Curr Hypertens Rep (2012) 14:548555
DOI 10.1007/s11906-012-0315-2
SPECIAL SITUATIONS IN THE MANAGEMENT OF HYPERTENSION (T KOTCHEN, SECTION EDITOR)
Hypertension and Mild Cognitive Impairment
Cristina Sierra & Mnica Domnech &
Miguel Camafort & Antonio Coca
Published online: 17 October 2012
# Springer Science+Business Media New York 2012
Abstract The brain is an early target for organ damage due to
high blood pressure. Hypertension is the major modifiable risk
factor for stroke and small vessel disease. It has been sug-
gested that cerebral microvascular disease contributes to vas-
cular cognitive impairment. The mechanisms underlying
hypertension-related cognitive changes are complex and not
yet fully understood. Both high and, especially in the elderly,
low blood pressure (BP) have been linked to cognitive decline
and dementia. There is some evidence that antihypertensive
drug treatment could play a role in the prevention of cognitive
impairment through BP control. The BP levels that should be
targeted to achieve optimal perfusion while preventing cogni-
tive decline are still under debate.
Keywords Hypertension . Blood pressure . Cognitive
impairment . Cerebral small vessel disease . Aging . White
matter lesions . Lacunar infarct . Cerebral microbleeds .
Circadian rhythm . Arterial stiffness . Pulse wave velocity .
Intima-media thickness . Antihypertensive therapy
Introduction
Cognitive impairment may increase the risk of cardiovascu-
lar (CV) events. In a recently study involving two very large
cohorts of people at increased CV risk, a graded, inverse
association was shown between baseline Mini-Mental State
Examination (MMSE) score and risk of stroke, hospitaliza-
tion for congestive heart failure and death [1]. This
C. Sierra (*) : M. Domnech : M. Camafort : A. Coca
Hypertension and Vascular Risk Unit, Department of Internal
Medicine, Hospital Clinic of Barcelona. IDIBAPS,
University of Barcelona,
Villarroel 170,
Barcelona 08036, Spain
e-mail: csierra@clinic.ub.es
relationship was independent of all other measured prog-
nostic factors. Loss of cognitive function and hypertension
are two common conditions in the elderly and both signif-
icantly contribute to loss of personal independence.
Over the past ten years, a growing body of literature
including several large population-based clinicopathologic
or clinicoradiologic studies has highlighted the important
contribution of vascular risk factors (especially hyperten-
sion, but also diabetes, high level of cholesterol and smok-
ing) in Alzheimers disease (AD) [2]. Apart from the
occurrence of a clinical stroke, the main mechanism for
developing vascular dementia (VD), the mechanisms by
which vascular risk factors increase the risk of AD or
accelerate cognitive deterioration among patients with AD
are not fully elucidated. Most of these factors, especially
hypertension, have been shown to be associated with sub-
cortical lesions seen on brain magnetic resonance imaging
(MRI): white matter lesions (WML), lacunar infarctions, or
cerebral microbleeds [2]. Cerebral small vessel disease is a
term used with various meanings and in different contexts
(pathological, clinical, and neuroimaging aspects). These
diseases are thought to be the most frequent pathological
neurological processes and have a crucial role in at least
three fields: stroke, dementia, and aging.
Chronic hypertension leads to concomitant remodeling of
the cardiac and vascular systems, and various organs, espe-
cially the brain, kidney, and retina [3, 4]. The brain is an early
target for organ damage due to high blood pressure (BP) [3, 4],
which is the major modifiable risk factor for ischemic and
hemorrhagic stroke in men and women [5], as well as small
vessel disease [3, 4, 6] predisposing to lacunar infarction,
WML, and cerebral microbleeds, which are frequently silent
[3, 4, 7]. The clinical significance and pathological substrate
of WML are incompletely understood, but it is known that
WML are an important prognostic factor for stroke, cognitive
impairment, dementia and death [8].
Curr Hypertens Rep (2012) 14:548555
The relationship between BP and cognitive outcomes in
the elderly has received increasing attention because of its
implications for global health care. Hypertension affects
more than a third of the population worldwide, especially
those older than 65 years, of whom 6575 % report having
hypertension [3, 4]. The prevalence of asymptomatic hypo-
tension in this age group is 16.2 % [9]. Both high and low
BP have been linked to cognitive decline and dementia. In
addition, in elderly patients at high-risk of CV disease
exaggerated long-term visit-to-visit BP fluctuations have
recently been shown to be significantly associated with
lower MMSE scores, higher global deterioration scale
(GDS) scores, and cognitive impairment independent of
average BP [10]. The pathophysiology of the relationship
between BP and cognition is unclear, but hypoperfusion and
neurodegeneration have emerged as possible underlying
mechanisms [11, 12].
The possibility of preventing cognitive impairment or
dementia via control of CV risk factors has not been dem-
onstrated. Observational and epidemiological studies have
shown that antihypertensive therapy could have protective
effects on cognitive impairment and dementia [13]. How-
ever few large BP-lowering trials have incorporated cogni-
tive assessment or a diagnosis of dementia and the results
are controversial. Meta-analyses of these trials neither prove
nor disprove the efficacy of antihypertensive treatment on
dementia risk [13].
