Childhood Hypertension and Effects on Cognitive Functions: Mechanisms and Future Perspectives

Author(s): Emma Tyner, Marie Oropeza, Johnny Figueroa, Ike C. dela Peña*.

Journal Name: CNS & Neurological Disorders - Drug Targets
(Formerly Current Drug Targets - CNS & Neurological Disorders)

Volume 18 , Issue 9 , 2019

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Graphical Abstract:


Abstract:

Pediatric hypertension is currently one of the most common health concerns in children, given its effects not only on cardiovascular but also cognitive functions. There is accumulating evidence suggesting neurocognitive dysfunction in hypertensive children that could persist even into adulthood. Identifying the precise mechanism(s) underlying the association between childhood hypertension and cognitive dysfunction is crucial as it could potentially lead to the discovery of “druggable” biological targets facilitating the development of treatments. Here, we discuss some of the proposed pathophysiological mechanisms underlying childhood hypertension and cognitive deficits and suggest strategies to address some of the current challenges in the field. The various research studies involving hypertensive adults indicate that long-term hypertension may produce abnormal cerebrovascular reactivity, chronic inflammation, autonomic dysfunction, or hyperinsulinemia and hypercholesterolemia, which could lead to alterations in the brain’s structure and functions, resulting in cognitive dysfunction. In light of the current literature, we propose that dysregulation of the hypothalamus-pituitaryadrenal axis, modifications in endothelial brain-derived neurotrophic factor and the gut microbiome may also modulate cognitive functions in hypertensive individuals. Moreover, the above-mentioned pathological states may further intensify the detrimental effects of hypertension on cognitive functions. Thus, treatments that target not only hypertension but also its downstream effects may prove useful in ameliorating hypertension-induced cognitive deficits.

Much remains to be clarified about the mechanisms and treatments of hypertension-induced cognitive outcomes in pediatric populations. Addressing the knowledge gaps in this field entails conducting not only clinical research but also rigorous basic and translational studies.

Keywords: Childhood hypertension, cognitive dysfunction, cerebrovascular reactivity, inflammation, hyperinsulinemia, gut dysbiosis, endothelial brain-derived neurotrophic factor, hypothalamus-pituitary-adrenal axis.

[1]
Bell CS, Samuel JP, Samuels JA. Prevalence of hypertension in children. Hypertension 2019; 73(1): 148-52.
[2]
Sharma M, Kupferman JC, Brosgol Y, et al. The effects of hypertension on the paediatric brain: A justifiable concern. Lancet Neurol 2010; 9(9): 933-40.
[3]
Cheung EL, Bell CS, Samuel JP, Poffenbarger T, Redwine KM, Samuels JA. Race and obesity in adolescent hypertension. Pediatrics 2017; 139(5) e20161433
[4]
Wühl E. Hypertension in childhood obesity. Acta Paediatr 2019; 108(1): 37-43.
[5]
Brady TM. The role of obesity in the development of left ventricular hypertrophy among children and adolescents. Curr Hypertens Rep 2016; 18(1): 3.
[6]
Lande MB, Batisky DL, Kupferman JC, et al. Neurocognitive function in children with primary hypertension. J Pediatr 2017; 180: 148-55. e1.
[7]
Lande MB, Adams HR, Kupferman JC, Hooper SR, Szilagyi PG, Batisky DL. A multicenter study of neurocognition in children with hypertension: Methods, challenges, and solutions. J Am Soc Hypertens 2013; 7(5): 353-62.
[8]
Shatat IF, Brady TM. Editorial: Pediatric hypertension: Update. Frontier Pediatr 2018; 6: 209.
[9]
Riley M, Hernandez AK, Kuznia AL. High blood pressure in children and adolescents. Am Fam Physician 2018; 98(8): 486-94.
[10]
Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity among adults and youth: United States, 2015-2016. NCHS Data Brief 2017; (288): 1-8.
[11]
Rao G. Diagnosis, epidemiology, and management of hypertension in children. Pediatrics 2016; 138(2): e20153616
[12]
Bucher BS, Ferrarini A, Weber N, Bullo M, Bianchetti MG, Simonetti GD. Primary hypertension in childhood. Curr Hypertens Rep 2013; 15(5): 444-52.
