About SVDs@target

Stroke and dementia rank among the most pressing health issues in Europe. Diseases in small blood vessels, known as cerebral small vessel diseases (SVDs) have emerged as a central link between these two major co-morbidities. SVDs account for more than 30% of strokes and at least 40% of dementia cases. They encounter multiple distinct diseases that can be separated based on their underlying genetic defects, risk factors, and clinical presentations. Despite this profound impact on human health, there are no treatments with proven efficacy against SVDs.

This network brings together basic scientists and academic clinicians and will make use of novel animal models, state-of-the art technologies (e.g. proteomics & ultra-high field MRI) and expertly phenotyped patient cohorts to identify key mechanisms common to multiple SVDs and determine how these mechanisms contribute to individual SVDs.

With the better understanding of small vessel diseases SVDs@target will develop novel therapeutic treatments and finally contribute to the prevention of stroke and dementia.
SVDs@target concept

Facts

Acronym:       SVDs@target
Start date:    January 1st, 2016
Duration:    60 months
End date: December 31st, 2020
Project coordinator:    Prof. Martin Dichgans, LMU München
Consortium:   12 partners from 7 countries
Total funding:    5,998,300 EUR

 

 

Context & Background

SVDs, or cerebral microangiopathies are a major cause of stroke and the leading cause of vascular cognitive impairment and it also contributes to other disabling symptoms such as gait disturbance and late-life depression. It is associated with vascular risk factors and its prevalence strongly increases with age, however there are also rare genetic variants of these diseases. CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) caused by mutations in the NOTCH3 gene, represents a pure form of SVD and has successfully been used as a model.SVDs@target partners have already made major progress in identifying key mechanisms underlying multiple SVDs. They recently identified blood pressure variability as a major independent risk factor for multiple SVDs, stroke, and dementia and illuminated the roles of the blood brain barrier and the extracellular matrix in small vessel function. Furthermore they identified novel molecular pathways (TIMP3, LTBP1, TGFß) that are shared between different SVDs pointing towards common mechanisms. This work has laid the groundwork for the identification of additional mechanisms and novel targets for the treatment and, importantly, prevention of SVDs.

Objectives

The ambition of SVDs@target is to identify key mechanisms common to multiple SVDs and to validate novel mechanisms through interventions, with the ultimate goal of reducing the burden of SVDs, stroke and dementia. More specifically, the network aims to
  • define common molecular, cellular, and physiological mechanisms underlying the regulation of blood flow, and barrier and clearing functions of microvessels that are comprised in different SVDs.
  • determine how these common mechanistic defects intersect to drive brain parenchymal damage, which lead to stroke and dementia as the major co-morbidities.
  • validate the relevance of mechanisms and biomarkers through interventions in experimental systems (isolated microvessels and in vivo) and in patients (exploratory proof of concept trials)
  
work package objectives

Expected Impacts

The five-year programme will combine pre-clinical with clinical research to gain a better understanding of the disease pathways and mechanisms common to multiple SVDs and their main comorbidities - stroke and dementia. This will offer new directions for clinical research for better prevention, health promotion, and therapy development, as well as for the management of patients with stroke and dementia.Specifically we expect the following impacts:
  • Better understanding of disease pathways
  • Novel mechanistic insights into normal brain physiology
  • New directions for clinical research (ultra-high-field MRI at 7T, telemetric blood pressure; monitoring, measurements of BBB integrity at 3T)
  • New biomarkers (blood, MRI, histo-pathology), for a group of conditions that are challenging to diagnose
  • Novel targets for testing in human interventions

Studies in Humans

A major strength of the project is the access to large, thoroughly phenotyped cohorts of patients with genetic (CADASIL, CARASIL; >200 patients, Partner 1) and sporadic (>1.000 patients, Partners 1, 5, 7 and 9) SVDs totaling more than 1.200 patients with stroke, and about 450 with dementia or other comorbidities of SVDs. Parts of the project will be performed using these pre-existing data. However, some of our analyses will require generating new data through three sub-studies with a common core data set:

ZOOM@SVDs, a MRI study at ultra-high resolution (7T) to assess microvascular function and parenchymal damage

INVESTIGATE-SVDs, a MRI study at 3T to assess blood brain barrier function, microvascular function, and perivascular flow

TREAT-SVDs, an interventional study to determine the effects of different blood pressure lowering agents on microvascular function in patients with distinct SVDs






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