SYSTEMATIC REVIEW AND META-ANALYSIS Arterial Stiffness and Cognition Among Adults: A Systematic Review and Meta-Analysis of Observational and Longitudinal Studies Celia Alvarez-Bueno, PhD; Pedro G. Cunha, MD, PhD; Vicente Martinez-Vizcaino, MD, PhD; Diana P. Pozuelo-Carrascosa, PhD; Maria Eugenia Visier-Alfonso, MSc; Estela Jimenez-Lopez, PhD; Ivan Cavero-Redondo, PhD Background-—To estimate the strength of the cross-sectional and longitudinal association between arterial stiffness, measured by pulse-wave velocity, and cognitive function, distinguishing between global cognition, executive functions, and memory and to examine the influence of demographic, clinical, and assessment characteristics on this relationship. Methods and Results-—Systematic review of MEDLINE (via PubMed), Scopus, and WOS databases from their inception to March 2019, to identify cross-sectional and longitudinal studies on the association between pulse-wave velocity and cognitive domains (ie, global cognition, executive functions, and memory) among adult population. A total of 29 cross-sectional and 9 longitudinal studies support the negative relationship between arterial stiffness and cognitive function, including global cognition, executive function, and memory. Demographic, clinical, and assessment characteristics did not substantially modify the strength of this association. Conclusions-—Evidence reveals a negative association between arterial stiffness, measured using pulse-wave velocity, and cognition, specifically executive function, memory, and global cognition. This association seems to be independent of demographic, clinical, and assessment characteristics. These results accumulate evidence supporting that pulse-wave velocity assessment could be a useful tool to identify individuals at high risk of cognitive decline or early stages of cognitive decline, to implement interventions aimed at slowing the progression to dementia. ( J Am Heart Assoc. 2020;9:e014621. DOI: 10.1161/JAHA.119. 014621.) Key Words: cognitive impairment • executive function • global cognition • memory • pulse-wave velocity C ognitive impairment is becoming an important health concern as the older population continuously grows worldwide.1 The World Health Organization estimates that by among older people, deteriorating quality of life and producing physical, cognitive, and social disabilities.3 Some cardiovascular risk factors, such as hypertension, 2050, 2 billion people will be aged >60 years and the number diabetes mellitus, hypercholesterolemia, smoking status, and of people living with dementia will be 115.4 million.2 As such, adiposity, have been traditionally recognized as playing a cognitive impairment is one of the major causes of disability primary role in the vascular pathogenesis of cognitive impair- ment and dementia.4 In addition, previous research suggests that cerebral small-vessel disease is involved in the patho- From the Universidad de Castilla-La Mancha, Health and Social Research Center, Cuenca, Spain (C.A.-B., V.M.-V., D.P.P.-C., M.E.V.-A., E.J.-L., I.C.-R.); physiological characteristics of cognitive decline, vascular Internal Medicine Department, Center for the Research and Treatment of dementia, and Alzheimer disease.5 The cross talk between Arterial Hypertension and Cardiovascular Risk, Guimar~aes, Portugal (P.G.C.); large and small arterial vessels produces a vicious retrofeeding Facultad de Ciencias de la Salud, Universidad Autonoma de Chile, Talca, Chile cycle through which the action of mechanic, inflammatory, (V.M.-V); Department of Psychiatry, Hospital Virgen de La Luz, Cuenca, Spain (E.J.-L.); and CIBERSAM (Biomedical Research Networking Centre in Mental metabolic, epigenetic, and hemodynamic factors determines Health), Barcelona, Spain (E.J.-L.). arterial dysfunction and decreases arterial distensibility.6 Accompanying Data S1 and Tables S1 through S6 are available at https:// Therefore, arterial stiffness could be considered as an indirect www.ahajournals.org/doi/suppl/10.1161/JAHA.119.014621 measure of small-vessel damage that serves to evaluate not Correspondence to: Vicente Martinez-Vizcaino, Social and Health Care Research Center, Universidad de Castilla-La Mancha, Cuenca, Spain. E-mail: only the quality of brain microcirculation but also the influence vicente.martinez@uclm.es that systemic changes in large arteries can produce in Received September 17, 2019; accepted December 19, 2019. microcirculation; thus, arterial stiffness could be the link ª 2020 The Authors. Published on behalf of the American Heart Association, between vascular health and cognitive decline.7 Inc., by Wiley. This is an open access article under the terms of the Creative Pulse-wave velocity (PWV) is generally accepted as the most Commons Attribution-NonCommercial License, which permits use, distribu- tion and reproduction in any medium, provided the original work is properly simple, noninvasive, robust, and reproducible method to quantify cited and is not used for commercial purposes. arterial stiffness.7,8 PWV is an index closely related to vascular DOI: 10.1161/JAHA.119.014621 Journal of the American Heart Association 1 Arterial Stiffness and Cognition Among Adults Alvarez-Bueno et al SYSTEMATIC REVIEW AND META-ANALYSIS authors declare that all supporting data are available within this Clinical Perspective article and that institutional review board approval and informed consent of patients were not required as the data What Is New? used for this work have exclusively been extracted from • This systematic review and meta-analysis synthesizes the published studies. In addition, all the included trials complied cross-sectional and longitudinal association between arte- with the current ethical standards and the Declaration of rial stiffness, measured by pulse-wave velocity, and global Helsinki. cognition, executive functions, and memory. • Our data confirm a negative cross-sectional and longitudinal association between pulse-wave velocity and executive Data Sources and Searches function, memory, and global cognition, regardless of demographic, clinical, and assessment characteristics. A literature search was performed on Medline (via PubMed), Web of Science, and Scopus to identify studies on the What Are the Clinical Implications? association between arterial stiffness, measured using PWV, and cognitive function among adult people, to March 25, • Our results claim for the usefulness of pulse-wave velocity 2019. The search strategy included the following terms: assessment in the identification of individuals at high risk of cognitive decline or early stages of cognitive decline. “central blood pressure,” “arterial stiffness,” “pulse-wave velocity,” “PWV,” “endothelial function,” “cognition,” “execu- tive,” “executive function,” “cognitive control,” “memory,” aging that when increased has been negatively associated with “attention,” “metacognition,” “life skills,” “goal setting,” global cognition independently of traditional cardiovascular risk “problem solving,” “self-regulation,” “brain development,” factors.8–10 Although less studied, this association has also been “brain health,” “neural,” “neuroelectric,” “neurotrophic,” “neu- observed for different cognitive function domains, such as rotrophin,” and “BDNF.” In addition, the reference lists of executive functions and memory.11–13 included studies were reviewed for any relevant study. Previous systematic reviews and meta-analyses9,14,15 have examined the association between arterial stiffness and cognitive decline. However, the association between arterial Study Selection stiffness and clinically relevant cognitive domains as well as This systematic review includes studies on the relationship the potential moderating effect of some variables on this between arterial stiffness, as measured using PWV, and relationship remain unclear. Thus, the aims of this systematic cognitive function among adults. Inclusion criteria were as review and meta-analysis were to: (1) provide a pooled follows: (1) participants: adults; (2) exposure: arterial stiffness estimate of the strength of the cross-sectional association measured through PWV; (3) outcome: cognitive function, between arterial stiffness, measured by PWV, and cognitive including global cognition, executive function, and memory, function, distinguishing between global cognition, executive measured using standardized tests; and (4) study design: functions, and memory; (2) examine whether this association cross-sectional and longitudinal studies including at least 100 is confirmed by longitudinal studies; and (3) examine the participants. influence of demographic (ie, age, sex, and body mass index Studies were excluded when: (1) they were focused on [BMI]), clinical (ie, systolic blood pressure [SBP] and diastolic children or adolescents, (2) arterial stiffness was measured blood pressure [DBP]), and PWV characteristics (ie, type of using indicators other than PWV, or (3) they were written in measure and devices used to measure PWV) on the relation- languages other than English, French, Portuguese, or Spanish. ship between arterial stiffness and cognitive function. Data Extraction and Quality Assessment The main characteristics of the included studies were summa- Methods rized in tables, including information on: (1) subject character- The data that support the findings of this study are available istics (ie, sample size; percentage of women; mean age, BMI, from the corresponding author upon reasonable request. This SBP, and DBP; and type of sample), (2) exposure (ie, type of PWV systematic review and meta-analysis was conducted following measured [carotid-femoral PWV {cfPWV}, brachial-ankle PWV the Preferred Reporting Items for Systematic Reviews16 and {baPWV} or aortic PWV]), device used to measure PWV, and Meta-Analysis of Observational Studies in Epidemiology17 mean PWV, and (3) outcome information (ie, test used to statements and the Cochrane Collaboration Handbook.18 The measure cognitive function and cognitive domain measured). protocol for this systematic review and meta-analysis has been The Quality Assessment Tool for Observational Cohort and previously registered on PROSPERO: CRD42019121426. The Cross-Sectional Studies was used to evaluate the risk of DOI: 10.1161/JAHA.119.014621 Journal of the American Heart Association 2 Arterial Stiffness and Cognition Among Adults Alvarez-Bueno et al SYSTEMATIC REVIEW AND META-ANALYSIS bias.19 This tool evaluates 14 criteria for longitudinal studies; model based on the Der Simonian and Laird method.20 Fixed for cross-sectional designs only, 11 were applied. Each effects models were used when heterogeneity was not criterion could be scored as “yes” when the study achieves excessive.21 Heterogeneity across studies was assessed the criterion or “no” when the study does not achieve the using the I2 statistic,22 whose values were considered as criterion. Criteria could be also scored as “not reported” when follows: not important (0%–40%), moderate (30%–60%), sub- studies did not clearly report the required information. stantial (50%–90%), and considerable (75%–100%). Moreover, Literature search, data extraction, and risk of bias assess- the corresponding P values were also taken into account.18 ment were independently performed by 2 researchers (C.A.