Higher Aortic Stiffness Is Related to Lower Cerebral …...cardiovascular function and brain health among aging adults. • Understanding the association between higher aortic stiffness

Circulation. 2018;138:1951–1962. DOI: 10.1161/CIRCULATIONAHA.118.032410 October 30, 2018 1951

Key Words: aging ◼ Alzheimer’s disease ◼ apolipoproteins ◼ arteries ◼ magnetic resonance imaging ◼ pulse wave analysis ◼ risk factors

Sources of Funding, see page 1960

BACKGROUND: Mechanisms underlying the association between age-related arterial stiffening and poor brain health remain elusive. Cerebral blood flow (CBF) homeostasis may be implicated. This study evaluates how aortic stiffening relates to resting CBF and cerebrovascular reactivity (CVR) in older adults.

METHODS: Vanderbilt Memory & Aging Project participants free of clinical dementia, stroke, and heart failure were studied, including older adults with normal cognition (n=155; age, 72±7 years; 59% male) or mild cognitive impairment (n=115; age, 73±7 years; 57% male). Aortic pulse wave velocity (PWV; meters per second) was quantified from cardiac magnetic resonance. Resting CBF (milliliters per 100 g per minute) and CVR (CBF response to hypercapnic normoxia stimulus) were quantified from pseudocontinuous arterial spin labeling magnetic resonance imaging. Linear regression models related aortic PWV to regional CBF, adjusting for age, race/ethnicity, education, Framingham Stroke Risk Profile (diabetes mellitus, smoking, left ventricular hypertrophy, prevalent cardiovascular disease, atrial fibrillation), hypertension, body mass index, apolipoprotein E4 (APOE ε4) status, and regional tissue volume. Models were repeated testing PWV×APOE ε4 interactions. Sensitivity analyses excluded participants with prevalent cardiovascular disease and atrial fibrillation.

RESULTS: Among participants with normal cognition, higher aortic PWV related to lower frontal lobe CBF (β=−0.43; P=0.04) and higher CVR in the whole brain (β=0.11; P=0.02), frontal lobes (β=0.12; P<0.05), temporal lobes (β=0.11; P=0.02), and occipital lobes (β=0.14; P=0.01). Among APOE ε4 carriers with normal cognition, findings were more pronounced with higher PWV relating to lower whole-brain CBF (β=−1.16; P=0.047), lower temporal lobe CBF (β=−1.81; P=0.004), and higher temporal lobe CVR (β=0.26; P=0.08), although the last result did not meet the a priori significance threshold. Results were similar in sensitivity models. Among participants with mild cognitive impairment, higher aortic PWV related to lower CBF in the occipital lobe (β=−0.70; P=0.02), but this finding was attenuated when participants with prevalent cardiovascular disease and atrial fibrillation were excluded. Among APOE ε4 carriers with mild cognitive impairment, findings were more pronounced with higher PWV relating to lower temporal lobe CBF (β=−1.20; P=0.02).

CONCLUSIONS: Greater aortic stiffening relates to lower regional CBF and higher CVR in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer’s disease. Central arterial stiffening may contribute to reductions in regional CBF despite preserved cerebrovascular reserve capacity.

© 2018 American Heart Association, Inc.

Angela L. Jefferson, PhDFrancis E. Cambronero, ABDandan Liu, PhDElizabeth E. Moore, BSJacquelyn E. Neal, BSJames G. Terry, MSSangeeta Nair, DVM, MSKimberly R. Pechman, PhDSwati Rane, PhDL. Taylor Davis, MDKatherine A. Gifford, PsyDTimothy J. Hohman, PhDSusan P. Bell, MBBS, MSCIThomas J. Wang, MDJoshua A. Beckman, MD,

MSJohn Jeffrey Carr, MD,

MSc

ORIGINAL RESEARCH ARTICLE

Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults

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Jefferson et al Aortic Stiffness and Cerebral Hemodynamics

October 30, 2018 Circulation. 2018;138:1951–1962. DOI: 10.1161/CIRCULATIONAHA.118.0324101952

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Arterial stiffness intensifies with age,1 and its es-timates such as pulse wave velocity (PWV) are associated with increased incidence of cardio-

vascular disease (CVD)2 and accelerated brain aging, in-cluding cognitive impairment and small vessel disease.3 An elastic aorta is critical for distributing blood and buff-ering pulsatile flow.4 Age-related reductions in aortic wall compliance can contribute to increased transmission of harmful pulsatile energy into the microcirculation, in-creased microvascular remodeling, and impaired oxygen delivery to tissue.4 Highly perfused organs like the brain may be particularly susceptible. In response to excessive pulsatility, larger cerebral arteries and smaller arterioles coordinate to limit penetration of pulsatile flow into the capillaries.4 The consequence of increased aortic stiffen-ing would thus be reduced cerebral perfusion with or without associated changes in cerebrovascular reactivity (CVR), defined as the ability of microvessels to increase blood flow in response to elevated demand.

Prior research relating arterial stiffness to cerebral he-modynamics has relied mostly on measures of velocity rather than cerebral blood flow (CBF; rate of blood de-livery to tissue)5 and middle-aged adults.6 More limited

research has attempted to understand aortic stiffening in the context of its influence on regional CBF patterns or CVR in older adults. Using the gold standard measure-ment of central arterial stiffening by directly measuring thoracic aortic PWV in the aortic arch on cardiac magnetic resonance (CMR),7 we related aortic stiffening to resting CBF and CBF in response to a hypercapnic challenge (CVR) in older adults free of clinical dementia or stroke. Apolipo-protein E ε4 allele (APOE ε4) is a well-known Alzheimer’s disease genetic susceptibility marker, but it also appears to be a molecular mediator of vascular damage8–10; it com-promises vascular function,11 and it enhances adverse ef-fects of clinical systemic vascular disease on brain health.12 Given that APOE ε4 mediates risk for cross-sectional13 and longitudinal CBF changes during aging,14 aortic stiffening may exert stronger effects and promote compromised ce-rebral hemodynamics in APOE ε4 carriers. Therefore, we also examined the interaction of aortic PWV and APOE ε4 on CBF and CVR measurements.

