Vascular Aspects in Dementia: Part 2

September 9, 2025 updated by: svanrooden, Leiden University Medical Center

Clarifying the Vascular Aspects of Dementia; Natural History Study

Cerebral amyloid angiopathy (CAA), a common cerebrovascular small vessel disease (SVD), is a frequently (98%) found co-morbidity at autopsy in patients with Alzheimer's disease (AD). Current in vivo hallmarks of CAA represent changes relatively late in the disease process and leaves CAA in AD often undetected. Recently, it was shown that decreased vascular reactivity (VR) measured with blood oxygen level dependent (BOLD) MRI, after visual stimulus, is an early CAA marker. With BOLD-MRI to detect decreased VR in different stages of AD, it was shown that increasing stages of AD associate with decreasing VR independent of age, classic SVD markers and atrophy. Moreover, VR is associated with cognitive deficits. Therefore, cross-sectional data indicate that decreased VR is an important co-morbidity already in early stages of AD with an independent effect on disease severity. In this respect, the study aim is to determine the natural course of the decrease of VR in both controls and (early stage) AD patients to monitor AD disease progression. This is an essential step to aid in the development and application of effective treatment as it is expected that CAA can cause/worsen AD pathology.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Rationale: Cerebral amyloid angiopathy (CAA), a common cerebrovascular small vessel disease (SVD), is a frequently (98%) found co-morbidity at autopsy in patients with Alzheimer's disease (AD). Current in vivo hallmarks of CAA represent changes relatively late in the disease process and leaves CAA in AD often undetected. Recently, it was shown that decreased vascular reactivity (VR) measured with blood oxygen level dependent (BOLD) MRI, after visual stimulus, is an early CAA marker. With BOLD-MRI to detect decreased VR in different stages of AD, it was shown that increasing stages of AD associate with decreasing VR independent of age, classic SVD markers and atrophy. Moreover, VR is associated with cognitive deficits. Therefore, cross-sectional data indicate that decreased VR is an important co-morbidity already in early stages of AD with an independent effect on disease severity. In this respect, the study aim is to determine the natural course of the decrease of VR in both controls and (early stage) AD patients to monitor AD disease progression. This is an essential step to aid in the development and application of effective treatment as it is expected that CAA can cause/worsen AD pathology.

Objective: To investigate longitudinal changes in VR in patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI) and AD dementia compared with controls. To investigate whether VR predicts progression of disease severity (cognitive decline) over a time period of 3 years and to investigate if decreased VR at baseline predicts increasing severity of other MRI markers for AD and SVD-markers at follow-up.

Study design: an longitudinal observational case - control study.

Study population: 30 AD patients, 30 patients with mild cognitive impairment and 30 patients with subjective cognitive impairment plus 30 controls, 50-90 yr old.

Main study parameters/endpoints: 1) 3T MRI: the amplitude of the BOLD response in percentage signal change between stimulus on and off, time-to-peak response (sec), and time-to-baseline (sec) after discontinuation of the visual stimulus, classic signs of CAA (intracranial hemorrhage, lobar microbleeds, subarachnoidal hemorrhage and superficial siderosis) and SVD markers (number of small subcortical infarcts and lacunes, volume of white matter hyperintensities (WMHs), perivascular spaces in the basal ganglia and centrum semiovale, number and location of deep microbleeds and grey matter volume). 2) Neuropsychological assessment 3) Baseline characteristics, 4) DNA: APOE ε genotype.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: This is a non-therapeutic group relatedness study in only capacitated subjects. In order to achieve the aim of the study AD patients are needed. Vascular reactivity has potential to determine the role of the vascular aspects in AD. The risks of this research are minimal (risk of every day life), because there are no consequences to the health of the participant. We will keep the burden at a minimum. The research will consist of a 60 minutes MRI scan, a neuropsychological assessment of 1 hour and collection of 2 ml saliva (if not already collected at baseline).

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
120

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Netherlands
      • Leiden, Netherlands, 2333 ZA
        • Leids Universitair Medisch Centrum

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Patients who attended a memory clinic and healthy controls

Description

Inclusion Criteria:

  • For this study three different routes for inclusion exists. Inclusion criteria for each group separately are shown below.

