Published online before print March 6, 2008, doi: 10.1161/STROKEAHA.107.498535
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(Stroke. 2008;39:1414.)
© 2008 American Heart Association, Inc.
Original Contributions |
Progression of White Matter Hyperintensities and Incidence of New Lacunes Over a 3-Year Period
The Leukoaraiosis and Disability Study
From the Alzheimer Center (A.A.G., W.M.v.d.F., E.C.W.v.S., P.S., F.B.), the Departments of Neurology (A.A.G., W.M.v.d.F., E.C.W.v.S., P.S.) and Radiology (F.B.), and the Image Analysis Center (IAC) (A.A.G., E.C.W.v.S., F.B.), Vrije Universiteit Medical Center, Amsterdam, The Netherlands; the Department of Neurological and Psychiatric Sciences (L.P., A.P., D.I.), University of Florence, Florence, Italy; the Memory Research Unit, Department of Clinical Neurosciences (T.E.), Helsinki University, Helsinki, Finland; the Neurotec Department, Section of Clinical Geriatrics (L.O.W.), Karolinska Institute, Huddinge, Sweden; the Memory Disorders Research Unit, Department of Neurology (G.W.), Copenhagen University Hospital, Copenhagen, Denmark; and the Department of Neurology and MRI Institute (F.F., R.S.), Medical University, Graz, Austria.
Correspondence to Alida A. Gouw, MD, Department of Neurology, Alzheimer Center and Image Analysis Center, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail AA.Gouw{at}vumc.nl
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Abstract |
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Background and Purpose— We studied the natural course of white matter hyperintensities (WMH) and lacunes, the main MRI representatives of small vessel disease, over time and evaluated possible predictors for their development.
Methods— Baseline and repeat MRI (3-year follow-up) were collected within the multicenter, multinational Leukoaraiosis and Disability study (n=396). Baseline WMH were scored on MRI by the Fazekas scale and the Scheltens scale. WMH progression was assessed using the modified Rotterdam Progression scale (absence/presence of progression in 9 brain regions). Baseline and new lacunes were counted per region. WMH and lacunes at baseline and vascular risk factors were evaluated as predictors of WMH progression and new lacunes.
Results— WMH progressed (mean±SD=1.9±1.8) mostly in the subcortical white matter, where WMH was also most prevalent at baseline. The majority of new lacunes, which were found in 19% of the subjects (maximum=9), also appeared in the subcortical white matter, mainly of the frontal lobes, whereas most baseline lacunes were located in the basal ganglia. Baseline WMH and lacunes predicted both WMH progression and new lacunes. Furthermore, previous stroke, diabetes, and blood glucose were risk factors for WMH progression. Male sex, hypertension, systolic blood pressure, previous stroke, body mass index, high-density lipoprotein, and triglyceride levels were risk factors for new lacunes.
Conclusion— WMH and lacunes progressed over time, predominantly in the subcortical white matter. Progression was observed especially in subjects with considerable WMH and lacunes at baseline. Moreover, the presence of vascular risk factors at baseline predicted WMH progression and new lacunes over a 3-year period.
Key Words: lacunes • leukoaraiosis • MRI • risk factors • white matter disease
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Introduction |
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Cerebral small vessel disease (SVD) is a major cause of vascular cognitive impairment and dementia.1 White matter hyperintensities (WMH) and lacunes are frequently observed in elderly subjects and are considered to be the main MRI representatives of SVD.2,3
Postmortem studies have shown that WMH correspond to heterogeneous pathological substrates with varying degrees of demyelination, arteriolosclerosis, and gliosis representing incomplete infarction, but also tissue degeneration.4,5 Lacunes are small cavities located in the white matter or subcortical gray matter. They have been regarded as small ischemic infarcts, but several pathogenetic mechanisms may exist.6
In cross-sectional studies, both WMH and lacunes have been shown to be associated with vascular risk factors such as hypertension and cardiovascular disease.3,7–9 WMH are clinically important because they are associated with cognitive impairment, gait disturbances, and depression.10,11 Although most lacunes appear to be "silent," ie, not accompanied by stroke-like symptoms, they have been associated with subtle cognitive dysfunction.3 Furthermore, both types of SVD are associated with an increased risk of future stroke.12
The interest in SVD is gradually shifting from cross-sectional studies to longitudinal designs. Earlier studies have assessed possible risk factors and clinical consequences of WMH progression,11,13–17 but little has been reported on the appearance of new lacunes.18,19 In this MRI study, we studied the natural course of both WMH and lacunes in a sample of initially independently living elderly, stratified by WMH grade at baseline, over a 3-year period. Furthermore, we investigated which baseline variables predicted WMH progression and new lacunes.
