Home WakeSpace Scholarship › Electronic Theses and Dissertations

THE EFFECTS AND PATHWAYS OF INTRANASAL INSULIN FOR THE TREATMENT OF MILD COGNITIVE IMPAIRMENT AND ALZHEIMER’S DISEASE

Electronic Theses and Dissertations

Item Files

Item Details

title
THE EFFECTS AND PATHWAYS OF INTRANASAL INSULIN FOR THE TREATMENT OF MILD COGNITIVE IMPAIRMENT AND ALZHEIMER’S DISEASE
author
Kellar, Derek
abstract
Alzheimer’s disease (AD) is the leading cause of dementia and is only expected to increase in prevalence as life expectancy continues to grow. Currently treatments targeting the hallmark proteins amyloid beta (Aβ) and tau have ignored the complexity of the age-related disease and have led to controversial results. There is a clear need for alternative approaches to this disease. One such approach, intranasal insulin (INI), has been testing in vitro, in murine models of AD, and in preclinical trials all yielding positive results. A large phase 2/3 12 month clinical trial with a 6 month open label extension was conducted to assess the effects of INI in a large population of mild cognitive impaired and AD patients, finding retention of cognition and improved Aβ and tau profile in a subset of participants using one of the two devices used to deliver insulin. Here we sought to characterize how the AD brain changed in response to INI. We measured changes in brain health using metrics of white matter hyperintensity volume, gray matter volume, cortical thickness, inflammation, immune function, and vascular function. Relationships between these variables and Aβ, tau, cognition, and function were examined. INI reduced white matter hyperintensity (WMH) progression in frontal and deep brain regions compared to placebo, with a similar trend observed in global white matter hyperintensity volume (WMHV). Changes in WMHV correlated with changes in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Clinical Disease Rating-Sum of Boxes (CDR-SOB) in the insulin group, while the placebo group only showed correlations between changes in WMHV and changes in a memory composite. INI significantly increased change in cerebral spinal fluid (CSF) interferon gamma and Eotaxin, and reduced interleukin-6 (IL-6) compared to placebo. CSF macrophage-derived chemokine (MDC) change trended to be higher in the placebo group than the INI group, while IL-2 change was greater in the insulin group compared to placebo. Complete separate relationships were observed between changes in the markers of inflammation, immune function, and vascular function and magnetic resonance imaging, tau and Aβ, and cognitive and functional measures. INI alters the typical progression of markers of inflammation, immune function, and WMHs seen in AD and is a promising therapeutic option for AD.
subject
Alzheimer's Disease
Insulin
Intranasal
Mild Cognitive Impairment
contributor
Craft, Suzanne (committee chair)
Lockhart, Samuel (committee member)
Macauley, Shannon (committee member)
Hughes, Timothy (committee member)
date
2021-09-01T08:35:38Z (accessioned)
2022-08-31T08:30:12Z (available)
2021 (issued)
degree
Physiology and Pharmacology (discipline)
embargo
2022-08-31 (terms)
identifier
http://hdl.handle.net/10339/99073 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

Usage Statistics