Imaging - Clinical Evaluation of Altered Nervous System Drainage (I-CLEANED)

Multi-signal Analysis of the Composition and Movement of Fluid in Various Cerebral Compartments in Healthy Subjects and Subjects With White Matter Pathology

The current study aims to evaluate the aspects of perfusion, fluid diffusivity in the interstitium and the T1 and T2 signal of the PVS and WMH. The current study has the following objectives: a) evaluate the perfusion aspects using the gadolinium-based contrast medium of brain tissues in the short term; b) the direction of flow of fluids at very low speed in the white matter using the DTI sequences configured for this purpose; c) T1-mapping of the lesions of interest.

The expected results will help us understand two aspects of neurofluid dynamics: a) how the fluid moves within the central nervous system in the first minutes after the injection of the tracer (in our case the gadolinium-based contrast medium) and b) what is the composition of the fluid within the PVS and WMH and how can investigators characterize them more accurately.

Study Overview

• Status: Recruiting
• Conditions: Autism Spectrum Disorder; Neuroinflammation
• Intervention / Treatment: Diagnostic test: Magnetic resonance imaging

Detailed Description

Among the various indirect markers of altered drainage of neuroglial waste metabolites, there is the widening of the perivascular spaces (PVS) and the presence of white matter signal alterations.

An increase in the number of PVS and their enlargement could represent an indirect marker of obstruction to the drainage of fluids and solutes along the arterial wall at the level of the white matter. This obstruction would also be the basis of tissue hypoxia resulting in the formation of areas of signal hyperintensity in the white matter (White Matter Hyperintensities, WMH) often observed in patients with neurodegenerative diseases and small vessel disease.

It is currently unclear what the main drainage route of brain waste metabolites is. Surely there are at least two.

The glymphatic theory proposes the entry of the cerebrospinal fluid (CSF) from the subarachnoid space towards the brain parenchyma in a centripetal direction and exit of the metabolic waste along the perivenous spaces. The drainage of metabolic waste could also be explained by the more recent "intramural periarterial drainage" (IPAD) theory which shows elimination along the arterial walls in a centrifugal direction.

In magnetic resonance imaging (MRI), the study of solute drainage requires a dynamic evaluation, which is able to evaluate the temporal movement of a tracer. There are several MRI techniques, already described in the literature, which can be used to obtain information relating to perfusion processes and the coupling of neuronal and vascular activity in different brain areas.

The circulation of CSF is well known, which is produced largely at the level of the choroid plexuses and is then partly reabsorbed by the arachnoid granulations at the level of the subarachnoid space. Recent studies demonstrate that the CSF re-enters the brain parenchyma in a centripetal manner, crossing the thickness of the gray matter and then the white matter. This movement is regulated by various factors, and in particular by the activity of the smooth muscle cells of the arterial walls, the aquaporin 4 receptors (water channels) and by the chemical-physical properties of the extracellular matrix in the extracellular space.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

Study Locations

• Italy
  • Lecco
    • Bosisio Parini, Lecco, Italy, 23842
      • Recruiting
      • Scientific Institute IRCCS E. Medea
      • Contact: Nivedita Agarwal, MD; Phone Number: 398 +39 031855; Email: nivedita.agarwal@lanostrafamiglia.it
      • Contact: Noemi Miscioscia; Email: noemi.miscioscia@lanostrafamiglia.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Patients with obvious white matter disease on T2 and FLAIR sequences will be included in this study. In particular patients with recent diagnosis of autism spectrum disorder, traumatic brain injury, Steinert's muscular dystrophy will be included.

Description

Inclusion Criteria:

• patients with white matter lesions and/or enlarged perivascular spaces

Exclusion Criteria:

• have contraindications to the use of contrast medium;
• are clinically unstable patients and prolonged sedation is inappropriate
• have tumors
• contraindications to perform MR.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients; patients with white matter hyperintensities, patients with enlarged perivascular spaces, Focus will be on patients with a clinical diagnosis of muscular dystrophy or autism spectrum disorder or traumatic brain injury.	Diagnostic test: Magnetic resonance imaging; Diagnostic and research scanning using magnetic resonance imaging.
Controls; Patients who need a diagnostic scan but do not carry a diagnosis of psychomotor or cognitive impairment or without a history of TBI and tumors. No white matter hyperintensities.	Diagnostic test: Magnetic resonance imaging; Diagnostic and research scanning using magnetic resonance imaging.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Perivascular space count	Number and distribution of enlarged perivascular spaces	once at recruitment
Volume of parasagittal dura	correlation of parasagittal dura and perivascular count	once at recruitment
fMRI signal during sedation	effect of sedation on BOLD signal	once at recruitment

Collaborators and Investigators

• Sponsor: IRCCS Eugenio Medea
• Collaborators: Ministry of Health, Italy

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2023
• Primary Completion (Estimated): October 31, 2025
• Study Completion (Estimated): January 31, 2026

Study Registration Dates

• First Submitted: May 15, 2024
• First Submitted That Met QC Criteria: May 21, 2024
• First Posted (Actual): May 29, 2024

Study Record Updates

• Last Update Posted (Actual): May 29, 2024
• Last Update Submitted That Met QC Criteria: May 21, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: magnetic resonance imaging; autism spectrum disorder; white matter disease; glymphatic system; brain waste clearance
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Inflammation; Neurodevelopmental Disorders; Child Development Disorders, Pervasive; Autism Spectrum Disorder; Neuroinflammatory Diseases
• Other Study ID Numbers: 1022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No