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Methods |
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Patients
Data were collected as part of the multicenter, multinational Leukoaraiosis and Disability (LADIS) study. The LADIS study investigates the role of WMH as an independent predictor of the transition to disability in initially nondisabled elderly. The rationale and design of the LADIS study have been described elsewhere.20 In short, 639 elderly subjects who had no or only mild disability in their instrumental activities of daily living were enrolled in a hospital-based setting. Among the reasons for presentation were mild memory loss, minor motor disturbances, minor focal cerebrovascular events, depressive symptoms, or nonspecific reasons for undergoing a cranial neuroimaging study (WMH as an incidental finding). To be included, subjects had to have an age between 65 and 84 years; WMH on MRI of any degree21; no or only mild disability as determined by the Instrumental Activities of Daily Living Scale22; presence of a regularly contactable informant; and agreement to sign an informed consent. Exclusion criteria were likelihood of dropping out because of the presence of severe illnesses, eg, cardiac, hepatic, or renal failure, cancer or other relevant systemic diseases; severe unrelated neurological diseases; leukoencephalopathy of nonvascular origin (immunological, demyelinating, metabolic, toxic, infectious, other); severe psychiatric disorders; inability to provide informed consent; and inability or refusal to undergo cerebral MRI. Subjects were selected and stratified for WMH severity according to the categorization into 3 severity classes of the modified Fazekas scale.21 Subjects were followed for 3 years.
Risk Factors
To assess vascular risk factors at baseline, a structured data questionnaire was used together with a review of available records by trained medical personnel. The risk factors used in this article are8,20 patient demographics (age [years], sex, medical history), history of hypertension (treatment with antihypertensive medications or with values 
140/90 mm Hg based on measurements taken on several separate occasions), history of diabetes mellitus (treatment with antidiabetic medications or at least 8-hour fasting plasma glucose 7.0 mmol/L or 126 mg/dL), clinical history of stroke, atrial fibrillation (based on history and/or available clinical records such as an electrocardiogram), history of myocardial infarction (documented by history, electrocardiogram, or cardiac enzymes), history of hypercholesterolemia (documented by total cholesterol >200, low-density lipoprotein >130, high-density lipoprotein <35 mg/dL, and/or hypertriglyceridemia based on serum triglyceride >200 mg/dL on at least 2 occasions), past or present cigarette smoking (pack-years, defined as packs of cigarettes per day multiplied by years smoked), physical examination, systolic and diastolic blood pressure (mm Hg), body mass index (weight [kg]/height [m]2), and laboratory examination (all in mmol/L)—total cholesterol, high-density lipoprotein, low-density lipoprotein, triglyceride, and glucose.
MRI Examinations
MRI scanning was performed at baseline (10 centers 1.5 T; one center 0.5 T) and repeated after 3 years using the same protocol. For follow-up evaluation (all 1.5 T), new MRI scanners were used in 3 centers. The MR protocol included the following sequences: T1-weighted magnetization prepared rapid-acquisition gradient-echo (scan parameters: coronal or sagittal plane, TE: 2 to 7 ms, TR: 9 to 26 ms, flip angle: 15 to 30, voxel size 1x1x1 to 1.5 mm3), T2-weighted fast spin echo (scan parameters: axial plane, TE:100 to 130 ms, TR: 4000 to 6600 ms, voxel size 1x1x5 mm3, 19 to 31 slices), and fluid-attenuated inversion recovery (FLAIR; scan parameters: axial plane, TE: 100 to 160 ms, TR: 6000 to 10 000 ms, TI: 2000 to 2400, voxel size 1x1x5 mm3, 19 to 31 slices).
