In older adults, cerebral small vessel disease (CSVD) is often implicated in dementia and cognitive impairment [1]. Despite its prevalence and negative impact on cognitive function, underlying CSVD mechanisms and effective treatments are limited. Previous studies have indicated that white matter damage (WMD) is a major contributor to cognitive impairment in CSVD [2, 3, 4], but the causes of such damage are not fully understood, multifaceted, and may include: low cerebral blood flow [5], blood-brain barrier leakage [6], neuroinflammation [7], and venous abnormalities [8]. These mechanisms have garnered significant research traction in recent years.

The deep medullary vein (DMV) complex is of particular interest and is the main venous blood drain in periventricular white matter and the corona radiata. DMVs are perpendicular to the ventricle, have limited variation, and are often used to examine deep venous changes in cerebral vascular disease. Studies have reported that magnetic resonance imaging (MRI)-derived DMV scores, based on DMV visibility on susceptibility-weighted imaging (SWI), are associated with the presence and burden of CSVD [9]. Subsequently, studies also find that DMV scores are related to cognitive impairment or dementia in individuals with CSVD [10]. According to previous studies, a higher DMV score is associated with venous lumen stenosis and venous hypertension [11], which may obstruct venous drainage in white matter and cause extracellular fluid (ECF) accumulation [12]. Increased ECF may facilitate harmful substance accumulation (e.g., plasma protein and metabolic waste) and, critically, cause WMD [13]. Therefore, we hypothesized that decreased DMV visibility was associated with WMD when mediated by increased ECF.

To evaluate ECF volumes, diffusion tensor imaging (DTI) is widely used in nervous-system-disease research [12, 14, 15]. According to the free water (FW) elimination 2-compartmental model [16], FW reflects ECF volume corrected for partial volume effects in cerebrospinal fluid, while fractional anisotropy (FA) indicates white matter integrity (WMI) after removing FW signals.

Therefore, CSVD is a significant health challenge for older adults; thus, deeper mechanistic insights are warranted. This study focused on the DMV complex in CSVD-associated WMD and investigated relationships between DMV scores, ECF volumes, and WMI using advanced multimodal magnetic resonance imaging (MRI) approaches.

We enrolled 140 patients (mean age = 60 $\pm$ 12 years, and 66 were men) with CSVD. Baseline clinical and imaging characteristics are shown (Table 1). Thirty-two (22.9%) patients showed HWMH, 53 (37.9%) showed CMBs, 20 (14.3%) showed HPVS and 56 (40%) showed LIs. The median (IQR) DMV score was 3 (0, 7), and mean FW and FA values in white matter were 0.25 $\pm$ 0.01 and 0.56 $\pm$ 0.03, respectively.

3.1 Relationship between DMV Scores and FA Values

As indicated (Fig. 3), Spearman’s correlation coefficients identified a significant correlation between DMV scores and FA values in white matter (r = –0.251, p 0.05). DMV scores were independently related to FA after adjusting for vascular risk factors, age, WMH volume, and CSVD burden [$\beta$ (95% confidence interval (CI)): –0.219 (–0.375, –0.061), p = 0.006, Table 2].

Fig. 3.

Graph showing the relationship between deep medullary vein (DMV) scores and fractional anisotropy (FA) values.

Table 2.Linear regression analysis of fractional anisotropy (FA) in patients with cerebral small vessel disease (CSVD).

Variables	$\beta$	$\beta$, 95% CI		p value
		Lowest	Highest
Age	–0.046	–0.226	0.133	0.610
Hypertension	0.031	–0.116	0.179	0.677
Diabetes mellitus	–0.104	–0.245	0.036	0.143
Current smoking	0.110	–0.026	0.245	0.111
Hyperlipidemia	0.045	–0.092	0.183	0.515
Total CSVD MR score	–0.020	–0.200	0.159	0.825
WMH volume	–0.085	–0.257	0.087	0.331
DMV score	–0.219	–0.375	–0.063	0.006

CSVD, cerebral small vessel disease; CI, confidence interval; MR, magnetic resonance.

3.2 Relationship between DMV Scores and FW Values

As indicated (Fig. 4A), Spearman’s correlation coefficient analyses identified significant correlations between DMV scores and FW values in white matter (r = 0.425, p 0.001). DMV scores were also independently associated with FW values after adjusting for age, vascular risk factors, CSVD burden, and WMH volume [$\beta$ (95% CI): 0.145 (0.019, 0.571), p = 0.037, Fig. 5].

Fig. 4.

Graphs showing relationships between deep medullary vein (DMV) scores, fractional anisotropy (FA), and free water (FW) values. A: There is a significant correlation between DMV scores and FW values in white matter (r = 0.425, p 0.001). B: There is a significant correlation between FW and FA values in white matter (r = –0.323, p 0.001).

Fig. 5.

Mediation model analyses exploring relationships between deep medullary vein (DMV) scores, fractional anisotropy (FA), and free water (FW) values (*p 0.05).

