Results of this study indicate that MRI ratings of silent, or subclinical, cerebrovascular disease are associated with higher levels of BP and/or PP among those in our youngest age cohort of </= 63 years (based on tertile distributions), which is comprised predominantly of middle-aged (range commonly defined as ages 40–59 years) to “young old” (range defined as 60–69 years) persons (see 29
).. Specifically, both systolic BP and PP were associated with greater WMH and silent brain infarction among those 63 years of age or younger. PP was also related to these endpoints among those aged 64–68 years (which would be defined as “young old” [29
]). Both systolic and diastolic BP was associated with greater brain atrophy in those aged 63 and younger.
Our findings are consistent with prior research linking elevated BP with greater extent of white matter disease and increased frequency of silent brain infarctions [8
]. In contrast, relatively little is known about relations between PP and white matter disease or silent brain infarction. Emerging evidence does suggest that pulse wave velocity, another measure of arterial stiffness, is related to degree of white matter disease and number of silent infarctions among older adults [21
]. The present study therefore suggests that these findings extend to PP.
Previous research has also identified associations between elevated BP and hypertension and indicators of brain atrophy [1
]. Limited evidence suggests that elevations in PP may also be associated with brain atrophy. For instance, cognitively-intact older adults with subclinical brain atrophy demonstrate steeper increases in PP with age than individuals without evidence of brain atrophy [19
]. Present study findings add to this growing literature and further emphasize the possible role of BP pulsatility in the development of multiple aspects of subclinical cerebrovascular disease.
Associations between elevated BP/PP and subclinical cerebrovascular disease noted here were most apparent among those ages 63 or younger. This pattern of findings is consistent with longitudinal research noting midlife BP to be a potent predictor of late-life brain-related endpoints, including cognitive function and dementia [34
]. When age cohorts are compared directly, however, BP levels are predictive of poor brain health across adulthood. For instance, Elias and colleagues found similar detrimental effects of elevated BP on longitudinal cognitive change among both younger and older adult cohorts in the Maine-Syracuse Longitudinal Study of Hypertension [36
]. Further, elevated BP is significantly associated with vascular and overall mortality among both middle-aged and older adults [37
]. Present study findings may therefore be attributable, in part, to a healthy survivor effect among our older participants, given the rather stringent inclusion and exclusion criteria utilized and increased hypertension/cardiovascular disease incidence with age. It has also been noted that mildly elevated BP may be beneficial to brain status among elderly persons.
Several neurophysiological mechanisms posited to underlie BP- and PP-brain associations include regional or global cerebral hypoperfusion, disruption of the blood-blain barrier, and/or endothelial dysfunction [38
]. With respect to PP, increased pulsatility associated with arterial stiffness may directly and negatively impact cerebral vessel integrity, particularly in watershed areas of the cerebral circulation. These neurophysiological mechanisms have been linked with both subclinical and clinical cerebrovascular diseases, including white matter disease, silent infarctions, cortical atrophy, and micro- and macro-vascular diseases [40
], which are in turn predictive of brain-related endpoints including cognitive dysfunction and decline, dementia, and stroke.
Our work extends prior research in three major ways. First, our PP findings suggest that the pulsatility component of BP may be particularly important to the development of WMH and silent brain infarction. Second, the relations of BP or PP to subclinical cerebrovascular disease are most pronounced for our middle-aged to “young old” cohort. This may, in part, reflect a healthy survivor effect on the oldest members of our sample. Third, it is rare to find simultaneous examination of BP, PP, age moderation, and multiple indicators of subclinical cerebrovascular disease in the existing literature. Lastly, the derived principal components and their transformation using normal scores represents a new methodological development that could be useful in future studies that utilize categorical ratings of brain pathology.
The present investigation had several limitations. First is use of a cross-sectional design. It is critical to determine the prognostic significance of BP and PP with respect to subclinical cerebrovascular disease. Second, the small, relatively homogeneous, and non-representative sample limits the generalizability of these findings. Third, because only those with mild to moderate hypertension, either untreated or on monotherapy, were studied in this protocol, associations of BP to subclinical cerebrovascular disease are likely underestimated in the present analyses. Fourth, the small sample size limits our statistical power. Fifth, use of ordinal MRI ratings limits power to detect associations.
To conclude, results of the present study demonstrate interactive relations of continuous levels of BP and PP with subclinical cerebrovascular disease such that those at middle-aged to “young old” ages showed the greatest pathology on MRI. Such subclinical cerebrovascular disease may confer risk for future cognitive decline, dementia, and stroke as a function of higher BP.