Genetic associations of leukoaraiosis indicate pathophysiological mechanisms in white matter lesions etiology

Abstract

<jats:title>Abstract</jats:title><jats:p>Leukoaraiosis (LA), also called white matter lesions (WMLs) and white matter hyperintensities (WMHs), is a frequent neuroimaging finding commonly seen on magnetic resonance imaging brain scans of elderly people with prevalence ranging from 50% to 100%. Although it remains asymptomatic, LA is not considered to be benign, and it is showed to be related to a host of poor clinical outcomes and increases the risk of disability, dementia, depression, stroke, and the overall morbidity and mortality. Pathologically, LA is characterized by loss of myelin and axons, patchy demyelination, and denudation of ependyma in regions of WMH. Age and hypertension are the most importantly established risk factors for LA. However, the precise pathogenic mechanisms remain unclear. Together with the previous findings, our recent genetic results strongly supported that LA is associated with immune response and neuroinflammation. Therefore, we confidently hypothesized that LA was not only a common neuroimaging phenomenon in the elderly but also an emerging neuroinflammatory disorder in the central nervous system. This article focusing on neuroimaging classification, genetics basis, and putative molecular mechanism introduced the basic knowledge and current status of LA and put forward some of our research ideas and results from our molecular genetics research, which may pave the way for deciphering the putative pathogenic mechanism, risk factor, epigenetic index, and its application in diagnostic agents or drug target for prevention and treatment. Thus, it could provide clinicians and researchers with a specific and modern overview of LA to enable the understanding of recent progress and future directions in this illness.</jats:p>

White Matter Hyperintensity Associations with Cerebral Blood Flow in Elderly Subjects Stratified by Cerebrovascular Risk

“…These factors are included in vascular risk measures such as the Framingham score used in this study. A genetic component may be involved in cases where evidence of CVD is lacking[27–31]. …”

Correlation between prefrontal-striatal pathway impairment and cognitive impairment in patients with leukoaraiosis

“…The axonal loss may compromise the barrier function and then the water will increase in tissues, leading to the changes in DTI-related parameters. [15] These characteristic changes in DTI are helpful for the early identification of brain lesions, disease monitoring, and evaluation of therapeutic efficacy.…”

Hypertension and Cerebral Microangiopathy (Cerebral Small Vessel Disease): Genetic and Epigenetic Aspects of Their Relationship

“…For example, the NDRG1 gene located on chromosome 8q24 was hypermethylated (the cytoplasmic protein encoded by this gene is involved in the protection of the myelin sheath in the peripheral nervous system, cell differentiation, tumor metastasis and hypoxia, inflammatory response, etc.) and the BRUNOL4 gene or the CELF4 gene (chromosome 18q12, BRUNO-like 4 protein involved in mRNA stabilization) was hypomethylated compared to the control group with a normal neuroimaging picture [111].…”

“…A study of the role of microRNA in the development of leukoaraiosis in CMA [111] revealed eight differentially expressed microRNAs associated with the regulation of pathogenetic gene activity and the molecular mechanisms of leukoaraiosis. It should be noted that the significance of these putative pathogenetic genes was confirmed by the results of GWAS (TRIM65, ACOX1), searches for candidate genes (AGTR2, MTH-FR, BDNF, MMP3, MMP13), gene expression profiles (CCR5, IL6, MAF, CALM1, COL24A1, EPHB2, MAP1B, CYB5A, CDC6, CTSC), and epigenetic studies (HLA-DQA1, TGFBR3, CD80, WDR41, RNF39, KIAA1199, AAK1).…”

“…It should be noted that the significance of these putative pathogenetic genes was confirmed by the results of GWAS (TRIM65, ACOX1), searches for candidate genes (AGTR2, MTH-FR, BDNF, MMP3, MMP13), gene expression profiles (CCR5, IL6, MAF, CALM1, COL24A1, EPHB2, MAP1B, CYB5A, CDC6, CTSC), and epigenetic studies (HLA-DQA1, TGFBR3, CD80, WDR41, RNF39, KIAA1199, AAK1). Most of these genes are associated with inflammation in the CNS [111].…”