The BP levels that should be targeted to achieve optimal
perfusion while preventing cognitive decline are still under
debate.
Clinical Aspects of Cognitive Impairment
Cognitive impairment is defined by a transitory and pro-
gressive decline of some cognitive functions that does not
satisfy the diagnostic criteria of dementia. It precedes at
least 50 % of dementia onsets. Cognitive impairment can
be assessed by neuropsychological tests, but is not neces-
sarily evident in daily living. Cognitive decline is measured
not only by alterations in memory but also in functions such
as language, perception, abstract thought, judgment, plan-
ning ability and attention. Dementia is characterized by an
intellective deterioration that includes memory loss and one
or more other neuropsychological alterations, such as aprax-
ia, agnosia and aphasia, which interfere with social and
occupational living. Mental alterations include progressive
memory loss, space and temporal disorientation, loss of self-
sufficiency, and emotional depersonalization.
Vascular cognitive impairment (VCI) refers to the entire
spectrum of vascular-related cognitive impairment, from mild
to severe. Assessment of VCI requires a comprehensive
549
cognitive battery that includes an evaluation of executive,
memory, language and spatial functions.
Cognitive impairment and dementia are one of the prin-
cipal neurological disorders in the elderly. Aging is associ-
ated with a marked increase in the prevalence and incidence
of both degenerative and vascular types of dementia. The
estimated prevalence is around 8 % in people aged
65 years, and 1520 % in those aged>80 years [11]. AD
accounts for 5060 % of cases of dementia and VD for
30 %. It is known that the prevalence of AD doubles every
4.3 years and that of VD every 5.3 years [13].
Hypertension is a major risk for cerebrovascular disease
and therefore for VD. Traditionally, AD has been considered
as a primary neurodegenerative disorder and not of vascular
origin. However, as mentioned before, emerging evidence
supports the view that vascular risk factors and disorders
may be involved in AD [14]. It appears that there is a
continuous spectrum ranging from patients with pure VD
to patients with pure AD and including a large majority of
patients with contributions from both Alzheimer and vascu-
lar pathologies [2].
Pathological Aspects of Cerebral Microvascular Disease
Related to Cognitive Impairment
There are different types of small vessel diseases catego-
rized according to their pathogenesis. As proposed by the
review of Pantoni [6] the two most frequent are arterio-
losclerosis and cerebral amyloid angiopathy.
Multiple biological systems are involved in the patho-
genesis of cerebrovascular disease (Table 1) [15]. Arterio-
losclerosis is also known as an age-related and vascular risk-
factor-related small vessel disease. From a pathological
point of view this kind of small vessel disease is mainly
characterized by loss of smooth muscle cells from the tunica
media, deposits of fibro-hyaline material, narrowing of the
lumen, and thickening of the vessel wall. This form of the
disease is a common and systemic type that also affects the
kidneys and retinas and is strongly associated with aging,
diabetes, and, in particular, hypertension [6]. For this
reason it is also named hypertensive small vessel disease.
Other possible pathological features of this form of micro-
angiopathy are distal manifestations of atherosclerosis
(microatheroma) and the presence of elongated and dilated
vessels (microaneurysms).
Cerebral amyloid angiopathy is characterized by the pro-
gressive accumulation of congophilic, A4 immunoreac-
tive, amyloid protein in the walls of small-to-medium
sized arteries and arterioles predominantly located in the
leptomeningeal space, the cortex, and to a lesser extent, also
in the capillaries and veins. Cerebral amyloid angiopathy is
a pathological hallmark of AD, in which it is almost
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Table 1 Mechanisms of vascular aging* and age-related brain
changes** that increase vascular vulnerability in the elderly and increase
the risk of cerebrovascular disease (Adapted from Sierra et al [15])
* Oxidative stress and endothelial dysfunction
* Low-grade inflammation
* Increased arterial stiffness
* Upregulation of renin-angiotensin system (RAS)
* Impaired endothelial progenitor cell function
** Increased brain blood barrier permeability
** Tortuosity of white matter arterioles
** Reduced brain weight, expanded ventricles, increased choroids plexus
volume
** Small vessel disease
** Cerebral amyloid angiopathy
invariably seen [16]. This angiopathy is also very frequent
in the general elderly population, and its frequency increases
with age, affecting as many as 50 % of individuals in the
ninth decade [17]. There is also an association of cerebral
amyloid angiopathy with microbleeds on MRI [18], and it
has also been associated with the presence of cerebral is-
chemic changes such as WML and microinfarcts [19].
Blood Pressure, Cerebral Perfussion, and Cognition
High BP influences the cerebral circulation, causing adap-
tive vascular changes. Chronic intraluminal pressure stim-
ulates the growth of smooth muscle cells and enhanced
media thickness in resistance arteries that results in hyper-
trophic remodeling. Alternatively, inward remodeling may
occur, leading to eutrophic remodeling. Thus, hypertension
influences the autoregulation of cerebral blood flow by
shifting both the lower and upper limits of autoregulatory
capacity towards higher BP, while hypertensive patients
may be especially vulnerable to episodes of hypotension,
which may play a role in the development of silent cerebro-
vascular damage such as WML [6].
