title: Validation of biomarkers in subcortical ischaemic vascular disease of the Binswanger type: approach to targeted treatment trials.
abstract: OBJECTIVE
  Vascular cognitive impairment (VCI) is a heterogeneous group of cerebrovascular diseases secondary to large and small vessel disease. We hypothesised that biomarkers obtained early in the disease could identify a homogeneous subpopulation with small vessel disease.
  
  
  METHODS
  We obtained disease markers in 62 patients with VCI that included neurological findings, neuropsychological tests, multimodal MR and cerebrospinal fluid measurements of albumin ratio, matrix metalloproteinases (MMPs), amyloid-β1-42 and phosphorylated-τ181. Proton MR spectroscopic imaging showed ischaemic white matter and permeability of the blood-brain barrier (BBB) was measured with dynamic contrast-enhanced MRI. We constructed a 10-point Binswanger disease score (BDS) with subjective and objective disease markers. In addition, an objective set of biomarkers was used for an exploratory factor analysis (EFA) to select patients with BD. Patients were followed for an average of 2 years to obtain clinical consensus diagnoses.
  
  
  RESULTS
  An initial BDS of 6 or greater was significantly correlated with a final diagnosis of BD (p<0.05; area under the curve (AUC)=0.79). EFA reduced nine objective biomarkers to four factors. The most predictive of BD was the factor containing the inflammatory biomarkers of increased BBB permeability, elevated albumin index and reduced MMP-2 index (factor 2; AUC=0.78). Both measures independently predicted a diagnosis of BD, and combining them improved the diagnostic accuracy.
  
  
  CONCLUSIONS
  Biomarkers predicted the diagnosis of the BD type of subcortical ischaemic vascular disease. Using pathophysiological biomarkers to select homogeneous groups of patients needs to be tested in targeted treatment trials.
authors.affiliation: Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA Department of Neurosciences, University of New Mexico, Albuquerque, New Mexico, USA Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Rosenberg
authors.affiliation: Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Jillian
authors.initials: J
authors.lastname: Prestopnik
authors.affiliation: Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Adair
authors.affiliation: Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Branko N
authors.initials: BN
authors.lastname: Huisa
authors.affiliation: Department of Geriatrics, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Knoefel
authors.affiliation: The MIND Research Network, Albuquerque, New Mexico, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Caprihan
authors.affiliation: The MIND Research Network, Albuquerque, New Mexico, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Gasparovic
authors.affiliation: Department of Neurology, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Department of Mathematics and Statistics, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Erik B
authors.initials: EB
authors.lastname: Erhardt
authors.affiliation: Clinical and Translational Science Center, Albuquerque, New Mexico, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Schrader
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000032:analysis / Q000134:cerebrospinal fluid; D002545:Brain Ischemia / Q000134:cerebrospinal fluid / Q000175:diagnosis*; D059345:Cerebral Small Vessel Diseases / Q000134:cerebrospinal fluid / Q000175:diagnosis*; D015140:Dementia, Vascular / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000628:therapy; D005163:Factor Analysis, Statistical; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000134:cerebrospinal fluid; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D011237:Predictive Value of Tests; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D020780:Matrix Metalloproteinase 9
keywords: BLOOD-BRAIN BARRIER; CEREBROVASCULAR DISEASE; COGNITION; CSF; VASCULAR DEMENTIA