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Stopping Cognitive Decline and Dementia by Fighting Covert Cerebral Small Vessel Disease (SHIVA)

Primary Purpose

Cerebral Small Vessel Diseases, Stroke, Dementia

Status

Recruiting

Phase

Not Applicable

Locations

France

Study Type

Interventional

Intervention

Retinal Imaging

Blood sample

Evaluation of cardiovascular risks

Brain imaging (MRI)

Cognitive Tests

Geriatric Depression Scale (GDS)

Instrumental Activities of Daily Living (IADL)

Unipodal standing test

Walking speed measurement

About this trial

This is an interventional other trial for Cerebral Small Vessel Diseases focused on measuring Cognitive decline, Dementia, Stroke, Small vessel disease, Healthy brain aging, Brain imaging, Adaptive optics, Optical coherence tomography angiography, Prevention, Risk prediction, Genomic, Multiomics, Proteomics, Metabolomics

Eligibility Criteria

60 Years - 88 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

For the extensive cSVD patient group

For the extensive cSVD patient group included in the LEOPOLD trial:
- Patients aged 60 to 88 years,
- Patients included in the LEOPOLD trial and having performed their brain MRI on SIEMENS PRISMA machine
- Being affiliated or beneficiary of the French national health insurance ("sécurité sociale"),
- Free, informed and written consent signed by the participant and the investigator (at the latest on the day of inclusion and before any examination required by the research study).
For the extensive cSVD patient group not included in the LEOPOLD trial:
- Patients aged 60 to 88 years,
- Patients with a cognitive complaint MMSE ≥ 20 performed in the 6 months before inclusion, associated or not with impaired cognitive tests and/or diaognosis of incipient dementia without pronounced cognitive deterioration,
- Patients with a socio-educational level ≥ 3,
- Patients with a moderate to high grade of hypersignals on an MRI OR on an CT scan performed prior inclusion (grades C and D of the modified Scheltens scale or grade 2/3 Fazekas),
- Patients with arterial hypertension defined by a Systolic Blood Pressure (SBP) and / or Diastolic Blood Pressure (DBP) ≥ 140/90 mmHg (according to the definition of the national health authority [HAS]), treated or not, confirmed within the previous 3 months or at the latest on the day of inclusion.
- Being affiliated or beneficiary of the French national health insurance ("sécurité sociale"),
- Free, informed and written consent signed by the participant and the investigator (at the latest on the day of inclusion and before any examination required by the research study)

For the minimal cSVD patient group:

Patients aged 60 to 88 years,
Patients with a cognitive complaint (MMSE ≥ 20 performed at the SHIVA inclusion visit or in the 6 monts prior the visit) associated or not with impaired cognitive tests and/or diagnosis of incipient dementia without pronounced cognitive deterioration,
Patients with little or no white matter hypertensities on brain MRI (grades 0 or 1 on the Fazekas scale); without lacunes or microbleeds,
Patients with arterial hypertension defined by a Systolic Blood Pressure (SBP) and / or Diastolic Blood Pressure (DBP) ≥ 140/90 mmHg (according to the definition of the national health authority [HAS]), treated or not, confirmed within the previous 3 months or at the latest on the day of inclusion. Blood pressure values for this inclusion criterion can be objectified by several self-measurements performed by the patient at home for 3 days in a sitting or lying position (3 measurements on sitting or lying position and 3 measurements in standing position).
Being affiliated or beneficiary of the French national health insurance ("sécurité sociale"),
Free, informed and written consent signed by the participant and the investigator (at the latest on the day of inclusion and before any examination required by the research study

Exclusion Criteria:

For Extensive cSVD patient group :