[13]
Re RN. Obesity-related hypertension. Ochsner J 2009; 9(3): 133-6.
[14]
Leggio M, Lombardi M, Caldarone E, et al. The relationship between obesity and hypertension: An updated comprehensive overview on vicious twins. Hypertens Res 2017; 40(12): 947.
[15]
Falkner B. Hypertension in children and adolescents: Epidemiology and natural history. Pediatr Nephrol 2010; 25(7): 1219-24.
[16]
Urbina EM, Khoury PR, McCoy C, Daniels SR, Kimball TR, Dolan LM. Cardiac and vascular consequences of prehypertension in youth. J Clin Hypertens 2011; 13(5): 332-42.
[17]
Lande MB, Kupferman JC. Blood pressure and cognitive function in children and adolescents. Hypertension 2019; 73(3): 532-40.
[18]
Kupferman JC, Lande MB, Adams HR, Pavlakis SG. Primary hypertension and neurocognitive and executive functioning in school-age children. Pediatr Nephrol 2013; 28(3): 401-8.
[19]
Lande MB, Kaczorowski JM, Auinger P, Schwartz GJ, Weitzman M. Elevated blood pressure and decreased cognitive function among school-age children and adolescents in the United States. J Pediatr 2003; 143(6): 720-4.
[20]
Lamballais S, Sajjad A, Leening MJG, et al. Association of blood pressure and arterial stiffness with cognition in 2 population-based child and adult cohorts. J Am Heart Assoc 2018; 7(21) e009847-e.
[21]
Ditto B, Séguin JR, Tremblay RE. Neuropsychological characteristics of adolescent boys differing in risk for high blood pressure. Ann Behav Med 2006; 31(3): 231-7.
[22]
Yaffe K, Vittinghoff E, Pletcher MJ, et al. Early adult to midlife cardiovascular risk factors and cognitive function. Circulation 2014; 129(15): 1560-7.
[23]
Schulte EE. Learning disorders: How pediatricians can help. Cleve Clin J Med 2015; 82(11)(Suppl. 1): S24-8.
[24]
Adams HR, Szilagyi PG, Gebhardt L, Lande MB. Learning and attention problems among children with pediatric primary hypertension. Pediatrics 2010; 126(6): e1425-9.
[25]
Krause I, Cleper R, Kovalski Y, Sinai L, Davidovits M. Changes in behavior as an early symptom of renovascular hypertension in children. Pediatr Nephrol 2009; 24(11): 2271-4.
[26]
Figaji AA. Anatomical and physiological differences between children and adults relevant to traumatic brain injury and the implications for clinical assessment and care. Front Neurol 2017; 8: 685.
[27]
Shukla V, Shakya AK, Perez-Pinzon MA, Dave KR. Cerebral ischemic damage in diabetes: An inflammatory perspective. J Neuroinflamm 2017; 14(1): 21.
[28]
Gund B, Jagtap P, Ingale V, Patil R. Stroke: A brain attack. IOSR J Pharm 2013; 3(8): 1-23.
[29]
South Carolina Department of Health and Environmental Control; American Heart Association. What is high blood pressure? South Carolina State Documents Depository, 2017. Available at:. http://DHEC_What_is_High_Blood_Pressure_Medicine_2017-07.pdf
[30]
Jennings JR. Autoregulation of blood pressure and thought: Preliminary results of an application of brain imaging to psychosomatic medicine. Psychosom Med 2003; 65(3): 384-95.
[31]
Balea M, Muresanu D, Alvarez A, et al. VaD - an integrated framework for cognitive rehabilitation. CNS Neurol Disord Drug Targets 2018; 17(1): 22-33.
[32]
Cha SD, Patel HP, Hains DS, Mahan JD. The effects of hypertension on cognitive function in children and adolescents. Int J Pediatr 2012; 2012: 891094
[33]
Pauletto P, Rattazzi M. Inflammation and hypertension: The search for a link. Nephrol Dial Transplant 2006; 21(4): 850-3.
