Skip to main content

Advertisement

SpringerLink
Log in

Impact of the AGTR1 A1166C polymorphism on subcortical hyperintensities and cognition in healthy older adults

  • Published:
AGE Aims and scope Submit manuscript

Abstract

Vascular aging consists of complex and multifaceted processes that may be influenced by genetic polymorphisms of the renin-angiotensin system. A polymorphism in the angiotensin II type 1 receptor gene (AGTR1/rs5186) has been associated with an increased risk for arterial stiffness, hypertension, and ischemic stroke. Despite these identified relationships, the impact of AGTR1 A1166C on white matter integrity and cognition is less clear in a healthy aging population. The present study utilized indices of neuroimaging and neuropsychological assessment to examine the impact of the A1166C polymorphism on subcortical hyperintensities (SH) and cognition in 49 healthy adults between ages 51–85. Using a dominant statistical model (CC + CA (risk) vs. AA), results revealed significantly larger SH volume for individuals with the C1166 variant (p < 0.05, partial eta2 = 0.117) compared with those with the AA genotype. Post hoc analyses indicated that increased SH volume in C allele carriers could not be explained by vascular factors such as pulse pressure or body mass index. In addition, cognitive performance did not differ significantly between groups and was not significantly associated with SH in this cohort. Results suggest that presence of the C1166 variant may serve as a biomarker of risk for suboptimal brain integrity in otherwise healthy older adults prior to changes in cognition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ando H, Zhou J, Macova M, Imboden H, Saavedra JM (2004) Angiotensin II AT1 receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive rats. Stroke 35(7):1726–1731

    Article  CAS  PubMed  Google Scholar 

  • Bigler ED, Neeley ES, Miller MJ, Tate DF, Rice SA, Cleavinger H et al (2004) Cerebral volume loss, cognitive deficit and neuropsychological performance: comparative measures of brain atrophy: I. Dementia. J Int Neuropsychol Soc 10(03):442–452

    PubMed  Google Scholar 

  • Ceolotto G, Papparella I, Bortoluzzi A, Strapazzon G, Ragazzo F, Bratti P et al (2010) Interplay between miR-155, AT1R A1166C polymorphism, and AT1R expression in young untreated hypertensives. Am J Hypertens 24(2):241–246

    Article  PubMed  Google Scholar 

  • Cook IA, Leuchter AF, Morgan ML, Dunkin JJ, Witte E, David S et al (2004) Longitudinal progression of subclinical structural brain disease in normal aging. Am J Geriatr Psychiatr 12(2):190–200

    Article  Google Scholar 

  • Diz DI, Arnold AC, Nautiyal M, Isa K, Shaltout HA, Tallant E (2011) Angiotensin peptides and central autonomic regulation. Curr Opin Pharmacol 11(2):131–137

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Duff K, Patton D, Schoenberg MR, Mold J, Scott JG, Adams RL (2003) Age-and education-corrected independent normative data for the RBANS in a community dwelling elderly sample. Clin Neuropsychol 17(3):351–366

    Article  PubMed  Google Scholar 

  • Duff K, Langbehn DR, Schoenberg MR, Moser DJ, Baade LE, Mold J et al (2006) Examining the repeatable battery for the assessment of neuropsychological status: factor analytic studies in an elderly sample. Am J Geriatr Psych 14(11):976–979

    Article  Google Scholar 

  • Duncan JA, Scholey JW, Miller JA (2001) Angiotensin II type 1 receptor gene polymorphisms in humans: physiology and pathophysiology of the genotypes. Curr Opin Nephrol Hypertens 10(1):111–116

    Article  CAS  PubMed  Google Scholar 

  • Ebrahimi AP (2009) Mechanical properties of normal and diseased cerebrovascular system. J Vasc Int Neurol 2(2):155

    Google Scholar 

  • Gontkovsky ST, Beatty WW, Mold JW (2004) Repeatable battery for the assessment of neuropsychological status in a normal, geriatric sample. Clin Gerontol 27(3):79–86

