Widespread Heterogeneous Neuronal Loss Across the Cerebral Cortex in Huntington's Disease

Article type: Research Article

Authors: Nana, Alissa L.^; | Kim, Eric H.^; | Thu, Doris C.V.^; | Oorschot, Dorothy E. | Tippett, Lynette J.^; | Hogg, Virginia M.^; | Synek, Beth J.^; | Roxburgh, Richard^; | Waldvogel, Henry J.^; | Faull, Richard L.M.^;

Affiliations: Department of Anatomy with Radiology, University of Auckland, Auckland, New Zealand | Centre for Brain Research, University of Auckland, Auckland, New Zealand | Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland | Department of Anatomy, Otago School of Medical Sciences, and the Brain Health Research Centre, University of Otago, Dunedin, New Zealand | Department of Psychology, University of Auckland, Auckland, New Zealand | Department of Forensic Pathology, Auckland City Hospital, Auckland, New Zealand | Department of Neurology, Auckland City Hospital, Auckland, New Zealand

Note: [] These authors contributed equally to this work.

Note: [] These authors contributed equally to this work.

Note: [] These authors contributed equally to this work.

Note: [] These authors contributed equally to this work.

Note: [] Correspondence to: Richard L.M. Faull, The Centre for Brain Research, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. Tel.: +649 923 6708; Fax: +649 373 7484; E-mail: [email protected]

Abstract: Huntington's disease is an autosomal dominant neurodegenerative disease characterized by neuronal degeneration in the basal ganglia and cerebral cortex, and a variable symptom profile. Although progressive striatal degeneration is known to occur and is related to symptom profile, little is known about the cellular basis of symptom heterogeneity across the entire cerebral cortex. To investigate this, we have undertaken a double blind study using unbiased stereological cell counting techniques to determine the pattern of cell loss in six representative cortical regions from the frontal, parietal, temporal, and occipital lobes in the brains of 14 Huntington's disease cases and 15 controls. The results clearly demonstrate a widespread loss of total neurons and pyramidal cells across all cortical regions studied, except for the primary visual cortex. Importantly, the results show that cell loss is remarkably variable both within and between Huntington's disease cases. The results also show that neuronal loss in the primary sensory and secondary visual cortices relate to Huntington's disease motor symptom profiles, and neuronal loss across the associational cortices in the frontal, parietal and temporal lobes is related to both Huntington's disease motor and to mood symptom profiles. This finding considerably extends a previous study (Thu et al., Brain, 2010; 133:1094–1110) which showed that neuronal loss in the primary motor cortex was related specifically to the motor symptom profiles while neuronal loss in the anterior cingulate cortex was related specifically to mood symptom profiles. The extent of cortical cell loss in the current study was generally related to the striatal neuropathological grade, but not to CAG repeat length on the HTT gene. Overall our findings show that Huntington's disease is characterized by a heterogeneous pattern of neuronal cell loss across the entire cerebrum which varies with symptom profile.

Keywords: Huntington disease, cerebral cortex, pathology, clinical, neuroanatomy

DOI: 10.3233/JHD-140092

Journal: Journal of Huntington's Disease, vol. 3, no. 1, pp. 45-64, 2014