Cerebrovascular Reactivity in Alzheimer's Disease

NCT03650816 | Completed

• 2 other identifiers: APHP180012IDRCB 2018-A01950-55
• Study Type: observational
• Target: 58
• Locations: 1 country
• Sites: 1

Brief Summary

The etiology of Alzheimer's disease (AD), the most common type of dementia, remains largely undefined and the early diagnostic and effective treatments are still not available. In addition to the neuropathological hallmarks, cerebrovascular dysfunction has been identified as an important component of AD. Using the experimental models, we showed that cerebrovascular reactivity (CVR), the ability of cerebral vessels to dilate or constrict in response to stimuli, is impaired very early in AD. We designed this trial to compare CVR to carbon dioxide (CVR CO2) in AD patients and in persons with subjective cognitive impairment (SCI), the cognitively healthy individuals which began to worry about worsening their memory, and to correlate CVR CO2 with AD markers in cerebrospinal fluid and the blood markers of endothelial function. We hypothesize that CVR represents a potential diagnostic/prognostic marker and an attractive target for the development of new therapeutics in AD.

Conditions

Alzheimer Disease; Subjective Cognitive Impairment

Keywords

Alzheimer Disease; Subjective cognitive impairment; Cognitive Dysfunction; Neurodegenerative Diseases; Cerebrovascular reactivity; Doppler ultrasonography; Biomarker; Endothelin-1; Big-Endothelin-1; ADMA; Renin

Outcome Measures

Primary Outcomes (1)

• Cerebrovascular reactivity during the CO2 inhalation test in AD patients and control subjects (SCI)

  Cerebrovascular reactivity during the CO2 inhalation test in AD patients and control subjects (SCI), determined from the measurements of blood flow in the internal and commun carotid arteries. Subjects will be screened and if applicable for the study will be scheduled for a Doppler ultrasonography. At the second visit they will complete Doppler ultrasonography measurements.

  Up to 2 months

Secondary Outcomes (5)

• Correlation between cognitive status and différences in CVR CO2

  Up to 2 months

• Correlation between cerebrospinal AD markers and CVR CO2

  Up to 2 months

• Z score of neuropsychological tests and CVR CO2

  Up to 2 months

• Plasma levels of ET-1, bigET-1, ADMA and their correlation with CVR CO2

  Up to 2 months

• Plasma renin activity and CVR CO2.

  Up to 2 months

Study Arms (2)

Alzheimer Disease

Patients with Alzheimer's disease, as defined by the established clinical consensus criteria (DSM IV-TR and NINCDS-ADRDA) Doppler ultrasonography will be used in these patients to assess CVR CO2 , as a change in blood flow in the internal and common carotid arteries during the 10th minute of inhalation of a gas mixture containing 5% CO2, 16% O2 and 79% N2, compared to the baseline blood flow value measured after 10 minutes rest in lying position. Biospecimen collection will be performed in these patients : a blood sample of 10 ml will be drawn in addition to the blood sample taken as part of patient usual care, to determine plasma concentration of ET-1, bigET-1, ADMA and plasma renin activity

Other: Doppler ultrasonography; Other: Biospecimen collection

Subjective Cognitive impairment

Patients with subjective cognitive impairment, who consulted for cognitive complaint without cognitive impairment on neuropsychological tests and normal performances according to daily life activities scores. Doppler ultrasonography will be used in these patients to assess CVR CO2 , as a change in blood flow in the internal and common carotid arteries during the 10th minute of inhalation of a gas mixture containing 5% CO2, 16% O2 and 79% N2, compared to the baseline blood flow value measured after 10 minutes rest in lying position. Biospecimen collection will be performed in these patients : a blood sample of 10 ml will be drawn in addition to the blood sample taken as part of patient usual care, to determine plasma concentration of ET-1, bigET-1, ADMA and plasma renin activity

Other: Doppler ultrasonography; Other: Biospecimen collection

Interventions

Doppler ultrasonography OTHER

Blood flow measurement in in the internal and common carotid arteries during the 10th minute of inhalation of a gas mixture containing 5% CO2, 16% O2 and 79% N2, compared to the baseline blood flow value measured after 10 minutes rest in lying position.

Alzheimer Disease; Subjective Cognitive impairment

Biospecimen collection OTHER

Blood: ET-1, bigET-1, ADMA plasma concentration; plasma renin activity

Alzheimer Disease; Subjective Cognitive impairment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

1. Patients with Alzheimer's disease 2. Patients with subjective cognitive impairment

You may qualify if:

• Age 18 years and more
• Alzheimer's disease as defined by the established clinical consensus criteria (DSM IV-TR and NINCDS-ADRDA) or
• Subjective cognitive impairment: subjects who consulted for cognitive complaint without cognitive impairment on neuropsychological tests defined by normal cognitive scores located between - 1.5 and + 1.5 standard deviations (σ) compared to the average of subjects in their reference group (same age, same socio-educational level) and normal performances according to daily life activities scores.

You may not qualify if:

• Non-Alzheimer's dementia (vascular dementia, Lewy body dementia, fronto-temporal dementia, dementia linked to Parkinson's disease and other)
• Other diseases that may interfere with cognitive performance evaluation (severe depression, epilepsy, Parkinson's disease, psychosis, bipolar syndrome)
• Active smoking
• Diabetes
• Uncontrolled hypertension (PAS / PAD\> 140/90 mmHg despite correctly dosed antihypertensive therapy)
• Heart failure
• Recent myocardial infarction
• Stroke
• Stenosis of the carotid commune or interne with plaque \> 20%
• Cerebrovascular lesions on MRI (major white matter lesions Fazekas 3,\> 2 deficiencies and sequelae of cerebral infarction)

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Fondation Plan Alzheimer: collaborator
• Naturalia & Biologia: collaborator

Study Sites (1)

Broca Hospital APHP

Paris, 75013, France

Location

Related Publications (2)

• Cifuentes D, Poittevin M, Dere E, Broqueres-You D, Bonnin P, Benessiano J, Pocard M, Mariani J, Kubis N, Merkulova-Rainon T, Levy BI. Hypertension accelerates the progression of Alzheimer-like pathology in a mouse model of the disease. Hypertension. 2015 Jan;65(1):218-24. doi: 10.1161/HYPERTENSIONAHA.114.04139. Epub 2014 Oct 20.

  PMID: 25331846 BACKGROUND

• Cifuentes D, Poittevin M, Bonnin P, Ngkelo A, Kubis N, Merkulova-Rainon T, Levy BI. Inactivation of Nitric Oxide Synthesis Exacerbates the Development of Alzheimer Disease Pathology in APPPS1 Mice (Amyloid Precursor Protein/Presenilin-1). Hypertension. 2017 Sep;70(3):613-623. doi: 10.1161/HYPERTENSIONAHA.117.09742.

  PMID: 28760945 BACKGROUND

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction; Neurodegenerative Diseases

Interventions

Ultrasonography, Doppler, Transcranial

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Intervention Hierarchy (Ancestors)

Echoencephalography; Neuroradiography; Neuroimaging; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Radiography; Ultrasonography; Ultrasonography, Doppler; Diagnostic Techniques, Neurological; Investigative Techniques

Study Officials

• Florence FAVREL-FEUILLADE

  Clinical Research and Innovation Delegation

  STUDY DIRECTOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Target Duration: 2 Months
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2018
• First Posted: August 29, 2018
• Study Start: October 22, 2019
• Primary Completion: February 15, 2023
• Study Completion: February 15, 2023
• Last Updated: June 24, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)