Variation in Blood Pressure Is Associated With White Matter
Microstructure but Not Cognition in African Americans
Elizabeth C. Leritz
VA Boston Healthcare System and Brigham
& Women’s Hospital
David H. Salat
Athinoula A. Martinos Center for Biomedical Imaging
and VA Boston Healthcare System
William P. Milberg
VA Boston Healthcare System and Harvard Medical School
Victoria J. Williams
VA Boston Healthcare System and Brigham
& Women’s Hospital
Caroline E. Chapman
VA Boston Healthcare System and Athinoula A. Martinos
Center for Biomedical Imaging
Laura J. Grande
VA Boston Healthcare System
James L. Rudolph
VA Boston Healthcare System and Brigham
& Women’s Hospital
David M. Schnyer
University of Texas at Austin
Colleen E. Barber
VA Boston Healthcare System
Lewis A. Lipsitz
Harvard Medical School and Beth Israel Deaconess
Regina E. McGlinchey
VA Boston Healthcare System and Harvard Medical School
Although hypertension is a major risk factor for cerebrovascular disease (CVD) and is highly prevalent in
African Americans, little is known about how blood pressure (BP) affects brain–behavior relationships in this
population. In predominantly Caucasian populations, high BP is associated with alterations in frontal–
subcortical white matter and in executive functioning aspects of cognition. We investigated associations
among BP, brain structure, and neuropsychological functioning in 52 middle–older-age African Americans
without diagnosed history of CVD. All participants underwent diffusion tensor imaging for examination of
white matter integrity, indexed by fractional anisotropy (FA). Three regions of interest were derived in the
anterior (genu) and posterior (splenium) corpus callosum and across the whole brain. A brief neuropsycho-
logical battery was administered from which composite scores of executive function and memory were
higher MABP was associated with lower FA in the genu, and there was a trend for this same relationship with
(medicated vs. nonmedicated), MABP was related to genu and whole-brain FA only in the nonmedicated
group. Neither MABP nor FA was significantly related to either neuropsychological composite score
regardless of medication use. These data provide important evidence that variation in BP may contribute
to significant alterations in specific neural regions of white matter in nonmedicated individuals without
symptoms of overt CVD.
Keywords: cerebrovascular risk, blood pressure, diffusion tensor imaging, cognition
Elizabeth C. Leritz, Geriatric Research, Education and Clinical Cen-
ter, VA Boston Healthcare System; Division of Aging, Brigham &
Women’s Hospital; David H. Salat, Athinoula A. Martinos Center for
Biomedical Imaging and VA Boston Healthcare System; William P.
Milberg and Regina E. McGlinchey, Geriatric Research, Education and
Clinical Center, VA Boston Healthcare System and Harvard Medical
School; Victoria J. Williams, Geriatric Research, Education and Clin-
ical Center, VA Boston Healthcare System; Division of Aging, Brigham
& Women’s Hospital; Caroline E. Chapman, Geriatric Research, Edu-
cation and Clinical Center, VA Boston Healthcare System; and Athi-
noula A. Martinos Center for Biomedical Imaging; Laura J. Grande and
Colleen E. Barber, Geriatric Research, Education and Clinical Center,
VA Boston Healthcare System; James L. Rudolph, Geriatric Research,
Education and Clinical Center, VA Boston Healthcare System; and
Division of Aging, Brigham & Women’s Hospital; David M. Schnyer,
Department of Psychology, University of Texas at Austin; Lewis
Lipsitz, Harvard Medical School; and Hebrew Senior Life Institute for
Aging Research, Beth Israel Deaconess Medical Center, Gerontology
This research was supported by Grants F32NS051942 and K23NS062148
from the National Institute of Neurologic Disorders and Stroke, Grant
R01NR010827 from the National Institute of Nursing Research,
Grants P60AG08812, PO1AG004390 and K01AG24898 from the Na-
tional Institute on Aging, and by Medical Research Service VA Merit
Review Awards to William Milberg and Regina McGlinchey. We thank
Marge Ahlquist for her assistance with BP collection on all parti-
Correspondence concerning this article should be addressed to Elizabeth
C. Leritz, 150 South Huntington Avenue, GRECC 182 (JP), Boston, MA
02130. E-mail: firstname.lastname@example.org
2010, Vol. 24, No. 2, 199–208
In the public domain
Elevated blood pressure (BP) is a significant risk factor for
cerebrovascular disease (CVD), and it is becoming more prevalent
as the population grows proportionally older and more sedentary.
