Skip to main content
AAN.com
Articles
September 3, 2012

Higher normal fasting plasma glucose is associated with hippocampal atrophy
The PATH Study

September 4, 2012 issue
79 (10) 1019-1026

Abstract

Objectives:

Substantial evidence showing an association between type 2 diabetes (T2D) and cerebral atrophy, cognitive impairment, and dementia is accumulating. However, relatively little is known about the subclinical effects of high plasma glucose levels within the normal range. The aim of this study was to investigate the association between plasma glucose levels and hippocampal and amygdalar atrophy in a sample of 266 cognitively healthy individuals free of T2D, aged 60–64 years, taking part in a longitudinal study of aging.

Methods:

Fasting plasma glucose was assessed at wave 1. Hippocampal and amygdalar volumes were manually traced on 1.5 T MRI scans collected at wave 1 and at wave 2 4 years later. General linear model analyses were used to assess the relationship between plasma glucose and incident medial temporal lobe atrophy after controlling for a range of sociodemographic and health variables.

Results:

Plasma glucose levels were found to be significantly associated with hippocampal and amygdalar atrophy and accounted for 6%–10% in volume change after controlling for age, sex, body mass index, hypertension, alcohol, and smoking.

Conclusions:

High plasma glucose levels within the normal range (<6.1 mmol/L) were associated with greater atrophy of structures relevant to aging and neurodegenerative processes, the hippocampus and amygdala. These findings suggest that even in the subclinical range and in the absence of diabetes, monitoring and management of plasma glucose levels could have an impact on cerebral health. If replicated, this finding may contribute to a reevaluation of the concept of normal blood glucose levels and the definition of diabetes.

Get full access to this article

View all available purchase options and get full access to this article.

Supplementary Material

File (tables_e-1_to_e-5.docx)