Hypertension accelerates arteriosclerotic changes in the
brain, predisposing it to atheroma formation in large diam-
eter blood vessels and arteriosclerosis and arteriolar tortu-
osity of small vessels of the cerebral vasculature. These
vascular changes, which include medial thickening and in-
timal proliferation, result in a reduced luminal diameter,
increased resistance to flow and a decline in perfusion
[6, 20]. This hypoperfusion can produce discrete regions
of cerebral infarction and diffuse ischemic changes in the
periventricular and deep white matter causing vascular cog-
nitive impairment, and may also contribute to the pathogen-
esis of AD by destabilizing neurons and synapses [20].
AD and VCI are the two leading causes of cognitive
impairment, with the former characterized by early loss of
Curr Hypertens Rep (2012) 14:548555
episodic memory and the latter typically involving impair-
ment of attention, information processing and executive
function [21].
High Blood Pressure and Risk of Cognitive Impairment
Results from cross-sectional [22] and longitudinal [2326]
studies have shown a correlation between BP and cognitive
function in the elderly. These studies have reported an associ-
ation between high systolic BP (SBP) (the Honolulu-Asia
Aging Study [24]), high diastolic BP (DBP) (the Uppsala
Study [25]), elevated SBP and DBP (the Framingham Study
[23]), and hypertension (National Heart, Lung, and Blood
Institute Twin Study [26]) at midlife and impaired cognitive
performance in late life. In addition, there is some evidence
that antihypertensive drug treatment could play a role in the
prevention of cognitive impairment [27] or vascular dementia
[28] through BP control.
The mechanisms underlying hypertension-related cogni-
tive changes are complex and not yet fully understood. It is
unclear whether the impact of elevated BP on cognitive
decline in late-life is mediated through its chronic negative
effect on the structural characteristics of the brain [29].
Some data suggest that high pulse pressure is associated
with an increased risk of AD [11]. Because increased pulse
pressure is a clinical indicator of arterial stiffness, it may be
postulated that functional changes in the arterial system are
involved in the pathogenesis of dementia.
However, some studies have reported an increased inci-
dence of dementia and AD in people with low diastolic or
systolic BP, especially in people aged 80 years [11]. The
severity of atherosclerosis increases with age, resulting in
high SBP and low DBP in later life. Severe atherosclerosis
in the very-elderly, as well as episodic or sustained hypo-
tension and, possibly, excessive treatment of hypertension,
may induce cerebral hypoperfusion, ischemia, and hypoxia
in this age group.
Cerebral WML are an important prognostic factor for
stroke [30, 31], stroke recurrence [3234], cognitive impair-
ment [3537], dementia [38] and death [8]. Various studies
have shown an association between cerebral WML and
cognitive function in both normotensive and hypertensive
elderly populations [35, 36, 3941].
Correlations between cerebral WML and elevated BP pro-
vide indirect evidence that structural and functional changes in
the brain over time may lead to reduced cognitive functioning
when BP control is poor or lacking. Skoog et al. [42] found an
association between elevated BP at age 70 and the develop-
ment of dementia 1015 years later, while patients with WML
at age 85 had a higher BP at age 70, suggesting that previously
increased BP may increase the risk of dementia by inducing
small-vessel disease and WML.
Curr Hypertens Rep (2012) 14:548555
Ambulatory Blood Pressure Monitoring and Cognitive
Impairment
Ambulatory blood pressure monitoring has proven to pro-
vide a better predictive value for CV events than clinic BP
measurement [43], although reproducibility of nocturnal BP
fall should be limited [44].
Some studies have shown that ambulatory BP variation is
associated with cognitive function. High nocturnal SBP
level [45], nondipper status [46], and exaggerated BP vari-
ability [47] are all suggested to be significant determinants
of cognitive impairment. WML or brain atrophy is sug-
gested to serve as a substantial pathophysiology.
High Blood Pressure and Cerebral Microvascular
Disease: Which Cognitive Domains are Affected?
As mentioned before, limited yet growing literature indi-
cates that microvascular brain damage is a potent risk factor
for cognitive decline in older individuals, especially hyper-
tensives, and for the onset of dementia. Neuropsychological
evaluation and also neuroimaging are needed for assessment
of its clinical consequences.
Each and every middle-aged or older individual with
high CV risk and/or evidence of stiffer and thicker large
artery should be screened for cognitive function and their
diagnosis monitored for cognitive deterioration. Mild cog-
nitive decline is a recently described syndrome that is
thought to constitute a transition phase between healthy
cognitive aging and dementia.
A major unsolved issue concerns whether there are cog-
nitive domains specifically affected by cerebral small vessel
disease and whether they differ from those more commonly
detected in age-associated cognitive decline or in AD [48].