[34]
Tanase DM, Gosav EM, Radu S, et al. Arterial hypertension and interleukins: Potential therapeutic target or future diagnostic marker? Int J Hypertens 2019; 2019: 1-17.
[35]
Teixeira BC, Lopes AL, Macedo RCO, et al. Inflammatory markers, endothelial function and cardiovascular risk. J Vasc Bras 2014; 13(2): 108-15.
[36]
Bautista L, Vera L, Arenas I, Gamarra G. Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-α) and essential hypertension. J Hum hypertens 2005; 19(2): 149.
[37]
Wright CB, Sacco RL, Rundek TR, Delman JB, Rabbani LE, Elkind MS. Interleukin-6 is associated with cognitive function: The Northern Manhattan study. J Stroke Cerebrovasc Dis 2006; 15(1): 34-8.
[38]
Marsland AL, Petersen KL, Sathanoori R, et al. Interleukin-6 covaries inversely with cognitive performance among middle-aged community volunteers. Psychosom Med 2006; 68(6): 895-903.
[39]
Sasayama D, Kurahashi K, Oda K, et al. Negative correlation between serum cytokine levels and cognitive abilities in children with autism spectrum disorder. J Intell 2017; 5(2): 19.
[40]
Hennessy E, Gormley S, Lopez-Rodriguez AB, Murray C, Murray C, Cunningham C. Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration. Brain Behav Immun 2017; 59: 233-44.
[41]
Holmes C, Cunningham C, Zotova E, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 2009; 73(10): 768-74.
[42]
Lande MB, Meagher CC, Fisher SG, Belani P, Wang H, Rashid M. Left ventricular mass index in children with white coat hypertension. J Pediatr 2008; 153(1): 50-4.
[43]
Hage F. C-reactive protein and hypertension. J Hum Hypertens 2014; 28(7): 410.
[44]
Watanabe Y, Kitamura K, Nakamura K, et al. Elevated C-reactive protein is associated with cognitive decline in outpatients of a general hospital: The project in SADO for total health (PROST). Dement Geriatr Cogn Disord Extra 2016; 6(1): 10-9.
[45]
Zheng F, Yan L, Yang Z, Zhong B, Xie W. HbA 1c, diabetes and cognitive decline: The English longitudinal study of ageing. Diabetologia 2018; 61(4): 839-48.
[46]
Noble JM, Manly JJ, Schupf N, Tang MX, Mayeux R, Luchsinger JA. Association of C-reactive protein with cognitive impairment. Arch Neurol 2010; 67(1): 87-92.
[47]
Ravaglia G, Forti P, Maioli F, et al. Serum C-reactive protein and cognitive function in healthy elderly Italian community dwellers. J Gerontol A Biol Sci Med Sci 2005; 60(8): 1017-21.
[48]
Eagan DE, Gonzales MM, Tarumi T, Tanaka H, Stautberg S, Haley AP. Elevated serum C-reactive protein relates to increased cerebral myoinositol levels in middle-aged adults. Cardiovasc Psychiatry and Neurol 2012; 2012 120540
[49]
Cullen AE, Tappin BM, Zunszain PA, et al. The relationship between salivary C-reactive protein and cognitive function in children aged 11–14 years: Does psychopathology have a moderating effect? Brain Behav Immun 2017; 66: 221-9.
[50]
Paul A, Ko KW, Li L, et al. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E–deficient mice. Circulation 2004; 109(5): 647-55.
[51]
Raz N, Rodrigue KM. Differential aging of the brain: Patterns, cognitive correlates and modifiers. Neurosci Biobehavioral Rev 2006; 30(6): 730-48.
[52]
Russo I, Barlati S, Bosetti F. Effects of neuroinflammation on the regenerative capacity of brain stem cells. J Neurochem 2011; 116(6): 947-56.
[53]
Norlander AE, Madhur MS, Harrison DG. The immunology of hypertension. J Exp Med 2018; 215(1): 21-33.
[54]
Li D-P, Li Y-L, Li J, Wang S. Neural mechanisms of autonomic dysfunction in neurological diseases. Neural Plast 2017; 2017 2050191
[55]
Waldstein SR, Brown JR, Maier KJ, Katzel LI. Diagnosis of hypertension and high blood pressure levels negatively affect cognitive function in older adults. Ann Behav Med 2005; 29(3): 174-80.
