Limits...
Regional brain metabolism in a murine systemic lupus erythematosus model.

Vo A, Volpe BT, Tang CC, Schiffer WK, Kowal C, Huerta PT, Uluğ AM, Dewey SL, Eidelberg D, Diamond B - J. Cereb. Blood Flow Metab. (2014)

Bottom Line: We previously identified a subset of anti-DNA antibodies (DNRAb) cross-reactive with the N-methyl-D-aspartate receptor, present in 30% to 40% of patients, able to enhance excitatory post-synaptic potentials and trigger neuronal apoptosis.Here, we used 18F-fluorodeoxyglucose (FDG) microPET to plot changes in brain metabolism after regional blood-brain barrier (BBB) breach.These findings suggest that local metabolic alterations in this model take place through different mechanisms with distinct time courses, with important implications for the interpretation of imaging data in SLE subjects.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.

ABSTRACT
Systemic lupus erythematosus (SLE) is characterized by multiorgan inflammation, neuropsychiatric disorders (NPSLE), and anti-nuclear antibodies. We previously identified a subset of anti-DNA antibodies (DNRAb) cross-reactive with the N-methyl-D-aspartate receptor, present in 30% to 40% of patients, able to enhance excitatory post-synaptic potentials and trigger neuronal apoptosis. DNRAb+ mice exhibit memory impairment or altered fear response, depending on whether the antibody penetrates the hippocampus or amygdala. Here, we used 18F-fluorodeoxyglucose (FDG) microPET to plot changes in brain metabolism after regional blood-brain barrier (BBB) breach. In DNRAb+ mice, metabolism declined at the site of BBB breach in the first 2 weeks and increased over the next 2 weeks. In contrast, DNRAb- mice exhibited metabolic increases in these regions over the 4 weeks after the insult. Memory impairment was present in DNRAb+ animals with hippocampal BBB breach and altered fear conditioning in DNRAb+ mice with amygdala BBB breach. In DNRAb+ mice, we observed an inverse relationship between neuron number and regional metabolism, while a positive correlation was observed in DNRAb- mice. These findings suggest that local metabolic alterations in this model take place through different mechanisms with distinct time courses, with important implications for the interpretation of imaging data in SLE subjects.

Show MeSH

Related in: MedlinePlus

Panel A shows a voxel-based comparison of 18F-fluorodeoxyglucose positron emission tomography images for mice carrying DNRAbs and controls. The strictly data-driven comparison of mice carrying DRNAbs (DNRAb+) and control (DNRAb−) mice reveals a single cluster in the ventral subiculum and entorhinal cortex (red) in which the metabolic changes significantly differ for the two groups over time. The red cluster in panel A was obtained by a statistical parametric mapping interaction analysis of two groups × two time points (0, 4 weeks) (voxel-wise P⩽0.01, k⩾220, cluster corrected P<0.05). The yellow cluster was obtained by a statistical parametric mapping interaction analysis of two groups × three time points (0, 2, 4 weeks) (voxel-wise P<0.005, k>500, cluster corrected P<0.05). The blue cluster was obtained by a statistical parametric mapping comparison of 0 and 2 weeks for the DNRAb+ mice (voxel-wise P<0.001, k>640, cluster corrected P<0.05). The significant clusters from these three analyses were located in the ventral subiculum and entorhinal hippocampus and overlapped in this region. (B) Before LPS administration at baseline (0 weeks), resting metabolism in this region is equivalent in the DNRAb− (circles) and DNRAb+ (triangles) groups. The DNRAb+ mice show decreased regional metabolism 2 weeks after LPS administration that is reversed by 4 weeks after LPS injection. In contrast, the DNRAb− mice demonstrate continuously increasing regional metabolism from 0 weeks through 2 and 4 weeks. Of note, the rate of metabolic increase between 2 and 4 weeks was relatively faster in DNRAb+ mice (0.4/week) than for DNRAb− mice (0.2/week). There was a significant difference in the metabolic changes between the two groups over time (group × time interaction effect: F[2,36]=4.8, P=0.01; two-way repeated measures analysis of variance (RMANOVA) on the data at all three time points). Further analyses revealed that this interaction effect occurred in the first 2 weeks after the injection (group × time interaction effect: F[1,18]=6.73, P=0.02; two-way RMANOVA on the data at baseline and 2 weeks ), but not over the subsequent 2 weeks (group × time interaction effect: F[1,18]=0.44, P=0.52; two-way RMANOVA on the data at 2 and 4 weeks). (C) DNRAb+ mice (n=10) and DNRAb− controls (n=10) were tested in the clock maze task 8 weeks post-LPS administration. DNRAb+ mice had impaired spatial memory F[2,7]=6.8, P=0.02, analysis of variance). A cohort of unmanipulated BALB/c mice was also tested. There was no difference between this cohort and the DNRAb− mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4126091&req=5

