-insulin interactions.
“Insulin plays a number of important roles in the brain, and many are functions of great relevance to Alzheimer’s disease,” she said in an interview.
Insulin normally crosses the blood-brain barrier to bind with receptors in the hippocampus, frontal cortex, and other regions involved in cognition. “It also enhances memory, we believe through mediating glucose metabolism in the hippocampus, as well as by mediating levels of neurotransmitters, including acetylcholine,” Dr. Craft said.
Insulin also improves blood flow to the brain and works to prevent beta-amyloid from aggregating on neurons. “It appears to help the beta-amyloid move from inside the brain cells to the interstitial space, where it can be cleared,” she said. “It also increases the availability of a specific enzyme that breaks down amyloid.”
In an extension of her previous work, Dr. Craft randomized 104 patients with mild cognitive impairment (MCI) or early Alzheimer’s disease to placebo or 20 IU daily or 40 IU daily of intranasal insulin. The compound is sprayed into the nose, where insulin bypasses the blood-brain barrier and travels directly into the brain along the perivascular channels around the olfactory and trigeminal nerves, allowing the drug to bind to brain receptors within 15-30 minutes of administration.
The patients’ average age was 73 years. Their mean combined score on three baseline Mini-Mental State Examination tests was about 82. All took the Alzheimer’s Disease Assessment Scale cognitive test for MCI (ADAS-cog/MCI), the Dementia Severity Rating Scale (DSRS), and the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) measures.
The 20-IU group experienced a significantly improved delayed story recall compared with the placebo group. The 20-IU group also showed significantly improved functional status on the DSRS. These improvements persisted for 2 months after insulin was ceased.
On the ADCS-ADL, placebo patients declined significantly more than 20-IU patients; 40-IU patients had no change in their score. On the ADAS-cog/MCI test, placebo patients scored significantly worse than both intervention groups, and the 40-IU group scored significantly better than did the 20-IU group.
Dr. Craft remarked that “it’s hard to say for certain in a 4-month study that this would translate into clinical improvement, but on the ADAS-cog, we saw a 25% difference between the highest dose insulin group and the placebo group. And we also saw improvements in a caregiver-rated functional scale. So I would say that these findings do suggest clinical improvement.”
The fact that the improvements were maintained throughout the study and even after treatment stopped suggests that insulin has a cumulative effect in improving brain function, she added. “It doesn’t appear to be just a temporary boost.”
In a subgroup of 26 patients who had a lumbar puncture at baseline and at 4 months, insulin-treated patients showed an alteration in their tau/beta-amyloid-42 level, indicating increased clearance of beta-amyloid.
Another subgroup of 40 patients underwent fluorodeoxyglucose PET scanning at baseline and during follow-up. Those taking placebo showed a slowing of the cerebral metabolic rate for glucose utilization. This slowing was not seen in either the 20-IU or 40-IU subjects – a finding that Dr. Craft suggested may show slowing of disease progression.
“This is a new and very encouraging finding,” she said.
The study was sponsored by the U.S. National Institute on Aging and the U.S. Department of Veterans Affairs. Dr. Craft had no relevant disclosures.
Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
一项为期4个月的随机、安慰剂对照试验表明，有轻度认知功能障碍并患早期阿尔茨海默病的患者经鼻应用胰岛素可改善认知功能甚至是大脑活动。
该研究在7月14日被公布于国际阿尔茨海默病大会，尽管在该理论应用于临床之前必须进行更多较大规模的研究，但该研究所提出的阿尔茨海默病疗法有着诱人的亮点——相对低廉且易于实施。
退伍军人事务部普吉特海湾医学中心和华盛顿大学(均位于西雅图)的Suzanne Craft博士说， 越来越多的证据表明胰岛素在认知功能方面可能发挥着关键性作用，而阿尔茨海默病患者的脑与胰岛素间的相互作用被严重扰乱。
她在一次受访中说：“胰岛素在脑部发挥着众多重要作用，许多功能与阿尔茨海默病有着很大关联。”
正常情况下，胰岛素可通过血脑屏障，与海马区、额叶皮质和其他与认知相关的脑区中相应的受体结合。Craft博士说：“我们认为，胰岛素还可以通过调节海马区的葡萄糖代谢以及调节乙酰胆碱等神经递质的水平增强记忆力。”
胰岛素还可以改善大脑血流量，防止β-淀粉样蛋白聚集在神经元表面。她说：“它可能有助于β-淀粉样蛋白从脑细胞内转移到细胞间隙并在此处被清除。胰岛素还可以增加一种特异性淀粉样蛋白降解酶的活性。”
在她先前研究的扩展部分，Craft博士将104例伴有轻度认知功能障碍(MCI)或患有早期阿尔茨海默病的患者随机分入安慰剂对照组或每日经鼻给予20 U或40 U的胰岛素治疗组。将复合物喷入鼻内后，胰岛素可在鼻内绕过血脑屏障沿着围绕嗅神经和三叉神经的血管周围通道直接进入大脑，这使该药在用药后的15~30 min内与脑内受体结合。
患者的平均年龄为73岁。3次基线简易精神状态检查测试的平均综合评分约为82分。所有受试者均采用阿尔茨海默病评价量表认知测试对MCI进行评分 (ADAS-cog/MCI)，接受痴呆程度评定量表(DSRS)和阿尔茨海默病合作研究-日常生活活动量表 (ADCS-ADL)的评定。
与安慰剂组相比，20 U胰岛素治疗组延迟故事回忆得到明显改善，DSRS评定的功能状态亦得到明显改善，这些效果在停用胰岛素后仍持续存在2个月。
对于ADCS-ADL，安慰剂组患者的评分较20 U胰岛素治疗组显著下降；40 U胰岛素治疗组患者的评分无变化。在ADAS-cog/MCI试验中，安慰剂组患者的评分较两干预组明显偏差，40 U胰岛素治疗组的评分显著优于20 U胰岛素治疗组。
Craft博士评论说：“4个月的研究难以断定此治疗方案能否使临床转归得到改善，但据观察，最大剂量胰岛素治疗组与安慰剂组之间在ADAS-cog方面存在25%的差异。同时我们也在护理者评定的功能量表中观察到改善。因此，我认为这些结果确实显示出临床疗效的改善。”
疗效的改善贯穿整个研究期，而且即便在治疗停止后仍存在，这一事实表明胰岛素在改善大脑功能方面具有累积效应，她补充说。“这看似并不只是暂时的改善。”
对26例在基线时及4个月时行腰椎穿刺的患者进行亚组分析显示，胰岛素治疗组患者tau 蛋白/β-淀粉样蛋白42的水平发生改变，表明β-淀粉样蛋白的清除率增加。
对40例在基线时及随访过程中行氟脱氧葡萄糖正电子发射计算机断层扫描(PET)的患者所做的另一项亚组分析显示，安慰剂对照组患者大脑内葡萄糖的代谢速率减慢，而在20 IU胰岛素治疗组和40 IU胰岛素治疗组未观察到此现象，Craft博士认为这一结果可能表明疾病的进展减慢。
她说，“这一研究结果前所未有且非常激励人心”。
该研究由美国国家老龄化研究所和美国退伍军人事务部资助。Craft博士无相关的披露内容。
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