Browsing by Author "Van Swieten, John C."
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- Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementiaPublication . Meeter, Lieke H. H.; Steketee, Rebecca M. E.; Salkovic, Dina; Vos, Maartje E.; Grossman, Murray; McMillan, Corey T.; Irwin, David J.; Boxer, Adam L.; Rojas, Julio C.; Olney, Nicholas T.; Karydas, Anna; Miller, Bruce L.; Pijnenburg, Yolande A. L.; Barkhof, Frederik; Sánchez-Valle, Raquel; Lladó, Albert; Borrego-Ecija, Sergi; Diehl-Schmid, Janine; Grimmer, Timo; Goldhardt, Oliver; Santillo, Alexander F.; Hansson, Oskar; Vestberg, Susanne; Borroni, Barbara; Padovani, Alessandro; Galimberti, Daniela; Scarpini, Elio; Rohrer, Jonathan D.; Woollacott, Ione O. C.; Synofzik, Matthis; Wilke, Carlo; De Mendonça, Alexandre; Vandenberghe, Rik; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Niessen, Wiro J.; Papma, Janne M.; Seelaar, Harro; Jiskoot, Lize C.; de Jong, Frank Jan; Donker Kaat, Laura; Del Campo, Marta; Teunissen, Charlotte E.; Bron, Esther E.; Van den Berg, Esther; Van Swieten, John C.Background: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. Methods: This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). Results: CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (rs =-0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (rs =-0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival. Conclusion: CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities.
- Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosisPublication . Wilson, Katherine M.; Katona, Eszter; Glaria, Idoia; Carcolé, Mireia; Swift, Imogen J.; Sogorb-Esteve, Aitana; Heller, Carolin; Bouzigues, Arabella; Heslegrave, Amanda J.; Keshavan, Ashvini; Knowles, Kathryn; Patil, Saurabh; Mohapatra, Susovan; Liu, Yuanjing; Goyal, Jaya; Sanchez-Valle, Raquel; Laforce, Robert Jr.; Synofzik, Matthis; Rowe, James B.; Finger, Elizabeth; Vandenberghe, Rik; Butler, Christopher R.; Gerhard, Alexander; Van Swieten, John C.; Seelaar, Harro; Borroni, Barbara; Galimberti, Daniela; De Mendonça, Alexandre; Masellis, Mario; Tartaglia, M. Carmela; Otto, Markus; Graff, Caroline; Ducharme, Simon; Schott, Jonathan M.; Malaspina, Andrea; Zetterberg, Henrik; Boyanapalli, Ramakrishna; Rohrer, Jonathan D.; Isaacs, Adrian M.; Maruta, Carolina; Ferreira, Catarina B.; Verdelho, AnaObjective: A GGGGCC repeat expansion in the C9orf72 gene is the most common cause of genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). As potential therapies targeting the repeat expansion are now entering clinical trials, sensitive biomarker assays of target engagement are urgently required. Our objective was to develop such an assay. Methods: We used the single molecule array (Simoa) platform to develop an immunoassay for measuring poly(GP) dipeptide repeat proteins (DPRs) generated by the C9orf72 repeat expansion in cerebrospinal fluid (CSF) of people with C9orf72-associated FTD/ALS. Results and conclusions: We show the assay to be highly sensitive and robust, passing extensive qualification criteria including low intraplate and interplate variability, a high precision and accuracy in measuring both calibrators and samples, dilutional parallelism, tolerance to sample and standard freeze-thaw and no haemoglobin interference. We used this assay to measure poly(GP) in CSF samples collected through the Genetic FTD Initiative (N=40 C9orf72 and 15 controls). We found it had 100% specificity and 100% sensitivity and a large window for detecting target engagement, as the C9orf72 CSF sample with the lowest poly(GP) signal had eightfold higher signal than controls and on average values from C9orf72 samples were 38-fold higher than controls, which all fell below the lower limit of quantification of the assay. These data indicate that a Simoa-based poly(GP) DPR assay is suitable for use in clinical trials to determine target engagement of therapeutics aimed at reducing C9orf72 repeat-containing transcripts.
- Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementiaPublication . Heller, Carolin; Foiani, Martha S.; Moore, Katrina; Convery, Rhian; Bocchetta, Martina; Neason, Mollie; Cash, David M.; Thomas, David; Greaves, Caroline V.; Woollacott, Ione O. C.; Shafei, Rachelle; Van Swieten, John C.; Moreno, Fermin; Sanchez-Valle, Raquel; Borroni, Barbara; Laforce Jr, Robert; Masellis, Mario; Tartaglia, Maria Carmela; Graff, Caroline; Galimberti, Daniela; Rowe, James B.; Finger, Elizabeth; Synofzik, Matthis; Vandenberghe, Rik; De Mendonça, Alexandre; Tagliavini, Fabrizio; Santana, Isabel; Ducharme, Simon; Butler, Christopher R.; Gerhard, Alex; Levin, Johannes; Danek, Adrian; Frisoni, Giovanni; Sorbi, Sandro; Otto, Markus; Heslegrave, Amanda J.; Zetterberg, Henrik; Rohrer, Jonathan D.Background: There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker. Methods: Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman's correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures. Results: Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, -61.3 to 54.6), MAPT mutations (12.7, -33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe. Conclusions: Raised GFAP concentrations appear to be unique to GRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.