fig1: Panel A shows a voxel-based comparison of 18F-fluorodeoxyglucose positron emission tomography images for mice carrying DNRAbs and controls. The strictly data-driven comparison of mice carrying DRNAbs (DNRAb+) and control (DNRAb−) mice reveals a single cluster in the ventral subiculum and entorhinal cortex (red) in which the metabolic changes significantly differ for the two groups over time. The red cluster in panel A was obtained by a statistical parametric mapping interaction analysis of two groups × two time points (0, 4 weeks) (voxel-wise P⩽0.01, k⩾220, cluster corrected P<0.05). The yellow cluster was obtained by a statistical parametric mapping interaction analysis of two groups × three time points (0, 2, 4 weeks) (voxel-wise P<0.005, k>500, cluster corrected P<0.05). The blue cluster was obtained by a statistical parametric mapping comparison of 0 and 2 weeks for the DNRAb+ mice (voxel-wise P<0.001, k>640, cluster corrected P<0.05). The significant clusters from these three analyses were located in the ventral subiculum and entorhinal hippocampus and overlapped in this region. (B) Before LPS administration at baseline (0 weeks), resting metabolism in this region is equivalent in the DNRAb− (circles) and DNRAb+ (triangles) groups. The DNRAb+ mice show decreased regional metabolism 2 weeks after LPS administration that is reversed by 4 weeks after LPS injection. In contrast, the DNRAb− mice demonstrate continuously increasing regional metabolism from 0 weeks through 2 and 4 weeks. Of note, the rate of metabolic increase between 2 and 4 weeks was relatively faster in DNRAb+ mice (0.4/week) than for DNRAb− mice (0.2/week). There was a significant difference in the metabolic changes between the two groups over time (group × time interaction effect: F[2,36]=4.8, P=0.01; two-way repeated measures analysis of variance (RMANOVA) on the data at all three time points). Further analyses revealed that this interaction effect occurred in the first 2 weeks after the injection (group × time interaction effect: F[1,18]=6.73, P=0.02; two-way RMANOVA on the data at baseline and 2 weeks ), but not over the subsequent 2 weeks (group × time interaction effect: F[1,18]=0.44, P=0.52; two-way RMANOVA on the data at 2 and 4 weeks). (C) DNRAb+ mice (n=10) and DNRAb− controls (n=10) were tested in the clock maze task 8 weeks post-LPS administration. DNRAb+ mice had impaired spatial memory F[2,7]=6.8, P=0.02, analysis of variance). A cohort of unmanipulated BALB/c mice was also tested. There was no difference between this cohort and the DNRAb− mice.

Mentions: A whole brain voxel-wise search was conducted to identify brain regions in which the time course of local metabolic activity differed for DNRAb+ and DNRAb− animals. This strictly data-driven analysis revealed only a single region, the ventral subiculum (Figure 1A) where a significant difference was found between the two groups of animals (P=0.01; overall analysis three time points). The significant interaction occurred in the first 2 weeks (P=0.01) but not in the subsequent 2 weeks (P=0.52). (Figure 1B).


