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Table of Contents
Vol. 32, No. 6, 2011
Issue release date: December 2011
Section title: Review
Free Access
Cerebrovasc Dis 2011;32:577–588
(DOI:10.1159/000334498)

2001–2011: A Decade of the LADIS (Leukoaraiosis And DISability) Study: What Have We Learned about White Matter Changes and Small-Vessel Disease?

The LADIS Study Group
aDepartment of Neurology, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, and bMolecular Imaging and Neurovascular Research Laboratory, Dongguk University Ilsan Hospital, Goyang, Departments of cComputer Science and dMedical Imaging Science, Inje University, Gimhae, and eDepartment of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea; fDepartment of Biochemistry and Cell Biology, William Marsh Rice University, and gDepartments of Radiology and Experimental Diagnostic Imaging, University of Texas, MD Anderson Cancer Center, Houston, Tex., USA
email Corresponding Author

Abstract

Over the last 20 years, evidence about the clinical correlates of cerebral white matter changes (WMC; also called leukoaraiosis) has been accumulating. WMC are now listed among the neuroimaging expressions of cerebral small-vessel disease and are no longer considered an innocuous finding because they are associated, in cross-sectional surveys, with various disturbances and, in follow-up studies, with poor prognosis. The Leukoaraiosis And DISability (LADIS) study has contributed substantially to this body of knowledge. LADIS is a European multicenter collaboration that was started in 2001 with the aim of assessing the independent role of WMC in predicting disability in subjects aged 65–84. The main results of the LADIS study have been released in 2009 with the demonstration that severe WMC more than double the risk of transition from an autonomous to a dependent status after 3 years of follow-up. The LADIS study has also contributed more focused substudies assessing the possible role of WMC in the decline of cognitive and motor performances, depressive symptoms associated with aging and cerebrovascular diseases, urinary disturbances, and also the role of other brain lesions (lacunar infarcts, cerebral atrophy, and corpus callosum morphology). The LADIS study provides a good example of harmonization of instruments (MRI protocol, clinical, neuropsychological, and functional scales) within an international collaboration. Currently, the LADIS study is providing data about the natural history of WMC. In this paper, we review the background and the main results of the LADIS study. This review puts forward some considerations for future studies in the field.

© 2011 S. Karger AG, Basel


  

Key Words

  • White matter changes
  • MRI
  • Elderly
  • Disability
  • Cognitive decline
  • Motor disturbances
  • Depression
  • Urinary disturbances

 Introduction

White matter changes (WMC) are frequently observed on CT and MRI in the brains of elderly subjects, particularly in those with vascular risk factors, appearing as bilateral, patchy or diffuse areas of hypodensity on CT or hyperintensities on T2-weighted MRI scans. These changes involve the periventricular white matter, the corona radiata, and the centrum semiovale with different severity, have irregular margins and do not follow specific vascular territories. WMC are nowadays recognized as one of the manifestations of cerebral small-vessel disease [1]. The clinical and pathologic significance of WMC has been the object of several investigations over the last 30 years. Today, sufficient evidence exists to affirm that, when WMC reach a certain severity degree, they are not an innocuous finding [2,3,4]. In the 1990s, some data existed about a possible association between WMC cognitive, motor, mood and urinary disorders, but full consensus on their clinical significance was lacking [5].

In order to reach an agreement on the significance of WMC and to harmonize and promote collaborative efforts in this field, the European Task Force on Age-Related White Matter Changes was founded in 1996 [6]. In the following years, the task force setting was the ideal basis for the planning of the Leukoaraiosis and Disability (LADIS) study.

The LADIS study was established as a European multicenter collaboration in 2001 with the support of the European Union (5th European Framework Program ‘Quality of life and management of living resources’) [7]. The study’s main aims were to assess the role of WMC as an independent predictor of the transition from an autonomous functional status to disability in elderly subjects and to assess the role of WMC progression in this transition. The study has been carried out in 11 European centers that shared a common interest in the investigation of the clinical consequences of vascular changes in the brain. To tackle specific research questions and to optimize technical aspects, 6 work packages were identified according to the main focuses of the study: (1) methodology, (2) disability, (3) neuroimaging, (4) cognition, (5) mood, and (6) gait, each with one coordinator and collaborators. The enrollment of subjects began in July 2001 and the follow-up ended after 3 years as scheduled. A prolonged follow-up took then part in 2008–2009 based on telephone interviews.

Over the last 5 years the LADIS collaboration has provided a number of publications concerning different aspects of WMC. The aim of this review is to provide an overview of the main results achieved by the collaboration and how these have influenced our understanding and future research efforts.

 The LADIS Study: Methods and Sample Characteristics

Six hundred and thirty-nine patients (mean age 74.1 ± 5.0, males 45%) were enrolled in the LADIS study [7]. The enrolled subjects were functionally autonomous elderly patients presenting for medical evaluation for different reasons: (1) mild cognitive complaints, (2) motor disturbances, (3) minor cerebrovascular events, (4) mood disturbances, and (5) other neurological problems. Two other enrollment settings were that of subjects in whom WMC were incidentally identified on brain imaging and subjects participating as controls in other studies. These heterogeneous referral pathways were deliberate so the population recruited reflected the various settings in which patients with WMC can be encountered in clinical practice.

Study inclusion and exclusion criteria are reported in detail in a methodological paper [7]. Subjects were aged 65–84, had to have WMC of any degree on MRI (categorized as mild, moderate, and severe according to a revised version of the scale of Fazekas et al. [8] (fig. 1) and no or only mild disability as assessed by the Instrumental Activities of Daily Living (IADL) scale [9] (no impairment at all or only one item compromised). The distribution of vascular risk factors and diseases and the respective association with WMC severity confirmed the strong association between WMC and age, hypertension and lacunar stroke [10].

FIG01
Fig. 1. White matter changes: 3 severity degrees (mild, moderate, and severe) according to the modified Fazekas scale.

 Clinical and Instrumental Assessment and Outcome Measures

For baseline and follow-up assessments, structured and standardized protocols were uniformly used in all the participating centers. The clinical instruments were prepared following literature revision and were accepted by consensus among the study principal investigators [for details, see [7] ]. In table 1 all instruments foreseen by the study protocol are listed.

TAB01
Table 1. Instruments of the LADIS study protocol

Patients were followed up for 3 years with a yearly repetition of the baseline clinical and functional assessments. Drop-out and death forms were developed to collect basic information including a phone interview on IADL to be administered to the informant of dropped-out or deceased patients. A checklist to classify causes of death using all available information was used.

The main study outcome was the transition from an autonomous status to disability, defined as the presence of 2 or more impaired IADL activities. Secondary outcomes were dementia, stroke, depression, and quality of life.

 MRI Study

All patients underwent an MRI study following a specific protocol. This included T1-, T2-, proton density-weighted and FLAIR (Fluid-Attenuated Inversion Recovery) pulse sequences [7]. Diffusion tensor and magnetization transfer techniques were employed by selected centers to further characterize tissue changes [26,28]. Image analyses of conventional MRI were performed centrally at the Department of Neuroradiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands, whereas magnetization transfer imaging and diffusion tensor imaging data were analyzed at the Department of Neurology, Medical University Graz, Austria. Corpus callosum assessment was done at the Danish Research Centre for Magnetic Resonance, Copenhagen, Denmark. The analyses included the application of visual rating scales and volumetric analysis of WMC. Other MRI measures were the assessment of lacunar and nonlacunar infarcts, rating of global atrophy and of medial temporal lobe atrophy (MTA), and quantification of the magnetization transfer ratio and of diffusivity in a global and regional manner. The MRI examination was repeated at the end of the 3-year follow-up with the aim of assessing possible progression of WMC and of other lesions.

 Validation and Harmonization of Instruments and Procedures

The handling of possible heterogeneity across the different transnational cultural and linguistic settings in the application of the procedures for assessing clinical outcomes was a topic of thorough discussion while finalizing study methods and instruments. The transcenter reliability of the IADL scale (main study instrument) scoring was tested before the start of the study [7]. A good intercenter agreement on each item of the IADL scale was shown (ĸ ranging from 0.69 to 0.85). A videotape with examples of the motor performance assessments was prepared and distributed to all centers. To check for the correct adhesion to the MRI protocol and the quality of scans, the performance of a dummy run was required before the beginning of the study. Besides the central evaluation, an experienced rater for each participating center independently rated the MRI changes according to provided illustrative examples in order to carry out an interrater trial on the agreement between the single centers and the central rating; the consistency turned out to be good.

The harmonization of cognitive assessment offered particular complexity and led to the construction of a specific neuropsychological test battery [29]. The development of the LADIS battery had to take into consideration that: (1) selected tests had to be available and familiar in the majority of the centers; (2) the tests had to be sensitive to cognitive decline; (3) the battery had to be innovative, easy to administer, comprehensive, but not too long; (4) all centers had to use the same version of each test, and (5) the original English version of tests had to be translated into each local language.

