The GFAP proteoform puzzle: How to advance GFAP as a fluid biomarker in neurological diseases.

Glial fibrillary acidic protein (GFAP) is a well-established biomarker of reactive astrogliosis in the central nervous system because of its elevated levels following brain injury and various neurological disorders. The advent of ultra-sensitive methods for measuring low-abundant proteins has significantly enhanced our understanding of GFAP levels in the serum or plasma of patients with diverse neurological diseases. Clinical studies have demonstrated that GFAP holds promise both as a diagnostic and prognostic biomarker, including but not limited to individuals with Alzheimer's disease. GFAP exhibits diverse forms and structures, herein referred to as its proteoform complexity, encompassing conformational dynamics, isoforms and post-translational modifications (PTMs). In this review, we explore how the proteoform complexity of GFAP influences its detection, which may affect the differential diagnostic performance of GFAP in different biological fluids and can provide valuable insights into underlying biological processes. Additionally, proteoforms are often disease-specific, and our review provides suggestions and highlights areas to focus on for the development of new assays for measuring GFAP, including isoforms, PTMs, discharge mechanisms, breakdown products, higher-order species and interacting partners. By addressing the knowledge gaps highlighted in this review, we aim to support the clinical translation and interpretation of GFAP in both CSF and blood and the development of reliable, reproducible and specific prognostic and diagnostic tests. To enhance disease pathology comprehension and optimise GFAP as a biomarker, a thorough understanding of detected proteoforms in biofluids is essential.

Rationale and design of the ABOARD project (A Personalized Medicine Approach for Alzheimer's Disease).

The key to stopping Alzheimer's disease (AD) lies in the pre-dementia stages, with the goal to stop AD before dementia has started. We present the rationale and design of the ABOARD (A Personalized Medicine Approach for Alzheimer's Disease) project, which aims to invest in personalized medicine for AD. ABOARD is a Dutch public-private partnership of 32 partners, connecting stakeholders from a scientific, clinical, and societal perspective. The 5-year project is structured into five work packages on (1) diagnosis, (2) prediction, (3) prevention, (4) patient-orchestrated care, and (5) communication and dissemination. ABOARD functions as a network organization in which professionals interact cross-sectorally. ABOARD has a strong junior training program "Juniors On Board." Project results are shared with society through multiple communication resources. By including relevant partners and involving citizens at risk, patients, and their care partners, ABOARD builds toward a future with personalized medicine for AD. Highlights: ABOARD (A Personalized Medicine Approach for Alzheimer's Disease) is a public-private research project executed by 32 partners that functions as a network organization.Together, the project partners build toward a future with personalized medicine for Alzheimer's disease.Although ABOARD is a Dutch consortium, it has international relevance.ABOARD improves diagnosis, prediction, prevention, and patient-orchestrated care.

Molecular Biomarkers for Adrenoleukodystrophy: An Unmet Need.

X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in the ABCD1 gene and the accumulation of very long-chain fatty acids in plasma and tissues. Patients present with heterogeneous clinical manifestations which can include adrenal insufficiency, myelopathy, and/or cerebral demyelination. In the absence of a genotype-phenotype correlation, the clinical outcome of an individual cannot be predicted and currently there are no molecular markers available to quantify disease severity. Therefore, there is an unmet clinical need for sensitive biomarkers to monitor and/or predict disease progression and evaluate therapy efficacy. The increasing amount of biological sample repositories ('biobanking') as well as the introduction of newborn screening creates a unique opportunity for identification and evaluation of new or existing biomarkers. Here we summarize and review the many studies that have been performed to identify and improve knowledge surrounding candidate molecular biomarkers for ALD. We also highlight several shortcomings of ALD biomarker studies, which often include a limited sample size, no collection of longitudinal data, and no validation of findings in an external cohort. Nonetheless, these studies have generated a list of interesting biomarker candidates and this review aspires to direct future biomarker research.