REFERENCES

1.
Luchsinger JA. Adiposity, hyperinsulinemia, diabetes and Alzheimer's disease: an epidemiological perspective. Eur J Pharmacol 2008; 585: 119– 129.
2.
Okura T, Heisler M, Langa KM. Association between cognitive function and social support with glycemic control in adults with diabetes mellitus. J Am Geriatr Soc 2009; 57: 1816– 1824.
3.
Anstey KJ, Cherbuin N, Budge M, Young J. Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies. Obes Rev 2011; 12: e426– e437.
4.
Bourdel-Marchasson I, Lapre E, Laksir H, Puget E. Insulin resistance, diabetes and cognitive function: consequences for preventative strategies. Diabetes Metab 2010; 36: 173– 181.
5.
Cherbuin N, Anstey KJ. The Mediterranean diet is not related to cognitive change in a large prospective investigation: the PATH Through Life Study. Am J Geriatr Psychiatry 2011; 20: 20.
6.
Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 2002; 106: 2067– 2072.
7.
Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38: S26– S34.
8.
Vaidyula VR, Rao AK, Mozzoli M, Homko C, Cheung P, Boden G. Effects of hyperglycemia and hyperinsulinemia on circulating tissue factor procoagulant activity and platelet CD40 ligand. Diabetes 2006; 55: 202– 208.
9.
Darvall KA, Sam RC, Silverman SH, Bradbury AW, Adam DJ. Obesity and thrombosis. Eur J Vasc Endovasc Surg 2007; 33: 223– 233.
10.
Roman GC. Brain hypoperfusion: a critical factor in vascular dementia. Neurol Res 2004; 26: 454– 458.
11.
Dahle CL, Jacobs BS, Raz N. Aging, vascular risk, and cognition: blood glucose, pulse pressure, and cognitive performance in healthy adults. Psychol Aging 2009; 24: 154– 162.
12.
Jorm AF, Anstey KJ, Christensen H, Rodgers B. Gender differences in cognitive abilities: the mediating role of health state and health habits. Intelligence 2004; 32: 7– 23.
13.
Anstey KJ, Maller JJ, Meslin C, et al. Hippocampal and amygdalar volumes in relation to handedness in adults aged 60–64. Neuroreport 2004; 15: 2825– 2829.
14.
Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption–II. Addiction 1993; 88: 791– 804.
15.
Watson C, Jack CR, Cendes F. Volumetric magnetic resonance imaging. Clinical applications and contributions to the understanding of temporal lobe epilepsy. Arch Neurol 1997; 9: 97– 113.
16.
Brierly B, Shaw P, David AS. The human amygdala: a systematic review and meta-analysis of volumetric magnetic resonance imaging. Brain Res 2002; 39: 84– 105.
17.
Maller JJ, Anstey KJ, Reglade-Meslin C, Christensen H, Wen W, Sachdev P. Hippocampus and amygdala volumes in a random community-based sample of 60–64 year olds and their relationship to cognition. Psychiatry Res 2007; 156: 185– 197.
18.
Cherbuin N, Sachdev PS, Anstey KJ. Mixed handedness is associated with greater age-related decline in volumes of the hippocampus and amygdala: the PATH Through Life Study. Brain Behav 2011; 1: 125– 134.
19.
Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 2011; 378: 31– 40.
20.
Raz N, Ghisletta P, Rodrigue KM, Kennedy KM, Lindenberger U. Trajectories of brain aging in middle-aged and older adults: regional and individual differences. Neuroimage 2010; 51: 501– 511.
21.
Johansen FF, Diemer NH. Influence of the plasma glucose level on brain damage after systemic kainic acid injection in the rat. Acta Neuropathol 1986; 71: 46– 54.
22.
van der Borght K, Kohnke R, Goransson N, et al. Reduced neurogenesis in the rat hippocampus following high fructose consumption. Regul Pept 2011; 167: 26– 30.
23.
Stranahan AM, Norman ED, Lee K, et al. Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus 2008; 18: 1085– 1088.
24.
Nichols GA, Hillier TA, Brown JB. Normal fasting plasma glucose and risk of type 2 diabetes diagnosis. Am J Med 2008; 121: 519– 524.
25.
Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T. Effect of intranasal insulin on cognitive function: a systematic review. J Clin Endocrinol Metab 2012; 97: 366– 376.
26.
Kriketos AD, Greenfield JR, Peake PW, et al. Inflammation, insulin resistance, and adiposity: a study of first-degree relatives of type 2 diabetic subjects. Diabetes Care 2004; 27: 2033– 2040.
27.
Alzahrani SH, Ajjan RA. Coagulation and fibrinolysis in diabetes. Diab Vasc Dis Res 2010; 16: 16.
28.
Dentali F, Squizzato A, Ageno W. The metabolic syndrome as a risk factor for venous and arterial thrombosis. Semin Thromb Hemost 2009; 35: 451– 457.
29.
Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 2008; 31: 2383– 2390.
30.
Kopelman TR, O'Neill PJ, Kanneganti SR, Davis KM, Drachman DA. The relationship of plasma glucose and glycosylated hemoglobin A1C levels among nondiabetic trauma patients. J Trauma 2008; 64: 30– 34.
31.
Das S, Basu A. Inflammation: a new candidate in modulating adult neurogenesis. J Neurosci Res 2008; 86: 1199– 1208.
32.
Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 2009; 10: 434– 445.
33.
McEwen BS. Plasticity of the hippocampus: adaptation to chronic stress and allostatic load. Ann NY Acad Sci 2001; 933: 265– 277.
34.
Woon FL, Sood S, Hedges DW. Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 1181– 1188.
35.
Brown ES, Woolston DJ, Frol AB. Amygdala volume in patients receiving chronic corticosteroid therapy. Biol Psychiatry 2008; 63: 705– 709.
36.
Desai S, Khanani S, Shad MU, Brown ES. Attenuation of amygdala atrophy with lamotrigine in patients receiving corticosteroid therapy. J Clin Psychopharmacol 2009; 29: 284– 287.
37.
Pannacciulli N, Del Parigi A, Chen K, Le DS, Reiman EM, Tataranni PA. Brain abnormalities in human obesity: a voxel-based morphometric study. Neuroimage 2006; 31: 1419– 1425.
38.
Taki Y, Kinomura S, Sato K, et al. Relationship between body mass index and gray matter volume in 1,428 healthy individuals. Obesity 2008; 16: 119– 124.
39.
Raji CA, Ho AJ, Parikshak NN, et al. Brain structure and obesity. Hum Brain Mapp 2010; 31: 353– 364.
40.
Brain Development Cooperative Group. Total and regional brain volumes in a population-based normative sample from 4 to 18 years: the NIH MRI Study of Normal Brain Development. Cereb Cortex 2012; 22: 1– 12.

