Clinico-genetic findings in 509 frontotemporal dementia patients

Abstract

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families.

Primary progressive aphasia and motor neuron disease: A review

“…Among FTDs, the behavioural variant (bvFTD) is the most prevalent phenotype associated with MNDs ( Saxon et al, 2017a , b ; Wagner et al, 2021 ): the co-occurrence of MND or UMN/LMN dysfunction and bvFTD has been indeed thoroughly explored ( Ahmed et al, 2021 ). By contrast, little is still known about the pathology, genetics and clinical features of co-occurring primary progressive aphasia (PPA) and MND ( Ulugut et al, 2021 ).…”

ATP-binding cassette transporter expression is widely dysregulated in frontotemporal dementia with TDP-43 inclusions

“…The elevated levels of ABCA2 and ABCA7 in FTLD-TDP reported here could be critical to compensatory mechanisms. Interestingly, rare variants of the ABCA7 gene have been identified in two sporadic cases of FTD ( Ciani et al, 2019 ) and a homozygous loss-of-function ABCA7 variant was also identified, suggesting ABCA7 as a candidate gene for monogenic FTD ( Wagner et al, 2021 ). A partial deletion in the ABCA7 gene and a variant in the GRN gene has been found in a patient with semantic variant of primary progressive aphasia ( Antonell et al, 2020 ), one of the clinical phenotypes associated with FTLD-TDP.…”

Multiclass prediction of different dementia syndromes based on multi-centric volumetric MRI imaging

“…Genetic analysis results had been not available for single subjects in our study. However, a recent study ( Wagner et al, 2021 ) involving partly overlapping 509 patients with bvFTD and PPA from the FTLD consortium study revealed by exome sequencing as well as C9orf72 repeat analysis that 18.1 % did show pathogenic variants, without any impact of distribution of APOE alleles. Note that necessary fulfillment of operationalized clinical criteria as a precondition for inclusion in our study prevented from circular approaches regarding imaging.…”