Abstract
Preclinical studies demonstrate that generalized endothelial cell dysfunction and microvascular impairment are potentially reversible causes of age-related vascular cognitive impairment and dementia (VCID). The present study was designed to test the hypothesis that severity of age-related macro- and microvascular dysfunction measured in the peripheral circulation is an independent predictor of cognitive performance in older adults. In this study, we enrolled 63 healthy individuals into young (< 45 years old) and aged (> 65 years old) groups. We used principal component analysis (PCA) to construct a comprehensive peripheral vascular health index (VHI) encompassing peripheral microvascular reactivity, arterial endothelial function, and vascular stiffness, as a marker of aging-induced generalized vascular dysfunction. Peripheral macrovascular and microvascular endothelial function were assessed using flow-mediated dilation (FMD) and laser speckle contrast imaging tests. Pulse waveform analysis was used to evaluate the augmentation index (AIx), a measure of arterial stiffness. Cognitive function was measured using a panel of CANTAB cognitive tests, and PCA was then applied to generate a cognitive impairment index (CII) for each participant. Aged subjects exhibited significantly impaired macrovascular endothelial function (FMD, 5.6 ± 0.7% vs. 8.3 ± 0.6% in young, p = 0.0061), increased arterial stiffness (AIx 29.3 ± 1.8% vs 4.5 ± 2.6% in young, p < 0.0001), and microvascular dysfunction (2.8 ± 0.2 vs 3.4 ± 0.1-fold change of perfusion in young, p = 0.032). VHI showed a significant negative correlation with age (r = − 0.54, p < 0.0001) and CII significantly correlated with age (r = 0.79, p < 0.0001). VHI significantly correlated with the CII (r = − 0.46, p = 0.0003). A decline in peripheral vascular health may reflect generalized vascular dysfunction and predict cognitive impairment in older adults.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barcelos A, Lamas C, Tibirica E (2017) Evaluation of microvascular endothelial function in patients with infective endocarditis using laser speckle contrast imaging and skin video-capillaroscopy: research proposal of a case control prospective study. BMC Res Notes 10:342. https://doi.org/10.1186/s13104-017-2660-3
Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF Jr, Lehman BT, Fan S, Osypiuk E, Vita JA (2004) Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham heart study. Circulation 109:613–619. https://doi.org/10.1161/01.CIR.0000112565.60887.1E
Berni A, Giuliani A, Tartaglia F, Tromba L, Sgueglia M, Blasi S, Russo G (2011) Effect of vascular risk factors on increase in carotid and femoral intima-media thickness. Identification of a risk scale. Atherosclerosis 216:109–114. https://doi.org/10.1016/j.atherosclerosis.2011.01.034
Boas DA, Dunn AK (2010) Laser speckle contrast imaging in biomedical optics. J Biomed Opt 15:011109. https://doi.org/10.1117/1.3285504
Briers D, Duncan DD, Hirst E, Kirkpatrick SJ, Larsson M, Steenbergen W, Stromberg T, Thompson OB (2013) Laser speckle contrast imaging: theoretical and practical limitations. J Biomed Opt 18:066018. https://doi.org/10.1117/1.JBO.18.6.066018
Butlin M, Qasem A (2017) Large artery stiffness assessment using SphygmoCor technology. Pulse (Basel) 4:180–192. https://doi.org/10.1159/000452448
Csipo T, Fulop GA, Lipecz A, Tarantini S, Kiss T, Balasubramanian P, Csiszar A, Ungvari Z, Yabluchanskiy A (2018) Short-term weight loss reverses obesity-induced microvascular endothelial dysfunction. Geroscience 40:337–346. https://doi.org/10.1007/s11357-018-0028-9
de M Matheus AS, Clemente EL, de Lourdes Guimaraes Rodrigues M, Torres Valenca DC, Gomes MB (2017) Assessment of microvascular endothelial function in type 1 diabetes using laser speckle contrast imaging. J Diabetes Complications 31:753–757. https://doi.org/10.1016/j.jdiacomp.2016.12.007