METHODSCohort SelectionThe Vanderbilt Memory & Aging Project (VMAP)15 is a longi-tudinal study investigating vascular health and brain aging. Inclusion required participants to be ≥60 years of age, to speak English, to have adequate auditory and visual acuity, and to have a reliable study partner. At eligibility, participants underwent a medical history and record review, a clinical interview (including functional questionnaire and Clinical Dementia Rating16 with the informant), and a neuropsy-chological assessment for cognitive diagnosis by consensus, including normal cognition (NC) or mild cognitive impairment (MCI) based on the National Institute on Aging/Alzheimer’s Association Workgroup clinical criteria.17 Specifically, MCI was defined as (1) a Clinical Dementia Rating of 0 or 0.5 (reflect-ing mild severity of impairment); (2) relatively spared activities of daily living; (3) objective neuropsychological impairment; (4) concern of a cognitive change by the participant, infor-mant, or clinician based on information obtained during the clinical interview; and (5) absence of a dementing syndrome. Participants were excluded for magnetic resonance imaging (MRI) contraindication, history of neurological disease (eg, stroke), heart failure, major psychiatric illness, head injury with loss of consciousness for >5 minutes, and systemic or terminal illness that could affect follow-up participation. At enrollment, participants completed a comprehensive evalua-tion, including fasting blood draw, physical examination, clini-cal interview with medication review, echocardiogram, CMR, and brain MRI. Participants were excluded here for missing CMR, brain MRI, or covariate data (Figure 1).

The Vanderbilt University Medical Center Institutional Review Board approved the protocol. Written informed con-sent was obtained from all participants before data collection. Because of participant consent restrictions in data sharing, a subset of data is available to others for purposes of reproduc-ing the results or replicating procedures. These data, analytical methods, and study materials can be obtained by contacting the corresponding author.

Clinical Perspective

What Is New?• Greater thoracic aortic stiffening quantified from

cardiac magnetic resonance is associated with lower cerebral blood flow in cognitively normal older adults free of clinical stroke, dementia, and heart failure.

• Aortic stiffening may be associated with cerebral hypoperfusion (reflected by reduced resting cere-bral blood flow) in the presence of preserved reac-tivity and associated vasodilatory capacity (reflected by cerebrovascular reactivity), particularly among participants without hypertension.

• Apolipoprotein ε4, a well-known genetic suscepti-bility risk factor for Alzheimer’s disease, appears to modify results with regionally specific and stronger cerebral blood flow and cerebrovascular reactiv-ity effects among apolipoprotein ε4 carriers in the temporal lobes where Alzheimer’s disease pathol-ogy first evolves.

What Are the Clinical Implications?• These findings add to a growing and insightful

body of research highlighting the interrelation of cardiovascular function and brain health among aging adults.

• Understanding the association between higher aortic stiffness and compromised brain health, including cerebral hemodynamics, may allow ear-lier detection and targeted interventions to prevent or mitigate the onset of more serious cerebrovascu-lar damage associated with higher aortic stiffening.

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CMR ImagingCMR imaging was acquired at Vanderbilt University Medical Center with a 1.5-T Siemens Avanto system (Siemens Medical Solutions USA, Inc, Malvern, PA) with a phased-array torso receiver coil. Velocity-encoded flow data were acquired from the ascending and descending thoracic aorta. Under the supervision of a board-certified radiologist (J.J.C), trained raters blinded to clinical information (J.G.T., S.N.) used the 2-dimensional flow sequence to draw contours on the ascending and descending aorta using the QFLOW 5.6 Enterprise Solution (Medis, Leiden, the Netherlands). The thoracic aorta centerline length (centimeters) from the ascending aorta to the descending aorta was measured with the OsiriX (PIXMEO SARL, Bernex, Switzerland). Transit time was calculated with a custom MATLAB script to calcu-late the difference in time (milliseconds) at half maximum between the leading edges of the ascending and descend-ing aortic flow curves. PWV (meters per second) was cal-culated as distance traveled across the aorta (meters) divided by time delay in onset of velocity waves (seconds). Interreader reliability (coefficient of variation, 6.6%) was determined by independent review of 34 scans by 2 read-ers (J.G.T, S.N.). Pulsatile wave transmission increases with decreasing arterial wall elasticity, such that a higher PWV indicates higher arterial stiffness.

Brain MRIParticipants were scanned at the Vanderbilt University Institute of Imaging Science on a 3-T Philips Achieva system (Best, the Netherlands) using 8-channel phased-array SENSE (sensitivity encoding) reception. T1-weighted magnetization-prepared rapid gradient echo (isotropic spatial resolution, 1 mm3) images were postprocessed with an established Multi-Atlas

Segmentation pipeline18,19 with parcellation of 5 regions of interest, including whole brain and frontal, temporal, parietal, and occipital lobes.

Pseudocontinuous arterial spin labeling (label duration, 1.65 seconds; postlabeling delay, 1.525 seconds; spatial reso-lution, 3×3×7 mm3; repetition time/echo time, 3900/13 mil-liseconds) assessed CBF (milliliters of blood per 100 g tissue per minute) using a reproducible protocol.20,21 Data were cor-rected for motion and baseline drift with the Functional MRI of the Brain (FMRIB) Software Library FMRIB’s Linear Image Registration Tool.22 Additional postprocessing was completed with MATLAB. Images were slice-time–corrected, normalized by the equilibrium magnetization (M0), which was calculated from a separately acquired image with identical geometry but repetition time of 20 seconds, and converted to absolute CBF units following recommended guidelines.23 This image was coregistered to the anatomic T1-weighted map and standard Montreal Neurological Institute template.24 Transformation matrixes were applied to CBF maps. Region-specific mean resting CBF was calculated in gray matter regions of interest described above.

To evaluate CVR, the pseudocontinuous arterial spin label-ing acquisition was repeated with identical parameters during a hypercapnic stimulus. A custom nonrebreathing facemask delivered 5% CO2 and 95% medical-grade room air (hyper-capnic normoxia) from compressed cylinders at a rate of 12 L/min. End-tidal CO2 and arterial oxygen saturation were recorded. The first 4 scan volumes during the challenge were removed from calculations to allow CBF to plateau. CVR was calculated as percentage change in CBF (from resting CBF as a result of the induced hypercapnia) normalized by the end-tidal CO2 change (millimeters of mercury). Region-specific mean CVR values were calculated for the 5 gray matter regions of interest described above.

Figure 1. Inclusion and exclusion criteria. Missing data categories are mutually exclusive. Missing arterial spin labeling (ASL) challenge data include participants unable to wear the non-rebreathing mask (determined by out-of-range end-tidal CO2 values between challenge and rest, <3 and >10 mm Hg). CBF indicates cerebral blood flow; CMR, cardiac magnetic resonance imaging; CVR, cerebrovascular reac-tivity; and MRI, magnetic resonance imaging. *Sensitivity analyses excluding cardiovascular disease (CVD) or atrial fibrillation removed 12 participants with normal cognition (NC) and 9 participants with mild cognitive impairment (MCI). †Sensitivity analyses excluding CVD or atrial fibrillation removed 10 participants with NC and 7 with MCI.

