Langbehn Douglas R, Stout Julie C, Gregory Sarah, Mills James A, Durr Alexandra, Leavitt Blair R, Roos Raymund A C, Long Jeffrey D, Owen Gail, Johnson Hans J, Borowsky Beth, Craufurd David, Reilmann Ralf, Landwehrmeyer G Bernhard, Scahill Rachael I, Tabrizi Sarah J
Department of Psychiatry, University of Iowa, Iowa City.
School of Psychology and Psychiatry, Monash University, Melbourne, Victoria, Australia.
JAMA Neurol. 2019 Nov 1;76(11):1375-1385. doi: 10.1001/jamaneurol.2019.2368.
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.
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.
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.
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.
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.
在亨廷顿舞蹈症（HD）中，突变严重程度由CAG三核苷酸序列的长度决定，这是临床发病年龄的一个众所周知的预测指标。与疾病轨迹的关联特征尚不明确。缺乏适用于疾病早期数十年进展情况的可量化轨迹汇总指标。准确的年龄-CAG与早期进展关联模型对于临床试验设计至关重要，可为样本量和干预时机提供依据。
简洁地描述HD长达数十年的早期进展及其对CAG重复长度的依赖性。
设计、地点和参与者：在4个学术性HD治疗和研究中心进行的前瞻性研究。参与者是来自TRACK-HD和Track-On HD研究的合并样本，包括290名基因携带者（症状前至II期），他们从参与中心的研究登记处招募，以及153名无生物学关系的对照者，通常是配偶或朋友。招募目标是匹配年龄、CAG重复长度和诊断状态的平衡、预先设定的范围。在TRACK-HD和Track-On HD研究中，分别有13名和5名潜在参与者未通过研究筛查。随访时间为0至6年。研究日期为2008年1月至2014年11月。这些分析在2015年12月至2019年1月之间进行。
结局指标是运动认知功能和脑容量的主成分汇总分数。主要结局是这些分数与年龄和CAG重复长度的关联。
我们分析了443名参与者（247名女性[55.8%]；平均[标准差]年龄为44.4[10.3]岁）的2065次就诊情况。运动认知测量指标高度相关，并且与年龄具有相似的CAG重复长度依赖性关联。一个综合汇总分数占其合并方差的67.6%。这个分数可以通过结合统一亨廷顿舞蹈症评定量表中的3个项目（总运动分数、符号数字模态测验和斯特鲁普单词阅读）的分数很好地近似。对于这两个分数中的任何一个，初始进展年龄以及随后的加速率都高度依赖于CAG重复长度。这种加速至少持续到II期疾病。相比之下，脑测量指标（基底神经节体积、灰质体积以及全脑、脑室和白质体积的组合）出现了3种不同模式。基底神经节模式显示即使是最年轻的参与者也有相当大的变化，但随着年龄增长损失的加速最小。每个临床和脑汇总分数都与总功能能力的下降起始和速率密切相关。
本研究结果表明，功能和脑损失的简洁汇总指标可描述HD在广泛疾病阶段的进展情况。CAG重复长度强烈预测其下降速率。这项工作有助于我们理解HD大脑变化与临床表现之间年龄和CAG重复长度依赖性关联。
