ORIGINAL RESEARCH published: 14 December 2021 doi: 10.3389/fneur.2021.785640 Prevalence and Predictors of Cerebral Microangiopathy Determined by Pulsatility Index in an Asymptomatic Population From the ILERVAS Project Francisco Purroy 1,2*, Enric Sánchez 3,4,5 , Albert Lecube 3,4,5,6 , Gloria Arqué 2 , Mikel Vicente-Pascual 2 , Gerard Mauri-Capdevila 1,2 , Núria Torreguitart 2,7 , Marta Hernández 3,4,5 , Ferrán Barbé 8,9 , Elvira Fernández 10 , Reinald Pamplona 11 , Cristina Farràs 12 , Dídac Mauricio 13 , Marcelino Bermúdez-López 10 and the ILERVAS project 1 Stroke Unit, University Hospital Arnau de Vilanova, Lleida, Spain, 2 Clinical Neurosciences Group, IRBLleida, University of Lleida, Lleida, Spain, 3 Endocrinology and Nutrition Department, University Hospital Arnau de Vilanova, Lleida, Spain, Edited by: 4 Obesity, Diabetes and Metabolism (ODIM) Research Group, IRBLleida, Lleida, Spain, 5 University of Lleida, Lleida, Spain, Marcos Lange, 6 CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Instituto de Salud Carlos III (ISCIII), Madrid, Spain, Federal University of Paraná, Brazil 7 Vascular Surgery Service, University Hospital Arnau de Vilanova, Lleida, Spain, 8 Pneumology Service, Translational Reviewed by: Research in Respiratory Medicine Research Group, IRBLleida, University Hospital Arnau de Vilanova, University of Lleida, Paola Maggio, Lleida, Spain, 9 CIBER de Enfermedades Respiratorias, CIBERES, Instituto de Salud Carlos III (ISCIII), Lleida, Spain, Bolognini Hospital, Italy 10 Vascular and Renal Translational Research Group, IRBLleida, ReinRen-ISCIII, University of Lleida, Lleida, Spain, Marek Czosnyka, 11 Department of Experimental Medicine, Metabolic Pathophysiology Research Group, IRBLleida, University of Lleida, Lleida, University of Cambridge, Spain, 12 DAP Lleida, Unitat de Suport a la Recerca - IDIAP Jordi Gol, Lleida, Spain, 13 Department of Endocrinology and United Kingdom Nutrition, CIBER of Diabetes and Associated Metabolic Diseases, Hospital de la Sant Creu i Sant Pau, Barcelona, Spain *Correspondence: Francisco Purroy fpurroygarcia@gmail.com Background: Little is known about the prevalence of cerebral microangiopathy (CM), which is related to cognitive impairment, in an asymptomatic population. Pulsatility index Specialty section: (PI) is an easily measurable parameter of cerebral vascular resistance in transcranial This article was submitted to Applied Neuroimaging, duplex of the middle cerebral artery (MCA) study. We aimed to determine the prevalence a section of the journal of CM measured by PI of MCA in low to moderate vascular risk subjects. Frontiers in Neurology Methods: We included 3,721 subjects between 45 and 70 years without previous Received: 29 September 2021 Accepted: 08 November 2021 history of vascular disease or diabetes mellitus and with at least one other vascular Published: 14 December 2021 risk factor from the cross-sectional study ILERVAS (Lleida, Spain). Patients underwent Citation: transcranial duplex to determine MCA-PI. Possible CM was defined by MCA-PI >1.1. Purroy F, Sánchez E, Lecube A, Carotid and femoral arteries ultrasound registration was done to determine the presence, Arqué G, Vicente-Pascual M, Mauri-Capdevila G, Torreguitart N, the number, and the area of atheromatous plaques. Body mass index (BMI), pulse Hernández M, Barbé F, Fernández E, pressure (PP) and laboratory data were also recorded. Pamplona R, Farràs C, Mauricio D, Bermúdez-López M and the ILERVAS Results: 439 (11.8%) subjects were excluded due to the low quality of transcranial project (2021) Prevalence and duplex images. Median age was 57 [IQR 52, 62] years. Possible CM was found in Predictors of Cerebral Microangiopathy Determined by 424 (12.9%) subjects. CM patients had higher prevalence of plaques than non-CM Pulsatility Index in an Asymptomatic (77.4 vs. 66.4%, p < 0.001). PI showed a positive linear correlation with the number Population From the ILERVAS Project. Front. Neurol. 