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ORIGINAL PAPER

Blood Pressure and All-Cause Mortality by Level of Cognitive Function in


the Elderly: Results From a Population-Based Study in Rural Greece
Marios K. Georgakis, MD;1 Athanasios D. Protogerou, MD, PhD;2 Eleni I. Kalogirou, MD;1 Evangelia Kontogeorgi, MD;1 Ioanna
Pagonari, MD;3 Fani Sarigianni, MD;3 Sokratis G. Papageorgiou, MD, PhD;4 Elisabeth Kapaki, MD, PhD;5 Charalampos
Papageorgiou, MD, PhD;6 Dimitrios Tousoulis, MD, PhD;7 Eleni Th. Petridou, MD, MPH, PhD1,7

From the Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens,
Greece;1 Cardiovascular Prevention and Research Unit, Department of Pathophysiology, School of Medicine, National and Kapodistrian University of
Athens, Athens, Greece;2 Health Centre of Velestino, Ahillopouleio General Hospital of Volos, Velestino, Volos, Greece;3 Second Department of
Neurology, Attikon University General Hospital, School of Medicine, National and Kapodistrian University of Athens, Chaidari, Athens, Greece;4 First
Department of Neurology, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece;5 First Department
of Psychiatry, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece;6 and First Department of
Cardiology, Hippokrateion Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece7

This study aimed to investigate whether the effect of blood with the second, was associated with mortality (hazard ratio,
pressure (BP) on mortality differs by levels of cognitive 1.85; 95% confidence intervals, 1.093.12) among cogni-
function. The associations of brachial systolic BP, diastolic tively impaired individuals. The fractional-polynomials
BP, mean arterial pressure (MAP), and pulse pressure with approach for BP confirmed this finding and further showed,
all-cause mortality were prospectively explored (follow-up solely in the MMSE <24 subcohort, U-shaped trends of MAP
7.02.2 years) in 660 community-dwelling individuals and systolic BP, with increased mortality risk in extremely
(60 years) using adjusted Cox models, stratified by cogni- low or high values; no such pattern was evident for patients
tive impairment (Mini-Mental State Examination [MMSE] with MMSE 24. Elderly individuals with cognitive impair-
<24). No association between brachial BP variables and ment might be more susceptible to the detrimental effects of
mortality was shown for the total sample in quartiles low and elevated MAP and systolic BP. J Clin Hypertens
analysis; however, MAP in the highest quartile, compared (Greenwich). 2016:19. 2016 Wiley Periodicals, Inc.

Arterial hypertension, the most common modifiable cognition,14 along with the consistent reports from
cardiovascular disease (CVD) risk factor worldwide, prospective studies about associations of cognitive
increases with age and affects 65% of individuals impairment with all-cause and CVD mortality,1519
70 years and older.1 Despite the strong evidence it could be assumed that the effects of BP on mortality
connecting hypertension to increased mortality,2 the are differentiated by levels of cognitive function. Indeed,
exact effect of blood pressure (BP), especially among systematic reviews of clinical trials conclude that there is
elderly individuals, remains unknown. Previous studies not sufficient evidence for benefit of antihypertensive
report J- or U-shaped associations of BP with mortal- treatment against mortality among hypertensive
ity,35 and suggest that among the oldest individuals patients with dementia.20,21
(>80 years), low rather than high BP is a predictor of Nevertheless, only a few previous studies have exam-
mortality.4,5 ined how cognitive function affects the association of BP
Cognitive impairment is a common late-life comor- with mortality.2225 A reinforcement of a detrimental
bidity, as 10% of individuals older than 60 years have effect of low diastolic BP (DBP) on mortality among
frank dementia.6 Increasing evidence links BP with individuals with cognitive impairment is the most
cognitive decline,7,8 attributing the observed associa- consistent finding, replicated in three studies,2224
tions to the hemodynamic consequences of elevated or whereas results regarding systolic BP (SBP) and pulse
low BP and increased pulsatility on cerebral vascula- pressure (PP) are conflicting.2225 Only one study
ture.9,10 Subsequent microvascular disease is considered explored mean arterial pressure (MAP).22 In view
a key player in the pathogenesis of not only vascular of the above, we hereby aim with the current study to
dementia, but also Alzheimers disease.1113 Consider- examine the association of brachial BP components
ing this association between BP parameters and (SBP, DBP, MAP, PP) with 8-year all-cause mortality by
levels of cognitive function in a community-dwelling
sample of elderly individuals from rural Greece.
Address for correspondence: Eleni Th. Petridou, MD, MPH, PhD,
Department of Hygiene, Epidemiology and Medical Statistics, School of
Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias MATERIALS AND METHODS
Street, Athens 11527, Greece
E-mail: epetrid@med.uoa.gr Study Sample
Manuscript received: April 1, 2016; revised: June 2, 2016; accepted: Velestino is a rural town in Thessaly, central Greece, of
June 9, 2016
DOI: 10.1111/jch.12880
around 4000 inhabitants. The recruitment for the

