The research project “The influence of white matter changes in the quality of life and in functional state in the process of ageing” is part of a European collaborative study on changes on brain white matter: the LADIS study.
Despite the first description of the clinical situation associated with changes in brain white matter having been made over one hundred years ago, studies on brain white matter changes have advanced mostly over the last twenty years, following their imaging description (called leukoaraiosis), and the use of Brain Tomography and/or MRI. Studies published over these years have produced controversial, even contradictory results on the implications of changes in brain white matter in cognition, gait, bladder control, and depression. The LADIS study was the result of a European multicentric effort to evaluate the impact of white matter changes in the transition from an autonomous health condition to a state of incapacity/dependency when ageing. The study was started in 2000 and was carried out at 11 European centres (Amsterdam, Copenhagen, Florence, Helsinki, Lisbon, Gothenburg, Graz, Huddinge, Manheim, Newcastle, and Paris). Some of the centres were in charge of coordinating research groups. The Lisbon group was formed by Professor José Manuel Ferro, Dr. Sofia Madureira and myself, and, from the onset, was responsible for the entire cognitive part. The latter consisted in harmonizing cognitive tests to be used by all centres, conceiving the battery for neuropsychological evaluation ((Madureira et al, 2006), producing the norms for battery use, defining the measures of cognitive defect and decline through time, supervising the quality of recorded data, confirming final cognitive diagnostics, establishing the statistic evaluation of cognitive data, coordinating publications about cognition and, finally, producing publications on the results of the study.
The same standardization of the evaluation and recording measures carried out by the Lisbon group, with regard to the cognitive component, was conducted in the several fields under study: global and functional condition, quality of life, and motor performance and gait by the remaining groups, organized around working groups according to their fields of interest. A guideline handbook with the results obtained was subsequently written for all participating centres (Pantoni et al, 2005).
The study included 639 persons above 65 years of age (average age 74.1 ± 5.0 years; 55% female), independent in their daily-life activities, defined according to the Instrumental Activities of Daily Living scale - IADL (Lawton et al), who presented changes in brain white matter of any seriousness, classified according with Fazekas’ scale (2) (light changes: 44%, moderate: 31%, severe: 25%, at the start), with a minimum 4 years of schooling (average schooling: 9.6±3.8 years), without major medical, neurological or psychiatric pathologies that could compromise their long term follow-up. The subjects were evaluated using the same registration battery used at point of entry, and, on a yearly basis, for a period of 3 years. CE-MRI was performed at the entry and at the end of the study. Additional follow up was carried out, mostly by telephone, 5 years after inclusion.
The LADIS study confirmed the marked impact of changes in brain white matter in the transition towards functional decline after 3 years, with a 30% risk of yearly transition into incapacity in the group of serious white matter changes, by contrast with a 11% risk in the group presenting mild changes. White mass changes became associated, in independent manner, to urinary urgency (Poggesi et al, 2008), changes in gait and balance (Baezner H et al, 2008) and depression (Teodorczuk A et al, 2010).
At a cognitive level, it was observed that, even at the onset of the study, elderly patients presenting serious changes in brain white matter performed worse in executive functions, attention span and speed tests, compared with those with mild or moderate changes in white matter (Verdelho et al, 2007). At the end of the 3-year follow-up period, 90 individuals were given a clinical diagnostic of dementia (vascular dementia, 54; Alzheimer’s disease, 22; Alzheimer’s disease with a vascular component, 12, frontotemporal dementia, 2), and 147 patients were diagnosed cognitive defect without dementia criteria (vascular cognitive defect with dementia criteria, 86; mild cognitive defect, 61). Over time, white matter changes were predictors of cognitive decline (Verdelho et al, 2010). Ultimately, it was equally possible to predict distinct types of dementia: vascular dementia was established due to serious changes in brain white matter and the presence of previous cerebrovascular accidents, whereas Alzheimer’s disease was determined by the atrophy of the temporal lobe, not due to changes in white matter (Verdelho et al, 2010).
Results of the LADIS study continue to be analysed and, so far, have given origin to 37 articles in international publications. This research project stems from the need to answer a very practical question posed by patients, who want a doctor to explain to them the consequences for their health of having “dots” on their heads discovered at a health exam they have underwent. Part of the cognitive predictors identified by our working group is available in the publications referred to above.
1. Pantoni L, Basile AM, Pracucci G, et al. 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.
2. Madureira S, Verdelho A, Ferro JM, et al. Development of a neuropsychological battery for a multinational study: the LADIS. Neuroepidemiology 2006;27:101–116.
3. Fazekas F, Chawluk JB, Alavi A, et al. MR signal abnormalities at 1.5T in Alzheimer’s dementia and normal aging. AJNR Am J Neuroradiol 1987;8:421–426.
4. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969;9:179–186.
5. Verdelho A, Madureira S, Ferro JM, et al. 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.
6. Poggesi A, Pracucci G, Chabriat H, Erkinjuntti T,et al. Urinary complaints in nondisabled elderly people with age-related white matter changes: the Leukoaraiosis And DISability (LADIS) StudyJAGS 2008; 56:1638–1643,
7. Teodorczuk A Firbank MJ, Pantoni L, Poggesi A, et al Relationship between baseline white-matter changes and development of late-life depressive symptoms: 3-year results from the LADIS study Psychol Med. 2010 Apr;40(4):603-10.
8. Baezner H, Blahak C, Poggesi A, Pantoni L, et al Association of gait and balance disorders with age-related white matter changes: the LADIS study Neurology® 2008;70:935–942
9. Verdelho A, Madureira S, Moleiro C, Ferro JM et al White matter changes and diabetes predict cognitive decline in the elderly: the LADIS study.Neurology® 2010;75:160–167