title: Cerebrovascular and blood-brain barrier impairments in Huntington's disease: Potential implications for its pathophysiology.
abstract: OBJECTIVE
  Although the underlying cause of Huntington's disease (HD) is well established, the actual pathophysiological processes involved remain to be fully elucidated. In other proteinopathies such as Alzheimer's and Parkinson's diseases, there is evidence for impairments of the cerebral vasculature as well as the blood-brain barrier (BBB), which have been suggested to contribute to their pathophysiology. We investigated whether similar changes are also present in HD.
  
  
  METHODS
  We used 3- and 7-Tesla magnetic resonance imaging as well as postmortem tissue analyses to assess blood vessel impairments in HD patients. Our findings were further investigated in the R6/2 mouse model using in situ cerebral perfusion, histological analysis, Western blotting, as well as transmission and scanning electron microscopy.
  
  
  RESULTS
  We found mutant huntingtin protein (mHtt) aggregates to be present in all major components of the neurovascular unit of both R6/2 mice and HD patients. This was accompanied by an increase in blood vessel density, a reduction in blood vessel diameter, as well as BBB leakage in the striatum of R6/2 mice, which correlated with a reduced expression of tight junction-associated proteins and increased numbers of transcytotic vesicles, which occasionally contained mHtt aggregates. We confirmed the existence of similar vascular and BBB changes in HD patients.
  
  
  CONCLUSIONS
  Taken together, our results provide evidence for alterations in the cerebral vasculature in HD leading to BBB leakage, both in the R6/2 mouse model and in HD patients, a phenomenon that may, in turn, have important pathophysiological implications.
authors: Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
authors: Janelle
authors: J
authors: Drouin-Ouellet
authors: Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors: Stephen J
authors: SJ
authors: Sawiak
authors: Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada.
authors: Giulia
authors: G
authors: Cisbani
authors: Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada.
authors: Marie
authors: M
authors: Lagacé
authors: Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
authors: Wei-Li
authors: WL
authors: Kuan
authors: Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada.
authors: Martine
authors: M
authors: Saint-Pierre
authors: Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom.
authors: Richard J
authors: RJ
authors: Dury
authors: Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada.
authors: Wael
authors: W
authors: Alata
authors: Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada.
authors: Isabelle
authors: I
authors: St-Amour
authors: Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
authors: Sarah L
authors: SL
authors: Mason
authors: Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada.|Faculté de Pharmacie, Université Laval, Québec, Québec, Canada.
authors: Frédéric
authors: F
authors: Calon
authors: Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada.|Département de Médecine Moléculaire, Université Laval, Québec, Québec, Canada.
authors: Steve
authors: S
authors: Lacroix
authors: Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom.
authors: Penny A
authors: PA
authors: Gowland
authors: Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom.
authors: Susan T
authors: ST
authors: Francis
authors: Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
authors: Roger A
authors: RA
authors: Barker
authors: Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada.|Département de Psychiatrie & Neurosciences, Université Laval, Québec, Québec, Canada.
authors: Francesca
authors: F
authors: Cicchetti
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology*; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018810:Magnetic Resonance Angiography; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D017072:Neostriatum / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D055420:Perfusion Imaging; D062725:Tight Junction Proteins / Q000378:metabolism; D057900:Transcytosis / Q000235:genetics
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D062725:Tight Junction Proteins