Assessment of White Matter Hyperintensities and Lacunes
Baseline WMH assessment and scoring of lacunes and infarcts were performed centrally by a single rater who was blinded to clinical information. The degree of WMH severity was rated visually on axial FLAIR images using the modified Fazekas scale (WMH grade=mild, moderate, severe)21 and the Scheltens rating scale (range, 0 to 84),23 in which scores 0 to 6 can be given in 13 subcortical regions (subcortical white matter, basal ganglia, and infratentorial region) and scores 0 to 2 for 3 periventricular regions. To identify lacunes, we used FLAIR, magnetization prepared rapid-acquisition gradient-echo, and T2 images. The combination of the 3 scan sequences was used to distinguish lacunes from Virchow Robin spaces and microbleeds. The intensities of lacunes and Virchow Robin spaces are similar to cerebrospinal fluid in all scan sequences, but lacunes mostly have a hyperintense rim around the cavity on FLAIR images in contrast to Virchow Robin spaces. When lacunes present without a hyperintense rim (eg, in the basal ganglia or infratentorial), they can often be distinguished by their size and shape; lacunes are defined as cavities 3 mm to 10 mm and are mostly ovoid/spheroid, whereas Virchow Robin spaces are smaller and follow the vessel (seen on coronal/sagittal magnetization prepared rapid-acquisition gradient-echo). T2 images were used to identify lacunes in the basal ganglia and infratentorial regions, because FLAIR images are less sensitive to detect lacunes in these areas and to distinguish lacunes from microbleeds, because microbleeds are hypointense on T2. Lacunes were scored in 5 brain regions (frontal, parietooccipital, temporal, basal ganglia, and infratentorial). Boundaries of the brain regions on axial slices were defined as follows: the division between frontal and parietal lobes is the central sulcus or at the halfway mark of the brain when the central sulcus is not evident. At and below the level of the splenium, the brain is divided among frontal, temporal, and occipital lobes. Temporal and occipital lobes are divided by 2 lines at a 90° angle extending from the occipital horns or stemming from the aqueduct at lower levels. Eighteen randomly selected scans were scored twice for the determination of the intrarater reliability (Fazekas scale: weighted Cohen’s kappa=0.84, Scheltens scale: intraclass correlation coefficient=0.92).
At follow-up, visual rating of WMH progression and new lacunes was performed in a side-by-side fashion blinded to clinical details. WMH progression was rated on FLAIR images according to the modified Rotterdam Progression scale,24 in which absence or presence of progression (0 and 1, respectively) was rated in 3 periventricular regions (frontal caps, occipital caps, bands), 4 subcortical white matter regions (frontal, parietal, occipital, temporal), basal ganglia, and infratentorial region. New lacunes were counted in the same regions. The intrarater reliability was determined on 20 randomly selected scans that were scored twice (WMH progression: weighted Cohen’s kappa=0.81, number of new lacunes: intraclass correlation coefficient=0.84). During the evaluation of follow-up MRI scans, a misclassification of 22 MRI scans was corrected in the baseline database. This correction does not affect the main results of the baseline analysis but has caused small differences in the numbers of the reported baseline data.
Statistical Analysis
Differences between groups were tested with Student t tests and 
2 tests where appropriate. Possible predictors of SVD progression were assessed with logistic regression analyses. The evaluated variables were categorized into patient demographics, medical history (dichotomized into yes/no), physical examination (recoded into quintiles), laboratory examination (recoded into quintiles), and baseline MRI variables (WMH grade, number of lacunes). Dichotomized WMH progression (highest quintile: 0 to 3 versus >3) and new lacunes (0 versus 1) were the dependent variables. First, all analyses were corrected for age, sex, and center. Subsequently, all baseline variables were entered simultaneously.
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Results |
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During follow-up, 43 subjects died and 73 subjects dropped out of the study. Therefore, at 3-year follow-up, 523 subjects could be evaluated clinically of which 43 subjects received a follow-up evaluation with a telephone interview. Thirty subjects were not scanned due to refusal and subjects of one center (47 subjects) could not be scanned because of lack of funding. Thus, follow-up MRI scans were available for 403 patients. Seven scans were excluded because of absent FLAIR images (6 scans) or inappropriate slice positioning (one scan). Therefore, 396 scans could be evaluated for this study (mean scan interval 3.1±0.3 years).
A baseline description of the study sample is given in Table 1. The subjects who received a follow-up MRI were younger, had more years of education, had higher Mini-Mental State Examination scores, and lower Alzheimer’s Disease Assessment Scale scores at baseline; and had higher diastolic blood pressure, lower total cholesterol, low-density lipoprotein, triglyceride, and glucose levels than subjects who were not scanned at follow-up. Baseline MRI characteristics were comparable between the groups with and without follow-up MRI.
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The relative frequency of the total Rotterdam Progression scores and number of new lacunes are shown in Figure 1. Over 3 years, WMH increased with 1.9±1.8 points (mean±SD) on the Rotterdam Progression scale (one-sample t test: P<0.001). The median (interquartile range) of the Rotterdam Progression score was 2 (0 to 3). A score of zero, which indicates no change in WMH, was present in 26% of the subjects, whereas 74% had a score of one or higher, reflecting WMH progression in one or more regions. More specifically, 21% of the subjects showed WMH progression in one region and 53% in at least 2 regions. At follow-up, 81% of the subjects had no new lacunes; one new lacune was present in 11% and 8% of the subjects had more than one new lacune (maximum=9). WMH progression was modestly correlated with the number of new lacunes (Spearman’s r=0.15; P<0.01). These results indicate that progression of SVD was present in a considerable proportion of our study sample.
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To investigate the spread of WMH through the brain, we compared the regional baseline WMH according to the Scheltens scale (Figure 2A) with WMH progression (Rotterdam Progression scale; Figure 2B). At baseline, half of the total Scheltens score was accounted for by hyperintensities in the subcortical white matter, mainly the frontal and parietal lobes. Progression of WMH is also most commonly seen in the subcortical white matter (54%), especially the frontal and parietal lobes, followed by the periventricular regions (33%). These figures roughly indicate that the regional distribution of WMH progression after 3 years is proportional to the distribution of WMH load at baseline. Because the difference in the range of the scales may influence the results of the distribution, we additionally transformed the Scheltens scale to match the range of the Rotterdam Progression scale (regional scores were dichotomized: score 0/1=0; score >1=1). Overall, results remained comparable with the original scales (data not shown).
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Lacunes at baseline and the occurrence of new lacunes were also compared by brain region (Figure 3). At baseline, the relative prevalence of lacunes was comparable between the basal ganglia (45%) and subcortical white matter (43%). During follow-up, new lacunes mostly occurred in the subcortical white matter, mainly the frontal lobes (41%), whereas new lacunes were less prevalent in the basal ganglia (28%). In contrast to WMH progression, the regional distribution of lacunes seemed to shift over time. An example of a patient who had lacunes in the basal ganglia at baseline and a new lacune in the frontal lobe is shown in Figure 4.
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To investigate which baseline variables predicted progression of WMH and incidence of new lacunes, we performed logistic regression analyses with baseline variables corrected for age, sex, and center (Table 2). Baseline WMH and lacunes predicted both WMH progression (Rotterdam Progression score >3) and new lacunes. Moreover, history of diabetes, higher blood glucose, and stroke predicted WMH progression. The occurrence of new lacunes was predicted by male sex, history of hypertension, higher systolic blood pressure, history of stroke, higher body mass index, lower high-density lipoprotein, and higher triglyceride. When all baseline variables were entered simultaneously, baseline WMH remained a significant predictor of WMH progression (OR [95% CI]: 2.8 [1.5 to 5.1]), whereas significance was lost for the other univariate risk factors. In addition, higher age became a significant predictor of WMH progression (OR [95% CI]: 1.1 [1.0 to 1.3]) and higher triglyceride appeared to protect for WMH progression (OR [95% CI]: 0.6 [0.4 to 0.9]). For the appearance of new lacunes, baseline WMH and lacunes, systolic blood pressure, and high-density lipoprotein remained significant predictors in the multivariate analysis (OR [95% CI]: 2.1 [1.2 to 3.6]; 1.2 [1.0 to 1.3]; 2.1 [1.4 to 3.3]; 0.5 [0.3 to 0.7], respectively). Also, unexpected associations appeared with high diastolic blood pressure (OR [95% CI]: 0.6 [0.4 to 0.9]) and high low-density lipoprotein (OR [95%CI]: 0.5 [0.3 to 1.0]) protecting for new lacunes. Additional analyses to correct for antihypertensive and antihyperlipemic medication did not change the results essentially.