 The Contribution of the LADIS Study to the Understanding of the Clinical Consequences of WMC

The main findings of the LADIS study in terms of the impact of WMC and other cerebral lesions on clinical aspects are summarized in table 2.

TAB02
Table 2. Main findings from the LADIS study concerning the role of neuroimaging features in clinical aspects

 WMC and Disability

The main objective of the LADIS study was the evaluation of the effects of WMC on the functional status of elderly subjects. A first result of the LADIS study was that already at baseline patients with the highest severity of WMC had a small but measurable degree of functional impairment as measured by the forty-item Disability Assessment for Dementia (DAD) scale despite the independence in everyday life [30]. A trend towards declining performance on the DAD scale was apparent with increasing WMC score severity. The statistical significance of these differences was confirmed in a multiple linear regression analysis, correcting for numerous factors known to influence disability in the elderly. Possible mediators of the relationship between the degree of WMC severity and functional performance were executive functions, which declined with increasing WMC severity and were significantly related to the DAD total score [30].

The hypothesis that WMC have an effect on disability was supported by data from the 1-year follow-up [31]. This interim analysis showed that the rate of transition from a functional autonomous status to disability was 9, 15 and 26%, respectively, in the mild, moderate, and severe group of WMC. Subjects with severe degrees of WMC had a risk of transition more than 2-fold higher compared to that of the mild group and this was independent of a large number of other predictors of disability entered in a multivariate model [31].

The analysis of the 3-year follow-up data offered the definite proof of the original hypothesis of the study [32]. After a median follow-up period of 2.9 years, information on the main outcome was available for 633 (>99%) patients. The annual rate of transition or death was 10.5, 15.1, and 29.5%, respectively, for patients with mild, moderate, and severe WMC (Kaplan-Meier log-rank test, p < 0.001). In a Cox model, comparing severe with mild WMC and adjusting for clinical factors of functional decline, the risk of transition to disability or death was more than 2-fold higher (hazard ratio: 2.43; 95% confidence interval: 1.70–3.47). The effect of severe WMC remained significant independently of the baseline degree of atrophy and the number of infarcts while incident stroke and dementia only slightly modified this effect [32].

 WMC and Cognitive Decline

The relationship between WMC and cognitive performance has been explored in the LADIS study under various aspects. Verdelho et al. [33 ] analyzed the respective role of WMC and vascular risk factors on neuropsychological performance. Severe WMC turned out to be associated with worse performances on global tests of cognition, executive functions, speed and motor control, attention, naming and visuoconstructional praxis. Vascular risk factors, namely diabetes, hypertension, and stroke interfered, independently of WMC severity, with different specific cognitive domains.

Because WMC often coexist with lacunar infarcts, and both can influence cognitive performances, Van der Flier et al. [25 ] studied their combined effect in the baseline LADIS cohort. Increasing severity of WMC and number of lacunes were each related to worse cognitive performances. When considered together, WMC remained significantly associated with cognitive status, whereas the association with lacunes became less prominent.

The joint effect of WMC and lacunes was further investigated by Jokinen et al. [50]. Patients with a combination of severe WMC and at least one lacune or of a multilacunar state and moderate-to-severe WMC performed more poorly on tests of global cognitive function, psychomotor speed, attention and executive functions, verbal fluency, and working memory compared to those with a combination of less severe changes.

Assessing the topographic distribution of lacunes and their impact on cognitive functions, Benisty et al. [36 ] found that the presence of lacunes in the thalamus was associated with lower Mini-Mental State Examination (MMSE) scores, and worse compound scores for speed and motor control and executive functions independently of the cognitive impact of WMC. There was also a significant negative association between the presence of lacunes in putamen/pallidum and the memory compound Z score. No significant association was found between cognitive parameters and the presence of lacunes in the internal capsule, lobar white matter and caudate nucleus.

The relationship between vascular and degenerative mechanisms in determining cognitive impairment is a subject of great interest that has also been tackled in the LADIS study. Van der Flier et al. [38 ] assessed the respective association of MTA, taken as a marker of Alzheimer-type pathology, and WMC with cognitive functions. While severe WMC and MTA were individually associated with a modest and nonsignificant increase in the frequency of mild cognitive deficits, subjects with the combination of MTA and severe WMC had a more than 4-fold increase in the frequency of mild cognitive deficits. These results suggest a combined involvement of Alzheimer and vascular pathology in the earliest stages of cognitive decline.

Several LADIS papers have focused on corpus callosum morphometry. The interest in this topic derives from the consideration that corpus callosum is the largest interconnecting white matter tract in the brain and that changes in its structure may be related to the presence of WMC. In the LADIS population, corpus callosum atrophy was found to be associated with cognitive and motor performances independently of WMC grade and global atrophy [39,40], and a predictor of future motor and cognitive decline [41]. Some LADIS data also suggest that WMC might be responsible for corpus callosum tissue loss [51].

Earlier studies have shown that changes in the white matter that are not visualized by conventional MRI techniques might be related to clinical disturbances [52]. The LADIS study has recently provided corroboration of such data. Using diffusion-weighted imaging, Schmidt et al. [26 ] found that changes in mean diffusivity of whole-brain tissue and normal appearing brain tissue were responsible for cognitive dysfunction (memory performance, executive dysfunction, and speed) and that this effect remained significant after adjustment for WMC lesion volume and brain atrophy. This argues for an additional and independent effect of subtle changes in normal appearing brain tissue on cerebral function in small-vessel disease.

The cognitive performances of the LADIS cohort have also been evaluated in a longitudinal way. The group of patients with a more severe combination of WMC and lacunes presented a significantly steeper decline of cognitive performance and a 3-fold risk of developing dementia during follow-up independently of age, sex, education and MTA [37]. At the end of the 3-year follow-up, 90 patients had developed dementia and 147 cognitive impairment, no dementia [34]. WMC severity turned out to be one of the strongest predictor of cognitive decline (dementia and not dementia), independently of age, education, and MTA. Among considered vascular risk factors, only diabetes independently predicted cognitive decline. Interestingly, considering subtypes of dementia, Alzheimer disease was predicted only by MTA, while vascular dementia was predicted by previous stroke, WMC severity, and MTA [34]. Another strong clinical predictor of dementia subtype proved to be the presence of baseline self-perceived memory complaints. This turned out to predict Alzheimer disease, independent of other confounders (depressive symptoms, WMC severity, MTA and global cognition status at baseline), but not vascular dementia [53]. A cross-sectional analysis already documented that self-perceived memory impairment was significantly associated with objective memory impairment independently of WMC severity, depressive symptoms and MTA [54].

Jokinen et al. [35 ] studied the additional effect of incident lacunes on cognitive performances. After controlling for demographic factors, baseline cognitive performance, baseline lacunar and WMC lesion load, and WMC progression, the number of new lacunes was related to a subtle decrease in compound scores for executive functions and speed and motor control, but not for memory or global cognitive function. Irrespective of lacunes, WMC progression was associated with a decrease in executive function score [35]. Thus, the LADIS study data confirm that in addition to WMC, lacunes determine (or modulate the development of) cognitive impairment in small-vessel disease, although the individual contribution of lacunes to cognition is modest.

The LADIS study also offered some additional methodological elements concerning neuropsychological assessment. Ylikoski et al. [55] found that the Alzheimer Disease Assessment Scale – Cognitive Subscale (ADAS-cog) differentiated only between the mild and severe WMC groups, while the differences among the three WMC groups were highly significant with the Vascular Dementia Assessment Scale – Cognitive Subscale (VADAS-cog), suggesting that in patients with vascular lesions a test modified to embrace also mental speed and executive functions (VADAS-cog) is more suited than the original one developed for patients with Alzheimer disease (ADAS-cog). The extent to which the baseline performance in specific neuropsychological tests was able to predict the clinical diagnosis of dementia has also been assessed [56]. As expected, patients with a final dementia diagnosis had lower scores in almost all baseline neuropsychological tests when compared with the participants without dementia. Using logistic regression analyses, controlling for age, education and WMC severity, worse performance on MMSE and VADAS-cog turned out to be independent predictors of dementia. Concerning sensitivity and specificity rates, the VADAS battery turned out to have higher sensitivity and specificity rates (area under the curve = 82%) in this specific population to identify dementia compared with the MMSE and ADAS.