For the extensive cSVD patient group also included in the LEOPOLD trial:
- patients with severe myopia greater than -6 dioptres
- partients with known allergy to Tropicamide (Mydriaticum®)
- patients with an extensive cataract
- patients with ptosis
For the extensive cSVD patient group not included in the LEOPOLD trial:
- Orthostatic hypotension defined by a decrease of 20 mmHg in SBP and / or 10 mmHg in DBP in a standing position at 3 minutes sought in the previous 3 months or on the day of inclusion,
- Very severe renal impairment (creatinine clearance less than 15 ml / min) on a blood test dating back less than one year,
- Secondary hypertension: renovascular hypertension, primary hyperaldosteronism, pheochromocytoma...
- Contraindication to MRI (presence of a ferromagnetic foreign body, in particular certain intracranial clips, certain heart valves, an intraocular foreign body, metal prosthesis, subject carrying a pacemaker, subject carrying prosthetic heart valves incompatible with MRI. ventricular shunt, claustrophobia),
- Associated severe diseases, with a life expectancy of less than 3 months,
- Physical problems likely to interfere with the feasibility of the tests (sight, hearing, etc.),
- Existence of dementia of which the etiology is distinct from Alzheimer's disease, vascular or mixed dementia
- Persons under tutorship or curatorship,
- Patients with loss of autonomy living in EHPAD (nursing home)
- patients with severe myopia greater than -6 dioptres
- participants with known allergy to Tropicamide (Mydriaticum®)
- patients with an extensive cataract
- patients with ptosis

For the minimal cSVD patient group:

Orthostatic hypotension defined by a decrease of 20 mmHg in SBP and / or 10 mmHg in DBP in a standing position at 3 minutes sought in the previous 3 months or on the day of inclusion,
Very severe renal impairment (creatinine clearance less than 15 ml / min) on a blood test dating back less than one year,
Secondary hypertension: renovascular hypertension, primary hyperaldosteronism, pheochromocytoma...
Contraindication to MRI (presence of a ferromagnetic foreign body, in particular certain intracranial clips, certain heart valves, an intraocular foreign body, metal prosthesis, subject carrying a pacemaker, subject carrying prosthetic heart valves incompatible with MRI. ventricular shunt, claustrophobia),
Associated severe diseases, with a life expectancy of less than 3 months,
Physical problems likely to interfere with the feasibility of the tests (sight, hearing, etc.),
Existence of dementia of which the etiology is distinct from Alzheimer's disease, vascular or mixed dementia
Persons under tutorship or curatorship,
Patients with loss of autonomy living in EHPAD (nursing home)
Patients with severe myopia greater than -6 dioptries
Patients with known allergy to Tropicamide (Mydriaticum®)
Patients with an extensive cataract
Patients with ptosis

Sites / Locations

Bordeaux HospitalRecruiting
Broca HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Minimal cSVD patient group

Extensive cSVD patient group

Arm Description

little or no white matter hyperintensities

moderate to severe white matter hyperintensities

Outcomes

Primary Outcome Measures

Comparison of images and the molecular data

This comparison should help identify relevant biomarkers to characterize and categorize cSVD. We will also more broadly look at the association of retinal microvascular markers and molecular biomarkers with all available MRI-markers of cSVD (beyond the presence or absence of extensive white matter hyperintensities that defines the cases and controls).

Secondary Outcome Measures

Degree of association between retinal and brain marker

Degree of association between brain, microvascular and retinal marker

Data relating to cardiovascular risk factors / clinic data / the results of the cognitive tests, /the results of pan-genomic genotypes obtained by pan-genome genotyping or sequencing (and from blood samples) and other molecular markers

Correlation between retinal micovascular biomarkers

SS-OCT-A (swept source optical coherence tomography angiography) and OA(Adaptive Optic)

Reproducibility and time course of retinal vascular biomarkers

SS-OCT-A (swept source optical coherence tomography angiography) and OA (Adaptive Optic)

Detecting, classifying and quantifying markers of retinal microvascular lesions

Performance image acquisition -OCT-A (swept source optical coherence tomography angiography) and OA (Adaptive Optic)

Comparison of the results in the Shiva study and SHIVA share study

Comparison of the association results and mean distributions observed in SHIVA with those observed in the SHIVA-Share

Occurrence of incident stroke, dementia and death during follow-up.

Association of all imaging or molecular biomarkers with the occurrence of incident stroke, dementia and death during follow-up.

