Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Sep;20(9):6527-6541.
doi: 10.1002/alz.14146. Epub 2024 Aug 1.

Characterization of white matter hyperintensities in Down syndrome

Alejandra O Morcillo-Nieto  1 , Sara E Zsadanyi  1 , Jose E Arriola-Infante  1 , Maria Carmona-Iragui  1   2   3 , Victor Montal  1   2   4 , Jordi Pegueroles  1   2 , Mateus Rozalem Aranha  1   2 , Lídia Vaqué-Alcázar  1   5 , Concepción Padilla  1   2   6 , Bessy Benejam  3 , Laura Videla  1   2   3 , Isabel Barroeta  1   2 , Susana Fernandez  3 , Miren Altuna  1   2   7 , Sandra Giménez  1   8 , Sofía González-Ortiz  9 , Núria Bargalló  9   10 , Laia Ribas  1   2 , Javier Arranz  1 , Soraya Torres  1   2 , Maria Florencia Iulita  1   2 , Olivia Belbin  1   2 , Valle Camacho  11 , Daniel Alcolea  1   2 , Alberto Lleó  1   2 , Juan Fortea  1   2   3 , Alexandre Bejanin  1   2
Affiliations

Characterization of white matter hyperintensities in Down syndrome

Alejandra O Morcillo-Nieto et al. Alzheimers Dement. 2024 Sep.

Abstract

Introduction: In Down syndrome (DS), white matter hyperintensities (WMHs) are highly prevalent, yet their topography and association with sociodemographic data and Alzheimer's disease (AD) biomarkers remain largely unexplored.

Methods: In 261 DS adults and 131 euploid controls, fluid-attenuated inversion recovery magnetic resonance imaging scans were segmented and WMHs were extracted in concentric white matter layers and lobar regions. We tested associations with AD clinical stages, sociodemographic data, cerebrospinal fluid (CSF) AD biomarkers, and gray matter (GM) volume.

Results: In DS, total WMHs arose at age 43 and showed stronger associations with age than in controls. WMH volume increased along the AD continuum, particularly in periventricular regions, and frontal, parietal, and occipital lobes. Associations were found with CSF biomarkers and temporo-parietal GM volumes.

Discussion: WMHs increase 10 years before AD symptom onset in DS and are closely linked with AD biomarkers and neurodegeneration. This suggests a direct connection to AD pathophysiology, independent of vascular risks.

Highlights: White matter hyperintensities (WMHs) increased 10 years before Alzheimer's disease symptom onset in Down syndrome (DS). WMHs were strongly associated in DS with the neurofilament light chain biomarker. WMHs were more associated in DS with gray matter volume in parieto-temporal areas.

Keywords: Alzheimer's disease; Down syndrome; magnetic resonance imaging; neuroimaging; small vessel disease; white matter hyperintensities.

PubMed Disclaimer

Conflict of interest statement

MRA has provided paid consultancy for Veranex, and is a partner and director of production at Masima—Soluções em Imagens Médicas LTDA. MFI is now a paid employee of Altoida Inc. and may hold stock options in the company. The work in this manuscript only relates to the reported affiliation. DA reported receiving personal fees for advisory board services and/or speaker honoraria from Fujirebio‐Europe, Roche, Nutricia, Krka Farmacéutica, Lilly, Zambon S.A.U., Grifols, and Esteve, outside the submitted work. AL has served as a consultant or on advisory boards for Fujirebio‐Europe, Roche, Biogen, Grifols, Novartis, Eisai, Lilly, and Nutricia, outside the submitted work. JF reported serving on the advisory boards, adjudication committees, or speaker honoraria from Roche, NovoNordisk, Esteve, Biogen, Laboratorios Carnot, Adamed, LMI, Novartis, Lundbeck, Roche, AC Immune, Alzheon, Zambon, Lilly, Spanish Neurological Society, T21 Research Society, Lumind foundation, Jérôme‐Lejeune Foundation, Alzheimer's Association, National Institutes of Health USA, and Instituto de Salud Carlos III. DA, AL, and JF report holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to ADx, EPI8382175.0). No other competing interests were reported. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Associations between white matter hyperintensity volume and demographic, clinical, and genetic factors. (A) Association between total WMH volume and age. The points represent individual participants, and the color indicates their clinical diagnosis. Shaded areas represent 95% CI: dark gray represents the age‐related change in DS and light gray in the HC group for visual reference. The dashed line indicates when the CI stops overlapping between DS and HC groups (43.8 years). (B) Spearman correlation coefficients between age and regional WMH volumes. The color scale represents the strength (rho) of Spearman correlation for significant results (p < 0.05). The star (*) indicates results surviving to the Bonferroni correction (α = 0.05, p < 0.0025). (C), (D) and (E) Boxplots showing the effect of sex, APOE haplotype, and intellectual disability, respectively, on the distribution of the total WMH volume in DS. Abbreviations: 1, first layer; 2, second layer; 3, third layer; 4, fourth layer; aDS, asymptomatic Down syndrome; APOE, apolipoprotein E; BG, basal ganglia; CI, confidence interval; DS, Down syndrome; F, frontal; HC, euploid cognitively unimpaired controls; dDS, Down syndrome with Alzheimer's disease dementia; O, occipital; P, parietal; pDS, prodromal Down syndrome; rho, strength of the correlation; T, temporal; WMH, white matter hyperintensity.
FIGURE 2
FIGURE 2
Lesion prevalence map of white matter hyperintensities in Down syndrome. Lesion frequency map of white matter hyperintensities is shown in the Montreal Neurological Institute 152 T1 template. The color of each voxel indicates the percentage of subjects that had white matter hyperintensities in this voxel, ranging from at least 5% (purple) to 40% or more (yellow).
FIGURE 3
FIGURE 3
Between‐group differences for total and regional white matter hyperintensity volumes. (A), (B), (C) and (D) The boxplots illustrate WMH volumes across the brain regions. Significant results at p < 0.05 using the Bonferroni correction. (E) Median of WMH volume per region represented in bull's‐eye plot. Colors represent the burden of WMH volume in log mm3, darker colors indicate higher WMH load. Abbreviations: ns, no significance; *p < 0.05; **p < 0.01; ***p < 0.001; 1, first layer; 2, second layer; 3, third layer; 4, fourth layer; aDS, asymptomatic Down syndrome; BG, basal ganglia; dDS, Down syndrome with Alzheimer's disease dementia; DS, Down syndrome; F, frontal; HC, euploid cognitively unimpaired controls; O, occipital; P, parietal; pDS, prodromal Down syndrome; T, temporal; WMH, white matter hyperintensity.
FIGURE 4
FIGURE 4
Associations between white matter hyperintensities and cerebrospinal fluid biomarkers in DS. (A) Correlation between total WMH volume and each corresponding CSF biomarker. Boxplots illustrate WMH volumes across the amyloid and tau status. The points represent individual participants, and the color indicates the clinical diagnosis. Shaded areas represent 95% CI. (B) Spearman correlation coefficients between each corresponding CSF biomarker and regional WMH volume in DS. The color scale represents the strength (rho) of Spearman correlation for significant results (p < 0.05). The star (*) indicates results surviving the Bonferroni correction (α = 0.05, p < 0.0025). (C) Standardized coefficient of univariate and multivariate linear regression models for the WMH volume. The triangles and circles represent the univariate and multivariate models, respectively. The lines represent the 95% CI. Gray color indicates non‐significant values, while orange color indicates significant values (p < 0.01) and blue color after applying Bonferroni correction (α = 0.05, p < 0.01). Abbreviations: 1, first layer; 2, second layer; 3, third layer; 4, fourth layer; A−, amyloid negative; A+, amyloid positive; Aβ42/Aβ40, concentration ratio between amyloid beta peptide 1‐42 and amyloid beta peptide 1‐40 (pg/mL); aDS, asymptomatic Down syndrome; BG, basal ganglia; CI, confidence interval; CSF, cerebrospinal fluid; dDS, Down syndrome with Alzheimer's disease dementia; DS, Down syndrome; F, frontal; GFAP, glial fibrillary acidic protein concentration (pg/mL); NfL, neurofilament light chain concentration (pg/mL); O, occipital; P, parietal; pDS, prodromal Down syndrome; pTau181, tau phosphorylated at threonine 181 concentration (pg/mL); sDS, symptomatic Down syndrome; T, temporal; T−, tau negative; T+, tau positive; WMH, white matter hyperintensity.
FIGURE 5
FIGURE 5
Voxelwise associations between white matter hyperintensities and gray matter volume. Results of voxelwise regression model showing gray matter volume negatively associated with WMH in (A) whole DS cohort and (B) aDS and (C) sDS subgroups. The significance of the results (T values) is shown using a threshold pFWE < 0.05. Abbreviations: aDS, asymptomatic Down syndrome; DS, Down syndrome; sDS, symptomatic Down syndrome; FWE, family‐wise error.
See this image and copyright information in PMC

References

    1. Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019;15:135‐147. 2019 153. doi:10.1038/s41582-018-0132-6 - DOI - PMC - PubMed
    1. Fortea J, Vilaplana E, Carmona‐Iragui M, et al. Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross‐sectional study. Lancet. 2020;395:1988‐1997. doi:10.1016/S0140-6736(20)30689-9 - DOI - PMC - PubMed
    1. Fortea J, Zaman SH, Hartley S, Rafii MS, Head E, Carmona‐Iragui M. Alzheimer's disease associated with Down syndrome: a genetic form of dementia. Lancet Neurol. 2021;20:930‐942. doi:10.1016/S1474-4422(21)00245-3 - DOI - PMC - PubMed
    1. McCarron M, McCallion P, Reilly E, Dunne P, Carroll R, Mulryan N. A prospective 20‐year longitudinal follow‐up of dementia in persons with Down syndrome. J Intellect Disabil Res. 2017;61:843‐852. doi:10.1111/JIR.12390 - DOI - PubMed
    1. Iulita MF, Garzón Chavez D, Klitgaard Christensen M, et al. Association of Alzheimer disease with life expectancy in people with Down syndrome. JAMA Netw Open. 2022;5:e2212910‐e2212910. doi:10.1001/JAMANETWORKOPEN.2022.12910 - DOI - PMC - PubMed

Grants and funding