Multicenter Study

. 2024 Jun 25;102(12):e209418.

doi: 10.1212/WNL.0000000000209418. Epub 2024 Jun 3.

Association of Plasma Amyloid, P-Tau, GFAP, and NfL With CSF, Clinical, and Cognitive Features in Patients With Dementia With Lewy Bodies

Katharina Bolsewig¹, Annemartijn A J M van Unnik¹, Elena R Blujdea¹, Maria C Gonzalez¹, Nicholas J Ashton¹, Dag Aarsland¹, Henrik Zetterberg¹, Alessandro Padovani¹, Laura Bonanni¹, Brit Mollenhauer¹, Sebastian Schade¹, Rik Vandenberghe¹, Koen Poesen¹, Milica G Kramberger¹, Claire Paquet¹, Olivier Bousiges¹, Benjamin Cretin¹, Eline A J Willemse¹, Charlotte E Teunissen¹, Afina W Lemstra¹; European-Dementia With Lewy Bodies (E-DLB) Consortium¹

Collaborators, Affiliations

Collaborators

European-Dementia With Lewy Bodies (E-DLB) Consortium:
Claudia Carrarini, Julien Dumurgier, Claire Hourregue, Sinead Gaubert, Maximilien Porché, Matthieu Lilamand, Frédéric Blanc, Pierre Anthony, Catherine Demuynck, Catherine Martin-Hunyadi, Cadice Muller, Nathalie Philippi, Alix Ravier, Anne Botzung, Timothée Albasser, Emmanuelle Epp-Ehrhardt, Jeanne Merignac, Laetitia Monjoin, Isabelle Cleynen, Mercè Boada, Adela Orellana

Affiliation

¹ From the Department of Laboratory Medicine (K.B., E.R.B., E.A.J.W., C.E.T.) and Alzheimer Center Amsterdam (A.A.J.M.U., A.W.L.), Amsterdam UMC, the Netherlands; Department of Quality and Health Technology (M.C.G.), University of Stavanger; The Norwegian Centre for Movement Disorders (M.C.G.) and the Centre for Age-Related Medicine (M.C.G., N.J.A., D.A.), Stavanger University Hospital, Norway; Department of Psychiatry and Neurochemistry (N.J.A., H.Z.), the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Old Age Psychiatry (N.J.A., D.A.), King's College London, United Kingdom; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology; UK Dementia Research Institute at UCL (H.Z.), London, United Kingdom; Hong Kong Center for Neurodegenerative Diseases (H.Z.), Hong Kong, China; Wisconsin Alzheimer's Disease Research Center (H.Z.), University of Wisconsin School of Medicine and Public Health, Madison; Neurology Unit (A.P.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Department of Medicine and Aging Sciences (L.B.), University G. d'Annunzio of Chieti-Pescara, Chieti, Italy; Department of Neurology (B.M.), University Medical Center Göttingen; Paracelsus-Elena-Klinik (B.M., S.S.), Germany; Department of Neurosciences (R.V., K.P.), KU Leuven, Belgium; Department of Neurology and Medical Faculty (M.G.K.), University Medical Center Ljubljana, Slovenia; Department of Neurobiology (M.G.K.), Karolinska Institutet, Huddinge, Sweden; Université de Paris Cité (C.P.), Centre de Neurologie Cognitive, Paris; Laboratory of Biochemistry and Molecular Biology (O.B.), University Hospital of Strasbourg; University of Strasbourg and CNRS (O.B., B.C.); Memory Resource and Research Centre (B.C.), University Hospital of Strasbourg, France; Department of Neurology (E.A.J.W.), Multiple Sclerosis Center; Research Center for Clinical Neuroimmunology and Neuroscience Basel (E.A.J.W.); and Departments of Biomedicine and Clinical Research (E.A.J.W.), University Hospital Basel and University of Basel, Switzerland.

PMID: 38830138
PMCID: PMC11244745
DOI: 10.1212/WNL.0000000000209418

Multicenter Study

Association of Plasma Amyloid, P-Tau, GFAP, and NfL With CSF, Clinical, and Cognitive Features in Patients With Dementia With Lewy Bodies

Katharina Bolsewig et al. Neurology. 2024.

