Journal of Human Hypertension (2012) 26, 295–305 & 2012 Macmillan Publishers Limited All rights reserved 0950-9240/12 www.nature.com/jhh ORIGINAL ARTICLE Regional grey matter shrinks in hypertensive individuals despite successful lowering of blood pressure JR Jennings1, DN Mendelson1, MF Muldoon1,CMRyan1, PJ Gianaros1, N Raz2, H Aizenstein1 and the Alzheimer’s Disease Neuroimaging Initiative3 1Department of Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, USA and 2Wayne State University, Detroit, MI, USA The aim of the study was to determine whether the compared with archival data from normotensive indivi- reduction in brain grey matter volume associated with duals. Reductions in regional grey matter volume over hypertension persisted or was remediated among hyper- the follow-up period were observed despite successful tensive patients newly treated over the course of a year. treatment of blood pressure (BP). The comparison A total of 41 hypertensive patients were assessed over group of older, but normotensive, individuals showed the course of a 1-year successful anti-hypertensive no significant changes over a year in the regions tested treatment. Brain areas identified previously in cross- in the treated hypertensive group. These novel results sectional studies differing in volume between hyperten- suggest that essential hypertension is associated with sive and normotensive individuals were examined with a regional grey matter shrinkage, and successful reduc- semi-automated measurement technique (automated tion of BP may not completely counter that trend. labelling pathway). Volumes of grey matter regions were Journal of Human Hypertension (2012) 26, 295–305; computed at baseline after a year of treatment and doi:10.1038/jhh.2011.31; published online 14 April 2011 Keywords: grey matter volume; brain atrophy; magnetic resonance imaging Introduction technology, nomenclature, analytic approach and areas examined across studies impede generaliza- Multiple in vivo and postmortem studies of brain tions, existing literature suggests in addition that morphology demonstrate that hypertensive indivi- the negative effects of hypertension on the brain duals show greater loss of tissue than age-matched 1 involve structures that are relatively age invariant. control individuals. Hypertension, even at mild Across studies, several regions emerge as especially levels, acts as a negative modifier of aging as it vulnerable to negative modification by essential enhances morphological alterations in brain indices hypertension. These include prefrontal cortex,6,8,9 typically associated with advanced age. Such effects hippocampus,6,10,11 the inferior temporal cortex7,12 and include expansion of ventricular and sulcal spaces, inferior parietal lobule.13 Hypertension also affects decreased total and regional grey matter volume, brain regions that are only moderately vulnerable to increased burden of white matter abnormalities (for aging, for example, supplementary motor areas,8,14 example, white matter hyperintensities) and dete- cuneus,12 thalamus15 and entorhinal cortex.13 Some rioration of the micro-structural organization of the 2–7 studies show that regions that are usually resistant to white matter. Although differences in imaging aging, such as the primary visual cortex, shrink in hypertensive individuals.7 The effects of hyperten- sion may differ between the sexes. Some studies find Correspondence: Dr JR Jennings, Department of Psychiatry and 8,12,14 Psychology, University of Pittsburgh, E1329 WPIC, 3811 O’Hara the vulnerability only in men, whereas others St., Pittsburgh, PA 15213, USA. report such effects only in women,12 with some E-mail: [email protected] (albeit not consistent) indication of lateralization. 3 Data used in the preparation of this article were obtained from The role of various anti-hypertensive medications the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://www.loni.ucla.edu/ADNI). As such, the investigators in the modifying effect of hypertension is unclear, as within the ADNI contributed to the design and implementation participants have been typically studied while of ADNI and/or provided data but did not participate in analysis medicated, although some samples were comprised or writing of this report. ADNI investigators include (complete of never-medicated patients8 or patients who dis- listing available at http://www.loni.ucla.edu/ADNI/Collaboration/ 15 ADNI_Citatation.shtml). continued medication before testing. Notably, most Received 20 October 2010; revised 3 March 2011; accepted 8 extant studies of hypertension and brain morpho- March 2011; published online 14 April 2011 logy were cross-sectional, and the longitudinal Brain grey matter and hypertension JR Jennings et al 296 studies13 included too few hypertensives to afford a United States of America. They were between 35 sufficient statistical power for discovering relatively and 65 years of age, and had arterial BP in excess of subtle effects. In light of the discussed inconsistency the cutoff established by the Joint National Commit- of the literature and the confounding of diagnosed tee on Prevention, Detection, Evaluation and Treat- hypertension with medication, we designed this ment of High Blood Pressure:22 an average diastolic longitudinal study. In a 1-year follow-up, we exam- fifth-phase BP of 90 mm Hg, systolic BP of 140 ined the impact of pre-existing untreated hyperten- mm Hg or both. For safety reasons, volunteers were sion and the potentially curative influence of its referred for separate clinical treatment rather than alleviation on the regional brain shrinkage. accepted in the study if diastolic pressure was above In addition to changes in brain structure, we 109 mm Hg or systolic pressure above 179 mm Hg. examined the impact of hypertension and anti- BP measures (auscultatory technique with a mer- hypertensive treatment on neuropsychological mea- cury manometer) were taken with a participant sures. Although both aging and hypertension are sitting after at least a 5-min rest. Baseline BP was associated with declines in cognitive performance,16 calculated from the average of the last two of three the literature concerned with specific associations readings performed on two occasions. Participants between structural change and cognitive function is were required to have either no previous pharma- inconsistent.1,8,15,17 cological treatment for hypertension or no more than The current longitudinal investigation focused on 6 months of BP medication within the past 5 years, 1-year changes in brain morphology among persons with no BP medication taken in the 6 months who received a diagnosis of hypertension and were preceding enrolment. For detailed inclusion/exclu- treated with medication to lower their blood pressure sion criteria for this study, see an earlier publica- (BP). If heightened BP proximally induces morpho- tion.23 Screening was designed to exclude secondary logical changes in the brain, it is plausible that hypertension, use of drugs/substances interfering reducing BP may normalize brain morphology. Even with accurate and safe treatment/assessment and if such intervention would not reverse the damage, it presence of other serious disease, notably coronary could at least attenuate further structural deterioration. or cerebrovascular disease. Of the 81 volunteer Hence, we compared the effect of two medications that patients, 36 did not meet the inclusion criteria and have been proven effective in reducing BP in un- of the remaining 45, 41 completed the entire study complicated hypertension: a b-blocker and an angio- and 40 had a full set of structural MRI and tensin-converting enzyme inhibitor. Although both neuropsychological measures. Among participants interventions were expected to reduce BP, the angio- analyzed for either MRI or neuropsychological tensin-converting enzyme inhibitor was expected to results, 27 entered the study with both systolic have a more favourable neuroprotective effect given its and diastolic pressure elevated, 9 with systolic reported action of normalizing the vascular wall.18,19 To elevated only and 6 with diastolic elevated only. assess brain morphology, we used techniques designed Participants were not selected for handedness or to extend methods employed in previous studies by race; 95% of completing individuals reported being using full-brain coverage, an automated identification right-handed and 85% were Caucasian. Participants of specific brain regions, and a focused statistical were similar to non-completing individuals in age, approach. We used a previously validated and widely education and personality factors. However, con- used automated labelling procedure (ALP). In this tinuing participants were significantly (w2-test, approach, after segmentation into grey matter, white Po0.05) more likely to be male, Caucasian and matter and cerebrospinal fluid (CSF) compartments, married. The University of Pittsburgh Institutional the algorithm identifies, labels and quantifies the Review Board approved all procedures as consistent volume of 194 areas based on whole-brain, structural with ethical principles and subjects provided magnetic resonance images.20,21 We selected brain informed consent. regions of interest (ROIs) according to the extant The imaging data for a comparison group of reports identifying them as discriminating between normotensive participants were obtained from a hypertensive and normotensive individuals, as dis- public database compiled by the