Clinical significance of fluid biomarkers in Alzheimer's Disease.

The number of patients with Alzheimer's Disease (AD) and other types of dementia disorders has drastically increased over the last decades. AD is a complex progressive neurodegenerative disease affecting about 14 million patients in Europe and the United States. The hallmarks of this disease are neurotic plaques consist of the Amyloid-ß peptide (Aß) and neurofibrillary tangles (NFTs) formed of hyperphosphorylated Tau protein (pTau). Currently, four CSF biomarkers: Amyloid beta 42 (Aß42), Aß42/40 ratio, Tau protein, and Tau phosphorylated at threonine 181 (pTau181) have been indicated as core neurochemical AD biomarkers. However, the identification of additional fluid biomarkers, useful in the prognosis, risk stratification, and monitoring of drug response is sorely needed to better understand the complex heterogeneity of AD pathology as well as to improve diagnosis of patients with the disease. Several novel biomarkers have been extensively investigated, and their utility must be proved and eventually integrated into guidelines for use in clinical practice. This paper presents the research and development of CSF and blood biomarkers for AD as well as their potential clinical significance. Upper panel: Aß peptides are released from transmembrane Amyloid Precursor Protein (APP) under physiological conditions (blue arrow). In AD, however, pathologic accumulation of Aß monomers leads to their accumulation in plaques (red arrow). This is reflected in decreased concentration of Aß1-42 and decreased Aß42/40 concentration ratio in the CSF. Lower panel: Phosphorylated Tau molecules maintain axonal structures; hyperphosphorylation of Tau (red arrow) in AD leads to degeneration of axons, and release of pTau molecules, which then accumulate in neurofibrillary tangles. This process is reflected by increased concentrations of Tau and pTau in the CSF.

Osteoinductive effect of cerebrospinal fluid from brain-injured patients.

Patients with traumatic brain injury (TBI) are predisposed to heterotopic ossification, which is believed to be due to osteoinductive factors released at the site of the brain injury. To date, little is known about the presence of such factors in human cerebrospinal fluid (CSF). This study investigated whether CSF of TBI patients is osteoinductive. In addition, known osteoinductive factors--such as bone morphogenetic protein (BMP)-2, BMP-4, and BMP-7, and S100B--were measured in CSF. Eighty-four consecutive patients were classified according to brain pathology: TBI (n = 11), non-traumatic brain pathology (NTBP) (n = 26), and no brain pathology (control group) (n = 47). The osteoinductive effect of CSF was measured repeatedly in proliferation assays using a fetal human osteoblast cell line. The mean proliferation rate (normalized to the internal negative control) of the TBI, NTBP, and control groups was 138.2% (SD 13.1), 110.0% (SD 22.1), and 118.8% (SD 16.9), respectively. The potentially confounding effect of age was investigated further by restricting the selection of patients for analysis to that of the oldest patient in the TBI group and use of multiple regression analysis. After implementation of both, it was shown that age is highly unlikely to account for the higher rates of proliferation observed among the TBI patients in this study. Of note, the TBI group had a significantly higher mean proliferation rate than the NTBP (p = 0.001) and the control group (p = 0.006). S100B and BMP-2, -4, or -7 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). There was no correlation between proliferation rates and S100B (r = 0.023). Only three of 36 CSF samples had measurable levels of BMP-2 and -7, and none had detectable concentrations of BMP-4. Consequently, it is unlikely that S100B or BMP-2, -4, or -7 are the putative osteoinductive factors. The results indicate that CSF from TBI patients has an osteoinductive effect in vitro. However, the osteoinductive factor has still to be characterized.

Cerebrospinal fluid contains biologically active bone morphogenetic protein-7.

Bone morphogenetic proteins (BMPs) regulate the development and function of many types of neurons. However, little is known of the actual concentrations of BMPs in the various parts of the brain. In this study, we considered the possibility that BMPs might be present in cerebrospinal fluid (CSF). Western blot analysis of normal adult bovine CSF revealed the presence of dimeric and monomeric forms of BMP-7, and the concentration of this molecule was found to be approximately 12 ng/ml in a radioimmunoassay. Since BMP-7 is known to induce dendritic growth in rat sympathetic neurons, this was used as a bioassay to examine the biological activity of the BMP-7 present in CSF. Addition of normal bovine CSF to cultures of sympathetic neurons produced a dose-dependent increase in dendritic growth and the magnitude of this response approximated that obtained with maximally effective concentrations of exogenous BMP-7. Moreover, CSF-induced dendritic growth was inhibited by follistatin, a protein that can sequester BMPs, and by either of two monoclonal antibodies that react with BMP-7. These results show that, unlike most other neurotrophic factors, BMP-7 is a constituent of normal CSF and is present at concentrations sufficient to elicit a near maximal biological response.