Association of CAG Repeats With Long-term Progression in Huntington Disease
Douglas Langbehn
(1)
,
Julie Stout
(2)
,
Sarah Gregory
(3)
,
James Mills
(4)
,
Alexandra Durr
(5)
,
Blair Leavitt
(6)
,
Raymund Roos
(7)
,
Jeffrey Long
(8)
,
Gail Owen
,
Hans Johnson
(1)
,
Beth Borowsky
,
David Craufurd
(9)
,
Ralf Reilmann
(10, 11, 12)
,
G. Bernhard Landwehrmeyer
(13)
,
Rachael Scahill
(14)
,
Sarah Tabrizi
(14)
,
Tanka Acharya
,
Sophie Andrews
,
Natalie Arran
,
Eric Axelson
,
Eric Bardinet
(5)
,
Natalie Bechtel
,
Claire Berna
,
Stefan Bohlen
,
Jenny Callaghan
,
Amy Cassidy
,
Allison Coleman
,
Helen Crawford
,
Rachelle Dar Santos
,
Joji Decolongon
,
Eve Dumas
,
Mannie Fan
,
Chris Frost
,
Rhia Ghosh
,
Claire Gibbard
,
Davina Hensman-Moss
,
Nicola Hobbs
,
Celine Jauffret
(5)
,
Eileanoir Johnson
,
Rebecca Jones
,
Caroline Jurgens
,
Damian Justo
(5)
,
Ruth Keogh
,
Tamara Koren
,
Izelle Labuschagne
,
Nayana Lahiri
,
Stephane Lehericy
(5)
,
Ian Malone
,
Cecilia Marelli
(5)
,
Peter Mccolgan
,
Kevin Nigaud
(5)
,
Alison O’regan
,
Marina Papoutsi
,
Tracey Pepple
,
Terri Petkau
,
Sarah Queller
,
Joy Read
,
Miranda Say
,
Anne Schoonderbeek
,
Cheryl Stopford
,
Aaron Sturrock
,
Ellen ’t Hart
,
Romain Valabrègue
(5)
,
Simon van Den Bogaard
,
Jeroen van Der Grond
,
Chiachi Wang
,
Nathalia Weber
,
Daisy Whitehead
,
Marie-Noelle Witjes-Ane
1
University of Iowa [Iowa City]
2 Monash University [Melbourne]
3 UCL - University College of London [London]
4 Emory University [Atlanta, GA]
5 ICM - Institut du Cerveau = Paris Brain Institute
6 UBC - University of British Columbia
7 LUMC - Leiden University Medical Center
8 Department of Chemistry [Berkeley]
9 University of Manchester [Manchester]
10 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
11 Hertie Institute for Clinical Brain Research [Tubingen]
12 Eberhard Karls Universität Tübingen = University of Tübingen
13 Universitätsklinikum Ulm - University Hospital of Ulm
14 Institute of Neurology [London]
2 Monash University [Melbourne]
3 UCL - University College of London [London]
4 Emory University [Atlanta, GA]
5 ICM - Institut du Cerveau = Paris Brain Institute
6 UBC - University of British Columbia
7 LUMC - Leiden University Medical Center
8 Department of Chemistry [Berkeley]
9 University of Manchester [Manchester]
10 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
11 Hertie Institute for Clinical Brain Research [Tubingen]
12 Eberhard Karls Universität Tübingen = University of Tübingen
13 Universitätsklinikum Ulm - University Hospital of Ulm
14 Institute of Neurology [London]
Gail Owen
- Fonction : Auteur
Beth Borowsky
- Fonction : Auteur
Tanka Acharya
- Fonction : Auteur
Sophie Andrews
- Fonction : Auteur
Natalie Arran
- Fonction : Auteur
Eric Axelson
- Fonction : Auteur
Natalie Bechtel
- Fonction : Auteur
Claire Berna
- Fonction : Auteur
Stefan Bohlen
- Fonction : Auteur
Jenny Callaghan
- Fonction : Auteur
Amy Cassidy
- Fonction : Auteur
Allison Coleman
- Fonction : Auteur
Helen Crawford
- Fonction : Auteur
Rachelle Dar Santos
- Fonction : Auteur
Joji Decolongon
- Fonction : Auteur
Eve Dumas
- Fonction : Auteur
Mannie Fan
- Fonction : Auteur
Chris Frost
- Fonction : Auteur
Rhia Ghosh
- Fonction : Auteur
Claire Gibbard
- Fonction : Auteur
Davina Hensman-Moss
- Fonction : Auteur
Nicola Hobbs
- Fonction : Auteur
Eileanoir Johnson
- Fonction : Auteur
Rebecca Jones
- Fonction : Auteur
Caroline Jurgens
- Fonction : Auteur
Ruth Keogh
- Fonction : Auteur
Tamara Koren
- Fonction : Auteur
Izelle Labuschagne
- Fonction : Auteur
Nayana Lahiri
- Fonction : Auteur
Ian Malone
- Fonction : Auteur
Peter Mccolgan
- Fonction : Auteur
Alison O’regan
- Fonction : Auteur