Complications arising from high BP are more widespread in Af-
rican American communities relative to other racial groups
(Howard et al., 2006; Taylor et al., 2008), and there is evidence to
suggest that, as a group, African Americans are more susceptible
to the serious consequences of CVD, such as stroke and vascular-
related cognitive decline (Singh, Cohen, Krupp, & Abedi, 1998;
Whitfield et al., 2008). It is possible that this increased suscepti-
bility to vascular events may also result in heightened risk for more
subtle brain changes and neuropsychological impairment.
Several studies have now provided substantial evidence that
long-standing hypertension can cause significant alterations to
brain structure (den Heijer et al., 2003; Firbank et al., 2007; Guo
et al., 2009; Taki et al., 2004; Wiseman et al., 2004). Damage to
white matter, in particular, is well documented, with many reports
that high BP is associated with a greater percentage of white matter
lesions (white matter hyperintensities measured on T2 or fluid-
attenuated inversion-recovery imaging; Murray et al., 2005; Ver-
delho et al., 2007). Although these lesions are commonly found in
periventricular brain areas (Henskens et al., 2009), they have also
been observed in frontal lobe white matter and subcortical brain
regions (Hoptman et al., 2009; Raz, Rodrigue, Kennedy, & Acker,
2007; van Es et al., 2008). In addition to causing white matter
lesions, hypertension or general indices of CVD risk can result in
damage to white matter fiber tracts. For example, a recent study
found that “stroke risk” (a classification that includes BP as part of
its formula) was associated with reduced tissue integrity in the
genu of the corpus callosum, a major white matter pathway pro-
viding interhemispheric connectivity (Delano-Wood et al., 2008).
The vulnerability of white matter pathways, such as the corpus
callosum, to vascular compromise has also been documented in
more severe cerebrovascular disorders such as vascular dementia
(Schmahmann, Smith, Eichler, & Filley, 2008; Zarei et al., 2009).
Schmahmann and colleagues (2008) have suggested that these
changes may arise from thickening of arterial walls, followed by
consistently restricted blood flow, particularly to microvascular
brain regions. White matter is thought to be particularly vulnerable
because many pathways are fed by these smaller blood vessels,
making them more susceptible to ischemic injury (Schmahmann et
al., 2008). Reduced flow results in lower oxygenation, which could
ultimately contribute to tissue degeneration and neuronal death
(Havlik et al., 2002; Knopman, Mosley, Catellier, & Sharrett,
2005; Skoog, 2005).
Regionally specific hypertension-related alterations to white
matter tissue have been reported, including frontal and prefrontal
brain regions (Raz, Rodrigue, & Acker, 2003; Raz, Rodrigue,
Kennedy, et al., 2007), connections associated with subcortical
nuclei (Jokinen et al., 2009; van Es et al., 2008), as well as more
posterior brain areas (Raz, Rodrigue, & Haacke, 2007). However,
despite evidence of seemingly widespread regional impact to brain
structure, the predominant finding has been that high BP has at
least an initial direct and selective impact on anterior brain re-
gions, particularly in the absence of overt dementia or severe
cognitive impairment. This impact includes damage to white mat-
ter connecting frontal and subcortical brain regions (Debette et al.,
2007; Gouw et al., 2008; Jouvent et al., 2008; Gold et al., 2005;
Wiseman et al., 2004) as well as anterior corpus callosum fibers
(Chen et al., 2009; Delano-Wood et al., 2008). The vulnerability of
anterior brain regions to high BP is supported by studies in patients
with more advanced CVD, such as vascular dementia (Chen et al.,
2009; Hallam et al., 2008; Zarei et al., 2009). For example, a recent
report found that patients with subcortical ischemic vascular de-
mentia, a disease for which hypertension is a risk factor, have
evidence of damage to the anterior (genu) corpus callosum, in
addition to white matter in bilateral frontal–subcortical brain re-
gions (Chen et al., 2009). However, the majority of these studies
examined high BP as a group classification as opposed to direct
association with BP values.