Although small vessel disease is commonly detected in
patients with AD, it is a general hypothesis that cerebral
small vessel disease electively and predominantly affects
executive function, with slower information processing,
impairments in the ability to shift from one task to another,
and deficits in the ability to hold and manipulate information
[48]. Executive functions cannot be explored by MMSE,
the most widely adopted test for clinical screening of global
cognitive function. It has a low sensitivity for VCI. The
National Institute of Neurological Disorders and Stroke-
Canadian Stroke Network harmonization standard has pro-
posed the use of the Montreal Cognitive Assessment
(MoCA) [49]. This newly designed screening test incorpo-
rates subtests assessing executive functions and psychomo-
tor speed [50] that are frequently impaired in VCI.
Ideally, neuropsychological evaluation should include
tests exploring multiple cognitive domains: executive func-
tion and activation, language, visuospatial ability, and
551
memory. Efforts are made to identify whether one brief test
can provide useful insight into different domains, anatomi-
cal regions, and brain networks [48].
Impairments of attention, perceptual processing and ex-
ecutive function reflect more specific damage to deep sub-
cortical white matter circuits, many of which are located in
the internal watershed area of the frontal lobe [51]. Chronic
hypertension has a disproportionate effect on these areas
because accelerated arteriosclerotic changes in non-
communicating perforating arteries may not be reversible
by BP reduction once established [52]. Furthermore, epi-
sodic or sustained hypotension and, possibly, excessive
treatment of hypertension, may induce cerebral hypoperfu-
sion, ischemia and hypoxia that may, in turn, compromise
neuronal function and eventually evolve to a neurodegener-
ative process [20].
Stroke and Cognitive Impairment: Connecting Large
Arteries and Cerebral Small Vessel Disease
Although a continuous relationship between both systolic
and diastolic BP and the occurrence of stroke has been well
established, there is epidemiological evidence from the
MRFIT study (Multiple Risk Factor Intervention Trial) that
the systolic component of BP may exert a strong deleterious
effect on cerebrovascular disease [53]. It is known that
increased arterial stiffness results in increased characteristic
impedance of the aorta and increased pulse wave velocity,
which increases systolic and pulse pressures. Large-artery
stiffness is the main determinant of pulse pressure. Data
from the SHEP (Systolic Hypertension Elderly Program)
study show an 11 % increase in stroke risk and a 16 %
increase in the risk of all-cause mortality for each 10-mm
Hg increase in pulse pressure [54]. Laurent et al. [55], in a
longitudinal study, found that aortic stiffness, assessed by
carotid-femoral pulse wave velocity (the gold standard mea-
sure for clinical assessment of arterial stiffness), is an inde-
pendent predictor of fatal stroke in patients with essential
hypertension. In addition, it has recently been shown that
brachial pulse pressure, which is considered a measure of
arterial stiffness, is associated with the presence of WML in
the elderly [56].
The association between large artery stiffening and cog-
nitive impairment has been reported by several cross-
sectional studies and has been confirmed in longitudinal
studies [5759]. The mechanism of such association has
not yet been firmly established. Cerebral circulation has
specific characteristics making the brain continually and
passively perfused at high flow throughout systole and
diastole [60]. As mentioned before, cerebrovascular autor-
egulation maintains cerebral blood flow relatively constant
in the face of changes in arterial pressure within a certain
552
range, protecting the brain from sudden changes in perfu-
sion pressure. It has been suggested as a pathophysiological
explanation on the basis of differential input impedance in
the brain, and also in the kidney, compared with other
systemic vascular beds [60]. The unique features of the
kidney and brain are that they are continually and passively
perfused at high flow throughout systole and diastole. Their
vascular resistance is very low, so that in comparison to
other vascular beds, resistance is closer to input and charac-
teristic impedance. Torrential flow and low resistance to
flow in these organs exposes small arterial vessels to the
high-pressure fluctuations that exist in the carotid, vertebral,
an renal arteries [55]. Exposure of small vessels to highly
pulsatile pressure and flow may explain microvascular dam-
age and resulting intellectual deterioration [48].
Microalbuminuria and Cognitive Impairment: What
Are They Sharing?
Both cross-sectional and prospective studies have shown a
graded association between a marker of microvascular dis-
ease, such as microalbuminuria and the development of
cognitive decline [61, 62]. As suggested before, it is hy-
pothesized that microalbuminuria and cognitive decline may
share a common microvascular pathogenesis and progres-
sion. Microvascular changes of the brain are difficult or
expensive to study (MRI, Transcranial Doppler, SPECT,
etc.) but WML, silent lacunar infarcts and cerebral micro-
bleeds are the lesions considered as indicators of having
cerebral microvascular disease.
Further evidence comes from cross-sectional studies of
the retinal vasculature. Retinal arterioles share common
anatomical and physiological characteristics with cerebral
arterioles and are affected by hypertension and age. In the
Atherosclerosis Risk in Communities Study, any form of
retinopathy was associated with increased odds of cognitive
impairment [63]. The greater the severity of the retinopathy
(microaneurysms, hemorrhages, and exudates), the greater
were the odds of impaired cognition. Similar findings were
observed in the Cardiovascular Health Study in an older
cohort [64].
Antihypertensive Therapy and Cognitive Function
A recent review by Birns et al. [52] of cross-sectional
studies of the relationship between BP and cognition found
conflicting relationships with positive, negative and J- and
U-shaped associations. The majority of longitudinal studies
have found elevated BP to be associated with cognitive
decline and a small number of randomized controlled trials
have demonstrated heterogeneous effects of BP lowering on
Curr Hypertens Rep (2012) 14:548555
cognitive function. These findings suggest a complex rela-
tionship between BP and cognitive function, consistent with
known biological mechanisms.
Clinical trials assessing the impact of antihypertensive
therapy on cognitive outcomes have had conflicting results.
The combined results of these trials are also not conclusive.
A pooled analysis of the SHEP [65], Syst-Eur [66], PROG-
RESS [67], and SCOPE [68] trials whose participants total
11,794 in the treatment group and 11,711 in the control
group, revealed a non-significant association between anti-
hypertensive treatment and the risk of developing dementia
(OR 0.89; 95 % CI: 0.751.04) [69], although the hetero-
geneity of the analysis was high, and the results were not
robust. A meta-analysis of published trials, including the
HYVET demonstrated that, when combined, these studies
point to a protective effect of antihypertensive therapy on
cognition [70]. However, more recently published trials do
not corroborate these findings. For example, in the PRo-
FESS trial [71], which used a 22 factorial design, angio-
tensin receptor blocker therapy (telmisartan) did not provide
cognitive protection after stroke. In addition, results from
the ONTARGET trial [72] suggest that SBP lowering below
the 130150 mm Hg range using ramipril and telmisartan
does not improve outcomes.
The inconsistencies in the results of these trials, whether
taken individually or combined in meta-analyses, are likely
to be related to age differences, follow-ups too short to
detect cognitive changes and, more importantly, differences
in the baseline cognitive function of the populations studied.
The cognitive domain being measured is also likely to be an
important cause of the heterogeneity observed. Furthermore,
many of the trials have used the MMSE, a fairly insensitive
and non-specific measure of cognitive change [12, 73].
Hypertension is more likely to be related to executive func-
tion than to overall cognitive performance [12, 74].
An MRI substudy of the PROGRESS randomized trial of
BP lowering with perindopril versus placebo in normoten-
sive and hypertensive subjects with cerebrovascular disease
has recently found that the mean total volume of new WML
was significantly reduced in the active treatment group
compared with placebo [75]. A post hoc analysis also indi-
cated that the greatest beneficial effect of antihypertensive
therapy on WML progression was observed in patients with
severe WML at entry.
Therefore, despite the stated limitations and methodolog-
ical differences, moderately-strong evidence exists to sup-
port the view that hypertension in midlife, especially if not
treated effectively, negatively affects cognition and contrib-
utes to the development of dementia and even AD in late
life. High BP in the middle-aged implies a long-term cumu-
lative effect, which leads to increased severity of atheroscle-
rosis and more vascular comorbidities in late life [11]. There
is less evidence that the same negative effect on cognition is
Curr Hypertens Rep (2012) 14:548555
present for hypertension in later life [11]. Indeed, some
reports on the harmful cognitive effect of low BP suggest
that, in older adults, and particularly the very-elderly, an
appropriate level of BP may be required to retain cognitive
function by maintaining adequate cerebral perfusion. How-
ever, optimum BP levels are unknown.
Conclusion
In recent years, accumulating evidence has suggested that
vascular risk factors (especially hypertension, and also dia-
betes, high level of cholesterol and smoking) contribute to
Alzheimers disease. Vascular dementia had traditionally
been considered secondary to stroke and vascular disease.
However it appears that there is a continuous spectrum of
disease, composed of a gradient of features of both types of
dementia.
Vascular risk factors, especially hypertension, have been
shown to be associated with subcortical lesions seen on brain
MRI: WML, lacunar infarctions, and cerebral microbleeds.
Cerebral small vessel diseases are thought to be the most
frequent pathological neurological processes and have a cru-
cial role in at least three fields: stroke, dementia, and aging.
There is substantial evidence supporting the link between
BP and cognition. This relationship might be mediated by
impairment of the vascular reserve and by microvascular
disease such as WML, lacunar infarct or microbleeds. Ob-
servational studies have consistently suggested a causal link
between hypertension, arterial stiffness, microvascular cere-
bral damage, and the risk of dementia.
Both hypertension and hypotension contribute to cogni-
tive decline, and a combination of vascular risk factors
during an individuals lifetime could accelerate functional
cognitive loss later in life. Diurnal BP variation disruption,
specifically sleep period, was associated with WML and
brain atrophy, which would serve as a pathophysiology for
cognitive impairment or dementia.
BP lowering is beneficial in the vast majority of patients
with vascular risk factors, but the effect of BP reduction on
cognition can only be assessed by randomized controlled trials
including appropriate cognitive end points. The majority of
longitudinal studies have found elevated BP to be associated
with cognitive decline and a small number of randomized
controlled trials have demonstrated heterogeneous effects of
BP lowering on cognitive function. These findings suggest a
complex relationship between BP and cognitive function con-
sistent with known biological mechanisms.
Disclosure No potential conflicts of interest relevant to this article
were reported.
