Francois Bernier

Circulating miRNA biomarkers for Alzheimer's disease.

A minimally invasive diagnostic assay for early detection of Alzheimers disease (AD) is required to select optimal patient groups in clinical trials, monitor disease progression and response to treatment, and to better plan patient clinical care. Blood is an attractive source for biomarkers due to minimal discomfort to the patient, encouraging greater compliance in clinical trials and frequent testing. MiRNAs belong to the class of non-coding regulatory RNA molecules of ∼22 nt length and are now recognized to regulate ∼60% of all known genes through post-transcriptional gene silencing (RNAi). They have potential as useful biomarkers for clinical use because of their stability and ease of detection in many tissues, especially blood. Circulating profiles of miRNAs have been shown to discriminate different tumor types, indicate staging and progression of the disease and to be useful as prognostic markers. Recently their role in neurodegenerative diseases, both as diagnostic biomarkers as well as explaining basic disease etiology has come into focus. Here we report the discovery and validation of a unique circulating 7-miRNA signature (hsa-let-7d-5p, hsa-let-7g-5p, hsa-miR-15b-5p, hsa-miR-142-3p, hsa-miR-191-5p, hsa-miR-301a-3p and hsa-miR-545-3p) in plasma, which could distinguish AD patients from normal controls (NC) with >95% accuracy (AUC of 0.953). There was a >2 fold difference for all signature miRNAs between the AD and NC samples, with p-values<0.05. Pathway analysis, taking into account enriched target mRNAs for these signature miRNAs was also carried out, suggesting that the disturbance of multiple enzymatic pathways including lipid metabolism could play a role in AD etiology.

Identification of a new plasma biomarker of Alzheimer's disease using metabolomics technology.

We performed unbiased analysis of steroid-related compounds to identify novel Alzheimers disease (AD) plasma biomarkers using liquid chromatography-atmospheric pressure chemical ionization-mass spectroscopy. The analysis revealed that desmosterol was found to be decreased in AD plasma versus controls. To precisely quantify variations in desmosterol, we established an analytical method to measure desmosterol and cholesterol. Using this LC-based method, we discovered that desmosterol and the desmosterol/cholesterol ratio are significantly decreased in AD. Finally, the validation of this assay using 109 clinical samples confirmed the decrease of desmosterol in AD as well as a change in the desmosterol/cholesterol ratio in AD. Interestingly, we could also observe a difference between mild cognitive impairment and control. In addition, the decrease of desmosterol was somewhat more significant in females. Receiver operating characteristic (ROC) analysis between controls and AD, using plasma desmosterol shows a score of 0.80, indicating a good discrimination power for this marker in the two reference populations and confirms the potential usefulness of measuring plasma desmosterol levels for diagnosing AD. Further analysis showed a significant correlation of plasma desmosterol with Mini-Mental State Examination scores. Although larger sample populations will be needed to confirm this diagnostic marker sensitivity, our studies demonstrate a sensitive and accurate method of detecting plasma desmosterol concentration and suggest that plasma desmosterol could become a powerful new specific biomarker for early and easy AD diagnosis.

Comparative lipidomics of mouse brain exposed to enriched environment.

Several studies have shown that housing conditions and environmental exposure to a series of stimuli lead to behavior improvement in several species. While more works have been focused on illustrating changes of the proteome and transcriptome following enriched environment exposure in mice, little has been done to understand changes in the brain metabolome in this paradigm due to the complexity of this type of analysis. In this paper, lipidomics focused on phospholipids and gangliosides were conducted for brain tissues of mice exposed to enriched or impoverished conditions. We optimized previously reported method and established a reliable relative comparison method for phospholipids and gangliosides in brain tissue using prefractionation with weak anion exchange cartridge. We used liquid chromatography mass spectrometry to explore metabolic signatures of the cerebral cortex and hippocampus after confirming the animals had significant memory differences using the fear conditioning paradigm and brain immunohistochemistry. Although both cerebral cortex and hippocampus regions did not show major alterations in ganglioside composition, we found significant differences in a series of phospholipids containing 22:6 fatty acid in the prefrontal cortex, indicating that environmental enrichment and impoverished housing conditions might be a relevant paradigm to study aberrant lipid metabolism of docosahexaenoic acid consumption. Our study highlights the hypothesis-generating potential of lipidomics and identifies novel region-specific lipid changes possibly linked not only to change of memory function in these models, but also to help us better understand how lipid changes may contribute to memory disorders.

A single dose of the beta-secretase inhibitor, e2609, decreases CSF bace1 enzymatic activity in cynomolgus monkeys

Figure 2. Correlation Between CSF BACE1 Activity Levels and CSF Ab 1-x levels in All Monkey Samples Mark Matijevic, Hideki Watanabe, Yoshiaki Sato, Francois Bernier, Shannon McGrath, Lynne Burns, Noboru Yamamoto, Makoto Ogo, Zoltan Dezso, Jesse Chow, Yoshiya Oda, June Kaplow, Bruce Albala, Eisai, Andover, MA, USA; Eisai, Tsukuba, Japan; Formerly Eisai (when work was completed), Worcester, MA, USA; Eisai, Woodcliff Lake, NJ, USA; Eisai,Woodcliffe Lake, NJ, USA. Contact e-mail: mark_matijevic@eisai.com

Reduced plasma desmosterol-to-cholesterol ratio and longitudinal cognitive decline in Alzheimer's disease

We here examined whether plasma desmosterol‐to‐cholesterol ratio (DES/CHO) is decreased in patients with Alzheimers disease (AD) and investigated the association between plasma DES/CHO and longitudinal cognitive decline.