Given the evidence of structural alterations to anterior brain
regions, it is not unexpected that there are associated decrements in
cognition, primarily in executive functions, a neuropsychological
domain that in aging has been linked to the frontal cortex and its
associated subcortical structures (Brady, Spiro, & Gaziano, 2005;
Sorond, Schnyer, Serrador, Milberg, & Lipsitz, 2008). Notably,
individuals with at least one CVD risk factor, such as elevated BP,
perform poorly on neuropsychological measures of attention, con-
centration, and higher order thinking (Brady et al., 2005; Raz et al.,
2003; Raz, Rodrigue, Kennedy, et al., 2007). Supporting the struc-
ture–function connection, these impairments have also been re-
ported in conjunction with white matter tissue changes. For exam-
ple, Raz, Rodrigue, and Haacke (2007) found a greater percentage
of frontal lobe white matter hyperintensities in individuals with
higher BP, and these markers were associated with executive
functioning impairments (Raz, Rodrigue, Kennedy, et al., 2007). A
more recent study found decreased executive functioning in un-
treated hypertensives that correlated with indicators of white mat-
ter integrity (mean diffusivity as assessed through diffusion tensor
imaging [DTI]; Hannesdottir et al., 2009). Thus, in summary, the
preponderance of evidence points to the anterior brain and exec-
utive functioning as primary targets of elevated BP.
Although there is substantial evidence indicating brain structural
and neuropsychological consequences of high BP and vascular
risk, there are few studies that have examined these associations
across a range of risk indexed quantitatively, as opposed to group-
ing individuals dichotomously by the presence or absence of risk
(i.e., hypertensive or nonhypertensive; low vs. high vascular risk),
and none of these studies, to our knowledge, have examined these
associations in an exclusively African American cohort. In the
current study, we examined relationships among continuous quan-
titative measures of white matter integrity, cognition, and BP. We
used advanced DTI acquisition and analysis procedures to inves-
tigate these quantitative relationships with three aims:
1.Determine how BP, a measure that is commonly used to
gauge CVD risk, is associated with brain structure (white
matter). Specific regions of interest (ROIs) included indices
of integrity of anterior (anterior corpus callosum, or genu),
posterior (posterior corpus callosum, or splenium), as well
as a whole-brain DTI measure. We predicted that higher
levels of BP and CVD risk would be associated with re-
duced fractional anisotropy (FA), an index of white matter
integrity, in the genu and on a whole-brain level, but not in
the splenium because of its posterior location.
Determine whether variation in BP affects cognition,
specifically executive and memory function, as these are
associated with anterior and posterior brain regions, re-
LERITZ ET AL.
spectively. We predicted that higher BP would be asso-
ciated with executive but not memory functioning.
Determine whether variation in each of the three diffusion
ROIs relates to cognition. We predicted that higher FA in
the genu of the corpus callosum, as well as whole-brain FA,
would be associated with higher scores (and thus better
performance) on the executive functioning composite score.
These collective predictions were based on the preponderance of
evidence in prior literature documenting frontal brain changes and
executive function deficits in individuals with relatively high risk for
CVD, particularly in those without any evidence of overt disease or
early dementia, as is the case in the current sample. Ultimately, we
expected that findings from this study would contribute significantly
to knowledge regarding risk in this specific population, as well as to
the larger literature on the relationship of quantitative indicators of
CVD risk such as BP to brain structure and cognition.
The study sample comprised 52 participants (23 men and 29
women) who were recruited by the Harvard Cooperative Program
on Aging (HCPA) Claude Pepper Older American Independence
Center. Participants in this program were recruited from the com-
munity in response to an advertisement appearing in the HCPA
newsletter asking for healthy community-dwelling older African
Americans to participate in a study to examine physical health and
cognition. Participants from this larger group who agreed to have
a MRI scan were included in the current study. Inclusion criteria
included age of 50–85 years. Participants were excluded for the
following reasons: a history of head trauma of “mild” severity or
greater according to the criteria of Fortuny, Briggs, Newcombe,
Ratcliff, and Thomas (1980); e.g., loss of consciousness for greater
cumulative neuropathological effects), diagnosis of any form of de-
mentia (i.e., Parkinson’s disease, Alzheimer’s disease), any severe
psychiatric illness, or any history of brain surgery. All participants
were literate with at least a sixth-grade education. Fifty of the partic-
ipants were right-handed. Mini-Mental State Examination scores
ranged from 24 to 30. These scores are in a range outside of a
dementia diagnosis, according to normative data in this particular
racial group (Bohnstedt, Fox, & Kohatsu, 1994; Wong & Baden,
MRI Image Acquisition
Each participant received a whole-head high-resolution DTI scan
(Siemens; 1.5 Tesla Sonata System), collected using the following
parameters: repetition time (TR) ? 7,200 ms, echo time ? 77 ms; 60
slices total; acquisition matrix (TE) ? 128 ? 128 (field of view
(FOV) ? 256 ? 256 mm); slice thickness ? 2 mm (for 2 mm3
isotropic voxels) with 0 mm gap, with a b value ? 700 s/mm2; 10 T2
and 60 diffusion-weighted images; and one image, the T2-weighted
“low b” image, with a b value ? 0 s/mm2as an anatomical reference
volume. Total acquisition time for the DTI scan was 8 min 31 s.
