Sie sind auf Seite 1von 9

State of the Art

Hypertension and Its Role in Cognitive Function: Current

Evidence and Challenges for theFuture
Timothy M.Hughes1 and Kaycee M.Sink1

This review summarizes evidence from studies of blood pressure and of strong evidence of biological mechanisms, results from randomized
dementia-related biomarkers into our understanding of cognitive trials of antihypertensive therapy for the prevention of cardiovascular
health and highlights the challenges facing studies, particularly rand- or cerebrovascular disease that include cognitive endpoints do not
omized trials, of hypertension and cognition. Several lines of research strongly support the observational evidence that treatment of hyper-
suggest that elevated blood pressure, especially at midlife, is associated tension should be better for cognition. We propose that future clini-
with cognitive decline and dementia and that treatment of hyperten- cal trials should consider including dementia biomarkers and assess
sion could prevent these conditions. Further, studies of hypertension genetic and cardiometabolic risk factors that have been associated
and brain structure show that blood pressure is associated with several with progression of the underlying disease pathology to help bridge
forms of small vessel disease that can result in vascular dementia or these gaps.
interact with Alzheimers pathology to lower the pathologic threshold
at which Alzheimers signs and symptoms manifest. In addition, recent
Keywords: Alzheimers disease; blood pressure; cognition; dementia;
studies of hypertension and Alzheimers biomarkers show that elevated
hypertension; review.
blood pressure and pulse pressure are associated with the extent of
brain beta amyloid (A) deposition and altered cerebral spinal fluid pro-
files of A and tau indicative of Alzheimers pathology. However, in spite doi:10.1093/ajh/hpv180

Hypertension is regarded as a key, modifiable risk factor for on the brain which can be also be captured by measures of
age-related dementia. It affects nearly two thirds of adults arteriosclerosis, and (iv) there is compelling evidence that
aged 65 and older in the United States.1 Several decades of hypertension is associated with vascular dysfunction and
observational research studies present substantial evidence evidence of cerebrovascular disease and beta amyloid (A)
linking hypertension and elevated blood pressure (BP) to deposition, 2 major pathologic factors in dementia; how-
general brain health,2 cognitive decline, and risk for demen- ever, (v) there is a lack of definitive support for BP lowering
tia that are summarized by several excellent review articles35 to prevent dementia from randomized placebo-controlled
and meta-analyses.6,7 Yet, a lack of supporting evidence from clinical trials. This review of human studies describes the
randomized clinical trials (RCTs) remains a critical barrier challenges of assessing the effects of hypertension and BP
to recommending BP lowering as prevention strategy for lowering on cognition and cognitive impairment. We pro-
preventing cognitive decline and dementia. pose that integrating dementia biomarkers, assessing genetic
Our review is not intended to be an exhaustive review risk and including a priori cognitive endpoints into future
of the mass of human studies linking BP and cognition or studies of hypertension and dementia, especially RCTs, will
even the much larger topic of brain health,2 but instead to help bridge thesegaps.
integrate evidence from studies of BP and dementia-related
biomarkers into our understanding of cognitive health and
highlight the challenges facing studies of BP and cognition. OVERVIEW OF STUDIES OF BP AND COGNITION
This review synthesizes the existing evidence to present the Observational studies linking BP and cognition
following salient conclusions: (i) the strongest evidence that
BP is a risk factor for dementia and cognitive decline comes Several decades of observational epidemiology stud-
from observational studies with midlife measures of BP and ies suggest that there are strong links between elevated BP
late-life measures of the cognitive performance, (ii) the asso- and cognitive impairment leading to dementia. The most
ciations between late-life measures of BP and cognition are consistent data come from longitudinal epidemiology stud-
less consistent, (iii) midlife hypertension likely better reflects ies evaluating midlife BP and cognition. They show that
the long-term effect and duration of hypertensions effect elevated BP in midlife is a strong, consistent risk factor for

1Department of Internal Medicine, Division of Gerontology and Geriatric

Correspondence: Kaycee M.Sink (
Medicine, Wake Forest School of Medicine, Winston-Salem, North
Initially submitted August 28, 2015; date of first revision September Carolina, USA.
15, 2015; accepted for publication October 6, 2015; online publication
November 11, 2015. American Journal of Hypertension, Ltd 2015. All rights reserved.
For Permissions, please email:

American Journal of Hypertension 29(2) February 2016 149

Hughes and Sink

incident cognitive impairment and dementia6,8,9 affecting be driven by cerebrovascular disease and abnormalities
global cognition and several cognitive domains,10 including in cerebral blood flow. Untreated hypertension, poorly
worse performance and declines in executive function and controlled hypertension, and high BP levels are associ-
processing speed, while associations with memory domains ated with a decline in cerebral blood flow.23,24 Among
are less marked. In contrast, studies of late-life BP suggest older individuals with lower cerebral blood flow, low SBP
that only the extremes of BP (systolic BP (SBP) >180mm and higher pulse pressure (PP=SBP DBP, discussed in
Hg and diastolic BP (DBP) <70mm Hg) increase the risk for detail below) are associated with lower gray matter vol-
dementia.5 Others show that declines in BP in late life are ume.23 Hypertension is a risk factor for cerebral small
associated with poor cognition and incident dementia.8,11 vessel disease, which includes white matter hyperin-
The discrepancy between midlife and late-life BP measures tensities (WMHs), cerebral microbleeds, and lacunar
and cognition may result from bias due to reverse causation infarcts. Careful longitudinal studies show that high BP
wherein the physiologic declines in BP late in life may be precedes WMHs and are associated with WMH progres-
secondary to dementia pathogenesis.12 sion.25 This relationship is strongest among untreated
Two recent longitudinal studies provide additional sup- hypertensive adults and those treated with inadequate
port for long-term temporal associations between elevated control.25 Uncontrolled hypertension is associated with
SBP in midlife and cognitive impairment 20years later.13,14 greater WMH volume, cerebral microbleeds, and lacunar
Although the 2 studies report different relationships infarcts,26 in some but not all studies.27 In the PROGRESS
between DBP and cognitive decline (linear vs. U-shaped), study, a large secondary prevention of stroke trial, active
the relationship between midlife SBP and cognitive decline BP lowering vs. placebo was shown to slow or stop the pro-
in both studies was linear and evident across several cogni- gression of WMH in patients with evident cerebrovascu-
tive domains. Interestingly, this relationship appears to be lar disease28 and those without.29 These findings support
stronger for Whites than for African-Americans.14 observational studies that show reduced WMH burden for
those under effective BP control.30
Supporting evidence from studies of BP and brain Evidence of other forms of cerebrovascular disease are being
structural abnormalities incorporated into studies of BP and brain health.3135 Large epi-
demiologic studies such as Framingham, Cardiovascular Health
Supporting evidence of a relationship between BP and Study, Rotterdam, Atherosclerosis Risk in Communities, etc.
cognitive function comes from studies using neuroimag- include measures of cerebrovascular disease beyond WMH,
ing and autopsy data to examine the relationship between such as cerebral microbleeds, infarcts, and lacunes. These stud-
BP and brain structural abnormalities underlying cognitive ies show that elevated BP is a risk factor for silent brain infarcts
decline and dementia. This includes evidence of atrophy in large and small cerebral arteries,36 prevalent and incident
and cerebrovascular disease defined by magnetic resonance lacunar infarcts,3740 and cerebral microbleeds.35,41 It is specu-
imaging, A deposition quantified by positron emission lated that the cerebral amyloid angiopathy may be responsible
tomography, and autopsy studies used to identify and quan- for the microbleeds in the parietal lobes of the brain.42 Recent
tify the pathologic correlates of dementia. advances in imaging microinfarcts will likely increase our
BP is related to smaller total brain volume and regional understanding of the relationship between BP and evidence of
brain volumes in Alzheimers disease (AD) prone regions. small vessel disease in the brain.43
Arecent meta-analysis of BP and brain volume showed that
higher BP levels are associated with smaller total, corti- BP and evidence of Alzheimers disease pathology
cal, and hippocampal brain volumes, which was evident in
both cross-sectional and longitudinal studies.15 These asso- AD often manifests as co-occurring neuropathology (e.g.,
ciations between high SBP and brain volume are evident a-synuclein, lewy bodies, etc.) with other neurodegenerative
regardless of treatment with antihypertensive medications.16 disorders and with evidence of cerebrovascular disease. In
While high SBP appears to be associated with brain struc- particular, the deposition of vascular A described as cerebral
tural abnormalities in studies of older adults, it may not be amyloid angiopathy is emerging as an important marker of
evident across the entire adult age range17,18 or consistent risk for AD, microinfarction, microhemorrhage and macrohe-
across all cognitive statuses. For example, in older adults morrhage of the brain, and vascular cognitive impairment.44
with mild cognitive deficits using antihypertensive medica- At autopsy, hypertensive older adults have evidence of greater
tion, a lower SBP, rather than a high SBP is associated with AD pathology in the brain, including neurofibrillary tangles
reduced volumes of thalamus, putamen, and hippocampus.19 and neuritic A plaques.4549 The frequency of AD pathology
In addition, low DBP is also associated with lower cortical increases with increasing SBP46 and with greater PP.50
thickness in older adults.20 Thus, in older adults, any ben- Recent in vivo positron emission tomography studies5153
efits of lowering SBP will have to be carefully balanced with show that the extent of A deposition in the brain is posi-
potential harms of simultaneously lowering DBP. BP targets tively associated with higher PP,53 SBP,52,54 and higher DBP.51
in older adults are currently controversial.21 The relationships between BP and brain A were consistent
While the mechanisms underlying these associations across cognitive groups (normal, mild cognitive impair-
between BP and atrophy are unclear, some evidence sug- ment, and AD),51 evident regardless of antihypertensive
gests that subcortical vascular pathology on cortical neu- therapy53,54 and could potentially be attributed to underly-
ronal apoptosis underlies brain atrophy.22 The relationship ing arterial stiffness.52,54,55 While these studies controlled for
between BP and cortical gray matter volume appears to antihypertensive medication use, they did not evaluate the

150 American Journal of Hypertension 29(2) February 2016

Hypertension and Its Role in Cognitive Function

effect of effective BP control or differences by drug class. In negatively bias results in both observational studies and
addition, the effect of clinically diagnosed hypertension on RCTs. These challenges include, but are not limited to, when
brain A burden may differ by apolipoprotein E (APOE) in the life course BP measures are assessed, using resting BP
genotype, with the greatest A burden among clinically as a surrogate measure for complex vascular dynamics in
diagnosed hypertensive APOE-4 allele carriers.53 the periphery and brain, treatment effects combined with
There is also emerging data on the relationship between physiologic BP declines in older adults, and the use of cog-
BP and cerebral spinal fluid (CSF) measures of AD pathology nitive outcomes as the primary aims of relatively short-term
(high phosphorylated tau (p-tau) and low amyloid (A142)). studies.
Nation etal. have published 2 recent studies showing that ele-
vated PP is associated with increased CSF p-tau and decreased
Heterogeneity and bias within BP loweringtrials
A142 in cognitively normal older adults consistent with CSF
patterns of AD progression.56,57 Further, individuals with ele- There are important distinctions to be made when evaluat-
vated PP progressed to dementia more rapidly,57 suggesting ing and comparing RCTs of hypertension treatment, includ-
that pulsatile hemodynamics may be related to amyloidosis ing: whether the BP treatment is intended for the primary or
and tau-related neurodegeneration underlying dementia.56 secondary prevention of vascular disease, the length of the
Another study reports longitudinal declines in mean arterial intervention, differences between antihypertensive classes
pressure in the elderly are associated increases in CSF p-tau and unmeasured potential confounders that are just now
and decline in cognition.58 There is additional evidence that being identified. First, it is important to appreciate that most
ACE protein levels and activity in CSF are associated with hypertension treatment trials are usually designed as inter-
lower CSF A142 and higher p-tau levels, suggesting that ventions for the primary or secondary prevention of cardio-
modulation of the renin angiotensin system is related to AD vascular disease or stroke and do not make a priori cognitive
pathology.59 As of yet, there is scant data from RCTs on the endpoints or use cognition as the primary endpoint. These
effect of BP lowering on CSF levels of AD biomarkers. One studies only assess cognition as a secondary outcome,
pilot study reported that ramipril therapy inhibited CSF ACE which is often underpowered.64 However, it is now generally
activity and improved PP, but did not influence CSF A142.60 accepted that cerebrovascular disease is not only an impor-
tant factor in vascular dementia but may also contributes to
cognitive dysfunction in AD.44,65 ACochrane review focused
BP LOWERING AND DEMENTIARISK specifically on individuals with no history of cerebrovascular
disease and found no convincing evidence that BP lowering
While there is ample evidence that hypertension is associ- in late life prevents the development of dementia or cogni-
ated with cognitive impairment and cerebral pathology and tive impairment in hypertensive patients with no apparent
observational studies consistently suggest that BP lowering has prior cerebrovascular disease.63
potential benefit for reducing cognitive decline and dementia Next, the length of time the brain is exposed to elevated BP
incidence, clinical trials of BP lowering do not strongly support and PP is an essential factor to consider. Longitudinal stud-
the observational evidence. In general, these studies, summa- ies of BP across the life span show that BP and the prevalence
rized in several systematic reviews and meta-analyses, do not of hypertension peaks in late-middle age.6668 Age-related
show definitive evidence that BP lowering with individual anti- increase in BP is associated with increases in central arte-
hypertensive drugs or classes has an effect on cognitive decline rial stiffness and PP.66,68 Further, the duration of hyperten-
or dementia.9,10,6164 Of the large RCTs, antihypertensive treat- sion may be a stronger risk factor for cognitive dysfunction
ment has resulted in positive results in terms of prevention of than age. This point is demonstrated by the AGES study69
dementia (SYST-EUR) and cognitive decline (PROGRESS, that recently showed having history of midlife hypertension
HOPE), but nonsignificant results in Medical Research Council appears to modify the relationship between late-life hyper-
trial, Systolic Hypertension in the Elderly Program trial, Study tension and brain health. Among those without history of
on Cognition and Prognosis in the Elderly, and HYpertension midlife hypertension, higher SBP and DBP in late life was
in the Very Elderly Trial cognitive function assessment.61 The associated greater evidence of cerebral small vessel disease. In
combined result trials reporting incidence of dementia indicated contrast, participants with a history of midlife hypertension,
no significant difference between treatment and placebo;61 and it was lower late-life DBP that was associated with smaller
the combined results from the trials reporting change in global brain volumes and lower cognitive function.69 Therefore the
cognition using the Mini-Mental State Examination did not duration of hypertension is an important factor to consider
indicate a benefit from treatment, despite modest reductions in for the chronicity of effect of high BP and excess pulsatile
both SBP and DBP levels.63 Challenges of these RCTs and for pressure on end organs and findings of protective associa-
the future of hypertension research as it relates to cognition and tions between hypertension and cognition may reflect the
prevention of cognitive impairment are presented below. study of persons with short duration of hypertension.6 Most
intervention trials do not assess the duration of hyperten-
TO COGNITION AND DEMENTIA The effect of individual agents on BP and cognitive func-
tion is an obvious consideration given the different mecha-
There are several challenges to relating BP and BP low- nisms employed by antihypertensive classes. Using a network
ering to cognition that if not properly addressed can meta-analysis approach, Levi Marpillat etal. determined the

