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000162632 037__ $$aDZNE-2021-01328
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000162632 1001_ $$aBayer, David$$b0
000162632 245__ $$aDisruption of orbitofrontal-hypothalamic projections in a murine ALS model and in human patients.
000162632 260__ $$aLondon$$bBiomed Central$$c2021
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000162632 520__ $$aIncreased 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.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.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.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.
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000162632 650_7 $$2Other$$aAgranular insula
000162632 650_7 $$2Other$$aAmyotrophic lateral sclerosis
000162632 650_7 $$2Other$$aHypermetabolism
000162632 650_7 $$2Other$$aLateral hypothalamus
000162632 650_7 $$2Other$$aOrbitofrontal cortex
000162632 650_7 $$2Other$$arAAV2
000162632 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: diagnostic imaging
000162632 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000162632 650_2 $$2MeSH$$aAnimals
000162632 650_2 $$2MeSH$$aBrain Mapping
000162632 650_2 $$2MeSH$$aCase-Control Studies
000162632 650_2 $$2MeSH$$aCohort Studies
000162632 650_2 $$2MeSH$$aDiffusion Tensor Imaging
000162632 650_2 $$2MeSH$$aEnergy Metabolism
000162632 650_2 $$2MeSH$$aHumans
000162632 650_2 $$2MeSH$$aHypothalamus: diagnostic imaging
000162632 650_2 $$2MeSH$$aHypothalamus: pathology
000162632 650_2 $$2MeSH$$aImmunohistochemistry
000162632 650_2 $$2MeSH$$aMice
000162632 650_2 $$2MeSH$$aMotor Cortex: growth & development
000162632 650_2 $$2MeSH$$aMotor Cortex: pathology
000162632 650_2 $$2MeSH$$aNeural Pathways: diagnostic imaging
000162632 650_2 $$2MeSH$$aNeural Pathways: pathology
000162632 650_2 $$2MeSH$$aPrefrontal Cortex: diagnostic imaging
000162632 650_2 $$2MeSH$$aPrefrontal Cortex: pathology
000162632 650_2 $$2MeSH$$aRNA-Binding Protein FUS: genetics
000162632 650_2 $$2MeSH$$aSuperoxide Dismutase-1: genetics
000162632 7001_ $$0P:(DE-HGF)0$$aAntonucci, Stefano$$b1
000162632 7001_ $$aMüller, Hans-Peter$$b2
000162632 7001_ $$aSaad, Rami$$b3
000162632 7001_ $$aDupuis, Luc$$b4
000162632 7001_ $$aRasche, Volker$$b5
000162632 7001_ $$0P:(DE-2719)2812855$$aBöckers, Tobias$$b6
000162632 7001_ $$0P:(DE-2719)2812633$$aLudolph, Albert$$b7
000162632 7001_ $$0P:(DE-2719)9001967$$aKassubek, Jan$$b8$$udzne
000162632 7001_ $$0P:(DE-2719)2812851$$aRoselli, Francesco$$b9$$eLast author
000162632 773__ $$0PERI:(DE-600)2653701-1$$a10.1186/s40035-021-00241-6$$gVol. 10, no. 1, p. 17$$n1$$p17$$tTranslational neurodegeneration$$v10$$x2047-9158$$y2021
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