Inter-individual variation in blood pressure is associated with regional white matter integrity in generally healthy older adults
Highlights
► Blood pressure is associated with white matter structure in healthy older adults. ► Associations are apparent in white matter well outside of lesioned tissue. ► Associations are apparent in even very low risk individuals. ► Variation in vascular physiology promotes age-associated white matter degeneration.
Introduction
A substantial literature exists describing the consequences of healthy aging (Kennedy and Raz, 2009a, Kennedy and Raz, 2009b, O'Sullivan et al., 2001, Pfefferbaum et al., 2000, Salat et al., 2005a, Salat et al., 2005b, Sullivan et al., 2001, Virta et al., 1999) as well as the impact of age-associated degenerative conditions including cerebrovascular disease, small vessel disease and stroke (de Laat et al., 2011, Gons et al., 2010, O'Sullivan, 2010, Pierpaoli et al., 1996, Pierpaoli et al., 1993) on magnetic resonance imaging (MRI) measures of cerebral white matter structure. Similarly, important work has attempted to differentiate the effects of aging, vascular disease, and dementia on white matter structure (Lee et al., 2009, Yoshita et al., 2006). Although the effects of age and the effects of vascular disease are typically considered distinct, accumulating evidence suggests that biological factors that simply increase the risk for a cerebrovascular event also exert their own influence on brain tissue. For example, various composite metrics of stroke risk, most notably, the Framingham Stroke Risk Profile (D'Agostino et al., 1994) have been shown to be associated with brain tissue damage (Jeerakathil et al., 2004, Seshadri et al., 2004). The FSRP is a calculated score comprising several health factors and predicts an individual's 10 year risk of stroke. Of the risk factors contributing to the FSRP, hypertension is a highly prevalent condition in older adults. Recent estimates suggest that 11% of individuals 65–74 years of age, and 17% of individuals 75 and over are hypertensive (He et al., 2005). Hypertension alone is associated with a range of histopathologic damage (for review see (Manolio et al., 2003)) as well as increased white matter lesion volume measured on magnetic resonance imaging (MRI) by white matter signal abnormalities (Longstreth et al., 1996). Given these intersecting factors, the dynamics between age and dementia-associated white matter lesions and microstructural damage has been an active area of investigation (Bastin et al., 2009, Benedetti et al., 2006, Lee et al., 2009). The diagnostic category of hypertension was conceptualized as a metric of risk for a cerebrovascular event. However, the specific diagnostic criteria for hypertension are somewhat arbitrary and more recent consensus groups have created additional classifications such as ‘pre-hypertension’ (Chobanian et al., 2003), an earlier stage of risk. It is thus unclear if hypertension per se is necessary for blood pressure to affect tissue structure, or if inter-individual variation in blood pressure is alone sufficient to impact neural health. Mild hypertension, controlled hypertension, and normal variation in blood and pulse pressure have all been shown to impact neural tissue (Breteler et al., 1994, DeCarli et al., 1995, Goldstein et al., 1998, Hoptman et al., 2009, Kennedy and Raz, 2009b, Leritz et al., 2010, Leritz et al., 2011, Raz et al., 2005, Raz et al., 2003). It is possible that this effect is due to slow progressive degenerative processes, as prior studies have demonstrated that blood pressure measured in mid-life is associated with late-life white matter lesions (Swan et al., 1998). Overall, these studies are of great interest because they demonstrate that subtle inter-individual variation in systemic physiology may influence neural health in the absence of overt damage due to stroke or other large-scale cerebrovascular incident.
Prior studies have examined the association between blood pressure and white matter integrity in clinical populations (Barrick et al., 2010, Gons et al., 2010, Hannesdottir et al., 2009, Patel and Markus, 2011). However, to date, few studies have reported direct associations between blood pressure and white matter tissue structure measured with imaging procedures such as diffusion tensor imaging (DTI) in a normative sample. Kennedy and Raz, 2009a, Kennedy and Raz, 2009b found an association between pulse pressure and anterior white matter integrity in older normotensive individuals (Kennedy and Raz, 2009b). Similarly, Leritz and colleagues (Leritz et al., 2010) demonstrated an association between mean arterial blood pressure (MABP) and white matter integrity in the anterior but not posterior corpus callosum in a population of subclinical to mildly hypertensive older African Americans. These findings demonstrate that DTI may provide a sensitive metric of regionally specific tissue damage due to variation in vascular integrity. To date, no studies have described the whole brain regional associations between blood pressure and white matter tissue structure. Thus, it is unclear whether blood pressure may influence white matter structure outside of the anterior regions described in prior work.
