Double-Blind Placebo-Controlled Pilot Investigation of the Safety of a Single Dose of Rapid-Acting Intranasal Insulin in Down Syndrome

Abstract

Background Individuals with Down syndrome are likely to develop clinical and neuropathological brain changes resembling Alzheimer's disease dementia by the ages of 35-40 years. Intranasal insulin is a potential treatment for neurodegenerative disease that has been shown to reduce amyloid plaque burden and improve verbal memory performance in normal as well as memory-impaired adults. Investigations have shown that rapid-acting insulins may result in superior cognitive benefits compared with regular insulin. Objectives The primary objective of this study was to measure the safety and feasibility of intranasal rapid-acting glulisine in subjects with Down syndrome. Secondarily, we estimated the effects of intranasal glulisine on cognition and memory in Down syndrome. Methods A single-center, single-dose, randomized, double-blind, placebo-controlled, cross-over pilot study was performed to test the safety of intranasal glulisine vs placebo in 12 subjects with Down syndrome aged ≥ 35 years. Intranasal administration utilized the Impel NeuroPharma I109 Precision Olfactory Delivery (POD ®) device. The primary outcomes were the occurrence of any or related adverse and serious adverse events. Secondary post-treatment cognitive outcome measures included performance on the Fuld Object-Memory Evaluation and Rivermead Behavioral Memory Test. Results Intranasal glulisine was safe and well tolerated in the Down syndrome population. No adverse or serious adverse events were observed. Conclusions Further investigations are necessary to better evaluate the potential cognitive-enhancing role of intranasal insulin in the Down syndrome population. ClinicalTrials.gov ID NCT02432716.

Effects of Intranasal Insulin Administration on Cerebral Blood Flow and Cognitive Performance in Adults: A Systematic Review of Randomized, Placebo-Controlled Intervention Studies

“…In MCI/AD patients, individuals carrying the APOE-ε4 allele showed no or even worsened memory scores, while in those without the allele intranasal insulin improved memory recall [41, 42, 44]. A dose of 20 IU improved immediate recall in adults at increased risk of dementia [43]. The 8-week application of a daily 160 IU improved delayed recall in normal-weight and overweight adults [46, 47, 54, 58].…”

Pharmacological Approaches to the Treatment of Dementia in Down Syndrome: A Systematic Review of Randomized Clinical Studies

“…The average age of the participants with DS included in this review was 50 years [ 3 , 4 , 27 , 28 , 29 , 30 ]. In relation to methodological quality, the risk of bias was low in all the articles evaluated, excepted for “unclear” in some analyzed criteria in two of them [ 4 , 30 ].…”

“…In this review, important points about the effectiveness of different pharmacological treatments for adults with DS, focusing on AD signs, were summarized; among them were the use of supplemental antioxidant therapies [ 3 ], donepezil [ 27 , 28 ], memantine [ 29 ], vitamin E [ 30 ], and intranasal insulin [ 4 ]. The effects of each treatment are reported in Table 1 .…”

“…The dosage and duration of the medication used and the gravity of the set of symptoms related to dementia could be correlated with the differences observed [ 34 ]. Rosenbloom et al (2020) [ 4 ] reported the importance of analyzing factors such as the daily dose of the drug and the longitudinal duration of treatment for a better response of the agent in regulating pathological changes in dementia cases. In their study, the authors detected no significant effect of the rapid-acting intranasal insulin on delayed recall and memory recognition between individuals with DS and a placebo group.…”

“…Down syndrome (DS) is considered the most frequent form of intellectual disability, with important expressions of cognitive decline and early dementia [ 1 , 2 ]. There has been an increase in the life expectancy of this population in recent years (to around 55 years), mainly influenced by greater inclusion into mainstream society, a drop in infant mortality rate, advances in medical care, and positive changes related to overall health [ 3 , 4 , 5 , 6 , 7 ]. According to the literature [ 1 , 2 ], alterations such as atrioventricular septal defects in the heart, leukemia, and early-onset Alzheimer’s disease (AD), among others, are common in this population.…”