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Research paper
Cognitive reserve moderates long-term cognitive and functional outcome in cerebral small vessel disease
  1. Hanna Jokinen1,
  2. Susanna Melkas1,
  3. Sofia Madureira2,
  4. Ana Verdelho2,
  5. José M Ferro2,
  6. Franz Fazekas3,
  7. Reinhold Schmidt3,
  8. Philip Scheltens4,
  9. Frederik Barkhof4,5,
  10. Joanna M Wardlaw6,
  11. Domenico Inzitari7,8,
  12. Leonardo Pantoni8,
  13. Timo Erkinjuntti1
  1. 1Department of Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  2. 2Serviço de Neurologia, Centro de Estudos Egas Moniz, Hospital de Santa Maria, Lisbon, Portugal
  3. 3Department of Neurology and MRI Institute, Medical University of Graz, Graz, Austria
  4. 4Department of Radiology and Neurology, VU University Medical Center, Amsterdam, The Netherlands
  5. 5UCL Institutes of Neurology & Healthcare Engineering, London, UK
  6. 6Division of Neuroimaging Sciences, Centre for Clinical Brain Sciences and Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
  7. 7Institute of Neuroscience, Italian National Research Council, Florence, Italy
  8. 8Department NEUROFARBA, University of Florence, Florence, Italy
  1. Correspondence to Dr Hanna Jokinen-Salmela, Clinical Neurosciences, Neurology Helsinki University Hospital, P.O. Box 302, Helsinki 00029 HUS, Finland; hanna.jokinen{at}


Background Cerebral small vessel disease (SVD) is characterised by progressive white matter hyperintensities (WMH), cognitive decline and loss of functional independence. The correspondence between neuroimaging findings and the severity of clinical symptoms has been modest, however, and thus the outcome may be affected by various host factors. We investigated the predictive value of educational and occupational attainments as proxy measures of cognitive reserve on long-term cognitive and functional outcome in patients with different degrees of WMH.

Methods In the Leukoaraiosis and Disability (LADIS) study, 615 older individuals with WMH were evaluated with brain MRI and detailed clinical and neuropsychological assessments at 3-year follow-up. A prolonged follow-up of functional and cognitive status was administered with a structured telephone interview after up to 7 years.

Results Higher levels of educational and occupational attainment were strongly related to baseline cognitive scores and predicted a slower rate of decline at 3-year follow-up in measures of processing speed, executive functions and memory independently of WMH volume and other confounders. The deleterious effect of WMH on processing speed and memory was moderated by education and occupation. Education mitigated the relation of WMH volume on 7-year cognitive status. Moreover, higher education and occupational attainments were related to favourable outcome at 7-year follow-up as defined by sustained functional independence and lower mortality.

Conclusions The results support the presumption that cognitive reserve plays a significant role as a buffer against the clinical manifestations of SVD and may in part explain high individual variability in outcome.

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  • Collaborators The collaborators of the LADIS study are listed in the online supplementary appendix.

  • Contributors HJ, SM, JMW and TE were involved in the conception and design of this study. JMF, FF, RS, PS, FB, DI, LP and TE planned and initiated the LADIS study. JMF, SM and AV constructed the cognitive test battery. FF, RS, PS and FB were responsible for the MRI methods. LP and DI coordinated the LADIS study. HJ conducted the statistical analyses, and drafted and finished the manuscript. All authors contributed to the critical revision of the manuscript and approved the final version of the manuscript to be published.

  • Funding The Leukoaraiosis and Disability study was supported by the European Union (grant QLRT-2000-00446). The work of HJ was supported by grants from the Clinical Research Institute and the Medical Research Fund of the Helsinki University Hospital. FB was supported by the NIHR Biomedical Research Centre at University College London Hospitals.

  • Competing interests JMF reports personal fees from Boheringer Ingelheim and Daiichi Sankyo. FB serves on the editorial boards of Brain, European Radiology, Neuroradiology, Neurology, Multiple Sclerosis Journal, and Radiology, serves as a consultant for Bayer-Schering Pharma, Sanofi-Aventis, Genzyme, Biogen-Idec, Teva, Novartis, Roche, Synthon BV, Merck-Serono, and Jansen Research, and reports grants from Dutch MS Society, EU-FP7. JMW reports honorarium for expert advice from GlaxoSmithKline. DI reports grants from Bayer and Shire.

  • Patient consent Obtained.

  • Ethics approval The ethics committees of each participating centre.

  • Provenance and peer review Not commissioned; externally peer reviewed.