Garcia-Polite F, Martorell J, del Rey-Puech P, Melgar-Lesmes P, O’Brien CC, Roquer J, Ois A, Principe A, Edelman ER, Balcells M (2017) Pulsatility and high shear stress deteriorate barrier phenotype in brain microvascular endothelium. J Cereb Blood Flow Metab 37:2614–2625. https://doi.org/10.1177/0271678X16672482
Gioscia-Ryan RA, LaRocca TJ, Sindler AL, Zigler MC, Murphy MP, Seals DR (2014) Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice. J Physiol 592:2549–2561. https://doi.org/10.1113/jphysiol.2013.268680
Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S, American Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:2672–2713. https://doi.org/10.1161/STR.0b013e3182299496
Hammer Ø, Harper, D.A.T., Ryan, P.D. (2001) PAST: Paleontological statistics software package for education and data analysis Palaeontologia Electronica 1:9pp
Houben A, Martens RJH, Stehouwer CDA (2017) Assessing microvascular function in humans from a chronic disease perspective. J Am Soc Nephrol 28:3461–3472. https://doi.org/10.1681/ASN.2017020157
Iadecola C, Gottesman RF (2018) Cerebrovascular alterations in Alzheimer disease. Circ Res 123:406–408. https://doi.org/10.1161/CIRCRESAHA.118.313400
Khalil A, Humeau-Heurtier A, Mahe G, Abraham P (2015) Laser speckle contrast imaging: age-related changes in microvascular blood flow and correlation with pulse-wave velocity in healthy subjects. J Biomed Opt 20:051010. https://doi.org/10.1117/1.JBO.20.5.051010
Kim DH, Grodstein F, Newman AB, Chaves PHM, Odden MC, Klein R, Sarnak MJ, Patel KV, Lipsitz LA (2014) Prognostic implications of microvascular and macrovascular abnormalities in older adults: cardiovascular health study. J Gerontol A Biol Sci Med Sci 69:1495–1502. https://doi.org/10.1093/gerona/glu074
Kim DH, Grodstein F, Newman AB, Chaves PHM, Odden MC, Klein R, Sarnak MJ, Lipsitz LA (2015) Microvascular and macrovascular abnormalities and cognitive and physical function in older adults: cardiovascular health study. J Am Geriatr Soc 63:1886–1893. https://doi.org/10.1111/jgs.13594
Lobo A, Launer LJ, Fratiglioni L, Andersen K, di Carlo A, Breteler MM, Copeland JR, Dartigues JF, Jagger C, Martinez-Lage J, Soininen H, Hofman A (2000) Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurol Dis Elderly Res Group Neurol 54:S4–S9
Muris DM, Houben AJ, Schram MT, Stehouwer CD (2012) Microvascular dysfunction is associated with a higher incidence of type 2 diabetes mellitus: a systematic review and meta-analysis. Arterioscler Thromb Vasc Biol 32:3082–3094. https://doi.org/10.1161/ATVBAHA.112.300291
Oomen CA, Farkas E, Roman V, van der Beek EM, Luiten PG, Meerlo P (2009) Resveratrol preserves cerebrovascular density and cognitive function in aging mice. Front Aging Neurosci 1:4. https://doi.org/10.3389/neuro.24.004.2009
Pase MP, Beiser A, Himali JJ, Tsao C, Satizabal CL, Vasan RS, Seshadri S, Mitchell GF (2016) Aortic stiffness and the risk of incident mild cognitive impairment and dementia. Stroke 47:2256–2261. https://doi.org/10.1161/STROKEAHA.116.013508
Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157–168
Rabbitt P, Lowe C (2000) Patterns of cognitive ageing. Psychol Res 63:308–316
Smith PJ, Need AC, Cirulli ET, Chiba-Falek O, Attix DK (2013) A comparison of the Cambridge automated neuropsychological test battery (CANTAB) with “traditional” neuropsychological testing instruments. J Clin Exp Neuropsychol 35:319–328. https://doi.org/10.1080/13803395.2013.771618
Tarantini S, Hertelendy P, Tucsek Z, Valcarcel-Ares MN, Smith N, Menyhart A, Farkas E, Hodges EL, Towner R, Deak F, Sonntag WE, Csiszar A, Ungvari Z, Toth P (2015) Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice. J Cereb Blood Flow Metab 35:1871–1881. https://doi.org/10.1038/jcbfm.2015.162
Tarantini S, Tran CHT, Gordon GR, Ungvari Z, Csiszar A (2017) Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol 94:52–58. https://doi.org/10.1016/j.exger.2016.11.004
Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Fulop GA, Hertelendy P, Gautam T, Farkas E, Perz A, Rabinovitch PS, Sonntag WE, Csiszar A, Ungvari Z (2018) Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. Aging Cell 17:e12731. https://doi.org/10.1111/acel.12731
