Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial

Craft S, Baker LD, Montine TJ, et al
Arch Neurol. 2011;Sept 12. [Epub ahead of print]

Summary

The goal of this randomized, double-blind, placebo-controlled trial was to assess the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid (CSF) biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD). At the clinical research unit of a Veterans Affairs medical center, 104 adults (64 with amnestic mild cognitive impairment and 40 with mild-moderate AD) were randomly assigned to receive placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months. A nasal drug delivery device was used to administer all study drugs.

The main study endpoints were delayed story recall score and the Dementia Severity Rating Scale score. Secondary measures were 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. Before and after treatment, 23 participants underwent lumbar puncture and 40 underwent positron emission tomography with fludeoxyglucose F-18 (FDG-PET).

Delayed memory was improved in the group receiving 20 IU of insulin (P < .05). Both insulin groups had preserved caregiver-rated functional ability (P < .01) and general cognition measured by the ADAS-cog score for younger participants and functional abilities measured by the ADCS-ADL scale for adults with AD (P < .05).

Among insulin-treated participants as a group, no changes were detected in CSF biomarkers. However, exploratory analyses revealed that changes in memory and function were associated with changes in the CSF amyloid beta-42 level and tau protein-to- amyloid beta-42 ratio.

Fludeoxyglucose F-18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions decreased in participants receiving placebo, whereas insulin appeared to minimize progression of these deficits. No treatment-related severe adverse events occurred, and the safety profile and compliance were excellent.

Viewpoint

Study limitations of this small, single-site pilot study include younger age in the 40-IU dose insulin group than in the placebo group (although age was a covariate in all analyses), availability of CSF and FDG-PET data for only a subset of participants, and lack of verification of increased insulin levels in CSF directly after insulin administration. In addition, treatment duration was relatively short. Nonetheless, on the basis of these findings, longer trials of intranasal insulin treatment are warranted in patients with amnestic mild cognitive impairment or AD. Further mechanistic studies may help clarify the role of insulin in the pathogenesis of AD.

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ABSTRACT
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Arch Neurol. 2011 Sep 12. [Epub ahead of print]
Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial.
Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B.
Source
Education, and Clinical Center (Drs Craft, Baker, Watson, Claxton, Callaghan, and Plymate and Mr Arbuckle) and Mental Illness Research, Education, and Clinical Center (Drs Leverenz and Gerton), Veterans Affairs Puget Sound Health Care System, and Departments of Psychiatry and Behavioral Sciences (Drs Craft, Baker, Watson, Claxton, and Leverenz), Pathology (Dr Montine), Radiology (Drs Minoshima and Cross), Medicine (Drs Tsai, Plymate, and Green), and Neurology (Drs Leverenz and Gerton), University of Washington School of Medicine, Seattle, Washington.
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.

PMID: 21911655 [PubMed - as supplied by publisher]

From : Medscape