-B. Finally, the Cochran’s test was also used to evaluate the and I.C.-R.), and disagreements were solved by consensus or heterogeneity, being significative when P<0.1.18 involving a third researcher (V.M.-V.). Following similar procedures for longitudinal reports, we estimated the pooled ES for the association between the baseline PWV and the pre-post change in cognitive domains. Data Synthesis and Statistical Analysis In addition, when studies reported baseline associations To perform the meta-analysis, measures of association between PWV and cognitive function, these reports were between PWV and cognitive function were included in the included in the cross-sectional pooled ES estimates. analysis. Three cognitive domains were considered for the Some methodological issues should be pointed out. When statistical analysis: (1) global cognition, (2) executive func- studies provided ≥2 measurements for the same cognitive tions, and (3) memory. Separate analyses for unadjusted cross- domain, these measurements were combined to calculate a sectional, adjusted cross-sectional, and longitudinal associa- single pooled ES for the corresponding domain. For longitu- tions were conducted. Finally, data from studies reporting odds dinal and adjusted cross-sectional analyses, those including ratio or relative risk were narratively summarized. the largest number of covariates were considered. Finally, Effect sizes (ESs) and 95% CIs were calculated for each when studies reported mean value trends by groups or observed correlation using Cohen’s d index. A pooled ES was associations using regression models or correlation coeffi- estimated for each cognitive domain using a random-effects cients, ES values were calculated. Figure 1. Preferred Reporting Items for Systematic Reviews flowchart. DOI: 10.1161/JAHA.119.014621 Journal of the American Heart Association 3 Table 1. Characteristics of the Studies Included in the Systematic Review and Meta-Analysis on the Association Between Cognition Parameters and PWV Subjects Characteristics Exposure Outcome Type of Cognitive Cognitive References Women, n (%) Age, y BMI, kg/m2 SBP, mm Hg DBP, mm Hg Sample Type of PWV PWV Device PWV Average, m/s Measurement Construct Abbatecola et al, 140 (NR) Normoalbuminuric: Normoalbuminuric: Normoalbuminuric: Normoalbuminuric: Impaired cfPWV Pulse trace Normoalbuminuric: MMSE Global cognitive 200823 78.0 (5.0) 27.4 (2.4) 135.0 (19.0) 83.0 (8.0) glucose 6000 Micro 11.4 (2.1) Trail Making Tests (A function Microalbuminuric: Microalbuminuric: Microalbuminuric: Microalbuminuric: tolerance Medical Microalbuminuric: and B) Executive and 78.0 (4.0) 27.8 (2.2) 155.0 (20.0) 88.0 (9.0) 13.7 (3.1) Verbal Fluency Test attention function DOI: 10.1161/JAHA.119.014621 Wechsler Adult Memory Intelligence Scale- Mental tracking Revised Digit Span Al Hazzouri et al, 2488 (52.3) 74.2 (2.9) 27.4 NR NR General cfPWV Model 810-a NR 3MS Global cognitive 201524 population function Angermann et al, 201 (29.9) 64.5 (15.1) NR 123.8 (16.6) 74.7 (12.5) Patients cfPWV Mobil-O-Graph 9.4 (2.2) Montreal Cognitive Global cognitive Arterial Stiffness and Cognition Among Adults 201725 undergoing Assessment function hemodialysis Benetos et al, 873 (79.0) 88.0 (5.0) 25.8 (4.5) 138.0 (17.0) 73.0 (9.0) General cfPWV PulsePen 14.4 (5.0) MMSE Global cognitive 201226 population function Cooper et al, 1820 (60.0) 80.0 (5.0) 26.5 (3.9) 144.0 (22.0) 64.0 (10.0) General cfPWV NIHem WF 13.6 (4.6) California Verbal Immediate and 201611 population Learning Test delayed recall Digit Symbol Processing speed Substitution Test, Executive function Alvarez-Bueno et al Figure Comparison, and Stroop Test (parts I and II) Digits Backward and the Stroop Test (part III) Elias et al, 409 (62.3) 61.3 (12.8) 29.3 (6.0) 128.9 (19.7) 77.5 (10.1) General cfPWV SphygmoCor 10.2 (2.8) Block Design, Object Visual-spatial 200927 population Assembly, Visual organization and Reproductions memory Immediate and Scanning and Delayed, Hooper tracking Visual Organization Verbal episodic Test, Matrix memory Reasoning Working memory Trail Making Tests (A and B), Digit Symbol Substitution, Symbol Search Logical Memory Immediate and Delayed, Hopkins Verbal Learning Test Digit Span Forward and Backward, Letter-Number Sequence, Controlled Oral Word Associations Fukuhara et al, 203 (42.9) 85.0 22.7 (0.2) 144.3 (1.7) 78.8 (1.0) General baPWV VaSera 23.7 (0.4) MMSE Global cognitive Journal of the American Heart Association 200628 population VS-1000 function 4 Continued SYSTEMATIC REVIEW AND META-ANALYSIS Table 1. Continued Subjects Characteristics Exposure Outcome Type of Cognitive Cognitive References Women, n (%) Age, y BMI, kg/m2 SBP, mm Hg DBP, mm Hg Sample Type of PWV PWV Device PWV Average, m/s Measurement Construct Geijselaers et al, 396 (54.6) 60 (8) 27.2 (4.4) 128 (14) 76 (7) General cfPWV SphygmoCor 8.9 (2.1) Verbal Learning Test Free recall 201629 population Stroop Color Word memory Test (parts I and II), Processing speed the Concept Shifting Executive function Test Part A and B, and attention DOI: 10.1161/JAHA.119.014621 and the Letter-Digit Substitution Test Stroop Color Word Test (part III) and the Concept Shifting Test Part C, Letter- Digit Substitution test Arterial Stiffness and Cognition Among Adults Hajjar et al, 591 (68.0) 48.8 (9.7) 28.0 (6.6) 121.0 (24.3) 77.0 (12.2) General cfPWV SphygmoCor 7.2 (1.5) Mental flexibility Executive 201612 population SPOTING the symbol function Digit Symbol Memory Substitution Test Working Digit Span Forward memory Executive Function Test Focused Attention Alvarez-Bueno et al Sustained Attention Delayed Memory Recall Visual Spatial Memory Visual Spatial Short- Term Recall Digit Span Backwards Hanon et al, 308 (64.3) NCF: 75.0 (8.0) NCF: 24.4 (4.0) NCF: 139.0 (18.0) NCF: 79.0 (11.0) Subjects cfPWV Complior NCF: 11.5 (2.0) MMSE Global cognitive 200530 MCI: 77.0 (8.0) MCI: 25.0 (4.0) MCI: 142.0 (17.0) MCI: 80.0 (9.0) with MCI: 12.6 (2.6) Cognitive Efficiency function AD: 80.0 (7.0) AD: 24.0 (4.0) AD: 145.0 (20.0) AD: 81.0 (12.0) complaint AD: 13.3 (2.9) Profile Cognitive VaD: 81.0 (7.0) VaD: 24.0 (4.0) VaD: 159.0 (21.0) VaD: 82.0 (13.0) of memory VaD: 15.2 (3.9) efficiency loss profile Karasavvidou 151 (33.6) 57.08 (13.7) 28.2 (5.1) 137.2 (18.1)– 77.4 (11.3)– Patients with cfPWV SphygmoCor 6.1 (1.9)– MMSE Global cognitive et al, 201831 142.8 (12.8) 84.7 (9.8) kidney 6.9 (2.3) function disease Kim et al, 370 (51.6) 55.2 (7.3) 24.4 (5.1) 130.8 (16.4) 80.4 (9.3) General baPWV Plethysmographic 15.3 (2.9) Korean version of Global cognitive 200932 population device the mini-mental function state examination (K-MMSE) Kim et al, 333 (42.0) 55.0 (13.0) NR NR NR Patients cfPWV SphygmoCor 10.0 (7.9–12.5) Trail Making Tests (A Executive function 201733 undergoing and B) Global cognitive hemodialysis 3MS function Lamballais et al, 5187 (42.9) 58.8 (7.3)– 26.8 (3.8)– 130 (18)– 80 (10)–86 (10) General cfPWV Complior 9.1 (1.6)– Color-Word G-factor 201834 63.6 (5.7) 27.4 (4.3) 150 (20) population 13.0 (2.8) Interference Stroop Task Letter Digit Substitution Test Verbal Fluency Test Delayed Recall Journal of the American Heart Association Purdue Pegboard Test 5 Continued SYSTEMATIC REVIEW AND META-ANALYSIS Table 1. Continued Subjects Characteristics Exposure Outcome Type of Cognitive Cognitive References Women, n (%) Age, y BMI, kg/m2 SBP, mm Hg DBP, mm Hg Sample Type of PWV PWV Device PWV Average, m/s Measurement Construct Lee et al, 201435 102 (29.0) 61.0 (9.0) 24.0 (4.0) 124.0 (13.0) 77.0 (9.0) Stroke patients cfPWV SphygmoCor 10.0 (2.0) K-MMSE Global cognitive function Lim et al, 201613 463 (43.2) MMSE MMSE NR NR General cfPWV SphygmoCor MMSE participants: MMSE Global cognitive DOI: 10.1161/JAHA.119.014621 participants: participants: population 5.0 (2.6–14.1) Digit Span-Forward function 63.0 (6.1) 25.0 (4.1) Neurocognitive Color Trails Test 1 Attention Neurocognitive Neurocognitive domain test Rey Auditory Verbal Verbal memory domain test domain test participants: Learning Test, Story Language function participants: participants: 4.9 (3.0–13.0) Memory and Recall Visuospatial ability 64.2 (6.4) 24.6 (3.5) Boston Naming Test Executive function Brief Visuospatial Memory Test- Arterial Stiffness and Cognition Among Adults Revised Digit Span- Backward Block Design, Color Trails Test 2 Categorical Verbal Fluency Mitchell et al, 668 (56.6) Women: 75.0 (4.0) Women: Women: Women: General cfPWV NIHem WF Women: 12.2 (3.7) California Verbal Memory 201136 Men: 76.0 (4.0) 27.0 (4.0) 141.0 (20.0) 67.0 (9.0) population Men: 13.4 (4.4) Learning Test Processing speed Men: 27.0 (4.0) Men: Men: Digits Forward Executive function Alvarez-Bueno et al 137.0 (18.0) 67.0 (10.0) Digit Symbol Global cognitive Substitution Test function Figure Comparison Stroop Test (parts I and II) Digits Backwards Cambridge Neuropsychological Test Automated Battery Spatial Working Memory Stroop Test (part