Information & Authors

Information

Published In

Neurology®
Volume 79Number 10September 4, 2012
Pages: 1019-1026
PubMed: 22946113

Publication History

Received: January 18, 2012
Accepted: April 19, 2012
Published online: September 3, 2012
Published in print: September 4, 2012

Permissions

Request permissions for this article.

Disclosure

The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

Authors

Affiliations & Disclosures

Nicolas Cherbuin, PhD
From the Centre for Research on Ageing, Health and Wellbeing (N.C., K.J.A.), Australian National University, Canberra, Australia; and School of Psychiatry (P.S.), University of New South Wales, Sydney, Australia.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers’ Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Perminder Sachdev, MD, PhD, FRANZCP
From the Centre for Research on Ageing, Health and Wellbeing (N.C., K.J.A.), Australian National University, Canberra, Australia; and School of Psychiatry (P.S.), University of New South Wales, Sydney, Australia.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
American Journal of Geriatric Psychiatry, Editorial Board, 2008-11 Acta Neuropsychiatrica, Editorial Board, 2006-11 Neuropsychiatric Disorders and Treatment, 2005-11 Current Opinion in Psychiatry, Section editor, 2008-12
Patents:
1.
NONE
Publishing Royalties:
1.
The Yipping Tiger and Other tales from the Neuropsychiatry clinic, University of New South Wales Press, 2009 Secondary Schizophrenia, Cambridge University Press, 2010 Akathisia and Restless legs, Cambridge University Press, 1993. The Ageing Brain, Wiley, 2000. Speakers’ Bureaus: Talk in 2011 to the Queensland Neuropsychiatry Group (sponsored by Eli Lilly). Talk to Alzheimer’s Master Class 2009 (sponsored by Pfizer)
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers’ Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NHMRC Capacity Building Grant – ID No 568940 – Sachdev P, Brodaty H, Andrews G, Lord S. Prevention and management of mental disorders in Older Australians. 5 years – 2009- 2013. UNSW Goldstar – ID No. 568785 – Sachdev P, Easteal S, Wen W. Neurocognitive and physical health in extreme old age: Sydney Centenarian Study – 1 year – 2009. NHMRC Program Grant – ID No. 568969 – Sachdev P, Brodaty H, Andrews G. The prevention early detection and effective management of neurocognitive disorders in the elderly. 2010-2014. NHMRC Project Grant – ID No. 630592 – Sachdev P, Richmond R, Kochan N, Wen W, Crawford J. A cognitive and neuroimaging study of exceptionally old individuals: Sydney Centenarian Study. 3 years - 2010-2012. Department of Health & Ageing. Dementia Collaborative Research Centre – Assessment and Better Care, Centre Funding – 2010-2013 - (4 years) (Brodaty / Sachdev / Broe / Draper). Department of Innovation, Industry, Science & Research (DIISR). Collaborative Research Networks Grant - – 2011-2013 (3 years) (Lead CI/Institution: Prof Annabelle Duncan/University of New England (UNE); Kelly B - UoN; Llewellyn G – USyd; Pitts M – LaTrobe; Moran G - UNSW); Sachdev P (AI). CSIRO Flagship Project Grant. SNP and CNV analysis of discordant neuropsychiatric and brain imaging traits in twins from the Older Australians Twin Study (OATS). – 2011 - (1 year) (Sachdev / Mather / Dusing).
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
Pacific Alzheimer Research Foundation (PARF) Operating Grant – ID No. PARF OP06-04-Beg. Improving sensitivity of early detection of Alzheimer’s disease (AD) via multi- dimensional analysis of longitudinal MRI scans. 3 years - 2007-2009.
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
Occasional expert opinion on medicolegal matters not related to the present study.
Kaarin J. Anstey, PhD
From the Centre for Research on Ageing, Health and Wellbeing (N.C., K.J.A.), Australian National University, Canberra, Australia; and School of Psychiatry (P.S.), University of New South Wales, Sydney, Australia.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
1) Commercial entity - Pfizer - speaker honoraria
Editorial Boards:
1.
Editorial Board member of the following journals: Aging, Neuropsychology and Cognition, Journals of Gerontology: Psychological Science; Ageing International; Gertontology; European Journal on Ageing
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
1) Non-profit entity: Australian Capital Territory Government 2) Non-profit entity: Alzheimer’s Australia 3) Commercial entity: Suncorp Insurance
Speakers’ Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
1)NHMRC of Australia Grant No. 973302, 179805, 157125, and from an Australian Rotary Health Research Fund grant. NC and KA are funded by Fellowships No. 471501 and 366756
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Study funding: Supported by NHMRC of Australia grants 973302, 179805, and 157125 and by an Australian Rotary Health Research Fund grant. Nicolas Cherbuin and Kaarin Anstey are funded by NHMRC Research Fellowships 471501 and 1002560. This research was partly undertaken at the National Computational Infrastructure facility in Canberra, Australia, which is supported by the Australian Commonwealth Government.
Correspondence & reprint requests to Dr. Cherbuin [email protected]

