title: A Novel Imaging Marker for Small Vessel Disease Based on Skeletonization of White Matter Tracts and Diffusion Histograms.
abstract: OBJECTIVE
  To establish a fully automated, robust imaging marker for cerebral small vessel disease (SVD) and related cognitive impairment that is easy to implement, reflects disease burden, and is strongly associated with processing speed, the predominantly affected cognitive domain in SVD.
  
  
  METHODS
  We developed a novel magnetic resonance imaging marker based on diffusion tensor imaging, skeletonization of white matter tracts, and histogram analysis. The marker (peak width of skeletonized mean diffusivity [PSMD]) was assessed along with conventional SVD imaging markers. We first evaluated associations with processing speed in patients with genetically defined SVD (n = 113). Next, we validated our findings in independent samples of inherited SVD (n = 57), sporadic SVD (n = 444), and memory clinic patients with SVD (n = 105). The new marker was further applied to healthy controls (n = 241) and to patients with Alzheimer's disease (n = 153). We further conducted a longitudinal analysis and interscanner reproducibility study.
  
  
  RESULTS
  PSMD was associated with processing speed in all study samples with SVD (p-values between 2.8 × 10(-3) and 1.8 × 10(-10) ). PSMD explained most of the variance in processing speed (R(2) ranging from 8.8% to 46%) and consistently outperformed conventional imaging markers (white matter hyperintensity volume, lacune volume, and brain volume) in multiple regression analyses. Increases in PSMD were linked to vascular but not to neurodegenerative disease. In longitudinal analysis, PSMD captured SVD progression better than other imaging markers.
  
  
  CONCLUSIONS
  PSMD is a new, fully automated, and robust imaging marker for SVD. PSMD can easily be applied to large samples and may be of great utility for both research studies and clinical use. Ann Neurol 2016;80:581-592.
authors: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University LMU, Munich, Germany.
authors: Ebru
authors: E
authors: Baykara
authors: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University LMU, Munich, Germany.
authors: Benno
authors: B
authors: Gesierich
authors: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University LMU, Munich, Germany.
authors: Ruth
authors: R
authors: Adam
authors: Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Department of Neurology, Nijmegen, the Netherlands.
authors: Anil Man
authors: AM
authors: Tuladhar
authors: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: J Matthijs
authors: JM
authors: Biesbroek
authors: Department of Geriatrics, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Huiberdina L
authors: HL
authors: Koek
authors: Department of Neurology, Medical University of Graz, Graz, Austria.
authors: Stefan
authors: S
authors: Ropele
authors: Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1161 National Institute for Health and Medical Research (INSERM), Paris, France.|Departement Hospitalo-Universitaire NeuroVasc Sorbonne Paris Cité, Paris, France.|Department of Neurology, Lariboisière Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors: Eric
authors: E
authors: Jouvent
authors: Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1161 National Institute for Health and Medical Research (INSERM), Paris, France.|Departement Hospitalo-Universitaire NeuroVasc Sorbonne Paris Cité, Paris, France.|Department of Neurology, Lariboisière Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors: Hugues
authors: H
authors: Chabriat
authors: Institute of Clinical Radiology, Klinikum der Universität München, Ludwig-Maximilians-University LMU, Munich, Germany.
authors: Birgit
authors: B
authors: Ertl-Wagner
authors: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University LMU, Munich, Germany.
authors: Michael
authors: M
authors: Ewers
authors: Department of Neurology, Medical University of Graz, Graz, Austria.
authors: Reinhold
authors: R
authors: Schmidt
authors: Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Department of Neurology, Nijmegen, the Netherlands.
authors: Frank-Erik
authors: FE
authors: de Leeuw
authors: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Geert Jan
authors: GJ
authors: Biessels
authors: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University LMU, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors: Martin
authors: M
authors: Dichgans
authors: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University LMU, Munich, Germany. marco.duering@med.uni-muenchen.de.
authors: Marco
authors: M
authors: Duering
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging*; D015415:Biomarkers; D059345:Cerebral Small Vessel Diseases / Q000150:complications / Q000000981:diagnostic imaging*; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging* / Q000209:etiology / Q000503:physiopathology; D056324:Diffusion Tensor Imaging / Q000379:methods* / Q000592:standards; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D066127:White Matter / Q000000981:diagnostic imaging*; D055815:Young Adult
chemical_list: D015415:Biomarkers