[56]
Kanemaru A, Kanemaru K. KUWAJIMA I. The effects of short-term blood pressure variability and nighttime blood pressure levels on cognitive function. Hypertens Res 2001; 24(1): 19-24.
[57]
Tohgi H, Chiba K, Kimura M. Twenty-four-hour variation of blood pressure in vascular dementia of the Binswanger type. Stroke 1991; 22(5): 603-8.
[58]
Palatini P, Penzo M, Racioppa A, et al. Clinical relevance of nighttime blood pressure and of daytime blood pressure variability. Arch Intern Med 1992; 152(9): 1855-60.
[59]
Forte G, Casagrande M. Heart rate variability and cognitive function: A systematic review. Front Neurosci 2019; 13: 710.
[60]
Singh JP, Larson MG, Tsuji H, Evans JC, O’Donnell CJ, Levy D. Reduced heart rate variability and new-onset hypertension: Insights into pathogenesis of hypertension: The Framingham Heart Study. Hypertension 1998; 32(2): 293-7.
[61]
Xie G-L, Wang J-h, Zhou Y, Xu H, Sun J-H, Yang S-R. Association of high blood pressure with heart rate variability in children. Iranian J Pediatr 2013; 23(1): 37.
[62]
Thayer JF, Lane RD. Claude Bernard and the heart-brain connection: Further elaboration of a model of neurovisceral integration. Neurosci Biobehav Rev 2009; 33(2): 81-8.
[63]
Carthy ER. Autonomic dysfunction in essential hypertension: A systematic review. Ann Med Surg 2014; 3(1): 2-7.
[64]
Schroeder Emily B, Liao D, Chambless Lloyd E, Prineas Ronald J, Evans Gregory W, Heiss G. Hypertension, blood pressure, and heart rate variability. Hypertension 2003; 42(6): 1106-11.
[65]
Suemoto CK, Baena CP, Mill JG, Santos IS, Lotufo PA, Benseñor I. Orthostatic hypotension and cognitive function: Cross-sectional results from the ELSA-Brasil study. J Gerontol A Biol Sci Med Sci 2018; 74(3): 358-65.
[66]
Udow SJ, Robertson AD, MacIntosh BJ, et al. ‘Under pressure’: Is there a link between orthostatic hypotension and cognitive impairment in α-synucleinopathies? J Neurol Neurosurg Psychiatry 2016; 87(12): 1311-21.
[67]
Kuusisto J, Koivisto K, Mykkänen L, et al. Essential hypertension and cognitive function. The role of hyperinsulinemia. Hypertension 1993; 22(5): 771-9.
[68]
Kumari M, Brunner E, Fuhrer R. Mini-Reviews: Mechanisms by which the metabolic syndrome and diabetes impair memory. J Gerontol A Biol Sci Med Sci 2000; 55(5): B228-32.
[69]
Sato N, Morishita R. Roles of vascular and metabolic components in cognitive dysfunction of Alzheimer disease: Short-and long-term modification by non-genetic risk factors. Front Aging Neurosci 2013; 5: 64.
[70]
Prins ND, Scheltens P. White matter hyperintensities, cognitive impairment and dementia: An update. Nat Rev Neurol 2015; 11(3): 157.
[71]
Wardlaw JM, Valdés Hernández MC, Muñoz‐Maniega S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J Am Heart Assoc 2015; 4(6) e001140
[72]
Hawkins KA, Emadi N, Pearlson GD, et al. Hyperinsulinemia and elevated systolic blood pressure independently predict white matter hyperintensities with associated cognitive decrement in the middle-aged offspring of dementia patients. Metab Brain Dis 2017; 32(3): 849-57.
[73]
Roriz-Filho JS, Sa-Roriz TM, Rosset I, et al. (Pre) diabetes, brain aging, and cognition. Biochim Biophys Acta Mol Basis Dis 2009; 1792(5): 432-43.
