revue neurologique volume 169 issue 10 2013 [doi 10.1016%2fj.neurol.2013.07.022] debette, s. --...
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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 : [email protected].
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:[email protected]://www.sciencedirect.com/science/journal/00353787http://dx.doi.org/10.1016/j.neurol.2013.07.022
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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.
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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
Abrous DN, Adriani W, Montaron MF, Aurousseau C, Rougon G,Le Moal M, et al. Nicotine self-administration impairshippocampal plasticity. J Neurosci 2002;22(9):365662.
Alonso A, Mosley Jr TH, Gottesman RF, Catellier D, Sharrett AR,Coresh J. Risk of dementia hospitalisation associated withcardiovascular risk factors in midlife and older age: theAtherosclerosis Risk in Communities (ARIC) study. J NeurolNeurosurg Psychiatry 2009;80(11):1194201.
Andersen G, Vestergaard K, Riis JO, Ingeman-Nielsen M.Intellectual impairment in the first year following stroke,compared to an age matched population sample.Cerebrovasc Dis 1996;6:3639.
Anderson C, Teo K, Gao P, Arima H, Dans A, Unger T, et al.Renin-angiotensin system blockade and cognitive functionin patients at high risk of cardiovascular disease: analysis ofdata from the ONTARGET and TRANSCEND studies. LancetNeurol 2011;10(1):4353.
Anstey KJ, von Sanden C, Salim A, OKearney R. Smoking as arisk factor for dementia and cognitive decline: a meta-analysis of prospective studies. Am J Epidemiol2007;166(4):36778.
Arvanitakis Z, Leurgans SE, Wang Z, Wilson RS, Bennett DA,Schneider JA. Cerebral amyloid angiopathy pathology andcognitive domains in older persons. Ann Neurol2011;69(2):3207.
Barba R, Martinez-Espinosa S, Rodriguez-Garcia E, Pondal M,Vivancos J, Del Ser T. Poststroke dementia: clinical featuresand risk factors. Stroke 2000;31(7):1494501.
Barnes DE, Yaffe K. The projected effect of risk factor reductionon Alzheimers disease prevalence. Lancet Neurol2011;10(9):81928.
Bombois S, Debette S, Bruandet A, Delbeuck X, Delmaire C, LeysD, et al. Vascular subcortical hyperintensities predictconversion to vascular and mixed dementia in MCI patients.Stroke 2008;39(7):204651.
Brass BJ, Nonner D, Barrett JN. Differential effects of insulin oncholine acetyltransferase and glutamic acid decarboxylaseactivities in neuron-rich striatal cultures. J Neurochem1992;59(2):41524.
Carmelli D, Swan GE, Reed T, Miller B, Wolf PA, Jarvik GP, et al.Midlife cardiovascular risk factors ApoE, and cognitivedecline in elderly male twins. Neurology 1998;50(6):15805.
Cordonnier C, Al-Shahi Salman R, Wardlaw J. Spontaneousbrain microbleeds: systematic review, subgroup analysesand standards for study design and reporting. Brain2007;130(Pt 8):19882003.
Cukierman-Yaffe T, Gerstein HC, Williamson JD, Lazar RM,Lovato L, Miller ME, et al. Relationship between baselineglycemic control and cognitive function in individuals withtype 2 diabetes and other cardiovascular risk factors: theaction to control cardiovascular risk in diabetes-memory indiabetes (ACCORD-MIND) trial. Diabetes Care 2009;32(2):2216.
Danielyan L, Klein R, Hanson LR, Buadze M, Schwab M, GleiterCH, et al. Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease.Rejuvenation Res 2010;13(23):195201.
de Koning I, van Kooten F, Koudstaal PJ, Dippel DW. Diagnosticvalue of the Rotterdam-CAMCOG in post-stroke dementia. JNeurol Neurosurg Psychiatry 2005;76(2):2635.
