Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial

Arch Neurol. 2012 Jan;69(1):29-38. doi: 10.1001/archneurol.2011.233. Epub 2011 Sep 12.

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).

Design: Randomized, double-blind, placebo-controlled trial.

Setting: Clinical research unit of a Veterans Affairs medical center.

Participants: 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).

Main outcome measures: 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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Intranasal
  • Aged
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Cognitive Dysfunction / diagnosis
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / metabolism
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Fluorodeoxyglucose F18
  • Follow-Up Studies
  • Hospitals, Veterans
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Immunoassay
  • Insulin / administration & dosage*
  • Least-Squares Analysis
  • Male
  • Neuropsychological Tests
  • Peptide Fragments / cerebrospinal fluid
  • Pilot Projects
  • Positron-Emission Tomography
  • Psychiatric Status Rating Scales
  • Spinal Puncture / methods
  • tau Proteins / cerebrospinal fluid

Substances

  • Amyloid beta-Peptides
  • Hypoglycemic Agents
  • Insulin
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Fluorodeoxyglucose F18

Associated data

  • ClinicalTrials.gov/NCT00438568