1 National Institute of Alcohol Abuse and Alcoholism, Rockville MD 20857, USA2 National Institute on Drug Abuse, Bethesda MD 20892, USA
1 National Institute of Alcohol Abuse and Alcoholism, Rockville MD 20857, USA.
Brain. 2014 Jun;137(Pt 6):1753-61. doi: 10.1093/brain/awu092. Epub 2014 Apr 17.
Ataxia-telangiectasia is a recessive genetic disorder (ATM is the mutated gene) of childhood with severe motor impairments and whereas homozygotes manifest the disorder, heterozygotes are asymptomatic. Structural brain imaging and post-mortem studies in individuals with ataxia-telangiectasia have reported cerebellar atrophy; but abnormalities of motor control characteristic of extrapyramidal dysfunction suggest impairment of broader motor networks. Here, we investigated possible dysfunction in other brain areas in individuals with ataxia-telangiectasia and tested for brain changes in asymptomatic relatives to assess if heterozygocity affects brain function. We used positron emission tomography and (18)F-fluorodeoxyglucose to measure brain glucose metabolism (quantified as µmol/100 g/min), which serves as a marker of brain function, in 10 adults with ataxia-telangiectasia, 19 non-affected adult relatives (12 siblings, seven parents) and 29 age-matched healthy controls. Statistical parametric mapping and region of interest analyses were used to compare individuals with ataxia-telangiectasia, asymptomatic relatives, and unrelated controls. We found that participants with ataxia-telangiectasia had lower metabolism in cerebellar hemispheres (14%, P < 0.001), anterior vermis (40%, P < 0.001) and fusiform gyrus (20%, P < 0.001) compared with controls or siblings, and lower metabolism in hippocampus (12%, P = 0.05) compared with controls, and showed significant intersubject variability (decreases in vermis ranged from 18% to 60%). Participants with ataxia-telangiectasia also had higher metabolism in globus pallidus (16%, P = 0.05), which correlated negatively with motor performance. Asymptomatic relatives had lower metabolism in anterior vermis (12%; P = 0.01) and hippocampus (19%; P = 0.002) than controls. Our results indicate that, in addition to the expected decrease in cerebellar metabolism, participants with ataxia-telangiectasia had widespread changes in metabolic rates including hyperactivity in globus pallidus indicative of basal ganglia involvement. Changes in basal ganglia metabolism offer potential insight into targeting strategies for therapeutic deep brain stimulation. Our finding of decreased metabolism in vermis and hippocampus of asymptomatic relatives suggests that heterozygocity influences the function of these brain regions.
共济失调毛细血管扩张症是一种儿童期隐性遗传疾病（ATM 是突变基因），伴有严重的运动障碍，纯合子表现出该疾病，而杂合子则无症状。对共济失调毛细血管扩张症患者的结构性脑成像和尸检研究报告称小脑萎缩；但是，与锥体外系功能障碍相关的运动控制异常表明更广泛的运动网络受损。在这里，我们研究了共济失调毛细血管扩张症患者其他大脑区域的可能功能障碍，并测试了无症状亲属的大脑变化，以评估杂合性是否影响大脑功能。我们使用正电子发射断层扫描和（18）F-氟脱氧葡萄糖来测量大脑葡萄糖代谢（以每 100 克/分钟的微摩尔表示），这是大脑功能的标志物，在 10 名共济失调毛细血管扩张症患者、19 名非受影响的成年亲属（12 名兄弟姐妹，7 名父母）和 29 名年龄匹配的健康对照组中进行了测量。统计参数映射和感兴趣区域分析用于比较共济失调毛细血管扩张症患者、无症状亲属和无关对照组。我们发现，共济失调毛细血管扩张症患者的小脑半球（14%，P < 0.001）、前蚓部（40%，P < 0.001）和梭状回（20%，P < 0.001）的代谢率低于对照组或兄弟姐妹，海马体（12%，P = 0.05）的代谢率也低于对照组，并且表现出显著的受试者间变异性（蚓部的下降范围为 18%至 60%）。共济失调毛细血管扩张症患者的苍白球代谢率也升高（16%，P = 0.05），这与运动表现呈负相关。无症状亲属的前蚓部（12%，P = 0.01）和海马体（19%，P = 0.002）的代谢率低于对照组。我们的结果表明，除了预期的小脑代谢降低外，共济失调毛细血管扩张症患者还存在广泛的代谢率变化，包括苍白球的过度活跃，表明基底节参与其中。基底节代谢的变化为深部脑刺激的靶向治疗策略提供了潜在的见解。我们发现无症状亲属的蚓部和海马体代谢降低表明，杂合性影响这些脑区的功能。