Debette S, Beiser A, Decarli C, Au R, Himali JJ, Kelly-Hayes M,et al. Association of MRI Markers of Vascular Brain InjuryWith Incident Stroke, Mild Cognitive Impairment, Dementia,and Mortality. The Framingham Offspring Study. Stroke2010a;41:6006.
http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0005http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0005http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0010http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0010http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0010http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0010http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0015http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0015http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0015http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0020http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0020http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0020http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0020http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0025http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0025http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0025http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0025http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0030http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0030http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0030http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0035http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0035http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0040http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0040http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0040http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0045http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0045http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0045http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0050http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0050http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0050http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0050http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0055http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0055http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0060http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0060http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0060http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0060http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0065http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0065http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0065http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0065http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0065http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0065http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0070http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0070http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0070http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0075http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0075http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0075http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0080http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0080http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0080http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0080
-
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 4762Debette S, Beiser A, Hoffmann U, Decarli C, ODonnell CJ,Massaro JM, et al. Visceral fat is associated with lower brainvolume in healthy middle-aged adults. Ann Neurol2010b;68(2):13644.
Debette S, Bombois S, Bruandet A, Delbeuck X, Lepoittevin S,Delmaire C, et al. Subcortical hyperintensities are associatedwith cognitive decline in patients with mild cognitiveimpairment. Stroke 2007;38(11):292430.
Debette S, Markus HS. The clinical importance of white matterhyperintensities on brain magnetic resonance imaging:systematic review and meta-analysis. BMJ 2010;341:c3666.
Debette S, Seshadri S. Vascular risk factors and dementiarevisited. J Neurol Neurosurg Psychiatry 2009;80(11):11834.
Debette S, Seshadri S, Beiser A, Au R, Himali JJ, Palumbo C, et al.Midlife vascular risk factor exposure accelerates structuralbrain aging and cognitive decline. Neurology 2011;77(5):4618.
Diener HC, Sacco RL, Yusuf S, Cotton D, Ounpuu S, Lawton WA,et al. Effects of aspirin plus extended-release dipyridamoleversus clopidogrel and telmisartan on disability andcognitive function after recurrent stroke in patients withischaemic stroke in the Prevention Regimen for EffectivelyAvoiding Second Strokes (PRoFESS) trial: a double-blind,active and placebo-controlled study. Lancet Neurol2008;7(10):87584.
Duering M, Zieren N, Herve D, Jouvent E, Reyes S, Peters N, et al.Strategic role of frontal white matter tracts in vascularcognitive impairment: a voxel-based lesion-symptommapping study in CADASIL. Brain 2011;134(Pt 8):236675.
Elias MF, Beiser A, Wolf PA, Au R, White RF, DAgostino RB. Thepreclinical phase of alzheimer disease: A 22-year prospectivestudy of the Framingham Cohort. Arch Neurol2000;57(6):80813.
Forette F, Seux ML, Staessen JA, Thijs L, Birkenhager WH,Babarskiene MR, et al. Prevention of dementia in randomiseddouble-blind placebo-controlled Systolic Hypertension inEurope (Syst-Eur) trial. Lancet 1998;352(9137):134751.
Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT,Chaturvedi S, et al. Guidelines for the primary prevention ofstroke: a guideline for healthcare professionals from theAmerican Heart Association/American Stroke Association.Stroke 2011;42(2):51784.
Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM,Iadecola C, et al. Vascular contributions to cognitiveimpairment and dementia: a statement for healthcareprofessionals from the american heart association/americanstroke association. Stroke 2011;42(9):2672713.
Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, et al. Cerebral microbleeds: aguide to detection and interpretation. Lancet Neurol2009;8(2):16574.
Hajjar I, Brown L, Mack WJ, Chui H. Impact of Angiotensinreceptor blockers on Alzheimer disease neuropathology in alarge brain autopsy series. Arch Neurol 2012;69(12):16328.
Hajjar I, Quach L, Yang F, Chaves PH, Newman AB, Mukamal K,et al. Hypertension, white matter hyperintensities, andconcurrent impairments in mobility, cognition, and mood:the Cardiovascular Health Study. Circulation2011;123(8):85865.
