WHIte MAtter Hyperintensity Shape and Glymphatics (WHIMAS)

White Matter Hyperintensity Shape and Glymphatics

In a society with increased life expectancy, the economic, social and personal burden of dementia increases. Dementia is often caused by a combination of neurovascular and neurodegenerative diseases. Impaired brain clearance is suggested to be closely related to dementia development, as waste products (e.g. amyloid beta) accumulate in the brain, leading to neurodegeneration. Cerebral small vessel disease (SVD) is the most common neurovascular disease that even contributes to about 45% of dementia pathophysiology in patients with a diagnosis of Alzheimer's dementia. White matter hyperintensities of presumed vascular origin (WMH) are the key brain MRI manifestation of cerebral SVD. There is evidence that the currently known and MRI-visible WMH are landmarks of an already progressed stage of the underlying pathology. The pathophysiology of WMH has been attributed to multiple underlying mechanisms, such as hypoperfusion, defective cerebrovascular reactivity and blood-brain barrier dysfunction. Furthermore, different anatomical locations and different types of WMH are related to different underlying pathological changes. Using ultra-high field 7T MR imaging techniques WMH lesions can be detected with a higher sensitivity and resolution than on 3T MRI. The hypothesis is that different pathological mechanisms of cerebral SVD lead to variations in WMH shape. Moreover, the brain clearance ('glymphatic') system of the brain appears to be tightly connected to dementia pathology. Thus, novel markers of glymphatic activity could aid to describe and understand the pathology.

Study Overview

• Status: Recruiting
• Conditions: Cognitive Impairment; Mild Cognitive Impairment; Cerebral Small Vessel Diseases; Dementia, Vascular; Cognitive Decline; Dementia, Mixed
• Intervention / Treatment: Other: 3T MRI scan; Other: 7T MRI scan; Behavioral: Neuropsychological assessment; Other: General baseline data

Detailed Description

Aim:

The overall aim is to study how different pathological mechanisms in cerebral SVD influence WMH shape.

Primary objective:

To study the association of a more complex WMH shape with abnormalities in small vessel morphology.

Secondary objectives:

To study the association between WMH shape and cognition/other cerebral small vessel disease markers. To study the association of novel MRI markers of glymphatics with cerebral SVD markers and cognition.

Study design: Cross-sectional study that will be conducted at the Leiden University Medical Center (LUMC). Patients will be included from the LUMC or the Alrijne Hospital Leiden. The study contains 3T and 7T MRI scans, as well as neuropsychological assessments. The data will be analyzed by performing association analysis.

Study population: Patients of the memory/geriatric clinic that are over 65 years of age.

Main study parameter/endpoint: In order to postulate underlying mechanisms related to WMH shape variations the investigators will study the association between a more complex WMH shape and structural and functional markers of cerebral SVD (such as lacunes and microbleeds).

WMH shape is assessed as follows: Convexity, solidity, concavity index, and fractal dimension are calculated for periventricular/confluent WMH. A lower convexity and solidity, and higher concavity index and fractal dimension indicate a more irregular shape of periventricular/confluent WMH. For deep WMH, fractal dimension and eccentricity are determined. A higher eccentricity and fractal dimension indicate a more complex shape of deep WMH.

Other study parameters: The investigators want to investigate WMH shape parameters and the association with cognition (mini-mental state exam, clinical dementia rating and cognitive domain scores). Another endpoint is to investigate if different WMH phenotypes can be identified (by machine learning models). Moreover, the association between SVD markers/cognition and novel glymphatics markers (such as size of perivascular spaces, CSF mobility and 4th ventricle CSF flow dynamics) will be investigated.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The participants will not directly benefit from the results of the study. However, their contribution to the study will add important information about the pathophysiology of the cerebrovascular pathology that contributes to dementia. Therefore, it is not possible to study the research question in a different population group. The ultra-high field 7T MRI system is widely used in a research setting and since its first introduction in the 1990s no serious adverse events have been reported. Important temporary side-effects are vertigo, nausea and involuntary eye motion due to forces on ion currents in the semicircular loops. As all MRI scans are performed within a maximum of 60 minutes and without any contrast agents, the participant burden is seen as a non-substantial burden.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Jeroen de Bresser, MD, PhD; Phone Number: 0031715262052; Email: J.H.J.M.de_Bresser@lumc.nl
• Study Contact Backup: Name: Ingmar Eiling, MSc; Phone Number: 0031715265411; Email: i.eiling@lumc.nl

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333ZA
    • Recruiting
    • Leiden University Medical Center
    • Contact: Jasmin Annica Keller, MSc; Phone Number: 0031715265411; Email: j.a.keller@lumc.nl
    • Contact: Jeroen de Bresser, MD, PhD; Phone Number: 0031715262052; Email: J.H.J.M.de_Bresser@lumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

We will prospectively include patients with memory complaints and/or vascular brain abnormalities (n=50; over 65 years of age) from the memory clinic at one of their first visits, prior to any diagnosis, at the Leiden University Medical Center, the Alrijne Hospital Leiden or the Haga Hospital the Hague. If not enough eligible patients are available from the memory clinic, we will include participants from the geriatric clinic.

Description

Inclusion Criteria:

• Admitted to the memory or the geriatric clinic of the LUMC, the Alrijne Hospital Leiden or the Haga Hospital the Hague
• From 65 years of age
• Eligible for MRI
• Native-level Dutch speaker

Exclusion Criteria:

• Claustrophobia
• Contraindications for MRI such as metal implants and pacemaker
• Use of benzodiazepines
• Initiated treatment with antidepressants less than 6 weeks prior to inclusion
• Not being able to provide written informed consent (assessed by the treating physician)
• Individuals that have been declared mentally incapacitated
• Other severe neurological disease besides dementia related
• Cognitive impairment due to known other neurological disease
• Previous brain surgery

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Memory clinic patients; We will prospectively include patients with memory complaints and/or vascular brain abnormalities (n=50; over 65 years of age) from the memory clinic (or geriatric clinic) at one of their first visits, prior to any diagnosis.

