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DOPA Decarboxylase (DDC) has been proposed as a cerebrospinal fluid (CSF) biomarker with increased concentrations in Lewy body disorders (LBDs) and highest levels in patients receiving dopaminergic treatment. Here we evaluate plasma DDC, measured by proximity extension assay, and the effect of dopaminergic treatment in three independent LBD (with a focus on dementia with Lewy bodies (DLB) and Parkinson's disease (PD)) cohorts: an autopsy-confirmed cohort (n = 71), a large multicenter, cross-dementia cohort (n = 1498) and a longitudinal cohort with detailed treatment information (n = 66, median follow-up time[IQR] = 4[4, 4] years). Plasma DDC was not altered between different LBDs and other disease groups or controls in absence of treatment. DDC levels increased over time in PD, being significantly associated to higher dosages of dopaminergic treatment. This emphasizes the need to consider treatment effect when analyzing plasma DDC, and suggests that plasma DDC, in contrast to CSF DDC, is of limited use as a diagnostic biomarker for LBD, but could be valuable for treatment monitoring. DOPA decarboxylase (DDC) in cerebrospinal fluid has great diagnostic potential for Lewy body disorders. Here, the authors report limited diagnostic potential of plasma DDC and a strong association with dopaminergic treatment. [ABSTRACT FROM AUTHOR] more...

Background: Alzheimer's disease (AD) co‐pathology is a common feature in dementia with Lewy bodies (DLB) and associated with a more rapid decline. Here, we aimed to evaluate plasma biomarkers as alternatives for CSF biomarkers for the detection of amyloid pathology, and for their diagnostic and prognostic value in DLB. Method: Plasma Aβ42/40, GFAP, NfL, pTau181 and pTau231, were measured by SIMOA in patients with DLB (n = 342), AD (n = 131), and healthy controls (n = 89) from the E‐DLB consortium cohort. Associations of biomarkers with CSF Aβ42 status were assessed with ANCOVA corrected for age and sex. ROC analyses were performed to assess biomarker's performance for amyloid detection and differential diagnosis. Associations of biomarkers with cognitive impairment and decline were determined by linear regression and mixed effects models. Result: Altered Aβ42/40 (β = ‐0.0076, 95%CI:‐0.0137 to ‐0.0016, p<.05), pTau181 (β = 0.2503, 95%CI: 0.0555 to 0.4451, p<.05) and pTau231 levels (β = 0.2269, 95%CI:0.0347 to 0.4191, p<.05) were associated with amyloid pathology in DLB, as assessed by CSF Aβ42. The combination of these biomarkers differentiated amyloid normal from abnormal DLB patients with an AUC of 0.728 (sensitivity = 64.6%, specificity = 75.0%). pTau181 best differentiated these groups as a single marker (AUC = 0.700, sensitivity = 62.5%, specificity = 73.1%). The combination of Aβ42/40, NfL and pTau231 differentiated DLB from AD with an AUC of 0.726 (sensitivity = 73.3%, specificity = 68.8%). In DLB, increased GFAP (β = ‐8.9, 95%CI:‐11.7 to ‐6.1, p<.001), NfL (β = ‐7.2, 95%CI:‐10.0 to ‐4.4, p<.001), pTau181 (β = ‐2.6, 95%CI:‐4.0 to ‐1.2, p<.001) and pTau231 (β = ‐2.4, 95%CI:‐3.7 to ‐1.2, p<.001) were associated with lower baseline MMSE scores and increased GFAP (annual change of ‐2.1 MMSE points (95%CI:‐2.9 to ‐1.3, p<.001) and NfL (annual change of ‐2.1 MMSE points (95%CI:‐3.0 to ‐1.3, p<.001) predicted faster cognitive decline. Conclusion: Plasma Aβ42/40, pTau181 and pTau231 were associated with amyloid abnormality in DLB. Their utility for differential diagnosis and identifying amyloid pathology in DLB was modest. Our findings suggest a prognostic value of GFAP and NfL for cognitive decline in DLB. [ABSTRACT FROM AUTHOR] more...

Introduction: We aimed to evaluate informal caregivers' attitudes toward undergoing and future implementation of blood-based biomarkers (BBBM) testing for Alzheimer's disease (AD)., Methods: We explored caregivers' perspectives, by combining an online survey ( n  = 107) with a subsequent focus group ( n  = 7). We used descriptive statistics and thematic content analysis to identify common themes in answers to open-ended survey questions and focus group data., Results: Most caregivers (72.0%) favored BBBM for AD diagnosis. Provided with hypothetical scenarios, confidence in a normal result decreased significantly if experienced symptoms were more severe (mild: 78.5% vs. severe: 48.6%). Caregivers' attitudes toward BBBM for screening purposes significantly improved with prospect of treatment (53.3% vs. 92.5%). Concerns toward BBBM testing included treatment unavailability, increased/prolonged distress, and AD-related stigma. Potential benefits were actionability, explanation for symptoms, and opportunities for better care and future treatment., Discussion: Emerging AD treatment and reduction of AD-related stigma could profoundly increase public interest in BBBM testing for AD., Highlights: Most informal caregivers would want blood-based biomarker (BBBM) testing for Alzheimer's disease (AD) diagnosis.Perceived (dis)advantages were related to diagnosing AD early.With severe symptoms, there was less confidence in normal BBBM results.Treatment availability would significantly increase interest in BBBM testing for AD.Informal caregivers showed uncertainty regarding the meaning of the term "AD.", Competing Interests: Leonie Visser (LNCV) has been an invited speaker for the Schwabe Group and her research has been funded by ZonMW, Health Holland, the Amsterdam Public Health research institute, Alzheimer Nederland, and private partners, including Eisai. All fees and funding are paid to her institution. Author disclosures are available in the supporting information., (© 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.) more...

