White Matter Lesions Are Associated With Progression of Medial Temporal Lobe Atrophy in Alzheimer Disease

Methods

Statistical Analysis

Progression of both WML and MTA was defined as an increase of 1 point or more on the rating scales between baseline and follow up. The Figure shows a typical example of MTA progression. We calculated the mean progression of MTA stratified on absence or presence of baseline and of progression of WML by means of age-and gender-adjusted analysis of variance. Odds ratios (ORs) were calculated to quantify the association between baseline and progression of WML (independent variable) and progression of MTA (dependent) by means of age- and gender-adjusted logistic regression analysis. Additional adjustments were made for the MMSE (as an indicator of dementia severity), systolic and diastolic blood pressure, and the duration of follow up. The relation between progression of WML and progression of MTA may be confounded by the severity of baseline WML because progression of WML has shown to be significantly related to baseline presence of WML¹¹ also in patients with AD.⁶ We therefore performed additional adjustments for baseline WML in all analysis in which progression of WML was the independent variable.

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Coronal slices at the level of the medial temporal lobe at baseline (A; MTA score=2) and after a follow-up period of 3 years (B; MTA score=4) in a 79-year-old man with AD with progression of MTA. Arrows indicate the right MTL.

Results

Patients with a follow-up scan were younger than those without (66.2 years, standard deviation [SD]: 8.6] versus 72.3 years, SD: 9.5, P<0.05). Roughly half of all patients were female both in the group with as well as without a follow-up scan. Mean MMSE at baseline was 21.1 (SD: 5.2). Other baseline characteristics are presented in Table 1. Except for age and MTA, there were no differences in baseline characteristics between those with or without follow-up MRI.

There were 25 patients (&70%) who showed MTA progression. Patients <70 years of age had a higher mean progression of MTA than those ≥70 years of age (0.7, SD: 0.5; and 0.3, SD: 0.5); however, this was not significant. There was no difference between men and women with respect to progression of MTA.

Progression of MTA was related to the presence of PVWML at baseline and to progression of PVWML. The mean MTA progression was 0.8 (SD: 0.5) and 0.3 (SD: 0.4) for patients with or without PVWML at baseline (P=0.01). Patients who showed progression of PVWML over the course of their disease had a significantly higher progression of MTA than those without PVWML progression (0.9, SD: 0.4; and 0.4, SD: 0.5; P=0.01). This was not found for SCWML (Table 2).

Patients with PVWML at baseline had a 40-fold increased risk for progression of MTA compared with those without baseline PVWML (OR=40.0; 95% CI=1.3 to 1.2×10³, P=0.03). Patients with progression of PVWML during the course of the disease had an increased risk for MTA progression (OR=3.7 per degree increase of progression of PVWML, 95% CI=1.1 to 12.9, P=0.04). There was higher risk for progression of MTA for those with progression of PVWML than those without (OR=10.9, 95% CI=1.0 to 122.5, P=0.05). This was not found for SCWML (Table 3).

Adjustment for confounding factors, including the degree of baseline WML, did not alter the magnitude of the association.

Discussion

We found that patients with WML at baseline and those with an increase of WML, especially the PVWML, over a mean 2-year period of follow up had a significantly higher risk for progression of MTA.

Strengths of our study are the prospective nature of the study and the fact that baseline and follow-up scans were rated independently from each other with high intrarater agreement.

Some methodological issues need attention. Selection bias may have influenced our findings in several ways. As a result of the nature of a follow-up study, only those participants who were still alive at follow up undergo serial MRI scanning. Therefore, it could be that selective survival of people with a relatively mild degree of WML at baseline and those with a relatively mild progression of WML has occurred because severity of WML is related to mortality.¹² Another form of selection bias may be the underrepresentation of those patients who are in a more advanced stage of the disease and presumably have the highest degree of WML, because those patients are not very likely to show up at regular outpatient clinic controls and at repeated MRI examination, for example, as a result of mobility-related problems.¹³ However, we do not think that these forms of bias significantly influenced our findings because in a previous study, we found a linear relation between the degree of WML and MTA; consequently, those with the most severe WML would most likely to have the most severe MTA.

WML and MTA were rated with the Rotterdam Scan Study Scale⁹ and with a semiquantitative MTA rating scale, respectively,¹⁰ which both were not developed for the detection of change in a longitudinal design. The use of the Rotterdam Scan Study Scale for this purpose proved to be poor in a recent validation study,¹⁴ especially for the detection of change of PVWML, but performed better for the detection of change of SCWML. A reason for this could be the so-called ceiling effect that presumably does not apply to the SCWML. PVWML that were already rated in the highest category at baseline (and which are most likely to progress) cannot contribute to progression on these scales because they are already in the highest category, whereas SCWML were counted taking into account number and size of lesions without a predefined maximum, thus avoiding a ceiling effect. However, the presumed influence of this ceiling effect is limited in our study because patients in our study had a median baseline PVWML of 1.0 (which is way below the maximum of 9.0) compared with 6.0 in the study of Prins et al.¹⁴

This type of validation study has never been done for the detection of MTA change over time with the semiquantitative MTA rating scale we used, but similar reasoning may apply, because mean MTA scores in our study were quite low and far below the maximum of the score.

Our finding of a relation between progression of WML and progression of MTA could be confounded by baseline WML because this has proven to be related to progression of WML.^6,11 However, adjustment for baseline WML did not alter the magnitude of the association rendering this explanation unlikely.

Our study does not provide an explanation on how WML may ultimately lead to MTA in AD. An explanation could be that the medial temporal lobe is disconnected from connected cortical areas by the vascular WML in the white matter tracts subserving the cortical association areas^15,16 leading to shrinkage of the medial temporal lobe resulting from Wallerian degeneration. Despite the fact that ours is a prospective study, both WML and MTA were already present at baseline examination; therefore, causal inference on the underlying mechanism cannot be made from our study. It is not known why periventricular and subcortical WML would have a differential influence on MTA. An explanation could be that the periventricular WML affect areas of long fiber tracts that connect several distant cortical areas with each other (including the MTA),^15,16 whereas subcortical WML mainly disrupt short loops of corticocortical connections not related to distant structures such as the MTA.¹⁷ Still, a remaining explanation for our finding includes the possibility of an identical underlying mechanism for both WML and MTA such as changes in the amyloid metabolism or vascular brain disease. The predominant pathology in MTA even early in the course of AD is the presence of amyloid_{β1 to 42} in amyloid plaques,¹⁸ whereas recent studies also indicated a relation between the level of circulation A_{β1 to 42} and the presence of WML.¹⁹ Consequently, by these mechanisms, progression of amyloid deposition could both lead to progression of both WML and MTA, thereby explaining our finding. Another underlying mechanism may be that cerebral ischemia not only results in WML, but also in MTA. Indeed, pathologic studies found microinfarcts in the medial temporal lobe in patients with AD.²⁰

Our findings suggest a relation between both baseline and progression of WML and progression of MTA. When our findings are substantiated, this may indicate that the presence of PVWML on an MRI scan can be used as a tool that is able to predict MTA progression (and as such, presumably progression of the disease) in still relatively mildly demented patients years before end stages of the disease. As such, they may function as a surrogate end point in clinical trials that aim at modifying the course of AD.²¹ If a causal relation between WML and MTA progression is to be proven, MTA progression may be prevented by modifying the progression of WML by, for example, treatment of the vascular risk factors for WML such as hypertension.²²