Journal of the American Society of Hypertension 6(5) (2012) 309315

ASH Position Paper

Blood pressure and treatment of persons with hypertension as it relates to cognitive outcomes including executive function
Philip B. Gorelick, MD, MPHa,* and David Nyenhuis, PhDb, On behalf of the American Society of Hypertension Writing Group
Translational Science & Molecular Medicine, Michigan State University College of Human Medicine, Hauenstein Neuroscience Center, Grand Rapids, MI, USA; and b Neuropsychology & Clinical Research, Department of Neurology & Rehabilitation, University of Illinois College of Medicine at Chicago, Chicago, IL, USA Manuscript Accepted August 14, 2012
a

Statement of Problem
There has been longstanding interest in a possible causeand-effect relationship between elevated blood pressure (BP) and cognitive outcome.1 The relationship has been debated over time24 and continues to be a focus of controversy, especially in terms of BP lowering as a means to prevent cognitive decline or dementia.57 Despite the uncertainty surrounding a benet of BP lowering to prevent cognitive decline or dementia, there is mounting mechanistic and epidemiologic evidence to link elevated BP to loss of cognition.5 Furthermore, it is estimated that midlife hypertension may account for w5% and 8% of Alzheimers disease (AD) cases worldwide and in the United States, respectively, and the relative risk for midlife hypertension in AD is w1.6.8 These metrics do not take into account, however, the potential inuence of later life hypertension on cognitive impairment. Later life hypertension and cognition are generally a more complex circumstance because many older persons are treated for high BP; therefore, the latter factor may introduce a confound based on specic class of antihypertensive treatment that has been administered, duration of and compliance with BP lowering therapy, success of reaching a prescribed BP target, and other factors. Although the topic remains one of clinical equipoise, viewing the glass as being half empty without results from robustly designed randomized, controlled trials (RCTs) may not do justice to the BPcognition relationship and should move us to design appropriate RCTs to answer germane questions about this relationship and overcome past disparate or awed methodologies in the eld.9
Conicts of Interest: None. *Corresponding author: Philip B. Gorelick, MD, MPH, Translational Science & Molecular Medicine, Michigan State University College of Human Medicine, Hauenstein Neuroscience Center, 220 Cherry Street SE, Grand Rapids, MI 49503. Tel: (616) 685-6455; Fax: (616) 685-4351. E-mail: pgorelic@trinity-health.org

In this American Society of Hypertension Position Statement, we explore mechanistic and epidemiologic associations including those of observational studies and RCTs of the BPcognition relationship, the role of executive function as a cognitive outcome in persons with hypertension, and practical recommendations for BP treatment to prevent cognitive impairment or dementia.

Scientic Background Mechanisms Linking Elevated BP to Cognitive Impairment or Dementia

Mechanisms linking elevated BP to cognitive impairment or dementia may be classied according to the following categories: functional, structural, pharmacologic, strokerelated, and other factors. Table 1 provides a brief overview of these factors. We emphasize the neurovascular unit composed of the cerebral arteriole, astrocyte, microglia, and neuron. The cerebral arteriole is susceptible to oxidative stress and inammation in the presence of lifestyle and conventional stroke and cardiovascular factors such as hypertension that spawn endothelial dysfunction or vascular dysregulation. In the presence of these stressors, the brain becomes susceptible to toxins (eg, beta amyloid) that may more readily pass through a dysfunctional bloodbrain barrier. Furthermore, disrupted vasoregulatory mechanisms that would normally assure adequate brain blood ow are now disrupted and are thought to make the brain more susceptible to ischemic brain injury and AD.10 For more information about these mechanistic consequences, the reader is referred to a review by Iadecola and Davisson.10 In addition, the presence of chronic hypertension may lead to brain white matter disease (ie, leukoaraiosis), lacunar infarcts, and cerebral micro- or macrobleeds; ndings that may be associated with cognitive impairment; and neuritic plaques, tangles, hippocampal atrophy, and general brain atrophy, all neuropathologic features of AD.1114 The