Acquisitions used a twice-refocused balanced echo to reduce eddy
current distortions (Reese, Heid, Weisskoff, & Wedeen, 2003).
Image Analysis and DTI Processing
Diffusion data were processed using a multistep procedure
involving the FreeSurfer image analysis suite (http://surfer
.nmr.mgh.harvard.edu) and FSL (http://www.fmrib.ox.ac.uk.fsl/)
processing streams. A T2-weighted structural volume, collected
using identical sequence parameters as the directional volumes
with no diffusion weighting and thus in register with the final
diffusion maps, was used for all registration and motion correction
using a 12-parameter affine mutual information procedure in
FMRIB’s Linear Image Registration Tool (FLIRT; Jenkinson,
2003; Jenkinson, Bannister, Brady, & Smith, 2002; Jenkinson &
Smith, 2001). The diffusion tensor was calculated for each voxel
using a least-squares fit to the diffusion signal (Pierpaoli & Basser,
1996), and brain-extracted using the brain extraction tool (BET)
(Smith, 2002). The FA metric was derived from the diffusion
tensor as described previously (Pierpaoli & Basser, 1996). Each
FA image was mapped to Talairach space. Then, FA data were
prepared for statistical analyses using Tract-Based Spatial Statis-
tics (TBSS; Smith et al., 2006), part of FSL. First, all participants’
FA data were aligned into a common space using the nonlinear
registration tool FNIRT (Andersson, Jenkinson, & Smith, 2007),
which uses a b-spline representation of the registration warp field
(Rueckert et al., 1999). Next, the mean FA image was created and
thinned to create a mean FA skeleton that represents the centers of all
fiber tracts common to the entire sample. Each subject’s aligned FA
data were then projected onto this skeleton and then transformed back
to native space, from which whole-brain and ROI voxel-based FA
data were derived.
Regional Analysis of Diffusion Data
Regions for ROI analysis included the anterior corpus callosum
(genu), posterior corpus callosum (splenium), and a global whole-
brain FA average. These regions were selected on the basis of the
premise that higher levels of CVD risk factors would have an impact
on major white matter pathways (such as the corpus callosum) and on
a whole-brain level, at least in the early stages of cerebrovascular
disease. The corpus callosum is a major white matter pathway in the
brain that runs from anterior to posterior brain regions, and thus is an
appropriate structure in which to examine the differential effects of
CVD risk on these specific brain regions.
Whole-brain FA was measured by segmenting the entire FA
skeleton for each individual to ensure that only white matter was
included and to avoid potential partial voluming. Genu and sple-
nium ROIs were derived from the Johns Hopkins University white
matter tractography atlas, a probabilistic atlas available as part of
the FSL toolbox (Hua et al., 2008; Mori, Wakana, Nagae-Poet-
scher, & van Zijl, 2005; Wakana et al., 2007). Mean FA values
were extracted for these atlas-defined regions on each volume. All
ROI analyses were performed on native space data by inverting the
transform to standard TBSS space (see above) and then applying
the inverted (deprojected) transform to the regional labels (genu,
splenium, whole brain).
All participants completed a neuropsychological battery de-
signed to assess both memory and executive functions. The fol-
lowing measures were included in the current study: the Trail
CEREBROVASCULAR RISK, BRAIN STRUCTURE, COGNITION
Making Test–Part B (Spreen & Strauss, 1998), California Verbal
Learning Test—Second Edition (CVLT–II) short-delay free recall
(SDFR) and long-delay free recall (LDFR) (Delis, Kramer,
Kaplan, & Ober, 2000), and Controlled Oral Word Association
(COWA) or Verbal Fluency (Spreen & Strauss, 1998). All raw
scores were converted to z scores based on the current sample. The
z scores from measures in each domain were added to create a
composite score. The executive function composite score com-
prised scores from COWA and Trail Making Test–Part B. The
memory function composite score was created by adding scores
from the CVLT–II SDFR and LDFR. Two individuals did not
complete COWA and two did not complete Trail Making Test–
Part B; thus, four individuals were not included in analyses with
the executive function subscore.