Regional brain metabolism in a murine systemic lupus erythematosus model.

Vo A, Volpe BT, Tang CC, Schiffer WK, Kowal C, Huerta PT, Uluğ AM, Dewey SL, Eidelberg D, Diamond B - J. Cereb. Blood Flow Metab. (2014)

Panel A shows a voxel-based comparison of 18F-fluorodeoxyglucose positron emission tomography images for mice carrying DNRAbs and controls. The strictly data-driven comparison of mice carrying DRNAbs (DNRAb+) and control (DNRAb−) mice reveals a single cluster in the ventral subiculum and entorhinal cortex (red) in which the metabolic changes significantly differ for the two groups over time. The red cluster in panel A was obtained by a statistical parametric mapping interaction analysis of two groups × two time points (0, 4 weeks) (voxel-wise P⩽0.01, k⩾220, cluster corrected P<0.05). The yellow cluster was obtained by a statistical parametric mapping interaction analysis of two groups × three time points (0, 2, 4 weeks) (voxel-wise P<0.005, k>500, cluster corrected P<0.05). The blue cluster was obtained by a statistical parametric mapping comparison of 0 and 2 weeks for the DNRAb+ mice (voxel-wise P<0.001, k>640, cluster corrected P<0.05). The significant clusters from these three analyses were located in the ventral subiculum and entorhinal hippocampus and overlapped in this region. (B) Before LPS administration at baseline (0 weeks), resting metabolism in this region is equivalent in the DNRAb− (circles) and DNRAb+ (triangles) groups. The DNRAb+ mice show decreased regional metabolism 2 weeks after LPS administration that is reversed by 4 weeks after LPS injection. In contrast, the DNRAb− mice demonstrate continuously increasing regional metabolism from 0 weeks through 2 and 4 weeks. Of note, the rate of metabolic increase between 2 and 4 weeks was relatively faster in DNRAb+ mice (0.4/week) than for DNRAb− mice (0.2/week). There was a significant difference in the metabolic changes between the two groups over time (group × time interaction effect: F[2,36]=4.8, P=0.01; two-way repeated measures analysis of variance (RMANOVA) on the data at all three time points). Further analyses revealed that this interaction effect occurred in the first 2 weeks after the injection (group × time interaction effect: F[1,18]=6.73, P=0.02; two-way RMANOVA on the data at baseline and 2 weeks ), but not over the subsequent 2 weeks (group × time interaction effect: F[1,18]=0.44, P=0.52; two-way RMANOVA on the data at 2 and 4 weeks). (C) DNRAb+ mice (n=10) and DNRAb− controls (n=10) were tested in the clock maze task 8 weeks post-LPS administration. DNRAb+ mice had impaired spatial memory F[2,7]=6.8, P=0.02, analysis of variance). A cohort of unmanipulated BALB/c mice was also tested. There was no difference between this cohort and the DNRAb− mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126091&req=5

