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Genotyping and Plasma/Cerebrospinal Fluid Profiling of a Cohort of Frontotemporal Dementia–Amyotrophic Lateral Sclerosis Patients
Brain Sciences ( IF 3.3 ) Pub Date : 2021-09-19 , DOI: 10.3390/brainsci11091239
Mara Bourbouli 1, 2 , George P Paraskevas 2, 3 , Mihail Rentzos 2 , Lambros Mathioudakis 1 , Vasiliki Zouvelou 2 , Anastasia Bougea 2 , Athanasios Tychalas 4 , Vasilios K Kimiskidis 5 , Vasilios Constantinides 2 , Spiros Zafeiris 1 , Minas Tzagournissakis 1 , Georgios Papadimas 2 , Georgia Karadima 2 , Georgios Koutsis 2 , Christos Kroupis 6 , Chrisoula Kartanou 2 , Elisabeth Kapaki 2 , Ioannis Zaganas 1
Affiliation  

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of the same pathophysiological spectrum and have common genetic and cerebrospinal fluid (CSF) biomarkers. Our aim here was to identify causative gene variants in a cohort of Greek patients with FTD, ALS and FTD-ALS, to measure levels of CSF biomarkers and to investigate genotype-phenotype/CSF biomarker associations. In this cohort of 130 patients (56 FTD, 58 ALS and 16 FTD-ALS), we performed C9orf72 hexanucleotide repeat expansion analysis, whole exome sequencing and measurement of “classical” (Aβ42, total tau and phospho-tau) and novel (TDP-43) CSF biomarkers and plasma progranulin. Through these analyses, we identified 14 patients with C9orf72 repeat expansion and 11 patients with causative variants in other genes (three in TARDBP, three in GRN, three in VCP, one in FUS, one in SOD1). In ALS patients, we found that levels of phospho-tau were lower in C9orf72 repeat expansion and MAPT c.855C>T (p.Asp285Asp) carriers compared to non-carriers. Additionally, carriers of rare C9orf72 and APP variants had lower levels of total tau and Aβ42, respectively. Plasma progranulin levels were decreased in patients carrying GRN pathogenic variants. This study expands the genotypic and phenotypic spectrum of FTD/ALS and offers insights in possible genotypic/CSF biomarker associations.

中文翻译:

一组额颞叶痴呆-肌萎缩侧索硬化患者的基因分型和血浆/脑脊液分析

额颞叶痴呆 (FTD) 和肌萎缩侧索硬化 (ALS) 属于相同的病理生理学谱,具有共同的遗传和脑脊液 (CSF) 生物标志物。我们在这里的目的是确定一组希腊 FTD、ALS 和 FTD-ALS 患者的致病基因变异,以测量 CSF 生物标志物的水平并研究基因型-表型/CSF 生物标志物的关联。在这组 130 名患者(56 FTD、58 ALS 和 16 FTD-ALS)中,我们进行了C9orf72六核苷酸重复扩增分析、全外显子组测序以及“经典”(Aβ 42、总 tau 和磷酸化 tau)和新( TDP-43) CSF 生物标志物和血浆颗粒蛋白前体。通过这些分析,我们确定了 14 名C9orf72患者重复扩增和 11 名在其他基因中具有致病变异的患者(三名在TARDBP 中,三名在GRN 中,三名在VCP 中,一名在FUS 中,一名在SOD1 中)。在 ALS 患者中,我们发现与非携带者相比,C9orf72重复扩增和MAPT c.855C>T (p.Asp285Asp) 携带者的磷酸 tau 水平较低。此外,罕见的C9orf72APP变体的携带者分别具有较低水平的总 tau 和 Aβ 42。携带GRN 的患者血浆颗粒蛋白前体水平降低致病变异。这项研究扩展了 FTD/ALS 的基因型和表型谱,并提供了对可能的基因型/CSF 生物标志物关联的见解。
更新日期:2021-09-19
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