WHIte MAtter Hyperintensity Shape and Glymphatics

NCT06010511 | Recruiting

• 1 other identifier: WHIMAS
• Study Type: observational
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cerebral Small Vessel Diseases; Dementia, Mixed; Dementia, Vascular; Mild Cognitive Impairment; Cognitive Impairment; Cognitive Decline

Keywords

dementia; cerebral small vessel disease; White matter hyperintensities; cognitive impairment; cognitive decline; Glymphatics

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Brain clearance

  at study visit during inclusion up to 3 years

• Perivascular space volume

  at study visit during inclusion up to 3 years

• WMH subtypes

  at study visit during inclusion up to 3 years

Study Arms (1)

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; Other: 7T MRI scan; Behavioral: Neuropsychological assessment; Other: General baseline data

Interventions

3T MRI scan OTHER

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.

Memory clinic patients

7T MRI scan OTHER

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.

Memory clinic patients

Neuropsychological assessment BEHAVIORAL

* 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

Memory clinic patients

General baseline data OTHER

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.

Memory clinic patients

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)
• 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.

You may qualify if:

• 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

You may not qualify if:

• Claustrophobia
• Contraindications for MRI such as metal implants and pacemaker
• Use of benzodiazepines
• 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

Sponsors & Collaborators

• Leiden University Medical Center: lead
• Alzheimer Nederland: collaborator

Study Sites (1)

Leiden University Medical Center

Leiden, 2333ZA, Netherlands

RECRUITING

Related Publications (5)

• 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.

  PMID: 29792871 BACKGROUND

• 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.

  PMID: 33727406 BACKGROUND

• 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.

  PMID: 30204039 BACKGROUND

• 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.

  PMID: 37303267 BACKGROUND

• Kuhn-Keller JA, Eiling I, Hirschler L, Vaclavu L, Witjes-Ane MN, Wijngaarden M, Nagtegaal M, Ercan E, Rius Ottenheim N, van der Elst M, Sohl E, van Buchem MA, Mooijaart S, van Osch MJ, de Bresser J. The White Matter Hyperintensity Shape and Brain Clearance (WHIMAS) Study for Identification of Novel 7T Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease: Protocol for a Cross-Sectional Study. JMIR Res Protoc. 2025 Dec 4;14:e77681. doi: 10.2196/77681.

  PMID: 41344663 DERIVED

MeSH Terms

Conditions

Cerebral Small Vessel Diseases; Mixed Dementias; Dementia, Vascular; Cognitive Dysfunction; Dementia

Interventions

Neuropsychological Tests

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Neurocognitive Disorders; Mental Disorders; Intracranial Arteriosclerosis; Intracranial Arterial Diseases; Leukoencephalopathies; Arteriosclerosis; Arterial Occlusive Diseases; Cognition Disorders

Intervention Hierarchy (Ancestors)

Psychological Tests; Behavioral Disciplines and Activities

Study Officials

• Jeroen de Bresser, MD, PhD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ingmar Eiling, MSc

CONTACT

0031715265411; i.eiling@lumc.nl

Jeroen de Bresser, MD, PhD

CONTACT

0031715262052; J.H.J.M.de_Bresser@lumc.nl

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator; MD; PhD

Study Record Dates

• First Submitted: July 18, 2023
• First Posted: August 24, 2023
• Study Start: January 18, 2023
• Primary Completion (Estimated): August 30, 2026
• Study Completion (Estimated): August 31, 2027
• Last Updated: April 13, 2025

Record last verified: 2025-04

Locations

NL (1)