    Article  Google Scholar 

  • Gorelick PB, Scuteri A, Black SE, DeCarli C, Greenberg SM, Iadecola C et al (2011) Vascular contributions to cognitive impairment and dementia a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42(9):2672–2713

    Article  PubMed Central  PubMed  Google Scholar 

  • Gunning-Dixon FM, Raz N (2000) The cognitive correlates of white matter abnormalities in normal aging: a quantitative review. Neuropsychol 14(2):224

    Article  CAS  Google Scholar 

  • Haas U, Sczakiel G, Laufer SD (2012) MicroRNA-mediated regulation of gene expression is affected by disease-associated SNPs within the 3′-UTR via altered RNA structure. RNA Biol 9(6):924–937

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hajnal JV, Bryant DJ, Kasuboski L, Pattany PM, De Coene B, Lewis PD et al (1992) Use of fluid attenuated inversion recovery (FLAIR) pulse sequences in MRI of the brain. J Comp Assist Tomogr 16(6):841–844

    Article  CAS  Google Scholar 

  • Haley AP, Forman DE, Poppas A, Hoth KF, Gunstad J, Jefferson AL et al (2007) Carotid artery intima-media thickness and cognition in cardiovascular disease. Int J Cardiol 121(2):148–154

    Article  PubMed Central  PubMed  Google Scholar 

  • Jefferson AL, Tate DF, Poppas A, Brickman AM, Paul RH, Gunstad J, Cohen RA (2007) Lower cardiac output is associated with greater white matter hyperintensities in older adults with cardiovascular disease. J Am Geriatr Soc 55(7):1044–1048

    Article  PubMed Central  PubMed  Google Scholar 

  • Kramer JH, Mungas D, Reed BR, Wetzel ME, Burnett MM, Miller BL et al (2007) Longitudinal MRI and cognitive change in healthy elderly. Neuropsychol 21(4):412

    Article  Google Scholar 

  • Kuo HK, Chen CY, Liu HM, Yen CJ, Chang KJ, Chang CC et al (2010) Metabolic risks, white matter hyperintensities, and arterial stiffness in high-functioning healthy adults. Int J Cardiol 143(2):184–191

    Article  PubMed  Google Scholar 

  • Lakatta EG (2002) Age-associated cardiovascular changes in health: impact on cardiovascular disease in older persons. Heart Fail Rev 7(1):29–49

    Article  PubMed  Google Scholar 

  • Lane EM, Paul RH, Moser DJ, Fletcher TD, Cohen RA (2011) Influence of education on subcortical hyperintensities and global cognitive status in vascular dementia. J Int Neuropsychol Soc 17(03):531–536

    Article  PubMed  Google Scholar 

  • Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D et al (2006) Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 27(21):2588–2605

    Article  PubMed  Google Scholar 

  • Lawton MP, Brody EM (1969) Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontol 9(3):179–186

    Article  CAS  Google Scholar 

  • McKinley MJ, Albiston AL, Allen AM, Mathai ML, May CN, McAllen RM et al (2003) The brain renin–angiotensin system: Location and physiological roles. Int J Biochem Cell Biol 35(6):901–918

    Article  CAS  PubMed  Google Scholar 

  • Natale F, Tedesco MA, Mocerino R, de Simone V, Di Marco GM, Aronne L et al (2009) Visceral adiposity and arterial stiffness: Echocardiographic epicardial fat thickness reflects, better than waist circumference, carotid arterial stiffness in a large population of hypertensives. Eur J Echocardio 10(4):549–555

    Article  Google Scholar 

  • Nation DA, Wierenga CE, Delano-Wood L, Jak AJ, Delis DC, Salmon DP, Bondi MW (2010) Elevated pulse pressure is associated with age-related decline in language ability. J Int Neuropsychol Soc 16(5):933

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nilsson PM, Lurbe E, Laurent S (2008) The early life origins of vascular ageing and cardiovascular risk: The EVA syndrome. J Hypertens 26(6):1049–1057

