Reduced myelin contributes to cognitive impairment in patients with monogenic small vessel disease

Denecke, Jannis; Dewenter, Anna; Lee, Jongho; Franzmeier, Nicolai; Valentim, Carolina; Kopczak, Anna; Dichgans, Martin; Pirpamer, Lukas; Gesierich, Benno; Duering, Marco; Ewers, Michael (2025): Reduced myelin contributes to cognitive impairment in patients with monogenic small vessel disease. Alzheimer's & Dementia, 21 (5): e70127. ISSN 1552-5260

Abstract

INTRODUCTION
Myelin is pivotal for signal transfer and thus cognition. Cerebral small vessel disease (cSVD) is primarily associated with white matter (WM) lesions and diffusion changes; however, myelin alterations and related cognitive impairments in cSVD remain unclear.

METHODS
We included 64 patients with familial cSVD (i.e., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) and 20 cognitively unimpaired individuals. χ separation applied to susceptibility weighted imaging was used to assess myelin and iron within WM hyperintensities, normal appearing WM, and two strategic fiber tracts. Diffusion-based mean diffusivity and free water were analyzed for comparisons. Cognitive impairment was assessed by the Trail Making Test.

RESULTS
CADASIL patients showed reduced myelin within WM hyperintensities and its penumbra in the normal appearing WM. Myelin was moderately correlated with diffusion and iron changes and associated with slower processing speed controlled for diffusion and iron alterations.

DISCUSSION
Myelin constitutes WM alterations distinct from diffusion changes and substantially contributes to explaining cognitive impairment in cSVD.

Highlights
χ-negative magnetic resonance signal was reduced within white matter hyperintensities and normal appearing white matter in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, suggesting widespread myelin decreases due to cerebral small vessel disease (cSVD).
χ-negative values were only moderately associated with diffusion tensor imaging derived indices including free water and mean diffusivity, suggesting that χ separation depicts distinct microstructural changes in cSVD.
Alterations in χ-negative values made a unique contribution to explain processing speed impairment, even when controlled for diffusion and iron changes.

• Dokumententyp: Artikel (Klinikum der LMU)
• Organisationseinheit (Fakultäten): 07 Medizin > Klinikum der LMU München > Institut für Schlaganfall- und Demenzforschung (ISD)
• DFG-Fachsystematik der Wissenschaftsbereiche: Lebenswissenschaften
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892