RESEARCH ARTICLE Cortical Interneuron Loss and Symptom Heterogeneity in Huntington Disease Eric H. Kim, PhD, 1,2 Doris C. V. Thu, PhD, 2,3 Lynette J. Tippett, PhD, 2,4 Dorothy E. Oorschot, PhD, 5,6 Virginia M. Hogg, MA, 2,4 Richard Roxburgh, MD, PhD, 2,7 Beth J. Synek, MD, 2,8 Henry J. Waldvogel, PhD, 1,2 and Richard L. M. Faull, MD, PhD, DSc 1,2 Objective: The cellular basis of variable symptoms in Huntington disease (HD) is unclear. One important possibility is that degeneration of the interneurons in the cerebral cortex, which play a critical role in modulating cortical output to the basal ganglia, might play a significant role in the development of variable symptomatology in HD. This study aimed to examine whether symptom variability in HD is specifically associated with variable degeneration of cortical interneurons. Methods: We undertook a double-blind study using stereological cell counting methods to quantify the 3 major types of c-aminobutyric acidergic interneurons (calbindin-D28k, calretinin, parvalbumin) in 13 HD cases of variable motor/mood symptomatology and 15 matched control cases in the primary motor and anterior cingulate cortices. Results: In the primary motor cortex, there was a significant loss (57% reduction) of only calbindin interneurons (p 5 0.022) in HD cases dominated by motor symptoms, but no significant interneuron loss in cases with a dominant mood phenotype. In contrast, the anterior cingulate cortex showed a major significant loss in all 3 interneuron popu- lations, with 71% loss of calbindin (p 5 0.001), 60% loss of calretinin (p 5 0.001), and 80% loss of parvalbumin inter- neurons (p 5 0.005) in HD cases with major mood disorder, and no interneuron loss was observed in cases with major motor dysfunction. Interpretation: These findings suggest that region-specific degeneration of cortical interneurons is a key component in understanding the neural basis of symptom heterogeneity in HD. ANN NEUROL 2014;75:717–727 H untington disease (HD) is an autosomal dominant neurodegenerative disorder with highly variable clin- ical expression, exemplified by the wide range in age of onset and remarkable symptom variability even among affected members in the same family. 1,2 The disease is caused by an unstable expansion of CAG repeats in the HTT gene. 3 Although the correlation between CAG repeat size and onset age is significant, it is widely acknowledged that the repeat size is a poor indicator of symptom variability. Consequently, there is considerable interest in whether there are any underlying pathological differences in the HD brain that might account for symptom heterogeneity. The pathology is extensive in the HD brain with major degeneration in the striatum and cerebral cortex. 4 Within the striatum, medium spiny projection neurons are the most vulnerable neuronal type 5 and in the cere- bral cortex it is well established that there is a major loss of pyramidal projection neurons. 6–8 Recent evidence suggests that the variation in clini- cal symptoms is strongly associated with variable neuro- degeneration in the striatum 9 and in different functional regions of the cerebral cortex. 10 In the striatum, degener- ation of striatal neurons involved in limbic circuits is postulated to be a possible substrate for mood symptoms in HD. 9 In the cerebral cortex, recent neuroimaging View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24162 Received Nov 10, 2013, and in revised form Apr 22, 2014. Accepted for publication Apr 23, 2014. Address correspondence to Dr Faull, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: rlm.faull@auckland.ac.nz From the 1 Department of Anatomy with Radiology and 2 Centre for Brain Research, University of Auckland, Auckland, New Zealand; 3 Brain Mind Insti- tute, Lausanne Federal Polytechnic School, Lausanne, Switzerland; 4 Department of Psychology, University of Auckland, Auckland, New Zealand; 5 Depart- ment of Anatomy and 6 Brain Health Research Centre, University of Otago, Dunedin, New Zealand; and Departments of 7 Neurology and 8 Forensic Pathology, Auckland City Hospital, Auckland, New Zealand. V C 2014 American Neurological Association 717