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BP Mortality Association by Cognitive Function Level | Georgakis et al.

second phase of the Velestino study was conducted MAP DBP (SBP  DBP=3;
during the period 20052006 and the target population
comprised all permanent residents aged 60 years or
older. During that time, 1080 individuals 60 years and PP SBP  DBP
older were recorded in the town registry; of them, 263
individuals had moved to other residence (nonperma- Evaluation of Cognition and Depressive Symptoms
nent inhabitants), leaving a total of 817 potentially The validated Greek version of the Mini-Mental State
eligible participants for the study. An attempt was Examination (MMSE) was administered to participants
made to contact all of the patients for inclusion into the to assess their global cognitive function. A score lower
study. However, 34 individuals died during the study than 24 of 30 was indicative of cognitive impairment.31
period, eight were severely physically or mentally Depressive symptomatology was determined using the
disabled and could not provide adequate information 15-item Geriatric Depression Scale (GDS), which has
for inclusion to the study, and 99 participants refused also been validated in the Greek population,32 with a
to participate. Finally, 676 individuals signed the score higher than six determining presence of depres-
informed consent and participated in the study; all sion.
participants were community-dwelling and noninstitu-
tionalized. Details on study recruitment can be found Assessment of Mortality
elsewhere.19,26,27 Among the participants, 660 individ- In collaboration with the Local Registry Office, death
uals had available BP and cognition measurements. certificates referring to the inhabitants of Velestino up to
Basic demographic characteristics of the included October 31, 2013, were accessed (mean duration of
participants (age, sex) were comparable to those of follow-up: 7.02.2 years); vital status and date of death
the entire elderly population. The study protocol was were recorded.
reviewed and approved by the ethics committee of the
Athens University Medical School and the Peripheral Statistical Analysis
General Hospital of Volos. The distribution of study variables by MMSE score
(<24 vs 24) was derived and P values were subse-
Assessment of Sociodemographic, Lifestyle, and quently calculated using chi-square or t test as appro-
Clinical Characteristics priate. Cox proportional hazard models were designed
Using a precoded standardized questionnaire, two local for all-cause mortality. Two approaches were followed
physicians interviewed participants at their residence or for BP variables in order to investigate potential
workplace. Questions regarding sociodemographic (age, nonlinear associations, as previously reported for the
education, and family support) and lifestyle (social detrimental effects of BP:3,2225 (1) in a quartile
activity, smoking habits, and alcohol consumption) categorical approach, SBP, DBP, MAP, and PP were
characteristics were included.26 Anthropometric mea- treated as categorical variables in quartiles with the
surements were carried out and body mass index (BMI) second as a reference category; the quartile approach
was calculated as weight divided by height squared. was preferred over tertiles, to more adequately illus-
History of previous diagnoses and use of medications trate potential nonlinear associations; and (2) we
were based on self-reported information, as well as on a further examined the effects of SBP, DBP, MAP, and
thorough review of medical records. Morning blood PP on all-cause mortality using fractional-polynomial
sample was collected for biochemical assessment, and modeling, and the results of the best-fitting model were
biochemical measurements combined with medical his- graphically presented.
tory allowed for the diagnoses of the diseases of interest. A basic model included age (continuous by 1-year
Particularly, hypercholesterolemia was determined by increment), sex, and BP variables (SBP, DBP, MAP, PP)
previous diagnosis or low-density lipoprotein choles- interchangeably (model 1), whereas in a fully adjusted
terol levels 160 mg/dL28 and diabetes mellitus type 2 model (model 2) the following variables were addi-
by medical history or fasting blood glucose levels tionally introduced: education level (ordered; <6, 68,
126 mg/dL.29 CVD was defined by history of coronary 9 years), social activity (optimal vs suboptimal),
artery disease or cerebrovascular disease. family support (adequate vs poor), BMI (continuous
by 1 kg/m2 increment), alcohol intake (ordered; no, up
BP Measurements to recommended limit, more), diabetes mellitus type 2,
Measurement of DBP and SBP was carried out by the hypercholesterolemia, CVD, use of antihypertensive
two physicians who conducted the interviews. The drugs, depression (GDS 6 vs >6), and cognitive
examinees were in a calm state and a sitting position impairment (MMSE <24 vs 24). Smoking (ever vs
and were at rest for at least 10 minutes. Two measure- never) was not introduced in the model because the
ments were conducted using manual mercury sphygmo- meager proportion of female smokers led to a high
manometers and the mean values of DBP and SBP were correlation with the sex variable. Similarly, use of
recorded. MAP and PP were thereafter calculated using lipid-lowering drugs and glucose-lowering drugs were
the following respective formulae:30 not included because of the entering of the related