fig1: Panel A shows a voxel-based comparison of 18F-fluorodeoxyglucose positron emission tomography images for mice carrying DNRAbs and controls. The strictly data-driven comparison of mice carrying DRNAbs (DNRAb+) and control (DNRAb−) mice reveals a single cluster in the ventral subiculum and entorhinal cortex (red) in which the metabolic changes significantly differ for the two groups over time. The red cluster in panel A was obtained by a statistical parametric mapping interaction analysis of two groups × two time points (0, 4 weeks) (voxel-wise P⩽0.01, k⩾220, cluster corrected P<0.05). The yellow cluster was obtained by a statistical parametric mapping interaction analysis of two groups × three time points (0, 2, 4 weeks) (voxel-wise P<0.005, k>500, cluster corrected P<0.05). The blue cluster was obtained by a statistical parametric mapping comparison of 0 and 2 weeks for the DNRAb+ mice (voxel-wise P<0.001, k>640, cluster corrected P<0.05). The significant clusters from these three analyses were located in the ventral subiculum and entorhinal hippocampus and overlapped in this region. (B) Before LPS administration at baseline (0 weeks), resting metabolism in this region is equivalent in the DNRAb− (circles) and DNRAb+ (triangles) groups. The DNRAb+ mice show decreased regional metabolism 2 weeks after LPS administration that is reversed by 4 weeks after LPS injection. In contrast, the DNRAb− mice demonstrate continuously increasing regional metabolism from 0 weeks through 2 and 4 weeks. Of note, the rate of metabolic increase between 2 and 4 weeks was relatively faster in DNRAb+ mice (0.4/week) than for DNRAb− mice (0.2/week). There was a significant difference in the metabolic changes between the two groups over time (group × time interaction effect: F[2,36]=4.8, P=0.01; two-way repeated measures analysis of variance (RMANOVA) on the data at all three time points). Further analyses revealed that this interaction effect occurred in the first 2 weeks after the injection (group × time interaction effect: F[1,18]=6.73, P=0.02; two-way RMANOVA on the data at baseline and 2 weeks ), but not over the subsequent 2 weeks (group × time interaction effect: F[1,18]=0.44, P=0.52; two-way RMANOVA on the data at 2 and 4 weeks). (C) DNRAb+ mice (n=10) and DNRAb− controls (n=10) were tested in the clock maze task 8 weeks post-LPS administration. DNRAb+ mice had impaired spatial memory F[2,7]=6.8, P=0.02, analysis of variance). A cohort of unmanipulated BALB/c mice was also tested. There was no difference between this cohort and the DNRAb− mice.
Mentions: A whole brain voxel-wise search was conducted to identify brain regions in which the time course of local metabolic activity differed for DNRAb+ and DNRAb− animals. This strictly data-driven analysis revealed only a single region, the ventral subiculum (Figure 1A) where a significant difference was found between the two groups of animals (P=0.01; overall analysis three time points). The significant interaction occurred in the first 2 weeks (P=0.01) but not in the subsequent 2 weeks (P=0.52). (Figure 1B).

Bottom Line: We previously identified a subset of anti-DNA antibodies (DNRAb) cross-reactive with the N-methyl-D-aspartate receptor, present in 30% to 40% of patients, able to enhance excitatory post-synaptic potentials and trigger neuronal apoptosis.Here, we used 18F-fluorodeoxyglucose (FDG) microPET to plot changes in brain metabolism after regional blood-brain barrier (BBB) breach.These findings suggest that local metabolic alterations in this model take place through different mechanisms with distinct time courses, with important implications for the interpretation of imaging data in SLE subjects.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.

ABSTRACT
Systemic lupus erythematosus (SLE) is characterized by multiorgan inflammation, neuropsychiatric disorders (NPSLE), and anti-nuclear antibodies. We previously identified a subset of anti-DNA antibodies (DNRAb) cross-reactive with the N-methyl-D-aspartate receptor, present in 30% to 40% of patients, able to enhance excitatory post-synaptic potentials and trigger neuronal apoptosis. DNRAb+ mice exhibit memory impairment or altered fear response, depending on whether the antibody penetrates the hippocampus or amygdala. Here, we used 18F-fluorodeoxyglucose (FDG) microPET to plot changes in brain metabolism after regional blood-brain barrier (BBB) breach. In DNRAb+ mice, metabolism declined at the site of BBB breach in the first 2 weeks and increased over the next 2 weeks. In contrast, DNRAb- mice exhibited metabolic increases in these regions over the 4 weeks after the insult. Memory impairment was present in DNRAb+ animals with hippocampal BBB breach and altered fear conditioning in DNRAb+ mice with amygdala BBB breach. In DNRAb+ mice, we observed an inverse relationship between neuron number and regional metabolism, while a positive correlation was observed in DNRAb- mice. These findings suggest that local metabolic alterations in this model take place through different mechanisms with distinct time courses, with important implications for the interpretation of imaging data in SLE subjects.

Show MeSH
Related in: MedlinePlus