Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease

Chin-Fu Liu; Laurent Younes; Xiao J Tong; Jared T Hinkle; Maggie Wang; Sanika Phatak; Xin Xu; Xuan Bu; Vivian Looi; Jee Bang; Sarah J Tabrizi; Rachael I Scahill; Jane S Paulsen; Nellie Georgiou-Karistianis; Andreia V Faria; Michael I Miller; J Tilak Ratnanather; Christopher A Ross

doi:10.1093/braincomms/fcad214

Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease

Brain Commun. 2023 Aug 18;5(5):fcad214. doi: 10.1093/braincomms/fcad214. eCollection 2023.

Authors

Chin-Fu Liu^{1

2

3}, Laurent Younes^{1

2

4}, Xiao J Tong⁵, Jared T Hinkle^{6

7}, Maggie Wang^{1

3}, Sanika Phatak^{1

3}, Xin Xu⁸, Xuan Bu^{1

2

9}, Vivian Looi^{1

2

3}, Jee Bang¹⁰, Sarah J Tabrizi¹¹, Rachael I Scahill¹¹, Jane S Paulsen¹², Nellie Georgiou-Karistianis¹³, Andreia V Faria⁸, Michael I Miller^{1

2

3}, J Tilak Ratnanather^{1

2

3}, Christopher A Ross^{5

6

10

14}

Affiliations

¹ Center for Imaging Science, Johns Hopkins University, Baltimore, MD 21218, USA.
² Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.
³ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
⁴ Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD 21218, USA.
⁵ Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore MD 21287, USA.
⁶ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA.
⁷ Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁸ Division of Magnetic Resonance, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁹ Huaxi MR Research Center, Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
¹⁰ Division of Neurobiology, Department of Psychiatry, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹¹ HD Research Centre, University College London Queen Square Institute of Neurology, UCL, London, UK.
¹² Department of Neurology, University of Wisconsin, Madison, WI 53705, USA.
¹³ School of Psychological Sciences and The Turner Institute for Brain and Mental Health, Monash University, Melbourne, Victoria 3800, Australia.
¹⁴ Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Abstract

Huntington's disease is caused by a CAG repeat expansion in the Huntingtin gene (HTT), coding for polyglutamine in the Huntingtin protein, with longer CAG repeats causing earlier age of onset. The variable 'Age' × ('CAG'-L), where 'Age' is the current age of the individual, 'CAG' is the repeat length and L is a constant (reflecting an approximation of the threshold), termed the 'CAG Age Product' (CAP) enables the consideration of many individuals with different CAG repeat expansions at the same time for analysis of any variable and graphing using the CAG Age Product score as the X axis. Structural MRI studies have showed that progressive striatal atrophy begins many years prior to the onset of diagnosable motor Huntington's disease, confirmed by longitudinal multicentre studies on three continents, including PREDICT-HD, TRACK-HD and IMAGE-HD. However, previous studies have not clarified the relationship between striatal atrophy, atrophy of other basal ganglia structures, and atrophy of other brain regions. The present study has analysed all three longitudinal datasets together using a single image segmentation algorithm and combining data from a large number of subjects across a range of CAG Age Product score. In addition, we have used a strategy of normalizing regional atrophy to atrophy of the whole brain, in order to determine which regions may undergo preferential degeneration. This made possible the detailed characterization of regional brain atrophy in relation to CAG Age Product score. There is dramatic selective atrophy of regions involved in the basal ganglia circuit-caudate, putamen, nucleus accumbens, globus pallidus and substantia nigra. Most other regions of the brain appear to have slower but steady degeneration. These results support (but certainly do not prove) the hypothesis of circuit-based spread of pathology in Huntington's disease, possibly due to spread of mutant Htt protein, though other connection-based mechanisms are possible. Therapeutic targets related to prion-like spread of pathology or other mechanisms may be suggested. In addition, they have implications for current neurosurgical therapeutic approaches, since delivery of therapeutic agents solely to the caudate and putamen may miss other structures affected early, such as nucleus accumbens and output nuclei of the striatum, the substantia nigra and the globus pallidus.

Keywords: IMAGE-HD; PREDICT-HD; TRACK-HD; caudate; putamen.

Abstract

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