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BP Mortality Association by Cognitive Function Level | Georgakis et al.

hypercholesterolemia and diabetes mellitus variables.


TABLE I. Sociodemographic, Lifestyle, and Clinical
All analyses were performed for the total sample
Characteristics of Study Participants (N=660) by
and were additionally stratified by presence of cogni-
MMSE Score
tive impairment (MMSE <24 and 24). Statistical
analysis was conducted using SAS statistical software MMSE <24 MMSE 24
(version 9.2; SAS Institute Inc, Cary, NC) and STATA Variables n=362 n=298 P Value
(version 12.0, STATA Corporation, College Station, Age y 75.77.8 71.17.4 <.001
TX). Male sex 131 (36.2) 155 (52.0) <.001
Education, y
RESULTS <6 271 (74.9) 134 (45.0) <.001
The mean age among participants at baseline was 68 83 (22.9) 127 (42.6)
73.67.9 years, whereas the mean MMSE score was 9 8 (2.2) 37 (12.4)
22.34.6. Of 660 participants, 54.8% had an MMSE Suboptimal social activity 148 (40.9) 75 (25.2) <.001
score <24. Table I shows the distribution of the study Poor family support 56 (15.5) 32 (10.7) .08
variables by MMSE score at baseline and serves BMI, kg/m2 30.45.0 30.35.3 .72
mostly descriptive purposes, as data are not mutually Alcohol intake, glasses per d
adjusted. Older age, female sex, lower education and 0 140 (38.7) 80 (26.9) .002
suboptimal social activity, depression, and diabetes 1 (women), 2 (men) 183 (50.6) 167 (56.0)
>1 (women), >2 (men) 39 (10.8) 51 (17.1)
were more common in cognitively impaired patients,
Ever smoking 85 (23.5) 114 (38.3) <.001
whereas smoking, alcohol intake, and use of antihy-
Depression (GDS 6) 209 (57.7) 120 (40.3) <.001
pertensive drugs were more common among patients
Hypercholesterolemia 121 (33.4) 103 (34.6) .76
without cognitive impairment. With regards to the BP
Total cholesterol, mg/dL 214.148.1 214.538.4 .91
variables, PP was higher and SBP marginally higher LDL cholesterol, mg/dL 133.037.7 128.831.5 .28
among patients with cognitive impairment; no differ- HDL cholesterol, mg/dL 54.511.8 54.511.3 .98
ence was recorded for DBP and MAP. Diabetes mellitus type 2 71 (19.6) 41 (13.8) .05
During a mean follow-up period of 7.02.2 years, Cardiovascular disease 101 (27.9) 74 (24.8) .37
196 patients died (29.7%). A larger proportion of History of CAD 75 (20.7) 50 (19.8) .77
participants in the cognitive impairment (MMSE <24) History of cerebrovascular 35 (9.7) 21 (7.1) .23
subcohort died (38.4%), compared with cognitively disease
normal (MMSE 24) patients (19.1%). Table II pre- Antihypertensive drugs 260 (71.8) 192 (64.4) .04
sents the multivariate Cox proportional hazard regres- Diuretics 85 (23.5) 53 (17.8) .07
sion analysis results for SBP, DBP, MAP, and PP in the Calcium channel blockers 78 (21.6) 39 (13.1) .005
total sample and by MMSE subcohorts, according to b-Blockers 54 (14.9) 67 (22.5) .01
the quartile approach. In the total sample, none of the ACEIs/ARBs 162 (44.8) 128 (43.0) .64
BP variables were independently associated with mor- Other antihypertensive drugs 20 (5.5) 14 (4.7) .63
tality. An increased all-cause mortality risk (hazard Glucose-lowering drugs 55 (15.2) 34 (11.4) .15
ratio [HR], 1.85; 95% confidence intervals [CI], 1.09 Lipid-lowering drugs 61 (16.9) 63 (21.1) .16
3.12, in model 2) was found for the highest MAP Systolic blood pressure 148.322.2 145.322.4 .09
quartile (112.0 mm Hg), compared with the second Diastolic blood pressure 81.113.0 81.812.0 .48
Mean arterial pressure, mm Hg 103.514.1 103.013.9 .64
(93.5101.9 mm Hg) among patients with MMSE
score <24. No such effect of MAP was noted for Pulse pressure, mm Hg 67.218.5 63.617.8 .01

