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Transdiagnostic Reductions in Glymphatic-Related Perivascular Diffusion Across Psychiatric Disorders: A Systematic
Alessandro Pascucci1, Luigi F Saccaro2, Silas Forrer3
1Psychiatry Department, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland; Synapsy Centre for Neuroscience and Mental Health Research, University of Geneva, Geneva, Switzerland; Fondation Pôle Autisme, Geneva, Switzerland.
Background:
The glymphatic system, a perivascular pathway supporting cerebrospinal and interstitial fluid exchange and clearance, has been implicated in neurodegenerative and psychiatric disorders. Diffusion tensor imaging along the perivascular space (DTI-ALPS) provides a non-invasive proxy for glymphatic-related processes, yet its role in psychiatric conditions remains uncertain.
Methods:
Following PRISMA guidelines, we systematically searched PubMed, PsycNET, and Embase for articles published up to September 25th, 2025. The protocol was pre-registered in PROSPERO (CRD420251155430). Studies reporting diffusion-based indices of glymphatic function in psychiatric populations were included. Standardised mean differences (Hedges' g) were calculated for patient-control comparisons and pooled using random-effects models. Heterogeneity, methodological moderators, and risk of bias were assessed.
Results:
Thirty-two studies met inclusion criteria for the systematic review, covering major psychiatric groups including mood disorders, autism spectrum disorder, ADHD, psychosis, sleep disorders, and substance-related conditions. Twenty-four studies (n = 2,855; 1,503 patients, 1,352 controls) reporting bilateral DTI-ALPS measures were included in the meta-analysis. The pooled random-effects model revealed a significant transdiagnostic reduction in DTI-ALPS index in psychiatric populations compared with healthy controls (Hedges' g = -0.78, 95% CI -1.01 to -0.55, p < 0.0001). Between-study heterogeneity was substantial (I² = 86.3%), and there was evidence of small-study effects.
Conclusions:
Bilateral DTI-ALPS index showed a robust but heterogeneous reduction across psychiatric disorders. These results suggest that impairments of perivascular diffusion, as indexed by DTI-ALPS, may reflect a shared transdiagnostic pattern across psychiatric conditions. Harmonised imaging pipelines and multimodal validation are needed to clarify the biological and clinical significance of these findings.