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Discussion |
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In this MRI study, we report 3 main findings. First, we found in a large group of initially independently living elderly, stratified for a wide range of WMH, that both WMH and lacunes progressed over time. Second, WMH progression seems to appear mostly in the subcortical white matter, where WMH was also most prevalent at baseline. New lacunes also preferentially occurred in the subcortical white matter, whereas baseline lacunes were equally prevalent in the basal ganglia. Third, WMH progression and new lacunes were observed especially in subjects with considerable WMH and lacunes at baseline. Moreover, history of diabetes, high blood glucose, and history of stroke predicted WMH progression, whereas for new lacunes, the following risk factors were found: male sex, history of hypertension, systolic blood pressure, history of stroke, low high-density lipoprotein and high triglyceride levels, and high body mass index.
This study is consistent with earlier publications with respect to the finding that WMH progress over time, mostly in subjects with considerable WMH at baseline.11,13,16,17,25,26 Our results suggest that WMH progression mainly results from an increase of existing WMH,17 raising the question when the baseline WMH have occurred and in what timeframe. Only 2 longitudinal studies described progression of lacunes.18,19 We found that one of 5 subjects had at least one new lacune in 3 years, which was associated with WMH and lacunes at baseline. Our finding of new lacunes in a fairly high proportion of subjects may be related to the stratification by WMH severity, which resulted in a relative overrepresentation of moderate and severe WMH. The regional distribution of lacunes seemed to shift over time because new lacunes occurred mostly in the subcortical white matter, especially in the frontal lobes, whereas at baseline, lacunes were equally prevalent in the basal ganglia. It is tempting to speculate that basal ganglia lacunes could have a different pathogenesis than lacunes in the subcortical white matter. Histopathology studies have proposed several pathogenetic mechanisms for lacunes, including thromboembolism, arteriolosclerosis, blood–brain barrier leakage, Wallerian degeneration, or collapse of sublethally damaged tissue.6,27 Differences in lacune morphology may also point to the direction of distinct pathogenetic mechanisms.28
We found a relation of diabetes, high blood glucose, and stroke with WMH progression. Earlier studies have suggested various risk factors, including diastolic blood pressure, diabetes, smoking, female sex, infarct at baseline, and interstitial cell adhesion molecule level as risk factors for WMH progression.15,16,25,26,29 In our study, hypertension was not a risk factor for WMH progression. We have found diabetes as a risk factor, which is consistent with one previous study.25 In the multivariate model, high triglyceride unexpectedly appeared to protect against WMH progression. Earlier studies also described that vascular risk factors such as hypercholesterolemia, hyperlipidemia, and low body mass index seemed to protect against WMH progression.16,17 In addition, some risk factors found after 3-year follow-up were lost at longer follow-up periods.13 For the appearance of new lacunes, we identified male sex, hypertension, high systolic blood pressure, stroke, high body mass index, low high-density lipoprotein, and high triglyceride levels as risk factors. Again, unexpected associations appeared in the multivariate analyses with high diastolic blood pressure and high low-density lipoprotein protecting for new lacunes.
Strengths of the present study are the large group of subjects and the representation of a broad range of WMH, supplying us with the statistical power to find subtle associations. Although stratification by WMH may hamper the generalizability of the results to the general population, the reasons for referral were those commonly leading to the discovery of WMH in elderly persons, so the LADIS sample likely reflects the patient population with WMH encountered in everyday clinical practice. The high attrition rate could be a limitation of our study because it could have led to a survival bias. Although patients without follow-up MRI had less favorable values for some baseline risk factors than our study population, the baseline MRI variables were comparable. Furthermore, the multicenter design of the study could have led to heterogeneity in the study sample. We have therefore corrected our analyses for the effect of center. Another potential limitation is the use of visual rating scales. Although a fully automated method was preferred over a crude visual method in a single center study,30 it has never been used in studies with multiple scanners. Automated assessment of WMH progression was difficult to implement in our study and would have led to the exclusion of far more scans. Visual rating scales have proven to be reliable for WMH assessment.31 We therefore feel that the Rotterdam Progression scale was the method of choice in this study. This scale, designed for side-by-side assessment of WMH progression, was found to be reliable and correlated well with a volumetric method.24 The nonlinear results, however, are less easily interpretable than absolute volume changes and the side-by-side rating may have resulted in an overestimation of WMH progression. We expect that computerized methods will be available for future multicenter studies. Furthermore, automated methods would provide an objective measure for new lacunes. Although the count of new lacunes was reliable, regional differences in reproducibility may exist because it is conceivable that new lacunes are harder to reproduce in areas with a higher density of lesions.