patients with MMSE scores in the normal range. Even Data are presented as n (%) or mean  standard deviation. Abbre-
though SBP, DBP, and PP were not significantly viations: ACEIs, angiotensin-converting enzyme inhibitors; ARB,
associated with mortality, a trend for a U-shaped angiotensin II receptor blockers; BMI, body mass index; CAD,
coronary artery disease; GDS, Geriatric Depression Scale; HDL, high-
association for SBP only in the cognitively impaired
density lipoprotein; LDL, low-density lipoprotein; MMSE, Mini-Mental
subcohort was noted; the lowest (130.0 mm Hg; HR,
State Examination.
1.50; 95% CI, 0.892.55 in model 2) and the highest
(>160.0 mm Hg; HR, 1.49; CI, 0.912.48 in model 2)
quartiles were positively but nonsignificantly associated
with mortality relative to the second (130.1 antihypertensive medications was negatively associated
145.0 mm Hg) quartile. Similar to MAP, such a trend with mortality (data not shown).
was not recorded for the cognitively normal patients. Figure depicts the best-fitting models for the associ-
Other factors associated with mortality were increasing ations of BP variables with all-cause mortality, as
age, male sex, presence of cardiovascular disease, derived by the multivariate fractional polynomial anal-
diabetes mellitus type 2, and cognitive impairment. In ysis. The results showed a U-shaped effect of SBP and
addition, among cognitively impaired patients, poor MAP on all-cause mortality in the total sample
family support, suboptimal social activity, and depres- (Figure a) with significantly increased risk in both the
sive symptoms increased all-cause mortality, whereas highest and the lowest values. For MAP, this pattern
among cognitively normal patients, use of was observed only among patients with MMSE score

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BP Mortality Association by Cognitive Function Level | Georgakis et al.

TABLE II. Multivariate Cox Regression Derived HRs and 95% CIs for All-Cause Mortality by BP Variables Stratified
According to MMSE Score
Total Sample (N=660) MMSE <24 (n=362) MMSE 24 (n=298)

Variable BP Quartiles HR (95% CIs) P Value HR (95% CIs) P Value HR (95% CIs) P Value