Other: 3T MRI scan; Conventional (3T) brain MRI scans will be used to determine global and functional markers of cerebral SVD, like WMH volume and presence of lacunes, microbleeds and superficial siderosis (3D T1, 3D FLAIR, SWI, DWI), hemodynamics (arterial spin labelling & flow territory mapping) and white matter structural integrity (diffusion tensor imaging (DTI)). Furthermore, we want to measure structural integrity with a novel MR fingerprinting sequence and an inhomogeneous magnetization transfer (ihMT) MRI scan. We also want to apply a fMRI scan technique to measure CSF fluctuations in the 4th ventricle as a measure of brain glymphatics. Also the flow-territory mapping sequence is a non-standard sequence. Heart rate and respiratory signal will be measured during the scans (3T and 7T MRI) with standard vendor-supplied equipment.; Other: 7T MRI scan; Ultra-high field (7T) brain MRI scans will be used to determine WMH shape and other markers of cerebral SVD in or surrounding the WMH, like local enlarged perivascular spaces, (cortical) microinfarcts and microbleeds (T1, T2, FLAIR and T2*) and vascular pulsatility (phase contrast MRI). Moreover, a recently implemented MRI technique to measure glymphatic flow in perivascular spaces will be used.; Behavioral: Neuropsychological assessment; Mini-mental state examination; Clock drawing; 15-Word Verbal Learning Test, immediate and delayed; Visual Association Test; Stroop Color Word Test, 40 item version; Trail Making Test A&B; Letter Digit Substitution Test; Animal fluency test; Hospital anxiety and depression scale; Informant Questionnaire on Cognitive Decline in the Elderly; Other: General baseline data; Baseline data, such as age, sex, psychiatric comorbidity and medication lists will be extracted from the patient files. Age (Year of birth); Years of education; BMI (height & weight); Sex; Verhage scale (education); Smoking status; Blood values; Sleep habits; Waste-hip ratio; Blood pressure; Current/general cardiovascular health; Psychiatric comorbidity; medical history related to cardiovascular health.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
WMH shape	The investigators will use an in-house developed analysis pipeline to calculate WMH shape on 3T and 7T brain MRI scans. Associations between WMH shape and other SVD markers and cognition will be investigated with linear and logistic regression (at least corrected for age and sex).	at study visit during inclusion up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain clearance	Measured on brain MRI as a marker of glymphatic activity.	at study visit during inclusion up to 3 years
Perivascular space volume	This marker will be measured on brain MRI.	at study visit during inclusion up to 3 years
WMH subtypes	Based on WMH parameters the investigators will study if subtypes of WMH can be identified.	at study visit during inclusion up to 3 years

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Alzheimer Nederland
• Investigators: Principal Investigator: Jeroen de Bresser, MD, PhD, Leiden University Medical Center

Publications and helpful links

General Publications

• Bos D, Wolters FJ, Darweesh SKL, Vernooij MW, de Wolf F, Ikram MA, Hofman A. Cerebral small vessel disease and the risk of dementia: A systematic review and meta-analysis of population-based evidence. Alzheimers Dement. 2018 Nov;14(11):1482-1492. doi: 10.1016/j.jalz.2018.04.007. Epub 2018 May 21.
• Ghaznawi R, Geerlings MI, Jaarsma-Coes M, Hendrikse J, de Bresser J; UCC-Smart Study Group. Association of White Matter Hyperintensity Markers on MRI and Long-term Risk of Mortality and Ischemic Stroke: The SMART-MR Study. Neurology. 2021 Apr 27;96(17):e2172-e2183. doi: 10.1212/WNL.0000000000011827. Epub 2021 Mar 16.
• Ghaznawi R, Geerlings MI, Jaarsma-Coes MG, Zwartbol MH, Kuijf HJ, van der Graaf Y, Witkamp TD, Hendrikse J, de Bresser J. The association between lacunes and white matter hyperintensity features on MRI: The SMART-MR study. J Cereb Blood Flow Metab. 2019 Dec;39(12):2486-2496. doi: 10.1177/0271678X18800463. Epub 2018 Sep 11.
• Keller JA, Sigurdsson S, Klaassen K, Hirschler L, van Buchem MA, Launer LJ, van Osch MJP, Gudnason V, de Bresser J. White matter hyperintensity shape is associated with long-term dementia risk. Alzheimers Dement. 2023 Dec;19(12):5632-5641. doi: 10.1002/alz.13345. Epub 2023 Jun 12.

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2023
• Primary Completion (Estimated): August 30, 2026
• Study Completion (Estimated): August 31, 2027

Study Registration Dates

• First Submitted: July 18, 2023
• First Submitted That Met QC Criteria: August 23, 2023
• First Posted (Actual): August 24, 2023

Study Record Updates

• Last Update Posted (Actual): April 13, 2025
• Last Update Submitted That Met QC Criteria: April 10, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: dementia; cognitive decline; cerebral small vessel disease; cognitive impairment; White matter hyperintensities; Glymphatics
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Arteriosclerosis; Arterial Occlusive Diseases; Leukoencephalopathies; Intracranial Arteriosclerosis; Intracranial Arterial Diseases; Cognitive Dysfunction; Dementia; Dementia, Vascular; Cerebral Small Vessel Diseases
• Other Study ID Numbers: WHIMAS

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
• product manufactured in and exported from the U.S.: No