American Journal of Hypertension 29(2) February 2016 151

Hughes and Sink

rank-order of benefit for each drug class on overall cogni- neuroimaging and biofluid markers discussed above. Relying
tion62 and found results similar to those reported by Duron solely on detecting cognitive decline and further expecting
et al.61 Benefit was highest for ARBs followed by calcium treatment to alter cognitive trajectories can be a challenge
channel blockers, -blockers, diuretics, and angiotensin- for short- and long-term RCTs. In AD research, it is increas-
converting enzyme inhibitors over placebo.62 However, BP ingly accepted that AD biomarkers of tau and A pathology
lowering appears to have beneficial effects on executive precede more salient features of neurodegeneration and cog-
function regardless of antihypertensive class.62 nitive decline by years and even decades.75 Therefore, RCTs
It is also possible that the goal of showing the differential testing agents that are proposed to alter the disease process
effectiveness of individual drug classes may have biased exist- can be hypothesized to alter dementia-related biomarkers
ing RCTs. Previous trials test the effect of specific agents on early with greater impact than can be expected for cogni-
cognition rather than assessing the effect of BP lowering itself tive endpoints in RCTs of a feasible length. Therefore, we
on cognition. The ongoing SPRINT trial is the first proof of propose that using dementia-related biomarkers underlying
concept clinical trial to directly test BP lowering itself on car- cognitive changes will be an essential component of future
diovascular, cognitive, and brain structural outcomes regard- RCTs that seek to prevent dementia and modify the disease
less of agent used to achieve randomized treatment goals.70 process.
There is emerging evidence that key unmeasured genetic
and physiologic factors may play an important role in the Limitations of standard clinical BP measurement may
effect of BP treatment on brain health and cognitive end- influence hypertensioncognition study results
points. The fact that APOE gene is the genetic risk factor for
both cardiovascular disease and AD71 is often overlooked. It is also important to consider the underlying physiology
As the primary genetic risk factor for late onset sporadic that resting BP is intended to represent in studies of cogni-
AD, carriage of the episilon 4 allele (APOE4) has broad tion (see Figure 1). At the instant resting BP is measured,
effects on neurocognitive function and may accelerate it is intended to represent the usual exposure to BP of an
the progression of AD pathology and cognitive decline.72 individual across hours and days. In the context of long-term
Recent studies show that APOE genotype moderates the exposure studies, this extends to make clinical BP a proxy of
association between BP and global cognition73,74 as well as usual BP over weeks, years, and even decades of exposure.
episodic memory and verbal ability.73 The presence of the Resting BP is often the preferred method of choice given its
APOE4 allele in hypertensive adults was associated with accessibility, convenience, and ease of use. The approach of
steeper cognitive decline over the following 19 to 2 dec- taking several BP measurements and then averaging reduces
ades.10 Taken together these studies suggest that APOE instrument variability; however, it is well known that clinical
genotype may predict who is likely to find cognitive ben- BP measures are susceptible to physiologic bias due to white
efit from antihypertensive therapy and clinical trials should coat hypertension or masked hypertension.76,77 Typically
consider this in their design. both of these phenomena are identified by ambulatory BP
Finally, most studies of antihypertensive treatment have monitoring (ABPM) and may contribute to some of the
included only cognitive testing and incident impairment as variability in serial BP measures over time in longitudinal
secondary outcomes to existing studies without surrogate studies.

Figure1. Diagram of the components contributing to arterial blood pressure, its antihypertensive targets and associated dementia-related brain out-
comes. *Proposed cardiovascular targets. ARBs, angiotensin receptor blockers; ACIs, angiotensin-converting enzymes; CCBs, calcium channel blockers.