12:785640. of territories with plaques (r = 0.130, p < 0.001), and the total plaque area (r = doi: 10.3389/fneur.2021.785640 0.082, p < 0.001). The predictors of possible CM were the age, male gender, and PP. Frontiers in Neurology | www.frontiersin.org 1 December 2021 | Volume 12 | Article 785640 Purroy et al. Cerebral Microangiopathy in Asymptomatic Population Conclusions: In low-to-moderate vascular risk asymptomatic population, the proportion of abnormal brain microvascular bed determined by MCA-PI is not negligible. The planned 10-year follow-up will describe the clinical relevance of these findings. Keywords: atheromatosis, cerebral microangiopathy, extracranial atheromatosis, pulsatility index (PI), transcranial Doppler (TCD), ultrasonography INTRODUCTION study, 3,721 people attended by a mobile unit were enrolled between September 2015 and December 2017 from Primary care Pulsatility index (PI) is an easily measurable parameter of centers across the entire province of Lleida, in West Catalonia cerebral vascular resistance in the transcranial duplex (TCD) of (Spain). The inclusion criteria were: between 45 and 70 years the middle cerebral artery (MCA) study. It is a surrogated marker old, without previous history of vascular disease or diabetes of cerebral microangiopathy (CM) that reflects the resistance mellitus and with at least one other vascular risk factor (obesity, of the microvascular distal bed of the measured vessel (1–9). hypertension, dyslipidemia, smoking, or a first degree relative MCA-PI is significantly correlated with white matter lesions with premature cardiovascular disease). Subjects with diagnosed severity in magnetic resonance imaging (MRI) (2, 4–9). In type diabetes, chronic kidney disease, history of vascular events 2 diabetes mellitus patients PI reflects extracranial (10) and (ischemic disease, stroke, or peripheral arteriopathy), active intracranial (3, 11) microvascular complications. Changes in the neoplasia, a life expectancy of <18 months, and pregnancy PI of the MCA have been proposed as a measure of the pleiotropic were excluded. action mechanism of selective phosphodiesterase inhibitors (12). Sociodemographic variables and anthropometrical data were Patients with CM have a neurovascular dysfunction (13) that registered. Weight and height were measured to determine contributes to a mismatch between neural activity and provided body mass index (BMI, kg/m2). Neck and waist circumferences oxygen and glucose (14). The neurovascular unit disbalance were measured in centimeters. Blood pressure was measured is related with impairment of the cerebral function, which 3 times with an Omron-M6 apparatus at 2-min intervals, and could be clinically expressed as depression, cognitive, and gait the mean of the last two measurements calculated. A pulse impairments (13–19). Neurovascular dysfunction is observed in pressure, the difference between systolic and diastolic pressures, the early disease stage of Alzheimer’s disease (20). As a result, was calculated. The pack-year smoking history and smoking CM is the main pathogenic finding in up to 45% of cases status (non-smoker/current/former smoker) were also recorded. of dementia (16), and prevalence of CM increases with age Smokers who stopped smoking ≥1 year prior to recruitment (13, 15–17). Hypertension is the main modifiable risk factor were considered former smokers. A dry analytical capillary blood (13, 15–17). However, CM remained asymptomatic several years sample to determine levels of glycosylated hemoglobin, total until onset clinical manifestations in many cases. Up to 20% cholesterol, and serum creatinine was used. A urine sample was of asymptomatic elderly people have shown CM on magnetic collected to determine creatinine levels and further estimated resonance imaging (MRI) studies (16). Early identification of glomerular filtration rate (GFR) by the chronic kidney disease patients with subclinical CM would provide an opportunity epidemiology collaboration (CKD-EPI) equation (25). to begin intensive effective treatment to avoid emergence of symptoms. Limited information exists on the presence of CM in low Cerebral Microangiopathy to moderate vascular risk subjects and its association with All patients underwent transcranial duplex (TCD) examinations extracranial and intracranial angiopathy (21, 22). In this context, to assess intracranial circulation. The ultrasound protocol we have designed a study to analyze data from the ILERVAS has been previously published (23). Two experienced project (ClinicalTrials.gov Identifier: NCT03228459) to describe examinators performed the examinations according to the prevalence of abnormal PI, as a surrogated marker of CM, in consensus recommendations for an optimal exploration an asymptomatic population (23, 24). (26), using General Electric Vivid I/Pro equipment (Horten, Norway). Experienced neurologists (FP MV GMC) directly reviewed the first 50 explorations. Afterwards, only explorations MATERIALS AND METHODS with doubts were reviewed. The transcranial arteries were Ethics Statement explored via transtemporal and transforaminal windows. Informed consent was obtained from all participants. The The gosling PI of each MCA was calculated automatically protocol was approved by the Hospital Universitari Arnau de by the equation [(systolic velocity-diastolic velocity)/mean Vilanova’s ethics committee (CEIC-1410). velocity] (27). To ensure accurate PI values, we only considered measurements if the Doppler spectrum wave- Study Design and Participants form envelope showed good quality, in at least, four The rationale and design of the ILERVAS study have been consecutive waveforms. Mean PI from both M1 segments extensively described and baseline data was published of MCA was calculated. Possible CM was defined by MCA-PI (www.elbusdelasalut.cat) (23, 24). Briefly, for the current >1.1 (27). Frontiers in Neurology | www.frontiersin.org 2 December 2021 | Volume 12 | Article 785640 Purroy et al. Cerebral Microangiopathy in Asymptomatic Population TABLE 1 | Anthropometrical data, cardiovascular risk factor criteria, smoking habit, laboratory results, and prevalence of atheroma plaque from the ILERVAS population according to cerebral microangiopathy. All population Possible CM patients Non-CM patients p-value Anthropometrical data n 3,282 424 2,858 Sex (male), n (%) 1,719 (52.4) 242 (57.1) 1,477 (51.7) 0.042 Age (years) 57 [52;62] 61 [56;65] 56 [52;61] <0.001 BMI (Kg/m2 ) 28.6 [25.8;31.8] 28.9 [26.3;32.2] 28.5 [25.6;31.7] 0.060 Waist circumference (cm) 100 [93;108] 102 [94;110] 100 [93;108] 0.001 Neck circumference (cm) 38 [35;41] 39 [36;42] 38 [35;41] 0.001 Systolic BP (mm Hg) 131 [120;142] 139 [127;151] 130 [119;141] <0.001 Diastolic BP (mm Hg) 82 [76;88] 79 [73;85] 83 [76;89] <0.001 Pulse pressure (mm Hg) 58 [41;57] 59 [50;69] 47 [40;55] <0.001 Vascular risk factor Hypertension, n (%) 1,315 (40.1) 235 (55.4) 1,080 (37.8) <0.001 Dyslipidemia, n (%) 1,686 (51.4) 217 (51.2) 1,469 (51.4) 0.932 Smoking habit <0.001 Non-smoker, n (%) 1,204 (36.7) 186 (43.9) 1,018 (35.6) Current smoker, n (%) 985 (30.0) 89 (21.0) 896 (31.4) Former smoker, n (%) 1,093 (33.3) 149 (35.1) 944 (33.0) Tobacco packages per year 20.8 [9.8;33.9] 23.8 [10.6;38.4] 20.5 [9.6;33.3] 0.051 Laboratory data HbA1c (%) 5.5 [5.3;5.7] 5.5 [5.3;5.8] 5.5 [5.3;5.7] 0.001 Total cholesterol (mg/dL) 202 [180;227] 196 [177;222] 203 [181;229] 0.001 GFR (mL/min per 1.73 m2 ) 96.9 [87.8;103.3] 94.5 [83.9;100.8] 97.4 [88.3;103.6] <0.001 Urine ACR (mg/g) 29 [29;29] 29 [29;29] 29 [29;29] 0.554 Atheroma plaque Anywhere, n (%) 2,226 (67.8) 328 (77.4) 1,898 (66.4) <0.001 Only in carotid arteries, n (%) 446 (14.2) 67 (15.8) 399 (14.0) 0.312 Only in femoral arteries, n (%) 777 (23.7) 88 (20.8) 689 (24.1) 0.128 Affected territories 1 [0;3] 2 [1;4] 1 [0;3] <0.001 Total plaque area (cm2 ) 0.5 [0.2;1.1] 0.6 [0.2;1.3] 0.5 [0.0;1.0] 0.014 Quantitative data are expressed as median [interquartile range] and qualitative variables are n (percentage). CM, cerebral microangiopathy; BMI, body mass index; BP, blood pressure; HbA1c, glycosylated hemoglobin; GFR, glomerular filtration rate; ACR, albumin to creatinine ratio. Extracranial Arterial Ultrasound Study interest to discriminate CM-patients from non-CM subjects was All subjects underwent a bilateral carotid and femoral ultrasound evaluated using a Receiver Operating Characteristic (ROC) curve exploration to assess the presence of atheromatous disease. analysis and a complete sensitivity/specificity report performed. Carotid exploration included common artery, bifurcation, The total area under the ROC curve value was interpreted internal, and external areas, whereas femoral exploration following these scores: 0.9–1.0 = excellent; 0.8–0.9 = good; included common and superficial areas. 