Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in Mild Cognitive Impairment and Alzheimer’s Disease

Abstract

Background: Intranasally administered insulin has shown promise in both rodent and human studies in Alzheimer’s disease; however, both effects and mechanisms require elucidation. Objective: We assessed the effects of intranasally administered insulin on white matter health and its association with cognition and cerebral spinal fluid biomarker profiles in adults with mild cognitive impairment or Alzheimer’s disease in secondary analyses from a prior phase 2 clinical trial (NCT01767909). Design: A randomized (1:1) double-blind clinical trial. Setting: Twelve sites across the United States. Participants: Adults with mild cognitive impairment or Alzheimer’s disease. Intervention: Participants received either twice daily placebo or insulin (20 IU Humulin R U-100 b.i.d.) intranasally for 12 months. Seventy-eight participants were screened, of whom 49 (32 men) were enrolled. Measurements: Changes from baseline in global and regional white matter hyperintensity volume and gray matter volume were analyzed and related to changes in cerebral spinal fluid biomarkers, Alzheimer’s Disease Assessment Scale-Cognition, Clinical Disease Rating-Sum of Boxes, Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale, and a memory composite. Results: The insulin-treated group demonstrated significantly reduced changes in white matter hyperintensity volume in deep and frontal regions after 12 months, with a similar trend for global volume. White matter hyperintensity volume progression correlated with worsened Alzheimer’s disease cerebral spinal fluid biomarker profile and cognitive function; however, patterns of correlations differed by treatment group. Conclusion: Intranasal insulin treatment for 12 months reduced white matter hyperintensity volume progression and supports insulin’s potential as a therapeutic option for Alzheimer’s disease.

Intranasal insulin modulates cerebrospinal fluid markers of neuroinflammation in mild cognitive impairment and Alzheimer’s disease: a randomized trial

“…www.nature.com/scientificreports/ Cross sectional analysis was performed to assess group differences at baseline in age, cognitive status, and sex using chi squared tests or general linear models when appropriate. Change in GMV and WMHV were constructed as previously described 13 . In the first phase of analysis, to determine whether there were treatmentrelated changes in neuroinflammatory/immune/vascular markers over the 12 month treatment period, general linear modeling was performed in SAS v 9.4 to conduct repeated measures analysis of variance, with treatment group (insulin vs. placebo) as the independent factor and time (baseline vs. 12 months) as the within group factor, and with inclusion of the following covariates: baseline concentration of the analyte, cognitive diagnosis, age, ApoE4 status, baseline MMSE, and sex.…”

“…Insulin treatment also improved CSF Aβ42/Aβ40 and Aβ42/T-tau ratios. Further, the device cohort that showed clinical benefit with insulin treatment also showed reduced progression of white matter hyperintensity volume 13 , a pathology that has been linked to inflammation and vascular injury either by amyloid or other factors 14 , 15 . These findings highlight the need for additional research identifying the mechanisms through which INI may provide therapeutic benefit in AD.…”

“…In the present study we examined the cohort of participants from the large phase 2 study that used the device associated with attenuated cognitive decline, better CSF AD biomarker profiles, and reduced WMHV 12 , 13 . In particular, we assessed the effects of INI on CSF markers of inflammation, immune function, and vascular function and their associations with clinical markers of AD progression: CSF Aβ and tau, magnetic resonance imaging (MRI) measures, and cognitive and functional performance.…”

Intranasal Delivery of Nerve Growth Factor in Neurodegenerative Diseases and Neurotrauma

“…By being a facilitator of metabolism and perfusion, IN-NGF may impact a broad neuro-pathological spectrum. It is worth noting that, similarly to IN-NGF, intranasal insulin was able to enhance brain energy levels, to improve memory loss and to reduce white matter degeneration in MCI and AD patients ( Craft et al, 2012 ; Jauch-Chara et al, 2012 ; Kellar et al, 2021 ). A synergistic combination of these intranasal growth factors may deserve, therefore, a specific investigation.…”

Cerebrovascular insulin receptors are defective in Alzheimerˈs disease

“…Using intranasal delivery to avoid hypoglycemic effect of systemically injected insulin, several small clinical trials have reported benefits on memory scores in cognitively impaired adults (Claxton et al, 2015;Craft et al, 2017;Reger et al, 2008). However, recent larger clinical trials brought mitigated results (Craft et al, 2020;Gwizdala et al, 2021;Kellar et al, 2021;Rosenbloom et al, 2021). Still, increasing insulin sensitivity remains a promising avenue and a wide range of repurposed diabetes drugs are in ongoing clinical trials, including metformin, thiazolidinediones and glucagon-like peptide 1 (GLP-1) analogs (Cummings et al, 2020;Hölscher, 2021;Moran et al, 2019).…”