Model 1: adjusted for age and sex


Systolic blood pressure, mm Hg 130 1.36 (0.902.05) .15 1.43 (0.862.38) .21 1.26 (0.612.60) .53
130.1145.0 Reference Reference
145.1160.0 1.30 (0.851.98) .23 1.24 (0.752.07) .40 1.35 (0.622.94) .45
>160.0 1.31 (0.852.01) .22 1.38 (0.842.28) .21 0.92 (0.382.23) .86
Diastolic blood pressure, mm Hg <75.0 1.08 (0.761.53) .67 0.99 (0.651.51) .95 1.09 (0.582.05) .79
75.080.9 Reference Reference Reference
81.090.0 0.93 (0.621.39) .73 0.91 (0.551.52) .72 0.98 (0.501.92) .94
>90.0 1.35 (0.852.13) .20 1.47 (0.882.46) .14 0.60 (0.201.78) .35
Mean arterial pressure, mm Hg <93.5 1.19 (0.821.74) .37 1.30 (0.812.10) .28 1.25 (0.632.49) .53
93.5101.9 Reference Reference Reference
102.0111.9 1.10 (0.731.67) .65 1.26 (0.752.11) .39 1.69 (0.843.41) .14
112.0 1.26 (0.831.93) .17 1.82 (1.103.03) .02 0.65 (0.261.62) .36
Pulse pressure, mm Hg 50.0 0.86 (0.571.31) .49 0.65 (0.391.10) .11 1.76 (0.813.83) .16
50.161.9 Reference Reference Reference
62.075.0 0.90 (0.591.37) .61 0.65 (0.401.08) .10 1.73 (0.793.78) .17
>75.0 1.02 (0.691.51) .93 0.92 (0.591.44) .72 1.23 (0.532.85) .64
Model 2: fully adjusted
Systolic blood pressure, mm Hg 130.0 1.33 (0.872.04) .19 1.50 (0.892.55) .14 1.08 (0.512.27) .85
130.1145.0 Reference Reference Reference
145.1160.0 1.21 (0.791.86) .38 1.33 (0.792.25) .28 1.25 (0.552.81) .59
>160.0 1.30 (0.842.02) .24 1.49 (0.912.48) .12 0.85 (0.342.09) .72
Diastolic blood pressure, mm Hg <75.0 0.91 (0.631.31) .60 0.79 (0.511.24) .31 1.14 (0.582.24) .70
75.080.9 Reference Reference Reference
81.090.0 0.92 (0.611.39) .69 0.87 (0.511.24) .59 1.00 (0.502.01) .99
>90.0 1.23 (0.812.04) .38 1.38 (0.812.35) .23 0.60 (0.201.85) .38
Mean arterial pressure, mm Hg <93.5 1.01 (0.661.55) .95 1.10 (0.661.82) .71 1.17 (0.572.43) .66
93.5101.9 Reference Reference Reference
102.0111.9 1.01 (0.681.49) .96 1.25 (0.732.13) .42 1.62 (0.763.45) .21
112.0 1.23 (0.801.88) .34 1.85 (1.093.12) .02 0.63 (0.251.61) .33
Pulse pressure, mm Hg 50.0 0.91 (0.591.40) .66 0.65 (0.381.12) .12 1.55 (0.683.52) .30
51.061.0 Reference Reference Reference
62.075.0 0.90 (0.581.35) .57 0.66 (0.391.11) .12 1.51 (0.673.40) .33
>75.0 1.00 (0.681.50) .97 0.87 (0.551.37) .55 1.17 (0.492.81) .72
Abbreviations: BP, blood pressure; CI, confidence interval; HR, hazard ratio; MMSE, Mini-Mental State Examination.
Model 1 is adjusted for age (continuous by 1 year) and sex.
Model 2 is adjusted for age (continuous by 1 year), sex, educational level (ordered; 1 level more), social activity (optimal vs suboptimal), family support
(poor vs normal), body mass index (continuous by 1-year increment), alcohol intake (ordered; three categories), depression (geriatric depression scale
score >6 vs 6), hypercholesterolemia (yes vs no), diabetes mellitus type 2 (yes vs no), cardiovascular disease (yes vs no), and antihypertensive
medications (yes vs no). Analyses for the total sample are further adjusted for cognitive impairment (MMSE <24 vs 24).