152 American Journal of Hypertension 29(2) February 2016

Hypertension and Its Role in Cognitive Function

In addition to circumventing these biases, ABPM offers calculate PP, but it can be derived from any point in the vas-
additional physiologic advantages over clinical BP measure- culature. In general, a PP greater than 60mm Hg increases
ments. These include: measurements averaging BP measures the risk for cerebrovascular events such as stroke. Higher
over a 24-hour period, diurnal patterns in BP, nocturnal PP is associated with severity of WMH91 and its progres-
assessment of BP, as well as heart rate and BP variability over sion over time25; abnormalities in cerebral blood flow23,24
the entire monitoring period. As a result, studies including and cerebrovascular pulstility,92 increased mean cortical A
24-hour ABPM show stronger associations between ABPM- deposition,52,53 CSF p-tau levels,56 severity of cerebrovascu-
defined BP measures and dementia-related outcomes than lar disease at autopsy,50 lower cortical gray matter volume,23
clinical resting BP alone78 including associations between and declines in cognition over time.93 It is important to note
higher 24-hour, daytime, and nighttime BP with lower gray that PP remains susceptible to the same biases as resting BP
matter volume79 and WMH volumes.80 Higher ABPM levels when derived from clinical BP measures.
and non-dipping circadian patterns are also associated with There are additional methods to more directly assess
greater WMH. Normally the BP declines as an individual the extent of underlying vascular stiffness. Arterial stiff-
sleeps. Nocturnal non-dippers (night-time SBP reduc- ness measured by pulse wave velocity (PWV) or ultrasound
tion <10%) and extreme nocturnal dippers (night-time can be assessed locally and regionally and provides a more
SBP reduction of >20%) tend to have a greater burden of accurate assessment of vascular compliance and stiffness
WMH81,82 than dippers with normal nocturnal BP patterns than brachial pressure alone. In essence, arterial stiffness
(night-time SBP reduction 1020%). Associations between directly relates central PP to kidneys and brain. The greater
different ABPM parameters (circadian pattern, short-term the stiffness the more pulsatile pressure is delivered to end
variability) and poorer performance scores in cognitive func- organs. Similar to PP, PWV increases with age,66,68 but it is
tion tests have been reported, especially in elderly hyperten- not as susceptible to late-life BP declines.94 Greater periph-
sives.78 Longitudinal studies using ABPM report similar and eral arterial stiffness, measured by PWV is a risk factor for
often stronger associations between diurnal BP and cogni- hypertension,95 stroke,96 cerebral small vessel disease,26,33
tion compared with resting BP measures alone. Individuals smaller brain volumes,97,98 age-related cognitive decline,7
with elevated 24-hour SBP tend to have with greater brain AD pathology,54,55 and dementia.4,7 Aortic arch PWV can
atrophy and greater progression of WMH over 5years of fol- also be measured with phase-contrast cardiac MR imaging.
low-up.83 Higher evening DBP on ABPM was also associated Imaging advances in transcranial doppler ultrasound and
with greater risk cognitive impairment 20years later.13 Taken cerebral blood flow magnetic resonance imaging may prove
together, these studies suggest that diurnal variations in BP to be the most accurate assessment of cerebral pulsatile flow
are important predictors of incident cognitive impairment and arterial stiffness. Cerebral blood flow of the middle cer-
and white matter abnormalities indicative of brain ischemia. ebral artery as measured by transcranial doppler ultrasound
This is particularly important for older adults because noc- is tightly correlated with peripheral PP and the extent of
turnal BP abnormalities (e.g., non-dipping) are more com- arterial stiffness.24 Transcranial doppler ultrasound derived
mon and have a greater impact on cognition.78 measures have been associated with cognitive decline and
Other metrics of BP homeostasis are emerging as impor- dementia,99 as well as smaller brain volume and larger ven-
tant factors related to brain health and cognition in aging tricles, supporting the notion that excessive cerebral arterial
adults. These include intervisit BP variability,8486 orthostatic pulsatility harms the brain.100
intolerance,87 and heart rate variability.88 In particular, inter-
visit variability in BP is emerging as an important marker CONCLUSIONS
of dyshomeostasis in innate BP control with initial studies
suggesting that variability in SBP over time is associated with To summarize the literature: (i) the strongest evidence that
greater atrophy, a higher rate of cortical atrophy and thin- elevated BP is a risk factor for dementia and cognitive decline
ning,84 global cognitive dysfunction,85,86 and worse psycho- comes from observational studies with midlife measures of
motor speed and verbal memory.86 BP and late-life measures of the cognitive performance, (ii)
the associations between late-life measures of BP and cogni-
The importance of assessing pulsatile flow from the heart to tion are less consistent, (iii) midlife hypertension likely better
thebrain reflects the long-term effect and duration of hypertensions
effect on the brain which can be also be captured by measures
As a result of its extensive microvasculature, the brain is a of arteriosclerosis (including PWV), and (iv) there is com-
high flow, low resistance organ that is continuously exposed pelling evidence that hypertension is associated with vascular
to the mechanical forces of cardiac pulsations.89 In the con- dysfunction and evidence of cerebrovascular disease and A
text of dementia, peripheral BP is only a surrogate marker deposition, 2 major pathologic factors in dementia; however,
for the degree of pulsatile energy to which the brain is (v) to date, there is a lack of definitive support for pharma-
exposed. In essence, arterial stiffness is the mechanism that cologic BP lowering to prevent dementia from randomized
relates the pulsatile force of the heart to the brain.90 Arterial placebo-controlled clinical trials. While non-pharmacologic
stiffness increases with age and is proposed to be accelerated interventions for BP reduction were outside the scope of this
by chronic hypertension.67,68 PP is often used as a surrogate review, it should be mentioned that exercise, in particular,
marker of arterial stiffness because it is often a readily avail- because of pluripotent effects on the vasculature, including
able metric of convenience. PP (SBP DBP) represents the the regulation of vascular tone, cerebral blood flow, endothe-
net pulsatility during systole. Most studies use brachial BP to lial function, microvascular recruitment, energy metabolism,

