International meeting of the French society of neurology 2013

Vascular risk factors and cognitive disorders

Facteurs de risque vasculaires et cognition

S. Debette a,*,b,c,d

aDepartment of neurology, hopital Lariboisiere, 2, rue Ambroise-Pare, 75475 Paris cedex 10, Franceb Inserm unit U740, universite Paris Diderot Paris 7, UFR de medecine Paris Diderot Paris 7 (site Villemin), 10, avenue

de Verdun, 75010 Paris, FrancecParis 7 university, DHU neurovasc Sorbonne Paris-Cite, 190, avenue de France, 75013 Paris, FrancedDepartment of neurology, Framingham heart study, Boston university school of medicine, 72 E Concord St, Boston,

MA 02118, USA

r e v u e n e u r o l o g i q u e 1 6 9 ( 2 0 1 3 ) 7 5 7 7 6 4

i n f o a r t i c l e

Article history:

Received 18 July 2013

Accepted 22 July 2013

Available online 12 September 2013

Keywords:

Vascular risk factors

Hypertension

Stroke

Dementia

Cognition

Mots cles :

Facteurs de risque vasculaire

Hypertension

AVC

Demence

Cognition

a b s t r a c t

Delaying the onset of dementia by just a few years could have a major impact on the

prevalence of the disease at the population level. Vascular risk factors are modifiable and

may offer an important opportunity for preventive approaches. Several studies have shown

that diabetes, hypertension, obesity, and smoking are associated with an increased risk of

cognitive decline and dementia, but other groups have not observed such a relation. Positive

associations were observed mainly in studies where risk factors were assessed in midlife,

suggesting that age is an important modulator in the relation between vascular risk factors

and cognition. The population attributable risk of dementia is particularly high for hyper-

tension. Associations of vascular risk factors with cognitive decline and dementia are

probably mediated largely by cerebrovascular disease, including both stroke and covert

vascular brain injury, which can have additive or synergistic effects with coexisting neu-

rodegenerative lesions. To date, randomized trials have not convincingly demonstrated that

treating vascular risk factors is associated with a reduction in cognitive decline or dementia

risk. Of eight randomized trials testing the effect of antihypertensive agents on dementia

risk, only one was positive, and another in a subgroup of individuals with recurrent stroke.

In most trials, cognition and dementia were secondary outcomes, follow-up was short and

treatment was initiated at an older age. No effect on cognitive decline or dementia could be

demonstrated for statins and intensive glycemic control. Future areas of investigation could

include differential class effects of antihypertensive drugs on cognitive outcomes and

identification of high risk individuals as target population for clinical trials initiated in

midlife.

# 2013 Published by Elsevier Masson SAS.

r e s u m e

Retarder la survenue de la demence de quelques annees seulement aurait un impact

Available online at

www.sciencedirect.commajeur sur la prevalenc

t mrisque vasculaires son* Correspondence. Department of neurology, ho pital Lariboisiere, 2,E-mail address : sdebette@bu.edu.

0035-3787/$ see front matter # 2013 Published by Elsevier Masson http://dx.doi.org/10.1016/j.neurol.2013.07.022e de cette maladie a lechelle de la population. Les facteurs de

odifiables et pourraient constituer une cible importante pour des rue Ambroise-Pare, 75475 Paris cedex 10, France.

SAS.

http://crossmark.crossref.org/dialog/?doi=10.1016/j.neurol.2013.07.022&domain=pdfhttp://crossmark.crossref.org/dialog/?doi=10.1016/j.neurol.2013.07.022&domain=pdfhttp://dx.doi.org/10.1016/j.neurol.2013.07.022mailto:sdebette@bu.eduhttp://www.sciencedirect.com/science/journal/00353787http://dx.doi.org/10.1016/j.neurol.2013.07.022

strategies de prevention. Plusieurs etudes ont montre que le diabete, lhypertension,

lobesite, et le tabac etaient associes a un risque accru de declin cognitif et demence, mais

dautres etudes nont pas pu mettre en evidence de telles associations. Des associations

