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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Publications with PubMed ID

Authors: Thrippleton MJ, Shi Y, Blair G, Hamilton I, Waiter G, Schwarzbauer C, Pernet C, Andrews PJ, Marshall I, Doubal F, Wardlaw JM

International journal of stroke : official journal of the International Stroke Society. 2018 Feb;13(2):195-206

PMID: 28933655

Authors: González-Castro V, Valdés Hernández MDC, Chappell FM, Armitage PA, Makin S, Wardlaw JM

Clinical science (London, England : 1979). 2017 Dec 15;131(24):2959

PMID: 29242272

Authors: Zietemann V, Kopczak A, Müller C, Wollenweber FA, Dichgans M

Stroke. 2017 Nov;48(11):2952-2957

PMID: 29042492

Authors: Rannikmäe K, Sivakumaran V, Millar H, Malik R, Anderson CD, Chong M, Dave T, Falcone GJ, Fernandez-Cadenas I, Jimenez-Conde J, Lindgren A, Montaner J, O'Donnell M, Paré G, Radmanesh F, Rost NS, Slowik A, Söderholm M, Traylor M, Pulit SL, Seshadri S, Worrall BB, Woo D, Markus HS, Mitchell BD, Dichgans M, Rosand J, Sudlow CLM, Stroke Genetics Network (SiGN), METASTROKE Collaboration, and International Stroke Genetics Consortium (ISGC).

Neurology. 2017 Oct 24;89(17):1829-1839

PMID: 28954878    Open Access: PMC5664302

Authors: Phuah CL, Dave T, Malik R, Raffeld MR, Ayres AM, Goldstein JN, Viswanathan A, Greenberg SM, Jagiella JM, Hansen BM, Norrving B, Jimenez-Conde J, Roquer J, Pichler A, Enzinger C, Montaner J, Fernandez-Cadenas I, Lindgren A, Slowik A, Schmidt R, Biffi A, Rost N, Langefeld CD, Markus HS, Mitchell BD, Worrall BB, Kittner SJ, Woo D, Dichgans M, Rosand J, Anderson CD, METASTROKE., NINDS-SiGN Consortium., International Stroke Genetics Consortium.

Brain : a journal of neurology. 2017 Oct 1;140(10):2663-2672

PMID: 28969386

Authors: Tiedt S, Prestel M, Malik R, Schieferdecker N, Duering M, Kautzky V, Stoycheva I, Böck J, Northoff BH, Klein M, Dorn F, Krohn K, Teupser D, Liesz A, Plesnila N, Holdt LM, Dichgans M

Circulation research. 2017 Sep 29;121(8):970-980

PMID: 28724745

Authors: de Leeuw FE, Nichols F 3rd

Neurology. 2017 Sep 5;89(10):984-985

PMID: 28794247

Authors: Wardlaw JM, Chappell FM, Valdés Hernández MDC, Makin SDJ, Staals J, Shuler K, Thrippleton MJ, Armitage PA, Muñoz-Maniega S, Heye AK, Sakka E, Dennis MS

Neurology. 2017 Sep 5;89(10):1003-1010

PMID: 28794252    Open Access: PMC5589793

Authors: van Veluw SJ, Shih AY, Smith EE, Chen C, Schneider JA, Wardlaw JM, Greenberg SM, Biessels GJ

The Lancet. Neurology. 2017 Sep;16(9):730-740

PMID: 28716371

Authors: Valdés Hernández MDC, González-Castro V, Chappell FM, Sakka E, Makin S, Armitage PA, Nailon WH, Wardlaw JM

Frontiers in neurology. 2017;8:327

PMID: 28769863    Open Access: PMC5515862

Authors: McHutchison CA, Backhouse EV, Cvoro V, Shenkin SD, Wardlaw JM

Epidemiology (Cambridge, Mass.). 2017 Jul;28(4):608-618

PMID: 28410350

Authors: Blair GW, Hernandez MV, Thrippleton MJ, Doubal FN, Wardlaw JM

Current treatment options in cardiovascular medicine. 2017 Jul;19(7):56

PMID: 28620783    Open Access: PMC5486578

Authors: Povlsen GK, Longden TA, Bonev AD, Hill-Eubanks DC, Nelson MT

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2016 Jul;36(7):1195-201

PMID: 27052838    Open Access: PMC4929704

Authors: Lubitz SA, Parsons OE, Anderson CD, Benjamin EJ, Malik R, Weng LC, Dichgans M, Sudlow CL, Rothwell PM, Rosand J, Ellinor PT, Markus HS, Traylor M, WTCCC2, International Stroke Genetics Consortium, and AFGen Consortia.

Stroke. 2017 Jun;48(6):1451-1456

PMID: 28468926

Authors: Uiterwijk R, Staals J, Huijts M, de Leeuw PW, Kroon AA, van Oostenbrugge RJ

Journal of hypertension. 2017 Jun;35(6):1263-1270

PMID: 28169884

Authors: The Lancet Neurology

The Lancet. Neurology. 2017 May;16(5):333

PMID: 28414641

Authors: Longden TA, Dabertrand F, Koide M, Gonzales AL, Tykocki NR, Brayden JE, Hill-Eubanks D, Nelson MT