. 2024 Jun 25;102(12):e209418.

doi: 10.1212/WNL.0000000000209418. Epub 2024 Jun 3.

Authors

Collaborators

European-Dementia With Lewy Bodies (E-DLB) Consortium:
Claudia Carrarini, Julien Dumurgier, Claire Hourregue, Sinead Gaubert, Maximilien Porché, Matthieu Lilamand, Frédéric Blanc, Pierre Anthony, Catherine Demuynck, Catherine Martin-Hunyadi, Cadice Muller, Nathalie Philippi, Alix Ravier, Anne Botzung, Timothée Albasser, Emmanuelle Epp-Ehrhardt, Jeanne Merignac, Laetitia Monjoin, Isabelle Cleynen, Mercè Boada, Adela Orellana

Affiliation

¹ From the Department of Laboratory Medicine (K.B., E.R.B., E.A.J.W., C.E.T.) and Alzheimer Center Amsterdam (A.A.J.M.U., A.W.L.), Amsterdam UMC, the Netherlands; Department of Quality and Health Technology (M.C.G.), University of Stavanger; The Norwegian Centre for Movement Disorders (M.C.G.) and the Centre for Age-Related Medicine (M.C.G., N.J.A., D.A.), Stavanger University Hospital, Norway; Department of Psychiatry and Neurochemistry (N.J.A., H.Z.), the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Old Age Psychiatry (N.J.A., D.A.), King's College London, United Kingdom; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology; UK Dementia Research Institute at UCL (H.Z.), London, United Kingdom; Hong Kong Center for Neurodegenerative Diseases (H.Z.), Hong Kong, China; Wisconsin Alzheimer's Disease Research Center (H.Z.), University of Wisconsin School of Medicine and Public Health, Madison; Neurology Unit (A.P.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Department of Medicine and Aging Sciences (L.B.), University G. d'Annunzio of Chieti-Pescara, Chieti, Italy; Department of Neurology (B.M.), University Medical Center Göttingen; Paracelsus-Elena-Klinik (B.M., S.S.), Germany; Department of Neurosciences (R.V., K.P.), KU Leuven, Belgium; Department of Neurology and Medical Faculty (M.G.K.), University Medical Center Ljubljana, Slovenia; Department of Neurobiology (M.G.K.), Karolinska Institutet, Huddinge, Sweden; Université de Paris Cité (C.P.), Centre de Neurologie Cognitive, Paris; Laboratory of Biochemistry and Molecular Biology (O.B.), University Hospital of Strasbourg; University of Strasbourg and CNRS (O.B., B.C.); Memory Resource and Research Centre (B.C.), University Hospital of Strasbourg, France; Department of Neurology (E.A.J.W.), Multiple Sclerosis Center; Research Center for Clinical Neuroimmunology and Neuroscience Basel (E.A.J.W.); and Departments of Biomedicine and Clinical Research (E.A.J.W.), University Hospital Basel and University of Basel, Switzerland.

PMID: 38830138
PMCID: PMC11244745
DOI: 10.1212/WNL.0000000000209418

Abstract

Background and objectives: Plasma β-amyloid-1-42/1-40 (Aβ42/40), phosphorylated-tau (P-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) have been widely examined in Alzheimer disease (AD), but little is known about their reflection of copathologies, clinical importance, and predictive value in dementia with Lewy bodies (DLB). We aimed to evaluate associations of these biomarkers with CSF amyloid, cognition, and core features in DLB.

Methods: This cross-sectional multicenter cohort study with prospective component included individuals with DLB, AD, and healthy controls (HCs), recruited from 2002 to 2020 with an annual follow-up of up to 5 years, from the European-Dementia With Lewy Bodies consortium. Plasma biomarkers were measured by single-molecule array (Neurology 4-Plex E kit). Amyloid status was determined by CSF Aβ42 concentrations, and cognition was assessed by Mini-Mental State Examination (MMSE). Biomarker differences across groups, associations with amyloid status, and clinical core features were assessed by analysis of covariance. Associations with cognitive impairment and decline were assessed by linear regression and linear mixed-effects models.