[74]
Yaribeygi H, Panahi Y, Javadi B, Sahebkar A. The underlying role of oxidative stress in neurodegeneration: A mechanistic review. CNS Neurol Disord Drug Targets 2018; 17(3): 207-15.
[75]
Kawamura T, Umemura T, Hotta N. Cognitive impairment in diabetic patients: Can diabetic control prevent cognitive decline? Journal of Diabetes Investigation 2012; 3(5): 413-23.
[76]
Kumar A, Datusalia AK. Metabolic stress and inflammation: Implication in treatment for neurological disorders. CNS Neurol Disord Drug Targets 2018; 17(9): 642-3.
[77]
Saedi E, Gheini MR, Faiz F, Arami MA. Diabetes mellitus and cognitive impairments. World J Diabetes 2016; 7(17): 412.
[78]
Talbot K. Brain insulin resistance in Alzheimer’s disease and its potential treatment with GLP-1 analogs. Neurodegener Dis Manag 2014; 4(1): 31-40.
[79]
Goldstein FC, Ashley AV, Endeshaw Y, Hanfelt J, Lah JJ, Levey AI. Effects of hypertension and hypercholesterolemia on cognitive functioning in patients with Alzheimer’s disease. Alzheimer Dis Assoc Disord 2008; 22(4): 336.
[80]
Desmond DW, Tatemichi TK, Paik M, Stern Y. Risk factors for cerebrovascular disease as correlates of cognitive function in a stroke-free cohort. Arch Neurol 1993; 50(2): 162-6.
[81]
Tong X-K, Trigiani LJ, Hamel E. High cholesterol triggers white matter alterations and cognitive deficits in a mouse model of cerebrovascular disease: Benefits of simvastatin. Cell Death Dis 2019; 10(2): 89.
[82]
Ma C, Yin Z, Zhu P, Luo J, Shi X, Gao X. Blood cholesterol in late-life and cognitive decline: A longitudinal study of the Chinese elderly. Mol Neurodegener 2017; 12(1): 24.
[83]
Herman J, McKlveen J, Ghosal S, et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol 2016; 6(2): 603-21.
[84]
Lupien S, Nair N, Briere S, et al. Increased cortisol levels and impaired cognition in human aging: Implication for depression and dementia in later life. Rev Neurosci 1999; 10(2): 117-40.
[85]
Bourdeau I, Bard Cl, NoeQl B, et al. Loss of brain volume in endogenous Cushing’s syndrome and its reversibility after correction of hypercortisolism. J Clin Endocrinol Metabol 2002; 87(5): 1949-54.
[86]
Reynolds RM, Walker BR, Syddall HE, et al. Altered control of cortisol secretion in adult men with low birth weight and cardiovascular risk factors. J Clin Endocrinol Metab 2001; 86(1): 245-50.
[87]
Burford N, Webster N, Cruz-Topete D. Hypothalamic-pituitary-adrenal axis modulation of glucocorticoids in the cardiovascular system. Int J Mol Sci 2017; 18(10): 2150.
[88]
Gold SM, Dziobek I, Rogers K, Bayoumy A, McHugh PF, Convit A. Hypertension and hypothalamo-pituitary-adrenal axis hyperactivity affect frontal lobe integrity. J Clin Endocrinol Metab 2005; 90(6): 3262-7.
[89]
Riedel B, Browne K, Silbert B. Cerebral protection: Inflammation, endothelial dysfunction, and postoperative cognitive dysfunction. Curr Opin Anaesthesiol 2014; 27(1): 89-97.
[90]
Marie C, Pedard M, Quirie A, et al. Brain-derived neurotrophic factor secreted by the cerebral endothelium: A new actor of brain function? J Cereb Blood Flow Metab 2018; 38(6): 935-49.
[91]
Xu W, Yu JT, Tan MS, Tan L. Cognitive reserve and Alzheimer’s disease. Mol Neurobiol 2015; 51(1): 187-208.
[92]
Gareau M. Cognitive function and the microbiome. Int Rev Neurobiol 2016; 131: 227-46.
[93]
Oriach CS, Robertson RC, Stanton C, Cryan JF, Dinan TG. Food for thought: The role of nutrition in the microbiota-gut-brain axis. Clin Nutr Exp 2016; 6: 25-38.