Henon H, Durieu I, Guerouaou D, Lebert F, Pasquier F, Leys D.Poststroke dementia: incidence and relationship toprestroke cognitive decline. Neurology 2001;57(7):121622.
HPS_Collaborative_Group. MRC/BHF Heart Protection Study ofcholesterol lowering with simvastatin in 20,536 high riskindividuals: a randomised placebo-controlled trial. Lancet2002;360(9326):722.
Iadecola C. Neurovascular regulation in the normal brain and inAlzheimers disease. Nat Rev Neurosci 2004;5(5):34760.Iadecola C. The overlap between neurodegenerative andvascular factors in the pathogenesis of dementia. ActaNeuropathol 2010;120(3):28796.
Inzitari D, Di Carlo A, Pracucci G, Lamassa M, Vanni P, RomanelliM, et al. Incidence and determinants of poststroke dementiaas defined by an informant interview method in a hospital-based stroke registry. Stroke 1998;29(10):208793.
Ivan CS, Seshadri S, Beiser A, Au R, Kase CS, Kelly Hayes M, et al.Dementia after stroke The Framingham Study. Stroke2004;35(6):12648.
Jack Jr CR, Shiung MM, Weigand SD, OBrien PC, Gunter JL, BoeveBF, et al. Brain atrophy rates predict subsequent clinicalconversion in normal elderly and amnestic MCI. Neurology2005;65(8):122731.
Kalaria RN. Neurodegenerative disease: Diabetes, microvascularpathology and Alzheimer disease. Nat Rev Neurol2009;5(6):3056.
Kase CS, Wolf PA, Kelly-Hayes M, Kannel WB, Beiser A,DAgostino RB. Intellectual decline after stroke: theFramingham Study. Stroke 1998;29(4):80512.
Kehoe PG. Angiotensins and Alzheimers disease: a bench tobedside overview. Alzheimers Res Ther 2009;1(1):3.
Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I,Winblad B, et al. Obesity and vascular risk factors at midlifeand the risk of dementia and Alzheimer disease. Arch Neurol2005;62(10):155660.
Klimkowicz A, Dziedzic T, Slowik A, Szczudlik A. Incidence ofpre- and poststroke dementia: cracow stroke registry.Dement Geriatr Cogn Disord 2002;14(3):13740.
Kloppenborg RP, van den Berg E, Kappelle LJ, Biessels GJ.Diabetes and other vascular risk factors for dementia: whichfactor matters most? A systematic review. Eur J Pharmacol2008;585(1):97108.
Kokmen E, Whisnant JP, OFallon WM, Chu CP, Beard CM.Dementia after ischemic stroke: a population-based study inRochester, Minnesota (1960-1984). Neurology 1996;46(1):1549.
Kramer JH, Mungas D, Reed BR, Wetzel ME, Burnett MM, MillerBL, et al. Longitudinal MRI and cognitive change in healthyelderly. Neuropsychology 2007;21(4):4128.
Kuller LH, Lopez OL, Newman A, Beauchamp NJ, Burke G,Dulberg C, et al. Risk factors for dementia in thecardiovascular health cognition study. Neuroepidemiology2003;22(1):1322.
Launer LJ, Hughes T, Yu B, Masaki K, Petrovitch H, Ross GW,et al. Lowering midlife levels of systolic blood pressure as apublic health strategy to reduce late-life dementia:perspective from the Honolulu Heart Program/Honolulu AsiaAging Study. Hypertension 2010;55(6):13529.
Launer LJ, Miller ME, Williamson JD, Lazar RM, Gerstein HC,Murray AM, et al. Effects of intensive glucose lowering onbrain structure and function in people with type 2 diabetes(ACCORD MIND): a randomised open-label substudy. LancetNeurol 2011;10(11):96977.