Nature neuroscience. 2017 May;20(5):717-726

PMID: 28319610    Open Access: PMC5404963

Authors: Joutel A, Chabriat H

Clinical science (London, England : 1979). 2017 Apr 25;131(8):635-651

PMID: 28351960

Authors: Hawkins VE, Takakura AC, Trinh A, Malheiros-Lima MR, Cleary CM, Wenker IC, Dubreuil T, Rodriguez EM, Nelson MT, Moreira TS, Mulkey DK

eLife. 2017 Apr 7;6

PMID: 28387198    Open Access: PMC5422071

Authors: Wang M, Ding F, Deng S, Guo X, Wang W, Iliff JJ, Nedergaard M

The Journal of neuroscience : the official journal of the Society for Neuroscience. 2017 Mar 15;37(11):2870-2877

PMID: 28188218    Open Access: PMC5354332

Authors: Backhouse EV, McHutchison CA, Cvoro V, Shenkin SD, Wardlaw JM

Neurology. 2017 Mar 7;88(10):976-984

PMID: 28188307

Authors: Traylor M, Malik R, Nalls MA, Cotlarciuc I, Radmanesh F, Thorleifsson G, Hanscombe KB, Langefeld C, Saleheen D, Rost NS, Yet I, Spector TD, Bell JT, Hannon E, Mill J, Chauhan G, Debette S, Bis JC, Longstreth WT Jr, Ikram MA, Launer LJ, Seshadri S, METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium., Hamilton-Bruce MA, Jimenez-Conde J, Cole JW, Schmidt R, Słowik A, Lemmens R, Lindgren A, Melander O, Grewal RP, Sacco RL, Rundek T, Rexrode K, Arnett DK, Johnson JA, Benavente OR, Wasssertheil-Smoller S, Lee JM, Pulit SL, Wong Q, Rich SS, de Bakker PI, McArdle PF, Woo D, Anderson CD, Xu H, Heitsch L, Fornage M, Jern C, Stefansson K, Thorsteinsdottir U, Gretarsdottir S, Lewis CM, Sharma P, Sudlow CL, Rothwell PM, Boncoraglio GB, Thijs V, Levi C, Meschia JF, Rosand J, Kittner SJ, Mitchell BD, Dichgans M, Worrall BB, Markus HS, International Stroke Genetics Consortium.

Annals of neurology. 2017 Mar;81(3):383-394

PMID: 27997041    Open Access: PMC5366092

Authors: Zhang CE, Wong SM, Uiterwijk R, Staals J, Backes WH, Hoff EI, Schreuder T, Jeukens CR, Jansen JF, van Oostenbrugge RJ

Stroke. 2017 Mar;48(3):658-663

PMID: 28196940

Authors: Chappell FM, Del Carmen Valdés Hernández M, Makin SD, Shuler K, Sakka E, Dennis MS, Armitage PA, Muñoz Maniega S, Wardlaw JM

Trials. 2017 Feb 21;18(1):78

PMID: 28222778    Open Access: PMC5320698

Authors: Dichgans M, Leys D

Circulation research. 2017 Feb 3;120(3):573-591

PMID: 28154105

Authors: Ghaznawi R, de Bresser J, van der Graaf Y, Zwartbol MH, Witkamp TD, Geerlings MI, Hendrikse J, SMART Study Group * .

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2017 Jan 1;:271678X17705974

PMID: 28436255

Authors: Dickie DA, Aribisala B, Mair G, Berge E, Lindley RI, Sandercock P, von Kummer R, von Heijne A, Peeters A, Cala L, Farrall A, Morris Z, Bradey N, Potter G, Adami A, Wardlaw JM

International journal of stroke : official journal of the International Stroke Society. 2017 Jan 1;:1747493017729267

PMID: 28872448

Authors: Uiterwijk R, van Oostenbrugge RJ, Huijts M, De Leeuw PW, Kroon AA, Staals J

Frontiers in aging neuroscience. 2016;8:301

PMID: 28018214    Open Access: PMC5149514

Authors: METACOHORTS Consortium. Electronic address: joanna.wardlaw@ed.ac.uk., METACOHORTS Consortium.

Alzheimer's & dementia : the journal of the Alzheimer's Association. 2016 Dec;12(12):1235-1249

PMID: 27490018    Open Access: PMC5399602

Authors: Jouvent E, Duchesnay E, Hadj-Selem F, De Guio F, Mangin JF, Hervé D, Duering M, Ropele S, Schmidt R, Dichgans M, Chabriat H

Neurology. 2016 Oct 25;87(17):1787-1795

PMID: 27694265    Open Access: PMC5089530

Authors: Khavandi K, Baylie RA, Sugden SA, Ahmed M, Csato V, Eaton P, Hill-Eubanks DC, Bonev AD, Nelson MT, Greenstein AS

Science signaling. 2016 Oct 11;9(449):ra100

PMID: 27729550    Open Access: PMC5154376

Authors: Pan C, Cai R, Quacquarelli FP, Ghasemigharagoz A, Lourbopoulos A, Matryba P, Plesnila N, Dichgans M, Hellal F, Ertürk A

Nature methods. 2016 Oct;13(10):859-67

PMID: 27548807

Authors: Dalsgaard T, Sonkusare SK, Teuscher C, Poynter ME, Nelson MT

Scientific reports. 2016 Sep 22;6:33841

PMID: 27653046    Open Access: PMC5031985

Authors: Capone C, Dabertrand F, Baron-Menguy C, Chalaris A, Ghezali L, Domenga-Denier V, Schmidt S, Huneau C, Rose-John S, Nelson MT, Joutel A

eLife. 2016 Aug 1;5

PMID: 27476853    Open Access: PMC4993587

Authors: Sonkusare SK, Dalsgaard T, Bonev AD, Nelson MT

The Journal of physiology. 2016 Jun 15;594(12):3271-85

PMID: 26840527    Open Access: PMC4908010