[94]
Al Khodor S, Reichert B, Shatat IF. The microbiome and blood pressure: Can microbes regulate our blood pressure? Front Pediatr 2017; 5: 138.
[95]
Proctor C, Thiennimitr P, Chattipakorn N, Chattipakorn SC. Diet, gut microbiota and cognition. Metabolic Brain Dis 2017; 32(1): 1-17.
[96]
Maqsood R, Stone TW. The gut-brain axis, BDNF, NMDA and CNS disorders. Neurochem Res 2016; 41(11): 2819-35.
[97]
Yang T, Santisteban MM, Rodriguez V, et al. Gut dysbiosis is linked to hypertension. Hypertension 2015; 65(6): 1331-40.
[98]
Yan Q, Gu Y, Li X, et al. Alterations of the Gut Microbiome in hypertension. Front Cell Infect Microb 2017; 7: 381.
[99]
Santisteban MM, Kim S, Pepine CJ, Raizada MK. Brain-gut-bone marrow axis. Circulation research 2016; 118(8): 1327-36.
[100]
Jama H, Kaye DM, Marques FZ. Population-based gut microbiome associations with hypertension: The need for more detailed phenotypes. Circ Res 2018; 123(11): 1185-7.
[101]
Lande MB, Batisky DL, Kupferman JC, et al. Neurocognitive function in children with primary hypertension after initiation of antihypertensive therapy. J Pediatr 2018; 195: 85-94. e1
[102]
Iadecola C, Yaffe K, Biller J, et al. Impact of hypertension on cognitive function: A scientific statement from the American Heart Association. Hypertension 2016; 68(6): e67-94.
[103]
Asher J, Houston M. Statins and C-reactive protein levels. J Clin Hypertens 2007; 9(8): 622-8.
[104]
Zhang H, Cui Y, Zhao Y, et al. Effects of sartans and low-dose statins on cerebral white matter hyperintensities and cognitive function in older patients with hypertension: A randomized, double-blind and placebo-controlled clinical trial. Hypertens Res 2019; 42(5): 717-29.
[105]
Schultz BG, Patten DK, Berlau DJ. The role of statins in both cognitive impairment and protection against dementia: A tale of two mechanisms. Transl Neurodegener 2018; 7: 5.
[106]
Eiland LS, Luttrell PK. Use of statins for dyslipidemia in the pediatric population. J Pediatr Pharmacol Ther 2010; 15(3): 160-72.
[107]
Benedict C, Grillo CA. Insulin resistance as a therapeutic target in the treatment of Alzheimer’s disease: A state-of-the-art review. Front Neurosci 2018; 12: 215.
[108]
Yarchoan M, Arnold SE. Repurposing diabetes drugs for brain insulin resistance in Alzheimer disease. Diabetes 2014; 63(7): 2253-61.
[109]
Kennedy G, Hardman RJ, Macpherson H, Scholey AB, Pipingas A. How does exercise reduce the rate of age-associated cognitive decline? a review of potential mechanisms. J Alzheimers Dis 2017; 55(1): 1-18.
[110]
Bazzano LA, Green T, Harrison TN, Reynolds K. Dietary approaches to prevent hypertension. Curr Hypertens Rep 2013; 15(6): 694-702.
[111]
Pandareesh MD, Kandikattu HK, Razack S, et al. Nutrition and nutraceuticals in neuroinflammatory and brain metabolic stress: implications for neurodegenerative disorders. CNS Neurol Disord Drug Targets 2018; 17(9): 680-8.
[112]
Telle-Hansen VH, Holven KB, Ulven SM. Impact of a healthy dietary pattern on gut microbiota and systemic inflammation in humans. Nutrients 2018; 10(11): pii: E1783
[113]
Robles-Vera I, Toral M, Romero M, et al. Antihypertensive effects of probiotics. Curr Hypertens Rep 2017; 19(4): 26.


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VOLUME: 18
ISSUE: 9
Year: 2019
Page: [677 - 686]
Pages: 10
DOI: 10.2174/1871527318666191017155442
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