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    Staining for Apoptosis: Now Neuropathologists Can “See”Leukoaraiosis | American Journal of Neuroradiology  
    



















    































    
  
  




    
    

  

      


    

      

  
  
  

    

  

    

  

                
    

      

  

    

  
      
  
  

    


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EditorialEDITORIAL

  
      

  
      
Staining for Apoptosis: Now Neuropathologists Can “See”Leukoaraiosis
  
    	
Geoffrey Murdoch

  
    	
American Journal of Neuroradiology January 2000,  21 (1) 42-43; 

  
  
  



  


  
  



			

		

	
	
 	
	  
  

		
		

			

			  

  
      
  
  

    
  


  
  



  
      
  
  

    

  

    

  
      
  
  

    
On a case-by-case basis, neuropathologists can have a challenging time explaining the abnormal T2 white matter hyperintensity referred to as leukoaraiosis. In some cases, such as that described by Brown et al (page 79), there is a very satisfying correlation between the MR-revealed lesion and a discrete, focal loss of myelinated fibers without the complete destruction of tissue that one sees in lacunar infarct. It is not uncommon, however, to see only some scattered reactive astrocytes, slightly faint myelin staining, or even nothing at all. Such an ephemeral lesion is disquieting to a pathologist who is less accustomed than a radiologist is to dealing with the “shadowy.” Brown et al have now identified a candidate underlying molecular process that has the potential to explain this range of microscopic morphologies. That process is apoptosis.
The literature contains about 30,000 reports on the mechanism, cause, and role of apoptosis in various processes. Twenty-five thousand of these have been published in the past 2 years. One almost expects this epidemic to appear on the cover of a weekly news magazine. Whatever the Greek roots of the term “apoptosis” originally meant, it is now best understood to mean a regulated cell death. It is an organism's way of actively eliminating a cell that is no longer functioning properly or that has a high likelihood of malfunctioning in the future. Apoptosis is an important part of normal cellular turnover in a variety of tissues. It is involved in removing cells irreversibly damaged in progressive degenerative diseases. A critical part of the survival strategy of cancer cells is to acquire mutations that inactivate the molecular machinery mediating this process. Programmed cell death is a developmental process in which excess precursor cells are pruned back apoptotically in the generation of normal tissue structures. Therefore, investigators in a wide range of disciplines have had to become familiar with this process, including neuroradiologists.
Conceptually there are three components to apoptotic cell death: 1) generating and sensing a signal that continued cell survival is no longer advantageous, 2) transducing this signal throughout the cell by activating a cascade of proteases (caspases) that activate downstream caspases and cleave various cellular, structural, and regulatory proteins, and 3) terminating the viability of the cell by cleaving the genomic DNA into small fragments. The purpose of this highly regulated process, disassembling the cell from the inside out, is to remove the cell in such away that there is no residual debris to incite inflammatory processes and scarring. There are many types of initiating signals, and important differences in the caspase cascade in different cell types, but the final effect is always systematic DNA cleavage. Therefore, documentation of this endpoint is the most comprehensive method of identifying apoptotic cell death. When the DNA is systematically cleaved, a large number of fragment ends are exposed; these can be labeled using a biochemical technique usually referred to as TUNEL staining. Although there are important biologic and technical caveats, a cell with a TUNEL-positive nucleus is a cell that is undergoing apoptosis.
The central observation of the Brown et al case report is that within a defined region of leukoaraiosis there are more oligodendroglia undergoing apoptosis than in adjacent areas. At first, the numbers may seem unimpressive; there are only twice as many TUNEL-positive nuclei within the defined region compared with control areas. Nonetheless, because the number of oligodendroglia within the area of leukoaraiosis is greatly depleted, the percentage of cells caught in the act of apoptosis is actually quite high. The presence of TUNEL-positive cells within control areas and in the vascular endothelium is a testament to the normal rate of physiologic cell turnover in these areas. Significantly more work is necessary to determine to what extent this rate can be increased before the replicative capacity of replacement cells is exceeded and net cell loss occurs.
The study of Brown et al goes a long way in explaining the troubling apparent lack of correlation between radiographic leukoaraiosis and pathologically observable morphologic lesions. Without the labeling of the TUNEL stain, it is very hard to see apoptosis. The nuclear morphologic changes observable by standard histologic stains are subtle, and may only persist for a matter of hours. It is likely that the TUNEL staining approach will document areas of increased oligodendroglial dropout in zones of leukoaraiosis that have previously appeared fairly normal by conventional histologic analysis. The ability to see these “early” zones of leukoaraiosis will open the door to a greater understanding of this pathophysiologic process. For example, is vascular collagenosis present in these early lesions, implying causality? Or are these changes merely part of the end-stage disease?
The biochemical and cellular meaning of MR hyperintensity is very complex. Clearly a region of decreased myelin and increased free water (extracellularly in the perivascular space as well as within astrocytic cytoplasm) such as exists in this case report should have increased signal on T2-weighted images. A more complex question is, how much molecular disorder is there in a degenerating apoptotic oligodendroglial cell or immature regenerative myelin created in the repair process? The development of this potential morphologic marker for foci of leukoaraiosis will certainly make neuropathologists more interested in these lesions. More extensive radiologic analyses such as diffusion-weighted MR imaging may subdivide foci of leukoaraiosis into different lesions, which can then be distinguished morphologically.
  


  
  



  
      
  
  

    
  


  
  



  




  


  
  



  
      
  
  

    
  


  
  



  
      
  
  

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Staining for Apoptosis: Now Neuropathologists Can “See”Leukoaraiosis
  
    	
Geoffrey Murdoch

  
    	
American Journal of Neuroradiology Jan 2000, 21 (1) 42-43; 

  
  
  



  


  
  



  
      
  
  

    

  
    
  
  
    
  
  
    
  


  


  
  



  
      
  
  

    
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