PMID- 23361394
OWN - NLM
STAT- MEDLINE
DCOM- 20130628
LR  - 20211021
IS  - 1559-7016 (Electronic)
IS  - 0271-678X (Print)
IS  - 0271-678X (Linking)
VI  - 33
IP  - 5
DP  - 2013 May
TI  - Induction of hyperhomocysteinemia models vascular dementia by induction of 
      cerebral microhemorrhages and neuroinflammation.
PG  - 708-15
LID - 10.1038/jcbfm.2013.1 [doi]
AB  - Vascular dementia (VaD) is the second leading cause of dementia behind 
      Alzheimer's disease (AD) and is a frequent comorbidity with AD, estimated to 
      occur in as many as 40% of AD patients. The causes of VaD are varied and include 
      chronic cerebral hypoperfusion, microhemorrhages, hemorrhagic infarcts, or 
      ischemic infarcts. We have developed a model of VaD by inducing 
      hyperhomocysteinemia (HHcy) in wild-type mice. By placing wild-type mice on a 
      diet deficient in folate, B6, and B12 and supplemented with excess methionine, we 
      induced a moderate HHcy (plasma level homocysteine 82.93 +/- 3.561 mumol). After 11 
      weeks on the diet, the hyperhomocysteinemic mice showed a spatial memory deficit 
      as assessed by the 2-day radial-arm water maze. Also, magnetic resonance imaging 
      and subsequent histology revealed significant microhemorrhage occurrence. We 
      found neuroinflammation induced in the hyperhomocysteinemic mice as determined by 
      elevated interleukin (IL)-1beta, tumor necrosis factor (TNF)alpha, and IL-6 in brain 
      tissue. Finally, we found increased expression and increased activity of the 
      matrix metalloproteinase 2 (MMP2) and MMP9 systems that are heavily implicated in 
      the pathogenesis of cerebral hemorrhage. Overall, we have developed a dietary 
      model of VaD that will be valuable for studying the pathophysiology of VaD and 
      also for studying the comorbidity of VaD with other dementias and other 
      neurodegenerative disorders.
FAU - Sudduth, Tiffany L
AU  - Sudduth TL
AD  - Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, 
      Lexington, Kentucky 40536, USA.
FAU - Powell, David K
AU  - Powell DK
FAU - Smith, Charles D
AU  - Smith CD
FAU - Greenstein, Abigail
AU  - Greenstein A
FAU - Wilcock, Donna M
AU  - Wilcock DM
LA  - eng
GR  - R01 NS079637/NS/NINDS NIH HHS/United States
GR  - NS079637/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130130
PL  - United States
TA  - J Cereb Blood Flow Metab
JT  - Journal of cerebral blood flow and metabolism : official journal of the 
      International Society of Cerebral Blood Flow and Metabolism
JID - 8112566
RN  - 0 (Interleukin-1beta)
RN  - 0 (Interleukin-6)
RN  - 8059-24-3 (Vitamin B 6)
RN  - 935E97BOY8 (Folic Acid)
RN  - AE28F7PNPL (Methionine)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - P6YC3EG204 (Vitamin B 12)
SB  - IM
MH  - Animals
MH  - Brain/enzymology/immunology/*pathology
MH  - Cerebral Hemorrhage/enzymology/*etiology/immunology/pathology
MH  - Dementia, Vascular/enzymology/*etiology/immunology/pathology
MH  - Diet
MH  - *Disease Models, Animal
MH  - Folic Acid/metabolism
MH  - Humans
MH  - Hyperhomocysteinemia/*complications/metabolism
MH  - Inflammation/etiology/immunology
MH  - Interleukin-1beta/analysis/immunology
MH  - Interleukin-6/analysis/immunology
MH  - Matrix Metalloproteinase 2/metabolism
MH  - Matrix Metalloproteinase 9/metabolism
MH  - Memory Disorders/*etiology
MH  - Methionine/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Vitamin B 12/metabolism
MH  - Vitamin B 6/metabolism
PMC - PMC3652696
EDAT- 2013/01/31 06:00
MHDA- 2013/07/03 06:00
PMCR- 2014/05/01
CRDT- 2013/01/31 06:00
PHST- 2013/01/31 06:00 [entrez]
PHST- 2013/01/31 06:00 [pubmed]
PHST- 2013/07/03 06:00 [medline]
PHST- 2014/05/01 00:00 [pmc-release]
AID - jcbfm20131 [pii]
AID - 10.1038/jcbfm.2013.1 [doi]
PST - ppublish
SO  - J Cereb Blood Flow Metab. 2013 May;33(5):708-15. doi: 10.1038/jcbfm.2013.1. Epub 
      2013 Jan 30.