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Cerebrospinal fluid levels of Alzheimer’s disease biomarkers in middle-aged patients with type 1 diabetes

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Abstract

Aims/hypothesis

Type 1 diabetes is associated with moderate cognitive decline and cerebral alterations and may lead to an increased risk of dementia, including Alzheimer’s disease. This study aimed to investigate the levels of risk markers for Alzheimer’s disease in middle-aged patients with type 1 diabetes and controls, and their potential associations with cognitive and cerebral measures.

Methods

Levels of β-amyloid (Aβ) 42, Tau, phosphorylated Tau (pTau), the soluble form of low-density lipoprotein receptor-related protein 1 (sLRP1) and macrophage colony-stimulating factor (MCSF) were quantified by ELISA in serum and cerebrospinal fluid (CSF) collected from 37 patients with type 1 diabetes and 15 controls. Associations between biomarkers and determinants of cognitive function and white matter integrity were assessed using hierarchical regression analysis controlling for age, HbA1c and estimated intelligence quotient (IQ).

Results

CSF levels of pTau, Aβ42 and LRP1 were higher in patients with type 1 diabetes than in controls (all p < 0.05). There was a trend towards increased Tau levels in patients with type 1 diabetes (p = 0.056), while CSF levels of MCSF were similar between patients with type 1 diabetes and controls. Regression analysis showed that elevated CSF sLRP1 levels were associated with better attention (β = 0.518; p = 0.002) and a better speed of information-processing (β = 0.368; p = 0.034), as well as increased integrity of the white matter of the right inferior fronto-occipital tract (β = 0.395; p = 0.022). Furthermore, elevated Tau levels were associated with decreased integrity of the white matter of right inferior fronto-occipital tract (β = –0.584; p = 0.002).

Conclusions/interpretation

CSF levels of biomarkers for Alzheimer’s disease are altered in patients with type 1 diabetes compared with controls, but the observed profile does not match the profile characterising pre-Alzheimer’s disease patients.

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Abbreviations

Aβ:

β-Amyloid

ApoE:

Apolipoprotein E

CSF:

Cerebrospinal fluid

IQ:

Intelligence quotient

LRP1:

Low-density lipoprotein receptor-related protein 1

MCSF:

Macrophage colony-stimulating factor

pTau:

Phosphorylated Tau

RAGE:

Receptor for advanced glycation end-products

sLRP1:

Soluble form of low-density lipoprotein receptor-related protein 1

sRAGE:

Soluble form of receptor for advanced glycation end-products

References

  1. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P (2006) Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 5:64–74

    Article  PubMed  Google Scholar 

  2. Brands AM, Biessels GJ, de Haan EH, Kappelle LJ, Kessels RP (2005) The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes Care 28:726–735

    Article  PubMed  Google Scholar 

  3. van Duinkerken E, Klein M, Schoonenboom NS et al (2009) Functional brain connectivity and neurocognitive functioning in patients with long-standing type 1 diabetes with and without microvascular complications: a magnetoencephalography study. Diabetes 58:2335–2343

    Article  PubMed Central  PubMed  Google Scholar 

  4. van Duinkerken E, Schoonheim MM, Ijzerman RG et al (2012) Diffusion tensor imaging in type 1 diabetes: decreased white matter integrity relates to cognitive functions. Diabetologia 55:1218–1220

    Article  PubMed Central  PubMed  Google Scholar 

  5. van Duinkerken E, Schoonheim MM, Sanz-Arigita EJ et al (2012) Resting-state brain networks in type 1 diabetic patients with and without microangiopathy and their relation to cognitive functions and disease variables. Diabetes 61:1814–1821

    Article  PubMed Central  PubMed  Google Scholar 

  6. Sims-Robinson C, Kim B, Rosko A, Feldman EL (2010) How does diabetes accelerate Alzheimer disease pathology? Nat Rev Neurol 6:551–559

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Blennow K, Hampel H (2003) CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2:605–613