 WMC and Depression

At the baseline evaluation, depressive symptoms, as assessed by the Geriatric Depression Scale (GDS), were found to be associated with WMC severity and quality of life, suggesting a causative role of WMC in this regard [42]. When examining the relationship between depressive symptoms and the location of WMC, deep, rather than periventricular lesions, and the frontal and temporal locations proved to have the strongest association [45,46]. The importance of lacunes as opposed to WMC in relation to depression remains controversial, and both are highly correlated. However, while WMC were strongly associated with GDS score, basal ganglia lacunes were only weakly correlated and lacunes in other regions showed no association [46]. A key issue is whether WMC predate depression, and so are causally related to mood changes, or whether they are a consequence of being depressed. Regarding the predictive role of baseline WMC on the development of depression, the severity of WMC independently and significantly predicted GDS score at 1 year, after controlling for baseline GDS score, quality of life, and worsening disability [43]. More prolonged follow-up analyses corroborated the 1-year follow-up data but also added information about the prediction of depressive episodes [44]. As expected, baseline GDS score significantly predicted future depressive symptoms. When the variable ‘transition to disability’ was included in the regression model, the severity of WMC continued to significantly predict GDS scores at 2 but not 3 years [44]. Furthermore, the baseline severity of WMC no longer predicted incident depression. These findings suggest that the independent effect of WMC on mood attenuates over time as patients in the sample become more disabled. One possible explanation for this could be that, in the more disabled 3-year population, transition to disability is also a driver of depressive outcomes and thus mediates the effect of the other significant covariates from the univariate analysis. Another explanation could be that disability and depression are both so strongly associated with WMC that it is difficult to determine causality using regression techniques.

In conclusion, concerning the mood profile, the LADIS study shows that baseline severity of WMC and lesion progression are both predictive of depressive symptoms, thus supporting the ‘vascular depression hypothesis’ and strongly implicating WMC in the pathogenesis of late-life depression.

 WMC, Gait and Urinary Disturbances

Gait problems and falls are a major feature of patients with WMC [57] and an important cause of morbidity and mortality in the elderly. Motor, coordination, and gait abilities are based on the integrity of the complex motor circuit network that connects basal ganglia and brainstem structures with the frontal cortex. This network’s function may be challenged by a critical number of lesions in the subcortical regions.

In the LADIS study, in order to quantify motor performance, several clinical measures including the Short Physical Performance Battery (SPPB), single leg stance time, and walking speed were used [47]. A significant difference in SPPB total score for the 3 categories of mild, moderate, and severe WMC was detected. In a logistic regression analysis, using a dichotomized SPPB score as the dependent variable, a significant association was found for all WMC categories (moderate vs. mild, severe vs. mild), pointing at a dose-dependent effect. In the multivariate analysis, adjusting for many possible confounders, the association remained significant when comparing the severe with the mild WMC group. Logistic regression analyses were also performed using pathological single leg stance time and walking speed as the dependent variables. Results were similar to what was found for SPPB scores. Interestingly, regular physical activity was associated with better motor performance and single leg stance time [47].

The study by Blahak et al. [48 ] has demonstrated the significant association between falls and WMC severity. The rate of falls and the severity of WMC were significantly associated with balance disturbances. WMC location was analyzed with respect to falls and balance performance. In multivariate analysis, periventricular and frontal deep WMC were independently associated with falls. Logistic regression identified frontal deep WMC, but not basal ganglia and infratentorial hyperintensities, as significantly associated with balance disturbances.

In conclusion, the LADIS results corroborate the hypothesis that subcortical vascular changes are among the major determinants of mobility problems in the elderly and also that physical activity might have the potential to reduce the risk of limitations in mobility. The association of frontal and periventricular WMC with falls supports the hypothesis that interruption of frontal-subcortical motor circuits leads to balance disturbances and hence to an increased risk of falls in WMC.

One major determinant of impaired functionality in relation to WMC, in addition to cognitive, motor and depressive disturbances, is represented by continence problems. In the LADIS baseline cohort of nondisabled subjects, severe WMC were associated with urinary urgency, independent of other potential confounders and vascular lesions of the brain [49].

 The Role of Neuroimaging in Age-Related Vascular Processes: The Contribution of the LADIS Study

The longitudinal design of the LADIS study, with repetition of MRI examination after 3 years from enrollment, gave us the opportunity to study the natural course of WMC and lacunes over time and the possible predictors of lesion evolution. Progression of WMC, assessed with the modified and validated version of the Rotterdam progression scale [58], developed mostly in the subcortical regions where WMC had also been most prevalent at baseline [59]. New lacunes mostly appeared in the subcortical white matter, mainly of the frontal lobes, whereas the majority of baseline lacunes were located in the basal ganglia. When assessing the contribution of baseline MRI features and clinical characteristics to disease progression, both WMC severity and the number of lacunes, together with previous stroke, were independent predictors of both WMC progression and of the occurrence of new lacunes. Diabetes and blood glucose levels were risk factors for WMC progression, while male sex, hypertension, systolic blood pressure, body mass index, high-density lipoprotein, and triglyceride levels were risk factors for new lacunes [59].

Almost half of the new subcortical lacunes after 3 years had occurred within areas of preexisting WMC or were associated with a significant local development of WMC at follow-up. This was significantly different from lacunes which had occurred in the basal ganglia or in infratentorial regions. Also the risk factors for incident lacunes specifically in the subcortical white matter (history of hypertension and stroke) were different from those predicting new basal ganglia and infratentorial lacunes (atrial fibrillation), hinting at a possibly different pathogenesis [60].

Concerning the evaluation of WMC severity, in the LADIS study both visual rating and semiautomated volumetric methods were implemented [58,61,62]. The ability of the two approaches to detecting an association between lesion severity and clinical parameters at baseline was particularly investigated [24]. It was found that, possibly due to a ceiling effect of visual rating scales, volumetric data were better suited to show differences between subjects regarding memory symptoms whereas associations were similar regarding age and gait disturbances. A clear but nonlinear relationship was established with WMC volume for all rating scales [24].

Regarding nonconventional MRI the LADIS study also explored the contribution of diffusion-weighted and magnetization transfer imaging for the assessment of WMC and normal appearing brain tissue. The severity of WMC and age were significant predictors of both global changes in diffusivity and magnetization transfer ratio and diffusion-weighted imaging appeared more robust for the application in a multicenter setting [28].

 Conclusion and Future Directions

The LADIS study is the first international collaboration entirely devoted to the assessment of the clinical impact of WMC in the elderly. The study results have shown that the severity of WMC is a strong and independent predictor of the transition from an autonomous status to disability (main study outcome). The LADIS study has also provided additional data on the specific influence of WMC and lacunar infarcts on other disturbances commonly seen in elderly patients such as cognitive, motor, depressive and urinary problems (table 2). It is to be noted that the LADIS study was mainly focused on WMC; other lesions were also assessed in the study, with the main aim of using them as covariates in the analyses of study outcome. Today, more profound knowledge exists that other lesions such as lacunar infarcts are strictly linked with the same underlying small-vessel pathogenesis of WMC. A more modern view would perhaps suggest considering these two lesion types together.

Despite the somehow heterogeneous study population, which has, however, proved to be no limitation in making important observations, and despite the absence of imaging sequences which now seem to be important in observing other sequels of small-vessel disease, such as susceptibility-weighted imaging and T2*, the LADIS study has made significant contributions to understanding the importance of WMC. The LADIS study represents a successful model of an integrated and collaborative effort among different European countries and, because of the strength of the existing network, provides a platform for subsequent endeavors. Future lines of development of the LADIS experience may be (1) the establishment of clinical trials for small-vessel disease-related functional impairment; (2) furthering the knowledge about the relation between vascular and degenerative changes in terms of cognition and functional outcome; (3) testing the role of new biomarkers (neuroimaging, cerebrospinal fluid components [for a preliminary experience, see [63] ]) in association with WMC; (4) development of the basis for the definition of vascular mild cognitive impairment criteria, and (5) exploration of the influence of genetic factors in small-vessel disease. The LADIS study group invites colleagues to join and widen the existing collaborative network, to jointly work in the coming 10 years on the elucidation of WMC and related pathology.

 Appendix


 List of Participating Centers and Personnel

Helsinki, Finland (Department of Neurology, Helsinki University Central Hospital and Department of Neurological Sciences, University of Helsinki, Finland): Timo Erkinjuntti, Tarja Pohjasvaara, Pia Pihanen, Raija Ylikoski, Hanna Jokinen, Meija-Marjut Somerkoski, Riitta Mäntylä, Oili Salonen; Graz, Austria (Department of Neurology and Department of Radiology, Division of Neuroradiology, Medical University Graz): Franz Fazekas, Reinhold Schmidt, Stefan Ropele, Brigitte Rous, Katja Petrovic, Ulrike Garmehi, Alexandra Seewann; Lisbon, Portugal (Serviço de Neurologia, Centro de Estudos Egas Moniz, Hospital de Santa Maria): José M. Ferro, Ana Verdelho, Sofia Madureira, Carla Moleiro; Amsterdam, The Netherlands (Department of Radiology and Neurology, VU Medical Centre): Philip Scheltens, van Straaten, Frederik Barkhof, Alida Gouw, Wiesje van der Flier; Göteborg, Sweden (Institute of Clinical Neuroscience, Göteborg University): Anders Wallin, Michael Jonsson, Karin Lind, Arto Nordlund, Sindre Rolstad, Ingela Isblad; Huddinge, Sweden (Karolinska Institutet, Department of Neurbiology, Care Sciences and Society, and Karolinska University Hospital Huddinge): Lars-Olof Wahlund, Milita Crisby, Anna Pettersson, Kaarina Amberla; Paris, France (Department of Neurology, Hôpital Lariboisière): Hugues Chabriat, Karen Hernandez, Annie Kurtz, Dominique Hervé, Sarah Benisty, Jean Pierre Guichard; Mannheim, Germany (Department of Neurology, University of Heidelberg, Klinikum Mannheim): Michael Hennerici, Christian Blahak, Hansjörg Baezner, Martin Wiarda, Susanne Seip; Copenhagen, Denmark (Memory Disorders Research Group, Department of Neurology, Rigshospitalet, and the Danish Research Centre for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospitals): Gunhild Waldemar, Egill Rostrup, Charlotte Ryberg, Tim Dyrby, Olaf B. Paulson, Ellen Garde; Kristian Steen Frederiksen; Newcastle-upon-Tyne, UK (Institute for Ageing and Health, Newcastle University): John O’Brien, Sanjeet Pakrasi, Mani Krishnan, Andrew Teodorczuk, Michael Firbank, Philip English, Thais Minett.