CVD Risk Assessment
BP was recorded in a seated position after 5 min of rest, with the
arm at rest at the level of the heart using a standard sphygmoma-
nometer. A second measurement was obtained 5 mins later, and
average systolic and average diastolic pressures were computed
across the two measurements. BP was always measured by the
study physician (JLR). Systolic and diastolic BP were then con-
sidered together to create a mean arterial BP (MABP) using the
following formula: MABP: 1/3 (systolic – diastolic) ? diastolic.
MABP is a metric commonly used in clinical settings to obtain an
accurate metric of overall BP because it contains both systolic and
diastolic measurements in its formula. MABP is believed to indi-
cate perfusion pressure, particularly in body organs. Thus, it is an
appropriate metric to use when examining associations between
BP and brain structure or BP and function. Prior studies have used
MABP, particularly when examining BP in the context of cogni-
tion or brain structure in older adults (Brown et al., 2008; Guo et
al., 2009). In our sample, systolic BP ranged from 105 to 172 mm
of pressure (mm HG) and diastolic BP ranged from 56 to 109.
MABP ranged from 74 to 130. Current convention for systolic BP
would consider a MABP of approximately 106 to be indicative of
mild hypertension, and a MABP of 126 to be indicative of mod-
erate hypertension (American Heart Association, 2009). Nine per-
cent (5 of 53) of the sample were considered to have mild hyper-
tension, and 0.2% (1 of 53) were classified as having moderate
An additional, potentially important variable relates to use of
medication to control BP. In the current sample, 25 individuals
(48%) were taking BP regulating medicine (such as beta blockers,
ace inhibitors, or calcium channel blockers). Given that approxi-
mately half of the sample was taking BP medications, we divided
the sample further and conducted analyses both across and in each
group separately (medicated and nonmedicated). These individuals
are also represented separately in the figures (see Figures 1 and 2)
of significant results, demonstrating how participants taking BP
medication fell across the distribution of each association.
Statistical analyses initially involved a series of bivariate corre-
lations to determine the relationship of age to all primary variables
(including MABP, genu FA, splenium FA, whole-brain FA, exec-
utive function composite score, and memory composite score).
Next, one-way analyses of variance (ANOVAs) were conducted to
determine any group differences (yes/no medication use) on all
primary variables. Primary analyses then involved a series of
partial correlation analyses examining (a) the relationship of
MABP to genu FA, splenium FA, and whole-brain FA; (b) the
relationship of MABP to each neuropsychological composite
score; and (c) the relationship of all three diffusion ROIs to each
neuropsychological composite score. Age was included as a co-
variate in those partial correlation analyses for which there was a
significant correlation with each dependent variable.
Demographic, Physiological, Neuropsychological and
Brain Structural Data
Demographic data, BP data (MABP), and mean neuropsycho-
logical test scores (including individual tests as well as composite
z scores) for the entire sample are presented in Table 1. Table 2
presents mean FA values for diffusion ROIs.
Relationship of Age to All Variables
Bivariate correlation analyses were conducted to determine
whether age was significantly related to any of the dependent
variables. All three diffusion ROIs were significantly related to age
(genu: r ? ?.42, p ? .01; splenium: r ? ?.34, p ? .05;
whole-brain FA: r ? ?.39, p ? .05). As expected, in all three
regions, age was negatively associated with FA such that FA
decreased as age increased across the sample. These results are
presented in Figure 1; medication groups are represented sepa-
rately. Age was not associated with MABP (r ? ?.007, p ? .05)
or with either neuropsychological variable (executive function:
r ? .23, p ? .05; memory: r ? ?.20, p ? .05). Thus, age was
included as a covariate only in analyses with diffusion ROIs.
Effects of Medication
As an initial means to determine the effect of medication usage
on all variables, we conducted a series of ANOVAs to determine
whether there were significant differences between individuals
taking or not taking BP medication. Seven one-way ANOVAs
were conducted with BP medication as a between-subjects variable
and either MABP, genu FA, splenium FA, whole-brain FA, exec-
utive function score, or memory score as the within-subjects de-
pendent variable. Group differences were found only for the genu,
F(1, 50) ? 5.49, p ? .05. Means and standard deviations for all
variables by group are presented in Table 3. Four participants did
not complete one of the two measures used for the executive
function composite score because of testing time constraints (two
in each group). Thus, analyses with the executive function variable
contained two fewer individuals per group (four total).