III) MMSE Muela et al, 211 (55.0) Normotension: Normotension: Normotension: Normotension: Patients with cfPWV Complior Normotension: MMSE Global cognitive 201837 52.2 (13.9) 26.7 (4.2) 121.9 (8.3) 76.5 (6.9) hypertension 7.5 (1.4) Montreal Cognitive function Hypertension Hypertension Hypertension Hypertension Hypertension Assessment Boston Language function stage 1: stage 1: stage stage 1: stage Naming Test Episodic memory 52.1 (13.0) 28.5 (4.6) 1: 135.0 (13.5) 83.1 (9.9) 1: 7.9 (1.2) Rey-Osterrieth Executive function Hypertension Hypertension Hypertension Hypertension Hypertension Complex Delayed Attention stage 2: stage stage 2: stage 2: stage 2: 7.9 (1.2) Recall Visuospatial 52.3 (10.1) 2: 30.1 (4.6) 147.5 (26.1) 90.3 (14.5) Semantic Verbal abilities Fluency animal Processing speed category Backward Digit Span Test Phonological Verbal Fluency Trail Making Test B Forward Digit Span Test Trail Making Test A Journal of the American Heart Association Clock Drawing Test Rey Auditory Verbal 6 Continued SYSTEMATIC REVIEW AND META-ANALYSIS Table 1. Continued Subjects Characteristics Exposure Outcome Type of Cognitive Cognitive References Women, n (%) Age, y BMI, kg/m2 SBP, mm Hg DBP, mm Hg Sample Type of PWV PWV Device PWV Average, m/s Measurement Construct Learning Test Digit Symbols Substitution Test Muller et al, 396 (0.0) No CVD: 54.5 (10.3) No CVD: No CVD: NR General cfPWV SphygmoCor No CVD: MMSE Global cognitive DOI: 10.1161/JAHA.119.014621 200738 Subclinical 25.9 (0.3) 134.2 (1.3) population Acuson Aspen 8.5 (0.2) Rey Auditory Verbal function CVD: 66.8 (8.1) Subclinical CVD: Subclinical CVD: Subclinical Learning Test Verbal episodic Prevalent 26.5 (0.3) 145.5 (1.7) CVD: 10.7 Doors Test memory CVD: 67.7 (8.8) Prevalent CVD: Prevalent CVD: (0.2) Digit Span Test Memory 27.3 (0.5) 140.2 (2.5) Prevalent List of nouns Visual memory CVD: 10.2 Digit Symbol Short-term (0.3) Substitution Test memory and Arterial Stiffness and Cognition Among Adults Trail Making Test (A working memory and B) Verbal fluency Dutch Adult Reading Cognitive and Test perceptual speed Attention and mental flexibility IQ Nilsson et al, 2637 (60.8) 72.1 (5.6) NR 135.6 (17.1) 75.6 (8.7) General cfPWV SphygmoCor 10.5 (2.5) MMSE Global cognitive 201439 population Quick test of cognitive function Alvarez-Bueno et al speed (AQT) Perceptual and cognitive speed Palta et al, 3703 (59.3) 75.2.(5.0) 27.8 (4.4) 129.9 (17.2) NR General cfPWV VP-1000 Plus NR Delayed word recall Memory 201940 population Logical memory Executive function/ Incidental learning processing Digit Symbol speed Substitution Test Language function Trail Making Test Digit Span Backwards Semantic and phonemic fluency Boston Naming Test Pase et al, 3207 (53.1) 46.0 (9.0) NR 116.0 (14.0) 74.0 (9.0) General cfPWV NIHem WF 6.8 (6.1–7.7) Trail Making Test (A Processing speed 201641 population and B) and executive Victoria Stroop function interference task Long-term storage Logical Memory and retrieval delayed Visual processing Visual Reproductions Working memory delayed Hooper visual organization test (VOT) Digit Span Forward and Backward Poels et al, 3714 (57.7) 72.0 (6.7) 26.8 (4.0) NR NR General cfPWV Complior 13.5 (3.0) MMSE Global cognitive 200742 population Letter-Digit function Substitution Task Executive function Stroop Test Word Fluency Test Journal of the American Heart Association Continued 7 SYSTEMATIC REVIEW AND META-ANALYSIS Table 1. Continued Subjects Characteristics Exposure Outcome Type of Cognitive Cognitive References Women, n (%) Age, y BMI, kg/m2 SBP, mm Hg DBP, mm Hg Sample Type of PWV PWV Device PWV Average, m/s Measurement Construct Ryu et al, 123 (70.7) PD-NC: 67.0 (9.6) NR NR NR Patients with baPWV VP 1000 PD-NC: 15.3 (3.0) MMSE Global cognitive 201743 PD-MCI: 70.1 (6.9) Parkinson PD-MCI: 18.7 (4.7) Seoul function PD-D: 73.9 (8.8) disease PD-D: 21.4 (4.1) Neuropsychological Language function DLB: 77.4 (4.9) and Lewy DLB: 21.2 (7.0) Screening Battery: Calculation DOI: 10.1161/JAHA.119.014621 AD: 76.2 (9.2) body AD: 20.4 (5.1) Korean-Boston Visuospatial disorders Naming Test and function and Digit Span Test memory Rey Complex Memory Figure Test Calculation test Seoul Verbal Learning Arterial Stiffness and Cognition Among Adults Test Control Oral Word Association Test Scuteri et al, 102 (70.2) 79.0 (6.0) 25.7 (4.1) 135.9 (19.2) 78.5 (11.9) Patients with cfPWV Complior 13.5 (2.2) MMSE Global cognitive 200744 complaints of function memory loss Singer et al, 319 (51.7) 79.6 (4.2) 26.7 (4.1) 140.9 (19.3) NR General cfPWV SphygmoCor 11.2 (2.4) Digit Symbol Coding Processing speed 201345 population and Trail Making Memory Alvarez-Bueno et al Test A Logical Language function Memory Story A Executive function (delayed) Visuospatial ability Rey Auditory Visual Verbal Learning Test Benton Visual Retention Test Animal Naming and the 30-item Boston Naming Test Phonemic Fluency (FAS) Trail Making Test B Stroop Test Block Design Triantafyllidi 110 (47.0) 56.1 (10.0) 29.7 (4.0) 147.0 (17.0) 88.0 (10.0) Patients with cfPWV Complior SP 10.1 (8.8, 11.2) MMSE Global cognitive et al, 200946 essential function hypertension Tsao et al, 1587 (55.0) 61.0 (9.0) NR 126.0 (19.0) 74.0 (10.0) General cfPWV SPT-301 9.0 (7.6, 11.0) Logical memory Memory 201347 population delayed Executive function Trail Making Test (A and B) Tsao et al, 1223 (56.0) 62.0 (9.0) NR 125.0 (18.0) NR General cfPWV SPT-301 9.0 (7.6, 10.9) Trail Making Test (A Executive function 201648 population and B) Abstract reasoning Similarities test Continued Journal of the American Heart Association 8 SYSTEMATIC REVIEW AND META-ANALYSIS Arterial Stiffness and Cognition Among Adults Alvarez-Bueno et al SYSTEMATIC REVIEW AND META-ANALYSIS 3MS indicates modified MMSE; aPWV, aortic PWV; AD, Alzheimer disease; baPWV, brachial-ankle PWV; BMI, body mass index; cfPWV, carotid-femoral PWV; CVD, cardiovascular disease; DBP, diastolic blood pressure; DLB, dementia with Lewy bodies; IQ, intelligence quotient; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; NCF, normal cognitive function; NR, not reported; PD-D, Parkinson disease with dementia; PD-MCI, Parkinson disease with MCI; Sensitivity analyses were performed excluding studies one by Verbal learning and Executive function, Perceptual speed Global cognitive Global cognitive attention, and one from the pooled estimates, to evaluate whether any Psychomotor Psychomotor speed and sustained attention particular study modified the original summary estimate. Meta- memory function function Construct Language Cognitive Memory speed speed regressions were calculated on the basis of sample character- istics: percentage of women and mean age, BMI, SBP, and DBP. Subgroup analyses were performed by: (1) type of sample Trail Making Test (A Verbal Fluency Test Rey Auditory Verbal Substitution Test Buschke Selective Pattern and Letter Reminding Test Boxes and Digit Learning Test identified, considering general population or specific disease Measurement Comparison Digit Symbol group; (2) type of PWV measured (baPWV or cfPWV), and (3) Copying Cognitive Outcome and B) MMSE device used to measure PWV, distinguishing between 3MS SphygmoCor, Complior, and others (including Pulse Trace PWV Average, m/s 6000 Micro Medical, model 810-a, Mobil-O-Graph, PulsePen, NIHem WF, VaSera VS-1000, plethysmographic device, SPT- 8.9 (3.9) 11 (3.6) 301, and Doppler-recorded model 810A). Finally, publication bias was estimated using Egger0 s test. model 810A Complior SP PWV Device Results recorded Doppler- Systematic Review The search retrieved 3957 studies, from which 29 cross- Type of PWV sectional studies* and 9 longitudinal studies† reported data Exposure cfPWV aPWV on the association between arterial stiffness and cognition (Figure 1). Studies involved 43 115 participants (Tables 1 and 2). The list of the excluded studies is available in Data S1. population population PD-NC, Parkinson disease with normal cognition; PWV, pulse-wave velocity; SBP, systolic blood pressure; VaD, vascular dementia. General General Type of Sample For participants’ characteristics: (1) 12 studies reported data from specific disease populations; (2) mean age ranged from 46.0 to 85.0 years; (3) mean BMI ranged from 22.7 to 30.2 kg/m2; (4) mean SBP ranged from 116.0 to 159.0 mm DBP, mm Hg Hg; and (5) mean DBP ranged from 64.0 to 90.3 mm Hg. PWV was measured using cfPWV procedures in all studies, NR NR but 4 that used baPWV and 1 that used aortic PWV. The reported mean PWV ranged from 4.9 to 6.9 m/s for cfPWV and from 15.3 to 23.7 for baPWV. The devices used to SBP, mm Hg measure PWV varied across studies, although SphygmoCor NR NR and Complior were the most widely used devices. The tests used to measure cognitive function aimed to cfPWV >12 m/s: measure global cognition, executive function, memory, lan- BMI, kg/m2 30.7 (5.7) 30.0 (5.5) >12 m/s: guage, attention, processing speed, and visuospatial ability. 