title: Clinical and pathological continuum of multisystem TDP-43 proteinopathies.
abstract: OBJECTIVE
  To determine the extent of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system of patients with clinically and autopsy-confirmed diagnoses of frontotemporal lobar degeneration with and without motor neuron disease and amyotrophic lateral sclerosis with and without cognitive impairment.
  
  
  METHODS
  Performance of immunohistochemical whole-central nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review.
  
  
  METHODS
  An academic medical center.
  
  
  METHODS
  We included 64 patients with clinically and pathologically confirmed frontotemporal lobar degeneration with ubiquitinated inclusions with or without motor neuron disease and amyotrophic lateral sclerosis with or without cognitive impairment.
  
  
  METHODS
  Neuronal and glial TDP-43 pathology.
  
  
  RESULTS
  We found evidence of neuronal and glial TDP-43 pathology in all disease groups throughout the neuraxis, albeit with variations in the frequency, morphology, and distribution of TDP-43 lesions. Moreover, the major clinical manifestations (eg, cognitive impairments, motor neuron signs, extrapyramidal symptoms, neuropsychiatric features) were reflected by the predominant distribution and burden of TDP-43 pathology.
  
  
  CONCLUSIONS
  These findings strongly suggest that amyotrophic lateral sclerosis, frontotemporal lobar degeneration with amyotrophic lateral sclerosis or motor neuron disease, and frontotemporal lobar degeneration with ubiquitinated inclusions are different manifestations of a multiple-system TDP-43 proteinopathy linked to similar mechanisms of neurodegeneration.
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Geser
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez-Lage
authors.forename: John
authors.initials: J
authors.lastname: Robinson
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Uryu
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandmeir
authors.forename: Sharon X
authors.initials: SX
authors.lastname: Xie
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.forename: Lauren
authors.initials: L
authors.lastname: Elman
authors.forename: Leo
authors.initials: L
authors.lastname: McCluskey
authors.forename: Chris M
authors.initials: CM
authors.lastname: Clark
authors.forename: Joe
authors.initials: J
authors.lastname: Malunda
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: Earl A
authors.initials: EA
authors.lastname: Zimmerman
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.forename: Vivianna
authors.initials: V
authors.lastname: Van Deerlin
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology* / Q000503:physiopathology; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D001931:Brain Mapping; D003072:Cognition Disorders / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D003704:Dementia / Q000473:pathology* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000473:pathology / Q000503:physiopathology; D009069:Movement Disorders / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012189:Retrospective Studies; D025801:Ubiquitin / Q000032:analysis / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D025801:Ubiquitin