0.7–0.8 = fair; 0.6–0.7 = poor; 0.5–0.6 = fail. A stepwise Plaques were defined as focal intrusions into the lumen multivariate regression analysis was used to explore the variables ≥1.5 mm thick according to Mannheim intima-media thickness independently related to PI. Variables with p < 0.10 in univariate consensus (28). The area of each plaque was quantified with testing were included. Statistical analyses were done using a caliper. The total plaque area was determined and expressed SPSS Statistics for Windows (version 20.0; IBM, Armonk, NY). in cm2 . Significance was considered at p < 0.05. Statistical Analysis Data Availability Statement Comparisons between groups were performed using the Mann– Request to access the data reported in this article will be Whitney U Test for numerical variables, and the Pearson’s considered by the corresponding author. chi-squared for categorical variables. The correlation between quantitative variables was analyzed using Spearman’s test. RESULTS Quantitative data are showed in median (interquartile range [IQR]). Qualitative data are given in absolute and relative A total of 3,721 subjects were initially evaluated. A number frequencies). The accuracy of pulse pressure as a measurement of of subjects, 439 (11.8%), were excluded due to low quality of Frontiers in Neurology | www.frontiersin.org 3 December 2021 | Volume 12 | Article 785640 Purroy et al. Cerebral Microangiopathy in Asymptomatic Population FIGURE 1 | Prevalence of atheromatosis between cerebral microangiopathy patients according to the location of atheroma plaque. CM, cerebral microangiopathy. TCD images. Therefore, 3,282 subjects were included in the presence of an abnormal PI [mean difference 5.1 (95% CI 4.1– study. Median age was 57 [IQR 52, 62] years and body mass 6.5)] in comparison with subjects with normal PI values. Finally, index (BMI) was 28.6 [IQR 25.8, 31.8] kg/m2 . The complete a stepwise multivariate regression analysis showed that age, anthropometrical data, vascular risk factor diagnosis, smoking male gender, and pulse pressure were predictors of possible CM habits, laboratory data, and prevalence of atheroma plaque (STATS) (Table 2). according to the presence of possible CM are shown in Table 1. There was a significant difference in all data between normal and DISCUSSION abnormal MCA-PI, except for BMI and dyslipidemia diagnosis. Median PI value in all population was 0.84 [IQR 0.76, 0.93]. In the current study, we have observed that one of ten patients Possible CM was found in 424 (12.9%) subjects. Possible CM from a cohort of middle-aged population with low-to-moderate prevalence was increased according to age (STATS, p < 0.001). vascular risk showed possible CM detected by abnormal MCA- CM patients had higher prevalence of plaque number on affected PI. Abnormal MCA-PI was related to sex male, age, pulse territories and its total plaque area compared to non-CM patients pressure, and the extension of the subclinical atheromatous. (Table 1). Equal prevalence of atheromatosis in both groups was Traditionally, modifiable vascular risk factors (VRF) and age detected when carotid and femoral were analyzed separately are both associated with atheromatous vascular disease which is (Figure 1). PI value had a positive linear correlation with several the main leading cause of mortality worldwide (29). Moreover, affected territories and its total plaque area in non-CM subjects. according to epidemiological studies VRF contribute to cognitive In addition, PI had a positive linear correlation with the number decline (30). Treatment of VRF is associated with a reduced of territories with plaques (r = 0.130, p < 0.001), the total plaque risk of Alzheimer’s disease conversion in mild cognitive patients area (r = 0.082, p < 0.001), the glycosylated hemoglobin levels (31). Initially, the ILERVAS study was designed as a randomized, (r = 0.065, p < 0.001), and a negative correlation with the interventional, longitudinal clinical trial to assess the prevalence, glomerular filtration rate (r = −0.120, p < 0.001). vascular distribution, severity and progression of subclinical Based on the ROC analysis, the pulse pressure was a good atheromatosis, and its impact on the incidence of vascular test to identify CM-patients among all subjects. The best cut-off events on a 10-year follow-up (23). However, among low-to- point for pulse pressure (combining sensitivity and specificity) moderate vascular risk patients it is also interesting to detect was 50 mmHg. At this value, the area under the curve was subclinical CM which could be related to cognitive impairment 0.760 (0.736–0.785), sensitivity was 74%, and specificity was 64% (13–15, 17, 32, 33). Previous studies have shown an elevation in (Figure 2). Concretely, the percentage of CM-patients increased PIs with small vessel disease (2–5) and cognitive impairment, from 39.3% with a skin pulse