Cerebrospinal fluid insulin concentration increases and correlates with memory improvements after intranasal insulin administration

Abstract

AbstractBackgroundThere are currently no effective treatments for Alzheimer’s disease (AD) which has prompted research into alternative therapeutic options; one such promising option is intranasal insulin (INI). Although INI treatment over 4 months improved memory, no study has verified whether INI administration elevates insulin in the central nervous system and whether elevations are accompanied by enhanced memory performance.MethodThis study examined the effect of acute INI administration on cerebrospinal fluid (CSF) insulin levels and memory measured by the auditory‐verbal learning task (AVLT) in mild cognitive impairment (MCI, n=11, mean age=68+‐4.8) and cognitively unimpaired adults (n=8, age=67.5+‐4.1). Participants were randomized to receive insulin (Humulin‐R 20 IU) or placebo at their first visit using an intranasal delivery device and returned two‐to‐six weeks later to repeat the visit with the other substance. Fasting participants underwent a blood draw, INI or placebo administration, AVLT, lumbar puncture (LP), blood draw, and delayed AVLT. CSF and plasma insulin measured with ultra‐sensitive ELISA and AVLT scores were compared between placebo and insulin visits. Linear modeling was performed in SAS with visit as a repeated factor and covariates BMI, cognitive status, sex, age, race, and Montreal Cognitive Assessment (MOCA) score. Non‐contributory covariates (p>0.15) were removed.ResultCSF insulin concentration increased after INI administration (p<0.05) while peripheral insulin levels remained unchanged. INI also trended to increased AVLT immediate recall (p<0.1). CSF insulin concentration changes and AVLT changes were positively correlated (p< 0.05). Participants with higher baseline MOCA scores showed greater increases in CSF insulin after INI relative to placebo administration (p<0.05).ConclusionINI is effectively transported into the CNS without modulating peripheral levels. In the brain, insulin may act to increase cognition in a concentration‐dependent manner. INI may be a good therapeutic option for adults with MCI or AD for whom CSF insulin levels are enhanced through intranasal delivery.