Able 4. Multiple logistic regression analysis of the effect of age on likelihood of having Scheltens deep WMH score in highest vs. lowest quartile (final model).B 1 APOEe4 alleleS.E. pOdds Ratio Exp. (B) (95 CI) Age (years)BS.E.pOdds Ratio Exp. (B) (95 CI)22.595 1.242 0.037 0.075 (0.007?.851)0.112 0.048 0.019 1.119 (1.018?.230)APOE = apolipoprotein E; WMH = white matter hyperintensities; CI = confidence interval. doi:10.1371/journal.pone.0052196.tAPOE = Apolipoprotein E; WMH = white matter hyperintensities; CI = confidence interval. doi:10.1371/journal.pone.0052196.thave lower standing systolic BP values than AD [23], whereas in our study the majority had AD. Furthermore, in these two last studies blood pressures were measured partly or only during carotid sinus massage, as opposed to our study, in which the blood pressures were measured only in the supine (or sitting) position and during active standing. Subjects with OH Epigenetic Reader Domain according to these two different methods may not be comparable, e.g. concerning the pathophysiology of WMH. In our study, the presence of at least one APOEe4 allele was associated with reduced odds of having high WMH volume, suggesting that other APOEe alleles (i.e. e2 and/or e3) may increase the odds of high WMH volume. This hypothesis is supported by at least two previous studies [41,42]. Notably, none of these included subjects with dementia. Alternatively, patients possessing the e4 allele may have more neurodegenerative changes and thus develop 25837696 dementia with a lower WMH load. However, the majority of studies in this field have not demonstrated any association between APOEe4 status and WMH burden [43?8]. In contrast to some previous studies (e.g. [49]), we did not find any significant associations between hypertension and WMH. This could have inhibitor several possible explanations, including different definitions of hypertension, different study designs, and differences regarding samples. This being a multicentre study, it is possible that the measured or scored WMH values might vary systematically according to scanning site. The results of the phantom studies, as well as the results of the multivariate analyses including scanning site as a variable, do not support this hypothesis. The strengths of our study include the use of both quantitative and semi-quantitative methods for evaluation of WMH severity. Furthermore, we had data on a number of potential causal or risk factors for WMH, enabling us to include these in the analyses. Limitations include the cross-sectional design, the relatively small sample size, and orthostatic BP measurements in a number of cases obtained from the sitting, instead of the supine position. It has previously been demonstrated that sit-stand testing for OH has a very low diagnostic accuracy [50]. However, 
sit-stand measurement only has been used in recent, similar studies [51,52]. In addition, no standing BP measurements were made after 3 minutes. According to a previous study [53], at least 20?0 of dementia patients have a delayed orthostatic response. Thus, our methodology would tend to underestimate the prevalence of OH, thereby possibly masking the potential association between OHand WMH. Furthermore, the consensus definition of OH, which was employed in the present study, does not in itself require the orthostatic BP to be measured on more than one occasion. This is a potential limitation, as this approach cannot distinguish those having only transient OH from those having more persist.Able 4. Multiple logistic regression analysis of the effect of age on likelihood of having Scheltens deep WMH 
score in highest vs. lowest quartile (final model).B 1 APOEe4 alleleS.E. pOdds Ratio Exp. (B) (95 CI) Age (years)BS.E.pOdds Ratio Exp. (B) (95 CI)22.595 1.242 0.037 0.075 (0.007?.851)0.112 0.048 0.019 1.119 (1.018?.230)APOE = apolipoprotein E; WMH = white matter hyperintensities; CI = confidence interval. doi:10.1371/journal.pone.0052196.tAPOE = Apolipoprotein E; WMH = white matter hyperintensities; CI = confidence interval. doi:10.1371/journal.pone.0052196.thave lower standing systolic BP values than AD [23], whereas in our study the majority had AD. Furthermore, in these two last studies blood pressures were measured partly or only during carotid sinus massage, as opposed to our study, in which the blood pressures were measured only in the supine (or sitting) position and during active standing. Subjects with OH according to these two different methods may not be comparable, e.g. concerning the pathophysiology of WMH. In our study, the presence of at least one APOEe4 allele was associated with reduced odds of having high WMH volume, suggesting that other APOEe alleles (i.e. e2 and/or e3) may increase the odds of high WMH volume. This hypothesis is supported by at least two previous studies [41,42]. Notably, none of these included subjects with dementia. Alternatively, patients possessing the e4 allele may have more neurodegenerative changes and thus develop 25837696 dementia with a lower WMH load. However, the majority of studies in this field have not demonstrated any association between APOEe4 status and WMH burden [43?8]. In contrast to some previous studies (e.g. [49]), we did not find any significant associations between hypertension and WMH. This could have several possible explanations, including different definitions of hypertension, different study designs, and differences regarding samples. This being a multicentre study, it is possible that the measured or scored WMH values might vary systematically according to scanning site. The results of the phantom studies, as well as the results of the multivariate analyses including scanning site as a variable, do not support this hypothesis. The strengths of our study include the use of both quantitative and semi-quantitative methods for evaluation of WMH severity. Furthermore, we had data on a number of potential causal or risk factors for WMH, enabling us to include these in the analyses. Limitations include the cross-sectional design, the relatively small sample size, and orthostatic BP measurements in a number of cases obtained from the sitting, instead of the supine position. It has previously been demonstrated that sit-stand testing for OH has a very low diagnostic accuracy [50]. However, sit-stand measurement only has been used in recent, similar studies [51,52]. In addition, no standing BP measurements were made after 3 minutes. According to a previous study [53], at least 20?0 of dementia patients have a delayed orthostatic response. Thus, our methodology would tend to underestimate the prevalence of OH, thereby possibly masking the potential association between OHand WMH. Furthermore, the consensus definition of OH, which was employed in the present study, does not in itself require the orthostatic BP to be measured on more than one occasion. This is a potential limitation, as this approach cannot distinguish those having only transient OH from those having more persist.
