Zhou Lan, Sun Hongyan, Li Cunzi, Luo Tianyi, Meng Ting, Wen Xiaojun, Chen Zilin, Hu Yan, Yang Ming-Ming
Department of Ophthalmology, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology, The Second Clinical Medical College, Jinan University), Shenzhen, China.
Post-doctoral Scientific Research Station of Basic Medicine, Jinan University, Guangzhou, China.
Front Med (Lausanne). 2025 Jul 16;12:1619819. doi: 10.3389/fmed.2025.1619819. eCollection 2025.
Hyperreflective materials (HRMs), enigmatic biomarkers observed in diabetic retinopathy (DR), exhibit poorly characterized pathophysiological origins and clinical implications.
This retrospective cross-sectional study investigates the spatial distribution patterns of HRMs subtypes and their integrative relationships with retinal microvascular architecture, structural remodeling, and systemic metabolic parameters in 205 DR eyes. HRMs were systematically classified via multimodal optical coherence tomography angiography (OCTA) analysis, incorporating topographic localization (inner vs. outer retinal), reflectivity profiles, morphometric dimensions, posterior shadowing artifacts, and decorrelation signal. Quantitative correlations were established between HRMs subtypes and OCTA-derived vascular parameters (intraretinal microvascular abnormalities [IRMA], non-perfusion [NP] areas, microaneurysms), diabetic macular edema (DME) status, and systemic metabolic indices (glycemic control, lipid profiles, renal function, inflammatory markers).
Six distinct HRMs phenotypes were identified: inner retinal hyperreflective spots (IRHFs), outer retinal hyperreflective spots (ORHFs), intraretinal hard exudates (IRHE), outer retinal hard exudates (ORHE), decorrelation-positive HRMs, and cotton-wool spots. Spatial mapping revealed predominant HRMs colocalization with IRMA territories (75.4% IRHFs, 89.5% ORHFs, 90.8% IRHE, 94% ORHE), while 19% of IRHFs and 8.7% of ORHFs overlapped NP zones. Decorrelation-positive HRMs demonstrated dual associations with IRMA (77.6%) and microaneurysms (21.0%). DME eyes exhibited significantly elevated HRMs density within IRMA and NP regions ( < 0.001). Multivariate analysis identified dyslipidemia as a strong predictor of HRMs burden.
These findings establish HRMs as spatially resolved biomarkers of diabetic retinal pathophysiology, reflecting compartment specific interactions between microvascular incompetence (IRMA-associated barrier failure), ischemic remodeling (NP zones), and systemic metabolic dysregulation. The colocalization of HRMs subtypes with IRMA walls and leakage-prone microaneurysms supports their putative role as optical signatures of lipoprotein extravasation and inflammatory lipidotoxicity in DR progression.
高反射性物质（HRMs）是在糖尿病视网膜病变（DR）中观察到的神秘生物标志物，其病理生理起源和临床意义尚不明确。
这项回顾性横断面研究调查了205只DR眼睛中HRMs亚型的空间分布模式及其与视网膜微血管结构、结构重塑和全身代谢参数的综合关系。通过多模态光学相干断层扫描血管造影（OCTA）分析对HRMs进行系统分类，包括地形定位（视网膜内与视网膜外）、反射率曲线、形态学尺寸、后部阴影伪像和去相关信号。在HRMs亚型与OCTA衍生的血管参数（视网膜内微血管异常[IRMA]、无灌注[NP]区域、微动脉瘤）、糖尿病性黄斑水肿（DME）状态和全身代谢指标（血糖控制、血脂谱、肾功能、炎症标志物）之间建立定量相关性。
确定了六种不同的HRMs表型：视网膜内高反射斑点（IRHFs）、视网膜外高反射斑点（ORHFs）、视网膜内硬性渗出物（IRHE）、视网膜外硬性渗出物（ORHE）、去相关阳性HRMs和棉絮斑。空间映射显示HRMs主要与IRMA区域共定位（75.4%的IRHFs、89.5%的ORHFs、90.8%的IRHE、94%的ORHE），而19%的IRHFs和8.7%的ORHFs与NP区域重叠。去相关阳性HRMs显示与IRMA（77.6%）和微动脉瘤（21.0%）有双重关联。DME眼睛在IRMA和NP区域内的HRMs密度显著升高（<0.001）。多变量分析确定血脂异常是HRMs负担的强预测因子。
这些发现将HRMs确立为糖尿病视网膜病理生理学的空间分辨生物标志物，反映了微血管功能不全（与IRMA相关的屏障破坏）、缺血重塑（NP区域）和全身代谢失调之间的特定区域相互作用。HRMs亚型与IRMA壁和易渗漏微动脉瘤的共定位支持了它们在DR进展中作为脂蛋白外渗和炎症性脂毒性光学特征的假定作用。
