Serum total TDP-43 levels are decreased in frontotemporal dementia patients with C9orf72 repeat expansion or concomitant motoneuron disease phenotype

Springer Science and Business Media LLC - Tập 14 - Trang 1-10 - 2022
Kasper Katisko1, Nadine Huber2, Tarja Kokkola1, Päivi Hartikainen3, Johanna Krüger4,5,6, Anna-Leena Heikkinen4,5,6,7, Veera Paananen4,5,6, Ville Leinonen8,9, Ville E. Korhonen10,8,9, Seppo Helisalmi11, Sanna-Kaisa Herukka1,3, Valentina Cantoni12, Yasmine Gadola12, Silvana Archetti13, Anne M. Remes14,15, Annakaisa Haapasalo2, Barbara Borroni12,13, Eino Solje10,3
1Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland
2A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
3Neuro center, Neurology, Kuopio University Hospital, Kuopio, Finland
4Research Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland
5MRC, Oulu University Hospital, Oulu, Finland
6Neurology, Neurocenter, Oulu University Hospital, Oulu, Finland
7Finnish Institute of Occupational Health, Work Ability and Working Careers, Helsinki, Finland
8Neuro Center, Neurosurgery, Kuopio University Hospital, Kuopio, Finland
9Institute of Clinical Medicine – Neurosurgery, University of Eastern Finland, Kuopio, Finland
10Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland
11Institute of Clinical Medicine/Internal Medicine, University of Eastern Finland, Kuopio, Finland
12Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
13ASST Spedali Civili, Brescia, Italy
14Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland
15Medical Research Center, Oulu University Hospital, Oulu, Finland

Tóm tắt

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. 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. 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. 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.

Tài liệu tham khảo

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