title: Asymmetric pathology in primary progressive aphasia with progranulin mutations and TDP inclusions.
abstract: OBJECTIVE
  To investigate quantitative regional distribution and hemispheric asymmetry of TDP-43 (TAR DNA-binding protein 43) inclusions, neurons, and activated microglia in primary progressive aphasia (PPA) with progranulin (GRN) mutations, and to determine concordance between distribution of pathology, clinical phenotype, and known atrophy patterns.
  
  
  METHODS
  Antibodies to phospho-TDP-43, NeuN (neuronal nuclei), and HLA-DR were used to visualize inclusions, neurons, and activated microglia in paraffin-embedded tissue sections from 4 participants with PPA: 2 of the agrammatic and 2 of the logopenic subtype. Unbiased stereological counting techniques were used for quantitation of immunoreactive profiles in language- and memory-related cortical areas bilaterally. Patterns of pathology across cortical areas and hemispheres were compared and their relationships with known patterns of atrophy investigated.
  
  
  RESULTS
  Numerical densities of TDP-43 inclusions, and less so of activated microglia, were greater in language-related areas compared with memory-related areas. In language areas, neuronal density displayed a pattern opposite to inclusions and activated microglia. Densities of inclusions and microglia were greater (p < 0.05), and densities of neurons were lower (p < 0.005), in the left hemisphere compared with the right. In agrammatic PPA, the highest densities of TDP-43 inclusions were observed in left inferior or middle frontal gyri, and in logopenic participants, the highest density of inclusions was seen in left inferior parietal lobule. This distribution is consistent with subtype-specific peak atrophy sites.
  
  
  CONCLUSIONS
  Distribution of TDP-43 inclusions and neurons, and to a smaller extent of activated microglia, show a regional and hemispheric pattern consistent with disease phenotype and known patterns of atrophy in PPA with GRN mutations.
authors.affiliation: From the Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Garam
authors.initials: G
authors.lastname: Kim
authors.affiliation: From the Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Saman S
authors.initials: SS
authors.lastname: Ahmadian
authors.affiliation: From the Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Melanie
authors.initials: M
authors.lastname: Peterson
authors.affiliation: From the Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Zach
authors.initials: Z
authors.lastname: Parton
authors.affiliation: From the Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Rohail
authors.initials: R
authors.lastname: Memon
authors.affiliation: From the Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Sandra
authors.initials: S
authors.lastname: Weintraub
authors.affiliation: From the Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Alfred
authors.initials: A
authors.lastname: Rademaker
authors.affiliation: From the Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: Eileen
authors.initials: E
authors.lastname: Bigio
authors.affiliation: From the Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: M-Marsel
authors.initials: MM
authors.lastname: Mesulam
authors.affiliation: From the Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL. c-geula@northwestern.edu.
authors.forename: Changiz
authors.initials: C
authors.lastname: Geula
mesh_terms: D000368:Aged; D018888:Aphasia, Primary Progressive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D007839:Functional Laterality; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D017628:Microglia / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009474:Neurons / Q000473:pathology; D010641:Phenotype; D000077153:Progranulins
chemical_list: D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; C000598624:TARDBP protein, human