We examined the relationship between MABP and white matter integrity in 128 generally healthy older adults with a focus on individuals in the normotensive to moderately hypertensive range. In contrast to prior work examining individuals categorized as ‘hypertensive’ or ‘normotensive’, we examined MABP as a quantitative variable across the full range of inter-individual variation in this population. We mapped the association between blood pressure and DTI-based measures of white matter integrity using complementary voxel-based and region of interest (ROI) procedures. Given the high prevalence of hypertension in older adults, it was hypothesized that blood pressure would be associated with white matter integrity in anterior brain regions, and that patterns would resemble those that have been traditionally ascribed to normal aging such as profound frontal white matter deterioration (O'Sullivan et al., 2001, Pfefferbaum et al., 2000, Salat et al., 2005a, Salat et al., 2005b, Sullivan et al., 2001). In particular, it is possible that myelin damage due to minor ischaemic events would manifest in an association between MABP and radial diffusivity, a putative marker of myelin damage (Sun et al., 2006). The results demonstrate strong associations between blood pressure and diffusion measures in several regions of the brain that are independent of age and apparent in even mild, controlled hypertensive individuals with a particular sensitivity of the radial diffusivity.
Section snippets
Participants
DTI and blood pressure data were acquired on 128 participants (78F/50M). Participants were recruited from two separate but overlapping studies examining how common cerebrovascular risk factors impact brain structure and cognition (Leritz et al., 2011). Thirty-four participants were recruited through the Harvard Cooperative Program on Aging (HCPA) Claude Pepper Older American Independence Center (OAIC). Participants in this program were recruited from the community in response to an
Associations between blood pressure and DTI measures: TBSS voxel-based GLMs
Associations were found between MABP and FA in several regions throughout the cerebral white matter with strong bilateral effects in the corpus callosum (particularly anterior regions), parietal white matter (particularly inferior and superior lateral parietal and precuneus), and superior and lateral frontal white matter (Fig. 3). Regional definitions of significance clusters are presented in Table 3, with the size and minimum P value for each cluster, and a weighting score for each region that
Discussion
The present study demonstrated regional associations between inter-individual variation in MABP and diffusion metrics of white matter integrity throughout the cerebral white matter in a large sample of generally healthy older adults. Effects were prominent in frontal and parietal white matter, were independent of age, remained after controlling for white matter lesions, and were apparent when the sample was limited to individuals who were either normotensive or controlled and/or
Acknowledgments
This research was supported by grants from the National Institute of Nursing Research (R01NR010827), National Institute of Neurologic Disorders and Stroke (K23NS062148 and ARRA funds K23NS062148S1), grants from the National Institute on Aging (P60AG08812 and K01AG24898), and by Medical Research Service VA Merit Review Awards to William Milberg and Regina McGlinchey. The authors would like to thank Marge Ahlquist for her assistance with blood pressure collection on all participants and Juli
References (57)
- et al.
White matter structural decline in normal ageing: a prospective longitudinal study using tract-based spatial statistics
Neuroimage
(2010) - et al.
Estimation of the effective self-diffusion tensor from the NMR spin echo
J. Magn. Reson. B
(1994) - et al.
Diffusion tensor and magnetization transfer MRI measurements of periventricular white matter hyperintensities in old age
Neurobiol. Aging
(2009) - et al.
Correlates of mini-mental status examination scores among elderly demented patients: the influence of race-ethnicity
J. Clin. Epidemiol.
(1994) - et al.
An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest
Neuroimage
(2006) - et al.
Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain
Neuron
(2002) - et al.
Accurate and robust brain image alignment using boundary-based registration
Neuroimage
(2009) - et al.
Blood pressure and white matter integrity in geriatric depression
J. Affect. Disord.
(2009) - et al.
Aging white matter and cognition: differential effects of regional variations in diffusion properties on memory, executive functions, and speed
Neuropsychologia
(2009) - et al.
Pattern of normal age-related regional differences in white matter microstructure is modified by vascular risk
Brain Res.
(2009)