Plasma ceramides and CERT proteins as prognostic biomarkers for AD

2016  -  Maastricht, Netherlands

Organizations

Maastricht University Medical Center

Project description

Accumulating research suggests that pathophysiological changes associated with Alzheimer’s Disease (AD) begin at least 10 to 25 years before dementia onset.  There are currently no means of identifying which patients are at greatest risk of developing AD.  While drug development has primarily focused on anti-amyloid therapies, they have been not very successful to date and other therapeutic targets are likely needed.  Sphingolipids, including ceramides and sphingomyelins, are particularly enriched in the central nervous system.  These lipids have important structural roles and also modulate a wide variety of signaling events including cellular differentiation and proliferation, apoptosis, cytokine production, and synaptic plasticity. Lipidomic, metabolomic and targeted approaches have identified pathways and products of sphingolipid metabolism that are altered early in the course of AD and contribute to the neuropathological alterations associated with AD.  Ceramide transporters (CERTs) are, the only proteins that are able to transport ceramide. The lipid ceramide and its transporter CERT are very abundant in the central nervous system.

Dr. Martinez’s group has previously demonstrated that CERT is present in rat and human brain and colocalizes with amyloid in plaques. The overall goal of the project is in 400 individuals to measure and examine levels of plasma ceramides and CERT proteins in relation to each other, cognitive performance and MRI using already collected data and samples from the Maastricht Study. This study is led by Dr Martinez and conducted at the Department of Psychiatry and Psychology at the School for Mental Health and Neuroscience in collaboration with the Cardiovascular Research Institute Maastricht, the Department of Neuropsychology and Psychopharmacology at Maastricht University and the Metabolomics Core, at Mayo Clinic in collaboration with Prof. Mielke.

Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging

The pathophysiological process of AD begins many years before the emergence of clinical symptoms, providing a window of opportunity to intervene. The optimal time for disease-modifying drug treatment may therefore be in the presymptomatic stage of AD, where the disease is still hidden. However, current AD treatments are aimed at individuals that are already demented and mainly provides symptomatic, short-term benefits, without affecting the underlying pathogenic mechanisms and the progression of the disease. A major challenge in the field is to identify which asymptomatic individuals are most likely to develop AD and to develop disease-modifying drugs that can be administered to these at-risk individuals to prevent or delay disease onset. It is likely that levels of specific sphingolipids and their transporters could be used as new biomarkers for early diagnosis, and lead to early recognition of such patients at the time they are cognitively normal and try to prevent them from progressing.

Anticipated outcome

The proposed study will determine whether plasma CERT and ceramide levels are associated with each other and with cognitive performance and neuroimaging measures. As the Maastricht Study aims to perform follow-up visits, future research will be able to determine the predictive value of CERT and ceramides for mild cognitive impairment and AD. We will also be able to examine the longitudinal relationships between CERT, ceramides, and neuroimaging measures. This study is critical in helping to better understand the relationship between CERT and ceramide levels in the blood. This research could lead to the identification of a blood based biomarker to predict cognitive decline.

Additionally, the proposed preclinical studies will help the development of therapeutics for neurodegenerative diseases of aging:
(i) Invigorate the use of drugs targeting the sphingolipid pathway for the prevention or delay of AD.
(ii) Identify which asymptomatic elderly individuals might benefit from sphingolipids modulation for the prevention or delay of AD.
(iii) Develop targeted therapies for select patient subgroups by stratifying patients according to their levels of sphingolipids metabolites.
(iv) Design targeted clinical trials which can dramatically reduce the number of patients required for the study and the associated costs.