V European Framework Programme
Quality of life and management of living resources
Key action: The ageing population and their disabilities

Impact of Age-related brain white matter changes on transition to disability in the elderly

LADIS: Leukoaraiosis And DISability
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Steering Committee
  • Domenico Inzitari, MD (study coordinator)
  • Timo Erkinjuntti, MD, PhD
  • Philip Scheltens, MD, PhD
  • Marieke Visser, MD, PhD
  • Peter Langhorne, MD, BSC, PhD, FRCP

Participating centers
  • Helsinki, Finland (Memory Research Unit, Department of Clinical Neurosciences, Helsinki University)
  • Graz, Austria (Department of Neurology and Department of Radiology, Division of Neuroradiology, Medical University Graz)
  • Lisboa, Portugal (Serviço de Neurologia, Centro de Estudos Egas Moniz, Hospital de Santa Maria)
  • Amsterdam, The Netherlands (Department of Radiology and Neurology, VU Medical Center)
  • Goteborg, Sweden (Institute of Clinical Neuroscience, Goteborg University)
  • Huddinge, Sweden (Karolinska Institutet, Department of Neurbiology, Care Sciences and Society; Karolinska University Hospital Huddinge)
  • Paris, France (Department of Neurology, Hopital Lariboisiere)
  • Mannheim, Germany (Department of Neurology, University of Heidelberg, Klinikum Mannheim)
  • Copenhagen, Denmark (Memory Disorders Research Group, Department of Neurology, Rigshospitalet, and the Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospitals)
  • Newcastle-upon-Tyne, UK (Institute for Ageing and Health, Newcastle University)
  • Florence, Italy (Coordinating centre, Department of Neurological and Psychiatric Sciences, University of Florence)
The introduction between the late '70s and the early '80s of neuroimaging techniques (CT, MRI) has led to recognize with increasing frequency changes in the cerebral subcortical white matter, called leukoaraiosis by Hachinski et al. [1987].
These alterations are of variable extension (limited to periventricular regions or involving the entire subcortical white matter), and appear as hypodense areas on CT or hyperintense areas on the T2-weighted sequences on MRI.
They are observed with the highest frequency in elderly subjects, particularly in those with vascular risk factors [Pantoni and Garcia, 1995].
Based on this epidemiological consideration, the term Age-Related White Matter Changes (ARWMC) has been chosen for the present study.
Although the pathogenesis of these changes is not yet completely elucidated, they are commonly considered of vascular origin, being produced through chronic ischemia or by brief and repeated ischemic insult of moderate severity in the subcortical white matter, that is high vulnerable to ischemia, given its peculiar, terminal type vascularization [Pantoni and Garcia, 1997].
Pathological changes of intraparenchymal small arteries and arterioles consequent to ageing and arterial hypertension are thought to represent the underlying vascular cause, in combination with fluctuations of systemic blood pressure [Pantoni and Garcia, 1997].
Frequency, associated risk factors, clinical and pathological correlates of ARWMC have been repeatedly studied, with partly controversial results, and with many issues remaining unsettled. One of the main reasons for the still inconclusive evidence is the retrospective nature of the large majority of studies carried out up to now.
Although the figures vary considerably [Pantoni and Garcia, 1995], the prevalence of these alterations in subjects over 60 years of age is considered high. Given the close correlation of these changes with increasing age, their prevalence is probably destined to increase in the forthcoming years, due to the progressive ageing of the population.
Most of the studies reporting functional and clinical abnormalities in patients with ARWMC are consistent in indicating an association with global or selective cognitive deficits, depression, motor abnormalities, particularly gait impairment [Pantoni and Garcia, 1995; Longstreth et al., 1996].
Notoriously, these deficits are main contributors to disability in the elderly.
Earlier observations did show that ARWMC were associated with dementia. Subsequent studies comparing large series of demented patients with non-demented controls provided the clear-cut evidence that ARWMC are not invariably linked with dementia [Inzitari et al., 1987].
Patients with ARWMC who are not demented may have selective cognitive deficits (impaired recalling, slowing of processing time, deficient executive strategy and planning) ) [Schimdt et al., 1993; Breteler et al., 1994b], possibly depending on damage of subcortico-frontal circuits [Ylikoski et al., 1993].
These deficits may produce difficulties in personal and social life activities, even in the absence of overt dementia. In addition, ARWMC are observed in patients with late-onset depression with higher frequency in comparison with age- and risk factor-matched controls [O’Brien et al., 1996].
Consistently, ARWMC are currently considered one of the cerebral abnormalities possibly underlying late-onset depression [O’Brien et al., 1998], a disease foreseen as one of the most common causes of disability in the next 20 years in the Western Countries. Since the earlier studies, ARWMC have been reported to be associated with motor deficits including rigidity, gait apraxia, impaired balance on walking, and increased risk of falls [Steingart et al., 1987; Masdeu et al., 1989], and have been found to be the strongest predictor on neuroimaging of poor balance in the elderly [Breteler et al., 1994a].
Recent studies point out the role of genetic factors in familial cases [Chabriat, 1995].
Since it has been recently observed that subjects with ARWMC have an increased risk of cardiovascular events and death from vascular causes [Inzitari et al., 1995; Inzitari et al. 1997], whether ARWMC has a role as determinant of disability predominantly through this way has to be ruled out.
Pathological processes involved in the transition from an independent to a disability status in the elderly are still incompletely defined.
Standardized tools and modern laboratory techniques may help identifying these processes. Cross-sectional studies have shown that the functional status in subjects with ARWMC is variable, from normal to severe, either physically or cognitively, disability. The fact that the functional expression of ARWMC is distributed along a spectrum of increasing severity may suggest that they may be one of the age-related processes involved in the transition to disability in the elderly.
However, what is their net contribution in relation to other possible determinants of disability remains to be established. Large subjects/patients cohorts of patients with ARWMC of different severity, careful baseline assessment of risk factors, and detailed follow-up observation may lead to elucidate these issues.
The present study primarily aims, through a longitudinal design, to provide more advanced and conclusive evidence that ARWMC play an independent role as determinant of transition to disability in the elderly.
Other questions relating to other selective clinical or functional outcomes may be answered owing to such design.
If the role of ARWMC in relation to disability in the elderly is demonstrated, intervention strategies for prevention, drug treatment, rehabilitation, and care can be designed in order to prevent or delay the transition linked with ARWMC.

The objectives of the study are summarized as follows:
  1. To evaluate age-related cerebral white matter changes (ARWMC) as independent determinant of the transition from healthy status to disability in elderly individuals. To this end, patients with ARWMC of different severity and no or mild disability will be followed-up for a period of 3 years to determine the proportion changing to a more severe disability status.
  2. To establish whether ARWMC is an independent predictor of: i) death from any cause or specific causes, ii) dementia, iii) cardiovascular events, iv) depression.
  3. To study progression of ARWMC on MRI images in relation to the functional and clinical outcomes.
  4. To determine quality of life in subjects with ARWMC of different severity degree on baseline and at the end of follow-up.
  5. To settle and validate criteria for identifying possible Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy [CADASIL] cases on a clinical and MRI basis.
The present study will be developed in the context of a Concerted Action granted by the European Union with funds made available by the V European Framework Programme (Proposal no: QLRT-2000-00446) (Quality of life and management of living resources 1998-2002).
These resources will be sufficient for the general organization and management of the multi-centre collaboration.
Facilities and extra-budgets will have to be necessarily achieved at a local level in each participating centre to carry out the clinical studies.
The principal coordinator of the study will be responsible for transmission of all necessary information to the participating centres, for convocation and organization of meetings, and for all the communications with the European Union in Brussels.
He will be assisted by a clinical coordinator, a clinical data manager and a secretary.
In the management of the project and in taking decisions he will be assisted by separating organisms, the Steering Committee and the Executive Committee.
The Steering Committee will be formed by five members including the coordinator, two other members of the collaboration, and two persons not involved in the project: a biostatistician and a bioethicist. The Steering Committee will be responsible for taking all major decisions concerning the project, for evaluating and solving problems, for examining periodically the progress of the study. Moreover it will care all the ethical aspects in the whole study.
The Executive Committee consisting of seven members (chosen among investigators of the study with different expertise) will be responsible, together with the principal coordinator and his staff, for monitoring functioning of participating centres, for checking quality of data, inter-centre consistency of data collection, quality of data-entry and analysis.