Lieb W, Beiser A, Vasan RS, Tan ZS, Au R, Harris T, et al.Association of plasma leptin levels with incidentAlzheimers disease and MRI measures of brain aging: theFramingham Study. JAMA 2009;302(23):256572.
Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B,et al. The Study on Cognition and Prognosis in the Elderly(SCOPE): principal results of a randomized double-blindintervention trial. J Hypertens 2003;21(5):87586.
Longstreth Jr WT. Brain vascular disease overt and covert.Stroke 2005;36(10):20623.
Longstreth Jr WT, Arnold AM, Beauchamp Jr NJ, Manolio TA,Lefkowitz D, Jungreis C, et al. Incidence, manifestations, andpredictors of worsening white matter on serial cranialmagnetic resonance imaging in the elderly: theCardiovascular Health Study. Stroke 2005;36(1):5661.
http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0085http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0085http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0085http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0090http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0090http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0090http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0095http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0095http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0095http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0100http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0100http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0105http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0105http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0105http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0110http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0110http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0110http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0110http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0110http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0110http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0110http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0115http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0115http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0115http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0120http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0120http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0120http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0120http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0125http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0125http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0125http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0130http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0130http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0130http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0130http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0135http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0135http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0135http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0135http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0140http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0140http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0140http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0145http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0145http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0145http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0145http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0150http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0150http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0150http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0150http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0155http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0155http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0160http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0160http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0160http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0160http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0165http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0165http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0170http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0170http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0170http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0175http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0175http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0175http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0180http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0180http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0185http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0185http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0185http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0190http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0190http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0190http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0195http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0195http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0200http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0200http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0205http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0205http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0205http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0210http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0210http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0210http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0215http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0215http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0215http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0220http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0220http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0220http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0225http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0225http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0230http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0230http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0230http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0235http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0235http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0235http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0235http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0240http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0240http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0240http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0240http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0250http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0250http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0250http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0255http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0255http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0255http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0260http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0260http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0265http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0265http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0265http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0265
-
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 763Moreno-Gonzalez I, Estrada LD, Sanchez-Mejias E, Soto C.Smoking exacerbates amyloid pathology in a mouse modelof Alzheimers disease. Nat Commun 2013;4:1495.
Mungas D, Harvey D, Reed BR, Jagust WJ, DeCarli C, Beckett L,et al. Longitudinal volumetric MRI change and rate ofcognitive decline. Neurology 2005;65(4):56571.
Nelson PT, Smith CD, Abner EA, Schmitt FA, Scheff SW, DavisGJ, et al. Human cerebral neuropathology of Type 2 diabetesmellitus. Biochim Biophys Acta 2009;1792(5):45469.
Nordahl CW, Ranganath C, Yonelinas AP, Decarli C, Fletcher E,Jagust WJ. White matter changes compromise prefrontalcortex function in healthy elderly individuals. J CognNeurosci 2006;18(3):41829.
Pasquier F, Boulogne A, Leys D, Fontaine P. Diabetes mellitusand dementia. Diabetes Metab 2006;32(5 Pt 1):40314.
Pasquier F, Leys D. Why are stroke patients prone to developdementia? J Neurol 1997;244(3):13542.
Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L,et al. Effects of a fixed combination of perindopril andindapamide on macrovascular and microvascular outcomesin patients with type 2 diabetes mellitus (the ADVANCEtrial): a randomised controlled trial. Lancet2007;370(9590):82940.
Pendlebury ST, Rothwell PM. Prevalence, incidence, and factorsassociated with pre-stroke and post-stroke dementia: asystematic review and meta-analysis. Lancet Neurol2009;8(11):100618.
Peters R, Beckett N, Forette F, Tuomilehto J, Clarke R, Ritchie C,et al. Incident dementia and blood pressure lowering in theHypertension in the Very Elderly Trial cognitive functionassessment (HYVET-COG): a double-blind, placebocontrolled trial. Lancet Neurol 2008;7(8):6839.
Petrovitch H, Ross GW, Steinhorn SC, Abbott RD, Markesbery W,Davis D, et al. AD lesions and infarcts in demented and non-demented Japanese-American men. Ann Neurol2005;57(1):98103.