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Table 1 Hypothesized mechanisms linking elevated blood pressure to cognitive impairment or dementia Functional factors: Endothelial dysfunction/vascular dysregulation, impaired hyperemic response (coordinates brain activity and blood ow), nocturnal blood pressure dipping (relative hypotension) or nondipping, and less clearance of beta amyloid Structural factors: Occurrence of white matter disease (leukoaraiosis), greater numbers of neuritic plaques and neurobrillary tangles (neuropathologic features of AD), and smaller brain size (ie, more atrophy) Pharmacologic factors: Renin-angiotensin system (RAS): angiotensin II inhibits acetylcholine release; AT 2 receptor stimulation as a neuroprotective factor Stroke-related: Strategic stroke (eg, thalamus, angular gyrus, subcortical white matter) or tissue loss with stroke(s) (large or small vessel territory) Other factors: Association of hypertension with insulin resistance and abnormal insulin signaling in the brain or metabolic syndrome and inammation AD, Alzheimers disease.

latter AD neuropathologic ndings, as well as others discussed in the following sections, have drawn a link between AD and elevated BP as both the occurrence of AD and the neuropathological ndings of AD may be more frequent when there is hypertension. In relation to the role of brain white matter integrity, intact brain white matter pathways are critical for proper brain function and to assure normal cognitive function. The brain radiologic nding of leukoaraiosis may be associated with the presence of both cognitive impairment and elevated BP. Hypertension is a major risk factor for stroke. In relation to other stroke-specic factors, brain tissue loss as a consequence of stroke has been associated with cognitive impairment; these strokes may be isolated or strategically located ones (eg, in the thalamus, angular gyrus, frontal white matter).15 Also, because hypertension often does not exist as a solitary factor but occurs in the presence of other metabolic risks, other stroke-related factors such as inammation or abnormal insulin signaling in the brain, or the presence of metabolic syndrome could exist and underlie cognitive impairment or dementia in persons with hypertension.16,17 Finally, there may be pharmacologic rationale for an association between elevated BP and cognitive impairment. It is well-known that the effector peptide angiotensin (Ang) II exerts a negative inuence by stimulating the AT-1 brain receptor with resultant vasoconstriction, cellular proliferation and inammation, whereas AT-2 brain receptor stimulation by Ang II has an opposite or neuroprotective effect of manifesting vasodilation and other neuroprotective properties.18 It has been shown that angiotensin receptor blockers (ARBs) not only block the AT-1 receptor but also allow Ang II access to the AT-2 receptor, whereas angiotensinconverting enzyme inhibitors decrease Ang II and thus may consequently diminish the protective effect of Ang II at the AT-2 receptor site.18 In addition, angiotensin-converting enzyme inhibitors may have shorter term advantages of cognitive enhancing qualities as has been demonstrated in an RCT (see the following section), but may increase brain beta amyloid deposition over time, making the brain possibly susceptible to cognitive dysfunction, whereas AT-1 receptor blockers (ARBs) may be associated with metabolic

degradation of amyloid, a potentially protective consequence in relation to cognition.19 Brain amyloid deposition is a neuropathologic feature of AD and may manifest in brain senile plaques in AD and in the media and adventitia of leptomeningeal and small cerebral cortical arteries as a condition called cerebral amyloid angiopathy that is a vascular manifestation associated with AD.20 Finally, Ang II may be involved in prevention of acetylcholine release.21 Acetylcholine is important for brain neurotransmission, especially in relation to such activities as memory. Table 2 provides a brief summary of how various classes of BP-lowering agents may be involved in overall cognitive outcomes.19

Epidemiologic Findings Observational Studies

Observational epidemiological studies have been replete with data linking cognitive impairment to elevated BP. Such articles began to appear in mass in the 1990s. For example, the Honolulu-Asia Aging Study showed that midlife systolic BP was a signicant predictor of reduced cognitive function in later life.22 In a 15-year longitudinal study of BP and dementia in 70 year olds in Sweden, persons who developed dementia at age 7985 years had higher mean systolic and diastolic BP at age 70 years (178/101 vs. 164/92 mm Hg) than those who did not develop dementia. The authors suggested that elevated BP might increase the risk of dementia by inducing small-vessel disease and white matter lesions of the brain.23 In a companion study using computed tomography brain studies, it was concluded that age-related changes in brain structure might contribute to a decrease in BP in these very elderly persons and that low BP in dementia might be a secondary phenomenon.24 In a series of elegant studies from the National Heart, Lung, and Blood Institute Twin Study, midlife systolic BP was a signicant predictor of cognitive function and volumetric brain measures of atrophy in late life.25,26 Furthermore, the ndings were independent of age effects and shared genetic or familial inuences, and midlife cardiovascular risk factors

P.B. Gorelick and D. Nyenhuis / Journal of the American Society of Hypertension 6(5) (2012) 309315 Table 2 Hypothesized mechanisms linking specic classes of blood pressure lowering drugs to cognitive outcomes* Drug Class b-blockers Diuretics ARBs ACEIs CCBs Hypothesized Mechanism of Cognitive Outcome