The Coordinating center is in Florence, Italy (Department of Neurological and Psychiatric Sciences, University of Florence): Domenico Inzitari (Study Coordinator), Luciano Bartolini, Anna Maria Basile, Eliana Magnani, Monica Martini, Mario Mascalchi, Marco Moretti, Leonardo Pantoni, Anna Poggesi, Giovanni Pracucci, Emilia Salvadori, Michela Simoni.

The LADIS Steering Committee is formed by Domenico Inzitari (Study Coordinator), Timo Erkinjuntti, Philip Scheltens, Marieke Visser, and Peter Langhorne, who replaced Kjell Asplund in this role, beginning in 2005.

 Acknowledgement

The study is supported by the European Union within the V European Framework Programme ‘Quality of life and management of living resources’ (1998–2002), contract No. QLRT-2000-00446 as a concerted action.


  

Footnotes

Footnote 1
Authors’ Contribution: Anna Poggesi and Leonardo Pantoni drafted the first version of the paper. The paper was then reviewed by the study principal investigator (Domenico Inzitari), the study workpackages coordinators (Franz Fazekas, Josè Ferro, John O’Brien, and Michael Hennerici), the LADIS Study steering committee members (Philip Scheltens, Timo Erkinjuntti, Marieke Visser and Peter Langhorne), and the remaining center coordinators (Hugues Chabriat, Gunhild Waldemar, Anders Wallin, Anders Wahlund).


References

  1. Pantoni L: Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010;9:689–701.
  2. Inzitari D: Leukoaraiosis: an independent risk factor for stroke? Stroke 2003;34:2067–2071.
  3. Pantoni L: Leukoaraiosis: from an ancient term to an actual marker of poor prognosis. Stroke 2008;39:1401–1403.
  4. Debette S, Markus HS: The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010 DOI: 10.1136/bmj.c3666.

    External Resources

  5. Pantoni L, Garcia JH: The significance of cerebral white matter abnormalities 100 years after Binswanger’s report. A review. Stroke 1995;26:1293–1301.
  6. Erkinjuntti T, Pantoni L, Scheltens P: Cooperation and networking on white matter disorders: the European Task Force on Age-Related White Matter Changes. Dement Geriatr Cogn Disord 1998;9(suppl 1):44–45.
  7. Pantoni L, Basile AM, Pracucci G, Asplund K, Bogousslavsky J, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D: Impact of age-related cerebral white matter changes on the transition to disability – the LADIS study: rationale, design and methodology. Neuroepidemiology 2005;24:51–62.
  8. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA: MR signal abnormalities at 1.5T in Alzheimer’s dementia and normal aging. AJNR Am J Neuroradiol 1987;8:421–426.

    External Resources

  9. Lawton MP, Brody EM: Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969;9:179–186.
  10. Basile AM, Pantoni L, Pracucci G, Asplund K, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D, LADIS Study Group: Age, hypertension, and lacunar stroke are the major determinants of the severity of age-related white matter changes. The LADIS (Leukoaraiosis and Disability in the Elderly) Study. Cerebrovasc Dis 2006;21:315–322.
  11. Gelinàs I, Gauthier L, McIntyre M, Gauthier S: Development of a functional measure for persons with Alzheimer’s disease: the disability assessment for dementia. Am J Occup Ther 1999;53:471–481.
  12. Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
  13. McLeod CM: Half a century of research on the Stroop effect: an integrative review. Psychol Bull 1991;109:163–203.
  14. Reitan RM: Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills 1958;8:271–276.