Full Information

NCT ID

NCT05306834

First Posted

February 25, 2022

Last Updated

July 25, 2023

Sponsor

University Hospital, Bordeaux

1. Study Identification

Unique Protocol Identification Number

NCT05306834

Brief Title

Stopping Cognitive Decline and Dementia by Fighting Covert Cerebral Small Vessel Disease

Acronym

SHIVA

Official Title

Stopping Cognitive Decline and Dementia by Fighting Covert Cerebral Small Vessel Disease

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Recruiting

Study Start Date

November 10, 2022 (Actual)

Primary Completion Date

November 2027 (Anticipated)

Study Completion Date

November 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital, Bordeaux

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Cerebral small Vessel Disease (cSVD), characterized by an alteration of the structure and function of small penetrating brain arteries, is highly prevalent in older persons from the general population and represents a leading cause of stroke and a major contributor to cognitive decline and dementia risk. In France >4 million persons aged 60+ are estimated to have moderate to extensive covert cSVD (ccSVD), i.e. features of SVD on brain imaging without a history of clinical stroke. Better detection and management of covert cSVD would have a major impact on preventing disability and costs related to stroke, cognitive impairment and dementia. However, there are no specific mechanistic treatments for cSVD and hardly any recommendations worldwide on how to prevent and treat cSVD and related cognitive impairment. The aim of the present study, through the identification of novel cutting-edge multimodal biomarkers, is to develop innovative diagnostic and risk prediction tools for cSVD and its complications and to contribute to accelerating the discovery of novel drug targets and therapeutics strategies for cSVD.

Detailed Description

cSVD is by far the most prevalent vascular contributor to cognitive impairment in the population. However, accurate quantitative estimates of the predictive ability of cSVD for dementia risk are lacking. Moreover, stratification of cognitive decline and dementia risk in cSVD patients according to imaging characteristics as well as evidence of coexisting neurodegenerative disease and vascular comorbidity are lacking. Hypertension is the strongest known risk factor for cSVD but there are currently no guidelines for the management of cSVD (or emerging guidelines based on weak evidence, and no specific mechanism-based treatments, leading to empirical and heterogeneous clinical practice, which in most instances consists of ignoring these lesions. This clinical blind spot represents a major "missed opportunity" for the prevention of cognitive decline and dementia. This study aims to explore the relation of brain and retinal microvasculature image characteristics (imaging biomarkers), as well as molecular biomarkers derived from blood, with presence or absence of extensive cSVD and with cognitive and other clinical characteristics in two groups of 200 patients 60+ years of age. The first group will consist of patients with little or no white matter hyperintensities on brain MRI (no or minor MRI features of cSVD); while the second will include patients with moderate to severe white matter hyperintensities (MRI features of extensive cSVD). This will create a unique deeply characterized resource for epidemiological and mechanistic investigations of cSVD, which can also serve as a pilot setting to test the trajectories and requirements for individualized patient care of cSVD patients. The combination of retinal microvascular measurements using innovative multimodal imaging is entirely novel to our knowledge. In the context of the RHU SHIVA program, the same retained imaging protocol will be implemented for 400 young adults, which will provide insight into trajectories of these retinal biomarkers across the adult lifespan). For the molecular biomarkers allow the validation of genomic, epigenomic, transcriptomic, proteomic, and metabolomic biomarkers for cSVD identified through secondary use of large existing cohort studies in the general population (3C, i-Share cohorts), in persons with memory complaints (MEMENTO cohort), and in collaboration with other cohorts with the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, also as part of the RHU SHIVA program.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cerebral Small Vessel Diseases, Stroke, Dementia

Keywords

Cognitive decline, Dementia, Stroke, Small vessel disease, Healthy brain aging, Brain imaging, Adaptive optics, Optical coherence tomography angiography, Prevention, Risk prediction, Genomic, Multiomics, Proteomics, Metabolomics

7. Study Design

Primary Purpose

Other

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

400 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Minimal cSVD patient group

Arm Type

Active Comparator

Arm Description

little or no white matter hyperintensities

Arm Title

Extensive cSVD patient group

Arm Type

Active Comparator

Arm Description

moderate to severe white matter hyperintensities

Intervention Type

Procedure

Intervention Name(s)

Retinal Imaging

Intervention Description

Auto-Refractometry / Adaptative Optics (OA) / Swept Source Optical Coherence Tomography (SS-OCT-A) / Globe Axial length measurements / Color Retinophotography of the retina.

