Bridging the Gap Between Fluid Biomarkers for Alzheimer’s Disease, Model Systems, and Patients

Abstract

Alzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of two proteins in fibrillar form: amyloid-β (Aβ) and tau. Despite decades of intensive research, we cannot yet pinpoint the exact cause of the disease or unequivocally determine the exact mechanism(s) underlying its progression. This confounds early diagnosis and treatment of the disease. Cerebrospinal fluid (CSF) biomarkers, which can reveal ongoing biochemical changes in the brain, can help monitor developing AD pathology prior to clinical diagnosis. Here we review preclinical and clinical investigations of commonly used biomarkers in animals and patients with AD, which can bridge translation from model systems into the clinic. The core AD biomarkers have been found to translate well across species, whereas biomarkers of neuroinflammation translate to a lesser extent. Nevertheless, there is no absolute equivalence between biomarkers in human AD patients and those examined in preclinical models in terms of revealing key pathological hallmarks of the disease. In this review, we provide an overview of current but also novel AD biomarkers and how they relate to key constituents of the pathological cascade, highlighting confounding factors and pitfalls in interpretation, and also provide recommendations for standardized procedures during sample collection to enhance the translational validity of preclinical AD models.

Tapping into the aging brain:In vivomicrodialysis reveals mirroring pathology between preclinical models and patients with Alzheimer’s disease

“…However, sampling from animals that model a progressive neurodegenerative disease is novel, and is thus of great value in the study of intra-variability of proteins that aggregate in AD. Importantly, our findings suggest that longitudinal CSF Aβ sampling in transgenic mice mirrors what is observed in AD patients and also correlates with what is observed with positron emission tomography (PET) scans 4,16 ; there is a gradual increase in both Aβ isoforms, with a gradual decrease in Aβ concentrations once Aβ plaques are deposited into the brain parenchyma followed by a slight increase and plateau in Aβ levels. Meanwhile, CSF tau levels are more variable early in the disease progression but appear to steadily increase after NFTs are deposited in the brain, as is observed in patients.…”

“…The application of our novel microdialysis technique for longitudinal CSF sampling thus further proves the translational validity of the 3xTg AD mouse model in the study of progressive AD pathology. Furthermore, successful application of longitudinal microdialysis can provide valuable insights into disease onset and staging, as well as aid the development and assessment of the efficacy of relevant treatments for AD neuropathology 4 . In contrast to classical CSF sampling in animals, such as drainage from the cisterna magna after sacrificing the animal 4 , our microdialysis method allows consecutive sampling from the same animal over time and causes minimal disturbance to the animal.…”

“…Furthermore, successful application of longitudinal microdialysis can provide valuable insights into disease onset and staging, as well as aid the development and assessment of the efficacy of relevant treatments for AD neuropathology 4 . In contrast to classical CSF sampling in animals, such as drainage from the cisterna magna after sacrificing the animal 4 , our microdialysis method allows consecutive sampling from the same animal over time and causes minimal disturbance to the animal. As a result, we can use animals as their own intrinsic controls, as done in the clinic with patients, and as such fully utilize these valuable experimental subjects by maximizing research data and relevant findings from preclinical models.…”

“…Direct comparison between microdialysis studies is not straightforward because the procedure may differ between study protocols and the microdialysis guide cannula can be implanted in different ways 4 4 . Meanwhile, in the APP/PS1 transgenic mouse line, CSF t-tau concentrations were approximately 500 pg/ml in young animals by collections from the cisterna magna 45 .…”

“…Intracerebral microdialysis can target ventricular CSF 4 , produced by the choroid plexus, which bathes the space between the arachnoid and pia mater. CSF is probably the most informative obtainable fluid for neurodegenerative disease prognosis, diagnosis and monitoring 5 .…”