pressure <50 mmHg to 76.9% or its progression (1, 32–34). In the Barcelona-Asymptomatic of CM-patients with a skin pulse pressure ≥50 mmHg (STATS, Intracranial Atherosclerosis (AsIA) study, which included 50– p < 0.001). This data indicated a 5-fold increased risk of the 65 year-old subjects free from dementia and without history of Frontiers in Neurology | www.frontiersin.org 4 December 2021 | Volume 12 | Article 785640 Purroy et al. Cerebral Microangiopathy in Asymptomatic Population acquired on a 3T-MRI and with poor performance in attention, psychomotor speed, and visuospatial skills (21). Our results are related to the previous evidence. We observed a relationship between age and abnormal MCA-PI. It is known that CM is directly related to age, and therefore, it is expected to observe a higher vascular resistance measured by MCA-PI in aged patients (13, 16, 17). Pulse pressure, which is associated with vascular dysfunction, has also been related to CM (35, 36). Interestingly, subjects with extended subclinical atheromatous disease with plaques in carotid and femoral territories had higher proportion of abnormal MCA-PI. So, in middle-aged subjects with low-to-moderate vascular risk macro and microvascular impairment could progress in parallel. The main limitation of our study is that we have assumed that abnormal MCA-PI was a surrogated marker of CM, and we have accepted a cut-off previously established in a different population. We have realized that MRI is the preferred brain diagnostic imaging modality to detect CM (13, 15–17). However, TCD is widely used and less expensive than MRI. Finally, MCA- PI can be affected by cerebral hemodynamics like hypertensive FIGURE 2 | Receiver Operating Characteristics (ROC) curve analysis to or hypotensive status, anemia, or heart failure (2) that were not evaluate the accuracy of pulse pressure as a measurement of interest to systematically recorded. discriminate cerebral microangiopathy patients from non-cerebral In conclusion, our data suggest that the proportion of microangiopathy together with a sensitivity/specificity report. AUC, area under subclinical potential CM is not insignificant. The clinical the ROC curve. relevance of abnormal baseline MCA-PI should be determined after the end of the 10-year follow-up of the project. Our hypothesis is that abnormal baseline MCA-PI could increase TABLE 2 | Multinomial Logistic Regression model for presence of possible cerebral microangiopathy for development cohort. the risk of brain microangiopathy (37), lacunar stroke, cognitive impairment, and motor impairment. OR (95% IC) p Gender Female Ref. DATA AVAILABILITY STATEMENT Male 2.21 (1.49–3.25) <0.001 Age (years) 1.04 (1.01–1.08) 0.008 The raw data supporting the conclusions of this article will be 2 made available by the authors, without undue reservation. BMI (kg/m ) 0.99 (0.96–1.02) 0.462 PP (mmHg) 1.07 (1.06–1.08) <0.001 Hypertension Diagnosis No Ref. ETHICS STATEMENT Yes 0.89 (0.64–1.23) 0.471 Dyslipidemia Diagnosis No Ref. The protocol was approved by the Arnau de Vilanova Yes 0.89 (0.69–1.29) 0.719 University Hospital Ethics Committee (CEIC-1410). The Never smoker Never Ref. patients/participants provided their written informed consent to Former - participate in this study. Current - Packages per year 1.00 (0.99–1.01) 0.295 ILERVAS PROJECT HbA1c (%) 1.33 (0.99–1.78) 0.056 Total cholesterol (mg/dL) 0.99 (0.99–1.00) 0.021 José Manuel Valdivielso, Vascular and Renal Translational GFR (mL/min per 1.73 m2 ) 1.00 (0.99–1.01) 0.702 Research Group, IRBLleida, ReinRen-ISCIII, University of Atheroma plaque No Ref. Lleida, Lleida, Spain; Serafí Cambray, Vascular and Renal Yes 0.84 (0.55–1.28) 0.414 Translational Research Group, IRBLleida, ReinRen-ISCIII, University of Lleida, Lleida, Spain; Eva Castro, Vascular and BMI, body mass index; PP, pulse pressure; HbA1c, glycosylated hemoglobin; GFR, glomerular filtration rate. Bold indicates significant p-values. Renal Translational Research Group, IRBLleida, ReinRen-ISCIII, University of Lleida, Lleida, Spain; Montserrat Martínez-Alonso, Applied Epidemiology Research Group, Lleida, Spain; Manuel Portero-otín, Department of Experimental Medicine, Metabolic vascular disease, MCA-PI was significantly associated with white Pathophysiology Research Group, Systems Biology and matter disintegration in different tracts (fornix, corticospinal Statistical Methods for Biomedical