Research ReportPattern of normal age-related regional differences in white matter microstructure is modified by vascular risk
Introduction
Differential aging of the brain has been amply demonstrated in multiple postmortem (Kemper, 1994) and in vivo studies (Raz and Kennedy, 2009). Whereas the cerebral cortex and subcortical nuclei exhibit predominantly linear age-related declines in volume during the adult life span, the trajectory of white matter volume maturation and decline fits an inverted U-shaped function. The volume of the cerebral white matter increases from infancy into young adulthood, reaches a plateau in middle age, and declines toward the later part of the life span (Allen et al., 2005, Bartzokis et al., 2004, Fotenos et al., 2005, Jernigan et al., 2001, Raz and Kennedy, 2009, Lenroot et al., 2007, Raz et al., 2005). Although multiple factors determine the volume of brain parenchyma, it is widely held that the size of its white matter fraction depends on the bulk of myelin. Thus, most significant age-related changes in white matter are believed to reflect changes in myelin structure and volume (Bartzokis et al., 2004, Peters, 2002).
Development of diffusion tensor imaging (DTI; Pierpaoli and Basser, 1996) enabled the investigation of age differences in white matter microstructure by quantifying its diffusion properties. The preponderance of the extant DTI studies shows widespread age-related declines in fractional anisotropy (FA) and elevations in diffusivity (Ardekani et al., 2007, Benedetti et al., 2006, Charlton et al., 2006, Chen et al., 2001, Grieve et al., 2007, Lehmbeck et al., 2006, O'Sullivan et al., 2001, Rovaris et al., 2003, Shenkin et al., 2003). However, white matter vulnerability to aging is not uniform, and many studies reported regional variability in the magnitude of age-related declines in FA and increases in apparent diffusion coefficient (ADC). According to some studies, the effect of age is greater in the anterior than posterior regions of the brain (Ardekani et al., 2007, Head et al., 2004, Hugenschmidt et al., 2008, Kochunov et al., 2007, Madden et al., 2007, O'Sullivan et al., 2001, Pfefferbaum et al., 2000, Pfefferbaum et al., 2005Salat et al., 2005, Sullivan et al., 2001, Sullivan and Pfefferbaum, 2006). Fiber-tracking analysis of DTI data also shows that the most prominent age-related deterioration of the white matter is observed in association fibers (Pagani et al., 2008, Stadlbauer et al., 2008, Sullivan et al., 2006), which connect the regions that are the latest to complete myelination in the course of development (Flechsig, 1901). However, age-related declines in the splenium of the corpus callosum have been reported as well (Abe et al., 2002, Aboitiz et al., 1996, Bhagat and Beaulieu, 2004, Chepuri et al., 2002, Head et al., 2004, Ota et al., 2006, Pfefferbaum et al., 2000, Pfefferbaum et al., 2005, Pfefferbaum and Sullivan, 2003, Salat et al., 2005, Sullivan et al., 2006).
It remains unclear what drives the observed morphological differences in cerebral white matter, and it is possible that they are influenced by cerebrovascular risk factors. White matter is highly vulnerable to major ischemic events (Pantoni and Garcia, 1997), and vascular risk factors contribute significantly to increases in crude indices of white matter integrity such as white matter hyperintensities (WMHs) (Artero et al., 2004, DeCarli et al., 1999, de Leeuw et al., 2002, Goldstein et al., 1998, Gunning-Dixon and Raz, 2000, Gunning-Dixon and Raz, 2003, Marstrand et al., 2002, Pantoni and Garcia, 1997, Raz, 2004, Raz and Rodrigue, 2006, Raz et al., 2007, Söderlund et al., 2003, Swan et al., 1998, Yoshita et al., 2006). It has been suggested that the disorganization of the normal white matter introduced by WMHs might play a major role in the genesis of age-related differences in white matter diffusion properties (Vernooij et al., 2008).
