Vascular Aspects in Dementia: Part 2

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: Active, not recruiting
• Conditions: Dementia
• Intervention / Treatment: Other: MRI

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: Observational
• Enrollment (Estimated): 120

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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

Outcome Measure	Measure Description	Time Frame
Vascular reactivity - BOLD amplitude	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	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	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

Outcome Measure	Measure Description	Time Frame
Intracranial hemorrhage	number	1,5 - 2 years between time point 1 and time point 2
Lobar microbleeds	number	1,5 - 2 years between time point 1 and time point 2
Subarachnoidal hemorrhage	number	1,5 - 2 years between time point 1 and time point 2
Superficial siderosis	absent / focal / disseminated	1,5 - 2 years between time point 1 and time point 2
Lacunes	number	1,5 - 2 years between time point 1 and time point 2
Volume of white matter hyperintensities (WMHs)	cm3	1,5 - 2 years between time point 1 and time point 2
Perivascular spaces in the basal ganglia	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	0= no PVS; < 10 PVS; 11-20 PVS; 21-40 PVS; >40 PVS	1,5 - 2 years between time point 1 and time point 2
Gray matter volume	cm3	1,5 - 2 years between time point 1 and time point 2

Collaborators and Investigators

• Sponsor: Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2023
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: December 11, 2023
• First Submitted That Met QC Criteria: March 18, 2024
• First Posted (Actual): March 20, 2024

Study Record Updates

• Last Update Posted (Estimated): September 15, 2025
• Last Update Submitted That Met QC Criteria: September 9, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia
• Other Study ID 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