    Article  CAS  PubMed  Google Scholar 

  8. Bell RD (2012) The imbalance of vascular molecules in Alzheimer’s disease. J Alzheimers Dis 32:699–709

    PubMed  Google Scholar 

  9. Du Yan S, Zhu H, Fu J et al (1997) Amyloid-beta peptide-receptor for advanced glycation endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease. Proc Natl Acad Sci U S A 94:5296–5301

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Bouwman FH, Schoonenboom SN, van der Flier WM et al (2007) CSF biomarkers and medial temporal lobe atrophy predict dementia in mild cognitive impairment. Neurobiol Aging 28:1070–1074

    Article  CAS  PubMed  Google Scholar 

  11. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L (2006) Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 5:228–234

    Article  CAS  PubMed  Google Scholar 

  12. Kester MI, van der Flier WM, Mandic G, Blankenstein MA, Scheltens P, Muller M (2010) Joint effect of hypertension and APOE genotype on CSF biomarkers for Alzheimer’s disease. J Alzheimers Dis 20:1083–1090

    CAS  PubMed  Google Scholar 

  13. de Jong D, Jansen RW, Kremer BP, Verbeek MM (2006) Cerebrospinal fluid amyloid beta42/phosphorylated tau ratio discriminates between Alzheimer’s disease and vascular dementia. J Gerontol A Biol Sci Med Sci 61:755–758

    Article  PubMed  Google Scholar 

  14. Mattsson N, Zetterberg H, Hansson O et al (2009) CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 302:385–393

    Article  CAS  PubMed  Google Scholar 

  15. Mulder C, Verwey NA, van der Flier WM et al (2010) Amyloid-beta(1–42), total tau, and phosphorylated tau as cerebrospinal fluid biomarkers for the diagnosis of Alzheimer disease. Clin Chem 56:248–253

    Article  CAS  PubMed  Google Scholar 

  16. Watson GS, Peskind ER, Asthana S et al (2003) Insulin increases CSF Abeta42 levels in normal older adults. Neurology 60:1899–1903

    Article  CAS  PubMed  Google Scholar 

  17. Kim B, Backus C, Oh S, Hayes JM, Feldman EL (2009) Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology 150:5294–5301

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Liu F, Shi J, Tanimukai H et al (2009) Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. Brain 132:1820–1832

    Article  PubMed Central  PubMed  Google Scholar 

  19. Deane R, Bell RD, Sagare A, Zlokovic BV (2009) Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer’s disease. CNS Neurol Disord Drug Targets 8:16–30

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Deane R, Du Yan S, Submamaryan RK et al (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9:907–913

    Article  CAS  PubMed  Google Scholar 

  21. Sagare A, Deane R, Bell RD et al (2007) Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med 13:1029–1031

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Sagare AP, Deane R, Zetterberg H, Wallin A, Blennow K, Zlokovic BV (2011) Impaired lipoprotein receptor-mediated peripheral binding of plasma amyloid-beta is an early biomarker for mild cognitive impairment preceding Alzheimer’s disease. J Alzheimers Dis 24:25–34

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Jaeger LB, Dohgu S, Hwang MC et al (2009) Testing the neurovascular hypothesis of Alzheimer’s disease: LRP-1 antisense reduces blood-brain barrier clearance, increases brain levels of amyloid-beta protein, and impairs cognition. J Alzheimers Dis 17:553–570

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Shi YM, Zhou H, Zhang ZJ et al (2009) Association of the LRP1 gene and cognitive performance with amnestic mild cognitive impairment in elderly Chinese. Int Psychogeriatr 21:1072–1080

    Article  PubMed  Google Scholar 

  25. Li G, Millard SP, Peskind ER et al (2014) Cross-sectional and longitudinal relationships between cerebrospinal fluid biomarkers and cognitive function in people without cognitive impairment from across the adult life span. JAMA Neurol 71:742–751

    Article  PubMed  Google Scholar 

  26. Heine RJ, Yki-Jarvinen H, Kahn SE, van Raalte DH (2014) In Memoriam: Michaela Diamant, 11 April 1962–9 April 2014. Diabetologia 57:1271

    Article  PubMed  Google Scholar 

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Acknowledgements

During the review process of this paper, professor Michaela Diamant passed away at the age of only 51 years. She was principal investigator and driving force of this study. This paper is dedicated to her memory. Please see her obituary in Diabetologia [26].

