The Role of Serum Vitamins in Mediating the Effect of Neurodegenerative Diseases on Subcortical Brain Volume - 26/03/25

Doi : 10.1016/j.tjpad.2025.100155

Haonan Li ^1,^{^{†
These authors contributed equally to this work.}}, Meng Cheng ^1,^{^{†
These authors contributed equally to this work.}}, Nannan Zhang ^1,^{^{†
These authors contributed equally to this work.}}, Siqi Wang ¹, Caihua Ye ¹, Haodong Li ², Shengnan Wang ¹, Zirui Wang ¹, Xuan Yang ^1,³, Zhixuan Liu ¹, Xingyu Zhang ¹, Jiayuan Xu ^1,^⁎,^{⁎
These authors jointly supervised this work.} , Qiang Xu ^1,^{⁎
These authors jointly supervised this work.}, ^⁎ , Junping Wang ^1,^{⁎
These authors jointly supervised this work.}, ^⁎
¹ Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin 300052, China
² Medical School, Tianjin University, Tianjin 300072, China
³ Department of Radiology, Jining No.1 People's Hospital, Jining, Shandong, 272000, China.

^#Corresponding authors at: Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin 300052, ChinaDepartment of RadiologyTianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General HospitalTianjin300052China

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Highlights

•	Genetical liability to AD is causally associated with atrophy of hippocampus and NAc, with low serum vitamin D level playing a partial mediating role.
•	High-dose vitamin D diet contributes to significant delay in hippocampus and NAc atrophy, significant reduction of Aβ deposit and increase of vitamin D receptor expression in hippocampus in AD mice.
•	Increasing serum vitamin D level at a population level may attenuate the damage to hippocampus. This is particularly necessary for those with high risk of developing AD.

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Abstract

Background

Neurodegenerative diseases (NDs) lead to a progressive loss of neuronal cells and link to atrophy of subcortical brain structures, but the causal intermediates are not known. To test whether major NDs (Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis) causally affects subcortical atrophy, and whether serum vitamin level play a mediating role in this process.

Methods

Using large-scale genome-wide association study (GWAS) summary data, we performed two-sample Mendelian randomization (MR) to assess the causal effect of NDs on the volume of seven subcortical structures, and then adopted two-step multivariable MR approach to quantify the proportion of the effect of NDs on the volume of subcortical regions mediated by serum vitamin level. Finally, we utilized animal experiments to validate results and explored the potential molecular mechanisms.

Results

Genetically predicted AD was associated with atrophy of the nucleus accumbens (NAc) (β = -0.09; p = 5.13 × 10^-5), amygdala (β = -0.07; p = 8.44 × 10^-4), and hippocampus (β = -0.07; p = 0.001), as well as with low serum vitamin D level (β = -0.02; p = 6.84 × 10^-6). Specifically, decreased serum vitamin D level mediated 3.99% (95% CI: -0.006 to -5.82 × 10^-5) and 3.97% (95% CI: -0.007 to -2.94 × 10^-4) of the total effect of AD on hippocampal and NAc atrophy, respectively. Animal experiments further confirmed significant delays in hippocampus and NAc atrophy, a significant reduction of β-amyloid deposits and an increase of vitamin D receptor expression in hippocampus in AD mice with high-dose vitamin D diet.

Conclusions

These findings provide important insights into the effect sizes of vitamin D-mediated roles in AD and atrophy of subcortical structures. Interventions to increase serum vitamin D levels at a population level might attenuate damage to hippocampus in patients with AD.

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Graphical Abstract

Mendelian randomization was adopted to evaluate and quantify the proportion of the effect of neurodegenerative diseases on the volume of subcortical regions mediated by serum vitamin level.

Animal experimentation was utilized to validate Mendelian randomization results and explore potential molecular mechanisms.