Blood biomarkers for diagnosing dementia

Alzheimer"s disease is a severe, progressive and chronic disorder with strong cognitive deficits. The number of patients suffering from Alzheimer`s disease and other forms of dementia is dramatically increasing the next 50 years. Thus, research must focus to develop novel therapeutic and diagnostic methods. We have previously established in our lab the diagnosis of Alzheimer`s disease by measuring three well established biomarkers in cerebrospinal fluid: beta-amyloid(1-42), total tau and phosphorylated tau-181. These three markers allow to significantly diagnose Alzheimer`s disease with high sensitivity, but do not selectively diagnose other forms of dementia. In addition, the detection of cerebrospinal fluid biomarkers is limited because lumbal puncture is an invasive treatment and only performed in hospitals. Thus we aim to find biomarkers in blood, especially in peripheral blood mononuclear cells (focusing on monocytes), and to transfer such a detection into routine diagnosis. We will focus on 3 issues: (1) we want to detect markers of cellular senescence, such tumor suppressor proteins p21 and p53, and telomer shortening, (2) we want to measure changes in the ubiquitin-proteasome system and (3) we want to find changes of cell adhesion molecules important for transmigration of monocytes through the blood-brain barrier. It will be the aim of this project to find specific and sensitive blood biomarkers for Alzheimer`s disease, mild cognitive impairment and vascular dementia and other forms of dementia. Furthermore these biomarkers should allow to determine the conversion from controls into mild cognitive impairment or Alzheimer`s disease. This project should be the basis to translate basic-oriented research into clinical routine diagnosis.

Alzheimers disease (AD) is a severe, progressive and chronic disorder with strong cognitive deficits. The number of patients suffering from AD and other forms of dementia is dramatically increasing the next 50 years. Thus, research must focus to develop novel therapeutic and diagnostic methods. We have previously established in our laboratory the diagnosis of AD by measuring three well established biomarkers in cerebrospinal fluid: beta-amyloid(1-42), total tau and phosphorylated tau-181. These three markers allow to significantly diagnose AD with high sensitivity, but do not selectively diagnose other forms of dementia. In addition, the detection of cerebrospinal fluid biomarkers is limited because lumbal puncture is an invasive treatment and only performed in hospitals. Thus the aim of this project was to find biomarkers in blood, especially focusing on (1) plasma, (2) peripheral blood mononuclear cells (PBMC), (3) monocytes and (4) platelets. In the present project, we measured 45 biomarkers in plasma and found only 1 interesting candate for diagnosing AD in blood: NT-proBNP (N-terminal pro-brain natriuretic peptide). When analysing blood cells, it seems that monocytes may partly reflect an AD pathology and we found reduced telomer lengths, and changed monocyte inhibitory protein-1 (MIP1) and tumor suppressor protein p21. It was very interesting to observe that AD patients display changes in platelets, reflecting a vascular pathology. We found that Amyloid-precursor protein and 2 other proteins were changed (Epidermal growth factor, EGF and Matrix metalloproteinase-2, MMP-2). Our data show that changes in blood of AD patients are very heterogenous and a single marker may not be useful to diagnose AD. We hope in follow up studies to combine 3-4 biomarkers (in plasma, monocytes and platelets) to diagnose AD in blood. The diagnosis of other forms of dementia (especially starting mild forms) are even more difficult to make. We hope in future to replace the invasive CSF diagnosis with a blood diagnosis. We aim to include even more patients in a study and to follow up patients over years but also to calculate any effects of therapy. And finally, all results must be reproduced internationally in other laboratories before entering routine diagnosis.