553
References
Papers of particular interest, published recently, have been
highlighted as:
Of importance
Of major importance
1. ODonnell M, Teo K, Gao P, et al. Cognitive impairment and risk
of cardiovascular events and mortality. Eur Heart J. 2012;33:1777
86. First prospective study that shows a relationship between
cognitive impairment and CV diseases.
2. Viswanathan A, Rocca WA, Tzourio C. Vascular risk factors and
dementia. How to move forward? Neurology. 2009;72:36874.
3. Mancia G, De Backer G, Dominiczak A, et al. Guidelines for the
management of arterial hypertension: The task force for the man-
agement of arterial hypertension of the European Society of Hy-
pertension (ESH) and of the European Society of Cardiology
(ESC). J Hypertens. 2007;25:110587.
4. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of Euro-
pean guidelines on hypertension management: a European Society
o f Hypertension Task Force document. J Hypertens.
2009;27:212158.
5. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the
primary prevention of stroke: a guideline for healthcare professio-
nals from the American Heart Association/American Stroke Asso-
ciation. Stroke. 2011;42:51784.
6. Pantoni L. Cerebral small vessel disease: from pathogenesis and
clinical characteristics to therapeutic challenges. Lancet Neurol.
2010;9:689701. A complete review about cerebral small vessel
disease.
7. Henskens LH, van Oostenbrugge RJ, Kroon AA, et al. Detection
of silent cerebrovascular disease refines risk stratification of hy-
pertensive patients. J Hypertens. 2009;27:84653.
8. Debette S, Markus HS. The clinical importance of white matter
hyperintensities on brain magnetic resonance imaging: systematic
review and meta-analysis. BMJ. 2010;341:c3666. doi:10.1136/
bmj.c3666. The only paper to analyze clinical evidences about
WML until now.
9. Rutan GH, Hermanson B, Bild DE, et al. Orthostatic hypotension
in older adults. The Cardiovascular Health Study. CHS Collabora-
tive Research Group. Hypertension. 1992;19:50819.
10. Nagai M, Hoshide S, Ishikawa J, et al. Visit-to-visit blood
pressure variations: new independent determinants for cognitive
function in the elderly at high risk of cardiovascular disease. J
Hypertens. 2012;30:155663. First study that shows a relationship
between visit-to-visit BP variability and cognitive decline.
11. Qiu C, Winblad B, Fratiglioni L. The age dependent relation of
blood pressure to cognitive function and dementia. Lancet Neurol.
2005;4:48799.
12. Novak V, Hajjar I. The relationship between blood pressure and
cognitive function. Nat Rev Cardiol. 2010;7:68698.
13. Gorelick PB, Scuteri A, Black SE, 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(9):2672713. Last review
about cognitive impairment from the American Stroke Association.
14. Launer LJ. Demonstrating the case that AD is a vascular disease:
epidemiologic evidence. Aging Res Rev. 2002;1:6177.
15. Sierra C, Coca A, Schiffrin EL. Vascular mechanisms in the
pathogenesis of stroke. Curr Hypertens Rep. 2011;13:2007.
16. Jellinger KA, Attems J. Incidence of cerebrovascular lesions in
Alzheimers disease: a postmortem study. Acta Neuropathol.
2003;105:147.
554
17. McCarron MO, Nicoll JA. Cerebral amyloid angiopathy and
thrombolysis-related intracerebral haemorrhage. Lancet Neurol.
2004;3:48492.
18. Koennecke HC. Cerebral microbleeds on MRI: prevalence, asso-
ciations, and potential clinical implications. Neurology.
2006;66:16571.
19. Imaoka K, Kobayashi S, Fujihara S, et al. Leukoencephalopathy
with cerebral amyloid angiopathy: a semiquantitative and morpho-
metric study. J Neurol. 1999;246:6616.
20. Birns J, Kalra L. Cognitive function and hypertension. J Hum
Hypertens. 2009;23:8696.
21. OBrien JT, Erkinjuntii E, Reisberg B, et al. Vascular cognitive
impairment. Lancet Neurol. 2003;2:8993.
22. Cacciatore F, Abete P, Ferrara N, et al. The role of blood pressure
in cognitive impairment in an elderly population. J Hypertens.
1997;15:13542.
23. Elias MF, Wolf PA, DAgostino RB, et al. Untreated blood pres-
sure level is inversely related to cognitive functioning: the Fra-
mingham Study. Am J Epidemiol. 1993;138:35364.
24. Launer LJ, Masaki K, Petrovitch H, et al. The association between
midlife blood pressure levels and late-life cognitive function.
JAMA. 1995;274:184651.
25. Kilander L, Nyman H, Boberg M, et al. Hypertension is related to
cognitive impairment; a 20-year follow-up of 999 men. Hyperten-
sion. 1998;31:7806.
26. Carmelli D, Swan GE, Reed T, et al. Midlife cardiovascular risk
factors, ApoE, and cognitive decline in elderly male twins. Neu-
rology. 1998;50:15805.
27. Farmer ME, Kittner SJ, Abbott RD, et al. Longitudinally measured
blood pressure, antihypertensive medication use, and cognitive
performance: the Framingham Study. J Clin Epidemiol.
1990;43:47580.
