DNA FRAGMENTATION IN HUMAN SUBSTANTIA-NIGRA - APOPTOSIS OR PERIMORTEMEFFECT

DNA fragmentation was examined in situ in flash-frozen human postmorte m midbrain as a marker for programmed cell death. A large series of ca ses comprising 16 pathologically confirmed idiopathic Parkinson's dise ase (IPD) cases, 14 control cases without brain pathology, and a group of 6 patients with other parkinsonian movement disorders were examine d using TdT-mediated dUTP-biotin 3' end-labeling histology. Labeling o f neurons and glia was seen in the substantia nigra of control and IPD cases and in other movement disorder cases. Labeled nuclei were seen in melanized nigral neurons; apoptotic bodies were also found but were more commonly associated with nigral glia. in the control group, labe ling of neurons and glia was strongly associated with poor agonal stat us, assessed by tissue pH, a marker for antemortem hypoxia. The mean t issue pH of the control group with neuronal labeling was 6.28 (SEM .05 7), which was significantly different from that of the unlabeled group 6.55 (SEM .055). Mean tissue pH for all cases was 6.38. There was no association of nigral neuronal labeling with poor agonal status in the IPD cases, which showed labeling throughout the range of pH values. H owever, extranigral labeling, seen in the mesencephalon, red nucleus, superior colliculus, rostral pens, and periaqueductal gray matter, in all three subject groups was associated with tissue pH values of less than 6.3. These findings suggest that DNA fragmentation is influenced by antemortem hypoxia and that apoptosis-like changes seen in the post mortem nigra may parallel those seen in experimental ischemia in the a nimal blain. The likely influence of perimortem factors on these chang es indicates that results from postmortem studies of apoptotic cell de ath in neurodegenerative disease should be treated with caution and un derlines the importance of determining postmortem markers for agonal s tatus in human brain.