    External Resources

  15. Ferris SH: General measures of cognition. Int Psychogeriatr 2003;15(suppl 1):215–217.
  16. Yesavage JA: Geriatric Depression Scale. Psychopharmacol Bull 1988;24:709–711.
  17. Alexopoulos GS, Abrams RC, Young RC, Shamoian CA: Cornell scale for depression in dementia. Biol Psychiatry 1988;23:271–284.
  18. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Washington, American Psychiatric Association, 1994.
  19. Guralnik JM, Ferrucci L, Simonsick EM, Salive ME, Wallace RB: Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability. N Engl J Med 1995;332:556–561.
  20. Guttmann CR, Benson R, Warfield SK, Wei X, Anderson MC, Hall CB, Abu-Hasaballah K, Mugler JP, Wolfson L: White matter abnormalities in mobility-impaired older persons. Neurology 2000;54:1277–1283.
  21. The Euro-Qol Group: Euro-Qol: a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199–208.
  22. Scheltens P, Barkhof F, Leys D, Pruvo JP, Nauta JJ, Vermersch P, Steinling M, Valk J: A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci 1993;114:7–12.
  23. Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjögren M, Wallin A, Ader H, Leys D, Pantoni L, Pasquier F, Erkinjuntti T, Scheltens P, European Task Force on Age-Related White Matter Changes: A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 2001;32:1318–1322.
  24. van Straaten EC, Fazekas F, Rostrup E, Scheltens P, Schmidt R, Pantoni L, Inzitari D, Waldemar G, Erkinjuntti T, Mäntylä R, Wahlund LO, Barkhof F, LADIS Group: Impact of white matter hyperintensities scoring method on correlations with clinical data: the LADIS study. Stroke 2006;37:836–840.
  25. van der Flier WM, van Straaten EC, Barkhof F, Verdelho A, Madureira S, Pantoni L, Inzitari D, Erkinjuntti T, Crisby M, Waldemar G, Schmidt R, Fazekas F, Scheltens P: Small vessel disease and general cognitive function in nondisabled elderly: the LADIS study. Stroke 2005;36:2116–2120.
  26. Schmidt R, Ropele S, Ferro J, Madureira S, Verdelho A, Petrovic K, Gouw A, van der Flier WM, Enzinger C, Pantoni L, Inzitari D, Erkinjuntti T, Scheltens P, Wahlund LO, Waldemar G, Rostrup E, Wallin A, Barkhof F, Fazekas F, LADIS study Group: Diffusion-weighted imaging and cognition in the leukoariosis and disability in the elderly study. Stroke 2010;41:e402–e408.
  27. Scheltens P, Leys D, Barkhof F, Huglo D, Weinstein HC, Vermersch P, Kuiper M, Steinling M, Wolters EC, Valk J: Atrophy of medial temporal lobes on MRI in “probable” Alzheimer’s disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry 1992;55:967–972.
  28. Ropele S, Seewann A, Gouw AA, van der Flier WM, Schmidt R, Pantoni L, Inzitari D, Erkinjuntti T, Scheltens P, Wahlund LO, Waldemar G, Chabriat H, Ferro J, Hennerici M, O’Brien J, Wallin A, Langhorne P, Visser MC, Barkhof F, Fazekas F, LADIS Study Group: Quantitation of brain tissue changes associated with white matter hyperintensities by diffusion-weighted and magnetization transfer imaging: the LADIS (Leukoaraiosis and Disability in the Elderly) study. J Magn Reson Imaging 2009;29:268–274.
  29. Madureira S, Verdelho A, Ferro J, Basile AM, Chabriat H, Erkinjuntti T, Fazekas F, Hennerici M, O’Brien J, Pantoni L, Salvadori E, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D, LADIS Study Group: Development of a neuropsychological battery for the Leukoaraiosis and Disability in the Elderly Study (LADIS): experience and baseline data. Neuroepidemiology 2006;27:101–116.
  30. Pantoni L, Poggesi A, Basile AM, Pracucci G, Barkhof F, Chabriat H, Erkinjuntti T, Ferro JM, Hennerici M, O’Brien J, Schmidt R, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D, LADIS Study Group: Leukoaraiosis predicts hidden global functioning impairment in nondisabled older people: the LADIS (Leukoaraiosis and Disability in the Elderly) Study. J Am Geriatr Soc 2006;54:1095–1101.
  31. Inzitari D, Simoni M, Pracucci G, Poggesi A, Basile AM, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, Langhorne P, O’Brien J, Barkhof F, Visser MC, Wahlund LO, Waldemar G, Wallin A, Pantoni L, LADIS Study Group: Risk of rapid global functional decline in elderly patients with severe cerebral age-related white matter changes: the LADIS study. Arch Intern Med 2007;167:81–88.
  32. Inzitari D, Pracucci G, Poggesi A, Carlucci G, Barkhof F, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, Langhorne P, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Pantoni L, LADIS Study Group: Changes in white matter as determinant of global functional decline in older independent outpatients: three year follow-up of LADIS (leukoaraiosis and disability) study cohort. BMJ 2009;339:b2477.
  33. Verdelho A, Madureira S, Ferro JM, Basile AM, Chabriat H, Erkinjuntti T, Fazekas F, Hennerici M, O’Brien J, Pantoni L, Salvadori E, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D, LADIS Study: Differential impact of cerebral white matter changes, diabetes, hypertension and stroke on cognitive performance among non-disabled elderly. The LADIS study. J Neurol Neurosurg Psychiatry 2007;78:1325–1330.
  34. Verdelho A, Madureira S, Moleiro C, Ferro JM, Santos CO, Erkinjuntti T, Pantoni L, Fazekas F, Visser M, Waldemar G, Wallin A, Hennerici M, Inzitari D, LADIS Study: White matter changes and diabetes predict cognitive decline in the elderly: the LADIS study. Neurology 2010;75:160–167.
  35. Jokinen H, Gouw AA, Madureira S, Ylikoski R, van Straaten EC, van der Flier WM, Barkhof F, Scheltens P, Fazekas F, Schmidt R, Verdelho A, Ferro JM, Pantoni L, Inzitari D, Erkinjuntti T, LADIS Study Group: Incident lacunes influence cognitive decline: the LADIS study. Neurology 2011;76:1872–1878.
  36. Benisty S, Gouw AA, Porcher R, Madureira S, Hernandez K, Poggesi A, van der Flier WM, Van Straaten EC, Verdelho A, Ferro J, Pantoni L, Inzitari D, Barkhof F, Fazekas F, Chabriat H, LADIS Study group: Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study. J Neurol Neurosurg Psychiatry 2009;80:478–483.
  37. Jokinen H, Kalska H, Ylikoski R, Madureira S, Verdelho A, Gouw A, Scheltens P, Barkhof F, Visser MC, Fazekas F, Schmidt R, O’Brien J, Hennerici M, Baezner H, Waldemar G, Wallin A, Chabriat H, Pantoni L, Inzitari D, Erkinjuntti T, LADIS group: MRI-defined subcortical ischemic vascular disease: baseline clinical and neuropsychological findings. The LADIS study. Cerebrovasc Dis 2009;27:336–344.
  38. van der Flier WM, van Straaten EC, Barkhof F, Ferro JM, Pantoni L, Basile AM, Inzitari D, Erkinjuntti T, Wahlund LO, Rostrup E, Schmidt R, Fazekas F, Scheltens P, LADIS study group: Medial temporal lobe atrophy and white matter hyperintensities are associated with mild cognitive deficits in non-disabled elderly people: the LADIS study. J Neurol Neurosurg Psychiatry 2005;76:1497–1500.
  39. Ryberg C, Rostrup E, Stegmann MB, Barkhof F, Scheltens P, van Straaten EC, Fazekas F, Schmidt R, Ferro JM, Baezner H, Erkinjuntti T, Jokinen H, Wahlund LO, O’Brien J, Basile AM, Pantoni L, Inzitari D, Waldemar G, LADIS study group: Clinical significance of corpus callosum atrophy in a mixed elderly population. Neurobiol Aging 2007;28:955–963.
  40. Jokinen H, Ryberg C, Kalska H, Ylikoski R, Rostrup E, Stegmann MB, Waldemar G, Madureira S, Ferro JM, van Straaten EC, Scheltens P, Barkhof F, Fazekas F, Schmidt R, Carlucci G, Pantoni L, Inzitari D, Erkinjuntti T, LADIS group: Corpus callosum atrophy is associated with mental slowing and executive deficits in subjects with age-related white matter hyperintensities: the LADIS Study. J Neurol Neurosurg Psychiatry 2007;78:491–496.
  41. Ryberg C, Rostrup E, Paulson OB, Barkhof F, Scheltens P, van Straaten EC, van der Flier WM, Fazekas F, Schmidt R, Ferro JM, Baezner H, Erkinjuntti T, Jokinen H, Wahlund LO, Poggesi A, Pantoni L, Inzitari D, Waldemar G, LADIS study group: Corpus callosum atrophy as a predictor of age-related cognitive and motor impairment: a 3-year follow-up of the LADIS study cohort. J Neurol Sci 2011;307:100–105.
  42. Firbank MJ, O’Brien JT, Pakrasi S, Pantoni L, Simoni M, Erkinjuntti T, Wallin A, Wahlund LO, van Straaten I, Inzitari D: White matter hyperintensities and depression – preliminary results from the LADIS study. Int J Geriatr Psychiatry 2005;20:674–679.
  43. Teodorczuk A, O’Brien JT, Firbank MJ, Pantoni L, Poggesi A, Erkinjuntti T, Wallin A, Wahlund LO, Gouw A, Waldemar G, Schmidt R, Ferro JM, Chabriat H, Bäzner H, Inzitari D, LADIS Group: White matter changes and late-life depressive symptoms: longitudinal study. Br J Psychiatry 2007;191:212–217.
  44. Teodorczuk A, Firbank MJ, Pantoni L, Poggesi A, Erkinjuntti T, Wallin A, Wahlund LO, Scheltens P, Waldemar G, Schrotter G, Ferro JM, Chabriat H, Bazner H, Visser M, Inzitari D, O’Brien JT, LADIS Group: Relationship between baseline white-matter changes and development of late-life depressive symptoms: 3-year results from the LADIS study. Psychol Med 2010;40:603–610.
  45. Krishnan MS, O’Brien JT, Firbank MJ, Pantoni L, Carlucci G, Erkinjuntti T, Wallin A, Wahlund LO, Scheltens P, van Straaten EC, Inzitari D, LADIS Group: Relationship between periventricular and deep white matter lesions and depressive symptoms in older people. The LADIS Study. Int J Geriatr Psychiatry 2006;21:983–989.
  46. O’Brien JT, Firbank MJ, Krishnan MS, van Straaten EC, van der Flier WM, Petrovic K, Pantoni L, Simoni M, Erkinjuntti T, Wallin A, Wahlund LO, Inzitari D, LADIS Group: White matter hyperintensities rather than lacunar infarcts are associated with depressive symptoms in older people: the LADIS study. Am J Geriatr Psychiatry 2006;14:834–841.
  47. Baezner H, Blahak C, Poggesi A, Pantoni L, Inzitari D, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Langhorne P, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Hennerici MG, LADIS Study Group: Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology 2008;70:935–942.
  48. Blahak C, Baezner H, Pantoni L, Poggesi A, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Langhorne P, O’Brien J, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D, Hennerici MG, LADIS Study Group: Deep frontal and periventricular age related white matter changes but not basal ganglia and infratentorial hyperintensities are associated with falls: cross-sectional results from the LADIS study. J Neurol Neurosurg Psychiatry 2009;80:608–613.
  49. Poggesi A, Pracucci G, Chabriat H, Erkinjuntti T, Fazekas F, Verdelho A, Hennerici M, Langhorne P, O’Brien J, Scheltens P, Visser MC, Crisby M, Waldemar G, Wallin A, Inzitari D, Pantoni L, Leukoaraiosis and Disability Study Group: Urinary complaints in nondisabled elderly people with age-related white matter changes: the Leukoaraiosis and Disability (LADIS) Study. J Am Geriatr Soc 2008;56:1638–1643.
  50. Jokinen H, Kalska H, Ylikoski R, Madureira S, Verdelho A, van der Flier WM, Scheltens P, Barkhof F, Visser MC, Fazekas F, Schmidt R, O’Brien J, Waldemar G, Wallin A, Chabriat H, Pantoni L, Inzitari D, Erkinjuntti T, LADIS group: Longitudinal cognitive decline in subcortical ischemic vascular disease – the LADIS Study. Cerebrovasc Dis 2009;27:384–391.
  51. Ryberg C, Rostrup E, Sjöstrand K, Paulson OB, Barkhof F, Scheltens P, van Straaten EC, Fazekas F, Schmidt R, Erkinjuntti T, Wahlund LO, Basile AM, Pantoni L, Inzitari D, Waldemar G, LADIS study group: White matter changes contribute to corpus callosum atrophy in the elderly: the LADIS study. AJNR Am J Neuroradiol 2008;29:1498–1504.
  52. Fazekas F, Ropele S, Enzinger C, Gorani F, Seewann A, Petrovic K, Schmidt R: MTI of white matter hyperintensities. Brain 2005;128:2926–2932.
  53. Verdelho A, Madureira S, Moleiro C, Santos CO, Ferro JM, Erkinjuntti T, Poggesi A, Pantoni L, Fazekas F, Scheltens P, Waldemar G, Wallin A, Inzitari D: Self-perceived memory complaints predict progression to Alzheimer disease. The LADIS Study. J Alzheimers Dis 2011, E-pub ahead of print.
  54. Miranda B, Madureira S, Verdelho A, Ferro J, Pantoni L, Salvadori E, Chabriat H, Erkinjuntti T, Fazekas F, Hennerici M, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitarion D, LADIS Study: Self-perceived memory impairment and cognitive performance in an elderly independent population with age-related white matter changes. J Neurol Neurosurg Psychiatry 2008;79:869–873.
  55. Ylikoski R, Jokinen H, Andersen P, Salonen O, Madureira S, Ferro J, Barkhof F, van der Flier W, Schmidt R, Fazekas F, Scheltens P, Waldemar G, Salvadori E, Pantoni L, Inzitari D, Erkinjuntti T, LADIS Study Group: Comparison of the Alzheimer’s Disease Assessment Scale Cognitive Subscale and the Vascular Dementia Assessment Scale in differentiating elderly individuals with different degrees of white matter changes. The LADIS Study. Dement Geriatr Cogn Disord 2007;24:73–81.
  56. Madureira S, Verdelho A, Moleiro C, Ferro JM, Erkinjuntti T, Jokinen H, Pantoni L, Fazekas F, Van der Flier W, Visser M, Waldemar G, Wallin A, Hennerici M, Inzitari D: Neuropsychological predictors of dementia in a three-year follow-up period: data from the LADIS study. Dement Geriatr Cogn Disord 2010;29:325–334.
  57. Zheng JJ, Delbaere K, Close JC, Sachdev PS, Lord SR: Impact of white matter lesions on physical functioning and fall risk in older people: a systematic review. Stroke 2011;42:2086–2090.
  58. Gouw AA, van der Flier WM, van Straaten EC, Pantoni L, Bastos-Leite AJ, Inzitari D, Erkinjuntti T, Wahlund LO, Ryberg C, Schmidt R, Fazekas F, Scheltens P, Barkhof F, LADIS study group: Reliability and sensitivity of visual scales versus volumetry for evaluating white matter hyperintensity progression. Cerebrovasc Dis 2008;25:247–253.
  59. Gouw AA, van der Flier WM, Fazekas F, van Straaten EC, Pantoni L, Poggesi A, Inzitari D, Erkinjuntti T, Wahlund LO, Waldemar G, Schmidt R, Scheltens P, Barkhof F, LADIS Study Group: Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period: the Leukoaraiosis and Disability Study. Stroke 2008;39:1414–1420.
  60. Gouw AA, van der Flier WM, Pantoni L, Inzitari D, Erkinjuntti T, Wahlund LO, Waldemar G, Schmidt R, Fazekas F, Scheltens P, Barkhof F, LADIS Study Group: On the etiology of incident brain lacunes: longitudinal observations from the LADIS study. Stroke 2008;39:3083–3085.
  61. Gouw AA, Van der Flier WM, van Straaten EC, Barkhof F, Ferro JM, Baezner H, Pantoni L, Inzitari D, Erkinjuntti T, Wahlund LO, Waldemar G, Schmidt R, Fazekas F, Scheltens P, LADIS Study Group: Simple versus complex assessment of white matter hyperintensities in relation to physical performance and cognition: the LADIS study. J Neurol 2006;253:1189–1196.
  62. Dyrby TB, Rostrup E, Baaré WF, van Straaten EC, Barkhof F, Vrenken H, Ropele S, Schmidt R, Erkinjuntti T, Wahlund LO, Pantoni L, Inzitari D, Paulson OB, Hansen LK, Waldemar G, LADIS Study Group: Segmentation of age-related white matter changes in a clinical multi-center study. Neuroimage 2008;41:335–345.
  63. Jonsson M, Zetterberg H, van Straaten E, Lind K, Syversen S, Edman A, Blennow K, Rosengren L, Pantoni L, Inzitari D, Wallin A: Cerebrospinal fluid biomarkers of white matter lesions – cross-sectional results from the LADIS study. Eur J Neurol 2010;17:377–382.