Intervention Type

Genetic

Intervention Name(s)

Blood sample

Intervention Description

Analyses of molecular biomarkers including

Intervention Type

Procedure

Intervention Name(s)

Evaluation of cardiovascular risks

Intervention Description

Measurement of blood pressure and arterial stiffness

Intervention Type

Procedure

Intervention Name(s)

Brain imaging (MRI)

Intervention Description

3DT1 / 3DFLAIR / T2GRE / DTI 15 directions (and B0MAP)

Intervention Type

Other

Intervention Name(s)

Cognitive Tests

Intervention Description

Mini Mental State Examination (MMSE) / Montreal Cognitive Assessment (MoCA) / 16 items Free and Cued Recall (RL/RI 16 items) / Trail Making Test A et B (TMT A et B) / Frontal Assessment Battery (FAB) / Phonemic (letter P) and semantic (animals) verbal fluency tests / Digit Symbol Substitution Test (DSST)

Intervention Type

Other

Intervention Name(s)

Geriatric Depression Scale (GDS)

Intervention Description

15 items

Intervention Type

Other

Intervention Name(s)

Instrumental Activities of Daily Living (IADL)

Intervention Description

Instrumental Activities of Daily Living (IADL)

Intervention Type

Diagnostic Test

Intervention Name(s)

Unipodal standing test

Intervention Description

Unipodal standing test

Intervention Type

Other

Intervention Name(s)

Walking speed measurement

Intervention Description

over 5 meters

Primary Outcome Measure Information:

Title

Comparison of images and the molecular data

Description

Time Frame

Day 0 and Year 3

Secondary Outcome Measure Information:

Title

Degree of association between retinal and brain marker

Description

Degree of association between retinal and brain marker

Time Frame

Day 0, Year 1 and Year 3

Title

Degree of association between brain, microvascular and retinal marker

Description

Time Frame

Day 0, Year 1, Year 2 and Year 3

Title

Correlation between retinal micovascular biomarkers

Description

SS-OCT-A (swept source optical coherence tomography angiography) and OA(Adaptive Optic)

Time Frame

Day 0, Year 1, Year 2 and Year 3

Title

Reproducibility and time course of retinal vascular biomarkers

Description

SS-OCT-A (swept source optical coherence tomography angiography) and OA (Adaptive Optic)

Time Frame

Between Day 0 and Year 1

Title

Detecting, classifying and quantifying markers of retinal microvascular lesions

Description

Performance image acquisition -OCT-A (swept source optical coherence tomography angiography) and OA (Adaptive Optic)

Time Frame

up to year 3

Title

Comparison of the results in the Shiva study and SHIVA share study

Description

Comparison of the association results and mean distributions observed in SHIVA with those observed in the SHIVA-Share

Time Frame

through study completion, an average of 3 year

Title

Occurrence of incident stroke, dementia and death during follow-up.

Description

Association of all imaging or molecular biomarkers with the occurrence of incident stroke, dementia and death during follow-up.

Time Frame

through study completion, an average of 3 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