significatives etaient observees principalement dans des etudes ou les facteurs de risque

vasculaires etaient evalues a un a ge moyen, suggerant un effet modulateur important de

la ge dans la relation entre facteurs de risque vasculaires et cognition. Le risque attribuable

de demence est particulierement eleve pour lhypertension arterielle. Lassociation des

facteurs de risque vasculaires avec le declin cognitif et la demence est probablement mediee

principalement par la pathologie cerebrovasculaire, incluant a la fois les accidents vascu-

laires cerebraux et les lesions cerebrovasculaires silencieuses , qui peuvent avoir des

effets additifs voire synergiques avec des lesions neurodegeneratives coexistantes. A ce

jour, les essais therapeutiques randomises nont pas demontre de facon convaincante que

traiter les facteurs de risque vasculaires etait associe a un ralentissement du declin cognitif

et une reduction du risque de demence. Parmi huit essais therapeutiques randomises

testant leffet de traitements antihypertenseurs sur le risque de demence, seul un etait

positif ; un autre essai etait positif dans un sous-groupe dindividus avec recidive daccident

vasculaire cerebral. Dans la plupart des essais, la cognition et la demence netaient que des

criteres de jugement secondaires, le suivi etait court et le traitement etait initie a un age

avance. Aucun benefice des statines ou dun contro le glycemique intensif na pu etre

demontre sur le declin cognitif et la demence. De futurs axes de recherche pourraient

inclure les effets differentiels de certaines classes dantihypertenseurs sur la cognition ainsi

que lidentification dindividus a haut risque comme population cible pour des essais

therapeutiques inities dans des populations dage moyen.

# 2013 Publie par Elsevier Masson SAS.

r e v u e n e u r o l o g i q u e 1 6 9 ( 2 0 1 3 ) 7 5 7 7 6 4758With expanding longevity, the number of dementia cases is

increasing worldwide and is expected to triple over the next 40

years. Delaying the onset of this disease by just a few years

could have a major impact on the prevalence of dementia at

the population level (Barnes and Yaffe, 2011). To date, no

effective mechanism-based preventive strategies are available

for dementia. Vascular risk factors are modifiable and, given

the strong relationship between cerebrovascular disease and

dementia, they may offer an important opportunity for

preventive approaches. Gathering evidence for associations

between vascular risk factors and dementia and evaluating

the impact of interventions modifying vascular risk factor

exposure on cognitive decline and dementia is therefore of

paramount importance.

1. Contribution of cerebrovascular disease tocognitive impairment and dementia

The importance of cerebrovascular disease for cognitive

impairment and dementia is now widely recognized (Viswa-

nathan et al., 2009; Gorelick et al., 2011). Vascular cognitive

impairment and dementia can occur after one of more strokes

(ischemic or hemorrhagic) or in the presence of silent infarcts

or diffuse subcortical cerebrovascular disease (Gorelick et al.,

2011). It is referred to as pure in the absence of Alzheimer

disease (AD) pathology or positive biomarkers for the latter

(e.g. positron emission tomography, cerebrospinal fluid

amyloid b or tau protein) (Gorelick et al., 2011). However,

the vascular contribution to cognitive disorders reaches far

beyond the concept of pure vascular cognitive decline

(Viswanathan et al., 2009). Indeed, cognitive impairment

and dementia is a continuum ranging from patients withpure vascular dementia to patients with pure AD and

including a large majority of patients with contributions from

both Alzheimer and vascular pathologies (Viswanathan et al.,

2009). Accordingly, neuropathological correlates of cognitive

impairment in late-life are most often a mix of AD pathology

(amyloid plaques and neurofibrillary tangles) and microvas-

cular brain damage. Moreover, in patients with AD, if

cerebrovascular disease is present concomitantly, less AD

pathology is needed to express the dementia syndrome. This

may be due to additive or even synergistic effects of

cerebrovascular damage and neurodegenerative processes

(Snowdon et al., 1997; Petrovitch et al., 2005).

2. Association of vascular risk factors withcognition in observational studies

Several studies have shown that diabetes, hypertension,

obesity, and smoking are associated with an increased risk of

dementia (Kivipelto et al., 2005; Whitmer et al., 2005; Anstey

et al., 2007), but other groups did not observe such a relation

(Kloppenborg et al., 2008; Barnes and Yaffe, 2011). Overall,

positive associations were observed mainly in studies where

risk factors were assessed in midlife, especially for blood

pressure and obesity, while most negative studies targeted

older populations (Kloppenborg et al., 2008; Barnes and Yaffe,

2011). In the ARIC study, the impact of vascular risk factors on

dementia was assessed in different age groups and at different

time points within the same cohort, demonstrating that age is

an important modulator, associations being stronger in

individuals aged less than 60 years when the vascular

risk factors were assessed (Alonso et al., 2009). There are

several possible explanations for these age-dependent effects.

r e v u e n e u r o l o g i q u e 1 6 9 ( 2 0 1 3 ) 7 5 7 7 6 4 759Epidemiological data suggest that the pathological processes

leading to the disease start operating many years before the

clinical onset (Elias et al., 2000; Jack et al., 2005), and that some

risk factors begin to exert their impact as early as midlife.

Exposure to risk factors in midlife may better capture these

effects and also better reflect cumulative lifetime exposure

that single late-life measurements. Moreover, vascular risk

factor measurements in older persons may be modified by

concomitant chronic diseases inducing weight loss, blood

pressure drop and other metabolic changes, and by concurrent

medications. Finally, associations with late-life risk factor

measurements may be modified by survival bias, due to

premature death of individuals exposed to a high risk factor

burden (Debette and Seshadri, 2009).

Recently, Barnes and Yaffe have reviewed evidence for

seven modifiable risk factors for AD (diabetes, midlife

hypertension, midlife obesity, smoking, physical inactivity,

depression, cognitive inactivity) and have calculated the

population attributable risk, i.e. the percentage of AD cases

attributable to each of these risk factors (Barnes and Yaffe,

2011). Based on this, they estimated that a 10%-reduction in all

seven risk factors could prevent 1.1 million AD cases

worldwide (Barnes and Yaffe, 2011). Of all vascular risk

factors, the population attributable risk of elevated blood

pressure for dementia is particularly high, given the high

prevalence of this condition in the general population

(Kloppenborg et al., 2008; Launer et al., 2010). In the Honolulu

Asia Aging Study, among participants who did not report

taking antihypertensive medication in midlife, 27% of

dementia cases could be attributed to systolic blood pressure

120 mm Hg (Launer et al., 2010).There is also important evidence that vascular risk factors

are associated with poorer cognitive performance and

accelerated cognitive decline in individuals without dementia,

the most prominent associations being observed with pro-

cessing speed and executive function (Carmelli et al., 1998;

Plassman et al., 2010; Debette et al., 2011).

3. Therapeutic trials

Few randomized trials have tested the impact of vascular risk

factor modification on the risk of dementia, mostly in

secondary analyses.

Eight randomized trials have evaluated the effect of

antihypertensive agents on dementia risk (SHEP_Cooperati-

ve_Research_Group, 1991; Forette et al., 1998; Lithell et al.,

2003; Tzourio et al., 2003; Patel et al., 2007; Diener et al., 2008;

Peters et al., 2008; Anderson et al., 2011). Only one of them, the

Syst-Eur trial, including 1238 individuals aged 65 years or

older, demonstrated a significantly reduced risk of dementia

(P = 0.04) in individuals taking nitrendipine, a calcium channel

blocker (CCB), vs. individuals taking placebo (Forette et al.,

1998). In the PROGRESS trial active treatment was associated

with reduced risks of dementia and cognitive decline in

individuals with recurrent stroke (Tzourio et al., 2003). In this

trial, patients with a history of stroke or transient ischemic

attack within five years and a wide range of blood pressure

were randomly assigned to take an angiotensin converting

enzyme (ACE) inhibitor (perindopril), associated or not with adiuretic (indapamide), or placebo, stroke recurrence being the

primary endpoint (PROGRESS_collaborative_group, 2001).

In a meta-analysis combining the eight randomized trials

of antihypertensive therapy for prevention of dementia, blood

pressure lowering did not reduce the risk significantly overall

(Staessen et al., 2011). However, when combining trials by

antihypertensive drug type, the reduction in dementia risk

was significant for trials involving a diuretic or dihydropyri-

dine CCB, but not in trials of renin system inhibitors (Staessen

et al., 2011).

In the ACCORD MIND trial, participants with type 2

diabetes, high glycated haemoglobin A1c (HbA1c

concentrations > 7.5%), and a high risk of cardiovascular

events were randomly assigned to receive intensive glycemic

control targeting HbA1c < 6.0% or a standard strategy target-

ing HbA1c to 7.07.9% (Launer et al., 2011) Although baseline

levels of HbA1c were associated with lower cognitive function

(Cukierman-Yaffe et al., 2009), the primary cognitive outcome

(Digit Symbol Substitution Test score, measuring processing

speed, at 40 months) was not different between the two

treatment arms (Launer et al., 2011). In an MRI-substudy, the

intensive therapy group had significantly greater total brain

volume compared to the standard group at follow-up, and

although total brain volume declined in both groups, it

declined less in the intensive therapy group (Launer et al.,

2011).

Two trials have examined the impact of statins on

dementia or cognition. The PROSPER trial (testing pravastatin

vs. placebo) showed no difference in cognitive function (Mini-

Mental State Examination) at four years between patients on

treatment and those on placebo (Trompet et al., 2010).

Likewise, there was no difference in incidence of dementia

nor in performance on the modified Telephone Interview for

Cognitive Status in the HPS trial (testing simvastatin vs.

placebo) (HPS_Collaborative_Group, 2002).

4. Mechanisms

The association of vascular risk factors with cognitive decline

and dementia is most likely mediated largely by cerebrovas-

cular disease, including both stroke and covert vascular brain

injury, which can have additive or synergistic effects with

coexisting neurodegenerative lesions. Other putative mecha-

nisms will be discussed briefly.

4.1. Vascular risk factors, stroke and cognition

Adverse effects of vascular risk factors on cognition can be

mediated by an increased risk of stroke and thereby post-

stroke cognitive decline and dementia. Of all vascular risk

factors, hypertension is the most powerful predictor of stroke,

both hemorrhagic stroke and ischemic stroke of all subtypes

(Goldstein et al., 2011), and thus also represents an important

risk factor for post-stroke dementia.

Numerous studies, both in a hospital-based (Tatemichi

et al., 1994; Andersen et al., 1996; Inzitari et al., 1998;

Pohjasvaara et al., 1998; Barba et al., 2000; Henon et al.,

2001; Klimkowicz et al., 2002; Tang et al., 2004; Zhou et al.,

2004; de Koning et al., 2005), and community setting (Kokmen

r e v u e n e u r o l o g i q u e 1 6 9 ( 2 0 1 3 ) 7 5 7 7 6 4760et al., 1996; Kase et al., 1998; Zhu et al., 2000; Ivan et al., 2004),

have shown that the incidence of dementia is substantially

increased in individuals with a history of stroke. In a recent

systematic review, the prevalence of post-stroke dementia

was estimated at 20.3% [95% CI: 18.222.5%] in hospitalized-

based studies and at 7.4% [4.810%] in population-based

studies, after excluding individuals with prestroke dementia

(Pendlebury and Rothwell, 2009).

Cerebrovascular lesions can accelerate the clinical expres-

sion of AD pathology through additive effects, by reducing the

threshold for cognitive impairment (Pasquier and Leys, 1997;

Iadecola, 2010). In addition, cerebral hypoperfusion may alter

clearance of amyloid b (Ab) peptide, thus favoring amyloid

plaque deposition, a key neuropathological feature of AD; Ab

in turn was shown to be a potent vasoconstrictor, potentially

contributing to impaired cerebrovascular regulation (Thomas

et al., 1996; Iadecola, 2004; Zlokovic, 2005). Injury to the

neurovascular unit (neurons, glia, perivascular, and vascular

cells), via vascular or neurodegenerative mechanisms, can

alter cerebral blood flow regulation, disrupt the bloodbrain

barrier, and reduce the brains repair capacity, thus further

amplifying the brain dysfunction leading to cognitive impair-

ment (Iadecola, 2010).