28. Forette F, Seux ML, Staessen JA, et al. The prevention of dementia
with antihypertensive treatment. New evidence from the Systolic
Hypertension in Europe (Syst-Eur) study. Arch Intern Med.
2002;162:204652.
29. Sierra C, Coca A. Silent cerebral damage in hypertension. Curr
Hypertens Rev 2007;3:838.
30. Vermeer SE, Hollander M, van Dijk EJ. et al; Rotterdam Scan
Study. Silent brain infarcts and white matter lesions increase stroke
risk in the general population: the Rotterdam Scan Study. Stroke.
2003;34:11269.
31. Kuller LH, Longstreth WT, Arnold AM, Cardiovascular Health
Study Collaborative Research Group, et al. White matter hyper-
intensity on cranial magnetic resonance imaging. A predictor of
stroke. Stroke. 2004;35:18215.
32. Miyao S, Takano A, Teramoto J, Takahashi A. Leukoaraiosis in
relation to prognosis for patients with lacunar infarction. Stroke.
1992;23:14348.
33. Fu JH, Lu CZ, Hong Z, et al. Extent of white matter lesions is
related to acute subcortical infarcts and predicts further stroke risk
in patients with first ever ischemic stroke. J Neurol Neurosurg
Psychiatry. 2005;76:7936.
34. Schmidt R, Fazekas F, Offenbacher H, et al. Magnetic resonance
imaging white matter lesions and cognitive impairment in hyper-
tensive individuals. Arch Neurol. 1991;48:41720.
35. De Groot JC, de Leeuw FE, Oudkerk M, et al. Periventricular
cerebral white matter lesions predict rate of cognitive decline.
Ann Neurol. 2002;52:33541.
36. Longstreth WT, Manolio TA, Arnold A, Cardiovascular Health
Study Collaborative Research Group, et al. Clinical correlates of
white matter findings on cranial magnetic resonance imaging of
3301 elderly people. The Cardiovascular Health Study. Stroke.
1996;27:127482.
37. Breteler MMB, van Swieten JC, Bots ML, et al. Cerebral white
matter lesions, vascular risk factors, and cognitive function in a
Curr Hypertens Rep (2012) 14:548555
population-based study: the Rotterdam Study. Neurology.
1994;44:124652.
38. Prins ND, van Dijk EJ, den Heijer T, et al. Cerebral white matter
lesions and the risk of dementia. Arch Neurol. 2004;61:15314.
39. De Groot JC, de Leeuw FE, Oudkerk M, et al. Cerebral white
matter lesions and cognitive function: the Rotterdam scan study.
Ann Neurol. 2000;47:14551.
40. Sierra C, de la Sierra A, Salamero M, et al. Silent cerebral white
matter lesions and cognitive function in middle-aged essential
hypertensive patients. Am J Hypertens. 2004;17:52934.
41. Kuller LH, Lopez OL, Newman A, et al. Risk factors for dementia
in the cardiovascular health cognition study. Neuroepidemiology.
2003;22:1322.
42. Skoog I, Lernfelt B, Landahl S, et al. 15-year longitudinal study of
blood pressure and dementia. Lancet. 1996;347:11415.
43. Pickering TG. Ambulatory blood pressure monitoring. Curr
Hypertens Rep. 2000;2:55864.
44. Cuspidi C, Meani S, Salerno M, et al. Reproducibility of nocturnal
blood pressure fall in early phases of untreated essential hyperten-
sion: a prospective observational study. J Hum Hypertens.
2004;18:5039.
45. 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;24:1924.
46. Yamamoto Y, Akiguchi I, Oiwa K, et al. The relationship between
24-hour blood pressure readings, subcortical ischemic lesions and
vascular dementia. Cerebrovasc Dis. 2005;19:3028.
47. Sakakura K, Ishikawa J, Okuno M, et al. Exaggerated ambulatory
blood pressure variability is associated with cognitive dysfunction
in the very elderly and quality of life in the younger elderly. Am J
Hypertens. 2007;20:7207.
48. Scuteri A, Nilsson PM, Tzourio C, et al. Microvascular brain
damage with aging and hypertension: pathophysiological consid-
eration and clinical implications. J Hypertens. 2011;29:146977.
Brief but complete review about microvascular brain damage and
hypertension, with considerations about things to do in the future
to improve understanding.
49. Hachinski V, Iadecola C, Petersen RC, et al. National Institute of
Neurological Disorders and Stroke-Canadian Stroke Network vas-
cular cognitive impairment harmonization standards. Stroke.
2006;37:222041.
50. Nasreddine ZS, Phillips NA, Bedirian C, et al. The Montreal
Cognitive Assessment, MoCA: a brief screening tool for mild
cognitive impairment. J Am Geriatr Soc. 2005;53:6959.
51. Cummings JL. Frontalsubcortical circuits and human behavior. J
Psychosom Res. 1998;44:6278.
52. Birns J, Markus H, Kalra L. Blood pressure reduction for vascular
risk: is there a price to be paid? Stroke. 2005;36:130813.
53. Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and dia-
stolic, and cardiovascular risks. Arch Intern Med. 1993;153:598615.