<24, whereas for the subcohort with a normal range on of peripheral BP variables with all-cause mortality
the MMSE, no association of MAP with mortality was emerged. In fully adjusted analyses, low and high
revealed. Regarding SBP, the U-shaped trend was MAP and SBP values were associated with increased
observed in both the cognitively impaired and cogni- all-cause mortality only among individuals with MMSE
tively normal group of individuals, but was stronger and scores indicative of cognitive impairment. DBP and PP
significant only in the former. Nonsignificant trends were not found to independently affect mortality in this
emerged for DBP and PP in the total sample or the study, whereas no significant association was found
MMSE subcohorts. among patients with MMSE scores in the normal range.
Only four studies have to our knowledge previously
DISCUSSION examined the BP-mortality association in view of
In this study, based on a community-dwelling popula- cognitive performance.2225 Two of them, population-
tion of elderly individuals followed for a period of based studies including individuals 65 years and older,
8 years, a differential by cognitive function association showed that only among cognitively impaired patients,

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BP Mortality Association by Cognitive Function Level | Georgakis et al.

(a)

(b)

FIGURE.

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BP Mortality Association by Cognitive Function Level | Georgakis et al.

(c)

FIGURE. Risk of all-cause mortality according to systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure.
Graphs refer to (a) the total sample (n=660), (b) individuals with a Mini-Mental State Examination (MMSE) score <24 (n=362), and (c) individuals
with an MMSE score 24 (n=298), and correspond to the best-fitting models derived from fractional polynomial analysis adjusted for age
(continuous by 1 year), sex (males vs females), education level (ordered; 1 level more), social activity (optimal vs suboptimal), family support
(poor vs normal), body mass index (continuous), alcohol intake (ordered; three categories), geriatric depression scale score (>6 vs 6),
hypercholesterolemia (yes vs no), diabetes mellitus type 2 (yes vs no), cardiovascular disease (yes vs no), and antihypertensive medications
(yes vs no). The blue lines represent hazard ratios by levels of blood pressure and shaded areas correspond to the respective 95% confidence
intervals. Mean values are used as references.

low DBP (lowest quartile and tertile compared with age differences in the study populations could cause
second and median, respectively) was associated with discrepancies.33 Furthermore, BP variables have been
mortality,22,24 whereas one of them that also presented treated categorically in all studies but different catego-
MAP and PP22 found that in patients with MMSE <24, rizations were implemented (dichotomous analysis,
significant associations emerged for low MAP and tertiles, quartiles, quintiles) corresponding to diverse
elevated PP. Similarly, a Swedish cohort of a relatively cutoff points, which could be responsible for the
older population (75 years)23 reported that low DBP variations in the findings between studies. In this study
increased mortality in patients with cognitive impair- we have additionally to the traditional quartile analysis,
ment and not in those with normal cognitive scores; encompassed a fractional polynomial analysis to assess
however, this study also found the same pattern for SBP. BP nonlinear effects.34 This analysis revealed some
Lastly, in a recent report of the oldest elderly significant associations for extreme values that were
(>80 years)25 researchers found that both low and high shadowed in the quartiles approach.
SBP values were associated with increased all-cause It is possible that this increased vulnerability of
mortality only in the subcohort of patients with patients with cognitive impairment to the detrimental
the most severe form of cognitive impairment (MMSE effects of low and high SBP and MAP is mediated by
010). In our population of elderly (older than 60 years) underlying CVD burden. Cognitive decline could be the
inhabitants of a rural community characterized by low expression of microvascular or macrovascular cerebral
educational level, our findings on a susceptibility of pathology35 possibly in the context of generalized
cognitively impaired individuals to the effects of BP on vascular disease.36 CVD is one of the most common
mortality are in line with past literature. What is causes of death among patients with dementia,37 and, as
differentiated, however, is the profile of this suscepti- we recently showed in this sample, cognitive impair-
bility. As BP characteristics change with increasing age, ment is also associated with increased risk of

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BP Mortality Association by Cognitive Function Level | Georgakis et al.