4.2. Vascular risk factors, covert vascular brain injuryand cognition

Brain imaging, especially MRI, performed in large population-

based samples has revealed that covert vascular brain injury is

very common in the elderly, suggesting that the burden of

cerebrovascular disease is far greater than suggested by the

occurrence of acute neurological events such as stroke

(Longstreth, 2005). Covert vascular brain injury, comprising

white matter hyperintensities (WMH) (Debette and Markus,

2010), covert brain infarcts (Vermeer et al., 2007), microbleeds

(Cordonnier et al., 2007), and dilated perivascular spaces (Zhu

et al., 2011), all mostly reflecting cerebral small vessel disease,

is an important mediator in the relation of vascular risk factors

with cognition.

WMH are particularly prevalent in the general population,

and increasingly so with advancing age. Over 90% of

individuals aged 80 years or more have some degree of

WMH (Debette and Markus, 2010), and the prevalence in the

late forties is already estimated around 50% (Wen et al., 2009).

Extensive WMH are associated with an increased risk of

incident dementia, according to a systematic review and

meta-analysis (HR = 1.9 [IC95%: 1.32.8]) (Debette and Markus,

2010). Associations are most prominent for vascular or mixed

dementia (Bombois et al., 2008; Debette and Markus, 2010),

although an association with increased risk of AD has also

been reported (Kuller et al., 2003). WMH also predict an

increased risk of cognitive decline (Debette and Markus, 2010;

Debette et al., 2010a), the strongest associations being

observed with executive function and processing speed

(Longstreth et al., 2005; Kramer et al., 2007; van Dijk et al.,

2008). A stronger association with cognitive impairment was

suggested for WMH in periventricular vs. deep subcortical

areas (Prins et al., 2004, 2005; Debette et al., 2007), or in

strategic regions, e. g. the anterior thalamic radiation (Duering

et al., 2011). Associations of covert brain infarcts, microbleeds,and dilated perivascular spaces with increased dementia risk

have also been reported (Vermeer et al., 2003, 2007; Greenberg

et al., 2009; Zhu et al., 2010; Poels et al., 2012).

Several putative mechanisms could be underlying the

association between covert vascular brain injury and cogni-

tion. Direct damage of cortico-subcortical neuronal circuits

passing through the white matter could contribute to cognitive

decline, especially for tasks involving executive function and

processing speed (Mungas et al., 2005; Nordahl et al., 2006). As

discussed above, cerebrovascular lesions can also interact

with neurodegenerative AD type lesions, with reciprocal

potentiation of disease processes and synergistic deleterious

effects on cognition. In some instances, covert vascular brain

injury could also be a marker of cerebral amyloid angiopathy,

which is highly prevalent in older people, and may contribute

to age-related cognitive impairment through various mecha-

nisms (Arvanitakis et al., 2011; Viswanathan and Greenberg,

2011; Tanskanen et al., 2012).

4.3. Other putative mechanisms

Whereas vascular brain injury is likely the principal mediator

of associations between vascular risk factors and cognitive

impairment, other mechanisms could also play a role (Hajjar

et al., 2011). In a longitudinal MRI analysis on non-demented

participants from the Framingham Heart Study, hypertension

led to an increase in WMH load, whereas diabetes was

associated with an accelerated rate of hippocampal atrophy,

and smoking predicted an accelerated rate of WMH progres-

sion, global and hippocampal atrophy (Debette et al., 2011).

Both vascular and neurodegenerative processes could be

involved in the relation of vascular risk factors with cognition.

A few examples of putative alternative mechanisms under

investigation are listed below.

