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Intranasal insulin improves cognition and modulates β-amyloid in early AD

From the Departments of Psychiatry and Behavioral Science (M.A.R., G.S.W., C.W.W., L.D.B., B.C., J.C.S.B., S.C.), Medicine (P.S.G., S.R.P.), and Neurology (M.A.F.), University of Washington School of Medicine, Seattle; Geriatric Research, Education, and Clinical Center (G.S.W., C.W.W., L.D.B., B.C., M.A.F., S.R.P., J.C.S.B., S.C.), Research and Development (P.S.G.), Veterans Affairs Puget Sound Health Care System, Seattle; Kurve Technology, Inc. (W.D.), Bothell, WA; and Department of Immunology (P.M.), Institute for Basic Research in Developmental Disabilities, Staten Island, NY.

Address correspondence and reprint requests to Dr. Suzanne Craft, GRECC S-182, VAPSHCS, 1660 S. Columbian Way, Seattle, WA 98108 scraft{at}u.washington.edu

Background: Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes.

Objective: We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, β-amyloid, and cortisol.

Methods: Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment.

Results: Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group (p = 0.0374). Insulin-treated subjects also showed improved attention (p = 0.0108) and functional status (p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the β-amyloid peptide (Aβ40; p = 0.0471) without affecting the longer isoform (Aβ42), resulting in an increased Aβ40/42 ratio (p = 0.0207).

Conclusions: The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.

Abbreviations: AD = Alzheimer disease; APP = amyloid precursor protein; BSA = bovine serum albumin; CBG = cortisol binding globulin; DSRS = Dementia Severity Rating Scale; MCI = mild cognitive impairment; PBS = phosphate buffered saline; RIA = radioimmunoassay.

e-Pub ahead of print on October 17, 2007, at www.neurology.org.

Supported by the Department of Veterans Affairs, the Institute for the Study on Aging, and National Institute on Aging RO1 AG027415.

Disclosure: W.D. is a founding member of Kurve Technology, the maker and patent holder of the electronic atomizer used in this study. W.D. holds equity interest in excess of $10,000 in Kurve Technology. The remaining authors have nothing to disclose.

Received March 15, 2007. Accepted in final form June 27, 2007.

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