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         headline:Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology
         description:TAR DNA-binding protein 43 (TDP-43) aggregation is the most common pathological hallmark in frontotemporal dementia (FTD) and characterizes nearly all patients with motor neuron disease (MND). The earliest stages of TDP-43 pathobiology are not well-characterized, and whether neurodegeneration results from TDP-43 loss-of-function or aggregation remains unclear. In the behavioral variant of FTD (bvFTD), patients undergo selective dropout of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices. Here, we examined TDP-43 pathobiology within these vulnerable neurons in the FI across a clinical spectrum including 17 patients with sporadic bvFTD, MND, or both. In an exploratory analysis based on our initial observations, we further assessed ten patients with C9orf72-associated bvFTD/MND. VENs and fork cells showed early, disproportionate TDP-43 aggregation that correlated with anatomical and clinical severity, including loss of emotional empathy. The presence of a TDP-43 inclusion was associated with striking nuclear and somatodendritic atrophy. An intriguing minority of neurons lacked detectable nuclear TDP-43 despite the apparent absence of a cytoplasmic TDP-43 inclusion. These cells showed neuronal atrophy comparable to inclusion-bearing neurons, suggesting that the loss of nuclear TDP-43 function promotes neurodegeneration, even when TDP-43 aggregation is inconspicuous or absent.
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      headline:Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology
      description:TAR DNA-binding protein 43 (TDP-43) aggregation is the most common pathological hallmark in frontotemporal dementia (FTD) and characterizes nearly all patients with motor neuron disease (MND). The earliest stages of TDP-43 pathobiology are not well-characterized, and whether neurodegeneration results from TDP-43 loss-of-function or aggregation remains unclear. In the behavioral variant of FTD (bvFTD), patients undergo selective dropout of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices. Here, we examined TDP-43 pathobiology within these vulnerable neurons in the FI across a clinical spectrum including 17 patients with sporadic bvFTD, MND, or both. In an exploratory analysis based on our initial observations, we further assessed ten patients with C9orf72-associated bvFTD/MND. VENs and fork cells showed early, disproportionate TDP-43 aggregation that correlated with anatomical and clinical severity, including loss of emotional empathy. The presence of a TDP-43 inclusion was associated with striking nuclear and somatodendritic atrophy. An intriguing minority of neurons lacked detectable nuclear TDP-43 despite the apparent absence of a cytoplasmic TDP-43 inclusion. These cells showed neuronal atrophy comparable to inclusion-bearing neurons, suggesting that the loss of nuclear TDP-43 function promotes neurodegeneration, even when TDP-43 aggregation is inconspicuous or absent.
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            address:
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            address:
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            address:
               name:Global Brain Health Institute, University of California, San Francisco, San Francisco, USA
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            address:
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            address:
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            address:
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      email:[email protected]
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      name:Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA
      name:Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA
      name:Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA
      name:Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA
      name:Department of Psychopharmacology, Qiqihar Medical University, Qiqihar, China
      name:Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA
      name:Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA
      name:Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA
      name:Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, USA
      name:Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA
      name:Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA
      name:Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, USA
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      name:Neurogenetics Program, Department of Neurology and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA
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