DMV scores were independently associated with FA values in white matter and mediated by FW values in patients with CSVD. Also, mediation effects were independent of vascular risk factors, age, WMH volume, and CSVD burden. Thus, relationships existed between DMV damage, increased ECF, and WMI loss in patients with CSVD.

With rapid improvements in MRI technology, SWI is widely used to investigate cerebral vascular and neurodegenerative diseases [20, 21]. Many studies have reported that MRI-based DMV scores may be correlated with CSVD presence and severity [9, 18, 22]. Higher DMV scores are putatively correlated with a higher CSVD probability and severity. Previous autopsy and animal studies indicated that DMV damage may be caused by collagen type I and III deposition on vessel walls, leading to a stenotic or occluded lumen [11, 23, 24]. Higher DMV scores may reflect this DMV damage, and DMV abnormalities may be implicated in CSVD development.

DMV scores correlated with cognitive impairment in patients with CSVD [10], while associations between microstructure changes and WMI loss and cognitive impairment were reported in these patients [2]. However, the relationship between DMV damage and WMI loss and the precise influence of DMV scores on WMD remains unclear. Here, we identified links between DMV damage, increased ECF, and WMI loss in patients with CSVD. When a DMV abnormality was present, increased ECF initially occurred, followed by white matter demyelination and axonal damage.

Based on DMV structure and function, we suggest that DMV-associated white matter abnormalities occur when the DMV lumen narrows and venous pressure increases, causing obstructed venous drainage and increased vascular permeability [11], with increased PVS and ECF leakage volumes. It was previously believed that the index of diffusion tensor image along the PVS near the DMV was related to glymphatic system function [25]. Thus, a DMV abnormality may have caused glymphatic system dysfunction and increased ECF volume. However, venous hypertension may also have decreased cerebral blood flow and vascular edema, thereby increasing ECF. Either way, increased ECF volume may have facilitated harmful substance (e.g., plasma proteins and metabolic waste) accumulation, which elicited neuroinflammation, and further increased the ECF volume, thus ensuring a vicious circle. These substances can potentially damage white matter microstructures (e.g., myelin and axons), leading to WMI loss [13, 26]. In considering WMI loss and cognitive impairment evidence, identifying DMV abnormality and cognitive impairment steps may uncover new CSVD venous-related prevention and control mechanisms.

CSVD is related to aging and associated with one or more vascular risk factors [27]. WMH volume and CSVD burden were often correlated with more severe WMD [28]. Therefore, in mediation analyses, we adjusted for age, vascular risk factors, WMH volume, and CSVD burden. This approach enhanced the practicality of our findings and suggested that cerebral venous abnormalities initially occurred with increased ECF volume, followed by WMD. Furtherly, this observation was consistent with other research [8], which confirmed links between DMV scores and FW and FA values in patients with CSVD. Although research has shown a correlation between WMH volume, CSVD burden, age, and cognitive decline [3, 29], this study reveals that they are not independently associated with FA or WMI. The possible explanation is that the underlying mechanism driving cognitive decline or WMI involves changes in the brain’s microenvironment and microstructure, contributing to the development of WMH volume and CSVD burden.

Our study was limited. It was conducted at a single center and had a small sample. Secondly, no follow-up was conducted to examine relationships between DMV scores, FW and FA values, and cognitive impairment. Thirdly, low cerebral blood flow and inflammatory edema may also increase FW [28, 30]; however, we did not include these factors or adjust for them in our models, thus introducing potential bias. Fourthly, although the DMV scores system has now been used in the serial study, the software automatically detecting and measuring DMV scores may be better to quantitatively assess DMV changes. We mainly focused on extracellular FW, while intracellular water content was not analyzed. Finally, capillary blood perfusion may have affected extracellular FW values. Thus a 3-compartment model may improve FW estimations. To address the limitations mentioned above, more multi-center investigations with more patients are required.

DMV scores were independently associated with WMI and mediated by ECF volume in white matter in patients with CSVD. This observation may underpin a venous element of WMD pathogenesis in CSVD.

SWI, susceptibility-weighted imaging; DMV, deep medullary vein; CSVD, cerebral small vessel disease; DTI, diffusion tensor imaging; FW, free water; FA, fractional anisotropy; HWMH, high-grade white matter hyperintensities; CMB, cerebral microbleeds; HPVS, high-grade perivascular spaces; LI, lacunar infarcts; WMD, white matter damage; WMI, white matter integrity.

Study datasets are available upon reasonable request from the corresponding author.

HW, XL and ZX designed the research. HW, HZ, ZC, YW and HL performed the research. HL and HZ assisted with the research. HW and ZX analyzed data. HW, XL and ZX wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was conducted according to the Declaration of Helsinki and approved by the Institutional Review Board of Tongde Hospital of Zhejiang Province (2022-042-JY). Written informed consent was provided prior to participation.

We thank our colleagues in the department of radiology for their support and assistance during data collection.

This research was funded by the Medical and Health Science and Technology Program of Zhejiang Provincial Health Commission of China, grant number 2022KY707.

The authors declare no conflict of interest.