Written by Song Lin

Editor-in-charge - Wang Sizhen

Editor — Binwei Yang

The kidney and brain expressed protein (KIBRA) is a post-synaptic protein encoded by the WWC1 gene that regulates synaptic plasticity and brain tissue volume [1-3].

To this end, the researchers based on the large sample (n=) collected by the team's previously established China Randomized Controlled Multimodal INterventions to Delay Dementia and Disability in Rural China (MIND-China).

In August 2022, Du Yifeng's research group in the Department of Neurology of the Provincial Hospital affiliated to Shandong First Medical University and the Qiu Chengxuan research group at Karolinska Institutet in Sweden published a paper entitled "Thalamic gray matter volume mediates the association between KIBRA polymorphism and olfactory function among" at Cerebral Cortex older adults: a population-based study" article

The study is the first to analyze the correlation between KIBRA rs17070145 polymorphisms and brain structure and olfactory function in older adults in large population cohorts

Figure 1 Overview of the STUDY of the MIND-China project

(Source: Wang Y, et al.

A total of 1178 subjects were recruited to undergo brain MRI scans at local hospitals and used 16 sniffin' Sticks identification tests (SSIT) to detect olfactory function

Figure 2 Study subjects were included in the flowchart

(Source: Song L, et al.
, Cereb Cortex, 2022)

The study first performed a statistical analysis of the general characteristics of the subjects: the average age of 1087 subjects was 69.
54 years, 57.
96% of the subjects were female, and 34.
50% were illiterate
.

Among all subjects, 58.
23%, 35.
79%, and 5.
98% carried kibra rs17070145 TT, CT, and CC genes, respectively, and there were no significant differences in demographic characteristics, body mass index, physical exercise, cardiovascular risk factors, APOE ε4 allele, sinus disease, and MMSE scores between kibra rs17070145 groups (Table 1
).

Table 1 General characteristics of subjects

(Table source: Song L, et al.
, Cereb Cortex, 2022)

After that, the researchers used VBM analysis to identify 5 brain masses, and compared with KIBRA TT allele carriers, the GMV of these clumps was significantly enlarged in KIBRA C allele carriers, mainly distributed in the bilateral orbitofrontal cortex, left thalamus, middle right cingulate gyrus and left complementary motor area
.

The largest mass is mainly located in the left orbital frontal region, where 54.
64% of the voxels are located in the left subfrontal ileobit, 33.
93% of the voxels are located in the left middle plorobital orbit, and 11.
05% of the voxels are located in the left suprafrontal ploroorbital region
.

The second largest mass is mainly located in the right orbital frontal region, where 66.
98% of the voxels are located in the right subfrontal ileoorbit and 28.
98% of the voxels are located in the right middle frontal ploreorbital region
.

All voxels of the third largest mass are located in the left thalamus (Figure 3
).

Figure 3 VBM analysis results KIBRA rs17070145 C carriers vs TT

(Source: Song L, et al.
, Cereb Cortex, 2022)

The researchers further used the differential brain region identified by VBM analysis as the region of interest, extracted the GMV of the region of interest, and analyzed the association
between the KIBRA rs17070145 genotype and the GMV of the region of interest.

The results showed that the KIBRA rs17070145 C allele was significantly associated with an increase in GMV in the left thalamus and bilateral orbital frontal cortex (including the left subfrontal ileobital region, the left middle ileoorbital orbit, the left supraphalus orbit, the right inferior ileoorbital orbit, and the right middle frontal ileobital region) after controlling for multiple confounding factors (Table 2
).

Table 2 Correlation analysis of KIBRA rs17070145 genotype and GMV in the region of interest

(Table source: Song L, et al.
, Cereb Cortex, 2022)

The researchers then conducted a correlation analysis of olfactory function with GMV in the region of interest, which showed that the GMV of the left thalamus and the GMV of the complementary motor area on the left were significantly associated
with a reduced risk of olfactory injury.

The researchers also conducted a correlation analysis between KIBRA rs17070145 genotype and olfactory function, and the results showed that the KIBRA rs17070145 C allele was significantly associated with a lower risk of olfactory damage, and the interaction analysis showed that the KIBRA rs17070145 genotype had a significant interaction with age grouping and APOE genotype, and further stratification analysis found that KIBRA The association of rs17070145 genotype with olfactory impairment was significant only in the older age group (age ≥70 years) and in APOE ε4 non-carriers (Figure 4
).

