The main aim of this proposal is to determine if mitochondria! dysfunction as reflected by low rates of oxidative metabolism is predictive of eventual brain volume loss after traumatic brain injury (TBI). TBI is a condition of widespread brain dysfunction in which secondary cell death and brain atrophy occur in normal appearing tissue despite a relatively confined area of primary anatomical damage. The mechanism of delayed brain atrophy is not clear but may be related to early and persistent impaired oxidative metabolism that is endemic after TBI. Reduced oxidative metabolism (CMRO2) is a result of impaired mitochondrial function and has been measured in TBI by positron emission tomography (PET). Our preliminary studies indicate that 1) CMRO2 is reduced in normal appearing brain regions as well as adjacent to contusions, 2) reduction in CMRO2 in normal regions can be monitored by cerebral microdialysis lactate/pyruvate values, 3) delayed atrophy is related to the duration of abnormal lactate/pyruvate values, and 4) delayed atrophy is related to neurologic/cognitive outcome. Hence, a persistent deficit in energy supply may be related to eventual cell loss and poor outcome. TBI provides a unique opportunity to study human brain tissue with invasive cerebral microdialysis monitoring and PET imaging, thus enabling independent measurements of mitochondrial function in space (PET) and acrosstime (microdialysis). The proposed studies will 1) Determine the magnitude and spatial distribution of impaired oxidative metabolism after TBI using PET and microdialysis, 2) Determine if brain regions of reduced oxidative metabolism are destined for brain atrophy on follow-up MR),3) Determine if acute impaired oxidative metabolism corresponds to poor clinical outcome, 4) Evaluate the validity of magnetic resonance spectroscopy N-Acetyl-Aspartate as a non-invasive surrogate marker of oxidative metabolism.
The fourth aim i s intended to be exploratory but could lead to widespread application of MRS in clinical care for TBI patients in centers lacking oxygen PET technology. This study can only be done within the context of traumatic brain injury, in which invasive monitoring methods are standard of care. The knowledge from the proposed studies will have widespread application to critical care of neurotrauma patients.
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