27.0 (4.6) No cfPWV Meta-Analysis No cfPWV >12 m/s: cfPWV >12 m/s: The unadjusted pooled ES values for the cross-sectional 73.3 (6.4) 78.4 (7.5) associations were 0.53 (95% CI, 0.67 to 0.39) for global 73.1 (2.7) Age, y Subjects Characteristics cognition, 0.35 (95% CI, 0.50 to 0.19) for executive function, and 0.39 (95% CI, 0.70 to 0.09) for memory. Women, n (%) The adjusted pooled ES values were 0.21 (95% CI, 0.30 to 1394 (57.2) 552 (52.5) Table 1. Continued 0.11) for global cognition, 0.08 (95% CI, 0.14 to 0.03) for executive function, and 0.13 (95% CI, 0.20 to 0.05) for memory (Figures 2 and 3). Watson et al, Zhong et al, References 201149 201450 *References 11, 13, 23, 25, 27–32, 34–39, 41, 43, 45–47, 50–57. † References 12, 24, 26, 33, 40, 42, 44, 48, 49. DOI: 10.1161/JAHA.119.014621 Journal of the American Heart Association 9 Table 2. Characteristics of the Studies Included in the Systematic Review and Meta-Analysis on the Association Between Cognition Parameters and PWV for Studies Reporting OR and RR Subjects Characteristics Exposure Outcome Cognitive Cognitive References Women, n (%) Age, y BMI, kg/m2 SBP, mm Hg DBP, mm Hg Type of Sample Type of PWV PWV Device PWV Average Measurement Construct DOI: 10.1161/JAHA.119.014621 Fujiwara et al, 200551 352 (61.1) MMSE <24: 75.0 MMSE <24: 22.8 MMSE <24: 155.2 MMSE <24: 84.8 General population baPWV AT-Form NR MMSE Global cognitive (4.6) (3.3) (20.3) (10.1) function MMSE >24: 76.9 MMSE >24: 23.2 MMSE >24: 147.2 MMSE >24: 84.5 (5.6) (3.2) (22.0) (11.0) Kearney-Schwartz 198 (52.0) 69.3 (6.2) 27.8 (4.3) 129.0 (12.0) 75.0 (9.0) Hypertensive cfPWV Complior NR Cognitive Global cognitive et al, 200952 patients with IOTEC Difficulties Scale function subjective of McNair Immediate and Arterial Stiffness and Cognition Among Adults memory MMSE delayed complains Grober-Buschke memory and Test language Benton Visual Visuoperceptual Retention Test and visuospatial Praxies scale Praxies Verbal Fluency Test Executive function and long-term verbal memory Alvarez-Bueno et al Meyer et al, 201753 4461 (58.8) White normal: 75.2 White normal: 27.7 White normal: White normal: 65.7 General population cfPWV VP-1000 Plus NR Digit Symbol Global cognitive (4.9) (4.4) 128.5 (17.0) (10.1) Substitution Test function White MCI: 76.8 White MCI: 27.6 White MCI: 130.6 White MCI: 65.1 Word recall task memory (5.2) (4.4) (18.3) (10.7) Word Fluency Test White dementia: White dementia: White dementia: White dementia: scores 78.7 (5.1) 26.6 (4.3) 133.3 (17.4) 65.1 (9.6) Black normal: 74.0 Black normal: 29.4 Black normal: Black normal: 70.0 (4.7) (4.8) 133.3 (18.0) (10.1) Black MCI: 75.8 Black MCI: 29.1 Black MCI: 135.2 Black MCI: 69.2 (5.1) (4.8) (18.8) (10.9) Black dementia: Black dementia: Black dementia: Black dementia: 79.4 (4.5) 26.4 (4.8) 135.6 (19.1) 68.7 (10.7) Nilsson et al, 201754 3056 (60.5) No dementia: 71.8 NR No dementia: No dementia: 75.7 General population cfPWV SphygmoCor No dementia: 10.5 MMSE Global cognitive (5.5) 135.6 (17.1) (8.7) (2.4) AQT Color-Form function Prevalent Prevalent Prevalent Prevalent dementia: dementia: 76.3 dementia: 136.5 dementia: 11.2 (2.6) (4.7) (18.8) 75.6 (12.3) Incident dementia: Incident dementia: Incident dementia: Incident dementia: 11.3 (2.7) 75.8 (4.7) 137.8 (17.9) 74.6 (8.6) Sugawara et al, 388 (64.2) Poor cognition: Poor cognition: Poor cognition: NR General population baPWV Form PWV/ABI Poor cognition: MMSE Global cognitive 201055 70.1 (4.9) 23.5 (3.3) 137.6 (17.8) 18.4 (4.1) function Control: 68.3 (5.6) Control: 23.3 (2.9) Control: 136.8 Control: 17.4 (3.0) (17.3) Taniguchi et al, 526 (57.8) 71.7 (5.6) Cognitive decline: Cognitive decline: Cognitive decline: General population baPWV BP-203 RPE III Cognitive decline: MMSE Global cognitive 201556 23.3 (2.9) 133.0 (20.0) 77.0 (11.0) 19.3 (3.8) function No cognitive No cognitive No cognitive No cognitive decline: 23.3 decline: 128.0 decline: 75.0 decline: 17.5 (3.3) (18.0) (11.0) (3.5) Journal of the American Heart Association Continued 10 SYSTEMATIC REVIEW AND META-ANALYSIS Arterial Stiffness and Cognition Among Adults Alvarez-Bueno et al SYSTEMATIC REVIEW AND META-ANALYSIS baPWV indicates brachial-ankle PWV; BMI, body mass index; cfPWV, carotid-femoral PWV; DBP, diastolic blood pressure; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; NR, not reported; OR, odds ratio; RR, relative The pooled ES values for the longitudinal association of PWV and global cognition, executive function, and memory Global cognitive were 0.21 (95% CI, 0.36 to 0.06), 0.12 (95% CI, 0.22 Construct Cognitive function to 0.02), and 0.05 (95% CI, 0.12 to 0.03), respectively (Figure 4). Measurement Cognitive Sensitivity analysis Outcome MMSE Sensitivity analysis showed that: (1) for the unadjusted analysis, pooled ES for memory was modified after excluding Muela et al37 study; (2) for the adjusted analysis, pooled ES diabetic foot: 14.3 for memory was modified after excluding Palta et al40 study; without diabetic foot: 11.9 (2.6) Diabetic subjects Healthy controls: PWV Average Subjects with and (3) the longitudinal pooled ES for executive functions was 9.2 (1.9) modified after removing 2 studies (Hajjar et al12 and Tsao (3.8) et al48) and for memory after removing the 3 studies included (Hajjar et al,12 Kim et al,33 and Poels et al42) (Tables S1 PWV Device SphygmoCor through S3). Subgroup analyses and meta-regressions Type of PWV Subgroup analyses by type of sample, type of PWV (ie, cfPWV, Exposure baPWV, and aortic PWV), and type of device (ie, SphygmoCor, cfPWV Complior, and others) are displayed in Table S4. Pooled ES values were not substantially different in any of the subgroup analyses. Patients with type Type of Sample Meta-regressions with longitudinal, unadjusted, and 2 diabetes mellitus adjusted cross-sectional analyses showed that none any of the considered variables (ie, percentage of women and mean age, BMI, SBP, and DBP) influences the relationship between foot: 70.9 (11.2) without diabetic Diabetic subjects arterial stiffness and cognitive function (Table S5). Healthy controls: diabetic foot: DBP, mm Hg Subjects with 67.9 (10.7) 71.3 (12.7) Publication Bias Publication bias, evaluated by Egger0 s test and funnel plot foot: 124.5 (16.8) without diabetic Diabetic subjects Healthy controls: diabetic foot: 135.0 (21.8) 116.3 (13.4) asymmetry, was found in the unadjusted cross-sectional SBP, mm Hg Subjects with analysis for global cognition (P=0.097) and in the adjusted cross-sectional analysis for memory (P=0.035). without diabetic foot: 29.9 (4.5) Diabetic subjects Healthy controls: diabetic foot: Risk of Bias Subjects with BMI, kg/m2 30.2 (6.4) 25.1 (4.3) Cross-sectional studies scored between 4 and 9 points, and longitudinal studies scored between 8 and 12 points. The 4 risk; PWV, pulse-wave velocity; SBP, systolic blood pressure. criteria in which most articles lacked information were: (1) foot: 60.6 (12.5) without diabetic Diabetic subjects Healthy controls: diabetic foot: sample size justification, power description, or variance; (2) Subjects with 61.6 (10.1) 63.0 (13.9) whether the measurement of the exposure of interest Age, y Subjects Characteristics precedes that of the outcome; (3) whether the outcome assessors were blinded to the exposure status of participants; Women, n (%) and (4) whether the participation rate of eligible people was at 153 (42.5) least 50% (Table S6). Table 2. Continued Tuttolomondo et al, Discussion References 201757 The relationship between arterial stiffness and cognition has been repeatedly reported, but mostly always has analyzed DOI: 10.1161/JAHA.119.014621 Journal of the American Heart Association 11 Arterial Stiffness and Cognition Among Adults Alvarez-Bueno et al SYSTEMATIC REVIEW AND META-ANALYSIS Figure 2. Forest plot for the unadjusted cross-sectional association between arterial stiffness, measured by pulse-wave velocity, and cognitive function domains. ES indicates effect size. cognition as a dimensionless construct. To our knowledge, Despite the scarcity of longitudinal studies included in each this is the first meta-synthesis elucidating this relationship, specific cognitive function, the general observed effect sug- distinguishing between the several domains that integrate the gests that arterial stiffness contributes to deteriorate global cognitive function construct. Our results support the negative cognition and executive function. Thus, these findings indicate relationship between arterial stiffness with each cognitive that interventions aimed to reduce arterial stiffness could help domain, including global cognition, executive function, and to delay or prevent cognitive impairment.59 Loss of memory is memory. Furthermore, analyses of longitudinal studies con- one of the most important reasons for consultations among firm this negative association. Finally, demographic (age, sex, people experiencing cognitive decline.60 However, more longi- and type of sample), clinical (BMI, SBP, DBP, or PWV), and tudinal research is needed to further elucidate on the potential assessment characteristics (type of measure and type of effects and mechanisms of arterial stiffness on memory. device) did not substantially modify the strength of this The negative association between arterial stiffness and association. cognitive function was maintained after controlling for Executive function has been defined as one of the cognitive covariates, such as age, sex, educational level, depression domains primarily affected by vascular aging.39 In addition, scale score, or cardiovascular risk factors, related to cognitive global cognition and memory are closely related to both vascular decline and vascular aging. Moreover, the consistency of aging and arterial stiffness, and it is clinically relevant to these associations was strengthened by the findings from measure cognitive decline and memory loss.32,58 Although some longitudinal studies, regardless of the duration of follow-up.61 tests, such as the Mini-Mental State Examination, lack sensi- Cardiovascular risk factors, such as diabetes mellitus, hyper- tivity to reflect small cognitive changes, the results of our cross- tension, or smoking, that influence the relationship between sectional meta-analyses are consistent with previous findings, cognitive function and arterial stiffness were also considered and confirm global cognition and memory as specific cognitive in some included studies.14 Finally, some studies accounted functions negatively associated with arterial stiffness.9,14 for additional factors not usually studied, such as DOI: 10.1161/JAHA.119.014621 Journal of the American Heart Association 12 Arterial Stiffness and Cognition Among Adults Alvarez-Bueno et al SYSTEMATIC REVIEW AND META-ANALYSIS Figure 3. Forest plot for the adjusted cross-sectional association between arterial stiffness, measured by pulse-wave velocity, and cognitive function domains. ES indicates effect size. apolipoprotein E 4 status, intracranial volume, estimated these covariates. However, individual subclinical cardiovascu- glomerular filtration rate, or minutes of leisure-time physical lar health factors could partially explain the present results.62 activity. Our findings indicate that the association between Arterial stiffness has been associated with brain damage and arterial