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Heterogeneity in age-related white matter changes

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Abstract

White matter changes occur endemically in routine magnetic resonance imaging (MRI) scans of elderly persons. MRI appearance and histopathological correlates of white matter changes are heterogeneous. Smooth periventricular hyperintensities, including caps around the ventricular horns, periventricular lining and halos are likely to be of non-vascular origin. They relate to a disruption of the ependymal lining with subependymal widening of the extracellular space and have to be differentiated from subcortical and deep white matter abnormalities. For the latter a distinction needs to be made between punctate, early confluent and confluent types. Although punctate white matter lesions often represent widened perivascular spaces without substantial ischemic tissue damage, early confluent and confluent lesions correspond to incomplete ischemic destruction. Punctate abnormalities on MRI show a low tendency for progression, while early confluent and confluent changes progress rapidly. The causative and modifying pathways involved in the occurrence of sporadic age-related white matter changes are still incompletely understood, but recent microarray and genome-wide association approaches increased the notion of pathways that might be considered as targets for therapeutic intervention. The majority of differentially regulated transcripts in white matter lesions encode genes associated with immune function, cell cycle, proteolysis, and ion transport. Genome-wide association studies identified six SNPs mapping to a locus on chromosome 17q25 to be related to white matter lesion load in the general population. We also report first and preliminary data that demonstrate apolipoprotein E (ApoE) immunoreactivity in white matter lesions and support epidemiological findings indicating that ApoE is another factor possibly related to white matter lesion occurrence. Further insights come from modern MRI techniques, such as diffusion tensor and magnetization transfer imaging, as they provide tools for the characterization of normal-appearing brain tissue beyond what can be expected from standard MRI scans. There is a need for additional pre- and postmortem studies in humans, including these new imaging techniques.

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Acknowledgments

The immunohistochemical study on apolipoprotein E was supported by Grant 7776 of the Austrian National Bank (Jubilaeumsfonds) to Helena Schmidt.

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Authors and Affiliations

  1. Division of Special Neurology, Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036, Graz, Austria

    Reinhold Schmidt, Marisa Loitfelder, Margherita Cavalieri & Stephan Seiler

  2. Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria

    Helena Schmidt

  3. Institute of Pathology, Medical University of Graz, Graz, Austria

    Johannes Haybaeck

  4. Laboratory of Neuropathology, Department of Pathology and Neuropathology, State Neuropsychiatric Hospital Wagner-Jauregg, Linz, Austria

    Serge Weis

  5. Division of General Neurology, Department of Neurology, Medical University of Graz, Graz, Austria

    Christian Enzinger, Stefan Ropele & Franz Fazekas

  6. Memory Research Unit, Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland

    Timo Erkinjuntti

  7. Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy

    Leonardo Pantoni

  8. Alzheimer Centre, Department of Neurology, VU University Medical Centre, Amsterdam, The Netherlands

    Philip Scheltens

  9. Institute of Clinical Neurobiology, Vienna, Austria

    Kurt Jellinger

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  1. Reinhold Schmidt
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Schmidt, R., Schmidt, H., Haybaeck, J. et al. Heterogeneity in age-related white matter changes. Acta Neuropathol 122, 171–185 (2011). https://doi.org/10.1007/s00401-011-0851-x

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