American Journal of Hypertension 29(2) February 2016 153

Hughes and Sink

and insulin actions on the vessel (all important for brain 4. Rabkin SW. Arterial stiffness: detection and consequences in cogni-
health), could be an effective intervention for mitigating the tive impairment and dementia of the elderly. J Alzheimers Dis 2012;
association between hypertension and cognitive impairment. 5. Gorelick PB, Nyenhuis D; American Society of Hypertension. Writing
There is growing consensus from AD studies that bio- G, Materson BJ, Calhoun DA, Elliott WJ, Phillips RA, Taler SJ,
markers related to dementia change years and decades prior Townsend RR. Blood pressure and treatment of persons with hyperten-
to neurodegeneration and brain atrophy most closely linked sion as it relates to cognitive outcomes including executive function.
Am Soc Hypertens 2012; 6:309315.
to cognitive dysfunction; therefore, biomarkers maybe use- 6. Power MC, Weuve J, Gagne JJ, McQueen MB, Viswanathan A, Blacker
ful as surrogate markers of AD pathology in clinical trials. D. The association between blood pressure and incident Alzheimer
Future clinical trials should focus on controlling midlife disease: a systematic review and meta-analysis. Epidemiology 2011;
hypertension, before arterial stiffening begins to transmit 22:646659.
excess pulsatility to the peripheral microvsculature, and 7. Pase MP, Herbert A, Grima NA, Pipingas A, ORourke MF. Arterial
stiffness as a cause of cognitive decline and dementia: a systematic
include dementia biomarkers and assess genetic and cardio- review and meta-analysis. Intern Med J 2012; 42:808815.
metabolic risk factors that have been associated with pro- 8. Qiu C, Winblad B, Fratiglioni L. The age-dependent relation of blood
gression of the underlying disease pathology. Though this pressure to cognitive function and dementia. Lancet Neurol 2005;
review was focused primarily on cognitive impairment in 4:487499.
9. Birns J, Kalra L. Cognitive function and hypertension. J Hum Hypertens
general and mechanistic links between hypertension and 2009; 23:8696.
AD, abnormalities in BP regulation may affect other neuro- 10. Birns J, Morris R, Donaldson N, Kalra L. The effects of blood pressure
degenerative disorders as well. For example, in patients with reduction on cognitive function: a review of effects based on pooled
Parkinsons disease, orthostatic hypotension and supine data from clinical trials. J Hypertens 2006; 24:19071914.
hypertension are associated with worse cognitive function. 11. Kennelly SP, Lawlor BA, Kenny RA. Blood pressure and the risk for
dementia: a double edged sword. Ageing Res Rev 2009; 8:6170.
Only one clinical trial has focused on BP lowering itself 12. Tolppanen AM, Solomon A, Soininen H, Kivipelto M. Midlife vascu-
and set a priori cognitive endpointsthe SPRINT trial. The lar risk factors and Alzheimers disease: evidence from epidemiological
SPRINT trial was designed to determine if intensive vs. studies. J Alzheimers Dis 2012; 32:531540.
standard BP lowering would affect the trajectory of cogni- 13. Taylor C, Tillin T, Chaturvedi N, Dewey M, Ferri CP, Hughes A, Prince
M, Richards M, Shah A, Stewart R. Midlife hypertensive status and cog-
tive decline, brain structural abnormalities, and/or incident nitive function 20years later: the Southall and Brent revisited study. J
dementia in middle-aged and older adults.70 The interven- Am Geriatr Soc 2013; 61:14891498.
tion was stopped early (press release 9 November 2015)for 14. Gottesman RF, Schneider AL, Albert M, Alonso A, Bandeen-Roche K,
cardiovascular disease benefit, before the majority of 4-year Coker L, Coresh J, Knopman D, Power MC, Rawlings A, Sharrett AR,
cognitive data were collected. However, efforts are now Wruck LM, Mosley TH. Midlife hypertension and 20-year cognitive
change: the atherosclerosis risk in communities neurocognitive study.
underway to collect the remaining cognitive data and we are JAMA Neurol 2014; 71:12181227.
hopeful that SPRINT may still be able to answer this impor- 15. Beauchet O, Celle S, Roche F, Bartha R, Montero-Odasso M, Allali
tant question. G, Annweiler C. Blood pressure levels and brain volume reduc-
tion: a systematic review and meta-analysis. J Hypertens 2013;
16. Jennings JR, Mendelson DN, Muldoon MF, Ryan CM, Gianaros PJ, Raz
N, Aizenstein H. Regional grey matter shrinks in hypertensive indi-
ACKNOWLEDGMENTS viduals despite successful lowering of blood pressure. J Hum Hypertens
2012; 26:295305.
K.M.S. is funded, in parts, by RFP NHLBI-HC-09-04, 17. Walhovd KB, Storsve AB, Westlye LT, Drevon CA, Fjell AM. Blood
markers of fatty acids and vitamin D, cardiovascular measures, body
NINDS R01 NS075107-01, NIA U01 AG022376, several mass index, and physical activity relate to longitudinal cortical thinning
Alzheimers Disease Cooperative Studies (NIA), and is the in normal aging. Neurobiol Aging 2014; 35:10551064.
site PI for an industry sponsored trial of an amyloid imag- 18. Taki Y, Thyreau B, Kinomura S, Sato K, Goto R, Wu K, Kawashima R,
ing agent (Navidea NAV4-02). funded in parts by Fukuda H. A longitudinal study of age- and gender-related annual rate
of volume changes in regional gray matter in healthy adults. Hum Brain
NIH HHSN268201100027C and the Department of Internal Mapp 2013; 34:22922301.
Medicine, Section on Gerontology and Geriatric Medicine. 19. Foster-Dingley JC, van der Grond J, Moonen JE, van den Berg-

Huijsmans AA, de Ruijter W, van Buchem MA, de Craen AJ, van der
Mast RC. Lower blood pressure is associated with smaller subcortical
DISCLOSURE brain volumes in older persons. Am J Hypertens 2015; 28:11271133.
20. van Velsen EF, Vernooij MW, Vrooman HA, van der Lugt A, Breteler
The authors declared no conflict of interest. MM, Hofman A, Niessen WJ, Ikram MA. Brain cortical thickness in
the general elderly population: the Rotterdam Scan Study. Neurosci Lett
2013; 550:189194.
21. Reisin E, Harris RC, Rahman M. Commentary on the 2014 BP guide-
lines from the panel appointed to the Eighth Joint National Committee
REFERENCES (JNC 8). J Am Soc Nephrol 2014; 25:24192424.
22. Viswanathan A, Gray F, Bousser MG, Baudrimont M, Chabriat
1. Crescioni M, Gorina Y, Bilheimer L, Gillum RF. Trends in health status and H. Cortical neuronal apoptosis in CADASIL. Stroke 2006;
health care use among older men. Natl Health Stat Report 2010; 21:118. 37:26902695.
2. Tzourio C, Laurent S, Debette S. Is hypertension associated with an 23. Muller M, van der Graaf Y, Visseren FL, Vlek AL, Mali WP, Geerlings
accelerated aging of the brain? Hypertension 2014; 63:894903. MI, Group SS. Blood pressure, cerebral blood flow, and brain volumes.
3. Wiesmann M, Kiliaan AJ, Claassen JA. Vascular aspects of cogni- The SMART-MR study. J Hypertens 2010; 28:14981505.
tive impairment and dementia. J Cereb Blood Flow Metab 2013; 24. Xu TY, Staessen JA, Wei FF, Xu J, Li FH, Fan WX, Gao PJ, Wang JG, Li
33:16961706. Y. Blood flow pattern in the middle cerebral artery in relation to indices