cardiovascular mortality.19 An intriguing explanation values were observed in cognitively impaired patients.
would include poor cerebral autoregulation among After adjusting for age, however, the association
patients with severe cognitive impairment. Although between PP and cognitive impairment was completely
loss of cerebral autoregulation has been systematically attenuated (results not shown), reflecting a confounding
described in animal models of Alzheimers disease, the role of aging. Published literature has shown inconsis-
evidence in humans is not robust.3840 Patients with tent results regarding the PP-cognition association.7
cognitive impairment in this sample were also charac- Under loss of arterial elasticity, impaired microvascular
terized by increased PP values, indicating potentially reactivity is observed and thus the negative effects of
advanced arterial stiffness, which has also been found to extremely high or low SBP and MAP values might
contribute to the loss of cerebral vasomotor reactivity.41 become more prominent.55
If this explanation is true, presence of dementia could
indicate susceptibility to hypoperfusion and ischemic STUDY LIMITATIONS
changes or uncontrolled flow and hemorrhagic injuries The study findings should be interpreted in view of
in the cerebral arteriolar bed caused by extremely low or certain limitations. Firstly, the use of surrogate formulae
high SBP and MAP values, respectively, especially under for brachial MAP and PP calculation and the lack of
presence of arterial stiffness.4244 It should be take into assessment of central values should be considered a
account, however, that patients with cognitive impair- drawback, and no invasive method was available for
ment who receive suboptimal care are also at higher risk their estimation. Secondly, the unavailability of 24-hour
for noncompliance to antihypertensive treatment,45 thus BP monitoring did not allow for the investigation of the
increasing their vulnerability to the negative effects of effect of BP variability over time, including orthostatic
hypertension. Lastly, regarding the association of low hypotension in the research question. Thirdly, no
SBP and MBP values with mortality, the potential neuroimaging data were available for assessment of
confounding role of cachexia at terminal stages of cerebral small vessel disease to investigate the potential
diseases should be taken into consideration, as under- underlying pathology of the associations. We should
weight is related to decreased BP.46 Yet, fully adjusted also note the unavailability of other measures of
models controlled for BMI levels, whereas the finding socioeconomic measurements, such as yearly income,
was evident only among cognitively normal patients which could give more information on the background
who are less likely to experience cachexia caused by of the individuals. Additionally, despite the fact that the
terminal diseases, compared with those with cognitive Greek version of the MMSE has been previously
impairment. validated in the elderly,31 the potential misclassification
Notably, baseline differences between the two groups of cognitive impairment cases as a result of a lack of
of participants in our study (MMSE <24 and 24) were clinical assessment cannot be precluded; the extremely
evident. Firstly, regarding sociodemographic and life- low educational level of the participants (61% of the
style characteristics, patients with cognitive impairment total sample <6 years of education) could possibly
were more likely women and of older age, whereas explain the high proportion of patients scoring <24 on
smoking and alcohol consumption were more common the MMSE. Lastly, because of a lack of statistical
among individuals without cognitive impairment, power, no stratification by age and sex could be
possibly as a result of a more active social life. The conducted, whereas despite the availability of cause-
lower educational level and the higher prevalence of specific mortality, analyses for cardiovascular and
depressive symptoms in patients with cognitive impair- noncardiovascular mortality could not be performed
ment was anticipated, as it is well-established in because the low number of death events in the subco-
previous literature,47,48 and we have shown in the same horts of cognitively impaired and cognitively normal
sample that they both represent independent risk factors individuals would hamper the reliability of the analysis.
for cognitive impairment.26 In terms of comorbidity, a All analyses are, however, adjusted for a wide range of
higher rate of diabetes mellitus, as well as a higher major sociodemographic and medical confounders.
proportion of antihypertensive medication use, likely
implying increased burden of hypertension, were STUDY STRENGTHS
recorded among patients with cognitive impairment, The strengths of the study include the population-based
as has been previously described.49,50 Even though design including community-dwelling individuals, the
fully adjusted analyses controlled for the aforemen- high participation rates among a homogeneous sample
tioned factors, it cannot be precluded that these differ- of those born and still residing in Velestino, the
ences partially explain the findings. In particular, older relatively long follow-up period of 8 years, and the
age, female sex, lack of physical activity, depression, high-quality data collection procedure by physicians
diabetes mellitus, and hypertension are all factors that familiar with the residents. Furthermore, in contrast to
are associated with arterial stiffness in the elderly.5154 previous studies, the use of fractional polynomial
Therefore, the observed susceptibility of cognitively analysis in addition to a categorical analysis for BP
impaired patients might be attributed to the higher allowed the emergence of relationships between extreme
prevalence of arterial stiffness. This is further supported values of BP and mortality that were concealed in
by the fact that among BP parameters, only higher PP quartiles.

