PMID- 23146994
OWN - NLM
STAT- MEDLINE
DCOM- 20130724
LR  - 20220129
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Linking)
VI  - 51
DP  - 2013 Mar
TI  - Characterizing infarction and selective neuronal loss following temporary focal 
      cerebral ischemia in the rat: a multi-modality imaging study.
PG  - 120-32
LID - S0969-9961(12)00365-8 [pii]
LID - 10.1016/j.nbd.2012.11.002 [doi]
AB  - BACKGROUND AND PURPOSE: Current models dictate that, depending on occurrence of 
      early reperfusion, the ischemic penumbra either undergoes or escapes infarction 
      (i.e., "pan-necrosis"). However, tissue outcome following temporary 
      middle-cerebral artery occlusion (tMCAo) in rodents can also include selective 
      neuronal loss (SNL), which even if subtle may impede functional recovery. In 
      order to explore the pathophysiology of ischemic stroke, determine potential 
      therapeutic targets and monitor effects of therapy, in vivo imaging surrogates of 
      these varied histopathological outcomes applicable in the clinical setting would 
      be useful. Although hyperintense signal on T(2)-weighted MRI in the chronic 
      post-stroke stage is considered a reliable surrogate of tissue infarction, SNL is 
      not associated with T(2)W abnormal signal. In the clinical setting, the 
      neuron-specific PET ligand (11)C-flumazenil (FMZ) has been used to identify both 
      pan-necrosis and peri-infarct SNL, but this inference has not been 
      histopathological confirmed so far. Here we investigated the late tissue sequelae 
      of tMCAo in the rodent using in vivo T(2)W MRI and FMZ-PET against post mortem 
      immunohistochemistry as gold standard. METHODS: Adult spontaneously hypertensive 
      rats (SHRs) underwent 45 min distal-clip middle-cerebral artery occlusion and, 28 
      days later, FMZ-PET and T(2)W-MRI, immediately followed by immunohistochemistry 
      for neuronal loss (NeuN), activated microglia and astrocytosis. Based on standard 
      histopathological definitions, ischemic lesions were classified into 
      pan-necrosis, partial infarction or SNL. NeuN changes and FMZ binding across the 
      whole hemisphere were quantified in the same set of 44 regions-of-interest 
      according to previously validated protocols; linear regressions between these two 
      measures were carried out both within and across subjects. RESULTS: Both cortical 
      pan-necrosis/partial infarction and SNL were present in all rats except one, 
      where SNL was isolated and extensive. Infarction/partial infarction, but not SNL, 
      was associated with T(2)W hyperintense signals and cortical atrophy. In contrast, 
      FMZ binding was decreased in all types of lesions including SNL, in proportion 
      with NeuN staining intensity both within (p<0.05 to <0.001) and across (p<0.001) 
      subjects, including the subject that showed pure SNL (p=0.01). CONCLUSION: This 
      novel study revealed three main facts: i) long-term histopathological cortical 
      changes following 45 min tMCAo in SHRs included all three of SNL, partial 
      infarction and frank infarction; ii) T2W MRI showed conspicuous high signal 
      lesions for complete or partial infarction, but no changes for SNL; and iii) 
      FMZ-PET was sensitive to all three types of tMCAo-induced histopathological 
      changes, including isolated SNL, suggesting it is a valid surrogate for the 
      histological sequelae of focal cerebral ischemia. In addition, the finding of 
      almost universal completed cortical infarction at 28 days differed from our 
      previous findings at 14-day survival using the same model and rat strain, where 
      SNL was the almost exclusive outcome, possibly representing delayed infarct 
      maturation. Prospective studies are needed to investigate this interesting 
      possibility.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Ejaz, Sohail
AU  - Ejaz S
AD  - Stroke Research Group, Department of Clinical Neurosciences, Addenbrooke's 
      Hospital, University of Cambridge, Cambridge, UK.
FAU - Williamson, David J
AU  - Williamson DJ
FAU - Ahmed, Tahir
AU  - Ahmed T
FAU - Sitnikov, Sergey
AU  - Sitnikov S
FAU - Hong, Young T
AU  - Hong YT
FAU - Sawiak, Stephen J
AU  - Sawiak SJ
FAU - Fryer, Tim D
AU  - Fryer TD
FAU - Aigbirhio, Franklin I
AU  - Aigbirhio FI
FAU - Baron, Jean-Claude
AU  - Baron JC
LA  - eng
GR  - G0001354/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121110
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
SB  - IM
MH  - Animals
MH  - Brain Ischemia/diagnostic imaging/*pathology
MH  - Immunohistochemistry
MH  - Infarction, Middle Cerebral Artery/diagnostic imaging/*pathology
MH  - *Magnetic Resonance Imaging
MH  - Neurons/diagnostic imaging/*pathology
MH  - *Positron-Emission Tomography
MH  - Rats
MH  - Rats, Inbred SHR
EDAT- 2012/11/14 06:00
MHDA- 2013/07/25 06:00
CRDT- 2012/11/14 06:00
PHST- 2012/07/23 00:00 [received]
PHST- 2012/10/05 00:00 [revised]
PHST- 2012/11/01 00:00 [accepted]
PHST- 2012/11/14 06:00 [entrez]
PHST- 2012/11/14 06:00 [pubmed]
PHST- 2013/07/25 06:00 [medline]
AID - S0969-9961(12)00365-8 [pii]
AID - 10.1016/j.nbd.2012.11.002 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2013 Mar;51:120-32. doi: 10.1016/j.nbd.2012.11.002. Epub 2012 Nov 
      10.