    Article  CAS  PubMed  Google Scholar 

  • Nishimura H (2001) Angiotensin receptors—evolutionary overview and perspectives. Comp Biochem Physiol, Part A: Mol Integr Physiol 128(1):11–30

    Article  CAS  Google Scholar 

  • Opherk C, Gonik M, Duering M, Malik R, Jouvent E, Hervé D et al (2014) Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL. Stroke 45(4):968–972

    Article  PubMed  Google Scholar 

  • Pacholczyk M, Ferenc T, Kowalski J, Adamczyk P, Chojnowski J, Ponikowska I (2013) Association of angiotensin-converting enzyme and angiotensin II type I receptor gene polymorphisms with extreme obesity in polish individuals. DNA and Cell Biology

  • Paul RH, Haque O, Gunstad J, Tate DF, Grieve SM, Hoth K et al (2005) Subcortical hyperintensities impact cognitive function among a select subset of healthy elderly. Arch Clin Neuropsychol 20(6):697–704

    Article  PubMed Central  PubMed  Google Scholar 

  • Paul R, Lane EM, Tate DF, Heaps J, Romo DM, Akbudak E et al (2011) Neuroimaging signatures and cognitive correlates of the Montreal cognitive assessment screen in a nonclinical elderly sample. Arch Clin Neuropsychol 26(5):454–460

    Article  PubMed Central  PubMed  Google Scholar 

  • Putzke JD, Williams MA, Rayburn BK, Kirklin JK, Boll TJ (1998) The relationship between cardiac function and neuropsychological status among heart transplant candidates. J Cardiac Fail 4(4):295–303

    Article  CAS  Google Scholar 

  • Randolph C (1998) RBANS manual: repeatable battery for the assessment of neuropsychological status. The Psychological Corporation, San Antonio, TX

  • Saavedra JM (2005) Brain angiotensin II: new developments, unanswered questions and therapeutic opportunities. Cell Mol Neurobiol 25(3–4):485–512

    Article  CAS  PubMed  Google Scholar 

  • Saavedra JM, Benicky J, Zhou J (2006) Mechanisms of the anti-ischemic effect of angiotensin II AT 1 receptor antagonists in the brain. Cell Mol Neurobiol 26(7–8):1097–1109

    Article  Google Scholar 

  • Saavedra JM, Sánchez-Lemus E, Benicky J (2011) Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: therapeutic implications. Psychoneuroendocrinol 36(1):1–18

    Article  CAS  Google Scholar 

  • Safar ME, Blacher J, Mourad JJ, London GM (2000) Stiffness of carotid artery wall material and blood pressure in humans: application to antihypertensive therapy and stroke prevention. Stroke 31(3):782–790

    Article  CAS  PubMed  Google Scholar 

  • Sanfilipo MP, Benedict RH, Zivadinov R, Bakshi R (2004) Correction for intracranial volume in analysis of whole brain atrophy in multiple sclerosis: the proportion vs. residual method. Neuroimage 22(4):1732–1743

    Article  PubMed  Google Scholar 

  • Saxby BK, Harrington F, McKeith IG, Wesnes K, Ford GA (2003) Effects of hypertension on attention, memory, and executive function in older adults. Health Psychol 22(6):587

    Article  PubMed  Google Scholar 

  • Schmidt R, Schmidt H, Haybaeck J, Loitfelder M, Weis S, Cavalieri M et al (2011) Heterogeneity in age-related white matter changes. Acta Neuropatholog 122(2):171–185

    Article  Google Scholar 

  • Sethupathy P, Borel C, Gagnebin M, Grant GR, Deutsch S, Elton TS et al (2007) Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the <i> AGTR1</i> 3′ untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes. Am J Hum Genet 81(2):405–413

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sierra C, Coca A, Schiffrin EL (2011) Vascular mechanisms in the pathogenesis of stroke. Cur Hypertens Rep 13(3):200–207

    Article  CAS  Google Scholar 

  • Söderlund H, Nyberg L, Adolfsson R, Nilsson LG, Launer LJ (2003) High prevalence of white matter hyperintensities in normal aging: relation to blood pressure and cognition. Cortex 39(4):1093–1105