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BP Mortality Association by Cognitive Function Level | Georgakis et al.

CONCLUSIONS 15. Wu CY, Chou YC, Huang N, et al. Cognitive impairment assessed at
annual geriatric health examinations predicts mortality among the
Our findings show that the association between BP and elderly. Prev Med. 2014;67:2834.
all-cause mortality in elderly individuals is dependent on 16. Dewey ME, Saz P. Dementia, cognitive impairment and mortality in
the level of cognitive function. Patients with cognitive persons aged 65 and over living in the community: a systematic review
of the literature. Int J Geriatr Psychiatry. 2001;16:751761.
impairment seem to be more susceptible to the detri- 17. ODonnell M, Teo K, Gao P, et al. Cognitive impairment and risk of
mental effects of low and high SBP and MAP. Future cardiovascular events and mortality. Eur Heart J. 2012;33:1777
1786.
research should focus on identifying the hemodynamic 18. Bassuk SS, Wypij D, Berkman LF. Cognitive impairment and
consequences of dementia in cerebral circulation in mortality in the community-dwelling elderly. Am J Epidemiol.
humans, as well as on unraveling the complex interplay 2000;151:676688.
19. Georgakis MK, Papadopoulos FC, Protogerou AD, et al. Comorbidity
between vascular pathology and cognition. Most impor- of cognitive impairment and late-life depression increase mortality:
tantly, given the lack of evidence on the effects of results from a cohort of community-dwelling elderly individuals in
antihypertensive treatment among individuals with rural Greece. J Geriatr Psychiatry Neurol. 2016;29:195204.
20. Beishon LC, Harrison JK, Harwood RH, et al. The evidence for
dementia, large prospective studies are needed to treating hypertension in older people with dementia: a systematic
confirm the differential effects of BP by cognitive review. J Hum Hypertens. 2014;28:283287.
21. van dWV, Logan P, Conroy S, et al. Antihypertensive treatment in
function level to determine ideal BP values for these people with dementia. J Am Med Dir Assoc. 2014;15:620629.
individuals and better target patients who could benefit 22. Cacciatore F, Abete P, de SD, et al. Mortality and blood pressure in
from BP-lowering interventions. elderly people with and without cognitive impairment. Gerontology.
2005;51:5361.
23. Guo Z, Viitanen M, Winblad B. Low blood pressure and five-year
Acknowledgments: Contributions are acknowledged to Anastasia Anastasiou, mortality in a Stockholm cohort of the very old: possible confounding
MD, PhD, Konstantinos Katsiardanis, MD, and Kalliopi-Penelopi Katsiardani, by cognitive impairment and other factors. Am J Public Health.
MD, in the collection of primary data, as well as Theodoros Michelakos, MD, 1997;87:623628.
and Christina Perlepe, MD, in cleaning primary and death certificate data. The 24. Post HG, Smulders YM, Maier AB, et al. Relation between blood
authors would also like to thank the Municipality of Velestino for contributing in pressure and mortality risk in an older population: role of chrono-
the planning and data collection phase, the inhabitants of Velestino, and logical and biological age. J Intern Med. 2015;277:488497.
Onassis Public Benefit Foundation. 25. Weidung B, Littbrand H, Nordstrom P, et al. The association between
SBP and mortality risk differs with level of cognitive function in very
Funding: None. old individuals. J Hypertens. 2016;34:745752.
26. Michelakos T, Kousoulis AA, Katsiardanis K, et al. Serum folate and
B12 levels in association with cognitive impairment among seniors:
Conflicts of Interest: None declared.
results from the VELESTINO study in Greece and meta-analysis.
J Aging Health. 2013;25:589616.
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