Midlife Consequences of Cumulative Blood Pressure Exposure
2020; Lippincott Williams & Wilkins; Volume: 141; Issue: 9 Linguagem: Inglês
10.1161/circulationaha.120.044447
ISSN1524-4539
Autores Tópico(s)Heart Rate Variability and Autonomic Control
ResumoHomeCirculationVol. 141, No. 9Midlife Consequences of Cumulative Blood Pressure Exposure Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMidlife Consequences of Cumulative Blood Pressure ExposureImportance of a Lifespan Approach Angela L. Jefferson, PhD Angela L. JeffersonAngela L. Jefferson Angela L. Jefferson, PhD, Vanderbilt Memory and Alzheimer's Center, 1207 17th Avenue South, Suite 204, Nashville, TN 37212. Email E-mail Address: [email protected] Vanderbilt Memory and Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN. Originally published2 Mar 2020https://doi.org/10.1161/CIRCULATIONAHA.120.044447Circulation. 2020;141:725–727This article is a commentary on the followingCumulative Blood Pressure Exposure During Young Adulthood and Mobility and Cognitive Function in MidlifeArticle, see p 712The worldwide prevalence of dementia is approximately 47.5 million, and Alzheimer disease (AD) is the most common cause. Despite this crisis, there are only four US Food and Drug Administration–approved AD medications, none of which are disease-modifying. To date, pharmacological interventions mainly targeting amyloid or tau protein have been ineffective in more than 200 clinical trials. Despite cerebrovascular disease contributing to nearly 90% of clinical dementia cases1 and cardiovascular and cerebrovascular abnormalities increasingly linked to cognitive impairment,2 pharmacological interventions do not currently address these important concomitant pathologies.Elevated blood pressure (BP), a well-established risk factor for cardiovascular and cerebrovascular disease, has been linked to dementia,2 making hypertension an attractive target for intervention. Indeed, cardiovascular health management is now recognized as a critical avenue for mitigating age-related neurodegeneration with recent data from SPRINT-MIND (Systolic Blood Pressure Intervention Trial-Memory and Cognition in Decreased Hypertension) showing aggressive lowering of BP reduces incident cognitive impairment.3Current cardiovascular treatment approaches focus on midlife and late life management of chronic conditions (eg, antihypertensive medication) rather than elucidating early, subclinical changes across the lifespan that may play a significant role in precipitating adverse brain outcomes. A focus on concomitant pathways of injury, such as cerebral small vessel disease, provides an exciting avenue to better understand molecular factors that increase susceptibility or resilience to cognitive decline. More recently, converging evidence points to midlife elevated BP exposure as an important predictor of cognitive decline,4 suggesting midlife hypertension or prehypertension has important consequences for dementia risk.Increasing midlife evidence begs the question of whether lifespan exposure to elevated BP has adverse effects earlier. In this issue, Mahinrad and colleagues5 address this question by studying the effect of cumulative BP exposure in young adulthood on midlife cognition and gait. Participants were drawn from the CARDIA study (Coronary Artery Risk Development in Young Adults) (n=191) and underwent serial, manual brachial artery BP measurements over a 30-year period.In models adjusting for relevant covariates, the authors found higher cumulative BP exposure over the 30-year follow-up period was associated with less optimal midlife gait performance and decreased midlife cognitive performance, including executive functioning and episodic memory. It is interesting to note that BP levels during young adulthood were on average below the current hypertension threshold (ie, mean BP of 108±10/66±10 mm Hg [mean ± standard deviation]). At midlife, BP rose to a mean of 120±15/74±11 mm Hg (mean ± standard deviation), suggesting at least 30% of the cohort had BP levels above 130/80 mm Hg. Thus, results suggest exposure to subclinical BP elevations in young adulthood through midlife have adverse midlife cognitive and gait consequences.In a smaller subset of participants with midlife magnetic resonance imaging acquisition (n=144), the authors found higher cumulative BP exposure related to a higher midlife burden of white matter changes. They found these white matter changes modified associations between cumulative BP exposure and gait but not cognition. The authors concluded this latter null result could be because BP affects cognition through another pathway or because the structural neuroimaging protocol was insensitive to midlife white matter changes. As lifespan data emerge, using more sensitive neuroimaging modalities will be important to detect early or subclinical changes.Lifespan data are sparse given the cost required to follow large samples with detailed phenotyping across decades; however, early, chronic risk factor exposure may have important consequences on late life brain health. Although most vascular risk factor and brain aging literature focuses on risk exposure at a single time point, the CARDIA study provides unprecedented lifespan data that are essential to improve our understanding. Previous work from this same cohort has shown that elevated BP4 and its variability6 in early adulthood are linked to worse midlife cognition. Other lifespan cohorts have reported similar data from as early as childhood. In the Young Finns Study, elevated BP in childhood (6–12 years), adolescence (12–18 years), and young adulthood (18–24 years) was linked to worse midlife episodic memory performances.7 Among participants from the Chicago Heart Association Detection Project in Industry, the cumulative incidence of late life dementia was increased with higher baseline BP levels at a mean age of 35 years.8 Although evidence suggests gait disturbances precede cognitive changes in late life,9 research linking BP across the lifespan to midlife or late life gait disturbances is sparse. Thus, the study by Mahinrad and colleagues5 expands the limited previous lifespan research linking cumulative elevations in BP exposure across a 30-year period to worse midlife cognitive and gait performances.Whereas white matter