geronageronaJournals of Gerontology Series A: Biomedical Sciences and Medical Sciences1758-535X1079-5006Oxford University Press10.1093/gerona/glp105Journal of Gerontology: Medical SciencesRapid CommunicationCardiac Autonomic Dysfunction Is Associated With White Matter Lesions in Patients With Mild Cognitive ImpairmentGalluzziSamantha1NicosiaFranco2GeroldiCristina13AlicandriAlberto2BonettiMatteo4RomanelliGiuseppe2ZulliRoberto2FrisoniGiovanni B.1351Laboratory of Epidemiology, Neuroimaging and Telemedicine (LENITEM), IRCCS San Giovanni di Dio-Fatebenefratelli, Brescia, Italy2Institute of Internal Medicine, Department of Medical Sciences, University of Brescia, Italy3Psychogeriatric Unit, IRCCS San Giovanni di Dio-Fatebenefratelli, Brescia, Italy4Service of Neuroradiology, Istituto Clinico Città di Brescia, Italy5Associazione Fatebenefratelli per la Ricerca (AFaR), Rome, ItalyAddress correspondence to Giovanni B. Frisoni, MD, Laboratory of Epidemiology Neuroimaging & Telemedicine (LENITEM), IRCCS San Giovanni di Dio FBF—The National Center for Research and Care of Alzheimer’s Disease, Via Pilastroni 4, 25125, Brescia, Italy. Email: gfrisoni@fatebenefratelli.itDecision Editor: Luigi Ferrucci, MD, PhD122009307200964A121312131529820082032009© The Author 2009. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.2009BackgroundCardiac autonomic dysfunction has been associated with cognitive impairment, but the underlying pathogenesis is complex and cerebral white matter lesions (WMLs) might be implicated.MethodsTime and frequency heart rate variability (HRV) and visual rating of WMLs were carried out in 42 patients with mild cognitive impairment.ResultsAfter adjustment for relevant demographic and clinical characteristics, including left ventricular mass, reduced HRV indices of parasympathetic (root mean square of successive difference of RR intervals, RMSSD) and sympathetic modulation (low-frequency [LF] power) were associated with increased WML score (RMSSD: B −0.30, 95% CI −0.52 to −0.08, p = .01; LF: B −0.24, 95% CI −0.46 to −0.02, p = .05). In a multiple-adjusted model, RMSSD was the major independent predictor of WMLs (B −0.35, 95% CI −0.57 to −0.13, p = .002).ConclusionThe evidence for an independent association of cardiac autonomic dysfunction with WMLs might suggest its role in the pathogenesis of WMLs.Heart rate variabilityCardiac autonomic dysfunctionWhite matter lesionsMild cognitive impairmentHEART rate variability (HRV) is a marker of cardiovascular autonomic function (1). Reduced HRV has recently gained attention in the dementia research field because of its association with cerebrovascular risk factors (2) and Alzheimer’s disease (3). Moreover, in a sample of older disabled women from the community, root mean square of successive difference of RR intervals (RMSSD) and high-frequency (HF) power, indicators of parasympathetic-mediated short-term variations in heart rate, were predictors of cognitive impairment development, being associated with 3.4 and 6.7 times greater odds of cognitive impairment, respectively (4).Understanding pathophysiological mechanisms leading to cognitive impairment is of great interest to develop preventive therapies. However, the pathway underlying the association between reduced HRV and cognitive impairment is unclear. Cerebral white matter lesions (WMLs) might have a mediating role (4), but brain imaging studies are lacking.The aim of this study was to evaluate the independent association of HRV with WMLs in patients with mild cognitive impairment (MCI). Given the higher prevalence of WMLs in MCI patients relative to cognitively normal elders, we focused this study on the former group in order to improve the power to detect an association with HRV.METHODSMCI PatientsPatients were recruited from a prospective study on the natural history of MCI (“Mild Cognitive Impairment in Brescia” study) carried out in the outpatients’ section of the Alzheimer’s Unit, IRCCS San Giovanni di Dio-Fatebenefratelli, Brescia, Italy. Inclusion criteria included the presence of subjective and objective memory or other cognitive domain disturbance in the absence of functional impairment. More details were published elsewhere (5).One hundred thirty-six patients were enrolled from April 2002 to March 2005. For the present study, only those 94 patients who performed both 24-hour electrocardiogram (ECG) monitoring and magnetic resonance (MR) imaging were selected. Twelve patients were excluded because of inadequate quality of the exams. Those 82 patients finally included in the study were not different from 54 excluded as education, sex, and vascular risk factors but were younger (69.3 + 7.3 vs 72.5 + 8.8 years, p = .03).Clinical AssessmentGlobal cognition and depressive symptoms were assessed using the Mini-Mental State Examination (6) and the depression subscale of the Brief Symptom Inventory (7), respectively, the latter ranging from 0 to 24 (higher scores indicated poorer depressive symptoms). Hypertension and diabetes mellitus and heart diseases (coronary artery disease, primary arrhythmias, and heart failure) were clinically diagnosed and defined present if currently treated. Echocardiography was made in 67 of 82 patients. The remaining 15 patients refused the examination because of logistic difficulties. The left ventricular (LV) mass was calculated from Devereux’s formula and indexed by height.HRV MeasurementTwenty-four-hour ECG recording (Accuplus 363; Del Mar Avionics, Irvine, CA) was used to analyze HRV using implemented software. In the time domain, standard deviation of the RR intervals, standard deviation of the 5-minute mean values of RRs for each 5-minute interval, average of standard deviations of RR for each 5-minute interval, and the RMSSD were calculated. In the frequency domain, low frequency (LF) 0.04–0.15 Hz, HF 0.15–0.40 Hz, and low- or high-frequency ratio were calculated. A detailed description of ECG recording procedures was available on http://www.centroalzheimer.it/public/Methods_HRV.MR ImagingMR images were acquired at the Service of Neuroradiology, Istituto Clinico Città di Brescia, Brescia, using a 1.0 Tesla Philips Gyroscan. Axial T2 weighted, proton density, and fluid-attenuated inversion recovery images were acquired. WMLs were assessed using the rating scale for age-related white matter changes (ARWMC) (8). Total score (range 0–30) was the sum of subscores for frontal, parieto-occipital, temporal, infratentorial areas, and basal ganglia areas (range 0–3) in the left and right hemispheres. In the present study, WMLs were considered as present when ARWMC scale total score was 4 or more or when beginning confluence of lesions (subscore 2) was observed in at least one area. Based on this criteria, patients were divided into 32 with and 50 without WMLs.Statistical AnalysisThe data were analyzed using SPSS version 13.0 (SPSS, Chicago, IL). Sociodemographic and clinical differences between MCI groups with and without WMLs were assessed with t test for normally distributed continuous variables, Mann–Whitney test for nonnormally distributed continuous variables, and chi-square for categorical variables. In the whole-MCI group, the association between each HRV index and WMLs (i.e., the ARWMC scale total score) was assessed with linear regression models and the power of HRV indices to predict the extent of WMLs with a stepwise multiple regression model. Confounders were chosen among the main demographic and clinical characteristics that, based on current knowledge, have been associated with WMLs (age, diabetes, heart disease, hypertension) or have been showed to affect cardiac autonomic function (beta-blockers use, LV mass).RESULTSTable 1 shows that MCI patients with WMLs were older than those without WMLs while cognition and depression were similar. All the vascular disease and risk factors were more prevalent in MCI with WMLs, only hypertension reaching statistical significance. Among HRV indices, the RMSSD and LF were reduced in MCI patients with WMLs relative to those without WMLs (unadjusted p < .001).Table 1.Demographic and Clinical Characteristics of 82 Patients With MCI by Presence of WMLsCharacteristicsWMLs Absent (n = 50)WMLs Present (n = 32)p*Demographics    Age67.6 ± 7.672.2 ± 5.9.005    Gender, female31 (62%)20 (63%).96    Education7.9 ± 4.56.6 ± 2.9.28Cognition and mood    Mini-Mental State Examination27.0 ± 1.527.3 ± 1.5.43    Depression, Brief Symptom Inventory4.1 ± 4.83.4 ± 4.2.72Vascular diseases and risk factors    Hypertension12 (24%)17 (53%).007    Heart disease8 (16%)7 (22%).50    Diabetes mellitus4 (8%)4 (13%).50    Beta-blocker use7 (14%)9 (28%).12    Left ventricular mass†105.1 ± 31.4116.1 ± 31.0.16Heart rate variability features    SD of the RR intervals, ms118.9 ± 36.8111.7 ± 36.9.39    SD of the 5-minute mean values of RR   for each 5-minute interval, ms68.3 ± 18.262.6 ± 16.9.16    Average of SDs of RR for each   5-minute interval, ms95.0 ± 38.589.0 ± 35.9.49    Root mean square of successive   difference of RR intervals, ms26.5 ± 8.720.2 ± 5.5<.001    Low-frequency power, ms2212.1 ± 152.5151.1 ± 118.8.05    High-frequency power, ms288.0 ± 65.570.4 ± 73.7.06Notes: *Significance on t test or Mann–Whitney test for normally or nonnormally distributed continuous variables and chi-square for categorical variables.