The Role of Changes in the Expression of Inflammation-Associated Genes in Cerebral Small Vessel Disease with Cognitive Impairments

• Published in: Neuroscience and behavioral physiology Vol. 54; no. 2; pp. 210 - 221
• Main Authors: Dobrynina, L. A., Makarova, A. G., Shabalina, A. A., Burmak, A. G., Shlapakova, P. S., Shamtieva, K. V., Tsypushtanova, M. M., Trubitsyna, V. V., Gnedovskaya, E. V.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-02-2024; Springer Nature B.V
• Subjects: Alzheimer's disease; Behavioral Sciences; Biomedical and Life Sciences; Biomedicine; Brain injury; Clinical Presentation and Treatment of Nervous and Mental Diseases; Clinical significance; Cognitive ability; Comorbidity; Gene expression; Genes; Genome-wide association studies; Genomes; Inflammation; Leukocytes; Neurobiology; Neurodegenerative diseases; Neurosciences; Vascular diseases; small vessel disease; cerebral small vessel disease; Alzheimer’s disease; inflammation; genome-wide association studies; gene expression
• ISSN: 0097-0549; 1573-899X
• DOI: 10.1007/s11055-024-01587-w

Objectives
. To clarify the role of changes in the expression of inflammation-associated genes in cerebral small vessel disease (cSVD).
Materials and methods
. A total of 44 patients with cSVD (mean age 61.4 ± 9.2 years) and 11 volunteers (mean age 57.3 ± 9.7 years) were investigated. Gene expression was assessed using a custom NanoString nCounter panel of 58 inflammation-associated genes and four reference genes. The gene set was formed on the basis of convergent results from genome-wide association studies (GWAS) in cSVD and Alzheimer’s disease and circulating markers associated with vascular wall and brain damage in cSVD. RNA was isolated from blood leukocytes and analyzed using the nCounter Analysis System, with subsequent analysis in nSolver 4.0. Results were verified by real-time PCR.
Results
. Patients with cSVD, as compared with controls, had significantly lower levels of expression of
BIN1
(log2FC = –1.272;
p
= 0.039) and
VEGFA
(log2FC = = –1.441;
p
= 0.038), which showed predictive ability for cSVD. The threshold value of
BIN1
expression was 5.76 U (sensitivity 73%, specificity 75%), and that of
VEGFA
was 9.27 U (sensitivity 64%, specificity 86%). Decreased expression of
VEGFA
(
p
= 0.011),
VEGFC
(
p
= 0.017), and
CD2AP
(
p
= 0.044) was associated with clinically significant cognitive impairment. A significant direct correlation between Montreal Cognitive Assessment Scale test results and
VEGFC
expression was found; delayed memory test results correlated with
BIN1
and
VEGFC
expression.
Conclusions
. The ability to predict the development of cSVD from low
BIN1
and
VEGFA
expression levels and the association between clinically significant cognitive impairments with low
VEGFA
and
VEGFC
indicate their importance in the development and progression of the disease. The demonstrated significance of these genes in the pathogenesis of Alzheimer’s disease indicates that similar changes in their expression profile in cSVD may be among the conditions for the comorbidity of the two pathologies.