changes in aging have been studied extensively, Mahinrad and colleagues5 report that the cumulative burden of BP exposure from young adulthood to midlife is related to greater midlife white matter hyperintensities. Given the sample had a low mean BP at study entry and fewer than 30% of participants were taking antihypertensive medications at the 30-year time point, this observation is an important one. It is feasible that these early effects on white matter integrity confer vulnerability across the lifespan such that common late life pathologies, such as AD or cerebral small vessel disease, have a greater impact on clinical manifestation and functional changes. This observation underscores the importance of lifelong monitoring and more aggressive BP control.The underlying mechanisms for these associations are unclear and likely multifactorial. Optimal brain function is highly reliant on a continuous supply of blood for access to oxygen and glucose. Whereas cerebral blood flow is thought to be tightly regulated by several mechanisms, increasing evidence suggests these mechanisms may be compromised in aging and disease.10 Thus, alterations in cerebral blood supply can have harmful consequences, even if subclinical and chronic over years or decades. Aging is associated with structural remodeling of the vasculature and loss of elastin, which contributes to arterial stiffness.11 Stiffness precedes the development of hypertension, raising the possibility that subclinical elevations in BP in young adulthood and midlife could be due to increased stiffness and reduced compliance. Over time, increased stiffness and compliance changes may affect wave reflectivity,11 resulting in harmful pressure pulsatility in the cerebral microcirculation and reducing cerebral blood flow.12 Such chronic, suboptimal changes in cerebral blood flow might have important implications for midlife and late life cognitive and gait functions. Given the relatively young and healthy composition of the CARDIA cohort, subclinical stiffness may not exist at such an early age or contribute to midlife cerebral blood flow changes with detectable consequences in cognition and gait.Thus, an alternate explanation may be some shared underlying genetic driver linking BP elevations and alterations in brain integrity. In the Framingham Heart Study, middle-aged and older adults with parental stroke (ie, a parent confirmed to have stroke onset before age 65 years) showed demonstrable longitudinal decline in cognition and increases in white matter hyperintensities, presumably implicating genetic vulnerability.13 Young and middle-aged autosomal dominant AD mutation carriers from the Dominantly Inherited Alzheimer Network showed increased white matter hyperintensities more than 2 decades before estimated symptom onset, suggesting genetic propensity to white matter damage despite a low prevalence of vascular risk factors.14 Finally, infant carriers of the apolipoprotein E ε4 allele, the largest genetic susceptibility risk factor for AD, showed differences in white matter integrity and smaller cerebral gray matter volumes than noncarriers.15 Thus, underlying genetic factors may have demonstrable implications for brain health even in asymptomatic or younger populations. More research is needed to understand the multitude of genetic or environmental contributors to the findings presented by Mahinrad and colleagues.5There are many strengths to the work put forth by Mahinrad and colleagues,5 including the emphasis on lifespan considerations, risk factor exposure starting in young adulthood, racial diversity, and integration of both cognitive and gait performances with structural neuroimaging data. Although the study offers important insights, it also generates important questions. First, midlife outcomes may be influenced by interim cardiovascular disease exposure. At the 30-year follow-up assessment, the cohort was on average at the threshold of obesity, approximately one third were hypertensive, and approximately one fifth were diabetic. Understanding whether incident disease versus chronic risk factor exposure drives findings is important. Second, it would be of great interest to know if a particular time frame within the 30-year exposure window had a stronger impact on midlife brain health. Considering these data cumulatively by decade might provide important information for risk factor monitoring and ideal intervention timing. Third, increased BP relates not only to cerebral white matter changes but also to cerebral gray matter changes, and cognitive and gait disturbances share underlying neurodegenerative processes, including AD pathology affecting the cerebral gray matter. Relating cumulative BP exposure to neuroimaging structural markers of gray matter and testing whether markers of neurodegeneration mediate associations with cognitive and gait performance would offer important insights.In summary, Mahinrad and colleagues5 suggest early life elevations in BP affect midlife cognition, gait, and white matter. If these findings are replicated, earlier intervention to prevent hypertension or age-related rise in BP may constitute a more effective approach to preserve brain health and prevent cognitive decline in later life.Sources of FundingThis work was supported by K24-AG046373, R01-AG034962, R01-NS100980, and R01-AG056534.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circAngela L. Jefferson, PhD, Vanderbilt Memory and Alzheimer's Center, 1207 17th Avenue South, Suite 204, Nashville, TN 37212. Email angela.[email protected]orgReferences1. Kapasi A, DeCarli C, Schneider JA. Impact of multiple pathologies on the threshold for clinically overt dementia.Acta Neuropathol. 2017; 134:171–186. doi: 10.1007/s00401-017-1717-7CrossrefMedlineGoogle Scholar2. Iadecola C, Gottesman RF. 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Circulation. 2020;141:712-724 March 3, 2020Vol 141, Issue 9 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.044447PMID: 32119589 Originally publishedMarch 2, 2020 Keywordsblood pressurecardiovascular diseaseepisodic memoryEditorialswhite matterexecutive functiongaithypertensionPDF download Advertisement SubjectsCADASILCost-EffectivenessHigh Blood PressureQuality and Outcomes
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