Longitudinal pathways of cerebrospinal fluid and positron emission tomography biomarkers of amyloid-β positivity
| Main Authors: | Arianna Sala, Agneta Nordberg, Elena Rodriguez-Vieitez |
|---|---|
| Format: | Article Journal |
| Terbitan: |
, 2020
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| Online Access: |
https://zenodo.org/record/4680561 |
Daftar Isi:
- Abstract: Mismatch between CSF and PET amyloid-β biomarkers occurs in up to ≈20% of preclinical/prodromal Alzheimer’s disease individuals. Factors underlying mismatching results remain unclear. In this study we hypothesized that CSF/PET discordance provides unique biological/clinical information. To test this hypothesis, we investigated non-demented and demented participants with CSF amyloid-β42 and [18F]Florbetapir PET assessments at baseline (n = 867) and at 2-year follow-up (n = 289). Longitudinal trajectories of amyloid-β positivity were tracked simultaneously for CSF and PET biomarkers. In the longitudinal cohort (n = 289), we found that participants with normal CSF/PET amyloid-β biomarkers progressed more frequently toward CSF/PET discordance than to full CSF/PET positivity (χ2(1) = 5.40; p < 0.05). Progression to CSF+/PET+ status was ten times more frequent in cases with discordant biomarkers, as compared to csf−/pet− cases (χ2(1) = 18.86; p < 0.001). Compared to the CSF+/pet− group, the csf−/PET+ group had lower APOE-ε4ε4 prevalence (χ2(6) = 197; p < 0.001; n = 867) and slower rate of brain amyloid-β accumulation (F(3,600) = 12.76; p < 0.001; n = 608). These results demonstrate that biomarker discordance is a typical stage in the natural history of amyloid-β accumulation, with CSF or PET becoming abnormal first and not concurrently. Therefore, biomarker discordance allows for identification of individuals with elevated risk of progression toward fully abnormal amyloid-β biomarkers, with subsequent risk of neurodegeneration and cognitive decline. Our results also suggest that there are two alternative pathways (“CSF-first” vs. “PET-first”) toward established amyloid-β pathology, characterized by different genetic profiles and rates of amyloid-β accumulation. In conclusion, CSF and PET amyloid-β biomarkers provide distinct information, with potential implications for their use as biomarkers in clinical trials.
- The project leading to this article has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 115952. This Joint Undertaking receives the support from the European Union's Horizon 2020 research and innovation program and European Federation of Pharmaceutical Industries and Associations (EFPIA). This work is also supported by the Swedish Alzheimer Foundation (Alzheimerfonden), Swedish Brain Foundation (Hjärnfonden), Swedish Dementia Association (Demensfonden), Swedish Foundation for Strategic Research (SSF) [project RB13-0192], Swedish Research Council [projects K2014-61X-05817, 2017-02965, 2017-06086], Åke Wiberg Foundation, and the Stockholm County Council-Karolinska Institutet regional agreement on medical training and clinical research (ALF grant). This publication solely reflects the author's view and neither IMI nor the European Union, and EFPIA are responsible for any use that may be made of the information contained herein.