154 American Journal of Hypertension 29(2) February 2016

Hypertension and Its Role in Cognitive Function

of arterial stiffness in the systemic circulation. Am J Hypertens 2012; a study of the association of microbleeds categorized on a basis of vas-
25:319324. cular territories and cardiovascular risk factors. J Stroke Cerebrovasc Dis
25. Verhaaren BF, Vernooij MW, de Boer R, Hofman A, Niessen WJ, van 2014; 23:e5e11.
der Lugt A, Ikram MA. High blood pressure and cerebral white mat- 43. van Veluw SJ, Zwanenburg JJ, Engelen-Lee J, Spliet WG, Hendrikse J,
ter lesion progression in the general population. Hypertension 2013; Luijten PR, Biessels GJ. In vivo detection of cerebral cortical microin-
61:13541359. farcts with high-resolution 7T MRI. J Cereb Blood Flow Metab 2013;
26. Poels MM, Zaccai K, Verwoert GC, Vernooij MW, Hofman A, van 33:322329.
der Lugt A, Witteman JC, Breteler MM, Mattace-Raso FU, Ikram MA. 44. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C,
Arterial stiffness and cerebral small vessel disease: the Rotterdam Scan Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider
Study. Stroke 2012; 43:26372642. JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT,
27. Vlek AL, Visseren FL, Kappelle LJ, Witkamp TD, Vincken KL, Mali WP, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S; American
van der Graaf Y, Group SS. Blood pressure and white matter lesions in Heart Association Stroke Council CoE, Prevention CoCNCoCR,
patients with vascular disease: the SMART-MR study. Curr Neurovasc Intervention, Council on Cardiovascular S, Anesthesia. Vascular
Res 2009; 6:155162. contributions to cognitive impairment and dementia: a statement
28. Dufouil C, Chalmers J, Coskun O, Besancon V, Bousser MG, Guillon for healthcare professionals from the American Heart Association/
P, MacMahon S, Mazoyer B, Neal B, Woodward M, Tzourio-Mazoyer American Stroke Association. Stroke 2011; 42:26722713.
N, Tzourio C; Investigators PMS. Effects of blood pressure lower- 45. Sparks DL, Scheff SW, Liu H, Landers TM, Coyne CM, Hunsaker JC III.
ing on cerebral white matter hyperintensities in patients with stroke: Increased incidence of neurofibrillary tangles (NFT) in non-demented
the PROGRESS (Perindopril Protection Against Recurrent Stroke individuals with hypertension. J Neurol Sci 1995; 131:162169.
Study) Magnetic Resonance Imaging Substudy. Circulation 2005; 46. Petrovitch H, Ross GW, Steinhorn SC, Abbott RD, Markesbery W,
112:16441650. Davis D, Nelson J, Hardman J, Masaki K, Vogt MR, Launer L, White
29. Firbank MJ, Wiseman RM, Burton EJ, Saxby BK, OBrien JT, Ford GA. LR. AD lesions and infarcts in demented and non-demented Japanese-
Brain atrophy and white matter hyperintensity change in older adults American men. Ann Neurol 2005; 57:98103.
and relationship to blood pressure. Brain atrophy, WMH change and 47. Petrovitch H, White LR, Izmirilian G, Ross GW, Havlik RJ, Markesbery
blood pressure. J Neurol 2007; 254:713721. W, Nelson J, Davis DG, Hardman J, Foley DJ, Launer LJ. Midlife blood
30. Godin O, Tzourio C, Maillard P, Mazoyer B, Dufouil C.
pressure and neuritic plaques, neurofibrillary tangles, and brain weight
Antihypertensive treatment and change in blood pressure are associ- at death: the HAAS. Honolulu-Asia aging Study. Neurobiol Aging 2000;
ated with the progression of white matter lesion volumes: the Three- 21:5762.
City (3C)-Dijon Magnetic Resonance Imaging Study. Circulation 48. Beach TG, Wilson JR, Sue LI, Newell A, Poston M, Cisneros R, Pandya
2011; 123:266273. Y, Esh C, Connor DJ, Sabbagh M, Walker DG, Roher AE. Circle of
31. Jeerakathil T, Wolf PA, Beiser A, Hald JK, Au R, Kase CS, Massaro JM, Willis atherosclerosis: association with Alzheimers disease, neuritic
DeCarli C. Cerebral microbleeds: prevalence and associations with plaques and neurofibrillary tangles. Acta Neuropathol 2007; 113:1321.
cardiovascular risk factors in the Framingham Study. Stroke 2004; 49. Hoffman LB, Schmeidler J, Lesser GT, Beeri MS, Purohit DP, Grossman
35:18311835. HT, Haroutunian V. Less Alzheimer disease neuropathology in medi-
32. Henskens LH, van Oostenbrugge RJ, Kroon AA, de Leeuw PW, Lodder cated hypertensive than nonhypertensive persons. Neurology 2009;
J. Brain microbleeds are associated with ambulatory blood pressure lev- 72:17201726.
els in a hypertensive population. Hypertension 2008; 51:6268. 50. Nation DA, Delano-Wood L, Bangen KJ, Wierenga CE, Jak AJ, Hansen
33. Henskens LH, Kroon AA, van Oostenbrugge RJ, Gronenschild
LA, Galasko DR, Salmon DP, Bondi MW. Antemortem pulse pres-
EH, Fuss-Lejeune MM, Hofman PA, Lodder J, de Leeuw PW. sure elevation predicts cerebrovascular disease in autopsy-confirmed
Increased aortic pulse wave velocity is associated with silent cerebral Alzheimers disease. J Alzheimers Dis 2012; 30:595603.
small-vessel disease in hypertensive patients. Hypertension 2008; 51. Toledo JB, Toledo E, Weiner MW, Jack CR Jr, Jagust W, Lee VM,
52:11201126. Shaw LM, Trojanowski JQ, Alzheimers Disease Neuroimaging
34. Gons RA, de Laat KF, van Norden AG, van Oudheusden LJ, van I.Cardiovascular risk factors, cortisol, and amyloid-beta deposition in
Uden IW, Norris DG, Zwiers MP, de Leeuw FE. Hypertension and Alzheimers Disease Neuroimaging Initiative. Alzheimers Dement 2012;
cerebral diffusion tensor imaging in small vessel disease. Stroke 2010; 8:483489.
41:28012806. 52. Langbaum JB, Chen K, Launer LJ, Fleisher AS, Lee W, Liu X, Protas
35. Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen HD, Reeder SA, Bandy D, Yu M, Caselli RJ, Reiman EM. Blood pres-
WJ, Hofman A, Krestin GP, Breteler MM. Prevalence and risk factors sure is associated with higher brain amyloid burden and lower glucose
of cerebral microbleeds: the Rotterdam Scan Study. Neurology 2008; metabolism in healthy late middle-age persons. Neurobiol Aging 2012;
70:12081214. 33:827.e11827.e19.
36. Prabhakaran S, Wright CB, Yoshita M, Delapaz R, Brown T, DeCarli C, 53. Rodrigue KM, Rieck JR, Kennedy KM, Devous MD Sr, Diaz-Arrastia
Sacco RL. Prevalence and determinants of subclinical brain infarction: R, Park DC. Risk factors for beta-amyloid deposition in healthy aging:
the Northern Manhattan Study. Neurology 2008; 70:425430. vascular and genetic effects. JAMA Neurol 2013; 70:600606.
37. Vlek AL, Visseren FL, Kappelle LJ, Geerlings MI, Vincken KL, Mali 54. Hughes TM, Kuller LH, Barinas-Mitchell EJ, Mackey RH, McDade EM,
WP, van der Graaf Y, Group SS. Blood pressure and progression of cer- Klunk WE, Aizenstein HJ, Cohen AD, Snitz BE, Mathis CA, Dekosky
ebral atrophy in patients with vascular disease. Am J Hypertens 2009; ST, Lopez OL. Pulse wave velocity is associated with -amyloid deposi-
22:11831189. tion in the brains of very elderly adults. Neurology 2013; 81:17111718.
38. Vermeer SE, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MM. 55. Hughes TM, Kuller LH, Barinas-Mitchell EJ, McDade EM, Klunk WE,
Prevalence and risk factors of silent brain infarcts in the population- Cohen AD, Mathis CA, Dekosky ST, Price JC, Lopez OL. Arterial stiff-
based Rotterdam Scan Study. Stroke 2002; 33:2125. ness and beta-amyloid progression in nondemented elderly adults.
39. Longstreth WT Jr, Bernick C, Manolio TA, Bryan N, Jungreis CA, Price JAMA Neurol 2014; 71:562568.
TR. Lacunar infarcts defined by magnetic resonance imaging of 3660 56. Nation DA, Edland SD, Bondi MW, Salmon DP, Delano-Wood L,
elderly people: the Cardiovascular Health Study. Arch Neurol 1998; Peskind ER, Quinn JF, Galasko DR. Pulse pressure is associated with
55:12171225. Alzheimer biomarkers in cognitively normal older adults. Neurology
40. Bezerra DC, Sharrett AR, Matsushita K, Gottesman RF, Shibata D, 2013; 81:20242027.
Mosley TH Jr, Coresh J, Szklo M, Carvalho MS, Selvin E. Risk factors 57. Nation DA, Edmonds EC, Bangen KJ, Delano-Wood L, Scanlon BK,
for lacune subtypes in the Atherosclerosis Risk in Communities (ARIC) Han SD, Edland SD, Salmon DP, Galasko DR, Bondi MW; Alzheimers
Study. Neurology 2012; 78:102108. Disease Neuroimaging Initiative I. Pulse pressure in relation to tau-
41. Yates PA, Villemagne VL, Ellis KA, Desmond PM, Masters CL, Rowe mediated neurodegeneration, cerebral amyloidosis, and progression to
CC. Cerebral microbleeds: a review of clinical, genetic, and neuroimag- dementia in very old adults. JAMA Neurol 2015; 72:546553.
ing associations. Front Neurol 2014; 4:205. 58. Glodzik L, Rusinek H, Pirraglia E, McHugh P, Tsui W, Williams S,
42. Jia Z, Mohammed W, Qiu Y, Hong X, Shi H. Hypertension increases the Cummings M, Li Y, Rich K, Randall C, Mosconi L, Osorio R, Murray
risk of cerebral microbleed in the territory of posterior cerebral artery: J, Zetterberg H, Blennow K, de Leon M. Blood pressure decrease

