title: Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial.
abstract: OBJECTIVE
  To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD).
  
  
  METHODS
  Randomized, double-blind, placebo-controlled trial.
  
  
  METHODS
  Clinical research unit of a Veterans Affairs medical center.
  
  
  METHODS
  The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention  Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington).
  
  
  METHODS
  Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment.
  
  
  RESULTS
  Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred.
  
  
  CONCLUSIONS
  These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD. Trial Registration  clinicaltrials.gov Identifier: NCT00438568.
authors.affiliation: Geriatric Research, Education, and Clinical Center, S-182, Veterans Affairs Puget Sound Health Care System, 1660 S Columbian Way, Seattle, WA 98108, USA. scraft@uw.edu
authors.forename: Suzanne
authors.initials: S
authors.lastname: Craft
authors.forename: Laura D
authors.initials: LD
authors.lastname: Baker
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: Satoshi
authors.initials: S
authors.lastname: Minoshima
authors.forename: G Stennis
authors.initials: GS
authors.lastname: Watson
authors.forename: Amy
authors.initials: A
authors.lastname: Claxton
authors.forename: Matthew
authors.initials: M
authors.lastname: Arbuckle
authors.forename: Maureen
authors.initials: M
authors.lastname: Callaghan
authors.forename: Elaine
authors.initials: E
authors.lastname: Tsai
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Plymate
authors.forename: Pattie S
authors.initials: PS
authors.lastname: Green
authors.forename: James
authors.initials: J
authors.lastname: Leverenz
authors.forename: Donna
authors.initials: D
authors.lastname: Cross
authors.forename: Brooke
authors.initials: B
authors.lastname: Gerton
mesh_terms: D000281:Administration, Intranasal; D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D019788:Fluorodeoxyglucose F18; D005500:Follow-Up Studies; D006787:Hospitals, Veterans; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007118:Immunoassay; D007328:Insulin / Q000008:administration & dosage*; D016018:Least-Squares Analysis; D008297:Male; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010865:Pilot Projects; D049268:Positron-Emission Tomography; D011569:Psychiatric Status Rating Scales; D013129:Spinal Puncture / Q000379:methods; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D019788:Fluorodeoxyglucose F18