Background: Imaging neuronal dysfunction in living transgenic mice has emerged as an important goal for drug development. A variety of hemodynamic correlates of metabolism can be measured with MRI, and all have been used to map brain dysfunction. Objective(s): We have focused on one particular hemodynamic correlate - cerebral blood volume (CBV) - because its superior spatial resolution visualizes individual hippocampal subregions. Regional CBV can be estimated by measuring the effect that an exogenous or endogenous contrast agent has on MR[ signal. We have explored a range of MRI approaches, in an effort to identify the one most suitable to image neuronal dysfunction in transgenic mouse models of Alzheimer's disease (AD). Methods: Experiments were carried out in our dedicated mouse-MP~ laboratory using a 9.4 T Braker scanner. We imaged two strains of transgenic mice, both expressing disease-causing mutations in amyloid-precursor protein (APP). Results: In our first experiment, we imaged TgCRND8 transgenics, which develop early onset changes, thereby precluding confounds of aging. CBV maps of the hippocampal formation was generated using oxygen-induced changes in T2*-weighted signal. Relative to wildtype littermates, imaging findings revealed deficits in the CA subregions of the hippocampal formation, with relative sparing of the dentate gyms. Functional imaging is only an indirect measure of underlying neuronal function, and therefore we needed to validate these findings with in vitro measures. First, slice electrophysiology confirmed and extended imaging findings, showing that synapfic dysfunction was localized to the CA subregions with no abnormalities detected in the dentate gyms. Second, cytochrome oxidase histochemistry further confirmed and extended imaging findings, showing that metabolic deficits were localized to pyramidal cells and not the granule ceils. In our second experiment, we are following a group of J20 transgenic mice prospectively, imaging repeatedly over their life-span. Thus far we have found that hippocampal deficits begin in the CA1 subregion and that these extend to other brain regions over time. Finally, we are also exploring alternative MR[ methods for generating measures of CBV. Conclusions: Taken together, these studies demonstrate the feasibility of using mouse MR[ for AD drug screening.
Imaging hippocampal dysfunction in transgenic mice with MRI
PUZZO, DANIELA;
2004-01-01
Abstract
Background: Imaging neuronal dysfunction in living transgenic mice has emerged as an important goal for drug development. A variety of hemodynamic correlates of metabolism can be measured with MRI, and all have been used to map brain dysfunction. Objective(s): We have focused on one particular hemodynamic correlate - cerebral blood volume (CBV) - because its superior spatial resolution visualizes individual hippocampal subregions. Regional CBV can be estimated by measuring the effect that an exogenous or endogenous contrast agent has on MR[ signal. We have explored a range of MRI approaches, in an effort to identify the one most suitable to image neuronal dysfunction in transgenic mouse models of Alzheimer's disease (AD). Methods: Experiments were carried out in our dedicated mouse-MP~ laboratory using a 9.4 T Braker scanner. We imaged two strains of transgenic mice, both expressing disease-causing mutations in amyloid-precursor protein (APP). Results: In our first experiment, we imaged TgCRND8 transgenics, which develop early onset changes, thereby precluding confounds of aging. CBV maps of the hippocampal formation was generated using oxygen-induced changes in T2*-weighted signal. Relative to wildtype littermates, imaging findings revealed deficits in the CA subregions of the hippocampal formation, with relative sparing of the dentate gyms. Functional imaging is only an indirect measure of underlying neuronal function, and therefore we needed to validate these findings with in vitro measures. First, slice electrophysiology confirmed and extended imaging findings, showing that synapfic dysfunction was localized to the CA subregions with no abnormalities detected in the dentate gyms. Second, cytochrome oxidase histochemistry further confirmed and extended imaging findings, showing that metabolic deficits were localized to pyramidal cells and not the granule ceils. In our second experiment, we are following a group of J20 transgenic mice prospectively, imaging repeatedly over their life-span. Thus far we have found that hippocampal deficits begin in the CA1 subregion and that these extend to other brain regions over time. Finally, we are also exploring alternative MR[ methods for generating measures of CBV. Conclusions: Taken together, these studies demonstrate the feasibility of using mouse MR[ for AD drug screening.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
