title: Astrogliopathy predominates the earliest stage of corticobasal degeneration pathology.
abstract: SEE KOBYLECKI AND MANN DOI101093/AWW267 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Animal models have shown that tau seeding and propagation are strain- and neural network-specific. The study of preclinical cases is valuable to gain insights into early pathological features of corticobasal degeneration and its progression. Three preclinical corticobasal degeneration cases and six age-matched end-stage corticobasal degeneration cases were included in this study. Tau immunohistochemistry performed in 20 brain regions and quantitative assessment of regional tau load using image analysis were performed. Semi-quantitative grading of tau-positive cellular lesions and neuronal loss in the frontal, parietal and temporal cortices, striatum, substantia nigra and subthalamic nucleus were assessed. All preclinical cases were clinically asymptomatic but had widespread tau lesions in the typically affected regions in corticobasal degeneration and the pathognomonic astrocytic plaques were the most prominent lesion type in the anterior frontal and striatal regions. Mean total tau load (sum of all regional tau load) of end-stage corticobasal degeneration cases were nine times greater than that of the preclinical cases (P = 0.04) and less tau load was found in all regions of the preclinical cases. An anterior-to-posterior tau load ratio in the frontal cortex in preclinical cases was 12-fold greater than in end-stage corticobasal degeneration cases. Relatively greater tau burden in the anterior frontal cortex, striatum and subthalamic nucleus suggests the striatal afferent connection to the dorsolateral prefrontal cortex and basal ganglia circuitry are the earliest neural network connections affected by corticobasal degeneration-related tau pathology. Differential distribution of the tau pathology to selective cortical regions in these preclinical cases implies phenotypic presentation may be predetermined at a very early stage of the disease process. Neuronal loss of the substantia nigra was either absent or very mild in the preclinical cases and was moderate to severe in end-stage corticobasal degeneration cases (P < 0.05). Our findings suggest that a threshold of pathological burden in the 'right' anatomical regions needs to be reached before the onset of clinical symptoms. The early prominence of the astrocytic plaques in relation to sparse neuronal lesions leads one to speculate that corticobasal degeneration may begin as an astrogliopathy at a very early disease stage but neuronal lesions gradually take over as the predominant lesion type in advanced disease.
authors: 1 Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, UK.|2 Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, University College London, London, UK.|3 Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
authors: Helen
authors: H
authors: Ling
authors: 4 Institute of Neurology, Medical University of Vienna, Austria.
authors: Gabor G
authors: GG
authors: Kovacs
authors: 5 Taub Institute for Research on AD and the Aging Brain, Columbia University Medical Center, New York, USA.
authors: Jean Paul G
authors: JP
authors: Vonsattel
authors: 1 Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, UK.|2 Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, University College London, London, UK.
authors: Karen
authors: K
authors: Davey
authors: 3 Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.|6 Division of Life Science, Hong Kong University of Science and Technology, Hong Kong SAR, China.
authors: Kin Y
authors: KY
authors: Mok
authors: 3 Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
authors: John
authors: J
authors: Hardy
authors: 7 Department of Clinical Neuroscience, UCL Institute of Neurology, University College London, London, UK.
authors: Huw R
authors: HR
authors: Morris
authors: 1 Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, UK.|2 Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, University College London, London, UK.|3 Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
authors: Thomas T
authors: TT
authors: Warner
authors: 1 Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, UK.|2 Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, University College London, London, UK.|3 Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
authors: Janice L
authors: JL
authors: Holton
authors: 1 Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, University College London, London, UK t.revesz@ucl.ac.uk.|2 Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, University College London, London, UK.|3 Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
authors: Tamas
authors: T
authors: Revesz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001480:Basal Ganglia Diseases / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000378:metabolism / Q000473:pathology; D062706:Prodromal Symptoms; D020531:Subthalamic Nucleus / Q000378:metabolism / Q000473:pathology; D014015:Tissue Banks; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins
keywords: astrocytic plaque; corticobasal degeneration; neurofibrillary tangles; progressive supranuclear palsy; tau