Research Group, IRBLleida, and anterior thalamic) measured by diffusion tensor images University of Lleida, Lleida, Spain; Mariona Jové, Department Frontiers in Neurology | www.frontiersin.org 5 December 2021 | Volume 12 | Article 785640 Purroy et al. Cerebral Microangiopathy in Asymptomatic Population of Experimental Medicine, Metabolic Pathophysiology Research authors commented on and approved submission of Group, Systems Biology and Statistical Methods for Biomedical this manuscript. Research Group, IRBLleida, University of Lleida, Lleida, Spain; Ferran Rius, Department of Endocrinology and FUNDING Nutrition, Research Group on Immunology and Metabolism, IRBLleida, University Hospital Arnau de Vilanova, University This work was supported by grants from the Diputacio de of Lleida, Lleida, Spain; Jessica González, Pneumology Service, Lleida, Instituto de Salud Carlos III (RETIC RD16/0009/0011) Translational Research in Respiratory Medicine Research Group, and Ministerio de Ciencia, Inovación y Universidades IRBLleida, University Hospital Arnau de Vilanova, University (IJC2018-037792-I). FP was supported by the Catalan of Lleida, Lleida, Spain; Silvia Barril, Pneumology Service, Autonomous Government’s Agència de Gestió d’Ajuts Translational Research in Respiratory Medicine Research Group, Universitaris i de Recerca (2017 suport a les activitats dels IRBLleida, University Hospital Arnau de Vilanova, University grups de recerca 1628). RP was supported by the Spanish of Lleida, Lleida, Spain; Gerard Torres, CIBER de Enfermedades Ministry of Science, Innovation, and Universities (grant Respiratorias, CIBERES, Instituto de Salud Carlos III (ISCIII), RTI2018-099200-B-I00), and the Generalitat of Catalonia: Lleida, Spain; Pere Godoy, Departament de Salut, Secretaria Agency for Management of University and Research de Salut Pública, Generalitat de Catalunya, Lleida, Spain; Eva Grants (2017SGR696). This study was co-financed by Miquel, DAP Lleida, Unitat de Suport a la Recerca - IDIAP FEDER funds from the European Union (A way to build Jordi Gol, Lleida, Spain; Marta Ortega, DAP Lleida, Unitat de Europe). IRBLleida is a CERCA Programme/Generalitat Suport a la Recerca - IDIAP Jordi Gol, Lleida, Spain; Esmeralda of Catalonia. Castelblanco, Applied Epidemiology Research Group, Lleida, Spain; Josep Franch-Nadal, Applied Epidemiology Research ACKNOWLEDGMENTS Group, Lleida, Spain. The authors would like to thank Virtudes María, Marta AUTHOR CONTRIBUTIONS Elias, Teresa Molí, Cristina Domínguez, Noemí Nova, Alba Prunera, Núria Sans, Meritxell Soria, Francesc Pons, FP, AL, FB, EF, RP, CF, DM, and MB-L conceived the study Rebeca Senar, Pau Guix, Fundació Renal Jaume Arnó, and the and procured funding. FP designed the experiments. AL, primary care teams of the province of Lleida for recruiting GA, MV-P, GM-C, NT, MH, FB, and CF were responsible for participants and their efforts in the accurate development the recruitment of patients and clinical data acquisition. of the ILERVAS project. Samples were obtained with GA, ES, AL, and FP conducted the sample processing support from IRBLleida Biobank (B.0000682) and Plataforma and data analysis. ES, AL, and FP wrote the paper. All Biobancos PT17/0015/0027. REFERENCES 8. Lee WJ, Jung KH Ryu YJ, Lee KJ, Kim JM, Lee ST, et al. Progression of Cerebral White Matter Hyperintensities and the Associated Sonographic 1. Lim EY, Yang DW, Cho AH, Shim YS. Cerebrovascular Hemodynamics Index. Radiology. (2017) 284:824–33. doi: 10.1148/radiol.2017162064 on Transcranial Doppler Ultrasonography and Cognitive Decline 9. Nam KW, Kwon HM, Lee YS. Distinct association between cerebral arterial in Mild Cognitive Impairment. J Alzheimers Dis. (2018) 65:651– pulsatility and subtypes of cerebral small vessel disease. PLoS ONE. (2020) 7. doi: 10.3233/JAD-180026 15:e0236049. doi: 10.1371/journal.pone.0236049 2. Kidwell CS. el-Saden S, Livshits Z, Martin NA, Glenn TC, 10. Sanahuja J, Alonso N, Diez J, Ortega E, Rubinat E, Traveset A, et al. Increased Saver JL. Transcranial Doppler pulsatility indices as a measure burden of cerebral small vessel disease in patients with type 2 diabetes and of diffuse small-vessel disease. J Neuroimaging. (2001) 11:229– retinopathy. Diabetes Care. (2016) 39:1614–20. doi: 10.2337/dc15-2671 35. doi: 10.1111/j.1552-6569.2001.tb00039.x 11. Lee KO, Lee KY, Lee SY, Ahn CW, Park JS. Lacunar infarction in type 2 3. Lee KY, Sohn YH, Baik