Thorin-Trescases N, de Montgolfier O, Pincon A, Raignault A, Caland L, Labbe P, Thorin E (2018) Impact of pulse pressure on cerebrovascular events leading to age-related cognitive decline. Am J Physiol Heart Circ Physiol 314:H1214–H1224. https://doi.org/10.1152/ajpheart.00637.2017
Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S, Deak F, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2013) Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab 33:1732–1742. https://doi.org/10.1038/jcbfm.2013.143
Toth P, Tarantini S, Tucsek Z, Ashpole NM, Sosnowska D, Gautam T, Ballabh P, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2014) Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and down-regulation of NADPH oxidas. Am J Physiol Heart Circ Physiol 306:H299–H308. https://doi.org/10.1152/ajpheart.00744.2013
Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, Menyhart A, Farkas E, Sonntag WE, Csiszar A, Ungvari Z (2015a) IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell 14:1034–1044. https://doi.org/10.1111/acel.12372
Toth P, Tarantini S, Davila A, Valcarcel-Ares MN, Tucsek Z, Varamini B, Ballabh P, Sonntag WE, Baur JA, Csiszar A, Ungvari Z (2015b) Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol 309:H1837–H1845. https://doi.org/10.1152/ajpheart.00463.2015
Toth P, Tarantini S, Csiszar A, Ungvari Z (2017) Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol 312:H1–H20. https://doi.org/10.1152/ajpheart.00581.2016
Tucsek Z, Toth P, Tarantini S, Sosnowska D, Gautam T, Warrington JP, Giles CB, Wren JD, Koller A, Ballabh P, Sonntag WE, Ungvari Z, Csiszar A (2014) Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci 69:1339–1352. https://doi.org/10.1093/gerona/glu080
Ungvari Z, Tarantini S, Kirkpatrick AC, Csiszar A, Prodan CI (2017) Cerebral microhemorrhages: mechanisms, consequences, and prevention. Am J Physiol Heart Circ Physiol 312:H1128–H1143. https://doi.org/10.1152/ajpheart.00780.2016
Ungvari Z, Tarantini S, Donato AJ, Galvan V, Csiszar A (2018) Mechanisms of vascular aging. Circ Res 123:849–867. https://doi.org/10.1161/CIRCRESAHA.118.311378
Wild K, Howieson D, Webbe F, Seelye A, Kaye J (2008) Status of computerized cognitive testing in aging: a systematic review. Alzheimers Dement 4:428–437. https://doi.org/10.1016/j.jalz.2008.07.003
Funding
This work was supported by grants from the American Heart Association (ST, ZU, and AC), the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, ZU), the National Center for Complementary and Alternative Medicine (R01-AT006526 to ZU), the National Institute on Aging (R01-AG055395, R01-AG047879; R01-AG038747), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS100782, R01-NS056218), the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (U54GM104938, to AY), the Presbyterian Health Foundation (to ZU, AC, AY), and the EU-funded Hungarian grant EFOP-3.6.1-16-2016-00008. The authors was supported by the NIA/NIH-funded Geroscience Training Program in Oklahoma (T32AG052363) and the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Supplemental Figure 1
A) Eigenvalues of the principal component solution for the vascular health characterization studies. The eigenvalues are relative to physiological variables correlation matrix. The variables are normalized to unit variance so that the sum of the eigenvalues is equal to the number of variables. B) Correlation coefficients (factor loadings) between original physiological variables and scores of the first principal component. (PPTX 97 kb)
Supplemental Figure 2
A) Eigenvalues of the principal component solution for the CANTAB cognitive tests. B) Correlation coefficients (factor loadings) between original cognitive test variables and scores of the first principal component. (PPTX 118 kb)
About this article
Cite this article
Csipo, T., Lipecz, A., Fulop, G.A. et al. Age-related decline in peripheral vascular health predicts cognitive impairment. GeroScience 41, 125–136 (2019). https://doi.org/10.1007/s11357-019-00063-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-019-00063-5