Biomarkers are extremely important in clinical research. The measurement of each biomarker provides the information needed to determine the stage of disease, resulting in selection of individuals to qualify for clinical trials. Biomarkers also provide the data needed to evaluate how effective a treatment may be during the trial. For AD, biomarker tests are available to determine levels of amyloid beta and tau. However, neuroinflammation mediated by disease-associated microglia and astrocytes is now accepted as a central driver of neurodegeneration in AD, and therefore the identification of meaningful biomarkers for neuroinflammation is also of high clinical importance.
Using state-of-the-art protein detection technology in the lab, a recent study identified a panel of glial proteins in cerebrospinal fluid that show potential as fluid biomarkers for neuroinflammation in AD. These proteins were found to directly relate to the disease-associated states of microglia and astrocytes in the AD brain.
The study was co-led by Cure Alzheimer’s Fund Investigators Matthias Jucker, Ph.D., and Stephan Kaeser, Ph.D., both from the University of Tübingen in Germany. “The ability to measure inflammatory responses in the cerebrospinal fluid would be a major advance,” Dr. Jucker explained in an interview. “This would allow us to better understand different disease stages and also to test anti-inflammatory substances in clinical trials.”
The cerebrospinal fluid (CSF) is a clear liquid that is primarily produced by the ventricles in the brain via filtration of blood. While most proteins in CSF are blood-derived, a portion of CSF proteins originates in the brain. Therefore, CSF is thought of as a window into the brain, and changes in the proteins may indicate changes taking place in the brain. In humans, however, CSF proteins show great dynamic ranges and vary between AD patients and the stages of the disease. How specific to AD these changes may be is further complicated as patients may also have contributing comorbidities.
To work around the challenges presented by the variability in patient cohorts, the scientists first zeroed in on a group of CSF inflammatory proteins in AD mouse models. The pathology and genetics of these models are well characterized and therefore do not raise the same variability issues as seen in patient cohorts. The investigators used AD and Parkinson’s disease (PD) mouse models that were genetically engineered to overproduce amyloid beta and alpha-synuclein, respectively, and both protein pathologies have been shown to promote neuroinflammation in the brain.
The scientists measured proteins in CSF using state-of-the-art mass spectroscopy. Thanks to technological advances in protein detection, protein levels were measured from as little as two microliters or a tiny drop of fluid. The results of the analysis revealed that the majority of proteins whose levels had changed in the CSF of older AD and PD mice but not in age-matched controls were linked to microglia. The scientists narrowed it down to a panel of 25 proteins that were elevated in both disease models and largely overlapped with previously described disease-associated microglial genes.
Then, to translate their findings to humans, the investigators studied if the CSF proteins identified in mice were also changed in CSF of AD patients. For this, the scientists examined already available datasets from two other studies that had compared CSF proteins from three large cohorts of AD patients and healthy participants. The researchers queried the cohort datasets and found that the levels of most of their candidate proteins were also changed in CSF from AD patients at different stages of the AD continuum. The cohorts in question were the Emory Goizueta Alzheimer’s Disease Research Center (ADRC), the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
One example of a CSF protein whose levels changed was TREM2. Rare mutations in the TREM2 gene have been found to increase the risk of developing AD. TREM2 is a receptor protein expressed on the surface of microglia that can shed into CSF. As soluble TREM2 has already been suggested as a potential biomarker for microglial activation, its identification further corroborates the results of the current study. Thus, the research led by Drs. Jucker and Kaeser demonstrates that a panel of inflammatory glial proteins in CSF show changes in AD and are promising biomarker candidates for neuroinflammation.
Christian Haass, Ph.D., DZNE, Germany; and Mathias Jucker, Ph.D., and Stephan Kaeser, Ph.D., both of University of Tübingen
A link to the primary research article published:
Proceedings of the National Academy of Sciences (PNAS) is provided below:
A link to the interview from the University of Tübingen is also below: