0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle–Aged Adults at Risk for Alzheimer Disease

Auriel A. Willette, PhD1,2; Barbara B. Bendlin, PhD3,4; Erika J. Starks, BS3; Alex C. Birdsill, PhD3; Sterling C. Johnson, PhD3,4,5; Bradley T. Christian, PhD6; Ozioma C. Okonkwo, PhD3,4; Asenath La Rue, PhD4; Bruce P. Hermann, PhD4; Rebecca L. Koscik, PhD4; Erin M. Jonaitis, PhD4; Mark A. Sager, MD4; Sanjay Asthana, MD3,5
[+] Author Affiliations
1Department of Food Science and Human Nutrition, Iowa State University, Ames
2Neuroscience Interdepartmental Program, Iowa State University, Ames
3Clinical Science Center, Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison
4Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison
5Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin
6Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison
JAMA Neurol. 2015;72(9):1013-1020. doi:10.1001/jamaneurol.2015.0613.
Text Size: A A A
Published online

Importance  Converging evidence suggests that Alzheimer disease (AD) involves insulin signaling impairment. Patients with AD and individuals at risk for AD show reduced glucose metabolism, as indexed by fludeoxyglucose F 18–labeled positron emission tomography (FDG-PET).

Objectives  To determine whether insulin resistance predicts AD-like global and regional glucose metabolism deficits in late middle–aged participants at risk for AD and to examine whether insulin resistance–predicted variation in regional glucose metabolism is associated with worse cognitive performance.

Design, Setting, and Participants  This population-based, cross-sectional study included 150 cognitively normal, late middle–aged (mean [SD] age, 60.7 [5.8] years) adults from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) study, a general community sample enriched for AD parental history. Participants underwent cognitive testing, fasting blood draw, and FDG-PET at baseline. We used the homeostatic model assessment of peripheral insulin resistance (HOMA-IR). Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. We used a voxelwise analysis to determine whether HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, apolipoprotein E ε4 genotype, AD parental history status, and a reference region used to normalize regional uptake.

Main Outcomes and Measures  Regional glucose uptake determined using FDG-PET and neuropsychological factors.

Results  Higher HOMA-IR was associated with lower global glucose metabolism (β = −0.29; P < .01) and lower regional glucose metabolism across large portions of the frontal, lateral parietal, lateral temporal, and medial temporal lobes (P < .05, familywise error corrected). The association was especially robust in the left medial temporal lobe (R2 = 0.178). Lower glucose metabolism in the left medial temporal lobe predicted by HOMA-IR was significantly related to worse performance on the immediate memory (β = 0.317; t148 = 4.08; P < .001) and delayed memory (β = 0.305; t148 = 3.895; P < .001) factor scores.

Conclusions and Relevance  Our results show that insulin resistance, a prevalent and increasingly common condition in developed countries, is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance. Midlife may be a critical period for initiating treatments to lower peripheral insulin resistance to maintain neural metabolism and cognitive function.

Figures in this Article

Figures

Place holder to copy figure label and caption
Figure 1.
Association Between the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and Global Uptake of Fludeoxyglucose F 18 (FDG) in Positron Emission Tomography (PET)

Participants included 150 late middle–aged adults. Uptake and HOMA-IR values were adjusted by the following covariates: age, sex, parental history of Alzheimer disease, apolipoprotein E ε4 genotype, body mass index, and the FDG-PET reference region. Glucose uptake is measured in arbitrary units. Circles indicate individual participants; line, the linear regression fit across all participants.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Association Between Higher Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and Lower Regional Uptake of Fludeoxyglucose F 18 (FDG) in Positron Emission Tomography (PET)

Participants included 150 late middle–aged adults. A, The FDG-PET results are displayed on 3-dimensional cross-sections of temporal, parietal, and frontal regions, with images oriented in neurologic space. The color bar depicts t values. B, Glucose uptake values (measured in arbitrary units) were adjusted by the following covariates: age, sex, parental history of Alzheimer disease, apolipoprotein E ε4 genotype, and glucose metabolism in the reference region. Circles indicate individual participants; line, the linear regression fit across all participants. FWE indicates familywise error correction; LMTL, left medial temporal lobe.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Association Between Left Medial Temporal Lobe (LTML) Uptake of Fludeoxyglucose F 18 (FDG) in Positron Emission Tomography (PET) Predicted by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) Analysis and Cognitive Function Factors

Higher FDG-PET in the LMTL as a function of lower HOMA-IR predicted better performance on the verbal learning (A) and immediate memory (B) factors. Factor scores are described in the Table, with higher scores representing better performance. The LMTL was not associated with the working memory factor (C) but was associated with the speed and flexibility factor (D). The FDG-PET signal was adjusted by the FDG reference region, age, sex, apolipoprotein E ε4 genotype, parental history of Alzheimer disease, and HOMA-IR. Glucose uptake is measured in arbitrary units. Circles indicate individual participants; line, the linear regression fit across all participants.

Graphic Jump Location

Tables

References

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

3,471 Views
19 Citations
×

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
Jobs
brightcove.createExperiences();