Marina Papoutsi
- Fonction : Auteur
Tracey Pepple
- Fonction : Auteur
Terri Petkau
- Fonction : Auteur
Sarah Queller
- Fonction : Auteur
Joy Read
- Fonction : Auteur
Miranda Say
- Fonction : Auteur
Anne Schoonderbeek
- Fonction : Auteur
Cheryl Stopford
- Fonction : Auteur
Aaron Sturrock
- Fonction : Auteur
Ellen ’t Hart
- Fonction : Auteur
Simon van Den Bogaard
- Fonction : Auteur
Jeroen van Der Grond
- Fonction : Auteur
Chiachi Wang
- Fonction : Auteur
Nathalia Weber
- Fonction : Auteur
Daisy Whitehead
- Fonction : Auteur
Marie-Noelle Witjes-Ane
- Fonction : Auteur
Résumé
Importance: In Huntington disease (HD), mutation severity is defined by the length of the CAG trinucleotide sequence, a well-known predictor of clinical onset age. The association with disease trajectory is less well characterized. Quantifiable summary measures of trajectory applicable over decades of early disease progression are lacking. An accurate model of the age-CAG association with early progression is critical to clinical trial design, informing both sample size and intervention timing. Objective: To succinctly capture the decades-long early progression of HD and its dependence on CAG repeat length. Design, setting, and participants: Prospective study at 4 academic HD treatment and research centers. Participants were the combined sample from the TRACK-HD and Track-On HD studies consisting of 290 gene carriers (presymptomatic to stage II), recruited from research registries at participating centers, and 153 nonbiologically related controls, generally spouses or friends. Recruitment was targeted to match a balanced, prespecified spectrum of age, CAG repeat length, and diagnostic status. In the TRACK-HD and Track-On HD studies, 13 and 5 potential participants, respectively, failed study screening. Follow-up ranged from 0 to 6 years. The study dates were January 2008 to November 2014. These analyses were performed between December 2015 and January 2019. Main outcomes and measures: The outcome measures were principal component summary scores of motor-cognitive function and of brain volumes. The main outcome was the association of these scores with age and CAG repeat length. Results: We analyzed 2065 visits from 443 participants (247 female [55.8%]; mean [SD] age, 44.4 [10.3] years). Motor-cognitive measures were highly correlated and had similar CAG repeat length-dependent associations with age. A composite summary score accounted for 67.6% of their combined variance. This score was well approximated by a score combining 3 items (total motor score, Symbol Digit Modalities Test, and Stroop word reading) from the Unified Huntington's Disease Rating Scale. For either score, initial progression age and then acceleration rate were highly CAG repeat length dependent. The acceleration continues through at least stage II disease. In contrast, 3 distinct patterns emerged among brain measures (basal ganglia, gray matter, and a combination of whole-brain, ventricular, and white matter volumes). The basal ganglia pattern showed considerable change in even the youngest participants but demonstrated minimal acceleration of loss with aging. Each clinical and brain summary score was strongly associated with the onset and rate of decline in total functional capacity. Conclusions and relevance: Results of this study suggest that succinct summary measures of function and brain loss characterize HD progression across a wide disease span. CAG repeat length strongly predicts their decline rate. This work aids our understanding of the age and CAG repeat length-dependent association between changes in the brain and clinical manifestations of HD.