60 Years

Maximum Age & Unit of Time

88 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: For the extensive cSVD patient group For the extensive cSVD patient group included in the LEOPOLD trial: Patients aged 60 to 88 years, Patients included in the LEOPOLD trial and having performed their brain MRI on SIEMENS PRISMA machine Being affiliated or beneficiary of the French national health insurance ("sécurité sociale"), Free, informed and written consent signed by the participant and the investigator (at the latest on the day of inclusion and before any examination required by the research study). For the extensive cSVD patient group not included in the LEOPOLD trial: Patients aged 60 to 88 years, Patients with a cognitive complaint MMSE ≥ 20 performed in the 6 months before inclusion, associated or not with impaired cognitive tests and/or diaognosis of incipient dementia without pronounced cognitive deterioration, Patients with a socio-educational level ≥ 3, Patients with a moderate to high grade of hypersignals on an MRI OR on an CT scan performed prior inclusion (grades C and D of the modified Scheltens scale or grade 2/3 Fazekas), Patients with arterial hypertension defined by a Systolic Blood Pressure (SBP) and / or Diastolic Blood Pressure (DBP) ≥ 140/90 mmHg (according to the definition of the national health authority [HAS]), treated or not, confirmed within the previous 3 months or at the latest on the day of inclusion. Being affiliated or beneficiary of the French national health insurance ("sécurité sociale"), Free, informed and written consent signed by the participant and the investigator (at the latest on the day of inclusion and before any examination required by the research study) For the minimal cSVD patient group: Patients aged 60 to 88 years, Patients with a cognitive complaint (MMSE ≥ 20 performed at the SHIVA inclusion visit or in the 6 monts prior the visit) associated or not with impaired cognitive tests and/or diagnosis of incipient dementia without pronounced cognitive deterioration, Patients with little or no white matter hypertensities on brain MRI (grades 0 or 1 on the Fazekas scale); without lacunes or microbleeds, Patients with arterial hypertension defined by a Systolic Blood Pressure (SBP) and / or Diastolic Blood Pressure (DBP) ≥ 140/90 mmHg (according to the definition of the national health authority [HAS]), treated or not, confirmed within the previous 3 months or at the latest on the day of inclusion. Blood pressure values for this inclusion criterion can be objectified by several self-measurements performed by the patient at home for 3 days in a sitting or lying position (3 measurements on sitting or lying position and 3 measurements in standing position). Being affiliated or beneficiary of the French national health insurance ("sécurité sociale"), Free, informed and written consent signed by the participant and the investigator (at the latest on the day of inclusion and before any examination required by the research study Exclusion Criteria: For Extensive cSVD patient group : For the extensive cSVD patient group also included in the LEOPOLD trial: patients with severe myopia greater than -6 dioptres partients with known allergy to Tropicamide (Mydriaticum®) patients with an extensive cataract patients with ptosis For the extensive cSVD patient group not included in the LEOPOLD trial: Orthostatic hypotension defined by a decrease of 20 mmHg in SBP and / or 10 mmHg in DBP in a standing position at 3 minutes sought in the previous 3 months or on the day of inclusion, Very severe renal impairment (creatinine clearance less than 15 ml / min) on a blood test dating back less than one year, Secondary hypertension: renovascular hypertension, primary hyperaldosteronism, pheochromocytoma... Contraindication to MRI (presence of a ferromagnetic foreign body, in particular certain intracranial clips, certain heart valves, an intraocular foreign body, metal prosthesis, subject carrying a pacemaker, subject carrying prosthetic heart valves incompatible with MRI. ventricular shunt, claustrophobia), Associated severe diseases, with a life expectancy of less than 3 months, Physical problems likely to interfere with the feasibility of the tests (sight, hearing, etc.), Existence of dementia of which the etiology is distinct from Alzheimer's disease, vascular or mixed dementia Persons under tutorship or curatorship, Patients with loss of autonomy living in EHPAD (nursing home) patients with severe myopia greater than -6 dioptres participants with known allergy to Tropicamide (Mydriaticum®) patients with an extensive cataract patients with ptosis For the minimal cSVD patient group: Orthostatic hypotension defined by a decrease of 20 mmHg in SBP and / or 10 mmHg in DBP in a standing position at 3 minutes sought in the previous 3 months or on the day of inclusion, Very severe renal impairment (creatinine clearance less than 15 ml / min) on a blood test dating back less than one year, Secondary hypertension: renovascular hypertension, primary hyperaldosteronism, pheochromocytoma... Contraindication to MRI (presence of a ferromagnetic foreign body, in particular certain intracranial clips, certain heart valves, an intraocular foreign body, metal prosthesis, subject carrying a pacemaker, subject carrying prosthetic heart valves incompatible with MRI. ventricular shunt, claustrophobia), Associated severe diseases, with a life expectancy of less than 3 months, Physical problems likely to interfere with the feasibility of the tests (sight, hearing, etc.), Existence of dementia of which the etiology is distinct from Alzheimer's disease, vascular or mixed dementia Persons under tutorship or curatorship, Patients with loss of autonomy living in EHPAD (nursing home) Patients with severe myopia greater than -6 dioptries Patients with known allergy to Tropicamide (Mydriaticum®) Patients with an extensive cataract Patients with ptosis

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Stéphanie DEBETTE, Pr

Phone

5.57.57.16.59

Ext

+33

stephanie.debette@u-bordeaux.fr

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Olivier HANON, Pr

Organizational Affiliation

Assistance Publique - Hôpitaux de Paris

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Marc JOLIOT, Dr

Organizational Affiliation

Unité CNRS UMR5296, Groupe d'Imagerie

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Cécile DELCOURT, Dr

Organizational Affiliation

Centre INSERM U1219 Bordeaux Population Health

Official's Role

Study Chair

Facility Information:

Facility Name

Bordeaux Hospital

City

Bordeaux

ZIP/Postal Code

33000

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

DEBETTE Stéphanie, Pr

Facility Name

Broca Hospital

City

Paris

ZIP/Postal Code

75014

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

HANON Olivier, Pr

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Stopping Cognitive Decline and Dementia by Fighting Covert Cerebral Small Vessel Disease

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