Age-related increase in vascular risk most commonly stems from changes in the circulatory system that produce up-regulation of the arterial blood pressure and eventually, chronic hypertension (Hajjar and Kotchen, 2003). Hypertension, even in its milder forms, has been linked to reduction in white matter volume (Raz et al., 2003, Raz et al., 2005, Strassburger et al., 1997) and increase in WMH burden (Breteler et al., 1994, Goldstein et al., 1998, Goldstein et al., 2005, Murray et al., 2005, Raz et al., 2007). Some studies have noted that, in addition to the effects on white matter volume and WMH burden that are observed in normal aging, in hypertensive adults, there is decline in posterior white matter as well (Artero et al., 2004, Raz et al., 2007, Strassburger et al., 1997). Given the acknowledged importance of hypertension in the genesis of WMH and its role as a threat to white matter integrity, surprisingly little is known about microstructural correlates of elevated blood pressure. In contrast to the detrimental effects of cerebrovascular diseases and untreated hypertension on diffusion-based parameters of the white matter (Hannesdottir et al., 2009, Hoptman et al., 2009, Nitkunan et al., 2008, Shenkin et al., 2005), the influence of milder vascular risk factors such as controlled hypertension, or high normal blood pressure is largely unknown (Huang et al., 2006).
Thus, the goals of the current study were to examine regional age-related differences in white matter microstructure in a sample of healthy adults and to assess whether controlled vascular risk factors act as a negative modifier of those aspects of brain aging. We hypothesized that in healthy aging, the declines would demonstrate predilection for anterior brain regions. In accord with the studies of its effect on white matter volume and WMH studies (Artero et al., 2004, Raz et al., 2007), we also hypothesized that hypertension, even controlled by medication, would be associated with reduced white matter integrity in more posterior regions.
White matter regions of interest (ROIs) are illustrated in Fig. 1. They included the corpus callosum (genu and splenium), the internal capsule (anterior, genu, and posterior limbs), and subcortical association white matter samples from prefrontal, parietal, temporal, and occipital regions.
Section snippets
Results
Descriptive statistics of the sample are presented in Table 1. The data were analyzed in a series of general linear models (GLMs). In each model, age (centered at the sample mean) served as a continuous independent variable; sex was a categorical independent variable, and regional FA and ADC were dependent variables with ROI as a within-subjects factor. To minimize rounding error and to simplify reporting, all ADC values (mm2/s) were multiplied by 103. Full models including all the interactions
Discussion
The results of this investigation demonstrate that advanced age is associated with differential regional deterioration of the white matter integrity and that vascular risk exacerbates age-related declines. Although we observed a negative effect of age on anisotropy and diffusivity in almost every region examined, the corpus callosum and prefrontal and occipital white matter showed the greatest vulnerability. Furthermore, in most regions, the increase in diffusivity (but not decline in
Participants
Participants were paid, healthy volunteers from the Detroit metropolitan community recruited through media advertisements and flyers. All participants were screened with a health questionnaire and augmented by telephone and personal interviews. Persons who reported a history of cardiovascular (except controlled and uncomplicated essential hypertension), neurological or psychiatric conditions, head trauma with loss of consciousness for more than 5 min, thyroid problems, diabetes mellitus, and/or
Acknowledgments
This study was supported in part by grants R37 AG-011230 and T32 HS-013819 and a Dissertation Award from the American Psychological Association, and was conducted in partial fulfillment of requirements for the doctoral degree. Portions of this paper were presented at Society for Neuroscience Annual Meeting in November 2007 and Cognitive Aging Conference in April 2008. We thank Yiqin Yang for her assistance in measuring white matter hyperintensities.
References (95)
- et al.
Normal aging in the central nervous system: quantitative MR diffusion-tensor analysis
Neurobiol. Aging
(2002) - et al.
Normal neuroanatomical variation due to age: the major lobes and a parcellation of the temporal region
Neurobiol. Aging
(2005) - et al.
Exploratory voxel-based analysis of diffusion indices and hemispheric asymmetry in normal aging
Magn. Reson. Imaging
(2007) Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease
Neurobiol. Aging
(2004)- et al.
Heterogeneous age-related breakdown of white matter structural integrity: implications for cortical “disconnection” in aging and Alzheimer's disease
Neurobiol. Aging
(2004) - et al.
Age-related slowing of memory retrieval: contributions of perceptual speed and cerebral white matter integrity
Neurobiol. Aging
(2008) - et al.
A structural equation modeling investigation of age-related variance in executive function and DTI measured white matter damage
Neurobiol. Aging
(2008) - et al.
“Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975) - et al.
Neuroanatomical correlates of selected executive functions in middle-aged and older adults: a prospective MRI study
Neuropsychologia
(2003) - et al.
Blood pressure and white matter integrity in geriatric depression
J. Affect Disord.
(2009)