Apoptosis in Leukoaraiosis
Abstract & Commentary
Synopsis: Brown and colleagues report finding evidence of apoptosis in an area of leukoaraiosis and suggest that apoptotic death of oligodendrocytes may be a mechanism of development of areas of T2 prolongation corresponding to areas of demyelination, loss of glial cells, and spongiosis that are observed histologically in these lesions.
Source: Brown WR, et al. Apoptosis in leukoaraiosis. AJNR Am J Neuroradiol 2000;21:79-82.
Leukoaraiosis is a term used to describe the age-related areas of T2 hyperintensity in the cerebral white matter, which, when severe, correlate with dementia. The white matter lesions have been characterized histologically as showing demyelination, loss of glial cells, and spongiotic change. The pathogenesis of this condition has not been firmly established, but it seems to relate to chronic ischemia and hypoperfusion. Periventricular venous collagenosis has been reported to occur in aging brains and to be more severe in those with leukoaraiosis, suggesting that it is a contributing factor. Because frank necrosis has not been described in these typical white matter lesions of leukoaraiosis, Brown and colleagues investigated the possibility that a non-necrotic mechanism of cell death (apoptosis) might occur in these lesions.
A nondemented 70-year-old man with multiple cardiovascular disease risk factors died of cardiac arrest and underwent autopsy and postmortem magnetic resonance (MR) imaging of the brain. Gross pathology showed his brain to be mildly atrophic with no focal lesions and demonstrated multiple atherosclerotic lesions of his intracranial vasculature. On MR examination, focal T2 hyperintensity in the left frontal white matter was found, which showed demyelination and periventricular venous collagenosis histologically. Specimens were also specially stained to detect apoptosis, and the number of cells that showed findings consistent with apoptosis was 2.5 times as great in the areas of leukoaraiosis as in the adjacent white matter and 25 times as great as in the nearby cortex. By a process of elimination, it was determined that the positively staining cells in the white matter were likely to be oligodendrocytes.
By no technique was any evidence of inflammation or necrosis found, suggesting that anti-inflammatory drugs are unlikely to be of benefit in the treatment or prevention of this condition. Furthermore, as apoptosis is a delayed cell death that can be inhibited by interruption of the cell death program, opportunities for intervention in prevention or mitigation of development of vascular dementia may exist in the future.
Comment by Nancy J. Fischbein, MD
All of us who read neuroimaging studies are familiar with the nonspecific areas of T2 prolongation that appear in aging brains and seem to correlate with age and cardiovascular risk factors.1 Many terms are used to describe these lesions, most commonly "leukoaraiosis," "high-intensity periventricular white matter lesions," or "small vessel ischemic changes." Periventricular venous collagenosis is strongly associated with leukoaraiosis,2 and stenosis or occlusion of deep cerebral veins due to collagen deposition may promote its development. Other contributing factors include structural changes involving intraparenchymal arteries and arterioles, altered cerebral blood flow autoregulation, and the unique arterial blood supply of the hemispheric white matter via long penetrating arteries.3 The work of Brown et al that is discussed now provides us with some insight into the mechanism by which leukoaraiotic lesions develop, possibly on the basis of apoptotic cell death induced by chronic ischemia. In the long term, influencing this process may allow new therapies to be directed at the prevention of development of subcortical dementia.
Apoptosis is a subject that has received tremendous attention in the basic science literature in recent years, but its role in disease is increasingly recognized.4,5 Under normal physiological conditions, certain cells undergo an active, energy-dependent, genetically programmed type of cell death termed apoptosis, which is important in embryologic development and cellular homeostatis. In some cases, however, apoptosis may be deficient (cancer) or excessive (neurodegenerative disorders). Apoptotic cell death contrasts with necrotic cell death, which occurs in acute, nonphysiological injury and results in cell swelling, lysis, and an inflammatory response. As apoptosis is better understood, it is likely that continuing research will yield a new armamentarium of potential disease therapies.
References
1. Ylikoski A, et al. White matter hyperintensities on MRI in the neurologically nondiseased elderly. Stroke 1995;26:1171-1177.
2. Moody DM, et al. Periventricular venous collagenosis: Association with leukoaraiosis. Radiology 1995;194: 469-476.
3. Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: A review. Stroke 1997;28:652-659.
4. Savitz SI, Rosenbaum DM. Apoptosis in neurological disease. Neurosurgery 1998;42:555-574.
5. Hetts SW. To die or not to die: An overview of apoptosis and its role in disease. JAMA 1998;279:300-307.
Which of the following does not characterize leukoaraiosis histologically?
a. Demyelination
b. Necrosis
c. Loss of glial cells
d. Spongiosis
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