Results: In our cohort consisting of 562 individuals (HC n = 89, DLB n = 342, AD n = 131; 250 women [44.5%], mean [SD] age of 71 [8] years), sex distribution did not differ between groups. Patients with DLB were significantly older, and had less years of education and worse baseline cognition than HC, but not AD. DLB participants stratified for amyloid status differed significantly in plasma Aβ42/40 ratio (decreased in amyloid abnormal: β = -0.008, 95% CI -0.016 to -0.0003, p = 0.01) and P-tau (increased in amyloid abnormal, P-tau181: β = 0.246, 95% CI 0.011-0.481; P-tau231: β = 0.227, 95% CI 0.035-0.419, both p < 0.05), but not in GFAP (β = 0.068, 95% CI -0.018 to 0.153, p = 0.119), and NfL (β = 0.004, 95% CI -0.087 to 0.096, p = 0.923) concentrations. Higher baseline GFAP, NfL, and P-tau concentrations were associated with lower MMSE scores in DLB, and GFAP and NfL were associated with a faster cognitive decline (GFAP: annual change of -2.11 MMSE points, 95% CI -2.88 to -1.35 MMSE points, p < 0.001; NfL: annual change of -2.13 MMSE points, 95% CI -2.97 to -1.29 MMSE points, p < 0.001). DLB participants with parkinsonism had higher concentrations of NfL (β = 0.08, 95% CI 0.02-0.14, p = 0.006) than those without.

Discussion: Our study suggests a possible utility of plasma Aβ42/40, P-tau181, and P-tau231 as a noninvasive biomarkers to assess amyloid copathology in DLB, and plasma GFAP and NfL as monitoring biomarkers for cognitive symptoms in DLB.

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Conflict of interest statement

K. Bolsewig, A.A.J.M. van Unnik, E.R. Blujdea, M.C. Gonzales, and N.J. Ashton report no disclosures relevant to the manuscript. D. Aarsland reports receiving research support and/or honoraria from AstraZeneca, H. Lundbeck, Novartis Pharmaceuticals, Biogen, Evonik, Sanofi, Roche, and GE Health and serving as a paid consultant for H. Lundbeck, Eisai, Heptares, and Mentis Cura. H. Zetterberg has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). A. Padovani reports no disclosures relevant to the manuscript. L. Bonanni reported receiving grants from the European Commission and the Italian Ministry of Health outside the submitted work. B. Mollenhauer reports no disclosures relevant to the manuscript. S. Schade received institutional salaries supported by the EU Horizon 2020 research and innovation program under grant agreement no. 863664 and by the Michael J. Fox Foundation for Parkinson's Research under grant agreement no. MJFF-021923. He is supported by a PPMI Early Stage Investigators Funding Program fellowship of the Michael J. Fox Foundation for Parkinson's Research under grant agreement no. MJFF-022656. R. Vandernberghe's institution has a clinical trial agreement (R. Vandenberghe as PI) with AviadoBio, Biogen, Denali, J&J, NovoNordisk, Prevail, Roche, UCB, Wave. R. Vandenberghe's institution has a consultancy agreement (R. Vandenberghe as a consultant) with ACImmune, Novartis, and Roche. K. Poesen and M.G. Kramberger report no disclosures relevant to the manuscript. C. Paquet reports serving as a member of the international advisory boards for Lilly; serving as a consultant for Fujiribio, Alzohis, Neuroimmune, Ads Neuroscience, Roche, AgenT, and Gilead; being involved as an investigator in several clinical trials for Roche, Eisai, Lilly, Biogen, AstraZeneca, Lundbeck, and Neuroimmune; and being a current member of the national boards of Roche, Lilly, and Biogen. O. Bousiges, B. Cretin, and E.A.J. Willemse report no disclosures relevant to the manuscript. C.E. Teunissen has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, PeopleBio, Roche, Siemens, Toyama, and Vivoryon. She is an editor of Alzheimer Research and Therapy, and serves on editorial boards of Medidact Neurologie/Springer, and Neurology: Neuroimmunology & Neuroinflammation. She had speaker contracts for Roche, Grifols, Novo Nordisk. A.W. Lemstra reports no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

Figures

**Figure 1. Overview of Sample Availability, Cohort Selection, and Data Availability Per Diagnostic Group**
The diagram depicts number of available samples, exclusion criteria, and number of participants in the final cohort, as well as available data for each diagnostic group.

**Figure 2. Plasma Biomarkers Across Diagnostic Groups**
Plasma biomarker differences of Aβ42/Aβ40 ratio (A), GFAP (B), NfL (C), P-tau181 (D), and P-tau231 (E) across diagnostic groups. Plasma Aβ42/Aβ40 ratio was significantly higher in patients with DLB and HCs compared with patients with AD. Both plasma P-tau species were significantly higher in DLB compared with HC and significantly lower in DLB and HC compared with AD. Plasma GFAP and NfL concentrations were significantly higher in DLB and AD compared with HC. Plasma biomarker differences were assessed across groups by ANCOVA corrected for age and sex, and subsequent post hoc analysis by the Tukey post hoc test. p Values were adjusted for multiple comparison. *p < 0.05, ***p < 0.001. Aβ = β-amyloid; AD = Alzheimer disease; ANCOVA = analysis of covariance; DLB = dementia with Lewy bodies; GFAP = glial fibrillary acidic protein; HC = healthy control; MMSE = Mini-Mental State Examination; NfL = neurofilament light; P-tau = phosphorylated tau.

**Figure 3. Plasma Biomarkers in CSF Aβ42 Abnormal DLB Participants**
Plasma biomarkers Aβ42/40 ratio (A), GFAP (B), NfL (C), P-tau181 (D), and P-tau231 (E) in patients with DLB by CSF Aβ42 status (A+: n = 48; A−: n = 53). Plasma Aβ42/40 ratio was significantly lower, and both plasma P-tau species were significantly higher in DLB A+ patients compared with DLB A− patients. Plasma GFAP and NfL concentrations did not differ between A− and A+ patients with DLB. Plasma biomarkers were compared between groups by ANCOVA corrected for age and sex. *p < 0.05. Aβ = β-amyloid; AD = Alzheimer disease; ANCOVA = analysis of covariance; DLB = dementia with Lewy bodies; GFAP = glial fibrillary acidic protein; HC = healthy control; MMSE = Mini-Mental State Examination; NfL = neurofilament light; P-tau = phosphorylated tau.

**Figure 4. Associations of Baseline Plasma GFAP and NfL With Cognitive Decline in Patients With Dementia With Lewy Bodies**
Association of cognitive decline with baseline plasma GFAP (A) and NfL (B) concentrations. Linear mixed-effects models, corrected for the effect of age and sex, were built to analyze the association of baseline plasma biomarker concentrations with cognitive decline, as measured by MMSE scores over time, for up to 5 years. The line represents the estimated marginal model of decrease in MMSE scores over up to 5 years of follow-up time with different baseline plasma biomarker concentrations. To illustrate the association of different baseline biomarker concentrations with rate of cognitive decline, low and high biomarker concentrations were defined as the first (Q1) and third quartile (Q3), respectively. The transparent areas show 95% CIs around the mean estimated values. AD = Alzheimer disease; GFAP = glial fibrillary acidic protein; HC = healthy control; MMSE = Mini-Mental State Examination; NfL = neurofilament light.

See this image and copyright information in PMC

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Association of Plasma Amyloid, P-Tau, GFAP, and NfL With CSF, Clinical, and Cognitive Features in Patients With Dementia With Lewy Bodies

Collaborators

Affiliation

Association of Plasma Amyloid, P-Tau, GFAP, and NfL With CSF, Clinical, and Cognitive Features in Patients With Dementia With Lewy Bodies

Authors

Collaborators

Affiliation

Abstract

Conflict of interest statement

Figures

References

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