Introduction: Cortical microinfarcts (CMI) are small ischemic lesions in the brain cortex that were, until recently, invisible on magnetic resonance imaging (MRI) and only detected in post-mortem studies. However, the development of ultra-high field 7T-MRI allowed their detection in-vivo. Recently, established guidelines for CMI visual detection on 3T-MRI enabled the study of such lesions in large cohorts, linking CMI to vascular risk factors, cardiac dysfunction, reduced cerebral perfusion, stroke, and vascular cognitive impairment. However, a few studies have suggested that CMI is also a common feature of cerebral amyloid angiopathy (CAA), together with cerebral microbleeds and superficial siderosis. Disentangling the potential underlying causes of CMI in the general population is challenging due to the frequent overlap between vascular risk factors and Alzheimer's disease (AD). In Down syndrome (DS), however, the prevalence of classic vascular risk factors is low, while CAA is highly prevalent due to the overproduction of amyloid-precursor protein and increased amyloid-[Beta] (A[Beta]) deposition in the brain parenchyma and vasculature. The combination of these features makes DS a great model for studying amyloid pathology as a possible cause of CMI. However, to our knowledge, no studies assessing CMI in this population have been conducted so far. _x000D_
Hypothesis: We hypothesize that, in DS, CMI are related to CAA pathology, given the ubiquitous brain amyloidosis and low prevalence of vascular risk factors in this population. _x000D_
Objectives: We aimed at characterizing CMI in DS by assessing their prevalence with age and along the AD continuum, their topographic distribution and their association with vascular risk factors, vascular neuroimaging findings, sex, APOE haplotype, fluid AT(N) biomarkers, and cognitive performance._x000D_
Methods: This single-center cross-sectional study with 3T-MRI scans included participants from a population-based cohort of adults with DS with multimodal AD biomarkers and from a cohort for multimodal biomarker discovery and validation that includes cognitively euploid healthy volunteers and participants with different neurodegenerative diseases. A total of 364 participants with 3T-MRI were included: 195 adults with DS (126 asymptomatic, 29 prodromal AD, and 40 AD-dementia patients), 63 with symptomatic sporadic AD (sAD: 43 prodromal AD and 20 AD-dementia patients), and 106 cognitively unimpaired controls. A neuroradiologist (blind to participant's data and diagnosis) visually analyzed 3T-MRI images to assess the presence and location of CMI (using a validated protocol), the burden of white matter FLAIR hyperintensities, the presence of lacunar infarcts, large corticosubcortical infarcts, microbleeds, and superficial siderosis. _x000D_
Results: CMI were present in 11.8% of participants with DS (6.7% in asymptomatic individuals and 17.4% in patients with symptomatic AD), 4.7% of controls, and 17.5% of symptomatic sporadic AD patients (p=0.061). CMI prevalence increased with age and along the AD clinical continuum in DS. CMI were predominantly located in the parietal lobes in DS and along the frontoparietal parasagittal lines in euploid participants. CMI were significantly related to lacunes (p=0.026), and corticosubcortical infarcts (p=0.004). Also, a trend towards significance was observed in the higher prevalence of WMH (Fazekas>=2) in DS participants with CMI (p=0.054). However, no association of CMI with vascular risk factors, hemorrhagic lesions, sex, APOE haplotype or cognitive performance was observed in DS, symptomatic sporadic AD or cognitively unimpaired controls._x000D_
Conclusion: Our data support our main hypothesis that cortical microinfarcts in Down syndrome are related to CAA, possibly related to a non-hemorrhagic imaging phenotype of the disease.
| Date of Award | 7 Nov 2023 |
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| Original language | English |
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| Supervisor | Juan Fortea Ormaechea (Director), Claudia Da Costa Leite (Director) & Artur Martins Novaes Coutinho (Director) |
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