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Neutral inuence or possible cognitive decline if they cross the BBB and blunt adrenergic pathways Potassium-sparing diuretics may decrease risk of AD (possible mechanism by raising or maintaining potassium) Block AT-1 receptor but allow access of Ang II to AT-2 neuro-protective receptor; prevent brain amyloid deposition Ambiguous inuence as brain ACE catabolizes cognitive enhancing brain peptides, but ACEIs may increase long term burden of toxic brain beta amyloid May assist in maintenance of intracellular calcium homeostasis

ACEIs, angiotensin-converting enzyme inhibitors; AD, Alzheimers disease; ARBs, angiotensin receptor blockers; AT, angiotensin receptor; BBB, bloodbrain barrier; CCB, calcium channel blockers. * For further details the reader is referred to previous work.19

including hypertension and lifestyle practices were predictors of structural brain changes such as white matter hyperintensities detected by brain magnetic resonance imaging.25 Other studies such as the Rotterdam Study and Framingham Study have linked elevated BP in mid or later life with risk of cognitive impairment or dementia.27 In an overview analysis of 28 cross-sectional studies, 22 longitudinal studies, and 8 RCTs, Birns and Kalra showed mixed associations between higher BP and cognition in cross-sectional studies, with some indicating no correlation or even J- or U-shaped relationships.27 The majority of longitudinal studies, however, demonstrated that BP elevation was associated with cognitive decline, whereas RCTs showed heterogeneity of ndings in association with this relationship.27 Healthy skepticism has existed in relation to the BP elevation-cognitive impairment hypothesis.28 Several studies have not supported the proposed association.2932 Also, attention has been focused on low BP or decline in BP over time in persons at risk of cognitive impairment and the structural brain accompaniments.33 BP may begin to decline before the diagnosis of dementia is made, for example, and low diastolic BP may be associated with an increase in risk of cognitive impairment.3438 The brain may not tolerate variability in BP and in relation to this circumstance may be more susceptible to cerebral brain injury manifesting as clinical or subclinical white matter disease (leukoaraiosis), brain lacunar or watershed infarcts, brain atrophy, and cognitive impairment.3941 Ambulatory BP monitoring may be superior to clinic BP determination to identify those at greater risk of progression of leukoaraiosis and cognitive impairment.42 Furthermore, patients with heart failure and consequent hypotension may be susceptible to cognitive impairment.5,43 Qui et al44 summarize their conclusions after reviewing potential linkages between agedependent BP, cognitive function and dementia (Table 3).

RCTs
Thoughtful reviews and analyses of BP lowering and maintenance of cognitive vitality have essentially concluded that there remains uncertainty about the benet of BP lowering and prevention of cognitive decline or dementia.5,27,4547 Results of observational studies such as one about centrally acting angiotensin-converting enzyme inhibitors (eg, captopril, fosinopril, lisinopril, perindopril, ramipril, trandolapril) and prevention of cognitive decline have generally not been substantiated in well-designed RCTs as of yet.48 The main sources of data in relation to RCTs, BP lowering, and cognition include individual trials such as the Medical Research Councils Trial of Hypertension Treatment in the Elderly, the Systolic Hypertension in Europe (Syst-Eur), Study on Cognition and Prognosis in the Elderly, the Systolic Hypertension in the Elderly Program, and the Hypertension in the Very Elderly Trial Cognitive Function Assessment. Also included are one trial that enrolled patients who had stroke, Perindopril Protection Against Recurrent Stroke Study (PROGRESS), an overview analyses of the data, and the Cochrane database.4956 Table 4 is a brief summary of these studies and includes the BP-lowering interventions, length of follow-up, BP ndings, cognitive tests, and main cognitive ndings. Overall, the most encouraging results for BP lowering to preserve cognitive vitality stem from the PROGRESS and Syst-Eur trials (Table 4). Although there are a number of neutral (or negative) results, in meta-analyses the ndings usually reach the level of borderline statistical signicance favoring the active BPlowering treatment arm.54,57 The individual RCTs have been substantially criticized, however, on the grounds of disparate study methodologies such as inclusion of patients with preexistent cognitive impairment, different BP level targets (if any at all) and variation in baseline factors, as non-primary analyses with insufcient power to detect modest