Animal studies have suggested that angiotensin II, angio-

tensin converting enzyme and other components of the renin-

angiotensin system, which play a key role in blood pressure

regulation, may directly modulate Ab production and meta-

bolism (Selkoe, 2000; Kehoe, 2009). Angiotensin receptor

blockers (ARBs) were shown to decrease Ab oligomerization

in animal models (Wang et al., 2007; Danielyan et al., 2010),

and more recently ARB exposure was found to be associated

with less neuropathological features of AD compared to other

antihypertensive medications in a large brain autopsy series

(Hajjar et al., 2012), supporting further research in this

direction.

Mechanisms underlying the association of diabetes with

cognitive impairment could involve potentiation of AD

neuropathology, via promoting oxidative stress, and forma-

tion of toxic advanced glycation end products (Tan et al.,

2011). Insulin has also been implicated in production of the

neurotransmitter acetylcholine (Brass et al., 1992), and in tau

phosphorylation and amyloid deposition (Pasquier et al.,

2006). However, in contrast with epidemiological findings,

neuropathological studies found that diabetes is not asso-

ciated with an increase in AD pathology, but with a

prominent increase in microinfarcts (Kalaria, 2009; Nelson

et al., 2009; Sonnen et al., 2009). Animal experiments have

demonstrated impaired hippocampal plasticity after nico-

tine exposure (Abrous et al., 2002), and suggested that

r e v u e n e u r o l o g i q u e 1 6 9 ( 2 0 1 3 ) 7 5 7 7 6 4 761smoking increases the severity of typical AD features,

including amyloidogenesis, inflammation and tau phospho-

rylation (Moreno-Gonzalez et al., 2013). Mechanisms under-

lying the relationship between midlife obesity, especially

central adiposity, and dementia could include inflammation

and insulin-resistance, as well as adipose-tissue derived

hormones promoting neurodegenerative processes (Lieb

et al., 2009; Debette et al., 2010b).

5. Current limitations and perspectives

Considering the overwhelming evidence that optimal

treatment of vascular risk factors should be targeted to

reduce the burden of vascular disease, investigating the

relation of these risk factors with dementia may seem

superfluous. Indeed, one may argue that management of

these risk factors should be optimal regardless of dementia

risk, given the substantial impact on vascular disease and

life expectancy. However, several questions remain unans-

wered. First, while there is currently no definitive evidence

that any class of antihypertensive agents offers special

protection against stroke (Goldstein et al., 2011), recent data

suggest that there could be differential class effects of

antihypertensive drugs on cognitive outcomes (Staessen

et al., 2011). Second, time of treatment onset may matter.

Indeed, various studies have shown that associations of

vascular risk factors with cognition are strongest when

exposure is measured in midlife, whereas associations with

vascular risk factors in late-life are less consistent and may

in some cases even show inverse relationships. Thus,

prevention of dementia by blood pressure lowering drugs

may not be efficient if initiated in older individuals. Setting

up a trial in middle-aged individuals is a challenge, as it

would require large numbers and a very long period of

follow-up, unless the trial is conducted on a group of

individuals selected to be at particularly high risk

of developing dementia. Third, simulations of the expected

impact of risk factor control on cognitive disorders at the

population level need to account for competing effects due

to the reduction in vascular disease and extended lifespan,

which increases the risk of developing dementia. Finally,

identifying the mechanisms and molecular pathways by

which vascular risk factors impact cognition may lead to the

identification of novel therapeutic targets for dementia

prevention and treatment.

Disclosure of interest

The author declares that he has no conflicts of interest

concerning this article.

Acknowledgements

Stephanie Debette is a recipient of a chair of excellence from

the National Research Agency (ANR), in collaboration with the

University of Versailles Saint-Quentin-en-Yvelines and

Inserm Unit U708.r e f e r e n c e s

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Vascular risk factors and cognitive disordersContribution of cerebrovascular disease to cognitive impairment and dementiaAssociation of vascular risk factors with cognition in observational studiesTherapeutic trialsMechanismsVascular risk factors, stroke and cognitionVascular risk factors, covert vascular brain injury and cognitionOther putative mechanisms

Current limitations and perspectivesDisclosure of interestAcknowledgementsReferences