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

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

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.

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.

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