Plassman BL, Williams Jr JW, Burke JR, Holsinger T, Benjamin S.Systematic review: factors associated with risk for andpossible prevention of cognitive decline in later life. AnnIntern Med 2010;153(3):18293.
Poels MM, Ikram MA, van der Lugt A, Hofman A, Niessen WJ,Krestin GP, et al. Cerebral microbleeds are associated withworse cognitive function: the Rotterdam Scan Study.Neurology 2012;78(5):32633.
Pohjasvaara T, Erkinjuntti T, Ylikoski R, Hietanen M, Vataja R,Kaste M. Clinical determinants of poststroke dementia.Stroke 1998;29(1):7581.
Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Jolles J,Koudstaal PJ, et al. Cerebral small-vessel disease and declinein information processing speed, executive function andmemory. Brain 2005;128(Pt 9):203441.
Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Koudstaal PJ,Oudkerk M, et al. Cerebral white matter lesions and the riskof dementia. Arch Neurol 2004;61(10):15314.
PROGRESS_collaborative_group. Randomised trial of aperindopril-based blood pressure lowering regimen among6105 individuals with previous stroke or transient ischaemicattack. Lancet 2001;358(9287):103341.
Selkoe DJ. Toward a comprehensive theory for Alzheimersdisease. Hypothesis: Alzheimers disease is caused by thecerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci 2000;924:1725.
SHEP_Cooperative_Research_Group. Prevention of stroke byantihypertensive drug treatment in older persons withisolated systolic hypertension. Final results of the SystolicHypertension in the Elderly Program (SHEP). SHEPCooperative Research Group. JAMA 1991;265(24):325564.
Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA,Markesbery WR. Brain infarction and the clinical expressionof Alzheimer disease. The Nun Study. JAMA 1997;277(10):8137.
Sonnen JA, Larson EB, Brickell K, Crane PK, Woltjer R, MontineTJ, et al. Different patterns of cerebral injury in dementiawith or without diabetes. Arch Neurol 2009;66(3):31522.
Staessen JA, Thijs L, Richart T, Odili AN, Birkenhager WH.Placebo-controlled trials of blood pressure-loweringtherapies for primary prevention of dementia. Hypertension2011;57(2):e67.
Tan ZS, Beiser AS, Fox CS, Au R, Himali JJ, Debette S, et al.Association of metabolic dysregulation with volumetricbrain magnetic resonance imaging and cognitive markers ofsubclinical brain aging in middle-aged adults: theFramingham Offspring Study. Diabetes Care 2011;34(8):176670.
Tang WK, Chan SS, Chiu HF, Ungvari GS, Wong KS, Kwok TC,et al. Frequency and determinants of poststroke dementia inChinese. Stroke 2004;35(4):9305.
Tanskanen M, Makela M, Myllykangas L, Notkola IL, PolvikoskiT, Sulkava R, et al. Prevalence and severity of cerebralamyloid angiopathy: a population-based study on veryelderly Finns (Vantaa 85+). Neuropathol Appl Neurobiol2012;38(4):32936.
Tatemichi TK, Paik M, Bagiella E, Desmond DW, Stern Y, SanoM, et al. Risk of dementia after stroke in a hospitalizedcohort: Results of a longitudinal study. Neurology1994;44:188591.
Thomas T, Thomas G, McLendon C, Sutton T, Mullan M. Beta-Amyloid-mediated vasoactivity and vascular endothelialdamage. Nature 1996;380(6570):16871.
Trompet S, van Vliet P, de Craen AJ, Jolles J, Buckley BM, MurphyMB, et al. Pravastatin and cognitive function in the elderly.Results of the PROSPER study. J Neurol 2010;257(1):8590.
