Developing BBB-ASL as non-invasive early biomarker of Alzheimer's disease (DEBBIE)

Developing BBB-ASL as non-invasive early biomarker of Alzheimer's disease (DEBBIE)

Funded by JPND COFUND TÜBİTAK 1071 Grants (121N030) 

Principal Investigator: Alp Dinçer 

Co-Investigators: Esin Öztürk Işık, Matthias Günther, Eric Achten, Henk Mutsaerts, Udunna Anazodo, Tormod Fladby, Catherine Morgan, David Thomas, Jennifer Linn, Saima Hilal

Researchers:  Ayse Irem Cetin, Gulce Turhan

Abstract

Alzheimer's Disease (AD) is a progressive neurodegenerative disease with multiple pathologies. Biomarkers that reliably detect the onset of the disease before any clinical symptoms appear are crucial for the diagnosis of AD and related dementias. One of the earliest pathological changes in AD is the loss of Blood-Brain-Barrier (BBB) integrity. Non-invasive arterial spin labeling magnetic resonance imaging (ASL-MRI) technique measures blood perfusion. Perfusion change measured quantitatively by the ASL-MRI technique can provide information in the diagnosis and follow-up of BBB integrity. The project '(Developing BBB-ASL as non-invasive early biomarker of Alzheimer's disease) (DEBBIE)' presented to the Joint Program for Neurodegenerative Disease Research (JPND) has proposed to be developed a clinical imaging biomarker called as "BBB-ASL" that maps the loss of BBB integrity in AD. The proposed DEBBIE project was entitled to receive support under the second call of JPND JPCOFUND-2 ERA-NET Cofund-2 2020. The European Union allowed this project consortium to expand, and the consortium Coordinator  Prof. Dr. Matthias Günther  reached Dr. Alp Dinçer at Mehmet Ali Aydınlar Acıbadem University professor and Assoc. Dr. Esin Öztürk Işık at Boğaziçi University in Turkey as partner. As a result of the interviews, the partners in Turkey have agreed to the application of the BBB-ASL technique in brain tumors. In this context, it is aimed to evaluate the BBB differences in different histopathological tumor grades in patients with glioma, a type of brain tumor, using the BBB-ASL technique. Moreover, the parameters of BBB integrity differences in histopathological tumor grades will be classified by machine learning algorithms. Additionally, the disruption in BBB integrity and water exchange differences between AD and glioma patients will be assessed.  

Keywords: Neurodegenerative disorders, dementia, brain imaging, brain tumors, blood-brain-barrier, arterial spin labeling

Objectives:

• The primary objective of the DEBBIE project is to develop the BBB-ASL MR technique, enabling the reliable acquisition of all relevant BBB maps within 5 minutes in a patient-specific and time-efficient manner. The technique will also incorporate adaptive auto-calibration for enhanced performance.
• Another goal is to standardize multicenter image processing, considering physiological parameters, and creating a reference atlas that showcases normal BBB integrity maps. This will aid in interpreting information from the obtained BBB-ASL images.
• The project will focus on comparing the BBB-ASL technique, which measures BBB integrity, with the PET technique within the DEBBIE project's scope.
• To evaluate the comprehensive statistical predictive analysis and clinical applicability of BBB-ASL, AD patients will be periodically screened using the BBB-ASL technique, and BBB integrity will be assessed.
• The DEBBIE project aims to apply the developed BBB-ASL techniques and analysis methods to glioma patients. Machine learning algorithms such as support vector machines and decision trees will be used to classify BBB integrity differences among different histopathological tumor grades. Furthermore, the project will investigate differences in water exchange parameters between AD and glioma, measured using BBB-ASL.

Results

In the initial studies, higher CBF and lower minimum Tex values (except in patient 2 with a grade 2 oligodendroglioma) were observed in contrast-enhancing tumor regions than in NAWM and NAGM. While patient 1 and 4 had very high maximum CBF, patient 2, with an oligodendroglioma, had lower CBF values. Although patient 3 had a GBM, he also had a lower maximum CBF due to the localization of the tumor, which was next to the ventricles. Minimum Tex values were lower in the tumor region than NAGM in all GBM patients. Especially, patients 1 and 4 had very low minimum Tex values, indicating highly leaky tumor vasculature. On the other hand, minimum Tex values for patients 2 and 3 were similar to their NAGM values, which might indicate that they had rather intact BBB. The maximum CBF in the tumor region over the mean CBF in NAGM were 1.3, 0.3, 0.4, and 1.3 for these four patients in order, respectively. On the other hand, minimum Tex in tumor region over the mean Tex in NAGM were 0.2, 1.3, 0.7, and 0.1 for these patients.

Figure. Post-contrast T1w MRI (tumor in green), T2w MRI, CBF, and Tex maps of an example GBM patient. 

Table. Mean, minimum, and maximum CBF and Tex values for volunteers and glioma patients at the tumor region, normal-appearing white matter and normal-appearing gray matter regions.

Publications

Conference Proceedings

1. Turhan G, Çetin Aİ, Mahroo A, Padrela BE, Konstandin S, Hoinkiss DC, Breutigam NJ, Eickel K, Petr J, Mutsaerts HJMM, Danyeli A, Ozduman K, Guenther M, Dincer A, Ozturk-Isik E. Perfusion and Time of Exchange Measurements Using BBB-ASL in Gliomas: The Initial Experience. International Society for Magnetic Resonance in Medicine. Toronto, Canada, June 3-8, 2023 (digital poster)
2. B. Padrela, M. Tee, M. Sneve, A. Mahroo, O. Geier, D. Thomas, C. Morgan, P. Moyaert, E. Ozturk-Isik, W. Nordhøy, L. Pålhaugen, J. Linn, P. Selnes, K. Eickel, S. Konstandin, J. Kuijer, D. Hoinkiss, N. Breutigam, M. Buck, R. Achten, F. Barkhof, S. Hilal, T. Fladby, U. Anazodo, J. Petr, H. Mutsaerts, and M. Günther, DEveloping Blood-Brain barrier arterial spin labeling as a non-Invasive Early biomarker (DEBBIE), International Society for Magnetic Resonance in Medicine, Toronto, Canada, June 3-8, 2023, pp. 367. (oral presentation)
3. Turhan G, Ozturk-Isik E. Classification of Histopathological Grades of Glial Tumors on Arterial Spin Labeling MRI Using Spatio-temporal Convolutional Neural Networks. GliMR 3rd Annual Meeting. Kuşadası, Turkey, September 28-30, 2022 (oral presentation) 
4. Çetin Aİ, Turhan G, Danyeli AE, Pamir MN, Ozduman K, Dincer A, Ozturk-Isik E. Classification of Gliomas using BBB-ASL and Machine Learning. GliMR 3rd Annual Meeting. Kuşadası, Turkey, September 28-30, 2022 (oral presentation)