In this study, we have investigated the natural course over time of WMH and lacunes, 2 MRI representatives of SVD, and established risk factors for their progression. Future studies should be aimed to include other expressions of small vessel disease such as changes in the normal-appearing white matter or microbleeds.
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Participating Center and Personnel
Helsinki, Finland (Memory Research Unit, Department of Clinical Neurosciences, Helsinki University): Timo Erkinjuntti, MD, PhD; Tarja Pohjasvaara, MD, PhD; Pia Pihanen, MD; Raija Ylikoski, PhD; Hanna Jokinen, LPsych; Meija-Marjut Somerkoski, MPsych; Riitta Mäntylä, MD, PhD; and Oili Salonen, MD, PhD. Graz, Austria (Department of Neurology and MRI Institute, Medical University Graz): Franz Fazekas, MD; Reinhold Schmidt, MD; Stefan Ropele, PhD; Brigitte Rous, MD; Katja Petrovic, MagPsychol; Ulrike Garmehi; and Alexandra Seewann, MD. Lisboa, Portugal (Serviço de Neurologia, Centro de Estudos Egas Moniz, Hospital de Santa Maria): José M. Ferro, MD, PhD; Ana Verdelho, MD; and Sofia Madureira, PsyD. Amsterdam, The Netherlands (Department of Radiology and Neurology, VU Medical Center): Philip Scheltens, MD, PhD; Ilse van Straaten, MD; Frederik Barkhof, MD, PhD; Alida Gouw, MD; and Wiesje van der Flier, PhD. Goteborg, Sweden (Institute of Clinical Neuroscience, Goteborg University): Anders Wallin, MD, PhD; Michael Jonsson, MD; Karin Lind, MD; Arto Nordlund, PsyD; Sindre Rolstad, PsyD; and Ingela Isblad, RN. Huddinge, Sweden (Karolinska Institute, Neurotec Department, Sektion of Clinical Geriatrics): Lars-Olof Wahlund, MD, PhD; Milita Crisby, MD, PhD; Anna Pettersson, physiotherapist; and Kaarina Amberla, PsyD. Paris, France (Department of Neurology, Hopital Lariboisiere): Hugues Chabriat, MD, PhD; Karen Hernandez, psychologist; Annie Kurtz, psychologist; and Dominique Hervé, MD. Mannheim, Germany (Department of Neurology, University of Heidelberg, Klinikum Mannheim): Michael Hennerici, MD; Christian Blahak, MD; Hansjorg Baezner, MD; Martin Wiarda, PsyD; and Susanne Seip, RN. Copenhagen, Denmark (Memory Disorders Research Unit, Department of Neurology, Rigshospitalet, and the Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital): Gunhild Waldemar, MD, DMSc; Egill Rostrup, MD, MSc; Charlotte Ryberg, MSc; Tim Dyrby MSc; and Olaf B. Paulson, MD, DMSc. Newcastle-on-Tyne, UK (Institute for Ageing and Health, University of Newcastle): John O’Brien, DM; Sanjeet Pakrasi, MRCPsych; Mani Krishnan, MRCPsych; Michael Firbank, PhD; and Philip English, DCR. The coordinating center is in Florence, Italy (Department of Neurological and Psychiatric Sciences, University of Florence): Domenico Inzitari, MD (Study Coordinator); Luciano Bartolini, PhD; Anna Maria Basile, MD, PhD; Eliana Magnani, MD; Monica Martini, MD; Mario Mascalchi, MD, PhD; Marco Moretti, MD; Leonardo Pantoni, MD, PhD; Anna Poggesi, MD; Giovanni Pracucci, MD; Emilia Salvadori, PhD; and Michela Simoni, MD. The LADIS Steering Committee is formed by Domenico Inzitari, MD (Study Coordinator), Timo Erkinjuntti, MD, PhD; Philip Scheltens, MD, PhD; Marieke Visser, MD, PhD; and Peter Langhorne, MD, BSC, PhD, FRCP, who replaced in this role Kjell Asplund, MD, PhD, beginning with 2005.
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Acknowledgments |
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We thank Tabe Kooistra for his help with the uploading of the MRI scans.
Source of Funding
The LADIS Study is supported by the European Union within the V European Framework Programme "Quality of life and management of living resources" (1998 to 2002), contract no. QLRT–2000-00446 as a concerted action. A.G. is supported by the Alzheimer Center, VUmc.
Disclosures
None.
Received July 6, 2007; accepted September 25, 2007.
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