This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Traditional methods used for dating cells are limited in the information they provide, or are not appropriate for human use. We developed a method for the retrospective birth dating of cells using bomb pulse carbon-14 (14C) dating as a method for measuring the approximate age of specific populations of cells in the adult human brain and other tissues. This method is based on establishing the proportion of the isotope 14C in genomic DNA. After a cell has terminally differentiated it does not divide again. Since the last cell division represents the last time point when the cell synthesized DNA, its chromosomal DNA will reflect the age when the cell was born. Traditionally, the slow decay of 14C relative to other carbon isotopes has given it a temporal resolution of many years, however due to nuclear tests in the late 1950s and early 1960s, the level of 14C in the atmosphere doubled. This level has since dropped off in an exponential fashion, allowing one to resolve 14C differences in the range of years. Because DNA has a 14C content reflective of the time when it was synthesized, establishing the 14C content of chromosomal DNA will enable us to retrospectively birth date cells, and thus establish cellular turnover. Rather than dating DNA, the objective of this study is to establish a method to date ruptured and unruptured intracranial aneurysms in patients treated with aneurysm clipping and excision. Subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysm is a major cause of morbidity and mortality in patients with cerebrovascular incidents, especially in younger patients. It accounts for 10% of strokes and affects 10 of every 100,000 inhabitants in North-America and Europe. Despite the efforts to optimize treatment, aneurysmal SAH continues to have a case fatality of 25 to 50%. Due to the poor prognosis of aneurysm rupture, there has been great interest in methods to detect and treat intracranial aneurysms prior to rupture. This study tests the hypothesis that ruptured aneurysms rapidly increase in size shortly before the time of rupture, and that their actual size thus would not correspond to the size of the aneurysm at any time before rupture. We hypothesize that rupture of intracranial aneurysms occurs as a result of instability and growth. Since the aneurysm grew acutely before rupture, the ruptured aneurysm should consist mainly of younger or new aneurysmal tissue. This hypothesis is supported by the observation that there are a large number of small aneurysms found after SAH in epidemiological studies, suggesting that a high proportion of aneurysms arise rapidly and quickly progress to rupture. Contrary to patients with SAH due to small ruptured aneurysms, epidemiological data show there are older patients with larger incidental aneurysms. These cases might be explained through a selection effect where if aneurysm growth does not result in rupture, it could lead to an enlarged but stable aneurysm. Until further investigation it will remain controversial whether older patients who present with unruptured aneurysms that measure above average in diameter (i.e. more than 7-8 mm in diameter), have older aneurysms or whether these aneurysms are young and have progressed and formed rapidly. The objective of this study is to establish a method to date ruptured and unruptured intracranial aneurysms in patients treated with aneurysm clipping and excision. However, these data are theoretical or observational and to date no study has analysed aneurysms from patients to determine the age of the aneurysm. We will test the hypothesis that unruptured aneurysms are older than ruptured aneurysms. The answer to our hypothesis would bear on the question of use of radiological screening of the population for incidental aneurysms. If aneurysms form rapidly and rupture or stabilize and never rupture, then screening may not be very useful. The results of the present study seek to determine whether this occurs. We will determine age of ruptured and unruptured intracranial aneurysms using 14C dating of aneurismal collagen, on the condition that the tissue is ultra-pure and not mixed with other tissues or cells. Hence, after isolation and purification of collagen from aneurysm walls excised from patients undergoing surgery, we will determine the age of the collagen using 14C birth dating in order to understand aneurysm formation in patients with ruptured aneurysms compared to unruptured aneurysms.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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Lawrence Livermore National Laboratory
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