JS, Kim GW, Kim JS. Arterial pulsatility as an diabetes is associated with an elevated intracranial arterial pulsatility index. index of cerebral microangiopathy in diabetes. Stroke. (2000) 31:1111– Yonsei Med J. (2007) 48:802–6. doi: 10.3349/ymj.2007.48.5.802 5. doi: 10.1161/01.STR.31.5.1111 12. Han SW, Lee SS, Kim SH, Lee JH, Kim GS, Kim OJ, et al. Effect of cilostazol 4. Mok V, Ding D, Fu J, Xiong Y, Chu WW, Wang D, et al. Transcranial Doppler in acute lacunar infarction based on pulsatility index of transcranial Doppler ultrasound for screening cerebral small vessel disease: a community study. (ECLIPse): a multicenter, randomized, double-blind, placebo-controlled trial. Stroke. (2012) 43:2791–3. doi: 10.1161/STROKEAHA.112.665711 Eur Neurol. (2013) 69:33–40. doi: 10.1159/000338247 5. Purkayastha S, Fadar O, Mehregan A, Salat DH, Moscufo N, Meier 13. Regenhardt RW, Das AS, Lo EH, Caplan LR. Advances in understanding the DS, et al. Impaired cerebrovascular hemodynamics are associated with pathophysiology of lacunar stroke: a review. JAMA Neurol. (2018) 75:1273– cerebral white matter damage. J Cereb Blood Flow Metab. (2014) 34:228– 81. doi: 10.1001/jamaneurol.2018.1073 34. doi: 10.1038/jcbfm.2013.180 14. Shabir O, Berwick J, Francis SE. Neurovascular dysfunction in vascular 6. Ghorbani A, Ahmadi MJ, Shemshaki H. The value of transcranial Doppler dementia, Alzheimer’s and atherosclerosis. BMC Neurosci. (2018) derived pulsatility index for diagnosing cerebral small-vessel disease. Adv 19:62. doi: 10.1186/s12868-018-0465-5 Biomed Res. (2015) 4:54. doi: 10.4103/2277-9175.151574 15. Caplan LR. Lacunar infarction and small vessel disease: pathology and 7. Fu S, Zhang J, Zhang H, Zhang S. Predictive value of transcranial pathophysiology. J Stroke. (2015) 17:2–6. doi: 10.5853/jos.2015.17.1.2 Doppler ultrasound for cerebral small vessel disease in elderly patients. 16. Cannistraro RJ, Badi M, Eidelman BH, Dickson DW, Middlebrooks EH, Arq Neuropsiquiatr. (2019) 77:310–4. doi: 10.1590/0004-282x201 Meschia JF, et al. small vessel disease: A clinical review. Neurology. (2019) 90050 92:1146–56. doi: 10.1212/WNL.0000000000007654 Frontiers in Neurology | www.frontiersin.org 6 December 2021 | Volume 12 | Article 785640 Purroy et al. Cerebral Microangiopathy in Asymptomatic Population 17. Cuadrado-Godia E, Dwivedi P, Sharma S, Ois Santiago A, Roquer Gonzalez a systematic analysis for the Global Burden of Disease Study 2017. Lancet. J, Balcells M, et al. Cerebral Small Vessel Disease: A Review Focusing on (2018) 392:1736–88. doi: 10.1016/S0140-6736(18)32203-7 Pathophysiology, Biomarkers, and Machine Learning Strategies. J Stroke. 30. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, (2018) 20:302–20. doi: 10.5853/jos.2017.02922 Alhainen K, et al. Midlife vascular risk factors and Alzheimer’s disease 18. Pinter D, Ritchie SJ, Doubal F, Gattringer T, Morris Z, Bastin ME, et al. in later life: longitudinal, population based study. BMJ. (2001) 322:1447– Impact of small vessel disease in the brain on gait and balance. Sci Rep. (2017) 51. doi: 10.1136/bmj.322.7300.1447 7:41637. doi: 10.1038/srep41637 31. Li J, Wang YJ, Zhang M, Xu ZQ, Gao CY, Fang CQ, et al. Vascular risk factors 19. van Sloten TT, Sigurdsson S, van Buchem MA, Phillips CL, Jonsson promote conversion from mild cognitive impairment to Alzheimer disease. PV, Ding J, et al. Cerebral Small Vessel Disease and Association Neurology. (2011) 76:1485–91. doi: 10.1212/WNL.0b013e318217e7a4 With Higher Incidence of Depressive Symptoms in a General Elderly 32. Altmann M, Thommessen B, Ronning OM, Benth JS, Reichenbach AS, Population: The AGES-Reykjavik Study. Am J Psychiatry. (2015) 172:570– Fure B. Middle Cerebral Artery Pulsatility Index is Associated with 8. doi: 10.1176/appi.ajp.2014.14050578 Cognitive Impairment in Lacunar Stroke. J Neuroimaging. (2016) 26:431– 20. Schaeffer S, Iadecola C. Revisiting the neurovascular unit. Nat Neurosci. (2021) 5. doi: 10.1111/jon.12335 24:1198–209. doi: 10.1038/s41593-021-00904-7 33. Chung CP, Lee HY, Lin PC, Wang PN. Cerebral Artery Pulsatility is Associated 21. Lopez-Oloriz J, Lopez-Cancio E, Arenillas JF, Hernandez M, Dorado L, with Cognitive Impairment and Predicts Dementia in Individuals with Dacosta-Aguayo R, et al. Diffusion tensor imaging, intracranial vascular Subjective Memory Decline or Mild Cognitive Impairment. J Alzheimers Dis. resistance and cognition in middle-aged