Comparative Study

. 2024 May 16;16(1):110.

doi: 10.1186/s13195-024-01478-9.

Comparison of plasma and neuroimaging biomarkers to predict cognitive decline in non-demented memory clinic patients

Augusto J Mendes^{1

2}, Federica Ribaldi^{3

4}, Aurelien Lathuiliere^{3

4}, Nicholas J Ashton^{5

6

7

8}, Henrik Zetterberg^{5

9

10

11

12

13}, Marc Abramowicz¹⁴, Max Scheffler¹⁵, Frédéric Assal¹⁶, Valentina Garibotto^{17

18

19}, Kaj Blennow²⁰, Giovanni B Frisoni^{3

4}

Affiliations

¹ Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland. augusto.martinsmendes@unige.ch.
² Geneva Memory Center, Department of Rehabilitation and Geriatrics,, Geneva University Hospitals, Geneva, Switzerland. augusto.martinsmendes@unige.ch.
³ Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland.
⁴ Geneva Memory Center, Department of Rehabilitation and Geriatrics,, Geneva University Hospitals, Geneva, Switzerland.
⁵ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁶ King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK.
⁷ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
⁸ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
⁹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁰ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
¹¹ UK Dementia Research Institute at UCL, London, UK.
¹² Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹³ Wisconsin Alzheimer?s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
¹⁴ Genetic Medicine, Diagnostics Dept, University Hospitals and University of Geneva, Geneva, Switzerland.
¹⁵ Division of Radiology, Geneva University Hospitals, Geneva, Switzerland.
¹⁶ Division of Neurology, Department of Clinical Neurosciences, Faculty of Medicine, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
¹⁷ Laboratory of Neuroimaging and Innovative Molecular Tracers (NIMTlab), Faculty of Medicine, Geneva University Neurocenter, University of Geneva, Geneva, Switzerland.
¹⁸ Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospitals, Geneva, Switzerland.
¹⁹ CIBM Center for Biomedical Imaging, Geneva, Switzerland.
²⁰ Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.

PMID: 38755703
PMCID: PMC11097559
DOI: 10.1186/s13195-024-01478-9

Comparative Study

Comparison of plasma and neuroimaging biomarkers to predict cognitive decline in non-demented memory clinic patients

Augusto J Mendes et al. Alzheimers Res Ther. 2024.

. 2024 May 16;16(1):110.

doi: 10.1186/s13195-024-01478-9.

Authors

Affiliations

¹ Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland. augusto.martinsmendes@unige.ch.
² Geneva Memory Center, Department of Rehabilitation and Geriatrics,, Geneva University Hospitals, Geneva, Switzerland. augusto.martinsmendes@unige.ch.
³ Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland.
⁴ Geneva Memory Center, Department of Rehabilitation and Geriatrics,, Geneva University Hospitals, Geneva, Switzerland.
⁵ Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁶ King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, UK.
⁷ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
⁸ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
⁹ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁰ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
¹¹ UK Dementia Research Institute at UCL, London, UK.
¹² Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹³ Wisconsin Alzheimer?s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
¹⁴ Genetic Medicine, Diagnostics Dept, University Hospitals and University of Geneva, Geneva, Switzerland.
¹⁵ Division of Radiology, Geneva University Hospitals, Geneva, Switzerland.
¹⁶ Division of Neurology, Department of Clinical Neurosciences, Faculty of Medicine, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
¹⁷ Laboratory of Neuroimaging and Innovative Molecular Tracers (NIMTlab), Faculty of Medicine, Geneva University Neurocenter, University of Geneva, Geneva, Switzerland.
¹⁸ Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospitals, Geneva, Switzerland.
¹⁹ CIBM Center for Biomedical Imaging, Geneva, Switzerland.
²⁰ Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.

PMID: 38755703
PMCID: PMC11097559
DOI: 10.1186/s13195-024-01478-9

Abstract

Background: Plasma biomarkers of Alzheimer's disease (AD) pathology, neurodegeneration, and neuroinflammation are ideally suited for secondary prevention programs in self-sufficient persons at-risk of dementia. Plasma biomarkers have been shown to be highly correlated with traditional imaging biomarkers. However, their comparative predictive value versus traditional AD biomarkers is still unclear in cognitively unimpaired (CU) subjects and with mild cognitive impairment (MCI).