Table 3 Conclusions regarding age-dependent blood pressure, cognitive function, and dementia44 1. 2. 3. 4. High blood pressure in midlife is a risk for dementia or cognitive decline in later life Elevated blood pressure (eg, systolic blood pressure >180 mm Hg) in elderly adults may be a risk for dementia Low diastolic blood pressure (eg, <70 mm Hg) in older adults is associated with increased dementia risk Elevated blood pressure in mid-life and low blood pressure in later life may be associated with Alzheimers disease

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Table 4 Overview of select randomized controlled trials of blood pressure lowering and cognitive outcomes4955 Trial MRC Research Design BP Reduction (mm Hg) 34 SBP (diuretic) 31 SBP (b-blocker) 16 SBP (placebo) Cognitive Tests/Diagnosis Trailmaking Paired associate learning Primary Cognitive Results No difference in cognitive test scores between groups

Subjects: n 2584, age 6574 Baseline SBP/DBP: 160209/<115 mm Hg BP intervention: randomized to diuretic, b-blocker, or placebo Length of follow-up: 54 months Syst-Eur Subjects: n 2418, age > 60 Baseline SBP/DBP: 160219/<95 mm Hg BP Intervention: randomized to nitrendipine/ enalapril, hydrochlorothiazide, or both versus placebo Length of follow-up: 24 months SCOPE Subjects: n [ 4964, age 7089 Baseline SBP/DBP: 160179/9099 mm Hg BP Intervention: randomized to candesartan or placebo with open label anti-HTN therapy add on as needed Length of follow-up: 3.7-year average SHEP Subjects: n 2034, age >60 Baseline SBP/DBP: 160219/<90 mm Hg BP Intervention: randomized to chlorthalidone in step 1 and atenolol or reserpine in step 2 versus placebo Length of follow-up: 5 years Subjects: n 3336, age >79 HY-VET COG Baseline SBP/DBP: 160200/<110 mm Hg BP intervention: randomized to indapamide/perindopril or placebo Length of follow-up: 24 months PROGRESS Subjects: n 6105 with stroke or TIA history, no age criteria Baseline SBP/DBP: no BP criteria (add-on therapy) BP intervention: randomized to perindopril / indapamide versus placebo Length of follow-up: 3.9 year average Cochrane Subjects: 4 trials, total n 15,936; mean Review age 75.4 Baseline BP: mean 171/86 mm Hg BP intervention: varied across trials Length of follow-up: varied across trials

22/6 (treatment) 13/3 (placebo)

MMSE Reduction in MMSE decline Dementia diagnosis 50% reduction in dementia incidence

22/11 (candesartan) 19/9 (placebo)

MMSE

No difference in MMSE decline between groups

27/9 (treatment) 15/5 (placebo)

30/13 (treatment) 15/7 (placebo)

Digit symbol No signicant differences Addition in test score changes Finding As between groups Boston naming Delayed recognition Letter set tests -2 stage dementia No signicant difference diagnosis in dementia incidence between groups

Treatment group showed MMSE 9/4 greater reduction than placebo group

Treatment group showed 19% relative risk reduction in cognitive decline

Treatment groups showed Dementia diagnosis No signicant difference in an average of 10/4 MMSE dementia incidence. greater reduction than No signicant difference in placebo groups MMSE decline

Addition, a timed calculation test requiring processing speed and attention; Boston naming, a confrontation naming test consisting of lined drawings of objects; BP, blood pressure; DBP, diastolic blood pressure; digit symbol, timed coding test of attention and executive function; delayed recognition, a test of immediate and delayed recognition memory; Finding As, a scanning test requiring attention and visual search skills; HTN, hypertension; HY-VET COG, Hypertension in the Very Elderly TrialCognitive function assessment; letter set tests, a test of abstract reasoning and hypothesis testing; MMSE, Mini-mental State Examination cognitive test descriptions; MRC, Medical Research Council; paired associate learning test, a paired-word verbal memory test; PROGRESS, Perindopril Protection against Recurrent Stroke Study; SBP, systolic blood pressure; SCOPE, Study on Cognition and Prognosis in the Elderly; SHEP, Systolic Hypertension in the Elderly Program; Syst-Eur, Systolic hypertension in Europe; Trailmaking Test, a timed test of visual scanning and executive function. All blood pressures measured in mm Hg.

treatment effects, for differential drop out, short follow-up, and measurement error in the diagnosis of dementia.55,57,58 An additional study, Prevention Regimen for Effectively Avoiding Second Strokes trial did not show a statistically

signicant difference in cognitive outcomes between the recurrent stroke prevention group that did or did not receive add-on BP-lowering therapy with telmisartan.59 Clearly, the eld is open to the development of well-designed RCTs to

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Table 5 American Heart Association/American Stroke Association blood pressure lowering guidance for practicing health care providers as it pertains to VCI5 1. Reduction of blood pressure according to standard guidelines (eg, JNC 7) reduces the risk of stroke, myocardial infarction and other major cardiovascular outcomes 2. For persons at risk of developing VCI, treatment of blood pressure is recommended according to standard guidelines to prevent VCI 3. For persons with a history of stroke, lowering blood pressure is effective for reducing the risk of post-stroke dementia 4. For middle-age persons and the young-elderly, lowering blood pressure can be useful for the prevention of late-life dementia 5. For persons >80 years, the usefulness of blood pressure lowering for the prevention of dementia is not well established VCI, vascular cognitive impairment.

answer important clinical questions in relation to the BP lowering preservation of cognitive vitality hypothesis. The ongoing Systolic Blood Pressure Intervention Trial (SPRINT) includes a substudy of cognition called SPRINT-MIND that promises to provide additional important results.60

4. Table 5 summarizes American Heart Association/ American Stroke Association5 BP-lowering guidance for practicing health care providers as it pertains to vascular cognitive impairment. Acknowledgments The American Society of Hypertension Writing Group Steering Committee: Barry J. Materson, MD, MBA, Chair; David A. Calhoun, MD; William J. Elliott, MD, PhD; Robert A. Phillips, MD, PhD; Sandra J. Taler, MD and Raymond R. Townsend, MD.

Executive Function as a Vulnerable Cognitive Outcome in Persons with Elevated BP

The construct of executive function encompasses several essential higher cognitive skills, including planning, activation, organization, impulse control, and working memory. Executive dysfunction is commonly associated with cerebral vascular brain injury61 and is especially related to diffuse subcortical small vessel disease (lacunar infarction and leukoaraiosis), conditions that have been linked to chronic hypertension. In the Canadian Study of Health and Aging, the presence of hypertension predicted progression to dementia in older persons with executive dysfunction but no memory impairment.62 Assessment of executive function has been designated as a key cognitive domain according to the National Institute of Neurological Disorders-Canadian Stroke Network neuropsychological protocols for use in vascular cognitive impairment.63 Executive dysfunction may be observed when there is subcortical white matter disease in persons with hypertension.

References
1. Shapiro AP, Miller RE, King E, Gincherreau EH, Fitzgibbon K. Behavioral consequences of mild hypertension. Hypertension 1982;4:35560. 2. Scherr PA, Hebert LE, Smith LA, Evans DA. Relation of blood pressure to cognitive function in the elderly. Am J Epidemiol 1991;134:130315. 3. Perez-Stable EJ, Coates TJ, Halliday R, Gardiner PS, Hauck WW. The effects of mild diastolic hypertension on the results of cognitive function in adults 22 to 59 years of age. J Gen Intern Med 1992;7:1925. 4. Elias PK, DAgostino RB, Elias MF, Wolf PA. Blood pressure, hypertension, and age as risk factors for poor cognitive performance. Experimental Aging Res 1995;21:393417. 5. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42:2672713. 6. Plassman BL, Williams JW, Burke JR, Holsinger T, Benjamin S. Systematic review: factors associated with risk for and possible prevention of cognitive decline in later life. Ann Intern Med 2010;153:18293. 7. Daviglus ML, Bell CC, Berrettini W, Bowen PE, Connolly ES, Cox NJ, et al. National Institutes of Health state-of-the-science conference statement: preventing Alzheimer disease and cognitive decline. Ann Intern Med 2010;153:17681.

Practical Recommendations
1. Additional well-designed RCTs of BP-lowering strategies are needed to provide high-level clinical evidence to guide the clinician in relation to BP management to prevent cognitive decline and dementia (eg, AD and the spectrum of vascular cognitive impairment) in persons who are in mid or later life and who do or do not have evidence of cognitive impairment. 2. Additional well-designed studies are needed to identify valid and reliable biomarkers of persons at high risk of developing cognitive decline or dementia later in life to identify persons who might benet from BP lowering earlier in life for preservation of cognitive vitality later in life. 3. Tests of executive function are key to understanding potential linkages between BP, cognitive impairment, and dementia and need to be included as primary outcome measures in RCTs of BP-lowering strategies.

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