Background:In vivo diffusion tensor imaging(DTI)of the mouse brain was used to identify TDP-43 associated alterations in a mouse model for amyotrophic lateral sclerosis(ALS).Methods:Ten mice with TDP-43^(G298S) overex...Background:In vivo diffusion tensor imaging(DTI)of the mouse brain was used to identify TDP-43 associated alterations in a mouse model for amyotrophic lateral sclerosis(ALS).Methods:Ten mice with TDP-43^(G298S) overexpression under control of the Thy1.2 promoter and 10 wild type(wt)underwent longitudinal DTI scans at 11.7 T,including one baseline and one follow-up scan with an interval of about 5months.Whole brain-based spatial statistics(WBSS)of DTI-based parameter maps was used to identify longitudinal alterations of TDP-43^(G298S) mice compared to wt at the cohort level.Results were supplemented by tractwise fractional anisotropy statistics(TFAS)and histological evaluation of motor cortex for signs of neuronal loss.Results:Alterations at the cohort level in TDP-43^(G298S) mice were observed cross-sectionally and longitudinally in motor areas M1/M2 and in transcallosal fibers but not in the corticospinal tract.Neuronal loss in layer V of motor cortex was detected in TDP-43^(G298S) at the later(but not at the earlier)timepoint compared to wt.Conclusion:DTI mapping of TDP-43^(G298S) mice demonstrated progression in motor areas M1/M2.WBSS and TFAS are useful techniques to localize TDP-43^(G298S) associated alterations over time in this ALS mouse model,as a biological marker.展开更多
Background:Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis(ALS).The hypothalamic systems have been shown to be involved in the metabolic dysfunction in AL...Background:Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis(ALS).The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS,but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined.Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients.Methods:The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A)ALS mouse model(hypermetabolic)and the FusΔNLS ALS mouse model(normo-metabolic).3 T diffusion tensor imaging(DTI)-magnetic resonance imaging(MRI)was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus(LHA)in ALS.Results:Symptomatic SOD1(G93A)mice displayed an expansion of projections from agranular insula,ventrolateral orbitofrontal and secondary motor cortex to the LHA.These findings were reproduced in an independent cohort by using a different analytic approach.In contrast,in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost.The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients.Conclusion:This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.展开更多
文摘Background:In vivo diffusion tensor imaging(DTI)of the mouse brain was used to identify TDP-43 associated alterations in a mouse model for amyotrophic lateral sclerosis(ALS).Methods:Ten mice with TDP-43^(G298S) overexpression under control of the Thy1.2 promoter and 10 wild type(wt)underwent longitudinal DTI scans at 11.7 T,including one baseline and one follow-up scan with an interval of about 5months.Whole brain-based spatial statistics(WBSS)of DTI-based parameter maps was used to identify longitudinal alterations of TDP-43^(G298S) mice compared to wt at the cohort level.Results were supplemented by tractwise fractional anisotropy statistics(TFAS)and histological evaluation of motor cortex for signs of neuronal loss.Results:Alterations at the cohort level in TDP-43^(G298S) mice were observed cross-sectionally and longitudinally in motor areas M1/M2 and in transcallosal fibers but not in the corticospinal tract.Neuronal loss in layer V of motor cortex was detected in TDP-43^(G298S) at the later(but not at the earlier)timepoint compared to wt.Conclusion:DTI mapping of TDP-43^(G298S) mice demonstrated progression in motor areas M1/M2.WBSS and TFAS are useful techniques to localize TDP-43^(G298S) associated alterations over time in this ALS mouse model,as a biological marker.
基金FR is supported by the Thierry Latran Foundation(projects“Trials”and“Hypothals”),the Radala Foundation,the Deutsche Forschungsgemeinschaft(German Research Foundation)-Project-ID 251293561-Collaborative Research Center(CRC)1149 and individual grants 431995586(RO-5004/8-1)and 443642953(RO5004/9-1)the Cellular and Molecular Mechanisms in Aging(CEMMA)Research Training Group,and BMBF(FKZ 01EW1705A,as member of the ERANET-NEURON consortium“MICRONET”)+1 种基金SA and DB are members of the International Graduate School in Molecular Medicine at Ulm UniversityDB is part of the Graduate School in Cellular and Molecular Mechanisms in Aging at Ulm University.Open Access funding enabled and organized by Projekt DEAL.
文摘Background:Increased catabolism has recently been recognized as a clinical manifestation of amyotrophic lateral sclerosis(ALS).The hypothalamic systems have been shown to be involved in the metabolic dysfunction in ALS,but the exact extent of hypothalamic circuit alterations in ALS is yet to be determined.Here we explored the integrity of large-scale cortico-hypothalamic circuits involved in energy homeostasis in murine models and in ALS patients.Methods:The rAAV2-based large-scale projection mapping and image analysis pipeline based on Wholebrain and Ilastik software suites were used to identify and quantify projections from the forebrain to the lateral hypothalamus in the SOD1(G93A)ALS mouse model(hypermetabolic)and the FusΔNLS ALS mouse model(normo-metabolic).3 T diffusion tensor imaging(DTI)-magnetic resonance imaging(MRI)was performed on 83 ALS and 65 control cases to investigate cortical projections to the lateral hypothalamus(LHA)in ALS.Results:Symptomatic SOD1(G93A)mice displayed an expansion of projections from agranular insula,ventrolateral orbitofrontal and secondary motor cortex to the LHA.These findings were reproduced in an independent cohort by using a different analytic approach.In contrast,in the FusΔNLS ALS mouse model hypothalamic inputs from insula and orbitofrontal cortex were maintained while the projections from motor cortex were lost.The DTI-MRI data confirmed the disruption of the orbitofrontal-hypothalamic tract in ALS patients.Conclusion:This study provides converging murine and human data demonstrating the selective structural disruption of hypothalamic inputs in ALS as a promising factor contributing to the origin of the hypermetabolic phenotype.
