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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Tweets by SVDS@target

Publications with PubMed ID

Authors: Stringer MS, Lee H, Huuskonen MT, MacIntosh BJ, Brown R, Montagne A, Atwi S, Ramirez J, Jansen MA, Marshall I, Black SE, Zlokovic BV, Benveniste H, Wardlaw JM

Translational stroke research. 2020 Sep 16;

PMID: 32936435

Authors: Elschot EP, Backes WH, Postma AA, van Oostenbrugge RJ, Staals J, Rouhl RPW, Jansen JFA

Investigative radiology. 2020 Sep 15;

PMID: 32932377

Authors: Hablitz LM, Plá V, Giannetto M, Vinitsky HS, Stæger FF, Metcalfe T, Nguyen R, Benrais A, Nedergaard M

Nature communications. 2020 Sep 2;11(1):4411

PMID: 32879313    Open Access: PMC7468152

Authors: Kerkhofs D, van Hagen BT, Milanova IV, Schell KJ, van Essen H, Wijnands E, Goossens P, Blankesteijn WM, Unger T, Prickaerts J, Biessen EA, van Oostenbrugge RJ, Foulquier S

Theranostics. 2020;10(21):9512-9527

PMID: 32863942    Open Access: PMC7449902

Authors: Lee YK, Rothwell PM, Payne SJ, Webb AJS

Physiological measurement. 2020 Aug 7;

PMID: 32764198

Authors: Gill D, Georgakis MK, Zuber V, Karhunen V, Burgess S, Malik R, Dichgans M

Journal of the American Heart Association. 2020 Jul 21;9(14):e016773

PMID: 32627641

Authors: Georgakis MK, Gill D, Malik R, Protogerou AD, Webb AJS, Dichgans M

Hypertension (Dallas, Tex. : 1979). 2020 Sep;76(3):953-961

PMID: 32623925    Open Access: PMC7418931

Authors: Asare Y, Campbell-James TA, Bokov Y, Yu LL, Prestel M, El Bounkari O, Roth S, Megens RTA, Straub T, Thomas K, Yan G, Schneider M, Ziesch N, Tiedt S, Silvestre-Roig C, Braster Q, Huang Y, Schneider M, Malik R, Haffner C, Liesz A, Soehnlein O, Bernhagen J, Dichgans M

Circulation research. 2020 Aug 28;127(6):811-823

PMID: 32546048

Authors: Georgakis MK, Gill D, Webb AJS, Evangelou E, Elliott P, Sudlow CLM, Dehghan A, Malik R, Tzoulaki I, Dichgans M

Neurology. 2020 Jul 28;95(4):e353-e361

PMID: 32611631    Open Access: PMC7455321

Authors: Mestre H, Mori Y, Nedergaard M

Trends in neurosciences. 2020 Jul;43(7):458-466

PMID: 32423764    Open Access: PMC7331945

Authors: Biessels GJ, Nobili F, Teunissen CE, Simó R, Scheltens P

The Lancet. Neurology. 2020 Aug;19(8):699-710

PMID: 32445622

Authors: Blair GW, Thrippleton MJ, Shi Y, Hamilton I, Stringer M, Chappell F, Dickie DA, Andrews P, Marshall I, Doubal FN, Wardlaw JM

Neurology. 2020 May 26;94(21):e2258-e2269

PMID: 32366534    Open Access: PMC7357294

Authors: Ratelade J, Klug NR, Lombardi D, Angelim MKSC, Dabertrand F, Domenga-Denier V, Salman RA, Smith C, Gerbeau JF, Nelson MT, Joutel A

Circulation. 2020 Jun 23;141(25):2078-2094

PMID: 32183562    Open Access: PMC7311305

Authors: Li Q, Aalling NN, Förstera B, Ertürk A, Nedergaard M, Møllgård K, Xavier ALR

Fluids and barriers of the CNS. 2020 Feb 11;17(1):15

PMID: 32046744    Open Access: PMC7014736

Authors: Georgakis MK, Malik R, Anderson CD, Parhofer KG, Hopewell JC, Dichgans M

Brain : a journal of neurology. 2020 Feb 1;143(2):597-610

PMID: 31968102    Open Access: PMC7009571

Authors: Sloots JJ, Biessels GJ, Zwanenburg JJM

NeuroImage. 2020 Apr 15;210:116581

PMID: 31982580

Authors: Mestre H, Du T, Sweeney AM, Liu G, Samson AJ, Peng W, Mortensen KN, Stæger FF, Bork PAR, Bashford L, Toro ER, Tithof J, Kelley DH, Thomas JH, Hjorth PG, Martens EA, Mehta RI, Solis O, Blinder P, Kleinfeld D, Hirase H, Mori Y, Nedergaard M

Science (New York, N.Y.). 2020 Mar 13;367(6483)

PMID: 32001524    Open Access: PMC7375109

Authors: Abraham G, Malik R, Yonova-Doing E, Salim A, Wang T, Danesh J, Butterworth AS, Howson JMM, Inouye M, Dichgans M

Nature communications. 2019 Dec 20;10(1):5819

PMID: 31862893    Open Access: PMC6925280