SVDs@target brings together basic researchers, academic clinicians and patient organizations. All our work packages are led by a pre-clinical and a clinical investigator who collaborate on a specific problem. Hence, there will be rapid and efficient transfer of new knowledge from laboratory to bedside and back.

The project is organized around four major risk factors and mechanisms that have recently emerged and for which evidence supports a role in SVDs:
  • Blood pressure variability (WP1)
  • Blood Brain Barrier (WP2)
  • Microvascular matrisome (WP3)
  • Inflammation (WP4)
 
New mechanisms will be validated in animal models and in humans (WP5).   

Work package 1

Blood pressure variability and microvascular dysfunction in SVDs

Leads: University of Vermont (pre-clinical) & University of Oxford (clinical)

Objectives of the Work package

  • To elucidate the mechanisms by which blood pressure hypertension and variability alter the primary functions of cerebral arterioles and to determine key mechanistic defects shared by different SVDs.
  • To identify novel therapeutic targets for validation through interventions in WP5
  • To determine the prognostic value of blood pressure  variability for SVDs, stroke, cognitive decline, and dementia, using cohort and trial data (>100,000 patients) and determine drug-class effects on consistency of control of blood pressure
  • To determine the relationship between blood pressure/ blood pressure variability and functional and structural MRI features of SVDs
Work package 1 will utilize currently untapped resources and elucidate the mechanisms by which BP elevation and variability (BPv) alter the primary functions of cerebral arterioles, including myogenic tone, autoregulation, and functional hyperemia, and determine key mechanistic defects shared by different SVDs. This will be combined with work in humans to determine 1) the prognostic value of BPv for SVDs, stroke, and dementia using cohort and trial data (>100,000 patients) and 2) drug-class effects on the consistency of BP control and development of brain lesions.

Work package 2

Blood brain barrier integrity and perivascular flow in SVDs

Leads: University of Edinburgh (clinical) & Kobenhavns Universitet (pre-clinical)

Objectives of the Work package

  • To assess blood brain barrier integrity and the interplay with microvessel function, including perivascular flow and vascular reactivity, in a range of models and clinical presentations of SVDs
  • To identify factors that contribute to the malfunction of blood brain barrier and perivascular flow such as blood pressure and its variability, that increase microvessel wall damage and are potential therapeutic targets for testing in WP5
  • To establish mechanistic links between malfunction of blood brain barrier perivascular flow, and the profile of brain parenchymal lesions in different SVDs
Work package 2 will assess blood brain barrier (BBB) integrity and its interplay with microvessel function, including perivascular flow and vascular reactivity, in a range of SVD models and clinical presentations. We will further identify factors that are decisive in the malfunction of BBB and perivascular flow, such as blood pressure (BP) and its variability, which increase microvessel wall damage and hence represent potential therapeutic targets for validation through interventions (WP5).   

Work package 3

Microvascular matrisome and vascular integrity in SVDs

Leads: Institut national de la santé et de la recherche médicale (pre-clinical) &
Universitair Medisch Centrum Utrecht (clinical)

Objectives of the Work package

  • To identify matrisome changes shared by distinct SVDs in rodent models and humans
  • To identify novel MRI markers of microvascular malfunction in patients with SVDs
  • To establish mechanistic links between matrisome changes, microvascular malfunction, and the profile of brain parenchymal lesions in different SVDs
Work package 3 will identify changes in the microvascular matrisome shared by distinct SVDs in rodent models and establish novel markers of microvascular malfunction in humans. By combining proteomics with detailed physiological, imaging and histo- pathological techniques, this WP will establish mechanistic links between matrisome changes, microvascular malfunction, and the profile of brain parenchymal lesions in rodent models and in humans with SVDs.   

Work package 4

Inflammatory mechanisms - immune cell binding and transmigration in SVDs

Leads:Westfaelische Wilhelms-Universitaet Muenster (pre-clinical) & Universiteit Maastricht (clinical)

Objectives of the Work package

  • To identify, localize and characterize immune cells and determine binding and transmigration of these cells in different SVDs
  • To identify novel mechanisms involved in immune cell mediated microvessel wall damage in different SVDs
  • To identify novel therapeutic targets for validation through interventions in WP5
Work package 4 will identify, localize and characterize immune cells and determine binding and transmigration of these cells in different SVDs. By combining experimental work with targeted (ultra-high-field MRI-guided) tissue sampling and immune cell pheno- typing in humans this work will reveal relevant novel targets for validation in WP5.   

Work package 5

Validation of mechanisms through interventions

Leads: Ludwig-Maximilians-Universitaet Muenchen (clinical) & University of Vermont (pre-clinical)

Objectives of the Work package

  • To validate novel mechanisms common to multiple SVDs through interventions that demonstrate a beneficial effect on microvascular function in brain vessels. This will be done in a broad range from animal models to clinical trials.
  • To identify predictors of a therapeutic response to agents already in use in patients.
Work package 5 will validate novel mechanisms common to multiple SVDs through interventions demonstrating a beneficial effect on microvascular function in isolated brain vessels and in vivo both in animals and in humans. Drawing on pre-existing data from clinical trials we will further identify predictors of the therapeutic response to agents already in use in humans.   

Work package 6

Project Management

Lead: Ludwig-Maximilians-Universitaet Muenchen

Objectives of the Work package

  • Ensure the proper overall management of the project so as to strengthen and support the ability of participants to achieve their objectives, complete milestones on time, and provide deliverables
  • Establish an effective communication infrastructure and foster an integrative process within the consortium
The coordinator LMU together with ART will manage all administrative, financial, and legal issues of the project in agreement with the decisions of the General Assembly (GA).

Work package 7

Dissemination, Exploitation, Communication

Lead: ARTTIC S.A.S.

Objectives of the Work package

  • Raise public and scientific awareness of the EU-funded project, and of prevention of SVDs, stroke, and dementia
  • Facilitate networking and mutual communication with the scientific community, the patient population, and the general public
  • Reach all potential clinical, scientific, and non-scientific audiences
  • Manage the processes for capturing and protecting intellectual property, addressing confidentiality issues and patent/ copyright acquisition
  • Ensure efficient exploitation of project results and achieve the highest possible benefit for scientists, industry, and European society
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Publications with PubMed ID

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 Jul 6;:HYPERTENSIONAHA12015136

PMID: 32623925

Authors: Asare Y, Campbell-James TA, Bokov Y, Yu LL, Prestel M, El Bounkari O, Roth S, Megens RT, 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 Jun 17;

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

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

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