Papers Published
  1. LADIS Study Group. 2001–2011: a decade of the LADIS (Leukoaraiosis And DISability) Study: what have we learned about white matter changes and small-vessel disease? Cerebrovasc Dis. 2011;32(6):577-88. PubMed
  2. Frederiksen KS, Garde E, Skimminge A, Barkhof F, Scheltens P, van Straaten EC, Fazekas F, Baezner H, Verdelho A, Ferro JM, Erkinjuntti T, Jokinen H, Wahlund LO, O'Brien JT, Basile AM, Pantoni L, Inzitari D, Waldemar G. Corpus Callosum Tissue Loss and Development of Motor and Global Cognitive Impairment: The LADIS Study. Dement Geriatr Cogn Disord. 2012 Jan 19;32(4):279-286. PubMed
  3. 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; LADIS Study. Self-perceived memory complaints predict progression to Alzheimer disease. The LADIS study. J Alzheimers Dis. 2011;27(3):491-8. PubMed
  4. 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 Aug 15;307(1-2):100-5. PubMed
  5. 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 May 31;76(22):1872-8. PubMed
  6. 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 Jul 13;75(2):160-7. PubMed
  7. 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(4):325-34. PubMed
  8. 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 Mar;17(3):377-82. PubMed
  9. 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. Relationship between baseline white-matter changes and development of late-life depressive symptoms: 3-year results from the LADIS study. Psychol Med. 2009 Aug 12:1-8. PubMed
  10. 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 Jul 6;339:b2477. doi: 10.1136/bmj.b2477. PubMed
  11. 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(4):384-91. PubMed
  12. 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(4):336-44. PubMed
  13. 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 May;80(5):478-83. PubMed
  14. 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 Jun;80(6):608-13. PubMed
  15. 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 Feb;29(2):268-74. PubMed
  16. 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 Nov;39(11):3083-5. PubMed
  17. 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 Sep;56(9):1638-43. PubMed
  18. 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 Sep;29(8):1498-504. PubMed
  19. Bastos-Leite AJ, Kuijer JP, Rombouts SA, Sanz-Arigita E, van Straaten EC, Gouw AA, van der Flier WM, Scheltens P, Barkhof F. Cerebral blood flow by using pulsed arterial spin-labeling in elderly subjects with white matter hyperintensities. AJNR Am J Neuroradiol. 2008 Aug;29(7):1296-301. PubMed
  20. 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 Jun;41(2):335-45. PubMed
  21. 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 Mar 18;70(12):935-42. PubMed
  22. 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 May;39(5):1414-20. PubMed
  23. 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(3):247-53. PubMed
  24. 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 Aug;79(8):869-73. PubMed
  25. Sjöstrand K, Rostrup E, Ryberg C, Larsen R, Studholme C, Baezner H, Ferro J, Fazekas F, Pantoni L, Inzitari D, Waldemar G; LADIS Study Group. Sparse decomposition and modeling of anatomical shape variation. IEEE Trans Med Imaging. 2007 Dec;26(12):1625-35. PubMed
  26. 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 Sep;191:212-7. PubMed
  27. 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(2):73-81. PubMed
  28. 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 Dec;78(12):1325-30. Epub 2007 Apr 30. PubMed
  29. Korf ES, van Straaten EC, de Leeuw FE, van der Flier WM, Barkhof F, Pantoni L, Basile AM, Inzitari D, Erkinjuntti T, Wahlund LO, Rostrup E, Schmidt R, Fazekas F, Scheltens P; LADIS Study Group. Diabetes mellitus, hypertension and medial temporal lobe atrophy: the LADIS study. Diabet Med. 2007 Feb;24(2):166-71. PubMed
  30. 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 Jan 8;167(1):81-8. PubMed
  31. 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 May;78(5):491-6. Epub 2006 Oct 6. PubMed
  32. 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 Oct;14(10):834-41. PubMed
  33. 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 Sep;253(9):1189-96. Epub 2006 Sep 22. PubMed
  34. 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 Oct;21(10):983-9. PubMed
  35. 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(2):101-16. PubMed
  36. 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 Jul;54(7):1095-101. PubMed
  37. 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 Jun;28(6):955-63. PubMed
  38. 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(5-6):315-22. PubMed
  39. 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 Mar;37(3):836-40. PubMed
  40. 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 Nov;76(11):1497-500. PubMed
  41. 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 Oct;36(10):2116-20. PubMed
  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 Jul;20(7):674-9. PubMed
  43. 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(1-2):51-62. PubMed