    1. Participants who were included in our previous CASCADE study (P19.039).

      • Capable of giving informed consent (see appendix)

    2. Patients who attended a memory clinic within one year ago

      • Diagnosed with (mixed) probable AD
      • Diagnosed as MCI
      • Diagnosed as SCI
      • Age between 50-90 years
      • Capable of giving informed consent (see appendix)

    3. Control subjects

      • Healthy adults without memory complaints
      • Age between 50 -90 years
      • Capable of giving informed consent

Exclusion Criteria:

  • Contra-indication to MRI scanning:

    • Claustrophobia
    • Pacemakers and defibrillators
    • Nerve stimulators
    • Intracranial clips
    • Intraorbital or intraocular metallic fragments
    • Cochlear implants
    • Ferromagnetic implants
    • Hydrocephaluspump
    • Intra-utrine device (not all types) Permanent make-up
    • Tattoos above the shoulders (not all)

  • Specific contraindications to fMRI

    • Seizure within prior year.
    • Noncorrectable visual impairment.
  • MMSE < 19 points (measured at moment of screening or at memory clinic with a maximum of 6 months in retrospect)
  • Severe physical restrictions (completely wheelchair dependent)
  • Age above 90

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Dementia patients
Patients with a dementia diagnosis; probable Alzheimer or mixed-type dementia
Other: MRI
Assessment of vascular reactivity and CAA/SVD MRI markers
MCI patients
Patients with a MCI diagnosis; patients demonstrating cognitive deficits on neuropsychological testing but not fulfilling the criteria for dementia.
Other: MRI
Assessment of vascular reactivity and CAA/SVD MRI markers
SCI patients
Patients not demonstrating cognitive deficits on neuropsychological testing are classified as SCI
Other: MRI
Assessment of vascular reactivity and CAA/SVD MRI markers
Controls
Control subject without cognitive complaints
Other: MRI
Assessment of vascular reactivity and CAA/SVD MRI markers

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Vascular reactivity - BOLD amplitude
Time Frame: 1,5 - 2 years between time point 1 and time point 2
The change in BOLD signal in response to visual stimulation as measured by the amplitude of the BOLD response in percentage signal change between stimulus on and off.
1,5 - 2 years between time point 1 and time point 2
Vascular reactivity - time-to-peak
Time Frame: 1,5 - 2 years between time point 1 and time point 2
The time-to-peak response (sec) is defined as the duration from the beginning of visual stimulation to the peak response.
1,5 - 2 years between time point 1 and time point 2
Vascular reactivity - time-to-baseline
Time Frame: 1,5 - 2 years between time point 1 and time point 2
The time-to-baseline response (sec) is defined as the duration from the end of the stimulus to baseline.
1,5 - 2 years between time point 1 and time point 2

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Intracranial hemorrhage
Time Frame: 1,5 - 2 years between time point 1 and time point 2
number
1,5 - 2 years between time point 1 and time point 2
Lobar microbleeds
Time Frame: 1,5 - 2 years between time point 1 and time point 2
number
1,5 - 2 years between time point 1 and time point 2
Subarachnoidal hemorrhage
Time Frame: 1,5 - 2 years between time point 1 and time point 2
number
1,5 - 2 years between time point 1 and time point 2
Superficial siderosis
Time Frame: 1,5 - 2 years between time point 1 and time point 2
absent / focal / disseminated
1,5 - 2 years between time point 1 and time point 2
Lacunes
Time Frame: 1,5 - 2 years between time point 1 and time point 2
number
1,5 - 2 years between time point 1 and time point 2
Volume of white matter hyperintensities (WMHs)
Time Frame: 1,5 - 2 years between time point 1 and time point 2
cm3
1,5 - 2 years between time point 1 and time point 2
Perivascular spaces in the basal ganglia
Time Frame: 1,5 - 2 years between time point 1 and time point 2
degree 1: <5 PVS degree 2: 5 - 10 PVS degree 3: >10 PVS (but still numerable) degree 4: an innumerable number of PVS
1,5 - 2 years between time point 1 and time point 2
Perivascular spaces in the centrum semiovale
Time Frame: 1,5 - 2 years between time point 1 and time point 2

0= no PVS

  1. < 10 PVS
  2. 11-20 PVS
  3. 21-40 PVS
  4. >40 PVS
1,5 - 2 years between time point 1 and time point 2
Gray matter volume
Time Frame: 1,5 - 2 years between time point 1 and time point 2
cm3
1,5 - 2 years between time point 1 and time point 2

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Leiden University Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 4, 2023

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 1, 2026

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 1, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 11, 2023

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 18, 2024

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 20, 2024

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 15, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 9, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NL83653.058.23

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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