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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.

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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 amygdala (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<0.005, k>370, cluster corrected P<0.05). (B) Before epinephrine 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 epinephrine administration that is reversed by 4 weeks after epinephrine 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]=9.59, P⩽0.001; two-way repeated measures analysis of variance (RMANOVA) on the data at all three time points). Furthermore, this interaction effect was present in the data at baseline and 2 weeks after the injection (group × time interaction effect: F[1,18]=10.76, P=0.005; two-way RMANOVA), but was absent between 2 and 4 weeks (group × time interaction effect: F[1,18]=0.10, P=0.75; two-way RMANOVA on the data at the last two time points). (C) Profile of freezing response. DNRAb+ mice (n=10) and DNRAb− controls (n=10) were tested in an associative learning fear paradigm 8 weeks post-epinephrine administration. DNRAb+ mice had impaired associative learning of the fear response in the tone memory test (P=0.0007, t-test). A cohort of unmanipulated BALB/c mice was also tested and their behavior was not different from the behavior of DNRAb− mice.
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fig3: 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 amygdala (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<0.005, k>370, cluster corrected P<0.05). (B) Before epinephrine 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 epinephrine administration that is reversed by 4 weeks after epinephrine 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]=9.59, P⩽0.001; two-way repeated measures analysis of variance (RMANOVA) on the data at all three time points). Furthermore, this interaction effect was present in the data at baseline and 2 weeks after the injection (group × time interaction effect: F[1,18]=10.76, P=0.005; two-way RMANOVA), but was absent between 2 and 4 weeks (group × time interaction effect: F[1,18]=0.10, P=0.75; two-way RMANOVA on the data at the last two time points). (C) Profile of freezing response. DNRAb+ mice (n=10) and DNRAb− controls (n=10) were tested in an associative learning fear paradigm 8 weeks post-epinephrine administration. DNRAb+ mice had impaired associative learning of the fear response in the tone memory test (P=0.0007, t-test). A cohort of unmanipulated BALB/c mice was also tested and their behavior was not different from the behavior of DNRAb− mice.

Mentions: To study the metabolic and behavioral changes after epinephrine in the SLE animal model, mice were immunized as before, but both DNRAb+ and DNRAb− cohorts received epinephrine (intrapertioneal 100 nmol/L epinephrine (Sigma)) in lactated Ringer's solution, as published, to breach the BBB in the amygdala, and underwent microPET at three time points: 1 week before LPS injection, and 2 weeks and 4 weeks after LPS administration.16, 17, 20 We determined if analogous DNRAb-mediated changes in metabolism occurred in the amygdala after localized epinephrine-induced BBB breach. Mice underwent FDG-PET 1 week before epinephrine administration and 2 and 4 weeks later. There was no significant difference in the course of global metabolism measured in the DNRAb+ and DNRAb− groups over time (P=0.12). The DNRAb− mice exhibited a continuous increase in globally normalized metabolism in the amygdala across the three time points. In contrast, DNRAb+ mice exhibited a metabolic decline in the amygdala at 2 weeks (Figure 3A), followed by increased activity in the same region at 4 weeks after epinephrine (P⩽0.001) (Figure 3B).


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 amygdala (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<0.005, k>370, cluster corrected P<0.05). (B) Before epinephrine 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 epinephrine administration that is reversed by 4 weeks after epinephrine 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]=9.59, P⩽0.001; two-way repeated measures analysis of variance (RMANOVA) on the data at all three time points). Furthermore, this interaction effect was present in the data at baseline and 2 weeks after the injection (group × time interaction effect: F[1,18]=10.76, P=0.005; two-way RMANOVA), but was absent between 2 and 4 weeks (group × time interaction effect: F[1,18]=0.10, P=0.75; two-way RMANOVA on the data at the last two time points). (C) Profile of freezing response. DNRAb+ mice (n=10) and DNRAb− controls (n=10) were tested in an associative learning fear paradigm 8 weeks post-epinephrine administration. DNRAb+ mice had impaired associative learning of the fear response in the tone memory test (P=0.0007, t-test). A cohort of unmanipulated BALB/c mice was also tested and their behavior was not different from the behavior of DNRAb− mice.
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fig3: 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 amygdala (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<0.005, k>370, cluster corrected P<0.05). (B) Before epinephrine 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 epinephrine administration that is reversed by 4 weeks after epinephrine 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]=9.59, P⩽0.001; two-way repeated measures analysis of variance (RMANOVA) on the data at all three time points). Furthermore, this interaction effect was present in the data at baseline and 2 weeks after the injection (group × time interaction effect: F[1,18]=10.76, P=0.005; two-way RMANOVA), but was absent between 2 and 4 weeks (group × time interaction effect: F[1,18]=0.10, P=0.75; two-way RMANOVA on the data at the last two time points). (C) Profile of freezing response. DNRAb+ mice (n=10) and DNRAb− controls (n=10) were tested in an associative learning fear paradigm 8 weeks post-epinephrine administration. DNRAb+ mice had impaired associative learning of the fear response in the tone memory test (P=0.0007, t-test). A cohort of unmanipulated BALB/c mice was also tested and their behavior was not different from the behavior of DNRAb− mice.
Mentions: To study the metabolic and behavioral changes after epinephrine in the SLE animal model, mice were immunized as before, but both DNRAb+ and DNRAb− cohorts received epinephrine (intrapertioneal 100 nmol/L epinephrine (Sigma)) in lactated Ringer's solution, as published, to breach the BBB in the amygdala, and underwent microPET at three time points: 1 week before LPS injection, and 2 weeks and 4 weeks after LPS administration.16, 17, 20 We determined if analogous DNRAb-mediated changes in metabolism occurred in the amygdala after localized epinephrine-induced BBB breach. Mice underwent FDG-PET 1 week before epinephrine administration and 2 and 4 weeks later. There was no significant difference in the course of global metabolism measured in the DNRAb+ and DNRAb− groups over time (P=0.12). The DNRAb− mice exhibited a continuous increase in globally normalized metabolism in the amygdala across the three time points. In contrast, DNRAb+ mice exhibited a metabolic decline in the amygdala at 2 weeks (Figure 3A), followed by increased activity in the same region at 4 weeks after epinephrine (P⩽0.001) (Figure 3B).

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