Deep phenotyping of white matter tissue composition in dementia with Lewy bodies

Abstract

Abstract Background White matter signal abnormalities (WMSA) on MRI are common in dementia with Lewy bodies (DLB), and more severe WMSA have been associated with increased neurodegeneration in DLB. However, the underlying mechanisms of WMSA remain unclear. Single-Shell 3-Tissue Constrained Spherical Deconvolution (SS3T-CSD) is a diffusion weighted MRI technique that enables detailed characterisation of white matter by estimating three tissue fractions: white matter-like (T W ), grey matter-like (T G ), and cerebrospinal fluid-like (T C ), though to reflect healthy white matter, gliosis, and neurodegeneration. Our aim was to investigate these tissue fractions in WMSA and normal-appearing white matter (NAWM) in the DLB continuum and controls in two independent cohorts, and explore potential differences between patients on the DLB continuum and patients on the Alzheimer’s disease (AD) continuum or with Parkinson’s disease with dementia (PDD). Methods Using two independent cohorts we included 105 individuals along the DLB continuum, 56 along the AD continuum, 14 with PDD, and 125 controls. We assessed group differences in SS3T-CSD measures within NAWM and three WMSA regions extending from the lateral ventricles (juxtaventricular, periventricular, and deep). Results In NAWM, patients on the DLB continuum showed higher T C and a lower T W than controls. Within WMSA, patients on DLB continuum demonstrated lower T G and higher T W and T C in juxtaventricular regions than controls. The findings regarding T W in NAWM and juxtaventricular WMSA and T C in NAWM were replicated in both cohorts. Exploratory comparisons with patients with PDD showed that patients on the DLB continuum had a similar WMSA volume but lower T G in NAWM and periventricular WMSA, and higher T C in juxtaventricular WMSA. There were no statistically significant differences between patients on the DLB and AD continuums in tissue fractions. Conclusion Patients on the DLB continuum have altered tissue compositions in juxtaventricular WMSA and in NAWM compared to controls, which may reflect neurodegeneration instead of processes primarily driven by neuroinflammation or cerebrovascular disease. Our exploratory analysis suggests different findings between patients on the DLB continuum and patients with PDD that should be replicated in an independent cohort. Future endeavours should investigate these findings further by including biomarkers of synucleinopathy and AD-related pathology.

The authors' abstract, as published at the source. Alzheimer s Research & Therapy, 2026 · DOI ↗