American Journal of Hypertension 29(2) February 2016 155

Hughes and Sink

correlates with tau pathology and memory decline in hypertensive 76. Franklin SS, Thijs L, Hansen TW, OBrien E, Staessen JA. White-coat
elderly. Neurobiol Aging 2014; 35:6471. hypertension: new insights from recent studies. Hypertension 2013;
59. Jochemsen HM, Teunissen CE, Ashby EL, van der Flier WM, Jones 62:982987.
RE, Geerlings MI, Scheltens P, Kehoe PG, Muller M. The association of 7 7. Peacock J, Diaz KM, Viera AJ, Schwartz JE, Shimbo D. Unmasking
angiotensin-converting enzyme with biomarkers for Alzheimers dis- masked hypertension: prevalence, clinical implications, diag-
ease. Alzheimers Res Ther 2014; 6:27. nosis, correlates and future directions. J Hum Hypertens 2014;
60. Wharton W, Stein JH, Korcarz C, Sachs J, Olson SR, Zetterberg H, 28:521528.
Dowling M, Ye S, Gleason CE, Underbakke G, Jacobson LE, Johnson 78. Coca A, Camafort M, Domenech M, Sierra C. Ambulatory blood pres-
SC, Sager MA, Asthana S, Carlsson CM. The effects of ramipril in indi- sure in stroke and cognitive dysfunction. Curr Hypertens Rep 2013;
viduals at risk for Alzheimers disease: results of a pilot clinical trial. J 15:150159.
Alzheimers Dis 2012; 32:147156. 79. Celle S, Annweiler C, Pichot V, Bartha R, Barthlmy JC, Roche F,
61. Duron E, Hanon O. Antihypertensive treatments, cognitive decline, Beauchet O. Association between ambulatory 24-hour blood pressure
and dementia. J Alzheimers Dis 2010; 20:903914. levels and brain volume reduction: a cross-sectional elderly population-
62. Levi Marpillat N, Macquin-Mavier I, Tropeano AI, Bachoud-Levi AC, based study. Hypertension 2012; 60:13241331.
Maison P. Antihypertensive classes, cognitive decline and incidence of 80. Henskens LH, Kroon AA, van Oostenbrugge RJ, Gronenschild EH,
dementia: a network meta-analysis. J Hypertens 2013; 31:10731082. Hofman PA, Lodder J, de Leeuw PW. Associations of ambulatory blood
63. McGuinness B, Todd S, Passmore P, Bullock R. Blood pressure lower- pressure levels with white matter hyperintensity volumes in hyperten-
ing in patients without prior cerebrovascular disease for prevention sive patients. J Hypertens 2009; 27:14461452.
of cognitive impairment and dementia. Cochrane Database Syst Rev 81. Schwartz GL, Bailey KR, Mosley T, Knopman DS, Jack CR Jr, Canzanello
2009:CD004034. VJ, Turner ST. Association of ambulatory blood pressure with ischemic
64. Zanchetti A, Liu L, Mancia G, Parati G, Grassi G, Stramba-Badiale brain injury. Hypertension 2007; 49:12281234.
M, Silani V, Bilo G, Corrao G, Zambon A, Scotti L, Zhang X, Wang 82. Nakamura K, Oita J, Yamaguchi T. Nocturnal blood pressure dip in
H, Zhang Y, Zhang X, Guan TR, Berge E, Redon J, Narkiewicz K, stroke survivors. Apilot study. Stroke 1995; 26:13731378.
Dominiczak A, Nilsson P, Viigimaa M, Laurent S, Agabiti-Rosei E, 83. Goldstein IB, Bartzokis G, Guthrie D, Shapiro D. Ambulatory

