Importance During a time with the potential for novel treatment strategies, early detection of disease manifestations at an individual level in presymptomatic carriers of a hexanucleotide repeat expansion in the C9orf72 gene (preSxC9) is becoming increasingly relevant.

Objectives To evaluate changes in glucose metabolism before symptom onset of amyotrophic lateral sclerosis or frontotemporal dementia in preSxC9 using simultaneous fluorine 18–labeled fluorodeoxyglucose ([¹⁸F]FDG positron emission tomographic (PET) and magnetic resonance imaging as well as the mutation’s association with clinical and fluid biomarkers.

Design, Setting, and Participants A prospective, case-control study enrolled 46 participants from November 30, 2015, until December 11, 2018. The study was conducted at the neuromuscular reference center of the University Hospitals Leuven, Leuven, Belgium.

Main Outcomes and Measures Neuroimaging data were spatially normalized and analyzed at the voxel level at a height threshold of P < .001, cluster-level familywise error–corrected threshold of P < .05, and statistical significance was set at P < .05 for the volume-of-interest level analysis, using Benjamini-Hochberg correction for multiple correction. W-score maps were computed using the individuals serving as controls as a reference to quantify the degree of [¹⁸F]FDG PET abnormality. The threshold for abnormality on the W-score maps was designated as an absolute W-score greater than or equal to 1.96. Neurofilament levels and performance on cognitive and neurologic examinations were determined. All hypothesis tests were 1-sided.

Results Of the 42 included participants, there were 17 with the preSxC9 mutation (12 women [71%]; mean [SD] age, 51 [9] years) and 25 healthy controls (12 women [48%]; mean [SD] age, 47 [10] years). Compared with control participants, significant clusters of relative hypometabolism were found in frontotemporal regions, basal ganglia, and thalami of preSxC9 participants and relative hypermetabolism in the peri-Rolandic region, superior frontal gyrus, and precuneus cortex. W-score frequency maps revealed reduced glucose metabolism with local maxima in the insular cortices, central opercular cortex, and thalami in up to 82% of preSxC9 participants and increased glucose metabolism in the precentral gyrus and precuneus cortex in up to 71% of preSxC9 participants. Other findings in the preSxC9 group were upper motor neuron involvement in 10 participants (59%), cognitive abnormalities in 5 participants (29%), and elevated neurofilament levels in 3 of 16 individuals (19%) who underwent lumbar puncture.

Conclusions and Relevance The results suggest that [¹⁸F]FDG PET can identify glucose metabolic changes in preSxC9 at an individual level, preceding significantly elevated neurofilament levels and onset of symptoms.

重要性 在具有新的治疗策略潜力的时期内，在C9orf72基因（preSxC9）的六核苷酸重复症状扩展前的症状前携带者中，在个体水平上早期检测疾病表现变得越来越重要。

目的 通过同时使用氟18标记的氟脱氧葡萄糖（[ ¹⁸ F] FDG正电子发射断层扫描（PET）和磁共振成像以及该突变与临床的关联性）来评估preSxC9中肌萎缩性侧索硬化症或额颞叶痴呆症状发作之前的葡萄糖代谢变化和流体生物标志物。

设计，背景和参与者 从2015年11月30日至2018年12月11日，前瞻性病例对照研究招募了46位参与者。该研究在比利时鲁汶大学医院神经肌肉参考中心进行。

主要结果和措施对 神经影像数据进行空间归一化，并在体素水平上以P  <.001的高度阈值，在簇级别家庭校正的阈值P  <.05的条件下对神经影像数据进行分析，并将统计学显着性设置为P  <.05使用Benjamini-Hochberg校正进行多次校正的兴趣量级别分析。W得分图的计算以个人为对照，以量化[ ¹⁸F] FDG PET异常。W分数图上的异常阈值被指定为大于或等于1.96的绝对W分数。确定了神经丝水平以及认知和神经系统检查的表现。所有假设检验均为单面。

结果 在42名参与者中，有17名患有preSxC9突变（12名妇女[71％]；平均[SD]年龄为51名[9]岁）和25名健康对照组（12名妇女[48％]；平均[SD]年龄） ，47 [10]年）。与对照参与者相比，在preSxC9参与者的额颞区，基底神经节和丘脑中发现了明显的相对低代谢簇，在Rolandic地区，上额额回和盲前皮层中发现了相对代谢亢进。W评分频率图显示，多达82％的preSxC9参与者的岛顶皮质，中央操作皮层和丘脑中的葡萄糖代谢降低，局部最大值最大；而多达71％的preSxC9参与者的中枢回和前穹neu皮质的葡萄糖代谢增加。preSxC9组的其他发现是10名参与者（59％）的上运动神经元受累，

结论与相关性 结果表明，[ ¹⁸ F] FDG PET可以在神经丝水平显着升高和症状发作之前，以个体水平识别preSxC9中的葡萄糖代谢变化。