Periodic Reporting for period 1 - DAI (Diagnose Alzheimer’s disease with isotopes)
Reporting period: 2023-06-01 to 2024-11-30
Biometals such as copper (Cu) and zinc (Zn) play critical roles in the normal functioning of the brain. Dysregulation of these metals is inherently linked to neurodegenerative disorders. In conditions like Alzheimer's disease (AD), the bonding environment in the brain changes, for instance, due to the accumulation and aggregation of amyloid-beta (Aβ) plaques. These alterations can lead to measurable shifts in the relative abundances of the natural stable isotopes of Cu and Zn in the affected regions through a process known as isotope fractionation.
These isotopic changes in brain tissues can be transferred to other bodily reservoirs, such as blood fractions, through various biological processes. During the ERC Pristine project, the Principal Investigator (PI) developed highly sensitive and precise methods to analyze the stable isotopic compositions of these metals, including Cu and Zn. These methods have enabled confirmation of the hypothesis in multiple murine models of AD. In particular, we have also validated this hypothesis in a small set of post-mortem human brain tissues, showcasing the application of geochemical and cosmochemical methodologies to medical science.
Building on this foundation, this project aims to validate the following hypotheses:
Excursions in Cu and Zn isotope compositions observed in brain tissues during AD progression (previously confirmed in post-mortem human samples) are also reflected in changes in the isotopic compositions of body fluid fractions.
Based on recent findings that Cu and Zn isotope compositions in human brain tissues correlate with Braak stages (a metric for AD progression based on neurofibrillary tangles), it is further hypothesized that the magnitude of isotopic excursions will correspond to Braak stage severity in bodily fluids, mirroring the pattern observed in brain tissues.
These isotopic changes in brain tissues can be transferred to other bodily reservoirs, such as blood fractions, through various biological processes. During the ERC Pristine project, the Principal Investigator (PI) developed highly sensitive and precise methods to analyze the stable isotopic compositions of these metals, including Cu and Zn. These methods have enabled confirmation of the hypothesis in multiple murine models of AD. In particular, we have also validated this hypothesis in a small set of post-mortem human brain tissues, showcasing the application of geochemical and cosmochemical methodologies to medical science.
Building on this foundation, this project aims to validate the following hypotheses:
Excursions in Cu and Zn isotope compositions observed in brain tissues during AD progression (previously confirmed in post-mortem human samples) are also reflected in changes in the isotopic compositions of body fluid fractions.
Based on recent findings that Cu and Zn isotope compositions in human brain tissues correlate with Braak stages (a metric for AD progression based on neurofibrillary tangles), it is further hypothesized that the magnitude of isotopic excursions will correspond to Braak stage severity in bodily fluids, mirroring the pattern observed in brain tissues.
During the project, we investigated the impact of aging on the evolution of the brain's copper (Cu) isotopic composition. Our findings demonstrated that normal aging significantly affects the brain's isotopic composition, an effect that must be accounted for when studying patients with Alzheimer's disease (AD). This work was published by PhD student Esther Lahoud in Metallomics (Lahoud et al., 2024).
Subsequently, we analyzed the Cu and zinc (Zn) isotopic compositions in multiple serum and cerebrospinal fluid (CSF) samples from both healthy individuals and AD patients. While no significant variations were observed in the serum samples, we identified a distinct effect in the CSF samples. This finding suggests the potential applicability of this isotopic approach for monitoring disease progression. This work is currently being prepared for publication.
Subsequently, we analyzed the Cu and zinc (Zn) isotopic compositions in multiple serum and cerebrospinal fluid (CSF) samples from both healthy individuals and AD patients. While no significant variations were observed in the serum samples, we identified a distinct effect in the CSF samples. This finding suggests the potential applicability of this isotopic approach for monitoring disease progression. This work is currently being prepared for publication.
In this project, we measured, for the first time, the copper (Cu) stable isotope composition in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients. Our results demonstrate that the Cu isotopic composition in the CSF is altered in AD patients, reflecting the formation of amyloid-beta plaques in the brain during disease progression. Furthermore, we show that the Cu isotopic composition in the CSF holds potential as a valuable biomarker for the accumulation of amyloid plaques in the brains of AD patients. This work highlights the potential of natural Cu isotopes in human CSF as diagnostic biomarkers for Alzheimer's disease.