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Covariate DefinitionsBody mass index was calculated as weight in kilograms divided by height in meters squared. Systolic blood pres-sure was the mean of 2 measurements. Diastolic blood pressure was the mean of 2 measurements. Hypertension was defined as antihypertensive medication use, systolic blood pressure ≥140 mm Hg, or diastolic blood pressure ≥90 mm Hg. Diabetes mellitus was defined as fasting blood glucose ≥126 mg/dL, hemoglobin A1c ≥6.5%, or oral hypo-glycemic or insulin medication use. Medication review deter-mined antihypertensive medication use. Left ventricular hypertrophy was defined on echocardiogram as left ventric-ular mass index >115 g/m2 in men or >95 g/m2 in women. Self-report or history of atrial fibrillation was corroborated by any one of the following sources: echocardiogram, CMR, documented prior procedure/ablation for atrial fibrillation, or medication use for atrial fibrillation. Current cigarette smoking (yes/no within the year before baseline) was ascer-tained by self-report. Self-report prevalent CVD with medi-cal record documentation included coronary heart disease, angina, or myocardial infarction (heart failure was a parent study exclusion). Framingham Stroke Risk Profile assigned points by sex for age, systolic blood pressure (accounting for antihypertensive medication use), diabetes mellitus, ciga-rette smoking, left ventricular hypertrophy, CVD, and atrial fibrillation.25 APOE genotyping was performed on whole blood. APOE ε4 status was defined as positive (ε2/ε4, ε3/ε4, ε4/ε4) or negative (ε2/ε2, ε2/ε3, ε3/ε3).

Analytical PlanBefore analyses, scatterplots with linear fit and locally weighted smoothing fit were visually inspected for linear-ity, and outliers were excluded (defined as ≥4 SDs from the sample mean). Linear regressions with ordinary least square estimates stratified by cognitive diagnosis related aortic PWV to resting CBF and CVR for whole brain and frontal, temporal, parietal, and occipital lobes. Models were adjusted for age, race/ethnicity, education, hypertension, modified Framingham Stroke Risk Profile score (excluding points assigned for age and systolic blood pressure account-ing for antihypertensive medication use), body mass index, APOE ε4, and corresponding gray matter region of interest to account for CBF reductions resulting from tissue volume loss26 (eg, gray matter in the temporal lobe was a covari-ate for temporal lobe CBF). Covariates were selected a pri-ori for their potential to confound the analytical models. To assess whether CVD or atrial fibrillation accounted for any significant results, models were repeated in sensitiv-ity analyses excluding participants with these conditions. To test hypotheses related to APOE ε4 status, models were repeated with a PWV×APOE ε4 interaction with follow-up models stratified by APOE ε4 status. In post hoc analyses, significant models were reanalyzed to assess allele dos-age effects in which APOE ε4 was coded with an additive coding scheme (0, 1, or 2 ε4 alleles). In post hoc analy-ses, the effect of hypertension was examined by relating a PWV×hypertension interaction to CBF and CVR outcomes and stratifying primary models by hypertension status (yes, no). Significance was set a priori at P<0.05. Analyses were conducted with R 3.2.3 (www.r-project.org).

RESULTSCharacteristicsThe sample included 155 participants with NC and 115 with MCI. Participants did not differ on covariates or global cognitive status (as assessed by the Montreal Cognitive Assessment) compared with those individuals missing data who were excluded from analyses (n=65). The mean sample age was 73±7 years (range, 60–92 years); 58% were men; and 86% self-identified as non-Hispanic white. Aortic PWV ranged from 3.5 to 25.5 m/s. Total sample and diagnostic group characteristics are presented in Table 1. To illustrate the pseudocon-tinuous arterial spin labeling method, maps for the NC group are presented for mean CBF (Figure 2A) and CVR (Figure 2B) by the lowest and highest quartile of PWV.

Aortic PWV and CBF in Participants With NCAmong participants with NC, aortic PWV related to frontal lobe CBF (β=−0.43; P=0.04; Figure 3A). Aortic PWV also related to CBF in the whole brain (β=−0.34; P=0.07) and temporal lobe (β=−0.36; P=0.08), but these associations did not meet a priori significance (Table 2). When participants with atrial fibrillation and CVD were excluded, results were similar. The PWV×APOE ε4 inter-action term related to CBF in the whole brain (β=−1.16; P=0.047) and temporal lobe (β=−1.81; P=0.004) such that associations between higher PWV and lower CBF were more pronounced among APOE ε4 carriers com-pared with noncarriers (Figure 4A). The PWV×APOE ε4 interaction term also related to resting frontal lobe CBF, but this association did not meet a priori significance (P=0.08; Table 3). In post hoc analyses examining APOE ε4 allele dosage effects, APOE ε4 allele count did not improve model fit, likely because small cell sizes limited power. However, visual inspection of the data suggests an additive effect whereby homozygous carriers of the APOE ε4 allele may have lower CBF in the temporal lobe at higher PWV values than heterozygous APOE ε4 carriers (Figure I in the online-only Data Supplement). When participants with atrial fibrillation and CVD were excluded, results were similar. In post hoc analyses ex-amining the interaction of PWV×hypertension on CBF outcomes, results were null (P≥0.57).

Aortic PWV and CBF in Participants With MCIAmong participants with MCI, aortic PWV related to occipital lobe CBF (β=−0.70; P=0.02), but results were attenuated in a sensitivity analysis excluding participants with atrial fibrillation and CVD (β=−0.54; P=0.15). Aortic PWV was unrelated to CBF in all re-maining regions (P>0.33; Table 2). The PWV×APOE

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ε4 interaction term related to temporal lobe CBF (β=−1.20; P=0.02) such that associations between higher PWV and lower CBF were more pronounced among APOE ε4 carriers compared with noncarriers. The PWV×APOE ε4 interaction term was unrelated to CBF in all remaining regions assessed (P>0.47; Ta-ble 3). When participants with atrial fibrillation and CVD were excluded, results were similar. In post hoc analyses examining PWV×hypertension on CBF out-comes, results were null (P≥0.44).

Aortic PWV and CVR in Participants With NCAmong participants with NC, higher aortic PWV relat-ed to higher CVR in the whole brain (β=0.12; P=0.02; Figure 3B), frontal lobes (β=0.12; P=0.048; Figure 3C), temporal lobes (β=0.11; P=0.02; Figure 3D), and oc-cipital lobes (β=0.14; P=0.01; Figure 3E). Higher aortic PWV corresponded to higher parietal lobe CVR (β=0.10; P=0.08), but results did not meet a priori significance.

Table 1. Participant Characteristics

Total (n=270) NC (n=155) MCI (n=115) P Value

Demographic and health characteristics

Age, y 73±7 72±7 73±7 0.36

Male, % 58 59 57 0.83

White non-Hispanic, % 86 86 86 0.93

Education, y 16±3 16±2 15±3 <0.001

Montreal Cognitive Assessment, total score 25±3 27±2 23±4 <0.001

APOE ε4, % 34 29 41 0.04

Body mass index, kg/m2 28±5 27±5 28±4 0.32

Aortic pulse wave velocity, m/s 8.2±3.2 8.2±3.0 8.2±3.3 0.74

Framingham Stroke Risk Profile score, total* 12.3±4.2 11.9±4.2 12.8±4.2 0.07

Systolic blood pressure, mm Hg 142±18 140±17 145±19 0.03

Antihypertensive medication use, % 53 53 52 0.91

Diabetes mellitus, % 18 17 20 0.50

Hypertension, % 74 71 77 0.24

Current cigarette smoking, % 2 1 3 0.43

Prevalent cardiovascular disease,† % 4 4 3 0.87

Atrial fibrillation,† % 5 5 5 0.79

Left ventricular hypertrophy, % 4 3 6 0.26

ΔEtco26.9±2.6 6.9±2.7 6.9±2.3 0.67

CBF, mL/100g/min

Whole brain 37.3±7.1 37.3±6.6 37.3±7.7 0.72

Frontal lobes 38.0±8.3 37.7±7.4 38.3±9.4 0.81

Temporal lobes 35.9±8.1 36.3±6.9 35.4±9.6 0.15

Parietal lobes 39.8±10.3 39.6±9.4 40.1±11.4 0.82

Occipital lobes 36.4±10.0 36.9±9.8 35.7±10.3 0.25

CVR,‡ % change

Whole brain 2.2±1.6 2.4±1.5 2.0±1.8 0.04

Frontal lobes 2.4±2.0 2.6±1.9 2.2±2.0 0.13

Temporal lobes 2.0±1.6 2.1±1.5 1.7±1.7 0.04

Parietal lobes 2.3±2.1 2.4±1.8 2.2±2.5 0.24

Occipital lobes 2.7±1.9 2.7±1.7 2.8±2.1 0.81

Values are presented as mean±SD or frequency. APOE indicates apolipoprotein E; CBF, cerebral blood flow; CVR, cerebrovascular reactivity calculated as (ΔCBF/CBF0)/ΔEtco2; ΔEtco2, challenge end-tidal CO2 (Etco2) minus baseline Etco2; MCI, mild cognitive impairment; mL/100g/min, milliliters of blood per 100 grams of tissue per minute; and NC, normal cognition.

*Modified score was included in models excluding points for age (NC, 6.1±2.8; MCI, 6.8±3.2).†Prevalent cardiovascular disease, n=10; atrial fibrillation, n=13; both, n=1; resulting in n=22 with prevalent

cardiovascular disease, atrial fibrillation, or both. ‡A total of 192 participants with usable challenge CBF data, including n=113 with NC and n=79 with MCI.

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When participants with atrial fibrillation and CVD were excluded, results were similar.

Among participants with NC, the PWV×APOE ε4 interaction term related to CVR in the temporal lobes (β=0.26; P=0.08; Figure 4B), but results did not meet a priori significance. Aortic PWV was unrelated to CVR in all remaining regions (P>0.24; Table 3). In post hoc analyses examining APOE ε4 allele dosage effects, the additive coding did not improve model fit, presumably because of limited power. However, visual inspection of the data suggests that homozygous carriers of the APOE ε4 allele may have greater CVR in the temporal lobe at higher PWV values than APOE ε4 heterozygotes (Figure II in the online-only Data Supplement). In post hoc analy-ses examining PWV×hypertension in relation to CVR outcomes, results suggest that hypertension modifies

the association between PWV and CVR across the whole brain (β=−0.22; P=0.04), especially the frontal (β=−0.28; P=0.04) and parietal (β=−0.24; P=0.06) lobes. Stratified results by hypertension status suggest that higher aortic stiffening is associated with higher reactivity throughout the entire brain (β=0.31; P=0.004), including the frontal (β=0.36; P=0.002) and parietal (β=0.33; P=0.02) lobes, among the nonhypertensive participants only.

Aortic PWV and CVR in MCI ParticipantsAmong participants with MCI, aortic PWV was unre-lated to CVR in all regions (P>0.45). The PWV×APOE ε4 interaction term was unrelated to CVR in all regions (P>0.54). In post hoc analyses examining the interac-tion of PWV×hypertension on CVR outcomes, results were null (P≥0.32).

Figure 2. Mean cerebral blood flow (CBF) and CBF change maps for participants with normal cognition. CBF images were created using the unadjusted group mean image of The Vanderbilt Memory & Aging Project (VMAP) participants with normal cognition who un-derwent CBF analyses (n=154) in the lowest or highest pulse wave velocity (PWV) quartile (A). CBF change images reflect change in CBF in response to hypercap-nia and were created using the unadjusted group mean image of the VMAP participants with normal cognition who underwent cerebrovascular reactivity analyses (n=113) in the lowest or highest PWV quartile (B).

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Power CalculationPost hoc power calculations for the PWV main models and PWV×APOE ε4 interaction models by diagnostic group were conducted on the basis of change in R2 using an F distribution. On the basis of R2 ranging from 0.10 to 0.25 (selected after a review of the total R2 across all model results) and given the available sample sizes, the minimum detectable variance (change in R2) explained by PWV in addition to covariates was calculated with 80% power and a type I error of 0.05. The minimum detect-able variance explained by the PWV×APOE ε4 interaction was calculated with the same approach. Although some of the models were sufficiently powered, increased R2 values for PWV and interaction terms in the models were consistently below threshold, suggesting that our study was possibly underpowered to detect some effects.

DISCUSSIONAmong community-dwelling older adults, greater aortic stiffness related to lower CBF and higher CVR globally. We observed an interaction between aortic stiffness and APOE ε4 such that greater stiffness was associated

with a more pronounced reduction of CBF and more pronounced increase of CVR in the temporal lobes among APOE ε4 carriers. In addition, we observed an interaction between aortic stiffness and hypertension such that greater stiffness was associated with greater global CVR among participants without hypertension. Associations were present only in the participants with NC and determined with gold standard measurements of aortic stiffness and cerebral hemodynamics. Results could not be statistically explained by prevalent CVD, atrial fibrillation, or cerebral atrophy.

To the best of our knowledge, this study is among the first to link higher aortic stiffness measured centrally in the thoracic aorta to lower CBF and higher CVR in older adults. Elevated aortic stiffness may affect brain health by reducing the efficacy of wave reflectivity,27 thus in-creasing the transmission of harmful pressure pulsatility into the microcirculation. Microcirculatory remodeling occurring in response to higher pulsatile energy may lead to increased resistance and lower CBF globally, as reported here (see Figure 5 for a theoretical model). These changes in CBF appear to persist despite largely preserved CVR and associated vasodilatory capacity, as seen here. Because arterial damage accumulates over

Figure 3. Aortic pulse wave velocity (PWV), cerebral blood flow (CBF), and cerebrovascular reactivity (CVR) in cognitively normal participants. Solid black line reflects fitted linear regressions between PWV (x axis) and frontal lobe CBF (A), whole-brain CVR (B), frontal lobe CVR (C), temporal lobe CVR (D), or occipital lobe CVR (E) outcomes (y axis). CVR is calculated as change in CBF normalized by change in end-tidal CO2. Shading reflects 95% CI.

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time (eg, with hypertension), CVR responses may adjust in a manner that parallels long-term changes in endo-thelial or smooth muscle integrity, resulting in unique CVR responses in increasingly damaged tissues. Ongo-ing follow-up of this cohort will allow us to test such longitudinal hypotheses in the future.

It is noteworthy that the global reactivity patterns we observed were specific to participants with NC, particu-larly those individuals without hypertension. This sub-set of participants continues to appropriately respond to changes in partial pressure of arterial CO2 over the range evaluated here, suggesting compliant cerebro-vasculature with arterioles that remain capable of ad-

justing cerebral blood volume in response to demand. Older adults with NC who are free of hypertension may have better quality cerebrovascular integrity as a result of less long-term exposure of elevated pressures over their lifetime compared with older adults with hyperten-sion who presumably have more long-term damage and compromised vasoreactivity.28,29 It is noteworthy that cell sizes for the subset of participants without hypertension are small, so stratified models may be underpowered. In addition to replication, future research is needed to ex-amine the long-term effects of hypertensive risk factor exposure and its magnitude on the association between peripheral and central vascular health.

Table 2. Aortic PWV, CBF, and CVR

NC MCI

β 95% CI P Value β 95% CI P Value

CBF*

Whole brain −0.34 −0.71 to 0.03 0.07 −0.23 −0.69 to 0.24 0.34

Frontal lobes −0.43 −0.85 to −0.01 0.04 −0.20 −0.69 to 0.28 0.41

Temporal lobes −0.36 −0.77 to 0.04 0.08 0.04 −0.53 to 0.60 0.90

Parietal lobes −0.24 −0.77 to 0.29 0.37 −0.27 −0.92 to 0.39 0.42

Occipital lobes −0.40 −0.94 to 0.15 0.15 −0.70 −1.27 to −0.13 0.02

CVR†

Whole brain 0.12 0.02 to 0.21 0.02 0.03 −0.09 to 0.16 0.58

Frontal lobes 0.12 0.001 to 0.25 0.048 0.03 −0.12 to 0.18 0.66

Temporal lobes 0.11 0.02 to 0.21 0.02 0.03 −0.11 to 0.16 0.71

Parietal lobes 0.10 −0.01 to 0.22 0.08 −0.03 −0.20 to 0.14 0.72

Occipital lobes 0.14 0.03 to 0.25 0.01 0.05 −0.08 to 0.18 0.45

CBF indicates cerebral blood flow; CVR, cerebrovascular reactivity; MCI, mild cognitive impairment; NC, normal cognition; and PWV, pulse wave velocity.

*CBF analyses included 155 participants in NC models and 115 participants in MCI models. †CVR analyses included 113 participants in NC models and 79 participants in MCI models.

Figure 4. Aortic pulse wave velocity (PWV)×apolipoprotein E (APOE ε4), cerebral blood flow (CBF), and cerebrovascular reactivity (CVR) in cogni-tively normal participants. Solid black line reflects fitted linear regressions between the interaction of PWV and APOE ε4 (x axis) on temporal lobe CBF (A) and temporal lobe CVR (B) out-comes (y axis). CVR is calculated as change in CBF normalized by change in end-tidal CO2. Shading reflects 95% CI.

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We provide preliminary evidence of a dominant in-teraction between PWV and APOE ε4 on temporal lobe hemodynamics coupled with more modest evidence of an additive effect of ε4 allele count because models ex-amining additive effects were underpowered with small cell sizes. APOE ε4 carriers may be more susceptible to cerebrovascular injury via elevated aortic PWV. In particu-lar, APOE ε4 has been shown to contribute to blood-brain barrier dysfunction11 and cerebrovascular damage before neuronal dysfunction.10,30 Furthermore, APOE ε4 carrier status strengthens vascular disease associations with brain health outcomes,12,31–33 and APOE ε4 carriers have more pronounced reductions in CBF and CVR.30 Among indi-viduals with NC, arterial stiffening may exert stronger ef-fects in APOE ε4 carriers and contribute to hypoperfusion in the face of preserved CVR. The interaction between aortic stiffness and APOE ε4 on CBF and CVR among par-ticipants with NC was regionally specific to the temporal lobes, where Alzheimer’s disease pathology first evolves.34

We observed null results between central arterial stiffening and cerebral hemodynamics in MCI. Individ-uals with MCI, who are at high risk for converting to clinical dementia,35 have alterations in CBF36 and may experience a narrowing of dynamic range and a fail-ing cerebrovascular reserve capacity.37 Such alterations in cerebral hemodynamics are presumably the result of neurodegenerative and cerebrovascular changes un-derlying the clinical presentation in MCI, which most commonly includes a combination of Alzheimer’s dis-ease and cerebral small vessel disease.38 Key features of Alzheimer’s disease pathogenesis, including amy-loid39,40 and upregulated transcription factors driving hypercontractility,41 disrupt vasoreactivity. Comparable vasoreactivity disturbances are associated with cerebral

small vessel disease.42–44 The combination of Alzheimer’s disease and cerebrovascular pathology underlying the MCI presentation, coupled with repeated exposure to higher pulsatility, may compromise arteriole health over time, eventually impairing blood flow regulation, ac-counting for the null results seen here. A similar expla-nation might apply to the aforementioned null findings among participants with hypertension. That is, arteriole damage resulting from long-term exposure to elevated blood pressure,28 taken together with ongoing exposure to higher pulsatility caused by aortic stiffness, might re-sult in severely compromised vasoreactivity, accounting for the null results seen among these participants. Col-lectively, cerebrovascular vulnerability to central pressure changes may be especially pertinent in the presence of conditions in which autoregulation may be compro-mised, including chronic risk factors such as hyperten-sion45,46 or pathological conditions such as cerebral small vessel disease47 and Alzheimer’s disease.40 Further inqui-ry to better understand our null results is warranted.