Correlation Analyses With MABP
Given that approximately half of the total sample reported
taking BP medications at the time of evaluation, correlation anal-
LERITZ ET AL.
yses were run in the entire sample as well as separately for those
individuals taking (“medicated”) and not taking (“nonmedicated”)
Relationship of MABP to diffusion ROIs.
tions, controlling for age, were computed relating MABP to all
three diffusion ROIs in the entire sample and in each group. Age
was included as a covariate because of its significant negative
association with all three brain regions. In the entire sample, the
relationship between MABP and genu FA was significant (p ?
.01), and the relationship between MABP and whole-brain FA
approached significance (p ? .08). The correlation between
MABP and splenium FA was nonsignificant (p ? .05; see
Table 4A). In the nonmedicated group, analyses revealed that
MABP was significantly related to the genu and to whole-brain
FA, but not to FA in the splenium (see Figure 2 and Table 4B). In
the medicated group, there were no significant relationships be-
tween MABP and spelnium or whole-brain FA; however, the
relationship between MABP and FA in the genu approached
significance (p ? .07; see Table 4C), and trends in this group were
similar to those in the nonmedicated group such that higher FA
was associated with lower MABP values. To more directly com-
pare correlation coefficients across the two samples, we conducted
Fisher r-to-z transformations for the significant correlations, in-
cluding the genu/MABP and the whole-brain/MABP comparisons.
These analyses revealed a z of 0.91 (p ? .05) for the genu
correlation and a z of 1.34 (p ? .10) for the whole-brain compar-
ison, indicating that these correlations were not statistically sig-
nificantly different across medicated and nonmedicated samples.
Relationship of MABP to neuropsychological composite
Bivariate correlation analyses revealed no significant re-
lationships between MABP and either cognitive score in the entire
sample or in either group, although the negative correlation be-
tween MABP and executive function score approached signifi-
cance in the entire sample (p ? .06), such that higher MABP was
associated with poorer executive function. This was also true in the
nonmedicated group (p ? .11; see Table 4).
Relationship of diffusion ROIs to neuropsychological com-
Partial correlation analyses, controlling for age,
also revealed no significant relationships between neuropsycho-
logical composite scores and any diffusion ROI for the whole
sample or for either group, although the relationship between the
memory score and genu FA approached significance in the non-
medicated group (p ? .11; see Table 4).
The present data demonstrate associations between MABP and
imaging measures of neural integrity. Increased MABP was asso-
ciated with decreased FA in the genu of the corpus callosum; this
relationship was the most significant in individuals who did not
report taking any BP medications. MABP was also associated with
FA on a whole-brain level in the nonmedicated group, and there
was a trend for this same relationship in the entire sample. Sple-
nium FA and MABP were not significantly correlated in the whole
sample or in either group. Neither neuropsychological composite
score was related to MABP or to any of the diffusion ROIs,
regardless of medication status. These data are in part consistent
with predictions and suggest that CVD risk (i.e., BP) may have a
regional impact to anterior brain white matter, as well as a global
impact. Our findings are particularly compelling because of the
increased prevalence of various CVD risk factors in the African
American community, and they raise the additional possibility of
Relationship of age to diffusion regions of interest.
Relationship of mean arterial blood pressure to diffusion regions of interest.
CEREBROVASCULAR RISK, BRAIN STRUCTURE, COGNITION
structural and cognitive changes in this population, whose clinical
significance may be underreported. To our knowledge, this is the
first study of its kind to investigate this set of issues in a predom-
inantly African American sample, and the nuances of the findings
must be further explored and replicated in a larger sample with
appropriate controls. Nonetheless, our study represents a novel
investigation of the neural and cognitive consequences across a
range of BP values, and it provides the first steps in understanding
the relationships among these complex systems.
The relationship of white matter integrity (FA) to MABP is
consistent with prior reports of a negative impact on the integrity
of white matter microstructure (Holtmannspotter et al., 2005; Taki
et al., 2004; van Dijk et al., 2004); furthermore, it appears that BP
is selectively related to anterior brain regions, evidenced by a
significant relationship between MABP and the anterior (genu),
but not posterior (splenium), corpus callosum. Degeneration of
anterior callosal fibers has previously been described in association
with hypertension and vascular risk, and is also supported by prior
studies demonstrating hypertension-related white matter signal
abnormalities primarily in frontal and subcortical brain regions
(van Dijk et al., 2004; Wu et al., 2006). Our findings are also
consistent with reports of a CVD-related impact on the anterior
callosum in more severe dementing disorders with vascular etiol-
ogy (Hallam et al., 2008), supporting the idea that the genu may be
vulnerable to CVD risk before a disease process is evident. White
matter disease is indeed thought to be an indicator of worsening
disease and cognitive function, particularly in individuals with a
history of CVD and CVD risk (Dufouil et al., 2009).
