Plasma proteome-wide analysis of cerebral small vessel disease identifies novel biomarkers and disease pathways
Insights
Researchers identified 13 plasma proteins linked to white matter hyperintensities (WMH), a marker of cerebral small vessel disease (SVD). Two proteins, OMG and NPTXR, show promise as biomarkers for SVD and dementia risk.
Area of Science:
- Neuroimaging and Biomarker Discovery
- Vascular Neurology
- Proteomics and Molecular Medicine
Background:
- Cerebral small vessel disease (SVD), characterized by white matter hyperintensities (WMHs), is common and linked to dementia.
- While hypertension is a known cause, underlying biological mechanisms and biomarkers remain largely unknown.
Purpose of the Study:
- To explore plasma proteomic profiles associated with SVD characteristics.
- To identify novel plasma biomarkers for SVD and its clinical sequelae, including dementia risk.
Main Methods:
- Proteome-wide association study of 4,877 plasma proteins in 1,508 Atherosclerosis Risk in Communities (ARIC) Study participants.
- Replication in external cohorts, Mendelian randomization, pathway analysis, and analysis of brain tissue proteomic data.
Main Results:
- 13 plasma proteins associated with WMH volume, involving synaptic function, endothelial integrity, and angiogenesis.
- Two proteins (OMG, NPTXR) identified as top candidate biomarkers for WMH.
- 11 of 13 proteins linked to future dementia risk; subset associated with Alzheimer's disease and cognitive decline.
Conclusions:
- Plasma proteomic analysis reveals key biological pathways in SVD development.
- Oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR) are promising biomarkers for SVD and dementia risk.
Abstract:
Cerebral small vessel disease (SVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although conditions such as hypertension are known to contribute to SVD, little is known about the diverse set of subclinical biological processes and molecular mediators that may also influence the development and progression of SVD. To better understand the mechanisms underlying SVD and to identify novel SVD biomarkers, we used a large-scale proteomic platform to relate 4,877 plasma proteins to MRI-defined SVD characteristics within 1,508 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Our proteome-wide analysis of older adults (mean age: 76) identified 13 WMH-associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis, two of which remained associated with late-life WMH volume when measured nearly 20 years earlier, during midlife. We replicated the relationship between 9 candidate proteins and WMH volume in one or more external cohorts; we found that 11 of the 13 proteins were associated with risk for future dementia; and we leveraged publicly available proteomic data from brain tissue to demonstrate that a subset of WMH-associated proteins was differentially expressed in the context of cerebral atherosclerosis, pathologically-defined Alzheimer's disease, and cognitive decline. Bidirectional two-sample Mendelian randomization analyses examined the causal relationships between candidate proteins and WMH volume, while pathway and network analyses identified discrete biological processes (lipid/cholesterol metabolism, NF-kB signaling, hemostasis) associated with distinct forms of SVD. Finally, we synthesized these findings to identify two plasma proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), as top candidate biomarkers for elevated WMH volume and its clinical manifestations.