Our study has several strengths, including gold stan-dard methods for noninvasively assessing central arterial stiffening and regional CBF at rest and in response to a challenge, stringent quality control procedures, and the use of a core laboratory for processing CMR and brain MRI measurements with blinded raters. Although analy-ses were cross-sectional, which cannot speak to causal-ity, the inclusion of older adults with NC and MCI allows us to speculate about the timing of associations between aortic stiffening and CBF and CVR across the cognitive spectrum. Our sample included predominantly white, well-educated, relatively healthy elders. Although gen-eralizability to other races, ethnicities, ages, and medical conditions is unknown, we speculate that associations

Table 3. Aortic PWV×APOE4, CBF, and CVR

NC MCI

β 95% CI P Value β 95% CI P Value

CBF*

Whole brain −1.16 −2.30 to 0.02 0.047 −0.32 −1.21 to 0.56 0.47

Frontal lobes −1.17 −2.47 to 0.14 0.08 −0.29 −1.21 to 0.63 0.53

Temporal lobes −1.81 −3.04 to −0.58 0.004 −1.20 −2.24 to −0.16 0.02

Parietal lobes −0.71 −2.37 to 0.95 0.40 0.17 −1.08 to 1.41 0.79

Occipital lobes −0.64 −2.33 to 1.04 0.45 −0.19 −1.27 to 0.89 0.73

CVR†

Whole brain 0.18 −0.12 to 0.47 0.24 0.02 −0.27 to 0.31 0.91

Frontal lobes 0.13 −0.25 to 0.52 0.50 −0.05 −0.39 to 0.29 0.77

Temporal lobes 0.26 0.04 to 0.56 0.08 0.10 −0.22 to 0.41 0.54

Parietal lobes 0.05 −0.30 to 0.41 0.76 −0.04 −0.42 to 0.34 0.84

Occipital lobes 0.17 −0.16 to 0.51 0.30 −0.03 −0.34 to 0.27 0.82

APOE indicates apolipoprotein E; CBF, cerebral blood flow; CVR, cerebrovascular reactivity; MCI, mild cognitive impairment; NC, normal cognition; and PWV, pulse wave velocity.

*CBF analyses included 155 participants in NC models and 115 participants in MCI models. †CVR analyses included 113 participants in NC models and 79 participants in MCI models.

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reported here would likely be stronger in a cohort with worse cardiovascular health. Multiple comparisons raise the possibility of a false-positive finding and emphasize the need for replication. Finally, we cannot rule out the possibility of residual confounding.

CONCLUSIONSAmong older adults free of clinical dementia, stroke, and heart failure, greater stiffening of the arch of the thoracic aorta was associated with worse cerebral he-modynamics statistically independent of concurrent cardiovascular risk factors, CVD, and atrial fibrillation. Data support a possible mechanism for central nervous system injury secondary to increased arterial stiffening with age.

ARTICLE INFORMATIONReceived January 8, 2018; accepted June 22, 2018.

The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/circulationaha.118.032410.

Guest Editor for this article was Jan A. Staessen, MD, PhD.

CorrespondenceAngela L. Jefferson, PhD, Vanderbilt Memory & Alzheimer’s Center, 1207 17th Ave S, Ste 204, Nashville, TN 37212. Email [email protected]

AffiliationsVanderbilt Memory & Alzheimer’s Center, Department of Neurology (A.L.J., F.E.C., E.E.M., K.R.P., K.A.G., T.J.H.), Division of Cardiovascular Medicine, De-partment of Medicine (A.L.J., S.P.B., T.J.W., J.A.B), Department of Biostatistics (D.L., J.E.N.), Radiology and Radiological Sciences (J.G.T., S.N., L.T.D., J.J.C.), and Center for Quality Aging, Division of General Internal Medicine, Depart-ment of Medicine (S.P.B.), Vanderbilt University Medical Center, Nashville, TN. Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN (F.E.C., E.E.M.). Department of Radiology, University of Washington Medical Center, Seattle (S.R.).

AcknowledgmentsThe authors thank the dedicated Vanderbilt Memory & Aging Project partici-pants and their families.

Sources of FundingFunding was provided by Alzheimer’s Association grant IIRG-08-88733 (Dr Jefferson); National Institutes of Health grants R01-AG034962 (Dr Jefferson), R01-NS100980 (Dr Jefferson), K24-AG046373 (Dr Jefferson), K23-AG030962 (Dr Jefferson), K23-AG045966 (Dr Gifford), K23-AG048347 (Dr Bell), T32-MH064913 (F.E. Cambronero), T32-GM007447 (E.E. Moore), R25-GM062459 (F.E. Cambronero), K12-HD043483 (Dr Gifford, Dr Bell, Dr Hohman), and K01-

Figure 5. Theoretical model of cerebral damage induced by aortic stiffening. A, A healthy aortic wall is compliant, and vascular segments gradually stiffen toward the periphery. Mismatch in vascular wall properties and gradual arterial branching creates beneficial wave reflection sites that reduce forward pulsatile transmission and reflect backward waves for cardiac reperfusion. B, A compliant aorta mediates continuous blood flow throughout the cardiac cycle and dampens pulsatility. C, Blood flow from the heart into the brain is further regulated by microvascular vasodilation and vasoconstriction. These mechanisms can ensure adequate delivery of energy substrate to tissue and serve to dampen pulsatile en-ergy. D, With advancing age, the aorta thickens and stiffens, reducing impedance mismatch, increasing transmission of damaging pulsatility into end organs, and contributing to early retrograde waves that augment systolic pressure and reduce diastolic flow over time. E, These changes may contribute to reduced perfusion in high-flow vulnerable organs and possibly more turbulent flow throughout the system. F, The effects of aortic stiffening on cerebrovascular structure and func-tion are less well studied. Existing evidence suggests that aortic stiffening contributes to altered vascular resistance, corresponding cerebral perfusion pressure, and compromises in blood-brain barrier integrity, potentially contributing to reduced brain perfusion.

