Preparing for CADASIL therapy

Gravesteijn, G. (2020)

Doctoral Thesis

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most prevalent hereditary small vessel disease. CADASIL patients typically develop recurrent strokes from mid-adult age onwards, leading to cognitive impairment and ultimately vascular dementia. As there is currently no therapy that can delay or prevent CADASIL, the CADASIL research group of the Leiden University Medical Center is developing a therapeutic approach for CADASIL, called “NOTCH3 cysteine correction”.
The aim of this PhD-project was to advance CADASIL therapy development.

The work in this thesis provides the first in human evidence that the therapeutic approach of NOTCH3 cysteine correction leads to reduced protein aggregation, by describing a family with naturally occurring NOTCH3 cysteine correction. Furthermore, this thesis includes the results of the longest follow-up study to date of individuals with CADASIL, as well as and the identification of Neurofilament Light-chain (NfL) as blood biomarker in CADASIL. In a pre-clinical CADASIL disease model, potential pre-clinical biomarkers were explored and this resulted in the development of a GOM deposit classification system.

• CADASIL
• small vessel disease (SVD)
• Vascular dementia
• stroke
• NOTCH3
• therapy development
• NOTCH3 cysteine correction
• Biomarkers
• Neurofilament Light-chain (NfL)
• Granular Osmiophilic Material deposits (GOM)

• All authors: Gravesteijn, G.
• Supervisor: Aartsma-Rus, A.
• Co-supervisor: Lesnik Oberstein, S.A.J.; Rutten, J.W.
• Committee: Meijer, O.C.; Duering, M.; Karlström, H.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center [LUMC], Leiden University
• Date: 2020-10-28
• ISBN (print): 9789463326704
• Sponsorship: The research described in this thesis was financially supported by the Netherlands Brain Foundation.