Genotyping and Plasma/Cerebrospinal Fluid Profiling of a Cohort of Frontotemporal Dementia-Amyotrophic Lateral Sclerosis Patients.

Mara Bourbouli,Chrisoula Kartanou,Christos Kroupis,Mihail Rentzos,Lambros Mathioudakis,Georgios Koutsis,Georgia Karadima,George P Paraskevas,Spiros Zafeiris,Vasilios K Kimiskidis,Georgios Papadimas,Athanasios Tychalas,Vasilios Constantinides,Minas Tzagournissakis,Anastasia Bougea,Vasiliki Zouvelou,Elisabeth Kapaki,Ioannis Zaganas

doi:10.3390/brainsci11091239

Abstract

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.

Highlights

It has been widely recognized that Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) occupy the two extremes of the same pathophysiological spectrum, sharing several histological features and genetic causes [1]
Analyses were performed separately for FTD patients, ALS patients ± FTD and all patients combined. These analyses revealed that in patients with ALS, the cerebrospinal fluid (CSF) levels of τP-181 were lower in C9orf72 repeat expansion carriers compared to noncarriers, whereas levels of TDP-43, Aβ42 and τT and the τP-181/τT ratio did not differ between the two groups (Figure 2)
We found that levels of τp-181 were lower in C9orf72 repeat expansion and MAPT c.855C>T (p.Asp285Asp) carriers compared to non-carriers

Summary

Introduction

It has been widely recognized that Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) occupy the two extremes of the same pathophysiological spectrum, sharing several histological features and genetic causes [1]. FTD is a highly inherited disorder, with 30–50% of patients reporting family history of a similar phenotype [2]. For this familial form of FTD, several genes, such as the C9orf, MAPT, GRN, TARDBP and VCP genes, have been found to harbor pathogenic variants [3,4]. Many patients display both the FTD and the ALS phenotype, often associated with a specific gene variant [6]. A pathogenic FTD/ALS gene variant can cause differing phenotypes (FTD, ALS or both FTD and ALS) in different members of the same family [1]

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Conclusion