has a modifying effect on the associations between BP and brain
structure. Prior studies have reported similar neuroanatomical and
example, Raz et al. (2003) found reduced prefrontal brain volumes
and lower executive functioning in both treated and untreated high
BP, suggesting that hypertension may be detrimental even when
controlled by medication (Raz et al., 2003). However, past work has
also described circumstances under which hypertensive medication
may harbor a protective effect on brain structure and function and
may serve to prevent or slow cognitive decline (Dufouil et al., 2001).
even demonstrated less neuropathology on autopsy when compared
idea that treatment may at the very least result in differences com-
pared with nontreatment, a recent study found that when compared
with normotensive individuals, medically treated hypertensives ex-
hibited deficits on tests of executive functions, whereas those with
untreated high BP demonstrated worse memory performance (Han-
nesdottir et al., 2009). The only association with brain structure was
found in the untreated group, in which poorer scores on tests of
executive function correlated with lower DTI mean diffusivity values
(Hannesdottir et al., 2009). Thus, there is certainly a sufficient amount
of evidence to suggest that medication use may influence brain–
behavior relationships. Our data are consistent with this idea, as we
found that BP only significantly related to brain structure in the
absence of controlling medication; in addition, there were also sig-
nificant between-groups differences only in the genu such that those
taking medication had a higher mean FA than those who were not.
to any other variable provides further support for the idea that BP
primarily has an effect on anterior white matter.
Despite these relatively consistent findings, our sample does
differ from prior work in that it did not focus exclusively on
hypertension; instead, it contained a fairly broad range of BP
readings, from “normotensive” to mild and moderately “hyperten-
sive.” In fact, the nonmedicated group represented a larger range
of BP values, whereas the medicated group was, not surprisingly,
more restricted in range. Taken with the fact that the association
with FA was similar, and with the fact that the actual correlations
were not significantly different, this suggests that group differ-
ences may be in part due to differences in BP variability. It may be
that with larger sample sizes, correlation magnitudes would be-
come more statistically different in medicated versus nonmedi-
cated groups. Although medication may influence the BP–brain
structure association, there might still be a relationship whereby
higher BP, even in a range that would not warrant treatment by
clinical standards, may have a negative impact on white matter.
However, on the basis of these results alone, we are not able to
make statements regarding the potentially protective role of BP
medication other than to speculate that it may prevent against
Demographic, Physiological, and Neuropsychological Data
(N ? 52)
Systolic blood pressure (mm HG)
Diastolic blood pressure (mm HG)
Trail Making–Part B (s) (n ? 50)
COWA (n ? 50)
Executive function composite z score (n ? 48)a
Memory composite z score
blood pressure; COWA ? Controlled Oral Word Association; CVLT ?
California Verbal Learning Test; SDFR ? short-delay free recall; LDFR ?
long-delay free recall. MMSE score is out of 30 possible points. CVLT
SDFR and LDFR scores are out of 16 total words; COWA: total words
beginning with F, A, and S given in 3 min.
aTotal N is reduced to 48 for the executive function composite score
because four individuals did not complete all tests.
MMSE ? Mini-Mental State Examination; MABP ? mean arterial
Fractional Anisotropy (FA) Data for Diffusion Regions of
FA values range from .1 (lowest anisotropy) to .9 (highest anisot-
LERITZ ET AL.
white matter disease (such as degeneration), as longitudinal studies
of the relationship between BP and white matter have demon-
strated (Guo et al., 2009). Our findings do shed additional light on
the impact that BP has on brain structure even in the mild to
moderate range of risk, and at the very least suggest that medica-
tion to control BP may mediate this physiology–structure relation-
We did not find any significant relationships between brain
structure (diffusion) and neuropsychological variables, which was
inconsistent with predictions and prior studies that have found
associations between FA and cognition even in samples with no
CVD or hypertensive medication usage (Madden et al., 2004;
Schiavone, Charlton, Barrick, Morris, & Markus, 2009). One
possibility for the lack of findings is that an observable structure–
function relationship with diffusion markers of white matter integ-
rity is not apparent until more advanced stages of cerebrovascular
disease. Indeed, there is substantial evidence to indicate that white
matter abnormalities such as “silent” lacunar infarcts often do not
manifest themselves clinically (Kramer, Kenenoff, & Chui, 2001;
Kurata, Okura, Watanabe, & Higaki, 2005; Takahashi et al., 2006).
