Fluid Biomarkers in Alzheimer’s Disease and Other Neurodegenerative Disorders: Toward Integrative Diagnostic Frameworks and Tailored Treatments

Abstract

The diagnosis of neurodegenerative diseases (NDDs) represents an increasing social burden, with the unsolved issue of disease-modifying therapies (DMTs). The failure of clinical trials treating Alzheimer′s Disease (AD) so far highlighted the need for a different approach in drug design and patient selection. Identifying subjects in the prodromal or early symptomatic phase is critical to slow down neurodegeneration, but the implementation of screening programs with this aim will have an ethical and social aftermath. Novel minimally invasive candidate biomarkers (derived from blood, saliva, olfactory brush) or classical cerebrospinal fluid (CSF) biomarkers have been developed in research settings to stratify patients with NDDs. Misfolded protein accumulation, neuroinflammation, and synaptic loss are the pathophysiological hallmarks detected by these biomarkers to refine diagnosis, prognosis, and target engagement of drugs in clinical trials. We reviewed fluid biomarkers of NDDs, considering their potential role as screening, diagnostic, or prognostic tool, and their present-day use in clinical trials (phase II and III). A special focus will be dedicated to novel techniques for the detection of misfolded proteins. Eventually, an applicative diagnostic algorithm will be proposed to translate the research data in clinical practice and select prodromal or early patients to be enrolled in the appropriate DMTs trials for NDDs.

Altering Brain Amyloidosis by Intra-Lingual and Extra-Nasal Exposure of Aβ Aggregates

“…The importance of peripheral Aβ pools in AD is further demonstrated by the fact that circulating monomeric Aβ contribute to brain amyloid plaques [ 36 , 37 , 38 ], and that damage in peripheral tissues associated with Aβ clearance enhance pathological progression [ 30 , 34 , 39 , 40 , 41 ]. Moreover, several reports suggest that disease-associated Aβ particles circulate in biological fluids such as the cerebral-spinal fluid and blood [ 42 , 43 , 44 , 45 ]. Considering the above-mentioned evidence and the well-established prion-like properties of misfolded Aβ [ 18 ], it is plausible that altering the equilibrium of this disease-associated protein in the periphery may have important implications in the progression of AD.…”

Current advances in our understanding of circular RNA (circRNA) in Alzheimer’s disease (AD); the potential utilization of synthetic circRNAs as a therapeutic strategy in the clinical management of AD

“…The detailed characterization of AD heterogeneity is essential for precision diagnostics, personalized predictions, and recruitment of relatively homogeneous sets of patients into clinical trials. This has also been referred to as a "precision", "personalized" or "individualized" medicinal approach to optimize the clinical management of the disease course for the individual AD patient, and in part involves a mapping of dysregulated miRNA-and mRNA-regulated gene expression patterns in individual AD patients (Dong et al, 2017;Hampel et al, 2019Hampel et al, , 2020Bellenguez et al, 2022;Giampietri et al, 2022;Wen et al, 2022;Wingo et al, 2022). More specifically, "precision" or "individualized" medicine is an emerging systematic undertaking that applies the most recent scientific and technological advances to overcome the limitations of Western medicine that involve sign-and symptom-based phenotypic diagnoses and the traditional "one-size-fits-all' approach.…”

“…Currently the "precision medicine" approach has been to investigate early pathophysiological changes of AD to fully capture the complexity of the disease, and has been essential to develop timely screening, detection, diagnostic, prognostic and therapeutic interventions in significantly heterogeneous AD patient populations. Importantly "precision medicine" delineates which therapeutic approach or treatment strategy would be the most effective for a specific individual, at a specified disease stage, across multiple medical research fields that include molecular-genetics, imaging technologies, neuroscience, neurology and psychiatry and the identification of miRNA-and/or mRNA-based biomarkers in the CSF and blood (Hampel et al, 2019;Lemercier et al, 2021;Giampietri et al, 2022;Jellinger 2022;Yamamoto et al, 2022). "Precision medicine" achieves the greatest success when multiple interdisciplinary diagnostic parameters are integrated to yield the most accurate diagnostic analysis of the AD patient who can be subsequently treated using an individualized combination therapy approach or multi-target-directed methodologies.…”

SIMOA Diagnostics on Alzheimer’s Disease and Frontotemporal Dementia

“…To date, the clinical diagnosis of ND patients, including AD and FTD, has mostly been based on imaging and biomarker measurements in CSF or blood (serum or plasma). Methods already used are the enzyme-linked immunosorbent assay (ELISA) [ 30 ] and the real-time quaking-induced conversion assay (RT-QuIC) [ 31 ]. Τhis combinatory diagnostic protocol currently in use could be improved by novel detection methods like electrochemiluminescence immunoassays (ECLIA) and immunomagnetic reduction (IMR) [ 30 ], or by the utilization of biomarker panels like Luminex xMAP [ 32 ], NeuroToolKit [ 17 ], and single-molecule array (SIMOA) [ 33 ].…”