Brain lesions previously considered permanent markers of vascular damage in individuals with Down syndrome may, in some cases, be reversible, according to a new study published in Alzheimer’s & Dementia. Researchers at the Institut de Recerca Sant Pau (IR Sant Pau) in Barcelona, Spain, found that white matter hyperintensities (WMH)—lesions visible on MRI scans—can fluctuate and even decrease over time, particularly after the onset of clinical symptoms of Alzheimer’s disease.
The study, which followed 80 adults with Down syndrome and 53 neurotypical adults as a control group, utilized longitudinal MRI scans taken at least six months apart. Researchers analyzed the evolution of WMH, traditionally associated with small vessel disease and cognitive impairment. Previous cross-sectional studies from IR Sant Pau had linked increasing lesion burden to Alzheimer’s biomarkers like beta-amyloid and phosphorylated tau proteins in individuals with Down syndrome, who have a significantly higher risk of developing the disease due to the presence of an extra copy of the amyloid precursor protein (APP) gene on chromosome 21. However, those studies offered only a snapshot in time.
“The cross-sectional analysis gives us a snapshot of each stage of the process, but it does not show how these alterations change within each individual over time,” explained Alejandra Morcillo-Nieto, researcher in the Brain Imaging and Aging group at IR Sant Pau and first author of the article. “With this study, we were able to spot the movie and confirm that the trajectory is not always linear.”
The research revealed minimal changes in WMH volume up to around age 40. After this point—when amyloid pathology is nearly universal in individuals with Down syndrome—greater variability in lesion evolution emerged. Over a period of two to three years, the predominant trend wasn’t a progressive increase, but a heterogeneous pattern where a significant proportion of participants with existing WMH experienced measurable reductions.
“When we saw that a relevant percentage of participants showed a reduction, we realized that we could no longer interpret these lesions as something fixed and irreversible,” Morcillo-Nieto stated. “At certain points, their behavior is more dynamic than we previously thought.”
The reduction in WMH volume was significantly more pronounced in individuals already exhibiting clinical symptoms of Alzheimer’s disease—either prodromal or dementia—compared to those in the asymptomatic stage and the control group. This suggests the decline occurs after the disease has become clinically manifest.
The most significant reductions were observed in the parietal and occipital regions, and in periventricular areas—locations previously identified as particularly affected in individuals with Down syndrome by IR Sant Pau research. This concentration reinforces the idea that WMH may reflect the interplay between amyloid burden, vascular alterations, and clinical progression, rather than a simple accumulation of damage.
Researchers explored potential biological mechanisms behind these fluctuations, considering neurodegeneration, inflammation, and cerebral amyloid angiopathy. While white matter atrophy linked to neurodegeneration could explain some reductions, it wasn’t sufficient for all observed cases, suggesting additional processes are at play. The presence of cerebral microbleeds—a marker of cerebral amyloid angiopathy—was associated with a greater longitudinal reduction in hyperintensities, pointing to a possible role of vascular changes related to amyloid deposition.
“In Down syndrome, amyloid does not only accumulate in brain tissue but also in the vessels. This can alter the barrier that protects the brain and allow fluid leakage, generating a signal visible on MRI. If this inflammatory process improves, that signal may decrease in subsequent scans,” Morcillo-Nieto explained.
Analysis of Alzheimer’s biomarkers in cerebrospinal fluid and plasma—including beta-amyloid and phosphorylated tau proteins—revealed no robust associations between annual WMH volume variation and changes in these biomarkers. This contrasts with previous cross-sectional studies from IR Sant Pau that showed a correlation between lesion burden and biomarker alterations. Researchers suggest this discrepancy may be due to the complex and non-linear biomarker trajectories observed in adults with Down syndrome.
“In cross-sectional analyses, we found associations between lesion burden and Alzheimer’s biomarkers. But when we evaluate how these lesions change year by year in the same individuals, that relationship does not appear with the same consistency. This may reflect that the evolution of these markers has quite unfamiliar and non-linear phases throughout adulthood,” Morcillo-Nieto said.
Dr. Alexandre Bejanin, head of the Brain Imaging and Aging group at IR Sant Pau and senior author of the study, emphasized the implications for the development of anti-amyloid therapies. “At a time when anti-amyloid therapies are being developed and evaluated, it is essential to understand the natural history of these lesions in Down syndrome,” he stated. “Knowing that these lesions show natural fluctuations requires us to be highly precise in clinical trials. If we can separate the true effect of treatment from the biological progression of the disease, we will be able to properly evaluate drugs and identify our ideal intervention window—that is, when is the best time to initiate these therapies safely and effectively.”
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