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

Stroke Clinical Trial

— SHIVA  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05306834
• Other study ID #: CHUBX 2021/22
• Status: Recruiting
• Phase: N/A
• Start date: November 10, 2022
• Est. completion date: November 2027

Study information

• Verified date: January 2024
• Source: University Hospital, Bordeaux
• Contact: Stéphanie DEBETTE, Pr
• Phone: 5.57.57.16.59
• Email: stephanie.debette[@]u-bordeaux.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: November 2027
• Est. primary completion date: November 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years to 88 Years

Eligibility

Inclusion Criteria:

For the extensive cSVD patient group

1. 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).

2. 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),

• 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 12 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,

• 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 12 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 :

1. 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

2. 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

Related Conditions & MeSH terms

• Cerebral Small Vessel Diseases
• Cognitive Dysfunction
• Dementia
• Stroke

Intervention

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

Genetic:
• Blood sample
Analyses of molecular biomarkers including

Procedure:
• Evaluation of cardiovascular risks
Measurement of blood pressure and arterial stiffness
• Brain imaging (MRI)
3DT1 / 3DFLAIR / T2GRE / DTI 15 directions (and B0MAP)

Other:
• Cognitive Tests
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)
• Geriatric Depression Scale (GDS)
15 items
• Instrumental Activities of Daily Living (IADL)
Instrumental Activities of Daily Living (IADL)

Diagnostic Test:
• Unipodal standing test
Unipodal standing test

Other:
• Walking speed measurement
over 5 meters

Locations

Country	Name	City	State
France	Bordeaux Hospital	Bordeaux
France	Broca Hospital	Paris

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Bordeaux

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	Day 0 and Year 3
Secondary	Degree of association between retinal and brain marker	Degree of association between retinal and brain marker	Day 0, Year 1 and Year 3
Secondary	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	Day 0, Year 1, Year 2 and Year 3
Secondary	Correlation between retinal micovascular biomarkers	SS-OCT-A (swept source optical coherence tomography angiography) and OA(Adaptive Optic)	Day 0, Year 1, Year 2 and Year 3
Secondary	Reproducibility and time course of retinal vascular biomarkers	SS-OCT-A (swept source optical coherence tomography angiography) and OA (Adaptive Optic)	Between Day 0 and Year 1
Secondary	Detecting, classifying and quantifying markers of retinal microvascular lesions	Performance image acquisition -OCT-A (swept source optical coherence tomography angiography) and OA (Adaptive Optic)	up to year 3
Secondary	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	through study completion, an average of 3 year
Secondary	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.	through study completion, an average of 3 year