As such, our findings of higher BP in relation to both global and
regionally reduced FA are potentially early indicators of silent
subclincal CVD. However, it is important to note that despite these
nonsignificant correlations, there were two instances in which the
direction of the observed correlation was in the opposite direction
of what was expected, such that higher splenium FA was associ-
ated with lower performance; this was the finding for executive
function in the medicated group and for memory function in the
nonmedicated group, whereas the correlation direction in the
whole sample was in the expected direction. Thus, it may be that
medication for BP affects associations specifically between the
splenium and cognition, and it is possible that with a larger sample
Partial and Bivariate Correlations Between MABP, Diffusion Regions of Interest, and
VariableMABP Genu FA Splenium FA Whole-brain FA
A. Entire sample (N ? 52)
Executive function score
(n ? 48)
B. Medicated group (n ? 25)
Executive function score
(n ? 23)
C. Nonmedicated group (n ? 27)
Executive function score
(n ? 25)
regions of interest (genu FA, splenium FA, and whole-brain FA) were partial correlations controlling for age.
?p ? .05.
MABP ? mean arterial blood pressure; FA ? fractional anisotropy. Correlations with all diffusion
??p ? .01.^Approached significance (p ? .10).
Demographic, MABP, Diffusion, and Neuropsychological Data, by Blood Pressure Medication
Medicated (n ? 25)Nonmedicated (n ? 27)
M SDM SD
Executive function composite
z score (n ? 23)
Memory composite z score
?p ? .05 between groups (one-way ANOVA).
MABP ? mean arterial blood pressure; FA ? fractional anisotropy.
CEREBROVASCULAR RISK, BRAIN STRUCTURE, COGNITION
size, such relationships would become more apparent and signif-
icant. However, in the present study, it is merely speculative to
comment on these potential findings.
The relationship of age to all diffusion ROIs is not surprising,
given prior evidence of a negative relationship between age and
FA in global and regional brain regions (Salat et al., 2005),
including anterior white matter (Yoon, Shim, Lee, Shon, & Yang,
2008). Although not a primary focus of the article, there were also
no significant relationships between BP and neuropsychological
functioning, with the exception of a trend for higher MABP and
lower executive function composite scores. This is consistent with
hypotheses and with what has been reported previously; perhaps,
it is the case that these relationships also become more evident as
CVD progresses. In addition, it is certainly possible that with
greater power (i.e., larger sample size), the associations between
neuropsychological functioning and both brain structure and BP
will become more significant.
Our results also provide important implications for the current
conceptualization of the phrase “normal cognitive aging.” Much of
the literature examining normal aging employs chronological age
as a primary independent variable for exploring age-related brain
and cognitive changes; historically, these studies have used self-
report of diseases such as hypertension and diabetes to define
groups of assumed healthy participants. The current study provides
evidence that these variables may be uncontrolled covariates that
should be considered as standard biological factors contributing to
variation in neural and cognitive aging. We present critical data
implying that a wide range of levels, including those in the
subclinical range, can have measurable effects on cognition and
brain structure in middle–older-age adults who are self-reported
“healthy,” the standard population for studies of normal aging.
It is important to note that the present study was cross-sectional,
and as such, does not allow for causal inferences to be made
regarding the directionality of the relationship between BP and
brain structure. For example, it is certainly possible that changes in
white matter precede any BP variation, and alternatively, that the
two are not as intrinsically connected as believed (Jennings &
Zanstra, 2009). As suggested by Jennings and Zanstra (2009), the
mechanisms underlying vasculature and the brain are still not
completely understood, and future studies, particularly those with
a longitudinal component, will be necessary to make more precise
statements (Jennings & Zanstra, 2009). Nonetheless, we present
preliminary but novel findings of a relationship between a physi-
ological risk factor and neural structure in a population that is
especially vulnerable to CVD. The fact that our data indicate that
manifestations of CVD risk factors such as BP may be operating
before a disease process is evident further underscores the impor-
tance of early detection treatment and monitoring. It may be that
over time, the brain becomes even more vulnerable to long-
standing elevated BP, and thus, longitudinal investigations are
critical. Furthermore, future studies focusing on how aging affects
the brain should consider BP, with and without medication usage,
as a potential mediator of change.
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Received October 30, 2008
Revision received September 8, 2009
Accepted September 17, 2009 ?
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