  

Author Contacts

Leonardo Pantoni, MD, PhD
Department of Neurological and Psychiatric Sciences
University of Florence
Largo Brambilla 3, IT–50134 Florence (Italy)
Tel. +39 055 794 5519, E-Mail pantoni@unifi.it

  

Article Information

Received: September 21, 2011
Accepted: October 18, 2011
Published online: December 1, 2011
Number of Print Pages : 12
Number of Figures : 1, Number of Tables : 2, Number of References : 63

  

Publication Details

Cerebrovascular Diseases

Vol. 32, No. 6, Year 2011 (Cover Date: December 2011)

Journal Editor: Hennerici M.G. (Mannheim)
ISSN: 1015-9770 (Print), eISSN: 1421-9786 (Online)

For additional information: http://www.karger.com/CED


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Over the last 20 years, evidence about the clinical correlates of cerebral white matter changes (WMC; also called leukoaraiosis) has been accumulating. WMC are now listed among the neuroimaging expressions of cerebral small-vessel disease and are no longer considered an innocuous finding because they are associated, in cross-sectional surveys, with various disturbances and, in follow-up studies, with poor prognosis. The Leukoaraiosis And DISability (LADIS) study has contributed substantially to this body of knowledge. LADIS is a European multicenter collaboration that was started in 2001 with the aim of assessing the independent role of WMC in predicting disability in subjects aged 65–84. The main results of the LADIS study have been released in 2009 with the demonstration that severe WMC more than double the risk of transition from an autonomous to a dependent status after 3 years of follow-up. The LADIS study has also contributed more focused substudies assessing the possible role of WMC in the decline of cognitive and motor performances, depressive symptoms associated with aging and cerebrovascular diseases, urinary disturbances, and also the role of other brain lesions (lacunar infarcts, cerebral atrophy, and corpus callosum morphology). The LADIS study provides a good example of harmonization of instruments (MRI protocol, clinical, neuropsychological, and functional scales) within an international collaboration. Currently, the LADIS study is providing data about the natural history of WMC. In this paper, we review the background and the main results of the LADIS study. This review puts forward some considerations for future studies in the field.

© 2011 S. Karger AG, Basel


  

Author Contacts

Leonardo Pantoni, MD, PhD
Department of Neurological and Psychiatric Sciences
University of Florence
Largo Brambilla 3, IT–50134 Florence (Italy)
Tel. +39 055 794 5519, E-Mail pantoni@unifi.it

  

Article Information

Received: September 21, 2011
Accepted: October 18, 2011
Published online: December 1, 2011
Number of Print Pages : 12
Number of Figures : 1, Number of Tables : 2, Number of References : 63

  

Publication Details

Cerebrovascular Diseases

Vol. 32, No. 6, Year 2011 (Cover Date: December 2011)

Journal Editor: Hennerici M.G. (Mannheim)
ISSN: 1015-9770 (Print), eISSN: 1421-9786 (Online)

For additional information: http://www.karger.com/CED


Article / Publication Details

First-Page Preview
Abstract of Review

Received: 9/21/2011
Accepted: 10/18/2011
Published online: 12/1/2011
Issue release date: December 2011

Number of Print Pages: 12
Number of Figures: 1
Number of Tables: 2

ISSN: 1015-9770 (Print)
eISSN: 1421-9786 (Online)

For additional information: http://www.karger.com/CED


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Pantoni L: Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010;9:689–701.
  2. Inzitari D: Leukoaraiosis: an independent risk factor for stroke? Stroke 2003;34:2067–2071.
  3. Pantoni L: Leukoaraiosis: from an ancient term to an actual marker of poor prognosis. Stroke 2008;39:1401–1403.
  4. Debette S, Markus HS: The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010 DOI: 10.1136/bmj.c3666.

    External Resources

  5. Pantoni L, Garcia JH: The significance of cerebral white matter abnormalities 100 years after Binswanger’s report. A review. Stroke 1995;26:1293–1301.
  6. Erkinjuntti T, Pantoni L, Scheltens P: Cooperation and networking on white matter disorders: the European Task Force on Age-Related White Matter Changes. Dement Geriatr Cogn Disord 1998;9(suppl 1):44–45.
  7. Pantoni L, Basile AM, Pracucci G, Asplund K, Bogousslavsky J, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D: Impact of age-related cerebral white matter changes on the transition to disability – the LADIS study: rationale, design and methodology. Neuroepidemiology 2005;24:51–62.
  8. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA: MR signal abnormalities at 1.5T in Alzheimer’s dementia and normal aging. AJNR Am J Neuroradiol 1987;8:421–426.

    External Resources

  9. Lawton MP, Brody EM: Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969;9:179–186.
  10. Basile AM, Pantoni L, Pracucci G, Asplund K, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D, LADIS Study Group: Age, hypertension, and lacunar stroke are the major determinants of the severity of age-related white matter changes. The LADIS (Leukoaraiosis and Disability in the Elderly) Study. Cerebrovasc Dis 2006;21:315–322.
  11. Gelinàs I, Gauthier L, McIntyre M, Gauthier S: Development of a functional measure for persons with Alzheimer’s disease: the disability assessment for dementia. Am J Occup Ther 1999;53:471–481.
  12. Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
  13. McLeod CM: Half a century of research on the Stroop effect: an integrative review. Psychol Bull 1991;109:163–203.
  14. Reitan RM: Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills 1958;8:271–276.

