Background

Sporadic cerebral small vessel disease (SVD) has a heterogeneous underlying pathology, and current SVD magnetic resonance imaging (MRI) markers do not accurately capture this heterogeneity. Novel ultrahigh-field (7T) brain MRI markers provide a window of opportunity to study early changes and potential determinants of SVD. White matter hyperintensity (WMH) shape is a relatively novel MRI marker of SVD and has shown prognostic potential. However, the exact microstructural changes within or surrounding WMHs or potential causes related to WMH shape variations are unknown. Furthermore, impaired brain clearance via the recently discovered brain clearance system may be another early change or potential cause of SVD.

Objective

In the White Matter Hyperintensity Shape and Brain Clearance (WHIMAS) study, we aim to assess the link between WMHs-their shape in particular-and brain clearance and other MRI markers on ultrahigh-field (7T) brain MRI and show whether these markers are associated with cognitive functioning in older adults with memory complaints.

Methods

This is a cross-sectional study conducted at the Leiden University Medical Center. A total of 50 outpatients from the memory or geriatric clinic aged ≥65 years will be recruited for a 3T and 7T MRI scan (including clinical structural scans, eg, 3D T1-weighted, 3D fluid-attenuated inversion recovery), and experimental scans such as cerebrospinal fluid (CSF)-selective T2-prepared readout with acceleration and mobility encoding (CSF-STREAM) and the relationship between blood oxygen level-dependent [BOLD] signals and CSF flow) and magnetic resonance fingerprinting, as well as a standardized neuropsychological test battery (domains: memory, executive function, visuoconstruction, and processing speed). We will assess WMH shape markers (solidity, convexity, concavity index, fractal dimension, and eccentricity) and brain clearance markers (CSF mobility and the relationship between blood oxygen level-dependent signals and CSF flow) and study their relationship to other MRI markers and cognitive functioning using multivariable regression analyses.

Results

Patient inclusion started in January 2023, and study enrollment of patients is expected to finish in the second quarter of 2027, whereas the main results are expected to be published in the first quarter of 2028.

Conclusions

We aim to understand variations in WMH shape and find their relationship to cerebral SVD and markers of brain clearance and cognitive functioning. WMH shape and brain clearance markers early in the disease process of SVD are extremely important as they may represent a basis for future patient selection for lifestyle interventions or for treatment trials aimed at the prevention of dementia.

Trial registration

ClinicalTrials.gov NCT06010511; https://clinicaltrials.gov/study/NCT06010511.

International registered report identifier (irrid)

DERR1-10.2196/77681.

©Jasmin Annica Kuhn-Keller, Ingmar Eiling, Lydiane Hirschler, Lena Václavů, Marie-Noëlle Witjes-Ané, Marjolein Wijngaarden, Martijn Nagtegaal, Ece Ercan, Nathaly Rius Ottenheim, Marjan van der Elst, Evelien Sohl, Mark A van Buchem, Simon Mooijaart, Matthias JP van Osch, Jeroen de Bresser. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 04.12.2025.