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

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.

Corpus callosum tissue loss and development of motor and global cognitive impairment: the LADIS study.

Objective: To examine the impact of corpus callosum (CC) tissue loss on the development of global cognitive and motor impairment in the elderly.

Methods: This study was based on the Leukoaraiosis and Disability (LADIS) study. Assessment of cognitive and motor functions and magnetic resonance imaging (MRI) were done at baseline and at a 3-year follow-up in nondemented elderly subjects.

Subjective memory complaints in general practice predicts future dementia: a 4-year follow-up study.

Objective: Many older patients in general practice have subjective memory complaints (SMC); however, not all share this information with their general practitioner (GP). The association between SMC and future cognitive decline or dementia is not clear, especially in a general practice population. The aim of this study was to determine the risk for receiving a subsequent hospital-based dementia diagnosis on the basis of patients' reports of SMC in a primary care setting.

Software tool for improved prediction of Alzheimer's disease.

Background: Diagnostic criteria of Alzheimer's disease (AD) emphasize the integration of clinical data and biomarkers. In practice, collection and analysis of patient data vary greatly across different countries and clinics.

Objective: The goal was to develop a versatile and objective clinical decision support system that could reduce diagnostic errors and highlight early predictors of AD.

White matter hyperintensities and prepulse inhibition in a mixed elderly population.

Prepulse inhibition (PPI) of the startle response, a measure for sensorimotor gating, exhibits a relatively high inter-individual variability in elderly subjects. The aim of this study was to investigate whether white matter hyperintensities (WMH), frequently identified on cranial magnetic resonance imaging (MRI) in elderly subjects with and without cognitive impairment, may contribute to variations in PPI. A passive acoustic PPI paradigm was applied in 92 human subjects (53 healthy and 39 patients with Alzheimer's disease or mild cognitive impairment) between 60 and 85years of age.

Collaborative research between academia and industry using a large clinical trial database: a case study in Alzheimer's disease.

Background: Large clinical trials databases, developed over the course of a comprehensive clinical trial programme, represent an invaluable resource for clinical researchers. Data mining projects sponsored by industry that use these databases, however, are often not viewed favourably in the academic medical community because of concerns that commercial, rather than scientific, goals are the primary purpose of such endeavours. Thus, there are few examples of sustained collaboration between leading academic clinical researchers and industry professionals in a large-scale data mining project.

Validity, reliability, and feasibility of clinical staging scales in dementia: a systematic review.

New staging systems of dementia require adaptation of disease management programs and adequate staging instruments. Therefore, we systematically reviewed the literature on validity and reliability of clinically applicable, multidomain, and dementia staging instruments. A total of 23 articles describing 12 staging instruments were identified (N = 6109 participants, age 65-87).

Self-perceived memory complaints predict progression to Alzheimer disease. The LADIS study.

Memory complaints are frequent in the elderly but its implications in cognition over time remain a controversial issue. Our objective was to evaluate the risk of self perceived memory complaints in the evolution for future dementia. The LADIS (Leukoaraiosis and Disability) prospective multinational European study evaluates the impact of white matter changes (WMC) on the transition of independent elderly subjects into disability.

A disease state fingerprint for evaluation of Alzheimer's disease.

Diagnostic processes of Alzheimer's disease (AD) are evolving. Knowledge about disease-specific biomarkers is constantly increasing and larger volumes of data are being measured from patients. To gain additional benefits from the collected data, a novel statistical modeling and data visualization system is proposed for supporting clinical diagnosis of AD.

Proxy-rated quality of life in Alzheimer's disease: a three-year longitudinal study.

Background: The study investigated the change in proxy rated quality of life (QoL) of a large cohort of home living patients with Alzheimer's disease (AD) over a period of 36 months.

Methods: The sample consisted of 102 patients with mild AD and their primary caregivers from the Danish Alzheimer's Disease Intervention Study. QoL was assessed with the proxy-rated (primary caregivers) Quality of Life in Alzheimer Disease scale (QOL-AD) and the EuroQuol Visual Analogue Scale (EQ-VAS) scale.

Quality of dementia diagnostic evaluation for ethnic minority patients: a nationwide study.

Background/aims: Diagnostic evaluation of dementia for ethnic minority patients may be challenging. This study aimed to evaluate the quality of diagnostic evaluation of dementia for patients from ethnic minorities in Denmark.

Methods: The Danish national hospital registers were used to identify patients from the main ethnic minority groups in Denmark, who were diagnosed with dementia in the period 2005-2007.

Corpus callosum atrophy in patients with mild Alzheimer's disease.

Background/objectives: Several studies have found atrophy of the corpus callosum (CC) in patients with Alzheimer's disease (AD). However, it remains unclear whether callosal atrophy is already present in the early stages of AD, and to what extent it may be associated with other structural changes in the brain, such as age-related white matter changes (ARWMC) and progression of the disease.

Methods: Twenty-eight patients in the early stages of AD and 50 non-demented elderly subjects with varying degrees of ARWMC were investigated using MRI.

Corpus callosum atrophy as a predictor of age-related cognitive and motor impairment: a 3-year follow-up of the LADIS study cohort.

The aim of this 3-year follow-up study was to investigate whether corpus callosum (CC) atrophy may predict future motor and cognitive impairment in an elderly population. On baseline MRI from 563 subjects with age-related white matter changes (ARWMC) from the Leukoaraiosis And DISability (LADIS) study, the CC was segmented and subdivided into five anterior-posterior regions (CC1-CC5). Associations between the CC areas and decline in motor performance and cognitive functions over a 3-year period were analyzed.

Multi-template tensor-based morphometry: application to analysis of Alzheimer's disease.