Fig.
4 Correlation analysis and interaction analysis between KIBRA rs17070145 genotype and olfactory damage

(Source: Song L, et al.
, Cereb Cortex, 2022)

The above studies show that there is a significant association between the left thalamus GMV and KIBRA rs17070145 genotype and olfactory function, so the researchers conducted a mediating effect analysis of the olfactory function of KIBRA rs17070145 genotype → left thalamus GMV → at the end of the article, and used 5000 bootstrapping self-service sampling methods to test the significance of the mediating effect, and the analysis showed that after controlling the relevant confounding factors, Left thalamus GMV significantly mediated the association between KIBRA rs17070145 genotype and olfactory impairment, with a mediating effect of 8.
08% (Figure 5).


In addition, in order to verify the robustness of the analysis results, the researchers conducted a sensitivity analysis in the supplementary material section, and repeatedly analyzed the relationship between the KIBRA rs17070145 genotype and brain structure and olfactory function after excluding 111 subjects with a history of sinus disease, and the results were basically the same as the above results (Figure 5).

Figure 5 Mediating effect analysis

(Source: Song L, et al.
, Cereb Cortex, 2022)

Conclusions and discussions, inspirations and prospects of the article In summary, this population-based large sample study used a combination of brain imaging analysis methods and epidemiological analysis methods to report for the first time a significant correlation between the KIBRA rs17070145 genotype in the elderly population and olfactory damage, and this correlation can be partially mediated by the GMV of the left thalamus, which has played a good role in verifying and supplementing previous studies
.

This study constructs a pathway analysis mode of gene polymorphism → brain image structure → appearance through the cohort population database, which also provides a certain reference and reference value
for follow-up related research.

In addition, olfactory damage is an important pathological feature in the early stages of Alzheimer's disease, and this study also brings some inspiration
to the search for early intervention targets for Alzheimer's disease.

It should be noted that due to the cross-sectional nature of the study design, it is impossible to determine the temporal relationship between brain structure and olfactory impairment, and future neurobiology and behavioral basic research is needed to further clarify the underlying neuropathological mechanism
between KIBRA rs17070145 genotype and olfactory injury.

Original link: https://doi.
org/10.
1093/cercor/bhac299

This study is supported by the National Key R&D Program (2017YFC1310100), the National Natural Science Foundation of China (82171175, 82011530139, 82001120), the Academic Improvement Program of Shandong First Medical University (2019QL020, 2020RC009), the Taishan Scholar Program of Shandong Province (ts20190977, Tsqn201909182), Jointly funded
by the Natural Science Foundation of Shandong Province (ZR2020QH098) and the Swedish Research Council Fund.

Corresponding author Du Yifeng

(Photo courtesy of: Du Yifeng/ Qiu Chengxuan Research Group)

Corresponding Author Research Group (swipe up and down to read)

Du Yifeng, Director of the Department of Neurology, Affiliated Provincial Hospital of Shandong First Medical University, Doctoral Supervisor of Shandong University/Shandong First Medical University, Second-level Professor, Chief Scientist of the National Key R&D Program, Taishan Scholar Distinguished Expert, has long been committed to the early prevention and treatment of Alzheimer's disease, in Alzheimers & Dementia, Nature Communications, JAMA Neurology, Lancet Public Health and other internationally renowned journals have published more than 200 academic papers
.

Selected articles from previous issues

[1] Mol Psychiatry-Wang Yingfei research group revealed the role of KDM6B protein in neuronal synaptic plasticity and learning and memory

[2] Cereb Cortex—The Team of Shanbao Tong/Xiangfei Hong reveals important influencing factors of EEG alpha rhythm in the visuospatial attention task

[3] Cereb Cortex— Excavation and analysis of imaging subtypes for the heterogeneity of schizophrenia

[4] Front Cell Neurosci Review:Gamma Neural Oscillation and Central Nervous System Diseases: Mechanisms and Therapeutic Advances

[5] The NAR-He Cheng/Su Zhida team found that topoisomerase IIA can regulate adult neurogenesis in the subependymal region

[6] The Sci Adv-Liao Wenbo team has made important progress in the adaptive evolution of amphibian brain volume

[7] J Neuroinflammation—From Changchun/Jian Zhang's team found that targeting proteoglycan receptors after hemorrhagic stroke protects white matter integrity and promotes the recovery of neurological function

[8] Front Aging Neurosci—Zeng Yanbing's team established a predictive model and revealed the effects of behavioral changes on cognitive impairment in the elderly

[9] Sci Adv-Zhao Cunyou/Chen Rongqing team revealed the mechanism of microRNA inducing social and memory abnormalities in mice: miR-501-3p expression defects enhance glutamate delivery

[10] Sci Adv-Zhang Yi's research group found important neurons that regulate drug addiction behavior

Recommended for high-quality scientific research training courses

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End of this article