Vascular Calcification-Induced Cognitive Impairment in Pseudoxanthoma Elasticum

Abstract

Background: With no approved effective therapies for cognitive impairment, the need for new targetable phenotypes is high. We hypothesize that medial arterial calcification of the intracranial arteries, which is a modifiable process, results in increased arterial pulsatility, brain damage, and cognitive decline. Pseudoxanthoma elasticum (PXE) is a monogenetic disorder which results in non-atherosclerotic medial arterial calcification and was therefore used to investigate the effect of medial calcification of the carotid siphon on arterial pulsatility, brain volumes, small vessel disease and cognition. Methods: Magnetic resonance imaging and neurocognitive testing in 50 PXE patients and 42 age-matched controls were performed to compare arterial pulsatility, brain volumes, small vessel disease burden and cognition. Also, in the PXE patients we tested the association of carotid siphon calcification, measured by computed tomography, with arterial pulsatility and its association with brain volumes, small vessel disease and cognition. Results: PXE patients had a significantly higher pulsatility index (1.05(0.94-1.20) vs. 0.94(0.82-1.04), p=0.01), lower grey matter volumes (598±53 vs. 632±53ml, p=0.004), more white matter lesions (WML) (2.6(0.5-7.6) vs. 1.1(0.5-2.4)ml, p=0.04) and more lacunar infarctions (total 64 vs. 8, p=0.04) than controls. Patients scored lower on concentration and processing speed, but higher on memory. Carotid siphon calcification was associated with higher pulsatility indexes (β:0.09, 95%CI: 0.01;0.18), more WMLs (β:5.7, 95%CI: 0.9;10.5) and infarctions (RR:2.8, 95%CI: 1.1;7.0). Higher pulsatility was associated with lower grey matter volumes (β:-54.1, 95%CI: -107.8;-0.5), more WMLs (β:15.5, 95%CI: 7.7;23.3) and lower concentration and processing speed (β:-0.9, 95%CI: -1.8;-0.1). Conclusions: In PXE patients, medial calcification of the carotid siphon, was associated with higher pulsatility index which might contribute to grey matter damage, small vessel disease and cognitive impairment, particularly involving concentration and processing speed. Since arterial calcification is a modifiable process, we identified a potential novel target for the treatment of cognitive impairment. Funding: Dr. Zwanenburg is supported by the European Reasearch Council under the European Union’s Seventh Framework Programme (FP7/2007-2013), grant agreement no. 337333. The research of Prof. Dr. Hendrikse has received funding from the European Research Council under the European Union's Horizon 2020 Programme (H2020)/ERC grant agreement n° 637024 (HEARTOFSTROKE) and H2020 grant agreement No 666881, SVDs@target. Declaration of Interest: J. Bartstra has nothing to disclose Dr. Spiering has nothing to disclose Dr. Kranenburg has nothing to disclose Dr. Geurts has nothing to disclose Dr. den Harder has nothing to disclose Dr. Witkamp has nothing to disclose Dr. Wolterink has nothing to disclose Dr. Zwanenburg reports grants from European research council, from null, during the conduct of the study. Dr. van Valen has nothing to disclose Dr. Koek has nothing to disclose Prof. dr. Mali has nothing to disclose Prof. dr. de Jong has nothing to disclose Prof. Dr. Hendrikse reports grants from European research council, from null, during the conduct of the study. Ethical Approval: The study was approved by the institutional review board of the UMCU (number 16-622/M-X) and written informed consent was obtained from all participants.