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mailto:[email protected]




AG049164 (Dr Hohman); UL1-TR000445 (Vanderbilt Clinical Translational Sci-ence Award); S10-OD023680 (Vanderbilt’s High-Performance Computer Clus-ter for Biomedical Research); and Vanderbilt Memory & Alzheimer’s Center.

DisclosuresNone.

REFERENCES 1. Mitchell GF, Parise H, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, Vasan RS,

Levy D. Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study. Hyperten-sion. 2004;43:1239–1245. doi: 10.1161/01.HYP.0000128420.01881.aa

2. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, Vita JA, Levy D, Benjamin EJ. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation. 2010;121:505–511. doi: 10.1161/CIRCULATIONAHA.109.886655

3. Singer J, Trollor JN, Baune BT, Sachdev PS, Smith E. Arterial stiffness, the brain and cognition: a systematic review. Ageing Res Rev. 2014;15:16–27. doi: 10.1016/j.arr.2014.02.002

4. Mitchell GF. Effects of central arterial aging on the structure and func-tion of the peripheral vasculature: implications for end-organ damage. J Appl Physiol (1985). 2008;105:1652–1660. doi: 10.1152/japplphysiol. 90549.2008

5. Xu TY, Staessen JA, Wei FF, Xu J, Li FH, Fan WX, Gao PJ, Wang JG, Li Y. Blood flow pattern in the middle cerebral artery in relation to indices of ar-terial stiffness in the systemic circulation. Am J Hypertens. 2012;25:319–324. doi: 10.1038/ajh.2011.223

6. Tarumi T, Shah F, Tanaka H, Haley AP. Association between central elastic artery stiffness and cerebral perfusion in deep subcortical gray and white matter. Am J Hypertens. 2011;24:1108–1113. doi: 10.1038/ajh.2011.101

7. Whitlock MC, Hundley WG. Noninvasive imaging of flow and vascular function in disease of the aorta. JACC Cardiovasc Imaging. 2015;8:1094–1106. doi: 10.1016/j.jcmg.2015.08.001

8. Holtzman DM, Fagan AM, Mackey B, Tenkova T, Sartorius L, Paul SM, Bales K, Ashe KH, Irizarry MC, Hyman BT. Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol. 2000;47:739–747.

9. Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, Zlokovic BV. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab. 2016;36:216–227. doi: 10.1038/jcbfm.2015.44

10. Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV. Apoli-poprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012;485:512–516. doi: 10.1038/nature11087

11. Alata W, Ye Y, St-Amour I, Vandal M, Calon F. Human apolipoprotein E ɛ4 expression impairs cerebral vascularization and blood-brain bar-rier function in mice. J Cereb Blood Flow Metab. 2015;35:86–94. doi: 10.1038/jcbfm.2014.172

12. DeCarli C, Reed T, Miller BL, Wolf PA, Swan GE, Carmelli D. Impact of apolipoprotein E epsilon4 and vascular disease on brain morphology in men from the NHLBI Twin Study. Stroke. 1999;30:1548–1553.

13. Wierenga CE, Clark LR, Dev SI, Shin DD, Jurick SM, Rissman RA, Liu TT, Bondi MW. Interaction of age and APOE genotype on cerebral blood flow at rest. J Alzheimers Dis. 2013;34:921–935. doi: 10.3233/JAD-121897

14. Thambisetty M, Beason-Held L, An Y, Kraut MA, Resnick SM. APOE epsi-lon4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol. 2010;67:93–98. doi: 10.1001/archneurol.2009.913

15. Jefferson AL, Gifford KA, Acosta LM, Bell SP, Donahue MJ, Davis LT, Gottli-eb J, Gupta DK, Hohman TJ, Lane EM, Libon DJ, Mendes LA, Niswender K, Pechman KR, Rane S, Ruberg FL, Su YR, Zetterberg H, Liu D. The Vander-bilt Memory & Aging Project: study design and baseline cohort overview. J Alzheimers Dis. 2016;52:539–559. doi: 10.3233/JAD-150914

16. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43:2412–2414.

17. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:270–279. doi: 10.1016/j.jalz.2011.03.008

18. Asman AJ, Landman BA. Non-local statistical label fusion for multi-atlas segmentation. Med Image Anal. 2013;17:194–208. doi: 10.1016/j.media.2012.10.002

19. Harrigan RL, Yvernault BC, Boyd BD, Damon SM, Gibney KD, Conrad BN, Phillips NS, Rogers BP, Gao Y, Landman BA. Vanderbilt University Institute of Imaging Science Center for Computational Imaging XNAT: a multimod-al data archive and processing environment. Neuroimage. 2016;124(pt B):1097–1101. doi: 10.1016/j.neuroimage.2015.05.021

20. Donahue MJ, Hussey E, Rane S, Wilson T, van Osch M, Hartkamp N, Hen-drikse J, Ally BA. Vessel-encoded arterial spin labeling (VE-ASL) reveals elevated flow territory asymmetry in older adults with substandard verbal memory performance. J Magn Reson Imaging. 2014;39:377–386. doi: 10.1002/jmri.24150

21. Donahue MJ, Faraco CC, Strother MK, Chappell MA, Rane S, Dethrage LM, Hendrikse J, Siero JC. Bolus arrival time and cerebral blood flow re-sponses to hypercarbia. J Cereb Blood Flow Metab. 2014;34:1243–1252. doi: 10.1038/jcbfm.2014.81

22. Jenkinson M, Smith S. A global optimisation method for robust affine registration of brain images. Med Image Anal. 2001;5:143–156.

23. Alsop DC, Detre JA, Golay X, Günther M, Hendrikse J, Hernandez-Garcia L, Lu H, MacIntosh BJ, Parkes LM, Smits M, van Osch MJ, Wang DJ, Wong EC, Zaharchuk G. Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: a consensus of the ISMRM Perfu-sion Study Group and the European Consortium for ASL in Dementia. Magn Reson Med. 2015;73:102–116. doi: 10.1002/mrm.25197

24. Jenkinson M, Beckmann CF, Behrens TE, Woolrich MW, Smith SM. FSL. Neuroimage. 2012;62:782–790. doi: 10.1016/j.neuroimage.2011.09.015

25. D’Agostino RB, Wolf PA, Belanger AJ, Kannel WB. Stroke risk profile: ad-justment for antihypertensive medication: the Framingham study. Stroke. 1994;25:40–43.