†Available in 41 and 26 MCI patients, respectively. Values denote mean ± SD or number (%). MCI = mild cognitive impairment; WMLs = white matter lesions.Table 2 shows that in the whole-MCI group, the RMSSD, LF, and HF were inversely associated with the extent of WMLs in the unadjusted models (p < .001), whereas only the association of decreased RMSSD with increased WML score retained significance in the adjusted models (p = .01). When also the confounding effect of LV mass was taken in account, the association was even significant for RMSSD (p = .01) and reached significance also for LF (p = .05).Table 2.Association of HRV Indices With White Matter Lesions in 82 Patients With Mild Cognitive ImpairmentHRV IndexUnadjustedAdjusted for Age, Diabetes Mellitus, Heart Disease, Hypertension, Beta-blockersAdjusted for the Previous Plus LV MassB95% CIpB95% CIpB95% CIpSDNN−0.08−0.30 to 0.14.480.10−0.12 to 0.32.350.06−0.16 to 0.28.61SDANN−0.18−0.40 to 0.04.11−0.03−0.25 to 0.19.78−0.08−0.30 to 0.14.51SDNN idx−0.05−0.27 to 0.17.680.13−0.09 to 0.35.230.10−0.12 to 0.32.43RMSSD−0.37−0.59 to −0.15.001−0.27−0.49 to −0.05.01−0.30−0.52 to −0.08.01LF−0.30−0.52 to −0.08.006−0.15−0.37 to 0.07.15−0.24−0.46 to −0.02.05HF−0.23−0.45 to −0.01.04−0.11−0.33 to 0.11.31−0.18−0.40 to 0.04.14Notes: Regression coefficients were computed in 18 separate linear regression models and denote the increase of the dependent for a 1-Unit increase of the independent variable. Models adjusted for LV mass included 67 patients.HF = high-frequency power; HRV = heart rate variability; LF = low-frequency power; LV = left ventricular; RMSSD = root mean square of successive difference of RR intervals; SDANN = standard deviation of the 5-minute mean values of RR for each 5-minute interval; SDNN = standard deviation of the RR intervals; SDNN idx = average of standard deviations of RR for each 5-minute interval.Stepwise multiple regression analysis including HRV indices significantly associated with WMLs in univariate models (RMSSD, LF, and HF) and confounders showed that the RMSSD and age were significant predictors of WMLs (B −0.30, 95% CI −0.52 to −0.08, p = .002; B 0.38, 95% CI 0.16–0.60, p < .0005, respectively), also in the model adjusted for LV mass (RMSSD: B −0.35, 95% CI −0.47 to −0.22, p = .002).DISCUSSIONThis study showed that in MCI patients, reduced RMSSD, an index of parasympathetic-mediated short-term component of HRV, was associated with extent of WMLs, suggesting a possible role of cardiac autonomic dysfunction in the WML pathogenesis.Studies assessing the relationship between HRV and WMLs are scanty and have used different methods to measure HRV, making results difficult to compare (9–11). To our best knowledge, the only study assessing HRV using power spectral analysis analyzed only frequency-domain measures and found that LF was significantly lower in hypertensive patients with lacunar infarctions than in those without lacunar infarctions (12).In the present study, RMSSD was the only HRV index to demonstrate an association with WMLs in multivariate models. This was in line with previous finding that proved RMSSD to be more closely associated with cognitive impairment than indicators of long-term variations in heart rate (4). The pathological mechanisms possibly linking cardiac autonomic dysfunction to WMLs might include abnormalities in heart rate control and vascular dynamics (13) or the role of intermediate factors (neurally mediated syncope, orthostatic hypotension, or increased blood pressure variability) that were found to be associated with both HRV (4,13,14) and WML development (15).A possible alternative explanation is that reduced HRV is a consequence and not a cause of WMLs. Although cerebrovascular diseases frequently cause disturbances to cardiovascular autonomic functions, this has been reported only in patients with clinically overt stroke due to large-vessel disease (16,17). Only longitudinal studies assessing causality might clarify this issue.There were some limitations to this study. First, this was a cross-sectional association study that prevents to determine the causal relationships and definitively indicate pathophysiological pathways leading from reduced HRV to WMLs. Second, the possible confounding role of neurodegeneration that, in addition to WMLs, might contribute to cardiac autonomic dysfunction and of vascular risk factors, such as dyslipidemia, has not been taken into account. Lastly, the clinical setting where the study has been implemented prevents generalizability before the results are replicated in a large population-based sample of older persons.In conclusion, we showed that reduced short-term component of HRV was associated with WMLs in patients with MCI. 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