DTI-ALPS Glymphatic Marker Fails to Predict Survival in Glioblastoma

A retrospective cohort study found that glymphatic dysfunction, as measured by the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, was reduced in patients with glioblastoma compared with healthy controls but did not independently predict overall survival once extent of resection and other established prognostic factors were accounted for.¹

The findings diverge from several previous reports that identified the ALPS index as an independent prognostic marker in glioma, though those studies did not adjust for MGMT promoter methylation status or extent of resection in their models.

Study design

The retrospective, single-center study included 47 patients who underwent surgical resection for IDH-wildtype glioblastoma (CNS WHO grade 4) at University Medical Center Mainz in Germany between January 2016 and December 2025, all of whom had preoperative DTI available, compared with 50 age- and sex-matched healthy controls. Patients with severe imaging artifacts or without an anatomically suitable region for ALPS analysis were excluded, and ALPS values were not available to treating clinicians at any point during the study.

The ALPS index was calculated separately for each hemisphere using regions of interest in projection and association fiber tracts, then averaged into a hemispheric score. The glymphatic system clears interstitial waste from the brain via aquaporin-4 channels on astrocytic end feet and drainage toward meningeal lymphatic vessels and the cervical lymph nodes, and has also been proposed to contribute to neuroinflammation and tumor immunosurveillance.² DTI-ALPS, an indirect imaging surrogate for glymphatic function, was first described in Alzheimer disease and has since been applied across a range of neurologic and oncologic conditions.³

Glymphatic impairment in glioblastoma

The hemispherically averaged ALPS index was significantly lower in patients with glioblastoma than in healthy controls (1.15 vs 1.27, P = .01). That difference was driven by the tumor-bearing hemisphere: ipsilateral ALPS was lower than in healthy controls (1.05 vs 1.27, P < .001) and lower than the contralateral hemisphere within the same patients (1.1 vs 1.22, P = .01), while contralateral ALPS did not differ significantly from healthy controls (1.22 vs 1.27, P = .29).¹

No significant correlations were observed between ALPS metrics and age, contrast-enhancing tumor volume, edema volume, or ECOG performance status, and ALPS values did not differ by MGMT promoter methylation status.

Survival analysis

Median follow-up for the survival analysis, which excluded 2 perioperative deaths, was 27 months, and median overall survival was 15 months (95% CI, 11-26). In Kaplan-Meier analysis, extent of resection was the only factor significantly associated with overall survival (P < .001); MGMT methylation showed a trend that did not reach significance (P = .11).¹

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Neither ipsilateral nor contralateral ALPS index was significantly associated with survival in univariable Cox regression. In multivariable models adjusting for age, sex, MGMT status, and extent of resection, ALPS remained non-significant in both the ipsilateral model (HR, 1.76; 95% CI, 0.38-8.12; P = .47) and the contralateral model (HR, 3.19; 95% CI, 0.59-17.14; P = .18); female sex and extent of resection were the only independent predictors of survival in both models.

Contrast with prior research

“In the key observation, our data thus diverges from observations by Hagiwara et al, Tian et al, and Zeng et al indicating ALPS as a prognostic factor for survival in glioblastoma,” the study authors wrote, noting that those earlier reports had not incorporated MGMT status and extent of resection into their survival models.¹

The 3 prior analyses include a 2026 study linking contralateral neurofluid dynamics to survival in IDH-wildtype glioblastoma,⁴ a 2025 evaluation of the glymphatic system in diffuse gliomas using DTI-ALPS,⁵ and a 2025 analysis of glymphatic system function in high-grade glioma.⁶

The authors suggested that glymphatic dysfunction in glioblastoma may be more a consequence of the tumor than a causal factor in disease progression, consistent with histopathologic correlation work tying glymphatic imaging changes to tumor-related tissue alterations.⁷ They also cautioned that DTI-ALPS is anatomically constrained to the corona radiata and vulnerable to confounding by tumor volume, infiltration, vascularity, and edema, and that the retrospective design may have introduced selection bias toward eloquently located lesions, for which DTI is more often ordered preoperatively.¹

“Glymphatic function assessed via DTI-ALPS appears to be reduced in the presence of glioblastoma but showed no association with overall survival in our cohort,” the authors concluded, adding that further investigation is needed to understand the mechanistic interactions between glioblastoma and glymphatic dysfunction.¹

REFERENCES
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2. Aspelund A, Antila S, Proulx ST, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015;212(7):991-999. doi:10.1084/jem.20142290
3. Taoka T, Masutani Y, Kawai H, et al. Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases. Jpn J Radiol. 2017;35(4):172-178. doi:10.1007/s11604-017-0617-z
4. Hagiwara A, Uchida W, Ozawa T, et al. Contralateral neurofluid dynamics predict survival in IDH wild-type glioblastoma: a DTI-ALPS and free water imaging study. Neurooncology. 2026;28(3):299-310.
5. Zeng S, Huang Z, Zhou W, et al. Noninvasive evaluation of the glymphatic system in diffuse gliomas using diffusion tensor image analysis along the perivascular space. J Neurosurg. 2025;142(1):187-196.
6. Tian B, Jiang X, Luo X, Zhang W. Analysis of the glymphatic system function in high-grade glioma patients using diffusion tensor imaging along perivascular spaces. BMC Neurol. 2025;25(1):181.
7. Gao M, Liu Z, Zang H, et al. A histopathologic correlation study evaluating glymphatic function in brain tumors by multiparametric MRI. Clin Cancer Res. 2024;30(21):4876-4886.