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Pathogenic mechanisms
A05 Cellular and regional gene expression changes in human Huntington's disease cortex correlate with symptom profiles
  1. D Thu1,2,3,
  2. D Oorschot4,
  3. L Tippett5,
  4. V Hogg5,
  5. H Waldvogel1,5,
  6. R Faull1,5,
  7. R Luthi-Carter3
  1. 1Department of Anatomy with Radiology, University of Auckland, Auckland, New Zealand
  2. 2Centre for Brain Research, University of Auckland, Auckland, New Zealand
  3. 3Brain Mind Institute, école Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
  4. 4Department of Anatomy and Structural Biology, Otago School of Medical Sciences, University of Otago, Auckland, New Zealand
  5. 5Department of Psychology, University of Auckland, Auckland, New Zealand


Background Huntington's disease (HD) presents with variable symptomatologies, including motor and mood changes. The regional, cellular and molecular underpinnings of symptom heterogeneity remain largely unknown, particularly in the cerebral cortex.

Aims This study addressed the hypotheses that varying symptomatologies of HD correlate with differential cortical cell loss and gene expression across cortical subregions.

Methods A double blind study of 12 HD and 15 control brains determined the extent of cell loss in four regions of the cerebral cortex comprising the motor (primary motor cortex), premotor (superior frontal gyrus), somatosensory (primary sensory cortex) and limbic (anterior cingulate gyrus) cortices. The HD cases were categorised into three groups according to their main early symptomatologies (motor, mood or mixed (motor/mood)). In parallel, we examined differential gene expression in the pyramidal neurons in layer V in a subset of the same brains comprising six control and eight HD cases (four with motor symptoms and four with mood symptoms) implementing laser capture microdissection combined with microarray analysis.

Results Stereological analyses revealed marked heterogeneous neuronal loss across cortical subregions that showed region specific correlations to particular HD symptomatologies. Specifically, motor symptom cases showed a greater cell loss in the motor, premotor and somatosensory cortices whereas mood symptoms showed greater loss in the limbic cortex, and mixed symptom cases showed cell loss in multiple cortical subfields. Gene expression changes also showed a symptom correlated distribution, with more changes in the primary motor cortex in motor cases and more changes in the anterior cingulate cortex in mood cases.

Conclusions These findings provide new quantitative evidence that the heterogeneity in the pattern of cell loss and gene expression in the cerebral cortex of the HD brain underlies variable clinical symptomatology. Ongoing studies will assess whether specific genes or molecular pathways can be implicated in these differential HD related effects.

  • Huntington's disease
  • cerebral cortex
  • symptomatology
  • cellular and gene expression changes

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