26. Wirth M, Pichet Binette A, Brunecker P, Köbe T, Witte AV, Flöel A. Diver-gent regional patterns of cerebral hypoperfusion and gray matter atro-phy in mild cognitive impairment patients. J Cereb Blood Flow Metab. 2017;37:814–824. doi: 10.1177/0271678X16641128

27. Mitchell GF, van Buchem MA, Sigurdsson S, Gotal JD, Jonsdottir MK, Kjar-tansson Ó, Garcia M, Aspelund T, Harris TB, Gudnason V, Launer LJ. Arte-rial stiffness, pressure and flow pulsatility and brain structure and func-tion: the Age, Gene/Environment Susceptibility–Reykjavik study. Brain. 2011;134(pt 11):3398–3407. doi: 10.1093/brain/awr253

28. Hajjar I, Zhao P, Alsop D, Novak V. Hypertension and cerebral vasoreactiv-ity: a continuous arterial spin labeling magnetic resonance imaging study. Hypertension. 2010;56:859–864. doi: 10.1161/HYPERTENSIONAHA. 110.160002

29. Peng SL, Chen X, Li Y, Rodrigue KM, Park DC, Lu H. Age-related chang-es in cerebrovascular reactivity and their relationship to cognition: a four-year longitudinal study. Neuroimage. 2018;174:257–262. doi: 10.1016/j.neuroimage.2018.03.033

30. Suri S, Mackay CE, Kelly ME, Germuska M, Tunbridge EM, Frisoni GB, Matthews PM, Ebmeier KP, Bulte DP, Filippini N. Reduced cerebrovascular reactivity in young adults carrying the APOE ε4 allele. Alzheimers Dement. 2015;11:648–657.e1. doi: 10.1016/j.jalz.2014.05.1755

31. Peila R, Rodriguez BL, Launer LJ; Honolulu-Asia Aging Study. Type 2 dia-betes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia Aging Study. Diabetes. 2002;51:1256–1262.

32. Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, Sekita A, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T. Insulin resistance is associated with the pathology of Alzheimer's disease: the Hisayama study. Neurol-ogy. 2010;75:764–770. doi: 10.1212/WNL.0b013e3181eee25f

33. Walker KA, Power MC, Hoogeveen RC, Folsom AR, Ballantyne CM, Knop-man DS, Windham BG, Selvin E, Jack CR Jr, Gottesman RF. Midlife sys-temic inflammation, late-life white matter integrity, and cerebral small vessel disease: the Atherosclerosis Risk in Communities Study. Stroke. 2017;48:3196–3202. doi: 10.1161/STROKEAHA.117.018675

34. Braak H, Braak E. Neuropathological stageing of Alzheimer-related chang-es. Acta Neuropathol. 1991;82:239–259.

35. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303–308.

36. Binnewijzend MA, Kuijer JP, Benedictus MR, van der Flier WM, Wink AM, Wattjes MP, van Berckel BN, Scheltens P, Barkhof F. Cerebral blood flow measured with 3D pseudocontinuous arterial spin-labeling MR imaging in Alzheimer's disease and mild cognitive impairment: a marker for disease severity. Radiology. 2013;267:221–230. doi: 10.1148/radiol.12120928

37. Cantin S, Villien M, Moreaud O, Tropres I, Keignart S, Chipon E, Le Bas JF, Warnking J, Krainik A. Impaired cerebral vasoreactivity to CO2 in Al-

Dow


ecember 11, 2018



ORIG

INAL

RES

EARC

H AR

TICL

E

zheimer’s disease using BOLD fMRI. Neuroimage. 2011;58:579–587. doi: 10.1016/j.neuroimage.2011.06.070

38. Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA. The neuropathol-ogy of probable Alzheimer's disease and mild cognitive impairment. Ann Neurol. 2009;66:200–208. doi: 10.1002/ana.21706

39. Niwa K, Porter VA, Kazama K, Cornfield D, Carlson GA, Iadecola C. A beta-peptides enhance vasoconstriction in cerebral circulation. Am J Physi-ol Heart Circ Physiol. 2001;281:H2417–H2424. doi: 10.1152/ajpheart. 2001.281.6.H2417

40. Niwa K, Kazama K, Younkin L, Younkin SG, Carlson GA, Iadecola C. Cerebrovascular autoregulation is profoundly impaired in mice over-expressing amyloid precursor protein. Am J Physiol Heart Circ Physiol. 2002;283:H315–H323. doi: 10.1152/ajpheart.00022.2002

41. Chow N, Bell RD, Deane R, Streb JW, Chen J, Brooks A, Van Nostrand W, Miano JM, Zlokovic BV. Serum response factor and myocardin mediate arterial hyper-contractility and cerebral blood flow dysregulation in Alzheimer’s phenotype. Proc Natl Acad Sci U S A. 2007;104:823–828. doi: 10.1073/pnas.0608251104

42. Marstrand JR, Garde E, Rostrup E, Ring P, Rosenbaum S, Mortensen EL, Larsson HB. Cerebral perfusion and cerebrovascular reactivity are reduced in white matter hyperintensities. Stroke. 2002;33:972–976.

43. Bakker SL, de Leeuw FE, de Groot JC, Hofman A, Koudstaal PJ, Breteler MM. Cerebral vasomotor reactivity and cerebral white matter lesions in the elderly. Neurology. 1999;52:578–583.

44. Terborg C, Gora F, Weiller C, Röther J. Reduced vasomotor reactivity in cerebral microangiopathy: a study with near-infrared spectroscopy and transcranial Doppler sonography. Stroke. 2000;31:924–929.

45. Jennings JR, Muldoon MF, Ryan C, Price JC, Greer P, Sutton-Tyrrell K, van der Veen FM, Meltzer CC. Reduced cerebral blood flow response and compensation among patients with untreated hypertension. Neu-rology. 2005;64:1358–1365. doi: 10.1212/01.WNL.0000158283. 28251.3C

46. Immink RV, van den Born BJ, van Montfrans GA, Koopmans RP, Kare-maker JM, van Lieshout JJ. Impaired cerebral autoregulation in patients with malignant hypertension. Circulation. 2004;110:2241–2245. doi: 10.1161/01.CIR.0000144472.08647.40

47. Brickman AM, Guzman VA, Gonzalez-Castellon M, Razlighi Q, Gu Y, Narkhede A, Janicki S, Ichise M, Stern Y, Manly JJ, Schupf N, Mar-shall RS. Cerebral autoregulation, beta amyloid, and white matter hy-perintensities are interrelated. Neurosci Lett. 2015;592:54–58. doi: 10.1016/j.neulet.2015.03.005

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