Methods: Plasma (Aβ42/40, p-tau181, p-tau231, NfL, and GFAP) and neuroimaging (hippocampal volume, centiloid of amyloid-PET, and tau-SUVR of tau-PET) biomarkers were assessed at baseline in 218 non-demented subjects (CU = 140; MCI = 78) from the Geneva Memory Center. Global cognition (MMSE) was evaluated at baseline and at follow-ups up to 5.7 years. We used linear mixed-effects models and Cox proportional-hazards regression to assess the association between biomarkers and cognitive decline. Lastly, sample size calculations using the linear mixed-effects models were performed on subjects positive for amyloid-PET combined with tau-PET and plasma biomarker positivity.

Results: Cognitive decline was significantly predicted in MCI by baseline plasma NfL (β=-0.55), GFAP (β=-0.36), hippocampal volume (β = 0.44), centiloid (β=-0.38), and tau-SUVR (β=-0.66) (all p < 0.05). Subgroup analysis with amyloid-positive MCI participants also showed that only NfL and GFAP were the only significant predictors of cognitive decline among plasma biomarkers. Overall, NfL and tau-SUVR showed the highest prognostic values (hazard ratios of 7.3 and 5.9). Lastly, we demonstrated that adding NfL to the inclusion criteria could reduce the sample sizes of future AD clinical trials by up to one-fourth in subjects with amyloid-PET positivity or by half in subjects with amyloid-PET and tau-PET positivity.

Conclusions: Plasma NfL and GFAP predict cognitive decline in a similar manner to traditional imaging techniques in amyloid-positive MCI patients. Hence, even though they are non-specific biomarkers of AD, both can be implemented in memory clinic workups as important prognostic biomarkers. Likewise, future clinical trials might employ plasma biomarkers as additional inclusion criteria to stratify patients at higher risk of cognitive decline to reduce sample sizes and enhance effectiveness.

PubMed Disclaimer

Conflict of interest statement

GBF has received unrestricted grants and support for event organisation from ROCHE Pharmaceuticals; OM Pharma; EISAI Pharmaceuticals; Biogen Pharmaceuticals. VG received grants and speaker fees through her institution from Siemens Healthineers, GE Healthcare, Novo Nordisk and Janssen. HZ 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). The other authors have nothing to disclose.

Figures

**Fig. 1**
Linear mixed model prediction in both CU and MCI subset based on baseline neuroimaging and plasma biomarkers. Biomarker positivity in MCI and CU was defined based on the 90% percentile of the distribution in the CU. *** p < 0.001; ** p < 0.01; * p < 0.05

**Fig. 2**
Kaplan-Meier Survival Curve plot showing the survival probability of cognitive decline in MCI over time considering the positivity in plasma and neuroimaging biomarkers. ** p < 0.01; * p < 0.05; + p < 0.1

**Fig. 3**
Number of amyloid positive MCI subjects per arm for preventive clinical trials with different percentages of cognitive decline slowing considering the positivity of plasma biomarkers in subjects positive to Amy-PET only or combined with Tau-PET

See this image and copyright information in PMC

References

1. Jack CR, Bennett DA, Blennow K, Carrillo MC, Feldman HH, Frisoni GB et al. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology [Internet]. 2016 [cited 2023 May 9];87:539–47. https://n.neurology.org/content/87/5/539. - PMC - PubMed
1. Mattsson N, Andreasson U, Zetterberg H, Blennow K, Weiner MW, Aisen P et al. Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease. JAMA Neurol [Internet]. 2017 [cited 2023 May 9];74:557–66. https://pubmed.ncbi.nlm.nih.gov/28346578/. - PMC - PubMed
1. Janelidze S, Mattsson N, Palmqvist S, Smith R, Beach TG, Serrano GE et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med [Internet]. 2020 [cited 2023 May 9];26:379–86. https://pubmed.ncbi.nlm.nih.gov/32123385/. - PubMed
1. Ashton NJ, Pascoal TA, Karikari TK, Benedet AL, Lantero-Rodriguez J, Brinkmalm G et al. Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol [Internet]. 2021 [cited 2023 Jun 29];141:709. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043944/. - PMC - PubMed
1. Altomare D, Stampacchia S, Ribaldi F, Tomczyk S, Chevalier C, Poulain G et al. Plasma biomarkers for Alzheimer’s disease: a field-test in a memory clinic. J Neurol Neurosurg Psychiatry [Internet]. 2023 [cited 2023 May 9];jnnp-2022-330619. https://pubmed.ncbi.nlm.nih.gov/37012066/. - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Comparison of plasma and neuroimaging biomarkers to predict cognitive decline in non-demented memory clinic patients

Affiliations

Comparison of plasma and neuroimaging biomarkers to predict cognitive decline in non-demented memory clinic patients

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous