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. 2025 Sep;46(9):4433-4443.
doi: 10.1007/s10072-025-08308-2. Epub 2025 Jun 16.

Implications of the glymphatic system in the diagnostic and surgical workup of normal pressure hydrocephalus

Morgan Broggi  1 , Edoardo M Barbieri  2 , Alessandro Gans  3 , Pascuzzo Riccardo  4 , Veronica Redaelli  3 , Domenico Aquino  4 , Francesco Restelli  2 , Marco Schiariti  2 , Francesco Acerbi  2   5   6 , Giuseppe Di Fede  3 , Paolo Ferroli  2 , Marina Grisoli  4 , Fabio Doniselli  4
Affiliations

Implications of the glymphatic system in the diagnostic and surgical workup of normal pressure hydrocephalus

Morgan Broggi et al. Neurol Sci. 2025 Sep.

Abstract

Background: Magnetic Resonance (MRI) Diffusion Tensor Imaging Analysis ALong the Perivascular Space (DTI-ALPS) is a promising technique that assesses the glymphatic system (GS) function in many neurodegenerative diseases. This study aims at evaluating the role of DTI-ALPS in the diagnostic and therapeutic management of normal pressure hydrocephalus (NPH).

Methods: Twenty-one NPH patients underwent 3 Tesla MRI DTI-ALPS before and after lumbar tap test (TT). Depending on the response to TT, patients were divided into a responsive cohort (15 responders, R) and non-responsive cohort (6 non-responders, NR). R patients underwent ventriculoperitoneal shunt (VPS) surgery, with clinical assessment upon discharge and at a 3-month follow-up (FU) visit; nine patients repeated DTI-ALPS MRI at FU. Besides, 8 matched healthy controls (HC) underwent the same MRI protocol.

Results: The pre-TT ALPS-index in NPH patients (R: 1.003 ± 0.108, NR: 0.960 ± 0.079) was significantly lower compared to the HC (1.263 ± 0.161, p < 0.01). The pre-TT ALPS-index in R patients was higher than in NR patients, though not significantly (p = 0.39). Compared to the pre-TT values, the ALPS-index of the R group increased both post TT (1.069 ± 0.122, p = 0.0499) and post VPS (1.120 ± 0.117, p = 0.041), in accordance to the clinical outcome.

Conclusions: DTI-ALPS, reflecting the GS function, resulted significantly lower in NPH patients than in healthy controls. Secondly, clinical improvement was associated with DTI-ALPS increase both after a positive response to TT and at long term follow-up following VPS surgery. Therefore, DTI-ALPS index could be a promising, rapid and non-invasive radiological biomarker for the pre-surgical evaluation and prognosis of NPH patients.

Keywords: ALPS-index; DTI-ALPS MRI; Glymphatic System; Normal pressure hydrocephalus.

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Conflict of interest statement

Declarations. Ethical Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Local Ethics Committee (blinded for review). Informed Consent: Informed consent was obtained from all subjects involved in the study. Conflicts of Interest: All the authors declare that the research was conducted in the absence of any commercial or financial relationship that could be constructed as a potential conflict of interest. Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Fondazione IRCCS Istituto Neurologico Carlo Besta (protocol code GlinfaNPH_2021, nr. 83/2021; date of approval: Aptil 14th, 2021).

Figures

Fig. 1
Fig. 1
Semi-automatic estimation of the diffusion tensor imaging (DTI) Analysis ALong the Perivascular Space (DTI-ALPS) index was performed by thresholding the fractional anisotropy (FA) color map to isolate projection and association fibers, followed by identification of peak FA voxels within manually defined rectangular Regions of Interest (ROIs) in the periventricular white matter. a Adapted from Taoka et al.,[31]; b original fractional anisotropy map with overlaid projection (blue) and association (green) fiber areas; c manually defined rectangular ROI; d two circular ROIs (5 mm) were automatically placed in regions of highest fractional anisotropy
Fig. 2
Fig. 2
Inclusion flowchart
Fig. 3
Fig. 3
Boxplots showing the distribution of diffusion tensor imaging (DTI) Analysis ALong the Perivascular Space (DTI-ALPS) values within groups and across timepoints. Asterisks denote significantly different DTI-ALPS values between timepoints. HCs = healthy controls; T0 = pre tap test; T1 = post tap test; T3 = post ventriculoperitoneal shunt
See this image and copyright information in PMC

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