Serum total TDP-43 levels are decreased in frontotemporal dementia patients with <em>C9orf72</em> repeat expansion or concomitant motoneuron disease phenotype
Katisko, Kasper; Huber, Nadine; Kokkola, Tarja; Hartikainen, Päivi; Krüger, Johanna; Heikkinen, Anna-Leena; Paananen, Veera; Leinonen, Ville; Korhonen, Ville E.; Helisalmi, Seppo; Herukka, Sanna-Kaisa; Cantoni, Valentina; Gadola, Yasmine; Archetti, Silvana; Remes, Anne M.; Haapasalo, Annakaisa; Borroni, Barbara; Solje, Eino (2022-10-11)
Katisko, K., Huber, N., Kokkola, T. et al. Serum total TDP-43 levels are decreased in frontotemporal dementia patients with C9orf72 repeat expansion or concomitant motoneuron disease phenotype. Alz Res Therapy 14, 151 (2022). https://doi.org/10.1186/s13195-022-01091-8
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https://urn.fi/URN:NBN:fi-fe2023030129065
Tiivistelmä
Abstract
Background: Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders with various clinical and neuropathological subtypes. The two major pathological proteins accumulating in the brains of FTD patients, depending on their genetic background, are TDP-43 and tau. We aimed to evaluate whether total TDP-43 levels measured from the serum associate with the genotype or clinical phenotype of the FTD patients and whether serum TDP-43 provides prognostic or diagnostic value in the FTD spectrum disorders.
Methods: The study cohort included 254 participants with a clinical diagnosis of FTD (including all major genotypes and clinical phenotypes) and 105 cognitively healthy controls. Serum total TDP-43 levels measured with a single-molecule array (Simoa) were compared within the FTD group according to the genotype, clinical phenotype, and predicted neuropathological subtype of the patients. We also evaluated the associations between the TDP-43 levels and disease severity or survival in FTD.
Results: Total TDP-43 levels in the serum were significantly lower in the FTD group as compared to the healthy control group (275.3 pg/mL vs. 361.8 pg/mL, B = 0.181, 95%CI = 0.014–0.348, p = 0.034). The lowest TDP-43 levels were observed in the subgroup of FTD patients harboring predicted TDP-43 brain pathology (FTD-TDP, 241.4 pg/mL). The low levels in the FTD-TDP group were especially driven by C9orf72 repeat expansion carriers (169.2 pg/mL) and FTD patients with concomitant motoneuron disease (FTD-MND, 113.3 pg/mL), whereas GRN mutation carriers did not show decreased TDP-43 levels (328.6 pg/mL). Serum TDP-43 levels showed no correlation with disease severity nor progression in FTD.
Conclusions: Our results indicate that the total levels of TDP-43 in the serum are decreased especially in FTD patients with the C9orf72 repeat expansion or FTD-MND phenotype, both subtypes strongly associated with TDP-43 type B brain pathology. Serum-based measurement of TDP-43 could represent a useful tool in indicating C9orf72 repeat expansion and FTD-MND-related TDP-43 neuropathology for future diagnostics and intervention studies.
Kokoelmat
- Avoin saatavuus [31995]