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.
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A, Areas of hypometabolism at baseline (scan 1) and month 4 (scan 2), along with
changes in hypometabolism ( time
2 – time 1) within each group, and differences in change between the placebo
group and the 20-IU or 40-IU dose insulin group ( nasal insulin – placebo). The red and orange colors, compared with the
green and blue colors, indicate areas of greater hypometabolism from time 1 to
time 2, and from placebo group to insulin groups. B, Change in mean regional
z scores with standard errors of mean (error bars) for the right and left
frontal regions and the left parietal region for the placebo, 20-IU dose
insulin, and 40-IU dose insulin groups. For the right and left frontal
volume-of-interest (VOI) values, placebo-assigned participants had reduced
activity during the 4-month period, whereas the 20-IU and 40-IU dose insulin
groups had preserved or slightly increased activity (treatment group x time interaction: P = .04 for comparison
between placebo group and 20-IU dose insulin group; P = .03 for similar
comparison between placebo group and 40-IU dose insulin group). Similar analyses
for left medial parietal VOI values revealed reduced activity over time for the
placebo group compared with the 40-IU dose insulin group (time x treatment group interaction: P = .05). |
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.
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