Finger Elizabeth, Malik Rubina, Bocchetta Martina, Coleman Kristy, Graff Caroline, Borroni Barbara, Masellis Mario, Laforce Robert, Greaves Caroline V, Russell Lucy L, Convery Rhian S, Bouzigues Arabella, Cash David M, Otto Markus, Synofzik Matthis, Rowe James B, Galimberti Daniela, Tiraboschi Pietro, Bartha Robert, Shoesmith Christen, Tartaglia Maria Carmela, van Swieten John C, Seelaar Harro, Jiskoot Lize C, Sorbi Sandro, Butler Chris R, Gerhard Alexander, Sanchez-Valle Raquel, de Mendonça Alexandre, Moreno Fermin, Vandenberghe Rik, Le Ber Isabelle, Levin Johannes, Pasquier Florence, Santana Isabel, Rohrer Jonathan D, Ducharme Simon
Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada.
Schulich School of Medicine & Dentistry, Graduate Program in Neuroscience, University of Western Ontario, London, Ontario, Canada.
Brain. 2023 May 2;146(5):2120-2131. doi: 10.1093/brain/awac446.
While frontotemporal dementia has been considered a neurodegenerative disease that starts in mid-life or later, it is now clearly established that cortical and subcortical volume loss is observed more than a decade prior to symptom onset and progresses with ageing. To test the hypothesis that genetic mutations causing frontotemporal dementia have neurodevelopmental consequences, we examined the youngest adults in the GENFI cohort of pre-symptomatic frontotemporal dementia mutation carriers who are between 19 and 30 years of age. Structural brain differences and improved performance on some cognitive tests were found for MAPT and GRN mutation carriers relative to familial non-carriers, while smaller volumes were observed in C9orf72 repeat expansion carriers at a mean age of 26 years. The detection of such early differences supports potential advantageous neurodevelopmental consequences of some frontotemporal dementia-causing genetic mutations. These results have implications for the design of therapeutic interventions for frontotemporal dementia. Future studies at younger ages are needed to identify specific early pathophysiologic or compensatory processes that occur during the neurodevelopmental period.
虽然额颞叶痴呆一直被认为是一种始于中年或更晚的神经退行性疾病，但现在已经明确，在症状出现前十多年就可观察到皮质和皮质下体积减少，且会随着年龄增长而进展。为了验证导致额颞叶痴呆的基因突变具有神经发育后果这一假设，我们研究了GENFI队列中最年轻的成年人，这些有症状前额颞叶痴呆基因突变携带者年龄在19至30岁之间。相对于家族性非携带者，我们发现MAPT和GRN基因突变携带者存在脑结构差异，并且在一些认知测试中表现有所改善，而在平均年龄为26岁的C9orf72重复扩增携带者中观察到脑容量较小。检测到这些早期差异支持了某些导致额颞叶痴呆的基因突变可能具有有利的神经发育后果。这些结果对额颞叶痴呆治疗干预措施的设计具有启示意义。需要开展更年轻年龄段的未来研究，以确定在神经发育阶段发生的特定早期病理生理或代偿过程。