asymptomatic subjects. Cerebrovasc (2017). doi: 10.3233/JAD-170349 Dis. (2014) 38:24–30. doi: 10.1159/000363620 34. Lim JS, Lee JY, Kwon HM, Lee YS. The correlation between cerebral arterial 22. Riba I, Jarca CI, Mundet X, Tovar JL, Orfila F, Nafria C, et al. Cognitive pulsatility and cognitive dysfunction in Alzheimer’s disease patients. J Neurol assessment protocol design in the ISSYS (Investigating Silent Strokes in Sci. (2017) 373:285–8. doi: 10.1016/j.jns.2017.01.001 hYpertensives: a magnetic resonance imaging Study). J Neurol Sci. (2012) 35. Reas ET, Laughlin GA, Hagler DJ Jr, Lee RR, Dale AM, McEvoy LK. 322:79–81. doi: 10.1016/j.jns.2012.06.015 Age and sex differences in the associations of pulse pressure with 23. Bermudez-Lopez M, Martinez-Alonso M, Castro-Boque E, Betriu A, Cambray white matter and subcortical microstructure. Hypertension. (2021) 77:938– S, Farras C, et al. Subclinical atheromatosis localization and burden in a 47. doi: 10.1161/HYPERTENSIONAHA.120.16446 low-to-moderate cardiovascular risk population: the ILERVAS study. Rev Esp 36. Wang Z, Wong A, Liu W, Yang J, Chu WC, Au L, et al. Pulse pressure Cardiol (Engl Ed). (2020). doi: 10.1016/j.rec.2020.09.015 and cognitive decline in stroke patients with white matter changes. J Clin 24. Betriu A, Farras C, Abajo M, Martinez-Alonso M, Arroyo D, Barbe F, et al. Hypertens (Greenwich). (2015) 17:694–8. doi: 10.1111/jch.12583 Randomised intervention study to assess the prevalence of subclinical vascular 37. Rodriguez I, Lema I, Blanco M, Rodriguez-Yanez M, Leira R, Castillo J. disease and hidden kidney disease and its impact on morbidity and mortality: Vascular retinal, neuroimaging and ultrasonographic markers of lacunar The ILERVAS project. Nefrologia: publicacion oficial de la Sociedad Espanola infarcts. Int J Stroke. (2010) 5:360–6. doi: 10.1111/j.1747-4949.2010.00462.x Nefrologia. (2016) 36:389–96. doi: 10.1016/j.nefroe.2016.07.006 25. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF. 3rd, Feldman Conflict of Interest: The authors declare that the research was conducted in the HI, et al. A new equation to estimate glomerular filtration rate. Ann absence of any commercial or financial relationships that could be construed as a Intern Med. (2009) 150:604–12. doi: 10.7326/0003-4819-150-9-200905050- potential conflict of interest. 00006 26. Nedelmann M, Stolz E, Gerriets T, Baumgartner RW, Malferrari G, Seidel Publisher’s Note: All claims expressed in this article are solely those of the authors G, et al. Consensus recommendations for transcranial color-coded duplex sonography for the assessment of intracranial arteries in clinical trials on and do not necessarily represent those of their affiliated organizations, or those of acute stroke. Stroke. (2009) 40:3238–44. doi: 10.1161/STROKEAHA.109. the publisher, the editors and the reviewers. Any product that may be evaluated in 555169 this article, or claim that may be made by its manufacturer, is not guaranteed or 27. Sharma VK, Tsivgoulis G, Lao AY, Malkoff MD, Alexandrov AV. endorsed by the publisher. Noninvasive detection of diffuse intracranial disease. Stroke. (2007) 38:3175– 81. doi: 10.1161/STROKEAHA.107.490755 Copyright © 2021 Purroy, Sánchez, Lecube, Arqué, Vicente-Pascual, Mauri- 28. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, Capdevila, Torreguitart, Hernández, Barbé, Fernández, Pamplona, Farràs, et al. Mannheim carotid intima-media thickness consensus (2004-2006). An Mauricio, Bermúdez-López and the ILERVAS project. This is an open-access article update on behalf of the Advisory Board of the 3rd and 4th Watching the distributed under the terms of the Creative Commons Attribution License (CC BY). Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, The use, distribution or reproduction in other forums is permitted, provided the Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis. (2007) 23:75– original author(s) and the copyright owner(s) are credited and that the original 80. doi: 10.1159/000097034 publication in this journal is cited, in accordance with accepted academic practice. 29. Collaborators GBDCoD. Global, regional, and national age-sex-specific No use, distribution or reproduction is permitted which does not comply with these mortality for 282 causes of death in 195 countries and territories, 1980-2017: terms. Frontiers in Neurology | www.frontiersin.org 7 December 2021 | Volume 12 | Article 785640