Alzheimer’s Disease (AD) and Microbleeds in Down Syndrome (DS) Populations: Their Localization and Association with Imaging and Cerebrospinal Fluid (CSF) Biomarkers

This study was conducted by a team led by Sara E. Zsadanyi and Alejandra O. Morcillo-Nieto, with contributors including Mateus R. Aranha, José E. Arriola-Infante, Lídia Vaqué-Alcázar, among others. The core authors Bejanin and Carmona-Iragui are listed as corresponding authors. This research was published in the journal Neurology, Volume 103, Issue 4, in 2024. The research team is primarily affiliated with Hospital de la Santa Creu i Sant Pau in Barcelona, Spain.

Research Background

Brain hemorrhage is a criterion for exclusion and a potential adverse reaction to anti-amyloid agents. Therefore, characterizing the natural history of cerebral microbleeds in populations genetically susceptible to Alzheimer’s disease (AD), such as those with Down syndrome (DS), is essential. This study aims to evaluate the occurrence of microbleeds in DS adults along the AD spectrum, define their localization, and their association with clinical variables, cognitive outcomes, and fluid and neuroimaging biomarkers.

Research Sources

This paper was written by a group of expert scholars, including researchers from Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Institut d’investigacions biomèdiques August Pi i Sunyer, Fundació Catalana Síndrome de Down, and others. The study was published in the journal Neurology, Volume 103, Issue 4, in 2024.

Research Methods

Study Design and Participants

This study is a cross-sectional study involving adults aged 18 and above from the Down Syndrome-Alzheimer Barcelona Neuroimaging Initiative (DABNI) and the Sant Pau Initiative on Neurodegeneration (SPIN). All participants, including DS patients and healthy controls, were excluded if they had significant neurological or psychiatric disorders.

Participants underwent comprehensive assessments, including: 1. APOE genotyping 2. Measurement of β-amyloid, tau protein, and neurofilament light chain in fluid and plasma 3. Cognitive outcome evaluations (Cambridge Cognitive Examination and Modified Cue Recall Test) 4. Assessment of vascular risk factors such as hypertension, diabetes, and dyslipidemia.

Scanning and Image Processing

The study used high-resolution 3D T1-weighted imaging and Susceptibility-Weighted Imaging (SWI) for brain scans, with multiple algorithms and software for image preprocessing and microbleed segmentation. Specifically, the methods included: - Computational Anatomy Toolbox (CAT12) - Advanced Normalization Tools (ANTS) - Lesion Segmentation Toolbox (LST) for processing white matter hyperintensities (WMH).

Microbleed segmentation was performed manually by trained evaluators to ensure high accuracy and consistency.

Results

Sample Characteristics

The study included 276 DS adults and 158 healthy controls. DS participants spanned the entire AD spectrum: 161 asymptomatic, 43 prodromal, and 57 demented. The control group was older and had a higher proportion of females compared to DS participants.

Analysis of Microbleed Associations

In DS participants, the number and severity of microbleeds were significantly higher than in the control group. The number of microbleeds increased significantly with age and AD clinical stages: 12% of DS participants in their 20s had one or more microbleeds, while this proportion reached 60% in those over 60.

APOEε4 allele carriers had a higher proportion of microbleeds than non-carriers (26% vs. 18.3%). In DS participants, although there was no significant influence from gender or intellectual disability (ID), vascular risk factors (such as hypertension, diabetes, dyslipidemia) were not significantly associated with microbleeds.

Localization of Microbleeds

Microbleeds in DS participants were mainly concentrated in the cerebellum (33.66%), occipital lobe (14.85%), and temporal lobe (21.29%). This pattern was consistent across the AD spectrum. Most microbleeds were lobar, with deep hemorrhages being rare (3.63%).

Association with Imaging and Fluid Biomarkers and Cognitive Outcomes

In DS participants, an increase in microbleeds was associated with increased WMH volume, bilateral hippocampal volume reduction, and overall gray matter volume reduction. Additionally, an increase in microbleeds was significantly associated with decreased CSF Aβ₁-₄₂/Aβ₁-₄₀ ratio and increased CSF p-tau-181 and NFL concentrations, mainly driven by individuals with two or more microbleeds.

In cognitive tests, although there were significant differences locally, overall the impact of microbleeds on cognitive performance was small. This suggests that multiple microbleeds may have a significant impact on AD biomarkers, while the impact of a single microbleed is relatively limited.

Sensitivity Analysis

To evaluate the specific impact of microbleeds on AD biomarkers, the study conducted sensitivity analyses. After controlling for the influence of disease severity, only hippocampal volume reduction and increased CSF p-tau-181 concentration remained significantly associated with microbleeds.

Conclusion

This study indicates that the number of microbleeds in DS adults is significantly higher than in healthy controls and increases with age and AD clinical stages. The proportion of microbleeds is higher in APOEε4 carriers. Overall, while microbleeds have a significant impact on AD biomarkers, their impact on cognitive performance is limited. Microbleeds are mainly concentrated in the posterior regions and cerebellum, suggesting a connection with cerebral amyloid angiopathy (CAA). The findings provide important references for future anti-amyloid therapy trials.

Significance of the Study

The results provide important insights into the role of microbleeds in the progression of AD in the DS population, particularly regarding the risk assessment related to anti-amyloid therapy. Furthermore, the study highlights the potential interaction between microbleeds, AD pathology, and cerebrovascular lesions in the DS population, emphasizing the complexity and specificity of genetic and disease processes in the development of microbleeds.

The observations derived from the study provide a scientific basis for developing treatment strategies and assessing adverse reactions to anti-amyloid therapy, underscoring the necessity of tailoring treatment plans for DS patients.