Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes

Keith A. Josephs, Alex Stroh, Brittany Dugger, Dennis W. Dickson

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Frontotemporal lobar degeneration (FTLD) can be classified as tau-positive (FTLD-tau) and tau-negative FTLD. The most common form of tau-negative FTLD is associated with neuronal inclusions that are composed of TAR DNA-binding protein 43 (TDP-43) (FTLD-TDP). Recent evidence suggests that FTLD-TDP can be further subdivided into at least three major histologic variants based on patterns of TDP-43 immunoreactive neuronal cytoplasmic inclusions (NCI) and dystrophic neurites (DN) in neocortex and hippocampus. The aim of this study was to extend the histologic analysis to other brain regions and to determine if there were distinct clinical and pathologic characteristics of the FTLD-TDP subtypes. Thirty-nine FTLD-TDP cases were analyzed (Mackenzie type 1 n = 24, Mackenzie type 2 n = 9, Mackenzie type 3 n = 6). There was a highly significant association between clinical syndrome and FTLD-TDP subtype, with progressive non-fluent aphasia associated with type 1, semantic dementia with type 2, and behavioral variant frontotemporal dementia with types 1, 2 and 3. Semi-quantitative analysis of NCI and DN demonstrated different patterns of involvement in cortical, subcortical and brainstem areas that were characteristic for each of the three types of FTLD-TDP. Type 1 had a mixture of NCI and DN, as well as intranuclear inclusions in most cases and TDP-43 pathology at all levels of the neuraxis, but less in brainstem than supratentorial structures. Type 2 cases were characterized by predominance of long, thick DN in the cortex, as well as numerous NCI in hippocampus, amygdala and basal ganglia, but virtually no NCI and only sparse DN in diencephalon and brainstem. Type 3 had a paucity of DN at all levels of the neuraxis and significantly more NCI in the hypoglossal nucleus than the other types. These findings extend previously described clinicopathological associations of FTLD-TDP subtypes and support the notion that FTLD-TDP subtypes may be distinct clinicopathologic disorders.

Original languageEnglish (US)
Pages (from-to)349-358
Number of pages10
JournalActa Neuropathologica
Volume118
Issue number3
DOIs
StatePublished - May 20 2009
Externally publishedYes

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Frontotemporal Lobar Degeneration
Clinical Pathology
Inclusion Bodies
Neurites
DNA-Binding Proteins
Brain Stem
Frontotemporal Dementia
Hippocampus
Intranuclear Inclusion Bodies
Diencephalon
Aphasia
Neocortex
Amygdala
Basal Ganglia

Keywords

  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • Immunohistochemistry
  • Progressive non-fluent aphasia
  • Semantic dementia
  • TDP-43

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes. / Josephs, Keith A.; Stroh, Alex; Dugger, Brittany; Dickson, Dennis W.

In: Acta Neuropathologica, Vol. 118, No. 3, 20.05.2009, p. 349-358.

Research output: Contribution to journalArticle

Josephs, Keith A. ; Stroh, Alex ; Dugger, Brittany ; Dickson, Dennis W. / Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes. In: Acta Neuropathologica. 2009 ; Vol. 118, No. 3. pp. 349-358.
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