Wu Z, Zhu D, Rodicio JL, Ruilope LM, Martell-Claros N, Pinto F, blood pressure and the brain: a 5-year follow-up. Neurology 2005;
Schmieder RE, Burnier M, Banach M, Cifkova R, Farsang C, Konradi 64:18461852.
A, Lazareva I, Sirenko Y, Dorobantu M, Postadzhiyan A, Accetto R, 84. Gonzalez CE, Pacheco J, Beason-Held LL, Resnick SM. Longitudinal
Jelakovic B, Lovic D, Manolis AJ, Stylianou P, Erdine S, Dicker D, Wei changes in cortical thinning associated with hypertension. J Hypertens
G, Xu C, Xie H, Coca A, OBrien J, Ford G. Blood pressure and low- 2015; 33:12421248.
density lipoprotein-cholesterol lowering for prevention of strokes and 85. Bhm M, Schumacher H, Leong D, Mancia G, Unger T, Schmieder R,
cognitive decline: a review of available trial evidence. J Hypertens 2014; Custodis F, Diener HC, Laufs U, Lonn E, Sliwa K, Teo K, Fagard R,
32:17411750. Redon J, Sleight P, Anderson C, ODonnell M, Yusuf S. Systolic blood
65. Provenzano FA, Muraskin J, Tosto G, Muraskin J, Tosto G, Narkhede pressure variation and mean heart rate is associated with cognitive dys-
A, Wasserman B, Griffith E, Guzman V, Meier I, Zimmerman M, function in patients with high cardiovascular risk. Hypertension 2015;
Brickman A. White matter hyperintensities and cerebral amyloidosis: 65:651661.
necessary and sufficient for clinical expression of alzheimer disease? 86. Yano Y, Ning H, Allen N, Reis JP, Launer LJ, Liu K, Yaffe K, Greenland
JAMA Neurol 2013; 70:455461. P, Lloyd-Jones DM. Long-term blood pressure variability throughout
66. AlGhatrif M, Strait JB, Morrell CH, Canepa M, Wright J, Elango P, young adulthood and cognitive function in midlife: the Coronary
Scuteri A, Najjar SS, Ferrucci L, Lakatta EG. Longitudinal trajecto- Artery Risk Development in Young Adults (CARDIA) study.
ries of arterial stiffness and the role of blood pressure: the Baltimore Hypertension 2014; 64:983988.
Longitudinal Study of Aging. Hypertension 2013; 62:934941. 87. Elmstahl S, Widerstrom E. Orthostatic intolerance predicts mild cogni-
67. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in tive impairment: incidence of mild cognitive impairment and dementia
cardiovascular disease enterprises: Part I: aging arteries: a set up for from the Swedish general population cohort Good Aging in Skane. Clin
vascular disease. Circulation 2003; 107:139146. Interv Aging 2014; 9:19932002.
68. Scuteri A, Morrell CH, Orr M, Strait JB, Tarasov KV, Ferreli LA, Loi F, 88. Santos WB, Matoso JM, Maltez M, Goncalves T, Casanova M, Moreira
Pilia MG, Delitala A, Spurgeon H, Najjar SS, AlGhatrif M, Lakatta EG. IF, Lourenco RA, Monteiro WD, Farinatti PT, Soares PP, Oigman W,
Longitudinal perspective on the conundrum of central arterial stiffness, Neves MF, Correia ML. Spectral analyses of systolic blood pressure and
blood pressure, and aging. Hypertension 2014; 64:12191227. heart rate variability and their association with cognitive performance
69. Muller M, Sigurdsson S, Kjartansson O, Aspelund T, Lopez OL, Jonnson in elderly hypertensive subjects. J Hum Hypertens 2014; 29:488494.
PV, Harris TB, van Buchem M, Gudnason V, Launer LJ, Age GES-RSI. 89. ORourke MF, Safar ME. Relationship between aortic stiffening and
Joint effect of mid- and late-life blood pressure on the brain: the AGES- microvascular disease in brain and kidney: cause and logic of therapy.
Reykjavik study. Neurology 2014; 82:21872195. Hypertension 2005; 46:200204.
70. Ambrosius WT, Sink KM, Foy CG, Berlowitz DR, Cheung AK,
90. Mitchell GF. Effects of central arterial aging on the structure and func-
Cushman WC, Fine LJ, Goff DC Jr, Johnson KC, Killeen AA, Lewis CE, tion of the peripheral vasculature: implications for end-organ damage.
Oparil S, Reboussin DM, Rocco MV, Snyder JK, Williamson JD, Wright J Appl Physiol (1985) 2008; 105:16521660.
JT Jr, Whelton PK; The SSRG. The design and rationale of a multicenter 91. Liao D, Cooper L, Cai J, Toole J, Bryan N, Burke G, Shahar E, Nieto
clinical trial comparing two strategies for control of systolic blood pres- J, Mosley T, Heiss G. The prevalence and severity of white matter
sure: The Systolic Blood Pressure Intervention Trial (SPRINT). Clin lesions, their relationship with age, ethnicity, gender, and cardiovas-
Trials 2014; 11:532546. cular disease risk factors: the ARIC Study. Neuroepidemiology 1997;
71. Lopez MF, Krastins B, Ning M. The role of apolipoprotein E in neuro- 16:149162.
degeneration and cardiovascular disease. Expert Rev Proteomics 2014; 92. Webb AJ, Simoni M, Mazzucco S, Kuker W, Schulz U, Rothwell PM.
11:371381. Increased cerebral arterial pulsatility in patients with leukoaraiosis:
72. Wisdom NM, Callahan JL, Hawkins KA. The effects of apolipoprotein arterial stiffness enhances transmission of aortic pulsatility. Stroke 2012;
E on non-impaired cognitive functioning: a meta-analysis. Neurobiol 43:26312636.
Aging 2011; 32:6374. 93. Waldstein SR, Rice SC, Thayer JF, Najjar SS, Scuteri A, Zonderman AB.
73. Andrews S, Das D, Anstey KJ, Easteal S. Interactive effect of APOE Pulse pressure and pulse wave velocity are related to cognitive decline in
genotype and blood pressure on cognitive decline: the PATH through the Baltimore Longitudinal Study of Aging. Hypertension 2008; 51:99104.
life study. J Alzheimers Dis 2015; 44:10871098. 94. Joas E, Bckman K, Gustafson D, Ostling S, Waern M, Guo X, Skoog I.
74. de Frias CM, Schaie KW, Willis SL. Hypertension moderates the
Blood pressure trajectories from midlife to late life in relation to demen-
effect of APOE on 21-year cognitive trajectories. Psychol Aging 2014; tia in women followed for 37years. Hypertension 2012; 59:796801.
29:431439. 95. Najjar SS, Scuteri A, Shetty V, Wright JG, Muller DC, Fleg JL, Spurgeon
75. Jack CR Jr, Holtzman DM. Biomarker modeling of Alzheimers disease. HP, Ferrucci L, Lakatta EG. Pulse wave velocity is an independent pre-
Neuron 2013; 80:13471358. dictor of the longitudinal increase in systolic blood pressure and of

156 American Journal of Hypertension 29(2) February 2016

Hypertension and Its Role in Cognitive Function

incident hypertension in the Baltimore Longitudinal Study of Aging. J 98. Katulska K, Wykretowicz M, Minczykowski A, Krauze T, Milewska A,
Am Coll Cardiol 2008; 51:13771383. Piskorski J, Marciniak R, Stajgis M, Wysocki H, Guzik P, Wykretowicz
96. Pereira T, Maldonado J, Pereira L, Conde J. Aortic stiffness is an inde- A. Gray matter volume in relation to cardio-vascular stiffness. J Neurol
pendent predictor of stroke in hypertensive patients. Arq Bras Cardiol Sci 2014; 343:100104.
2013; 100:437443. 99. Demarin V, Morovic S. Ultrasound subclinical markers in assessing
97. Tsao CW, Seshadri S, Beiser AS, Westwood AJ, Decarli C, Au R, vascular changes in cognitive decline and dementia. J Alzheimers Dis
Himali JJ, Hamburg NM, Vita JA, Levy D, Larson MG, Benjamin EJ, 2014; 42(Suppl 3):S259S266.
Wolf PA, Vasan RS, Mitchell GF. Relations of arterial stiffness and 100. Whlin A, Ambarki K, Birgander R, Malm J, Eklund A. Intracranial
endothelial function to brain aging in the community. Neurology pulsatility is associated with regional brain volume in elderly individu-
2013; 81:984991. als. Neurobiol Aging 2014; 35:365372.

American Journal of Hypertension 29(2) February 2016 157