Tzourio C, Anderson C, Chapman N, Woodward M, Neal B,MacMahon S, et al. Effects of blood pressure lowering withperindopril and indapamide therapy on dementia andcognitive decline in patients with cerebrovascular disease.Arch Intern Med 2003;163(9):106975.
van Dijk EJ, Prins ND, Vrooman HA, Hofman A, Koudstaal PJ,Breteler MM. Progression of cerebral small vessel disease inrelation to risk factors and cognitive consequences:Rotterdam Scan study. Stroke 2008;39(10):27129.
Vermeer SE, Longstreth Jr WT, Koudstaal PJ. Silent braininfarcts: a systematic review. Lancet Neurol 2007;6(7):6119.
Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ,Breteler MM. Silent brain infarcts and the risk of dementiaand cognitive decline. N Engl J Med 2003;348(13):121522.
Viswanathan A, Greenberg SM. Cerebral amyloid angiopathy inthe elderly. Ann Neurol 2011;70(6):87180.
Viswanathan A, Rocca WA, Tzourio C. Vascular risk factors anddementia: how to move forward? Neurology 2009;72(4):36874.
Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, et al. Valsartanlowers brain beta-amyloid protein levels and improvesspatial learning in a mouse model of Alzheimer disease. JClin Invest 2007;117(11):3393402.
Wen W, Sachdev PS, Li JJ, Chen X, Anstey KJ. White matterhyperintensities in the forties: their prevalence andtopography in an epidemiological sample aged 44-48. HumBrain Mapp 2009;30(4):115567.
Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlifecardiovascular risk factors and risk of dementia in late life.Neurology 2005;64(2):27781.
Zhou DH, Wang JY, Li J, Deng J, Gao C, Chen M. Study onfrequency and predictors of dementia after ischemic stroke:the Chongqing stroke study. J Neurol 2004;251(4):4217.
Zhu L, Fratiglioni L, Guo ZC, Basun H, Corder EH, Winblad B,et al. Incidence of dementia in relation to stroke and theapolipoprotein E epsilon 4 allele in the very old - Findings
http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0270http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0270http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0275http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0275http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0280http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0280http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0285http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0285http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0285http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0290http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0290http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0295http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0295http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0300http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0300http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0300http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0300http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0300http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0305http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0305http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0305http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0305http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0310http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0310http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0310http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0310http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0315http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0315http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0315http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0320http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0320http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0320http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0325http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0325http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0325http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0330http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0330http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0335http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0335http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0335http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0340http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0340http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0345http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0345http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0345http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0345http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0350http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0350http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0350http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0350http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0355http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0355http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0355http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0355http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0355http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0360http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0360http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0360http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0365http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0365http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0370http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0370http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0370http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0375http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0375http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0375http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0375http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0375http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0380http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0380http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0385http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0385http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0385http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0385http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0390http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0390http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0390http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0395http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0395http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0395http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0400http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0400http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0405http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0405http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0405http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0405http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0410http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0410http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0410http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0415http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0415http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0420http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0420http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0425http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0425http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0430http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0430http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0430http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0435http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0435http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0435http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0435http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0440http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0440http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0440http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0440http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0445http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0445http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0445http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0450http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0450http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0450http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0455http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0455
-
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 4764from a population-based longitudinal study. Stroke2010;31(1):5360.
Zhu YC, Dufouil C, Mazoyer B, Soumare A, Ricolfi F, Tzourio C,et al. Frequency and location of dilated Virchow-Robinspaces in elderly people: a population-based 3D MR imagingstudy. AJNR Am J Neuroradiol 2011;32(4):70913.Zhu YC, Dufouil C, Soumare A, Mazoyer B, Chabriat H, TzourioC. High degree of dilated Virchow-Robin spaces on MRI isassociated with increased risk of dementia. J Alzheimers Dis2010;22(2):66372.
Zlokovic BV. Neurovascular mechanisms of Alzheimersneurodegeneration. Trends Neurosci 2005;28(4):2028.
http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0455http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0455http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0460http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0460http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0460http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0465http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0465http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0465http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0470http://refhub.elsevier.com/S0035-3787(13)00881-3/sbref0470
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