Introduction: Our previous antibody-based cerebrospinal fluid (CSF) proteomics study showed that Thimet oligopeptidase (THOP1), an amyloid beta (Aβ) neuropeptidase, was increased in mild cognitive impairment with amyloid pathology (MCI-Aβ+) and Alzheimer's disease (AD) dementia compared with controls and dementia with Lewy bodies (DLB), highlighting the potential of CSF THOP1 as an early specific biomarker for AD. We aimed to develop THOP1 immunoassays for large-scale analysis and validate our proteomics findings in two independent cohorts., Methods: We developed in-house CSF THOP1 immunoassays on automated Ella and Simoa platforms. The performance of the different assays were compared using Passing-Bablok regression analysis in a subset of CSF samples from the discovery cohort ( n = 72). Clinical validation was performed in two independent cohorts (cohort 1: n = 200; cohort 2: n = 165) using the Ella platform., Results: THOP1 concentrations moderately correlated between proteomics analysis and our novel assays ( Rho  > 0.580). In both validation cohorts, CSF THOP1 was increased in MCI-Aβ+ (>1.3-fold) and AD (>1.2-fold) compared with controls; and between MCI-Aβ+ and DLB (>1.2-fold). Higher THOP1 concentrations were detected in AD compared with DLB only when both cohorts were analyzed together. In both cohorts, THOP1 correlated with CSF total tau (t-tau), phosphorylated tau (p-tau), and Aβ40 ( Rho  > 0.540) but not Aβ42., Discussion: Validation of our proteomics findings underpins the potential of CSF THOP1 as an early specific biomarker associated with AD pathology. The use of antibody-based platforms in both the discovery and validation phases facilitated the translation of proteomics findings, providing an additional workflow that may accelerate the development of biofluid-based biomarkers., Competing Interests: Y.S.H., K.B., D.R., A.W.L., and M.C. report no conflicts of interest. D.A. participated in advisory boards from Fujirebio‐Europe and Roche Diagnostics and received speaker honoraria from Fujirebio‐Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U., and Esteve Pharmaceuticals S.A., D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). A.L. participated in advisory boards from Fujirebio‐Europe, Grifols, Eisai, Novartis, Roche Diagnostics, Otsuka Pharmaceutical, Nutricia, Zambón S.A.U., and Biogen, and received speaker honoraria from Eli Lilly, Biogen, KRKA, and Zambon. A.L. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). Research programs of W.F. have been funded by ZonMW, NWO, EU‐FP7, EU‐JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes‐Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis‐NL, Life‐MI, AVID, Roche BV, Fujifilm, Eisai, and Combinostics. W.F. holds the Pasman chair. W.F. is recipient of ABOARD, which is a public‐private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). W.F. has been an invited speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, NovoNordisk, and European Brain Council. W.F. is a consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. W.F. participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. All funding is paid to her institution. W.F. is member of the steering committee of PAVE and Think Brain Health. W.F. was associate editor of Alzheimer's Research & Therapy in 2020/2021. W.F. is associate editor at Brain. C.T. has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, and performed contract research or received grants from AC‐Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, and Vivoryon. C.T. serves on editorial boards of Medidact Neurologie/Springer, Alzheimer's Research & Therapy, and Neurology: Neuroimmunology & Neuroinflammation and is editor of a Neuromethods book (Springer). She had speaker contracts for Roche, Grifols, and Novo Nordisk. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.) more...

Proteomics studies have shown differential expression of numerous proteins in dementias but have rarely led to novel biomarker tests for clinical use. The Marie Curie MIRIADE project is designed to experimentally evaluate development strategies to accelerate the validation and ultimate implementation of novel biomarkers in clinical practice, using proteomics-based biomarker development for main dementias as experimental case studies. We address several knowledge gaps that have been identified in the field. First, there is the technology-translation gap of different technologies for the discovery (e.g., mass spectrometry) and the large-scale validation (e.g., immunoassays) of biomarkers. In addition, there is a limited understanding of conformational states of biomarker proteins in different matrices, which affect the selection of reagents for assay development. In this review, we aim to understand the decisions taken in the initial steps of biomarker development, which is done via an interim narrative update of the work of each ESR subproject. The results describe the decision process to shortlist biomarkers from a proteomics to develop immunoassays or mass spectrometry assays for Alzheimer's disease, Lewy body dementia, and frontotemporal dementia. In addition, we explain the approach to prepare the market implementation of novel biomarkers and assays. Moreover, we describe the development of computational protein state and interaction prediction models to support biomarker development, such as the prediction of epitopes. Lastly, we reflect upon activities involved in the biomarker development process to deduce a best-practice roadmap for biomarker development., Competing Interests: SD is an employee of ADx NeuroSciences, Gent, Belgium. SC is an employee of National Measurement Laboratory at LGC, London, UK. CT has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Bioconnect, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, PeopleBio, Quanterix, Roche, Toyama, and Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology & Neuroinflammation, and is editor of a Neuromethods book Springer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mavrina, Kimble, Waury, Gogishvili, Gómez de San José, Das, Coppens, Fernandes Gomes, Mravinacová, Wojdała, Bolsewig, Bayoumy, Burtscher, Mohaupt, Willemse, Teunissen and the MIRIADE consortium.) more...