title: Matrix metalloproteinases are associated with increased blood-brain barrier opening in vascular cognitive impairment.
abstract: OBJECTIVE
  Subcortical ischemic vascular disease (SIVD) is a major form of vascular cognitive impairment (VCI) due to small vessel disease. Matrix metalloproteinases (MMPs) are neutral proteases that disrupt the blood-brain barrier and degrade myelin basic protein under conditions of neuroinflammation. Brain tissues and cerebrospinal fluid (CSF) of patients with VCI have increased levels of MMPs. We hypothesized that patients with SIVD have increased MMPs in the CSF, which are associated with increased CSF albumin.
  
  
  METHODS
  We studied 60 patients with suspected VCI. Twenty-five were classified as SIVD, whereas other groups included mixed Alzheimer disease and VCI, multiple strokes, and leukoaraiosis when white matter lesions were present and the diagnosis of VCI was uncertain. MMP-2 and MMP-9 in CSF and plasma were measured by gel zymography and indexed to CSF and plasma albumin. MMP-3 activity was measured by fluorescent assay.
  
  
  RESULTS
  We found reduced MMP-2 index (P<0.001) in the CSF for the full group of patients (SIVD, multiple strokes, mixed Alzheimer disease and VCI, and leukoaraiosis) compared with control subjects, whose CSF was obtained during spinal anesthesia. MMP-3 activity was increased in VCI compared with control subjects (P<0.01). In SIVD, MMP-2 index showed a negative correlation with albumin index, which was absent with the MMP-9 index. Combining MMP-2 index and MMP-3 activity separated the patients with SIVD from the control subjects with high specificity (P<0.0005).
  
  
  CONCLUSIONS
  Our results support the hypothesis that MMPs are associated with increased CSF albumin and suggest that they may contribute to the pathophysiology of SIVD.
authors: Department of Neurology, MSC 10 5620, 1 University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors: Eduardo
authors: E
authors: Candelario-Jalil
authors: Jeffrey
authors: J
authors: Thompson
authors: Saeid
authors: S
authors: Taheri
authors: Mark
authors: M
authors: Grossetete
authors: John C
authors: JC
authors: Adair
authors: Elaine
authors: E
authors: Edmonds
authors: Jillian
authors: J
authors: Prestopnik
authors: John
authors: J
authors: Wills
authors: Gary A
authors: GA
authors: Rosenberg
mesh_terms: D000418:Albumins / Q000134:cerebrospinal fluid; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D001812:Blood-Brain Barrier / Q000502:physiology*; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006801:Humans; D049292:Leukoaraiosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020521:Stroke / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D014652:Vascular Diseases / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000418:Albumins; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9