Funding

This study was supported by grant 2006.00.051 of the Dutch Diabetes Research Foundation, by a grant of the European Foundation for the Study of Diabetes, and by the Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW) and the German Federal Ministry of Health (BMG).

Duality of interest

CET is member of the medical advisory boards of Innogenetics and Roche. The other authors declare that they have no conflicts of interest regarding the study.

Contribution statement

DMO wrote and drafted the manuscript and participated in biomarker determinations and data analysis. EvD wrote and drafted the manuscript, participated in the design of the study, was responsible for participant recruitment and performed the statistical analysis. SNMS and LvG contributed to the data acquisition by performing the lumbar punctures by which CSF was obtained, and reviewed the manuscript. DHW performed biomarker analyses and reviewed the manuscript. ACM, FJS, MK, FB and PS participated in the design of the study and reviewed the manuscript. CET participated in the design and supervised the CSF analyses of Aβ42, Tau and pTau, and reviewed the manuscript. PJWP participated in the design of the white matter integrity analyses, supervised these analyses, interpreted the data and reviewed the manuscript. MD designed the study, obtained funding and reviewed the manuscript. All authors approved the final version of the manuscript. DMO and EvD are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Author information

Authors and Affiliations

  1. Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Centre, Auf’m Hennekamp 65, 40225, Düsseldorf, Germany

    D. Margriet Ouwens & Daniella Herzfeld de Wiza

  2. Department of Endocrinology, Ghent University Hospital, Ghent, Belgium

    D. Margriet Ouwens

  3. Department of Internal Medicine/Diabetes Centre, VU University Medical Centre, Amsterdam, the Netherlands

    Eelco van Duinkerken, Larissa van Golen & Michaela Diamant

  4. Department of Medical Psychology, VU University Medical Centre, Amsterdam, the Netherlands

    Eelco van Duinkerken, Martin Klein & Frank J. Snoek

  5. Department of Neurology, VU University Medical Centre, Amsterdam, the Netherlands

    S. Niki M. Schoonenboom & Philip Scheltens

  6. Department of Physics and Medical Technology, VU University Medical Centre, Amsterdam, the Netherlands

    Petra J. W. Pouwels

  7. Department of Radiology and Nuclear Medicine, VU University Medical Centre, Amsterdam, the Netherlands

    Frederik Barkhof

  8. Department of Ophthalmology, VU University Medical Centre, Amsterdam, the Netherlands

    Annette C. Moll

  9. Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, the Netherlands

    Charlotte E. Teunissen

Authors
  1. D. Margriet Ouwens
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  2. Eelco van Duinkerken
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  3. S. Niki M. Schoonenboom
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  4. Daniella Herzfeld de Wiza
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  5. Martin Klein
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  6. Larissa van Golen
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  7. Petra J. W. Pouwels
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  8. Frederik Barkhof
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  9. Annette C. Moll
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  10. Frank J. Snoek
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  11. Charlotte E. Teunissen
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  12. Philip Scheltens
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  13. Michaela Diamant
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Corresponding author

Correspondence to D. Margriet Ouwens.

Additional information

M. Ouwens and E. van Duinkerken contributed equally to this study.

This paper is dedicated to the memory of Professor Michaela Diamant.

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Ouwens, D.M., van Duinkerken, E., Schoonenboom, S.N.M. et al. Cerebrospinal fluid levels of Alzheimer’s disease biomarkers in middle-aged patients with type 1 diabetes. Diabetologia 57, 2208–2214 (2014). https://doi.org/10.1007/s00125-014-3333-6

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  • DOI: https://doi.org/10.1007/s00125-014-3333-6

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