stiffness and cognitive function is not confounded by cognitive decline through several mechanisms. First, it has DOI: 10.1161/JAHA.119.014621 Journal of the American Heart Association 13 Arterial Stiffness and Cognition Among Adults Alvarez-Bueno et al SYSTEMATIC REVIEW AND META-ANALYSIS Figure 4. Forest plot for the longitudinal association between arterial stiffness, measured by pulse-wave velocity, and cognitive function domains. ES indicates effect size. been proposed that cerebral small vessels offer low resistance cardiovascular outcomes and cognitive decline. However, to the high-pressure fluctuations from large arteries, and this further studies using a neuroimaging approach are needed to flow transmission could damage small vessels, resulting in overcome the limitations of the research published until now, cognitive function decline.63 Second, small vessels tend to such as small sample sizes, different covariates adjusted in progressively reduce their diameter to counteract changes in the analysis, and short follow-up times. pulse pressure. This strategy increases microvascular resis- Some limitations of this systematic review and meta- tance and, therefore, may result in cognitive damage.64 Finally, analysis may make us consider these findings with caution. some genetic factors, such as increased b-amyloid levels, First, there are limitations from meta-analysis design, such as mediated by the presence of the apolipoprotein E e4 allele may publication bias and selection bias. Additional sources of bias induce vascular damage and cognitive decline.65,66 could be: (1) the pooled ES was not estimated using the The results from this study confirm that arterial stiffness, original data, but those reported in the included articles, (2) measured by PWV, is a predictor of cognitive decline. the methods and tools used to measure cognitive function Furthermore, this study shows that this association is widely varied across the included studies, (3) substantial independent of specific demographic and PWV characteris- heterogeneity was found among the included studies, (4) tics. PWV is a low-cost, accurate, and easy method to publication bias was found for some of the observed determine arterial stiffness and, therefore, vascular outcomes, (5) a cause-effect could not be inferred from the aging.14,62,67 Tools for early cognitive decline detection may cross-sectional analyses, and (6) language restrictions may be relevant from a global and public health perspective, given have limited the number of included studies. Finally, to include that the onset of cognitive decline at early ages is associated a sample as large as possible, populations included in this with higher rates of progression to dementia.59,68 Thus, PWV meta-analysis come from different settings and vary across assessment could be included as a routine examination in studies, but the data of our meta-analysis corroborate findings adults at high risk for cognitive decline. Therefore, hemody- of the FHS (Framingham Heart Study)11 and the SLAS namic measurements, such as PWV, should be included in the (Singapore Longitudinal Ageing Studies),13 precluding an prevention and control indexes for healthy adults at risk of enlarged (transcontinental) external validity of results. DOI: 10.1161/JAHA.119.014621 Journal of the American Heart Association 14 Arterial Stiffness and Cognition Among Adults Alvarez-Bueno et al SYSTEMATIC REVIEW AND META-ANALYSIS 14. Singer J, Trollor JN, Baune BT, Sachdev PS, Smith E. Arterial stiffness, the brain Conclusions and cognition: a systematic review. Ageing Res Rev. 2014;15:16–27. In conclusion, this systematic review and meta-analysis 15. van Sloten TT, Protogerou AD, Henry RM, Schram MT, Launer LJ, Stehouwer CD. Association between arterial stiffness, cerebral small vessel disease and reveals a negative association between arterial stiffness, cognitive impairment: a systematic review and meta-analysis. Neurosci measured using PWV, and cognition, specifically executive Biobehav Rev. 2015;53:121–130. 16. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting function, memory, and global cognition. This association items for systematic reviews and meta-analyses: the PRISMA statement. PLoS seems to be independent of sex, age, blood pressure levels, Med. 2009;6:e1000097. and PWV measurement characteristics. Separate analyses of 17. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thecker SB; for the Meta-analysis Of Observational longitudinal studies support the negative association between Studies in Epidemiology (MOOSE) Group. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2008;283:2008– arterial stiffness and cognitive function found in cross- 2012. sectional studies. Our results accumulate evidence supporting 18. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of that PWV assessment could be a useful tool to identify Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collabora- tion, 2011. Available at: www.handbook.cochrane.org. individuals at high risk of cognitive decline or early stages of 19. National Heart, Lung, and Blood Institute. Quality assessment tool for cognitive decline, to implement interventions aimed at observational cohort and cross-sectional studies. https://www.nhlbi.nih.gov/ health-topics/study-quality-assessment-tools. Accessed January 31, 2018. slowing the progression to dementia. 20. DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials. 2007;28:105–114. 21. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–748. Sources of Funding 22. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat This study was funded by Apadrina la Ciencia funds. Med. 2002;21:1539–1558. 23. Abbatecola AM, Barbieri M, Rizzo MR, Grella R, Laieta MT, Quaranta E, Molinari AM, Cioffi M, Fioretto P, Paolisso G. Arterial stiffness and cognition in elderly persons with impaired glucose tolerance and microalbuminuria. J Gerontol A Disclosures Biol Sci Med Sci. 2008;63:991–996. 24. Al Hazzouri AZ, Vittinghoff E, Sidney S, Reis JP, Jacobs DR Jr, Yaffe K. Intima- None. media thickness and cognitive function in stroke-free middle-aged adults: findings from the Coronary Artery Risk Development in Young Adults Study. Stroke. 2015;46:2190–2196. References 25. Angermann S, Baumann M, Wassertheurer S, Mayer CC, Steubl D, Hauser C, Suttmann Y, Reichelt AL, Satanovskij R, Lorenz G, Lukas M, Haller B, 1. The World Health Report: Primary Health Care Now More Than Ever. Geneva, Heemann U, Grimmer T, Schmaderer C. Pulse-wave velocity is associated Switzerland: World Health Organization; 2008. with cognitive impairment in hemodialysis patients. Clin Sci. 2017;131:1483– 2. Mavrodaris A, Powell J, Thorogood M. Prevalences of dementia and cognitive 1493. impairment among older people in sub-Saharan Africa: a systematic review. 26. Benetos A, Watfa G, Hanon O, Salvi P, Fantin F, Toulza O, Manckoundia P, Bull World Health Organ. 2013;91:773–783. Agnoletti D, Labat C, Gautier S; PARTAGE Study Investigators. Pulse wave 3. Barberger-Gateau P, Fabrigoule C. Disability and cognitive impairment in the velocity is associated with 1-year cognitive decline in the elderly older than elderly. Disabil Rehabil. 1997;19:175–193. 80 years: the PARTAGE study. J Am Med Dir Assoc. 2012;13:239–243. 4. Dao E, Hsiung GYR, Liu-Ambrose T. The role of exercise in mitigating subcortical 27. Elias MF, Robbins MA, Budge MM, Abhayaratna WP, Dore GA, Elias PK. Arterial ischemic vascular cognitive impairment. J Neurochem. 2018;144:582–594. pulse wave velocity and cognition with advancing age. Hypertension. 2009;53:668–673. 5. Rosenberg GA, Wallin A, Wardlaw JM, Markus HS, Montaner J, Wolfson L, Iadecola C, Zlokovic BV, Joutel A, Dichgans M, Duering M, Schmidt R, Korczyn 28. Fukuhara M, Matsumura K, Ansai T, Takata Y, Sonoki K, Akifusa S, Wakisaka AD, Grinberg LT, Chui HC, Hachinski V. Consensus statement for diagnosis of M, Hamasaki T, Fujisawa K, Yoshida A, Fujii K, Iida M, Takehara T. Prediction of subcortical small vessel disease. J Cereb Blood Flow Metab. 2016;36:6–25. cognitive function by arterial stiffness in the very elderly. Circ J. 2006;70:756– 761. 6. Lacolley P, Regnault V, Avolio AP. Smooth muscle cell and arterial aging: basic and clinical aspects. Cardiovasc Res. 2018;114:513–528. 29. Geijselaers SL, Sep SJ, Schram MT, van Boxtel MP, van Sloten TT, Henry RM, Reesink KD, Kroona AA, Koster A, Schapera NC, Dagnelie PC, van der 7. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Kallena CJH, Biessels GJ, Stehouwer CDA. Carotid stiffness is associated Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H; on behalf of the with impairment of cognitive performance in individuals with and without European Network for Non-invasive Investigation of Large Arteries. Expert type 2 diabetes: the Maastricht Study. Atherosclerosis. 2016;253:186– consensus document on arterial stiffness: methodological issues and clinical 193. applications. Eur Heart J. 2006;27:2588–2605. 30. Hanon O, Haulon S, Lenoir H, Seux ML, Rigaud AS, Safar M, Girerd X, Forette 8. Scuteri A, Wang H. Pulse wave velocity as a marker of cognitive impairment in F. Relationship between arterial stiffness and cognitive function in elderly the elderly. J Alzheimers Dis. 2014;42:S401–S410. subjects with complaints of memory loss. Stroke. 2005;36:2193–2197. 9. Pase MP, Herbert A, Grima NA, Pipingas A, O’rourke MF. Arterial stiffness as a 31. Karasavvidou D, Boutouyrie P, Kalaitzidis R, Kettab H, Pappas K, Stagikas D, cause of cognitive decline and dementia: a systematic review and meta- Antonakis N, Tsalikakis D, Elisaf M, Laurent S. Arterial damage and cognitive analysis. Intern Med J. 2012;42:808–815. decline in chronic kidney disease patients. J Clin Hypertens. 2018;20:1276– 10. Rabkin SW, Jarvie G. Comparison of vascular stiffness in vascular dementia, 1284. Alzheimer dementia and cognitive impairment. Blood Press. 2011;20:274–283. 