Author Contributions

Dr. Cherbuin contributed to the design of the study, conducted all statistical analyses, and managed all aspects of manuscript preparation and submission. Prof. Sachdev contributed to the design of the study, provided methodologic input and theoretical expertise, and contributed to writing and editing of the manuscript. Prof. Anstey contributed to the design of the study, provided methodologic input and theoretical expertise, advised on statistical analyses, and contributed to writing and editing of the manuscript.

Metrics & Citations

Metrics

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

Cited By
  1. Identification of structural motifs critical for human G6PC2 function informed by sequence analysis and an AlphaFold2-predicted model, Bioscience Reports, 44, 1, (2024).https://doi.org/10.1042/BSR20231851
    Crossref
  2. Metabolic Profile of Alzheimer’s Disease: Is 10-Hydroxy-2-decenoic Acid a Pertinent Metabolic Adjuster?, Metabolites, 13, 8, (954), (2023).https://doi.org/10.3390/metabo13080954
    Crossref
  3. Glycemic variability correlates with medial temporal lobe atrophy and decreased cognitive performance in patients with memory deficits, Frontiers in Aging Neuroscience, 15, (2023).https://doi.org/10.3389/fnagi.2023.1156908
    Crossref
  4. Association between Type 2 Diabetes Mellitus and Brain Atrophy: A Meta-Analysis, Diabetes & Metabolism Journal, 46, 5, (781-802), (2022).https://doi.org/10.4093/dmj.2021.0189
    Crossref
  5. Glucometabolic Changes Are Associated with Structural Gray Matter Alterations in Prodromal Dementia, Journal of Alzheimer's Disease, 89, 4, (1293-1302), (2022).https://doi.org/10.3233/JAD-220490
    Crossref
  6. High-Intense Interval Training Prevents Cognitive Impairment and Increases the Expression of Muscle Genes FNDC5 and PPARGC1A in a Rat Model of Alzheimer's Disease, Current Alzheimer Research, 19, 12, (830-840), (2022).https://doi.org/10.2174/1567205020666221207103109
    Crossref
  7. Is Evening Carbohydrate Intake in Healthy Individuals Associated with Higher Postprandial Glycemia and Insulinemia When Compared to Morning Intake? A Systematic Review and Meta-Analysis of Randomized Crossover Studies, Journal of the American Nutrition Association, 42, 4, (349-360), (2022).https://doi.org/10.1080/07315724.2022.2043199
    Crossref
  8. Prevention of Neurologic Disease with Fasting, Seminars in Neurology, 42, 05, (549-557), (2022).https://doi.org/10.1055/a-1957-8449
    Crossref
  9. Alteration in glucose metabolism in the brain associated with tamoxifen treatment: Study in postmenopausal animal model, Toxicology and Applied Pharmacology, 442, (116002), (2022).https://doi.org/10.1016/j.taap.2022.116002
    Crossref
  10. Inside the diabetic brain: Insulin resistance and molecular mechanism associated with cognitive impairment and its possible therapeutic strategies, Pharmacological Research, 182, (106358), (2022).https://doi.org/10.1016/j.phrs.2022.106358
    Crossref
  11. See more
Loading...

View Options

Get Access

Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Purchase Options

Purchase this article to get full access to it.

Purchase Access, $39 for 24hr of access

View options

Full Text

View Full Text

Full Text HTML

View Full Text HTML

Media

Figures

Other

Tables

Share

Share

Share article link

Share