Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease
Open accessAbstract
Although brain neuroinflammation may play an instrumental role in the pathophysiology of Alzheimer's disease, its actual impact on disease progression remains controversial, being reported as either detrimental or protective. This work aimed at investigating the temporal relationship between microglial activation and clinical progression of Alzheimer's disease. First, in a large cohort of patients with Alzheimer's disease we analysed the predictive value of microglial activation assessed by 18F-DPA-714 PET imaging on functional, cognitive and MRI biomarkers outcomes after a 2-year follow-up. Second, we analysed the longitudinal progression of 18F-DPA-714 binding in patients with Alzheimer's disease by comparison with controls, and assessed its influence on clinical progression. At baseline, all participants underwent a clinical assessment, brain MRI, 11C-PiB, 18F-DPA-714 PET imaging and TSPO genotyping. Participants were followed-up annually for 2 years. At the end of the study, subjects were asked to repeat a second 18F-DPA-714-PET imaging. Initial 18F-DPA-714 binding was higher in prodromal (n = 33) and in demented patients with Alzheimer's disease (n = 19) compared to controls (n = 17). After classifying patients into slow and fast decliners according to functional (Clinical Dementia Rating change) or cognitive (Mini-Mental State Examination score decline) outcomes, we found a higher initial 18F-DPA-714 binding in slow than fast decliners. Negative correlations were observed between initial 18F-DPA-714 binding and the Clinical Dementia Rating Sum of Boxes score increase, the MMSE score loss and the progression of hippocampal atrophy. This suggests that higher initial 18F-DPA-714 binding is associated with better clinical prognosis. Twenty-four patients with Alzheimer's disease and 15 control subjects performed a second DPA-PET. We observed an increase of 18F-DPA-714 in patients with Alzheimer's disease as compared with controls (mean 13.2% per year versus 4.2%) both at the prodromal (15.8%) and at the demented stages (8.3%). The positive correlations between change in 18F-DPA-714 binding over time and the three clinical outcome measures (Clinical Dementia Rating, Mini-Mental State Examination, hippocampal atrophy) suggested a detrimental effect on clinical Alzheimer's disease progression of increased neuroinflammation after the initial PET examination, without correlation with PiB-PET uptake at baseline. High initial 18F-DPA-714 binding was correlated with a low subsequent increase of microglial activation and favourable clinical evolution, whereas the opposite profile was observed when initial 18F-DPA-714 binding was low, independently of disease severity at baseline. Taken together, our results support a pathophysiological model involving two distinct profiles of microglial activation signatures with different dynamics, which differentially impact on disease progression and may vary depending on patients rather than disease stages.
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Alzheimer's disease can be associated with other brain pathologies, including α-synucleinopathy, vascular pathology, non-Alzheimer's disease tauopathies, and TDP-43 pathology.
“Alzheimer’s disease can be associated with other brain pathologies, including α-synucleinopathy,56 vascular pathology, non-Alzheimer’s disease tauopathies, and TDP-43 pathology.40,42–44”
From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [56]
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- Authors
- Hamelin, L., Lagarde, J., Dorothée, G., Potier, M. C., Corlier, F., Kuhnast, B., Caillé, F., Dubois, B., Fillon, L., Chupin, M., Bottlaender, M., & Sarazin, M.
- Affiliations
- Université Paris-Sud (FR)
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- University of Southern California (US)
- UMR 1023 IMIV, Service Hospitalier Frédéric Joliot, CEA, Inserm, Université Paris Sud, CNRS, Université Paris-Saclay, Orsay, France
- ICM Institut du Cerveau et de la Moelle épinière, CNRS UMR7225, INSERM U1127, Hôpital de la Pitié-Salpêtrière, Paris, France
- Corresponding author
- Bottlaender, Michel
- Sarazin, Marie
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-03-28
- Volume
- 141
- Issue
- 6
- Pages
- 1855-1870
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2794659745
- Cited by
- 177
- References
- 37
- Citations by year
- 2026: 12 · 2025: 25 · 2024: 33 · 2023: 28 · 2022: 13 · 2021: 26 · 2020: 20 · 2019: 16 · 2018: 4
- FWCI
- 7.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- European Commission (278850)
- Agence Nationale de la Recherche (ANR-10-IAIHU06, 10-IAIHU-06, ANR-10-IAHU-0006)
- Université Paris Descartes
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- 's disease, microglial activation, neuroinflammation, disease progression, clinical deterioration, hippocampal atrophy, prodromal Alzheimer's disease, clinical prognosis, [11C]PIB, cognitive decline, functional decline, Clinical Dementia Rating, Mini-Mental State Examination
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Analysis of Variance, Aniline Compounds, Brain Mapping, Female, Hippocampus, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Mental Status Schedule, Middle Aged, Neuropsychological Tests, Organoplatinum Compounds, Prospective Studies, Pyrazoles, Pyrimidines, Thiazoles, Amyloid beta-Peptides, Microglia, Disease Progression, Radiopharmaceuticals, Positron-Emission Tomography
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