32. Kim YS, Kim DH, Choi BH, Sohn EH, Lee AY. Relationship between brachial- 11. Cooper LL, Woodard T, Sigurdsson S, van Buchem MA, Torjesen AA, Inker LA, ankle pulse wave velocity and cognitive function in an elderly community- Aspelund T, Eiriksdottir G, Harris TB, Gudnason V, Launer LJ, Gary F, Mitchell dwelling population with metabolic syndrome. Arch Gerontol Geriatr. GF. Cerebrovascular damage mediates relations between aortic stiffness and 2009;49:176–179. memory. Hypertension. 2016;67:176–182. 33. Kim ED, Meoni LA, Jaar BG, Shafi T, Kao WHL, Estrella MM, Parekh R, Sozio 12. Hajjar I, Goldstein FC, Martin GS, Quyyumi AA. Roles of arterial stiffness and SM. Association of arterial stiffness and central pressure with cognitive blood pressure in hypertension-associated cognitive decline in healthy adults. function in incident hemodialysis patients: the PACE Study. Kidney Int Rep. Hypertension. 2016;67:171–175. 2017;2:1149–1159. 13. Lim SL, Gao Q, Nyunt MSZ, Gong L, Lunaria JB, Lim ML, Lingb A, Su-Ping Lama 34. Lamballais S, Sajjad A, Leening MJ, Gaillard R, Franco OH, Mattace-Raso FU, C, Richardsc AM, Linga LH, Ng TP. Vascular health indices and cognitive Jaddoe VWV, Roza SJ, Tiemeier H, Ikram MA. Association of blood pressure domain function: Singapore longitudinal ageing studies. J Alzheimers Dis. and arterial stiffness with cognition in 2 population-based child and adult 2016;50:27–40. DOI: 10.1161/JAHA.119.014621 Journal of the American Heart Association 15 Arterial Stiffness and Cognition Among Adults Alvarez-Bueno et al SYSTEMATIC REVIEW AND META-ANALYSIS cohorts. J Am Heart Assoc. 2018;7:e009847. DOI: 10.1161/JAHA.118. function in an elderly community-dwelling population. J Gerontol A Biol Sci Med 009847. Sci. 2005;60:607–612. 35. Lee YH, Yoon ES, Park SH, Heffernan KS, Lee C, Jae SY. Associations of arterial 52. Kearney-Schwartz A, Rossignol P, Bracard S, Felblinger J, Fay R, Boivin JM, stiffness and cognitive function with physical fitness in patients with chronic Lecompte T, Lacolley P, Benetos A, Zannad F. Vascular structure and function stroke. J Rehabil Med. 2014;46:413–417. is correlated to cognitive performance and white matter hyperintensities in 36. Mitchell GF, van Buchem MA, Sigurdsson S, Gotal JD, Jonsdottir MK, older hypertensive patients with subjective memory complaints. Stroke. Kjartansson O, Garcia M, Aspelund T, Harris TB, Gudnason V, Launer LJ. 2009;40:1229–1236. Arterial stiffness, pressure and flow pulsatility and brain structure and 53. Meyer ML, Palta P, Tanaka H, Deal JA, Wright J, Knopman DS, Griswold ME, function: the Age, Gene/Environment Susceptibility-Reykjavik study. Brain. Mosley TH, Heiss G. Association of central arterial stiffness and pressure 2011;134:3398–3407. pulsatility with mild cognitive impairment and dementia: the Atherosclerosis 37. Muela HC, Costa-Hong VA, Yassuda MS, Moraes NC, Memoria CM, Machado Risk in Communities Study-Neurocognitive Study (ARIC-NCS). J Alzheimers Dis. MF, Bor-Seng-Shu E, Nogueira RC, Mansur AJ, Massaro AR, Nitrini R, Macedo 2017;57:195–204. TA, Bortolotto LA. Higher arterial stiffness is associated with lower cognitive 54. Nilsson ED, Elmst ahl S, Minthon L, Pihlsg ard M, Nilsson PM, Hansson O, N€agga performance in patients with hypertension. J Clin Hypertens. 2018;20:22–30. K. No independent association between pulse wave velocity and dementia: a 38. Muller M, Grobbee DE, Aleman A, Bots M, Van der Schouw YT. Cardiovascular population-based, prospective study. J Hypertens. 2017;35:2462–2467. disease and cognitive performance in middle-aged and elderly men. 55. Sugawara N, Yasui-Furukori N, Umeda T, Kaneda A, Sato Y, Takahashi I, Atherosclerosis. 2007;190:143–149. Matsuzaka M, Danjo K, Nakaji S, Kaneko S. Comparison of ankle-brachial 39. Nilsson ED, Elmstahl S, Minthon L, Nilsson PM, Pihlsgard M, Tufvesson E, pressure index and pulse wave velocity as markers of cognitive function in a N€agga K. Non-linear association between pulse wave velocity and cognitive community-dwelling population. BMC Psychiatry. 2010;10:46. function: a population-based study. J Hypertens. 2014;32:2152–2157. 56. Taniguchi Y, Fujiwara Y, Nofuji Y, Nishi M, Murayama H, Seino S, Tajima R, 40. Palta P, Sharrett AR, Wei J, Meyer ML, Kucharska-Newton A, Power MC, Deal Matsuyama Y, Shinkai S. Prospective study of arterial stiffness and JA, Jack CR, Knopman D, Wright J, Griswold M, Tanaka H, Mosley TH, Heiss G. subsequent cognitive decline among community-dwelling older Japanese. J Central arterial stiffness is associated with structural brain damage and poorer Epidemiol. 2015;25:592–599. cognitive performance: the ARIC study. J Am Heart Assoc. 2019;8:e011045. 57. Tuttolomondo A, Casuccio A, Guercio G, Maida C, Del Cuore A, Di Raimondo D, DOI: 10.1161/JAHA.118.011045. Simonetta I, Di Bona D, Pecoraro R, Della Corte V, Gulotta E, Gulotta G, Pinto 41. Pase MP, Himali JJ, Mitchell GF, Beiser A, Maillard P, Tsao C, Larson MG, A. Arterial stiffness, endothelial and cognitive function in subjects with type 2 DeCarli C, Vasan RS, Seshadri S. Association of aortic stiffness with cognition diabetes in accordance with absence or presence of diabetic foot syndrome. and brain aging in young and middle-aged adults: the Framingham Third Cardiovasc Diabetol. 2017;16:2. Generation Cohort Study. Hypertension. 2016;67:513. 58. Scuteri A, Tesauro M, Guglini L, Lauro D, Fini M, Di Daniele N. Aortic stiffness 42. Poels MM, van Oijen M, Mattace-Raso FU, Hofman A, Koudstaal PJ, Witteman and hypotension episodes are associated with impaired cognitive function in JC, Breteler MMB. Arterial stiffness, cognitive decline, and risk of dementia: older subjects with subjective complaints of memory loss. Int J Cardiol. the Rotterdam study. Stroke. 2007;38:888–892. 2013;169:371–377. 43. Ryu DW, Kim JS, Lee JE, Park JW, Oh YS, An JY, Lee KS. Association of arterial 59. Blondell SJ, Hammersley-Mather R, Veerman JL. Does physical activity prevent stiffness with cognition in patients with Lewy body disorder. Neurol Sci. cognitive decline and dementia? A systematic review and meta-analysis of 2017;38:1307–1313. longitudinal studies. BMC Public Health. 2014;14:510. 44. Scuteri A, Tesauro M, Appolloni S, Preziosi F, Brancati AM, Volpe M. Arterial 60. Adams ML, Deokar AJ, Anderson LA, Edwards VJ. Self-reported increased stiffness as an independent predictor of longitudinal changes in cognitive confusion or memory loss and associated functional difficulties among adults function in the older individual. J Hypertens. 2007;25:1035–1040. aged≥ 60 years—21 states, 2011. MMWR Morb Mortal Wkly Rep. 2013;62:345–350. 45. Singer J, Trollor JN, Crawford J, O’Rourke MF, Baune BT, Brodaty H, Samaras K, Kochan NA, Campbell L, Sachdev PS, Smith E. The association between pulse 61. Sun X, Rundek T. Does increased arterial stiffness herald cognitive impair- wave velocity and cognitive function: the Sydney Memory and Ageing Study. ment? Stroke. 2016;47:2171–2172. PLoS One. 2013;8:e61855. 62. Pase MP. Modifiable vascular markers for cognitive decline and dementia: the 46. Triantafyllidi H, Arvaniti C, Lekakis J, Ikonomidis I, Siafakas N, Tzortzis S, importance of arterial aging and hemodynamic factors. J Alzheimers Dis. Trivilou P, Zerva L, Stamboulis E, Kremastinos DT. Cognitive impairment is 2012;32:653–663. related to increased arterial stiffness and microvascular damage in patients 63. O’Rourke MF, Safar ME. Relationship between aortic stiffening and microvas- with never-treated essential hypertension. Am J Hypertens. 2009;22:525–530. cular disease in brain and kidney: cause and logic of therapy. Hypertension. 47. Tsao CW, Seshadri S, Beiser AS, Westwood AJ, DeCarli C, Au R, Himali JJ, 2005;46:200–204. Hamburg NM, Vita JA, Levy D, Larson MG, Benjamin EJ, Wolf PA, Vasan RS, 64. Scuteri A, Nilsson PM, Tzourio C, Redon J, Laurent S. Microvascular brain Mitchell GF. Relations of arterial stiffness and endothelial function to brain damage with aging and hypertension: pathophysiological consideration and aging in the community. Neurology. 2013;81:984–991. clinical implications. J Hypertens. 2011;29:1469–1477. 48. Tsao CW, Himali JJ, Beiser AS, Larson MG, DeCarli C, Vasan RS, Mitchell GF, 65. Panza F, D’Introno A, Colacicco AM, Capurso C, Del Parigi A, Capurso SA, Seshadri S. Association of arterial stiffness with progression of subclinical Caselli RJ, Pilotto A, Scafato E, Capurso A, Solfrizzi V. Cognitive frailty: brain and cognitive disease. Neurology. 2016;86:619–626. predementia syndrome and vascular risk factors. Neurobiol Aging. 49. Watson NL, Sutton-Tyrrell K, Rosano C, Boudreau RM, Hardy SE, Simonsick 2006;27:933–940. EM, Najjar SS, Launer LJ, Yaffe K, Atkinson HH, Satterfield S, Newman AB. 66. Cambronero FE, Liu D, Neal JE, Moore EE, Gifford KA, Terry JG, Nair S, Pechman Arterial stiffness and cognitive decline in well-functioning older adults. J KR, Osborn KE, Hohman TJ, Bell SP, Sweatt JD, Wang TJ, Beckman JA, Carr JJ, Gerontol A Biol Sci Med Sci. 2011;66:1336–1342. Jefferson AL. APOE genotype modifies the association between central arterial 50. Zhong W, Cruickshanks KJ, Schubert CR, Carlsson CM, Chappell RJ, Klein BE, stiffening and cognition in older adults. Neurobiol Aging. 2018;67:120–127. Acher CW. Pulse wave velocity and cognitive function in older adults. 67. Takeda JRT, Matos TM, Souza-Talarico JND. Cardiovascular risk factors and Alzheimer Dis Assoc Disord. 2014;28:44–49. cognitive performance in aging. Dement Neuropsychol. 2017;11:442–448. 51. Fujiwara Y, Chaves PH, Takahashi R, Amano H, Yoshida H, Kumagai S, Fujita K, 68. Scuteri A, Volpe M, Asmar R. Arterial stiffness and cognitive impairment in the Wang DG, Shinkai S. Arterial pulse wave velocity as a marker of poor cognitive elderly. High Blood Press Cardiovasc Prev. 2007;14:33–37. DOI: 10.1161/JAHA.119.014621 Journal of the American Heart Association 16 Supplemental Material Data S1. References excluded from the meta-analysis 1. Arntzen KA, Schirmer H, Johnsen SH, Wilsgaard T, Mathiesen EB. Carotid atherosclerosis predicts lower cognitive test results: a 7-year follow-up study of 4,371 stroke-free subjects - the Tromsø study. Cerebrovasc Dis. 2012; 33:159-165.: report on IMT 2. Borror A. Brain-derived neurotrophic factor mediates cognitive improvements following acute exercise. Med Hypotheses. 2017; 106: 1-5.: report on BDNF 3. Brant L, Bos D, Araujo LF, Ikram MA, Ribeiro AL, Barreto SM. Microvascular endothelial function and cognitive performance: The ELSA-Brasil cohort study. Vasc Med. 2018;23:212-218.: report on peripheral arterial tonometry and microvascular endothelial function. 4. Casado-Naranjo I, Romero Sevilla R, Portilla Cuenca JC, Duque de San Juan B, Calle Escobar ML, Fernández Pereira L, Fuentes JM, Ramírez-Moreno JM. Association between subclinical carotid atherosclerosis, hyperhomocysteinaemia and mild cognitive impairment. Acta Neurol. Scand. 2016;134;154-159.: report on subclinical markers of atherosclerosis. 5. Cohen RA, Poppas A, Forman DE, Hoth KF, Haley AP, Gunstad J, Jefferson AL, Tate DF, Paul RH, Sweet LH, Ono M, Jerskey BA, Gerhard-Herman M. Vascular and cognitive functions associated with cardiovascular disease in the elderly. J. Clin. Exp. Neuropsychol. 2009;31:96-110.: report on flow mediated brachial artery reactivity, and carotid intima media thickness. 6. Cooper LL, Himali J, Torjesen A, Tsao CW, Beiser A, Hamburg NM, DeCarli C, Vasan RS, Seshadri S, Pase MP, Mitchell G. Inter-Relations of Orthostatic Blood Pressure Change, Aortic Stiffness, and Brain Structure and Function in Young Adults. J Am Heart Assoc. 2017;17:e006206.: report on brain structure. 7. Dias Eda M1, Giollo LT Jr, Martinelli DD, Mazeti C, Júnior HM, Vilela-Martin JF, Yugar-Toledo JC. Carotid intima-media thickness is associated with cognitive deficiency in hypertensive patients with elevated central systolic blood pressure. Cardiovasc Ultrasound. 2012;10:41.: report on intima-media thickness. 8. Espeland MA, Beavers KM, Gibbs BB, Johnson KC, Hughes TM, Baker LD, Jakicic J, Korytkowski M, Miller M, Bray GA. Ankle-brachial index and inter-artery blood pressure differences as predictors of cognitive function in overweight and obese older adults with diabetes: results from the Action for Health in Diabetes movement and memory study. Int J Geriatri Psychiatry. 2015;30:999-1007.: report on ankle-brachial index 9. Espeland MA, Newman AB, Sink K, Gill TM, King AC, Miller ME, Guralnik J, Katula J, Church T, Manini T, Reid KF, McDermott MM; LIFE Study Group. Associations Between Ankle-Brachial Index and Cognitive Function: Results From the Lifestyle Interventions and Independence for Elders Trial. J AM Med Dir Assoc. 2015;16:682- 689.: report on ankle-brachial index 10. van Exel E1, Gussekloo J, Houx P, de Craen AJ, Macfarlane PW, Bootsma-van der Wiel A, Blauw GJ, Westendorp RG. Atherosclerosis and cognitive impairment are linked in the elderly. The Leiden 85-plus Study. Atherosclerosis. 2002;165:353-359.: report assessing the atherosclerotic burden. 11. Feinkohl I, Keller M, Robertson CM, Morling JR, Williamson RM, Nee LD, McLachlan S, Sattar N, Welsh P, Reynolds RM, Russ TC, Deary IJ, Strachan MW, Price JF; Edinburgh Type 2 Diabetes Study (ET2DS) Investigators. Clinical and subclinical macrovascular disease as predictors of cognitive decline in older patients with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes care. 2013;36:2779-2786.: report on ankle-brachial index, and intima media thickness. 12. Fergenbaum JH1, Bruce S, Spence JD, Lou W, Hanley AJ, Greenwood C, Young TK. Carotid atherosclerosis and a reduced likelihood for lowered cognitive performance in a Canadian First Nations population. Neuroepidemiology. 2009;33:321-328.: report on carotid values. 13. Frazier DT, Seider T, Bettcher BM, Mack WJ, Jastrzab L, Chao L, Weiner MW, DeCarli C, Reed BR, Mungas D, Chui HC, Kramer JH. The role of carotid intima-media thickness in predicting longitudinal cognitive function in an older adult cohort. Cerebrovasc Dis. 2014;38:441-447.: report on intima media thickness 14. Forman DE, Cohen RA, Hoth KF, Haley AP, Poppas A, Moser DJ, Gunstad J, Paul RH, Jefferson AL, Tate DF, Ono M, Wake N, Gerhard-Herman M. Vascular Health and Cognitive Function in Older Adults with Cardiovascular Disease. Artery Res. 2008;2:35- 43.: report on flow-mediated. 15. Gale CR1, Deary IJ, Fowkes FG, Batty GD. Intelligence in early adulthood and subclinical atherosclerosis in middle-aged men: the Vietnam Experience Study. J Epidemiol Community Health. 2012;66:e13.: report on ankle brachial index. 16. Gardener H, Caunca MR, Dong C, Cheung YK, Elkind MSV, Sacco RL, Rundek T, Wright CB. Ultrasound Markers of Carotid Atherosclerosis and Cognition: The Northern Manhattan Study. Stroke. 2017;48:1855-1861.: report on intima media thickness 17. Gatto NM, Henderson VW, St John JA, McCleary C, Detrano R, Hodis HN, Mack WJ Subclinical atherosclerosis is weakly associated with lower cognitive function in healthy hyperhomocysteinemic adults without clinical cardiovascular disease. Int J Geriatr Psychiatry. 2009;24:390-399.: report on intima media thickness 18. Gutierrez J, Marshall RS, Lazar RM. Indirect measures of arterial stiffness and cognitive performance in individuals without traditional vascular risk factors or disease. JAMA Neurol. 2015;72:309-315.: report on increasing age, sedentary lifestyle, and the use of dihydropyridine calcium channel blockers 19. Huck DM, Hanna DB, Rubin LH, Maki P, Valcour V, Springer G, Xue X, Lazar J, Hodis HN, Anastos K, Kaplan RC, Kizer JR. Carotid Artery Stiffness and Cognitive Decline Among Women With or at Risk for HIV Infection. J Acquir Immune Defic Syndr. 2018;78:338-347.: report on carotid artery stiffness 20. Johnson NF, Gold BT, Brown CA, Anggelis EF, Bailey AL, Clasey JL, Powell DK. Endothelial Function Is Associated with White Matter Microstructure and Executive Function in Older Adults. Front Aging Neurosci. 2017;9:255.: report on brain structure. 21. Kidher E, Harling L, Sugden C, Ashrafian H, Casula R, Evans P, Nihoyannopoulos P, Athanasioua T. Aortic stiffness is an indicator of cognitive dysfunction before and after aortic valve replacement for aortic stenosis. Interact Cardiovasc Thorac Surg. 2014;19: 595-604.: less than 100 participants. 22. Kuller LH, Lopez OL, Gottdiener JS, Kitzman DW, Becker JT, Chang Y, Newman AB. Subclinical Atherosclerosis, Cardiac and Kidney Function, Heart Failure, and Dementia in the Very Elderly. J Am Heart Assoc. 2017;6.: report on predictors of arterial stiffness. 23. Masley SC, Masley LV, Gualtieri CT. Cardiovascular biomarkers and carotid IMT scores as predictors of cognitive function. J Am Coll Nutr. 2014;33:63-69.: report on intima media thickness. 24. Mehrabian S, Raycheva M, Gateva A, Todorova G, Angelova P, Traykova M, Angelova P, Traykova M, Stankova T, Kamenov Z, Traykova L. Cognitive dysfunction profile and arterial stiffness in type 2 diabetes. J Neurol Sci. 2012;322:152-156.: less than 100 participants. 25. Nieboer D, Douw L, van Dijk BW, Heymans MW, Stam CJ, Twisk JW. Relation between carotid stiffness, cognitive performance and brain connectivity in a healthy middle-aged population: an observational neurophysiological cohort study with magnetoencephalography. BMJ Open. 2016;6:e013441.: report on carotid stiffness. 26. Rogne SO1, Solbu MD, Arntzen KA, Herder M, Mathiesen EB, Schirmer H. Albuminuria and carotid atherosclerosis as predictors of cognitive function in a general population. Eur Neurol. 2013;70:340-348.: report on carotid intima-media thickness and carotid total plaque area. 27. Scuteri A, Brancati AM, Gianni W, Assisi A, Volpe M. Arterial stiffness is an independent risk factor for cognitive impairment in the elderly: a pilot study. J Hypertens. 2005;23:1211-1216.: less than 100 participants. 28. Suleman R, Padwal R, Hamilton P, Senthilselvan A, Alagiakrishnan K. Association between central blood pressure, arterial stiffness, and mild cognitive impairment. Clin Hypertens. 2017;23:2.: less than 100 participants. 29. Tarumi T, Gonzales MM, Fallow B, Nualnim N, Pyron M, Tanaka H, Andreana P. Central artery stiffness, neuropsychological function, and cerebral perfusion in sedentary and endurance-trained middle-aged adults. J Hypertens. 2013;31:2400-2409: less than 100 participants. 30. Viticchi G, Falsetti L, Vernieri F, Altamura C, Bartolini M, Luzzi S, Provinciali L, Silvestrini M. Vascular predictors of cognitive decline in patients with mild cognitive impairment. Neurobiol Aging. 2012;33:1127.e1-9.: report on intima-media thickness and carotid plaque index 31. Wendell CR, Waldstein SR, Evans MK, Zonderman AB. Subclinical carotid atherosclerosis and neurocognitive function in an urban population. Atherosclerosis. 2016;249:125-131.: report on carotid measurements. 32. Xiang J, Zhang T, Yang QW, Liu J, Chen Y, Cui M, Yin ZG, Li L, Wang YJ, Li J, Zhou HD. Carotid artery atherosclerosis is correlated with cognitive impairment in an elderly urban Chinese non-stroke population. J Clin Neurosci. 2013;20:1571-1575: research on intima-media thickness. Table S1. Sensitivity analyses by removing studies one by one for unadjusted cross- sectional analysis. Global cogniton Author es ll ul I2 Q- p Cochrane Abbatecola et al., 2008 23 -0.53 -0.68 -0.39 74.1 30.86 <0.001 Angermann et al., 2017 25 -0.44 -0.53 -0.35 26.4 10.87 0.209 Fukuhara et al., 2006 28 -0.54 -0.70 -0.39 74.1 30.88 <0.001 Hanon et al., 2005 30 -0.53 -0.68 -0.38 73.5 30.15 <0.001 Lee et al., 2014 35 -0.49 -0.62 -0.36 66.4 23.83 0.002 Lim et al., 2016 13 -0.55 -0.70 -0.40 73.9 30.68 <0.001 Muela et al., 2018 37 -0.55 -0.70 -0.40 73.9 30.68 <0.001 Nilsson et al., 2014 39 -0.56 -0.72 -0.40 70.3 26.97 0.001 Triantafyllidi et al., 2009 46 -0.54 -0.69 -0.39 74.1 30.90 <0.001 Zhong et al., 2014 50 -0.56 -0.73 -0.38 73.6 30.32 <0.001 Executive function Author es ll ul I2 Abbatecola et al., 2008 23 -0.30 -0.41 -0.18 0.0 1.77 0.413 Kim et al., 2017 33 -0.42 -0.57 -0.26 0.0 2.00 0.368 Muela et al., 2018 37 -0.37 -0.59 -0.15 58.6 4.83 0.089 Zhong et al., 2014 50 -0.36 -0.59 -0.12 53.5 4.30 0.117 Memory Author es ll ul I2 Cooper et al., 2016 11 -0.53 -0.74 -0.32 56.3 2.29 0.130 Muela et al., 2018 37 -0.28 -0.61 0.06 95.2 20.82 <0.001 Zhong et al., 2014 50 -0.38 -0.94 -0.18 93.3 14.91 <0.001 Table S2. Sensitivity analyses by removing studies one by one for adjusted cross- sectional analysis. Global cognition Author es ll ul I2 Q- p Cochrane Elias et al., 2009 27 -0.22 -0.32 -0.12 77.6 49.19 <0.001 Fukuhara et al., 2006 28 -0.20 -0.30 -0.10 77.2 48.26 <0.001 Hanon et al., 2005 30 -0.21 -0.31 -0.11 77.9 49.72 <0.001 Karasavvidou et al., 2018 31 -0.21 -0.31 -0.11 77.9 49.78 <0.001 Kim et al., 2009 32 -0.13 -0.16 -0.09 0.0 9.10 0.613 Lamballais et al., 2018 34 -0.23 -0.35 -0.10 77.6 49.16 <0.001 Lee et al., 2014 35 -0.21 -0.31 -0.11 77.9 49.67 <0.001 Lim et al., 2016 13 -0.22 -0.32 -0.12 77.8 49.63 <0.001 Muela et al., 2018 37 -0.21 -0.30 -0.11 77.6 49.19 <0.001 Palta et al., 2019 40 -0.23 -0.34 -0.11 77.4 48.59 <0.001 Ryu et al., 2017 43 -0.19 -0.29 -0.10 76.2 46.18 <0.001 Singer et al., 2013 45 -0.22 -0.32 -0.12 77.5 48.87 <0.001 Zhong et al., 2014 50 -0.23 -0.33 -0.12 77.2 48.21 <0.001 Executive function Author es ll ul I2 Geijselaers et al., 2016 29 -0.10 -0.15 -0.04 52.5 18.95 0.026 Kim et al., 2017 32 -0.09 -0.14 -0.03 61.0 23.06 0.006 Lim et al., 2016 13 -0.07 -0.12 -0.02 49.5 17.83 0.037 Mitchell et al., 2011S36 -0.08 -0.13 -0.02 58.3 21.56 0.010 Muller et al., 2006 38 -0.08 -0.14 -0.02 60.9 23.01 0.006 Palta et al., 2019 40 -0.09 -0.16 -0.02 56.6 20.73 0.014 Pase et al., 2016 41 -0.08 -0.14 -0.02 59.7 22.32 0.008 Ryu et al., 2017 43 -0.06 -0.11 -0.02 44.1 16.10 0.065 Singer et al., 2013 45 -0.09 -0.14 -0.03 60.1 22.58 0.007 Tsao et al., 2013 47 -0.07 -0.13 -0.02 55.6 20.25 0.016 Zhong et al., 2014 50 -0.09 -0.16 -0.03 59.3 22.11 0.009 Memory Author es ll ul I2 Cooper et al., 2016 11 -0.13 -0.21 -0.05 81.7 60.18 <0.001 Elias et al., 2009 27 -0.14 -0.22 -0.06 81.9 60.74 <0.001 Geijselaers et al., 2016 29 -0.13 -0.21 -0.06 81.9 60.88 <0.001 Lim et al., 2016 13 -0.13 -0.20 -0.05 81.8 60.54 <0.001 Mitchell et al., 2011 36 -0.12 -0.20 -0.05 81.2 58.48 <0.001 Muela et al., 2018 37 -0.11 -0.18 -0.04 79.5 53.70 <0.001 Muller et al., 2006 38 -0.13 -0.021 -0.06 81.9 60.89 <0.001 Palta et al., 2019 40 -0.14 -0.22 0.05 81.8 60.40 <0.001 Pase et al., 2016 41 -0.14 -0.22 -0.06 77.6 49.20 <0.001 Ryu et al., 2017 43 -0.07 -0.12 -0.03 50.1 22.06 0.024 Singer et al., 2013 45 -0.13 -0.20 -0.05 81.8 60.30 <0.001 Tsao et al., 2013 47 -0.14 -0.22 -0.07 80.8 57.33 <0.001 Zhong et al., 2014 50 -0.13 -0.21 -0.06 81.9 60.91 <0.001 Table S3. Sensitivity analyses by removing studies one by one for longitudinal analysis. Global cognition Author es ll ul I2 Q- p Cochrane Al Hazzouri et al., 2013 24 -0.15 -0.26 -0.04 62.2 10.59 0.032 Benetos et al., 2012 26 -0.22 -0.41 -0.03 89.9 39.73 <0.001 Palta et al., 2019 40 -0.22 -0.40 -0.04 89.9 39.73 <0.001 Poels et al., 2007 42 -0.26 -0.37 -0.16 54.8 8.86 0.065 Scuteri et al., 2007 44 -0.20 -0.36 -0.04 89.7 38.97 <0.001 Watson et al., 2011 49 -0.21 -0.39 -0.03 89.9 39.56 <0.001 Executive function Author es ll ul I2 Hajjar et al., 2016 12 -0.11 -0.25 0.02 64.0 5.55 0.062 Kim et al., 2017 33 -0.12 -0.23 -0.01 67.0 6.06 0.048 Poels et al., 2007 42 -0.18 -0.27 -0.09 0.0 0.39 0.822 Tsao et al., 2013 48 -0.06 -0.13 0.00 0.0 1.67 0.434 Memory Author es ll ul I2 Hajjar et al., 2016 12 -0.05 -0.17 0.07 46.8 1.88 0.170 Kim et al., 2017 42 -0.11 -0.23 0.03 0.0 0.18 0.675 Poels et al., 2007 49 -0.02 -0.09 0.04 0.0 0.79 0.375 Table S4. Subgroup analyses for the association between PWv and cognition domains by type of sample, PWv measured and device used. Cross-sectional data Longitudinal data Unadjusted Adjusted n ES (95%CI) I2 Q- p n ES (95%CI) I2 Q- p n ES (95%CI) I2 Q- p Cochrane Cochrane Cochrane Global cognition Type of sample General population 5 -0.20 (-0.36, -0.04) 89.7 38.97 <0.001 4 -0.39 (-0.47, -0.32) 0.0 0.70 0.872 8 -0.19 (-0.31; -0.08) 84.5 45.22 <0.001 Specific disease population 1 -0.36 (-0.76, 0.04) NA NA NA 6 -0.67 (-0.92, -0.41) 73.8 19.10 0.002 5 -0.25 (-0.38, -0.11) 0.0 2.42 0.659 Type pf PWv cfPWv 5 -0.21 (-0.39, -0.03) 89.9 39.56 <0.001 9 -0.55 (-0.70, -0.39) 74.1 30.88 <0.001 10 -0.12 (-0.16, -0.08) 0.0 2.98 0.965 baPWv 0 NA NA NA NA 1 -0.42 (-0.70, -0.14) NA NA NA 3 -0.56 (-0.88, -0.23) 76.6 8.55 0.014 aPWv 1 -0.22 (-0.39, -0.05) NA NA NA 0 NA NA NA NA 0 NA NA NA NA Type of device Sphygmocor 0 NA NA NA NA 3 -0.52 (-0.81, -0.24) 78.0 9.11 0.011 5 -0.09 (-0.20, 0.02) 0.0 0.91 0.923 Complior 2 -0.13 (-0.45, 0.18) 63.6 2.75 0.097 4 -0.44 (-0.53, -0.35) 0.0 1.33 0.723 4 -0.13 (-0.17, -0.08) 0.0 1.73 0.210 Other 4 -0.26 (-0.37, -0.14) 65.7 8.74 0.033 3 -0.70 (-1.19, -0.22) 83.8 12.37 0.002 4 -0.43 (-0.81, -0.05) 92.9 42.25 <0.001 Executive function Type of sample General population 3 -0.12 (-0.23, -0.01) 67.0 6.06 0.048 3 -0.36 (-0.59, -0.12) 53.5 4.30 <0.001 9 -0.07 (-0.12, -0.01) 50.3 16.10 0.041 Specific disease population 1 -0.09 (-0.80,0.41) NA NA NA 1 -0.39 (-0.60, -0.19) NA NA NA 2 -0.16 (-0.38, 0.05) 70.7 3.41 0.065 Type of PWv cfPWv 4 -0.12 (-0.22, -0.02) 83.1 6.06 0.001 4 -0.35 (-0.51, -0.20) 38.4 4.87 0.182 10 -0.06 (-0.11, -0.02) 44.1 16.10 0.065 baPWv 0 NA NA NA NA 0 NA NA NA NA 1 -0.27 (-0.43, -0.11) NA NA NA aPWv 0 NA NA NA NA 0 NA NA NA NA 0 NA NA NA NA Type of device Sphygmocor 2 -0.15 (-0.29, 0.00) 0.0 0.04 0.836 1 -0.22 (-0.39, -0.05) NA NA NA 5 -0.05 (-0.19, 0.08) 56.1 9.12 0.058 Complior 1 -0.04 (-0.11, 0.04) NA NA NA 2 -0.38 (-0.54, -0.21) 0.0 0.05 0.819 1 -0.02 (-0.10, 0.06) NA NA NA Other 1 -0.20 (-0.31, -0.09) NA NA NA 1 -0.72 (-1.18, -0.27) NA NA NA 5 -0.12 (-0.19, -0.04) 67.0 12.11 0.017 Memory Type of sample General population 3 -0.05 (-0.12, 0.03) 13.8 2.32 0.314 2 -0.28 (-0.61, 0.06) 95.2 20.82 <0.001 11 -0.06 (-0.10, -0.02) 30.4 14.38 0.156 Specific disease population 0 NA NA NA NA 1 -0.68 (-0.96, -0.41) NA NA NA 2 -0.58 (-0.73, -0.43) 0.0 0.10 0.753 Type of PWv cfPWv 2 -0.02 (-0.09, 0.04) 0.0 0.79 0.375 3 -0.39 (-0.70, -0.10) 93.4 30.08 <0.001 12 -0.08 (-0.12, -0.03) 50.1 22.06 0.024 baPWv 0 NA NA NA NA 0 NA NA NA NA 1 -0.59 (-0.76, -0.43) NA NA NA aPWv 1 -0.14 (-0.31, 0.03) NA NA NA 0 NA NA NA NA 0 NA NA NA NA Type of device Sphygmocor 1 -0.09 (-0.25, 0.07) NA NA NA 0 NA NA NA NA 5 -0.07 (-0.15, 0.00) 0.0 1.18 0.881 Complior 1 -0.01 (-0.09, 0.07) NA NA NA 2 -0.53 (-0.74, -0.32) 56.3 2.29 0.130 2 -0.27 (-0.72, 0.04) 84.6 6.48 0.011 Other 1 -0.14 (-0.31, 0.03) NA NA NA 1 -0.11 (-0.20, -0.02) NA NA NA 6 -0.14 (-0.25, -0.03) 90.5 52.52 <0.001 PWv: Pulse Wave Velocity; cf: carotid-femoral; ba: brachial-ankle; a: aortic; NA: Not Available Table S5. Meta-regression of PWV and cognition domains by percentage of females and mean age, BMI, SBP and DBP of included studies. % female Age BMI SBP DBP n ß (95%CI) p n ß (95%CI) p n ß (95%CI) p n ß (95%CI) p n ß (95%CI) p Global cognition Longitudinal data 4 -0.00 0.690 6 -0.01 0.643 6 -0.04 0.727 4 -0.02 0.227 3 -0.02 0.142 (-0.03, 0.02) (-0.04, 0.03) (-0.31, 0.24) (-0.07, 0.03) (-0.04, 0.01) Cross-sectional data Unadjusted 9 0.00 0.497 10 0.00 0.649 8 0.02 0.338 8 0.02 0.062 8 0.03 0.256 (-0.01, 0.02) (-0.02, 0.02) (-0.02, 0.05) (-0.00, 0.05) (-0.03, 0.09) Adjusted 13 -0.00 0.991 13 0.01 0.348 12 0.04 0.173 10 0.01 0.554 8 -0.01 0.878 (-0.01, 0.01) (-0.01, 0.02) (-0.02, 0.11) (-0.02, 0.04) (-0.13, 0.11) Executive function Longitudinal data 4 -0.00 0.910 4 0.01 0.449 3 -0.05 0.512 3 -0.01 0.824 2 NA NA (-0.05, 0.05) (-0.02, 0.03) (-0.79, 0.68) (-0.27, 0.25) Cross-sectional data Unadjusted 3 -0.00 0.993 4 -0.01 0.286 3 0.06 0.640 2 NA NA 2 NA NA (-0.05, 0.05) (-0.03, 0.02) (-1.19, 1.31) Adjusted 11 -0.00 0.548 11 0.00 0.839 7 0.03 0.127 7 0.00 0.837 4 0.00 0.757 (-0.01, 0.00) (-0.01, 0.01) (-0.01, 0.08) (-0.01, 0.01) (-0.05, 0.06) Memory Longitudinal data 3 0.00 0.949 3 0.00 0.833 3 -0.05 0.684 1 NA NA 1 NA NA (-0.12, 0.12) (-0.06, 0.07) (-1.28, 1.18) Cross-sectional data Unadjusted 3 0.01 0.404 3 0.02 0.492 3 -0.09 0.587 2 NA NA 2 NA NA (-0.06, 0.07) (-0.11, 0.15) (-1.53, 1.35) Adjusted 13 0.00 0.853 13 -0.00 0.584 10 0.01 0.343 10 -0.00 0.027 7 -0.01 0.653 (-0.01, 0.01) (-0.01, 0.01) (-0.02, 0.05) (-0.01, -0.00) (-0.03, 0.02) NA: Not Available Table S6. Risk of bias of cross-sectional and longitudinal included studies. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Total Abbatecola et al., 2008 23 Y Y NR Y NR NR Y N Y Y Y NR Y Y 9 Al Hazzouri et al., 2013 24 Y Y Y Y NR Y Y Y Y Y Y Y Y Y 12 Angermann et al., 2017 25 Y Y NR Y NR Y - Y Y - Y NR - N 7 Benetos et al., 2012 26 Y Y NR Y NR Y Y Y Y N Y NR N Y 9 Cooper et al., 2016 11 Y Y Y Y NR NR - N Y - Y NR - Y 7 Elias et al., 2009 27 Y Y Y Y NR Y - Y Y - Y NR - Y 9 Fujiwara et al., 2005 51 Y Y N Y NR NR - Y Y - Y NR - Y 7 Fukuhara et al., 2006 28 Y Y Y Y NR NR - N Y - Y NR - Y 7 Geijselaers et al., 2016 29 Y Y Y Y NR NR - Y Y - Y NR - Y 8 Hajjar et al., 2016 12 Y Y NR Y NR NR Y Y Y Y Y NR Y Y 10 Hanon et al., 2005 30 Y Y NR Y NR NR - Y Y - Y Y - Y 8 Karasavvidou et al., 2018 31 Y Y Y Y NR NR - Y Y - Y NR - Y 8 Kearney-Schwartz et al., 2009 52 Y Y Y Y Y NR - Y Y - Y Y - Y 10 Kim et al., 2009 32 Y Y N Y NR NR - N Y N NR - N 4 Kim et al., 2017 33 Y Y Y Y NR NR Y Y Y Y Y NR Y Y 11 Lamballais et al, 2018 34 Y Y Y Y NR NR - N Y - Y NR - Y 7 Lee et al., 2014 35 Y Y Y Y NR NR - N Y - Y NR - Y 7 Lim et al., 2016 13 Y Y NR Y NR NR - N Y - Y NR - Y 6 Meyer et al, 2017 53 Y Y N Y N NR - Y Y - Y NR - Y 7 Mitchell et al., 2011 36 Y Y N Y NR NR - Y Y - Y NR - Y 7 Muela et al., 2018 37 Y Y NR Y NR NR - Y Y - Y Y - Y 8 Muller et al., 2006 38 Y Y N Y NR NR - Y Y - Y NR - Y 7 Nilson et al., 2014 39 Y Y N Y NR NR - Y Y - Y NR - Y 7 Nilson et al., 2017 54 Y Y N Y NR NR - Y Y - Y NR - Y 7 Palta et al., 2019 40 Y Y Y Y NR Y Y Y Y N Y NR N Y 10 Pase et al., 2016 41 Y Y Y Y NR NR - Y Y - Y Y - Y 9 Poels et al., 2007 42 Y Y N Y NR NR Y N Y Y Y Y N Y 9 Ryu et al., 2017 43 Y Y NR Y NR NR - N Y - Y N - N 5 Scuteri et al., 2007 44 Y Y Y Y NR NR - N Y - Y Y - Y 8 Singer et al., 2013 45 Y Y N Y NR NR - Y Y - Y NR - Y 7 Sugawara et al., 2010 55 Y Y Y Y NR NR - Y Y - Y NR - Y 8 Taniguchi et al., 2014 56 Y Y Y Y NR NR - Y Y - Y Y - Y 9 Triantafyllidi et al., 2009 46 Y Y Y Y NR NR - Y Y - Y Y - Y 9 Tsao et al., 2013 47 Y Y Y Y NR NR - N Y - Y Y - Y 8 Tsao et al., 2016 48 Y Y Y Y NR Y Y Y Y N Y Y Y Y 12 Tuttolomondo et al., 2017 57 Y Y NR Y NR NR - Y Y - Y NR - Y 7 Watson et al., 2011 49 Y Y NR Y NR Y Y Y Y N Y NR Y Y 10 Zhong et al., 2014 50 Y Y NR NR NR NR - Y Y - Y NR - Y 6 Y: Yes; N: No; NR: Not Reported