    External Resources

  15. Ferris SH: General measures of cognition. Int Psychogeriatr 2003;15(suppl 1):215–217.
  16. Yesavage JA: Geriatric Depression Scale. Psychopharmacol Bull 1988;24:709–711.
  17. Alexopoulos GS, Abrams RC, Young RC, Shamoian CA: Cornell scale for depression in dementia. Biol Psychiatry 1988;23:271–284.
  18. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Washington, American Psychiatric Association, 1994.
  19. Guralnik JM, Ferrucci L, Simonsick EM, Salive ME, Wallace RB: Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability. N Engl J Med 1995;332:556–561.
  20. Guttmann CR, Benson R, Warfield SK, Wei X, Anderson MC, Hall CB, Abu-Hasaballah K, Mugler JP, Wolfson L: White matter abnormalities in mobility-impaired older persons. Neurology 2000;54:1277–1283.
  21. The Euro-Qol Group: Euro-Qol: a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199–208.
  22. Scheltens P, Barkhof F, Leys D, Pruvo JP, Nauta JJ, Vermersch P, Steinling M, Valk J: A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci 1993;114:7–12.
  23. Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjögren M, Wallin A, Ader H, Leys D, Pantoni L, Pasquier F, Erkinjuntti T, Scheltens P, European Task Force on Age-Related White Matter Changes: A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 2001;32:1318–1322.
  24. van Straaten EC, Fazekas F, Rostrup E, Scheltens P, Schmidt R, Pantoni L, Inzitari D, Waldemar G, Erkinjuntti T, Mäntylä R, Wahlund LO, Barkhof F, LADIS Group: Impact of white matter hyperintensities scoring method on correlations with clinical data: the LADIS study. Stroke 2006;37:836–840.
  25. van der Flier WM, van Straaten EC, Barkhof F, Verdelho A, Madureira S, Pantoni L, Inzitari D, Erkinjuntti T, Crisby M, Waldemar G, Schmidt R, Fazekas F, Scheltens P: Small vessel disease and general cognitive function in nondisabled elderly: the LADIS study. Stroke 2005;36:2116–2120.
  26. Schmidt R, Ropele S, Ferro J, Madureira S, Verdelho A, Petrovic K, Gouw A, van der Flier WM, Enzinger C, Pantoni L, Inzitari D, Erkinjuntti T, Scheltens P, Wahlund LO, Waldemar G, Rostrup E, Wallin A, Barkhof F, Fazekas F, LADIS study Group: Diffusion-weighted imaging and cognition in the leukoariosis and disability in the elderly study. Stroke 2010;41:e402–e408.
  27. Scheltens P, Leys D, Barkhof F, Huglo D, Weinstein HC, Vermersch P, Kuiper M, Steinling M, Wolters EC, Valk J: Atrophy of medial temporal lobes on MRI in “probable” Alzheimer’s disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry 1992;55:967–972.
  28. Ropele S, Seewann A, Gouw AA, van der Flier WM, Schmidt R, Pantoni L, Inzitari D, Erkinjuntti T, Scheltens P, Wahlund LO, Waldemar G, Chabriat H, Ferro J, Hennerici M, O’Brien J, Wallin A, Langhorne P, Visser MC, Barkhof F, Fazekas F, LADIS Study Group: Quantitation of brain tissue changes associated with white matter hyperintensities by diffusion-weighted and magnetization transfer imaging: the LADIS (Leukoaraiosis and Disability in the Elderly) study. J Magn Reson Imaging 2009;29:268–274.
  29. Madureira S, Verdelho A, Ferro J, Basile AM, Chabriat H, Erkinjuntti T, Fazekas F, Hennerici M, O’Brien J, Pantoni L, Salvadori E, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D, LADIS Study Group: Development of a neuropsychological battery for the Leukoaraiosis and Disability in the Elderly Study (LADIS): experience and baseline data. Neuroepidemiology 2006;27:101–116.
  30. Pantoni L, Poggesi A, Basile AM, Pracucci G, Barkhof F, Chabriat H, Erkinjuntti T, Ferro JM, Hennerici M, O’Brien J, Schmidt R, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D, LADIS Study Group: Leukoaraiosis predicts hidden global functioning impairment in nondisabled older people: the LADIS (Leukoaraiosis and Disability in the Elderly) Study. J Am Geriatr Soc 2006;54:1095–1101.
  31. Inzitari D, Simoni M, Pracucci G, Poggesi A, Basile AM, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, Langhorne P, O’Brien J, Barkhof F, Visser MC, Wahlund LO, Waldemar G, Wallin A, Pantoni L, LADIS Study Group: Risk of rapid global functional decline in elderly patients with severe cerebral age-related white matter changes: the LADIS study. Arch Intern Med 2007;167:81–88.
  32. Inzitari D, Pracucci G, Poggesi A, Carlucci G, Barkhof F, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, Langhorne P, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Pantoni L, LADIS Study Group: Changes in white matter as determinant of global functional decline in older independent outpatients: three year follow-up of LADIS (leukoaraiosis and disability) study cohort. BMJ 2009;339:b2477.
  33. Verdelho A, Madureira S, Ferro JM, Basile AM, Chabriat H, Erkinjuntti T, Fazekas F, Hennerici M, O’Brien J, Pantoni L, Salvadori E, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D, LADIS Study: Differential impact of cerebral white matter changes, diabetes, hypertension and stroke on cognitive performance among non-disabled elderly. The LADIS study. J Neurol Neurosurg Psychiatry 2007;78:1325–1330.
  34. Verdelho A, Madureira S, Moleiro C, Ferro JM, Santos CO, Erkinjuntti T, Pantoni L, Fazekas F, Visser M, Waldemar G, Wallin A, Hennerici M, Inzitari D, LADIS Study: White matter changes and diabetes predict cognitive decline in the elderly: the LADIS study. Neurology 2010;75:160–167.
  35. Jokinen H, Gouw AA, Madureira S, Ylikoski R, van Straaten EC, van der Flier WM, Barkhof F, Scheltens P, Fazekas F, Schmidt R, Verdelho A, Ferro JM, Pantoni L, Inzitari D, Erkinjuntti T, LADIS Study Group: Incident lacunes influence cognitive decline: the LADIS study. Neurology 2011;76:1872–1878.
  36. Benisty S, Gouw AA, Porcher R, Madureira S, Hernandez K, Poggesi A, van der Flier WM, Van Straaten EC, Verdelho A, Ferro J, Pantoni L, Inzitari D, Barkhof F, Fazekas F, Chabriat H, LADIS Study group: Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study. J Neurol Neurosurg Psychiatry 2009;80:478–483.
  37. Jokinen H, Kalska H, Ylikoski R, Madureira S, Verdelho A, Gouw A, Scheltens P, Barkhof F, Visser MC, Fazekas F, Schmidt R, O’Brien J, Hennerici M, Baezner H, Waldemar G, Wallin A, Chabriat H, Pantoni L, Inzitari D, Erkinjuntti T, LADIS group: MRI-defined subcortical ischemic vascular disease: baseline clinical and neuropsychological findings. The LADIS study. Cerebrovasc Dis 2009;27:336–344.
  38. van der Flier WM, van Straaten EC, Barkhof F, Ferro JM, Pantoni L, Basile AM, Inzitari D, Erkinjuntti T, Wahlund LO, Rostrup E, Schmidt R, Fazekas F, Scheltens P, LADIS study group: Medial temporal lobe atrophy and white matter hyperintensities are associated with mild cognitive deficits in non-disabled elderly people: the LADIS study. J Neurol Neurosurg Psychiatry 2005;76:1497–1500.
  39. Ryberg C, Rostrup E, Stegmann MB, Barkhof F, Scheltens P, van Straaten EC, Fazekas F, Schmidt R, Ferro JM, Baezner H, Erkinjuntti T, Jokinen H, Wahlund LO, O’Brien J, Basile AM, Pantoni L, Inzitari D, Waldemar G, LADIS study group: Clinical significance of corpus callosum atrophy in a mixed elderly population. Neurobiol Aging 2007;28:955–963.
  40. Jokinen H, Ryberg C, Kalska H, Ylikoski R, Rostrup E, Stegmann MB, Waldemar G, Madureira S, Ferro JM, van Straaten EC, Scheltens P, Barkhof F, Fazekas F, Schmidt R, Carlucci G, Pantoni L, Inzitari D, Erkinjuntti T, LADIS group: Corpus callosum atrophy is associated with mental slowing and executive deficits in subjects with age-related white matter hyperintensities: the LADIS Study. J Neurol Neurosurg Psychiatry 2007;78:491–496.