In this paper methods for using multiple templates in tensor-based morphometry (TBM) are presented and compared to the conventional single-template approach. TBM analysis requires non-rigid registrations which are often subject to registration errors. When using multiple templates and, therefore, multiple registrations, it can be assumed that the registration errors are averaged and eventually compensated.

Prognostic factors for weight loss over 1-year period in patients recently diagnosed with mild Alzheimer Disease.

The aim of the study was to identify prognostic factors for weight loss in patients recently diagnosed with mild Alzheimer disease (AD), with special emphasis on the patients' social participation and living arrangements. The data used in this study was part of the Danish Alzheimer Intervention StudY. The patients were home-living patients with a clinical diagnosis, within the past 12 months, of probable AD or mixed AD; age ≥50 years; mini-mental state examination score ≥20; informed consent; and data available at 1-year follow-up.

Fast and robust extraction of hippocampus from MR images for diagnostics of Alzheimer's disease.

Assessment of temporal lobe atrophy from magnetic resonance images is a part of clinical guidelines for the diagnosis of prodromal Alzheimer's disease. As hippocampus is known to be among the first areas affected by the disease, fast and robust definition of hippocampus volume would be of great importance in the clinical decision making. We propose a method for computing automatically the volume of hippocampus using a modified multi-atlas segmentation framework, including an improved initialization of the framework and the correction of partial volume effect.

The Danish Alzheimer intervention study: rationale, study design and baseline characteristics of the cohort.

Background: There is a lack of appropriately designed trials investigating the efficacy of psychosocial interventions for patients with mild dementia and their family caregivers. This paper reports the rationale and design of the Danish Alzheimer Disease Intervention Study and baseline characteristics of the cohort.

Methods: The study was a 1-year multicentre randomized controlled rater-blinded trial with randomization to follow-up and a multifaceted semitailored intervention programme or to follow-up only (with extension of follow-up to 3 years).

Over- and under-diagnosis of dementia in ethnic minorities: a nationwide register-based study.

Objective: Among dementia professionals in several European countries, it is believed that dementia is under-diagnosed and under-treated to a greater extent among ethnic minorities than in the native population. It is unknown whether this belief holds true. The objective of this study was to compare the prevalence of register-based dementia diagnoses in the largest ethnic minority groups in Denmark with the prevalence of register-based dementia diagnoses in the general Danish population.

Predicting cognitive decline in Alzheimer's disease: an integrated analysis.

Background: Numerous patient- and disease-related factors increase the risk of rapid cognitive decline in patients with Alzheimer's disease (AD). The ability of pharmacological treatment to attenuate this risk remains undefined.

Methods: Pooled data from 14 randomized clinical studies of donepezil in the treatment of AD (N = 3748) were analyzed to identify predictors of fast decline and determine the effect of donepezil on the risk of fast decline.

Generic and disease-specific measures of quality of life in patients with mild Alzheimer's disease.

Background/aim: The aim of the study was to investigate the pattern of association of generic and disease-specific quality of life (QoL) scales with standard clinical outcome variables in Alzheimer's disease (AD).

Methods: The participants were 321 home-living patients with mild AD and their primary caregivers from the Danish Alzheimer Intervention Study. QoL was assessed using the generic EuroQol-5D with visual analogue scale (VAS) and the disease-specific Quality of Life in Alzheimer's Disease (QOL-AD) scales (both caregiver and patient rated).

Hysterectomy, oophorectomy and risk of dementia: a nationwide historical cohort study.

Background: This study aimed to determine whether there is an association between hysterectomy and dementia.

Methods: All female Danish residents born before 1966, alive on their 40th birthday and without a dementia diagnosis prior to 1977 (n = 2,313,388) were followed from January 1, 1977, or the age of 40, whichever came later, until dementia diagnosis, death, emigration or December 31, 2006, whichever came first. The relative risks (RR) for developing dementia in women with hysterectomy/oophorectomy compared to referent women were calculated.

Effect of donepezil on cognition in severe Alzheimer's disease: a pooled data analysis.

To better characterize response to donepezil in patients with severe AD, Severe Impairment Battery (SIB) data were pooled from four donepezil clinical trials (N=904). Changes in SIB total and domain scores from baseline to week 24 were compared between placebo and donepezil treatment groups (observed case analysis). Analyses were stratified by baseline severity (Mini-Mental State Examination [MMSE] scores 1-5, 6-9, 10-12 and 13-17) to allow investigation of responses at different stages of cognitive impairment.

White matter changes and diabetes predict cognitive decline in the elderly: the LADIS study.

Objective: We aimed to study if age-related white matter changes (WMC) and vascular risk factors were predictors of cognitive decline in elderly subjects with WMC living independently.

Methods: The Leukoaraiosis and Disability prospective multinational European study (LADIS) evaluates the impact of WMC on the transition of independent elderly subjects into disability. Independent elderly were enrolled due to the presence of WMC.

Assessment of dementia in ethnic minority patients in Europe: a European Alzheimer's Disease Consortium survey.

Background: In most European countries the ethnic minority migrant populations are currently reaching an age where dementia becomes an increasingly important issue. There is no European consensus on good clinical practice with these patient groups, who often have special needs and expectations with regard to dementia services.

Methods: A survey was conducted in clinical dementia centers in 15 European countries.

Proteomic investigations of the ventriculo-lumbar gradient in human CSF.

Cerebrospinal fluid (CSF) is an ideal biological material in which to search for new biomarkers for improved diagnosis of neurological diseases. During a lumbar puncture between 5 and 15 mL of CSF are obtained. Previous studies have assessed the ventriculo-lumbar concentration gradient of a number of specific proteins.