Elsevier

Neurobiology of Disease

Volume 40, Issue 3, December 2010, Pages 544-554
Neurobiology of Disease

Cerebral cortex structure in prodromal Huntington disease

https://doi.org/10.1016/j.nbd.2010.07.014Get rights and content

Abstract

Neuroimaging studies of subjects who are gene-expanded for Huntington Disease, but not yet diagnosed (termed prodromal HD), report that the cortex is “spared,” despite the decrement in striatal and cerebral white-matter volume. Measurement of whole-cortex volume can mask more subtle, but potentially clinically relevant regional changes in volume, thinning, or surface area. The current study addressed this limitation by evaluating cortical morphology of 523 prodromal HD subjects. Participants included 693 individuals enrolled in the PREDICT-HD protocol. Of these participants, 523 carried the HD gene mutation (prodromal HD group); the remaining 170 were non gene-expanded and served as the comparison group. Based on age and CAG repeat length, gene-expanded subjects were categorized as “Far from onset,” “Midway to onset,” “Near onset,” and “already diagnosed.” MRI scans were processed using FreeSurfer. Cortical volume, thickness, and surface area were not significantly different between the Far from onset group and controls. However, beginning in the Midway to onset group, the cortex showed significant volume decrement, affecting most the posterior and superior cerebral regions. This pattern progressed when evaluating the groups further into the disease process. Areas that remained mostly unaffected included ventral and medial regions of the frontal and temporal cortex. Morphologic changes were mostly in thinning as surface area did not substantially change in most regions. Early in the course of HD, the cortex shows changes that are manifest as cortical thinning and are most robust in the posterior and superior regions of the cerebrum.

Research Highlights

►Changes of cerebral cortex are detected in subjects up to a decade prior to onset. ►Structural changes are mostly in thinning rather than in reduction of surface area. ►Affected areas include superior and posterior cerebrum while ventral frontal is spared.

Introduction

Huntington disease (HD) is a neurodegenerative disorder that manifests in a triad of symptoms including cognitive, motor, and behavioral abnormalities. The discovery of the gene in 1993 (Huntington's Disease Collaborative Research Group, 1993) provided an opportunity to study individuals who carry the mutant gene, but have not yet manifested significant disease signs and are therefore referred to as prodromal HD.

HD is part of a family of poly-glutamine diseases in which the mutant gene (huntingtin in the case of HD) contains a triplet CAG repeat coding for an expanding polyglutamine repeat and resulting in an abnormal or toxic protein. Another property of polyglutamine diseases is that despite the fact that the mutant proteins are expressed ubiquitously, the disease manifestation is specific to brain tissue and also to specific regions of the brain. For HD, the area of the brain most affected is that of the striatum. Therefore, most of the studies of HD, using either neuropathologic methods or neuroimaging methods have focused on measuring the effects of the disease on this brain region. However, more recently, there have been a number of studies evaluating “extra-striatal” brain structure such as the morphology of the cerebral white matter and cortex in subjects with early HD or prodromal HD. As a whole, these studies support an interesting pattern in which the cerebral white matter volume is substantially lower than normal, while in contrast, the cerebral cortex is relatively “spared” (Aylward et al., 1998, Beglinger et al., 2005, Ciarmiello et al., 2006, Douaud et al., 2006, Fennema-Notestine et al., 2004, Jernigan et al., 1991, Muhlau et al., 2007, Rosas et al., 2003).

PREDICT-HD is a long-term observational study of a large population of prodromal HD subjects (Paulsen et al., 2006). In a recent cross-sectional analysis of 657 participants, the volume of the cerebral cortex was indeed found to be significantly reduced in volume in the prodromal HD subjects. However, the effect size for the comparison of volume decrement in prodromal HD subjects to controls in the cerebral cortex (0.699) was substantially smaller than the effect size of the comparison of volumes across groups for the cerebral white matter (1.445) or striatum (2.456) (Paulsen et al., 2010). One important caveat for this and other analyses that use the global measure of cerebral cortex is that this measure is a gross one and may very well miss regional variation of structure within the cortex, as the cortex is divided up into many small structurally and functionally distinct regions.

Few studies have evaluated regional morphology of the cerebral cortex in HD. Rosas, in a study of HD subjects post-diagnosis, showed that cortical thinning was indeed gradual in onset and regionally specific (Rosas et al., 2002). In more recent studies, cortical thickness maps of both small (Rosas et al., 2005) and large (Tabrizi et al., 2009) samples of prodromal HD subjects show an interesting pattern in which cortical thinning occurs in an unexpected pattern that is heavily superior and posterior, with what appears to be frontal lobe sparing. This is surprising given the fact that, although the striatum receives input from all over the cortex, the output of the striatum (via basal ganglia and thalamic connections) is predominantly to the frontal cortex.

In regard to cerebral cortex morphology, studies have typically focused on measures of volume or cortical thickness. However, volume is a function of both thickness and surface area. Moreover, recent studies have shown the importance of distinguishing the measures of cortical thickness and cortical surface area. For instance, two studies have shown that the genetic influences of cortical thickness appear to be independent of those driving cortical surface area (Panizzon et al., 2009, Winkler et al., 2009). In addition, one of these studies (Winkler et al., 2009) showed that in a non-diseased population, measures of cortical volume were more highly correlated to surface area than to cortical thickness. These studies highlight the importance of looking at both thickness and surface area when evaluating cortical morphology.

The current study is designed to extensively evaluate the morphology of the cerebral cortex in a large sample of prodromal HD subjects. This is the first study to comprehensively examine cortical morphology in prodromal HD subjects using volume, surface area, and thickness measures. Unlike previous studies that have reported only cortical thickness maps in prodromal HD, this study also measures and reports volumes of cortical regions.

Section snippets

Participants

Participants were recruited from the PREDICT-HD study, an ongoing longitudinal study conducted at 32 sites in the United States, Canada, Australia, Germany, Spain, and the United Kingdom (Paulsen et al., 2006). The study was approved by the Institutional Review Board at each participating institution. Study participants signed informed consents to participate and allow their de-identified research data to be analyzed by collaborative institutions. All participants underwent detailed motor,

Regional cortical volume analysis of prognostic groups compared to controls

Table 2 displays results of the ANOVAs comparing mean cortical volumes of 33 regions among all prodromal HD subjects combined and the control group. Volumes in this table are ordered by group effect sizes. After correction for multiple comparisons, 20 of the 33 regions showed significant group differences. In all of these 20 regions, volumes were reduced in the HD group compared to controls, with the exception of the rostral anterior cingulate region wherein volume was increased. Most of the

Discussion

This study is the first comprehensive analysis of cortical morphology in a large sample of prodromal HD subjects compared to healthy controls. Beginning in the midway to onset group (9–15 years from diagnosis), the cortex shows significant decrement in volume in a pattern that is initially specific to superior and posterior regions of the cortex, but by onset of diagnosis represents a pattern that is quite extensive and includes most of the entire cerebrum. Nevertheless, the superior and

Acknowledgments

This research is supported by the National Institutes for Health, National Institute of Neurological Disorders and Stroke (NS40068) and CHDI Foundation, Inc. We thank the PREDICT-HD sites, the study participants, and the National Research Roster for Huntington Disease Patients and Families.

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