In this study, we examined whether a specific WML profile (density and location) could be associated with an increased risk of MCI/dementia. In our study population, we found that people with high total WML load and high percentage of WML in the temporal lobe (≥0.65%) were more at risk of MCI/dementia over a 7-year period, independently of potential confounders and other structural brain changes detected by MRI.
Previous studies compared WML distribution in healthy and dementia groups that were determined using clinical criteria which are the results of heterogeneous pathologic processes (top-down approach). In this analysis, we employed an original bottom-up approach in which all participants were initially included in one single group that comprised all cognitive statuses and then the regional and total WML volumes were the only components used in a decision tree to specifically discriminate between healthy and cognitively impaired subjects. Our approach focused on the specific relationship between WML distribution and risk of MCI/dementia, independently of the influence of other known contributors to cognitive impairment. The groups provided by the optimized decision tree therefore did not perfectly discriminate between healthy and MCI/dementia subjects. This relative low sensitivity is due to the fact that WML alone cannot predict the risk of MCI/dementia. However the robust specificity and negative predictive values indicate that WML distribution can be used to differentiate people who are unlikely to decline cognitively. We then verified that these findings were independent of potential confounders, which were not considered in the decision tree, by multivariate analysis (Cox proportional-hazard regression models).
The optimized decision tree revealed three separate WML patterns. Although the WML load was more severe in the frontal region in all patterns, the relative frontal volume (WMLr volume) was significantly lower in pattern 2 and 3 than in pattern 1. Conversely, the total and the parietal and occipital WML volumes were higher in pattern 2 and 3 than in pattern 1. Although MRI data were collected only at baseline, these results suggest a spatial progression of WML and are in agreement with previous findings about the antero-posterior progression of WM deterioration 
The decision tree identified two different patterns (2 and 3) in participants with severe WML load, but only pattern 3 was significantly associated with higher risk of transition to MCI/dementia, suggesting that severe WML load is not sufficient to explain this association. Although the total WML load was similar in patterns 2 and 3, pattern 3 was characterized by a significantly higher temporal WML load (both absolute and as a percentage of the total volume) than pattern 2. As age and hypertension were not significantly different in these two groups, they cannot explain this location difference. On the other hand, the temporal region is the first brain area to be affected by AD pathology 
. Further research is needed to investigate whether, in addition to its ischemic origin, a severe WML load in the temporal region could be related to the grey matter pathology observed specifically in the temporal region in AD 
Our findings suggest that beyond a given level of WML load, a specific WML distribution is observed with an increased proportion of WML in the temporal region. This feature is in turn associated with increased risk of progression towards MCI/dementia. This result is in agreement with previous reports indicating that WM deterioration in the temporal region is the most consistent finding in patients with AD 
. In addition, our study shows a disease-specific WML localization (pattern 3) that is independent of the global WM changes. Pattern 3 (associated with higher risk of transition to MCI/dementia) was observed before the onset of symptoms, because all subjects were considered cognitively normal when MRI was carried out. These findings may thus be more useful for the detection of patients in the early prodrome of dementia than cognitive testing, and also for selecting elderly people at increased risk for clinical trials.
Pattern 2 was characterized by higher frequency of depressive symptomatology. The association between cerebrovascular disease and depressive symptoms is well-known 
. However, further investigations are needed to determine whether there is a WML distribution pattern that may be specifically associated with depressive symptomatology independently of multiple confounding factors.
Some limitations of our study should be considered. Our study sample shows a relative low incidence of dementia (4.2 per 1000 person-year) 
, certainly because it included only participants aged 80 years and younger. However, despite the low number of dementia cases, our results are consistent with previous studies. Moreover, we mapped the WML load in the different brain lobes, while some other studies distinguished periventricular from deep WML. However, the different impact of these WML locations upon cognitive function is controversial 
. Finally, our method quantified WML load per lobe but did not determine which particular WM structure in the temporal region was involved. The strengths of our study include the large number of available MRI scans and the length of the follow-up period (7 years).