Longitudinal white matter hyperintensities in Down’s syndrome

Abstract

AbstractBackgroundDown’s syndrome (DS) is a genetically determined form of Alzheimer’s disease (AD). Typically not complicated by systemic vascular risk factors, the DS population represents a unique opportunity to unravel the complex relationship between AD and cerebrovascular disease. Here, we aim at studying the evolution over time of white matter hyperintensities (WMHs), a key hallmark of cerebrovascular disease frequently found in AD, and to assess their topographical progression and associations with AD biomarkers in adults with DS.MethodThis longitudinal study included 43 DS adults (age = 39.8±10.4y; females = 41.9%; n = 37 asymptomatic AD, n = 6 symptomatic AD) and 81 euploid controls (age = 53.7±6.2y; females = 67.3%) from the Down‐Alzheimer Barcelona Neuroimaging Initiative, with at least 2 MRI visits with T1 and FLAIR acquisitions (time delay = 3.4±1.6y). WMHs were segmented using the Lesion Prediction Algorithm implemented in the Lesion Segmentation Toolbox (SPM12). WMH volumes were extracted in 36 regions of interest and used to compute total and regional annual volume changes. Non‐parametric statistical tests were performed to assess the effect of disease severity on WMH volume changes over time and define associations between longitudinal WMHs and baseline demographic and genetic data, and fluid biomarkers.ResultTotal annual WMH volume change increased in symptomatic DS compared to both asymptomatic DS and controls (Figure 1A). Regionally, WMH load increased in regions showing WMH at baseline in all groups (Figure 2). These changes were greater and more distributed, involving layers more distant from the ventricles (especially in occipito‐parietal regions) in symptomatic DS. Age, but not sex, intellectual disability, or APOEε4 status, was associated with longitudinal WMH in DS (Figure 1B‐F): the annual WMH volume changes in DS differed from controls at age ∼45y. Finally, WMH volume changes were negatively related to CSF‐Aβ42/40 and positively related to plasma and CSF ptau‐181 and neurofilament light (Figure 3).ConclusionPathological increases in WMH volume start ∼10 years before the mean age at onset for AD (53.8y) in DS and relate to underlying AD pathology and neurodegeneration. Regional analyses suggest that WMH volume changes increase with disease progression and progressively involve deeper white matter areas. Together, these results support that WMHs are tightly related to AD pathogenesis.