54. Domanski MJ, Davis BR, Pfeffer MA, et al. Isolated systolic
hypertension. Prognostic information provided by pulse pressure.
Hypertension. 1999;34:37580.
55. Laurent S, Katsahian S, Fassot C, et al. Aortic stiffness is an
independent predictor of fatal stroke in essential hypertension.
Stroke. 2003;34:12036.
56. Kim CK, Lee SH, Kim BJ, et al. Age-independent association of
pulse pressure with cerebral white matter lesions in asymptomatic
elderly individuals. J Hypertens. 2011;29:3259.
57. Scuteri A, Tesauro M, Appolloni S, et al. Arterial stiffness as
an independent predictor of longitudinal changes in cognitive
function in the older individual. J Hypertens. 2007;25:1035
40.
58. Waldstein SR, Rice SC, Thayer JF, et al. Pulse pressure and pulse
wave velocity are related to cognitive decline in the Baltimore
Longitudinal Study of Aging. Hypertension. 2008;51:99104.
Curr Hypertens Rep (2012) 14:548555
59. Poels MM, van Oijen M, Mattace-Raso FU, et al. Arterial stiffness,
cognitive decline, and risk of dementia: the Rotterdam study.
Stroke. 2007;38:88892.
60. ORourke MF, Safar ME. Relationship between aortic stiffening
and microvascular disease in brain and kidney: cause and logic of
therapy. Hypertension. 2005;46:2004.
61. Barzilay JI, Gao P, ODonnell M, et al. Albuminuria and decline in
cognitive function. The ONTARGET/TRANSCEND Studies.
Arch Intern Med. 2011;171:14250.
62. Barzilay JI, Fitzpatrick AL, Luchsinger J, et al. Albuminuria and
dementia in the elderly: a community study. Am J Kidney Dis.
2008;52:21626.
63. Wong TY, Klein R, Sharrett AR, et al. Retinal microvascular abnor-
malities and cognitive impairment in middle-aged persons: the Athero-
sclerosis risk in Communities study. Stroke. 2002;33:148792.
64. Baker ML, MarinoLarsen EK. KullerLH, et al. Retinal microvas-
cular signs, cognitive function, and dementia in older persons: the
Cardiovascular Health Study. Stroke. 2007;38:20417.
65. SHEP Cooperative Research Group. Prevention of stroke by anti-
hypertensive drug treatment in older persons with isolated systolic
hypertension: final results of the Systolic Hypertension in the
Elderly Program (SHEP). JAMA. 1991;24:325564.
66. Staessen JA, Fagard R, Thijs L, et al. For the Systolic Hyperten-
sion in Europe (Syst-Eur) Trial Investigators. Randomised double-
blind comparison of placebo and active treatment for older patients
with isolated systolic hypertension. Lancet. 1997;350:75764.
67. The PROGRESS Collaborative Group. Effects of blood pressure
lowering with perindopril and indapamide therapy on dementia
and cognitive decline in patients with cerebrovascular disease.
Arch Intern Med. 2003;163:106975.
68. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and
Prognosis in the Elderly (SCOPE): principal results of a random-
ized double-blind intervention trial. J Hypertens. 2003;21:87588.
555
69. Staessen JA, Richart T, Birkenhger WH. Less atherosclerosis and
lower blood pressure for a meaningful life perspective with more
brain. Hypertension. 2007;49:389400.
70. Peters R, Beckett N, Forette F, HYVET Investigators, et al.
Incident dementia and blood pressure lowering in the Hyperten-
sion in the Very Elderly Trial cognitive function assessment
(HYVET-COG): a double-blind, placebo controlled trial. Lancet
Neurol. 2008;7:6839. Includes a meta-analysis about main pub-
lished trials about cognitive impairment.
71. Diener HC, Sacco RL, Yusuf S, et al. for the PRoFESS Study
Group. Effects of aspirin plus extended-release dipyridamole ver-
sus clopidogrel and telmisartan on disability and cognitive function
after recurrent stroke in patients with ischaemic stroke in the
Prevention Regimen for Effectively Avoiding Second Strokes
(PRoFESS) trial: a double-blind, active and placebo-controlled
study. Lancet Neurol. 2008;7:87584.
72. Sleight P, Redon J, Verdecchia P, et al. for the ONTARGET
Investigators. Prognostic value of blood pressure in patients with
high vascular risk in the Ongoing Telmisartan Alone and in com-
bination with Ramipril Global Endpoint Trial study. J Hypertens.
2009;27:13609.
73. Pendlebury ST, Cuthbertson FC, Welch SJ, et al. Underestimation
of cognitive impairment by mini-mental state examination versus
the Montreal cognitive assessment in patients with transient ische-
mic attack and stroke: a population-based study. Stroke.
2010;41:12903.
74. Oveisgharan S, Hachinski V. Hypertension, executive dysfunction,
and progression to dementia: the Canadian study of health and
aging. Arch Neurol. 2010;67:18792.
75. Dufouil C, Chalmers J, Coskun O, et al. Effects of blood pressure
lowering on cerebral white matter hyperintensities in patients with
stroke. The PROGRESS Magnetic resonance imaging substudy.
Circulation. 2005;112:164450.