  • Strazzullo P, D'Elia L, Cairella G, Garbagnati F, Cappuccio FP, Scalfi L (2010) Excess body weight and incidence of stroke meta-analysis of prospective studies with 2 million participants. Stroke 41(5):e418–e426

    Article  PubMed  Google Scholar 

  • Tate DF, Khedraki R, Neeley ES, Ryser DK, Bigler ED (2011) Cerebral volume loss, cognitive deficit, and neuropsychological performance: comparative measures of brain atrophy: II. Traumatic brain injury. J Int Neuropsychol Soc 17(02):308–316

    Article  PubMed  Google Scholar 

  • Taylor WD, Steffens DC, Ashley-Koch A, Payne ME, MacFall JR, Potocky CF, Krishnan KRR (2009) Angiotensin receptor gene polymorphisms and 2-year change in hyperintense lesion volume in men. Mol Psychiatr 15(8):816–822

    Article  Google Scholar 

  • Taylor WD, Zhao Z, Ashley Koch A, Payne ME, Steffens DC, Krishnan RR, MacFall JR (2013) Fiber tract specific white matter lesion severity: findings in late life depression and by AGTR1 A1166C genotype. Hum Brain Map 34(2):295–303

    Article  Google Scholar 

  • Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H et al (2010) Fat tissue, aging, and cellular senescence. Aging Cell 9(5):667–684

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Thalmann S, Meier CA (2007) Local adipose tissue depots as cardiovascular risk factors. Cardiovasc Res 75(4):690–701

    Article  CAS  PubMed  Google Scholar 

  • Verstynen TD, Weinstein AM, Schneider WW, Jakicic JM, Rofey DL, Erickson KI (2012) Increased body mass index is associated with a global and distributed decrease in white matter microstructural integrity. Psychosomat Med 74(7):682–690

    Article  Google Scholar 

  • Zieman SJ, Melenovsky V, Kass DA (2005) Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler, Thromb, Vasc Biol 25(5):932–943

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was financially supported by National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) grants R01 NS052470 and R01 NS039538, NIH/National Institute of Mental Health (NIMH) grant R21 MH090494, and Australian National Health and Medical Research Council (NHMRC) grant 1037196. DNA extractions were performed by Genetic Repositories Australia, an Enabling Facility, which is supported by NHMRC grant (401184). Recruitment database searches were supported in part by NIH/National Center for Research Resources (NCRR) grant UL1 TR000448.

Conflict of interest

There are no actual or potential conflicts of interest for any of the authors on this manuscript.

Author information

Authors and Affiliations

  1. Department of Psychology, University of Missouri-Saint Louis, 1 University Boulevard, Stadler Hall 442 A, St. Louis, MO, 63121, USA

    Lauren E. Salminen, Jodi M. Heaps, Jacob D. Bolzenius, Laurie M. Baker & Robert H. Paul

  2. Neuroscience Research Australia, Barker Street Randwick, Sydney, NSW, 2031, Australia

    Peter R. Schofield & Kerrie D. Pierce

  3. School of Medical Sciences, University of New South Wales, Sydney, NSW, 2052, Australia

    Peter R. Schofield

  4. Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway, St. Louis, MO, 63110, USA

    Thomas E. Conturo & Erbil Akbudak

  5. San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam, Houston, TX, 78234-6200, USA

    David F. Tate

  6. Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA

    Elizabeth M. Lane

Authors
  1. Lauren E. Salminen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter R. Schofield
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kerrie D. Pierce
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas E. Conturo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David F. Tate
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elizabeth M. Lane
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jodi M. Heaps
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jacob D. Bolzenius
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Laurie M. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Erbil Akbudak
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Robert H. Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lauren E. Salminen.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salminen, L.E., Schofield, P.R., Pierce, K.D. et al. Impact of the AGTR1 A1166C polymorphism on subcortical hyperintensities and cognition in healthy older adults. AGE 36, 9664 (2014). https://doi.org/10.1007/s11357-014-9664-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11357-014-9664-x

Keywords

Search

Navigation