  41. Ryberg C, Rostrup E, Paulson OB, Barkhof F, Scheltens P, van Straaten EC, van der Flier WM, Fazekas F, Schmidt R, Ferro JM, Baezner H, Erkinjuntti T, Jokinen H, Wahlund LO, Poggesi A, Pantoni L, Inzitari D, Waldemar G, LADIS study group: Corpus callosum atrophy as a predictor of age-related cognitive and motor impairment: a 3-year follow-up of the LADIS study cohort. J Neurol Sci 2011;307:100–105.
  42. Firbank MJ, O’Brien JT, Pakrasi S, Pantoni L, Simoni M, Erkinjuntti T, Wallin A, Wahlund LO, van Straaten I, Inzitari D: White matter hyperintensities and depression – preliminary results from the LADIS study. Int J Geriatr Psychiatry 2005;20:674–679.
  43. Teodorczuk A, O’Brien JT, Firbank MJ, Pantoni L, Poggesi A, Erkinjuntti T, Wallin A, Wahlund LO, Gouw A, Waldemar G, Schmidt R, Ferro JM, Chabriat H, Bäzner H, Inzitari D, LADIS Group: White matter changes and late-life depressive symptoms: longitudinal study. Br J Psychiatry 2007;191:212–217.
  44. Teodorczuk A, Firbank MJ, Pantoni L, Poggesi A, Erkinjuntti T, Wallin A, Wahlund LO, Scheltens P, Waldemar G, Schrotter G, Ferro JM, Chabriat H, Bazner H, Visser M, Inzitari D, O’Brien JT, LADIS Group: Relationship between baseline white-matter changes and development of late-life depressive symptoms: 3-year results from the LADIS study. Psychol Med 2010;40:603–610.
  45. Krishnan MS, O’Brien JT, Firbank MJ, Pantoni L, Carlucci G, Erkinjuntti T, Wallin A, Wahlund LO, Scheltens P, van Straaten EC, Inzitari D, LADIS Group: Relationship between periventricular and deep white matter lesions and depressive symptoms in older people. The LADIS Study. Int J Geriatr Psychiatry 2006;21:983–989.
  46. O’Brien JT, Firbank MJ, Krishnan MS, van Straaten EC, van der Flier WM, Petrovic K, Pantoni L, Simoni M, Erkinjuntti T, Wallin A, Wahlund LO, Inzitari D, LADIS Group: White matter hyperintensities rather than lacunar infarcts are associated with depressive symptoms in older people: the LADIS study. Am J Geriatr Psychiatry 2006;14:834–841.
  47. Baezner H, Blahak C, Poggesi A, Pantoni L, Inzitari D, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Langhorne P, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Hennerici MG, LADIS Study Group: Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology 2008;70:935–942.
  48. Blahak C, Baezner H, Pantoni L, Poggesi A, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Langhorne P, O’Brien J, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitari D, Hennerici MG, LADIS Study Group: Deep frontal and periventricular age related white matter changes but not basal ganglia and infratentorial hyperintensities are associated with falls: cross-sectional results from the LADIS study. J Neurol Neurosurg Psychiatry 2009;80:608–613.
  49. Poggesi A, Pracucci G, Chabriat H, Erkinjuntti T, Fazekas F, Verdelho A, Hennerici M, Langhorne P, O’Brien J, Scheltens P, Visser MC, Crisby M, Waldemar G, Wallin A, Inzitari D, Pantoni L, Leukoaraiosis and Disability Study Group: Urinary complaints in nondisabled elderly people with age-related white matter changes: the Leukoaraiosis and Disability (LADIS) Study. J Am Geriatr Soc 2008;56:1638–1643.
  50. Jokinen H, Kalska H, Ylikoski R, Madureira S, Verdelho A, van der Flier WM, Scheltens P, Barkhof F, Visser MC, Fazekas F, Schmidt R, O’Brien J, Waldemar G, Wallin A, Chabriat H, Pantoni L, Inzitari D, Erkinjuntti T, LADIS group: Longitudinal cognitive decline in subcortical ischemic vascular disease – the LADIS Study. Cerebrovasc Dis 2009;27:384–391.
  51. Ryberg C, Rostrup E, Sjöstrand K, Paulson OB, Barkhof F, Scheltens P, van Straaten EC, Fazekas F, Schmidt R, Erkinjuntti T, Wahlund LO, Basile AM, Pantoni L, Inzitari D, Waldemar G, LADIS study group: White matter changes contribute to corpus callosum atrophy in the elderly: the LADIS study. AJNR Am J Neuroradiol 2008;29:1498–1504.
  52. Fazekas F, Ropele S, Enzinger C, Gorani F, Seewann A, Petrovic K, Schmidt R: MTI of white matter hyperintensities. Brain 2005;128:2926–2932.
  53. Verdelho A, Madureira S, Moleiro C, Santos CO, Ferro JM, Erkinjuntti T, Poggesi A, Pantoni L, Fazekas F, Scheltens P, Waldemar G, Wallin A, Inzitari D: Self-perceived memory complaints predict progression to Alzheimer disease. The LADIS Study. J Alzheimers Dis 2011, E-pub ahead of print.
  54. Miranda B, Madureira S, Verdelho A, Ferro J, Pantoni L, Salvadori E, Chabriat H, Erkinjuntti T, Fazekas F, Hennerici M, O’Brien J, Scheltens P, Visser MC, Wahlund LO, Waldemar G, Wallin A, Inzitarion D, LADIS Study: Self-perceived memory impairment and cognitive performance in an elderly independent population with age-related white matter changes. J Neurol Neurosurg Psychiatry 2008;79:869–873.
  55. Ylikoski R, Jokinen H, Andersen P, Salonen O, Madureira S, Ferro J, Barkhof F, van der Flier W, Schmidt R, Fazekas F, Scheltens P, Waldemar G, Salvadori E, Pantoni L, Inzitari D, Erkinjuntti T, LADIS Study Group: Comparison of the Alzheimer’s Disease Assessment Scale Cognitive Subscale and the Vascular Dementia Assessment Scale in differentiating elderly individuals with different degrees of white matter changes. The LADIS Study. Dement Geriatr Cogn Disord 2007;24:73–81.
  56. Madureira S, Verdelho A, Moleiro C, Ferro JM, Erkinjuntti T, Jokinen H, Pantoni L, Fazekas F, Van der Flier W, Visser M, Waldemar G, Wallin A, Hennerici M, Inzitari D: Neuropsychological predictors of dementia in a three-year follow-up period: data from the LADIS study. Dement Geriatr Cogn Disord 2010;29:325–334.
  57. Zheng JJ, Delbaere K, Close JC, Sachdev PS, Lord SR: Impact of white matter lesions on physical functioning and fall risk in older people: a systematic review. Stroke 2011;42:2086–2090.
  58. Gouw AA, van der Flier WM, van Straaten EC, Pantoni L, Bastos-Leite AJ, Inzitari D, Erkinjuntti T, Wahlund LO, Ryberg C, Schmidt R, Fazekas F, Scheltens P, Barkhof F, LADIS study group: Reliability and sensitivity of visual scales versus volumetry for evaluating white matter hyperintensity progression. Cerebrovasc Dis 2008;25:247–253.
  59. Gouw AA, van der Flier WM, Fazekas F, van Straaten EC, Pantoni L, Poggesi A, Inzitari D, Erkinjuntti T, Wahlund LO, Waldemar G, Schmidt R, Scheltens P, Barkhof F, LADIS Study Group: Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period: the Leukoaraiosis and Disability Study. Stroke 2008;39:1414–1420.
  60. Gouw AA, van der Flier WM, Pantoni L, Inzitari D, Erkinjuntti T, Wahlund LO, Waldemar G, Schmidt R, Fazekas F, Scheltens P, Barkhof F, LADIS Study Group: On the etiology of incident brain lacunes: longitudinal observations from the LADIS study. Stroke 2008;39:3083–3085.
  61. Gouw AA, Van der Flier WM, van Straaten EC, Barkhof F, Ferro JM, Baezner H, Pantoni L, Inzitari D, Erkinjuntti T, Wahlund LO, Waldemar G, Schmidt R, Fazekas F, Scheltens P, LADIS Study Group: Simple versus complex assessment of white matter hyperintensities in relation to physical performance and cognition: the LADIS study. J Neurol 2006;253:1189–1196.
  62. Dyrby TB, Rostrup E, Baaré WF, van Straaten EC, Barkhof F, Vrenken H, Ropele S, Schmidt R, Erkinjuntti T, Wahlund LO, Pantoni L, Inzitari D, Paulson OB, Hansen LK, Waldemar G, LADIS Study Group: Segmentation of age-related white matter changes in a clinical multi-center study. Neuroimage 2008;41:335–345.
  63. Jonsson M, Zetterberg H, van Straaten E, Lind K, Syversen S, Edman A, Blennow K, Rosengren L, Pantoni L, Inzitari D, Wallin A: Cerebrospinal fluid biomarkers of white matter lesions – cross-sectional results from the LADIS study. Eur J Neurol 2010;17:377–382.