title: Brain inflammation is induced by co-morbidities and risk factors for stroke.
abstract: Chronic systemic inflammatory conditions, such as atherosclerosis, diabetes and obesity are associated with increased risk of stroke, which suggests that systemic inflammation may contribute to the development of stroke in humans. The hypothesis that systemic inflammation may induce brain pathology can be tested in animals, and this was the key objective of the present study. First, we assessed inflammatory changes in the brain in rodent models of chronic, systemic inflammation. PET imaging revealed increased microglia activation in the brain of JCR-LA (corpulent) rats, which develop atherosclerosis and obesity, compared to the control lean strain. Immunostaining against Iba1 confirmed reactive microgliosis in these animals. An atherogenic diet in apolipoprotein E knock-out (ApoE(-/-)) mice induced microglial activation in the brain parenchyma within 8 weeks and increased expression of vascular adhesion molecules. Focal lipid deposition and neuroinflammation in periventricular and cortical areas and profound recruitment of activated myeloid phagocytes, T cells and granulocytes into the choroid plexus were also observed. In a small, preliminary study, patients at risk of stroke (multiple risk factors for stroke, with chronically elevated C-reactive protein, but negative MRI for brain pathology) exhibited increased inflammation in the brain, as indicated by PET imaging. These findings show that brain inflammation occurs in animals, and tentatively in humans, harbouring risk factors for stroke associated with elevated systemic inflammation. Thus a "primed" inflammatory environment in the brain may exist in individuals at risk of stroke and this can be adequately recapitulated in appropriate co-morbid animal models.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Drake
authors.forename: Hervé
authors.initials: H
authors.lastname: Boutin
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Jones
authors.forename: Adam
authors.initials: A
authors.lastname: Denes
authors.forename: Barry W
authors.initials: BW
authors.lastname: McColl
authors.forename: Johann R
authors.initials: JR
authors.lastname: Selvarajah
authors.forename: Sharon
authors.initials: S
authors.lastname: Hulme
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Georgiou
authors.forename: Rainer
authors.initials: R
authors.lastname: Hinz
authors.forename: Alexander
authors.initials: A
authors.lastname: Gerhard
authors.forename: Andy
authors.initials: A
authors.lastname: Vail
authors.forename: Christian
authors.initials: C
authors.lastname: Prenant
authors.forename: Peter
authors.initials: P
authors.lastname: Julyan
authors.forename: Renaud
authors.initials: R
authors.lastname: Maroy
authors.forename: Gavin
authors.initials: G
authors.lastname: Brown
authors.forename: Alison
authors.initials: A
authors.lastname: Smigova
authors.forename: Karl
authors.initials: K
authors.lastname: Herholz
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
authors.forename: David
authors.initials: D
authors.lastname: Crossman
authors.forename: Sheila
authors.initials: S
authors.lastname: Francis
authors.forename: Spencer D
authors.initials: SD
authors.lastname: Proctor
authors.forename: James C
authors.initials: JC
authors.lastname: Russell
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Hopkins
authors.forename: Pippa J
authors.initials: PJ
authors.lastname: Tyrrell
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Rothwell
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Allan
mesh_terms: D000368:Aged; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000453:epidemiology / Q000209:etiology / Q000473:pathology; D001923:Brain Chemistry; D002097:C-Reactive Protein / Q000032:analysis; D015897:Comorbidity; D004036:Diet, Atherogenic; D004660:Encephalitis / Q000000981:diagnostic imaging / Q000453:epidemiology* / Q000473:pathology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008055:Lipids / Q000032:analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology / Q000235:genetics; D010586:Phagocytes / Q000473:pathology; D049268:Positron-Emission Tomography; D051381:Rats; D011922:Rats, Mutant Strains; D012307:Risk Factors; D020521:Stroke / Q000453:epidemiology*
chemical_list: D001057:Apolipoproteins E; C508600:IL6 protein, human; D015850:Interleukin-6; D008055:Lipids; D002097:C-Reactive Protein