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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Tweets by SVDS@target

Publications with PubMed ID

Authors: Sundaresan V, Zamboni G, Rothwell PM, Jenkinson M, Griffanti L

Medical image analysis. 2021 Jul 18;73:102184

PMID: 34325148

Authors: Li L, Zuurbier SM, Kuker W, Warlow CP, Rothwell PM

Stroke. 2021 Jul 8;:STROKEAHA121034432

PMID: 34233466

Authors: Hamilton OKL, Cox SR, Okely JA, Conte F, Ballerini L, Bastin ME, Corley J, Taylor AM, Page D, Gow AJ, Muñoz Maniega S, Redmond P, Valdés-Hernández MDC, Wardlaw JM, Deary IJ

Translational psychiatry. 2021 Jul 6;11(1):376

PMID: 34226517    Open Access: PMC8257729

Authors: Zwartbol MH, Rissanen I, Ghaznawi R, de Bresser J, Kuijf HJ, Blom K, Witkamp TD, Koek HL, Biessels GJ, Hendrikse J, Geerlings MI

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2021 Jun 30;:271678X211025447

PMID: 34187229

Authors: Koide M, Ferris HR, Nelson MT, Wellman GC

Frontiers in physiology. 2021;12:688468

PMID: 34168571    Open Access: PMC8218876

Authors: Kerkhofs D, Wong SM, Zhang E, Uiterwijk R, Hoff EI, Jansen JFA, Staals J, Backes WH, van Oostenbrugge RJ

GeroScience. 2021 Jun 23;

PMID: 34160780

Authors: Stringer MS, Blair GW, Shi Y, Hamilton I, Dickie DA, Doubal FN, Marshall IM, Thrippleton MJ, Wardlaw JM

Frontiers in physiology. 2021;12:644837

PMID: 34149442    Open Access: PMC8207286

Authors: Neitzel J, Franzmeier N, Rubinski A, Dichgans M, Brendel M, Alzheimer’s Disease Neuroimaging Initiative (ADNI)., Malik R, Ewers M

Nature communications. 2021 Jun 22;12(1):3825

PMID: 34158479    Open Access: PMC8219708

Authors: Wiegertjes K, Dinsmore L, Drever J, Hutchison A, Stephen J, Valdés Hernández MC, Bhatnagar P, Minks DP, Rodrigues MA, Werring DJ, de Leeuw FE, Klijn CJ, Al-Shahi Salman R, White PM, Wardlaw JM

Journal of neurology, neurosurgery, and psychiatry. 2021 Jun 8;

PMID: 34103345

Authors: Betrie AH, Brock JA, Harraz OF, Bush AI, He GW, Nelson MT, Angus JA, Wright CE, Ayton S

Nature communications. 2021 Jun 1;12(1):3296

PMID: 34075043    Open Access: PMC8169932

Authors: Humphreys CA, Smith C, Wardlaw JM

Neuropathology and applied neurobiology. 2021 May 26;

PMID: 34037264

Authors: Hamilton O, Cox SR, Ballerini L, Bastin ME, Corley J, Gow AJ, Muñoz Maniega S, Redmond P, Valdés Hernández MDC, Wardlaw JM, Deary IJ

Neurobiology of aging. 2021 Sep;105:25-34

PMID: 34022536

Authors: Stewart CR, Stringer MS, Shi Y, Thrippleton MJ, Wardlaw JM

Frontiers in neurology. 2021;12:647848

PMID: 34017302    Open Access: PMC8129542

Authors: Fani L, Georgakis MK, Ikram MA, Ikram MK, Malik R, Dichgans M

Translational psychiatry. 2021 May 17;11(1):291

PMID: 34001857    Open Access: PMC8129147

Authors: Arts T, Meijs TA, Grotenhuis H, Voskuil M, Siero J, Biessels GJ, Zwanenburg J

Frontiers in neuroscience. 2021;15:665480

PMID: 33981198    Open Access: PMC8107291

Authors: Rasmussen MK, Mestre H, Nedergaard M

Physiological reviews. 2021 May 5;

PMID: 33949874

Authors: Sloots JJ, Biessels GJ, de Luca A, Zwanenburg JJM

NeuroImage. 2021 Aug 1;236:118078

PMID: 33878376

Authors: Arba F, Mair G, Phillips S, Sandercock P, Wardlaw JM, Third International Stroke Trial Collaborators.

Stroke. 2020 May;51(5):1411-1418

PMID: 32268853    Open Access: PMC7185055

Authors: Jochems ACC, Blair GW, Stringer MS, Thrippleton MJ, Clancy U, Chappell FM, Brown R, Jaime Garcia D, Hamilton OKL, Morgan AG, Marshall I, Hetherington K, Wiseman S, MacGillivray T, Valdés-Hernández MC, Doubal FN, Wardlaw JM

Stroke. 2020 May;51(5):1503-1506

PMID: 32264759    Open Access: PMC7185057

Authors: Dabertrand F, Harraz OF, Koide M, Longden TA, Rosehart AC, Hill-Eubanks DC, Joutel A, Nelson MT

Proceedings of the National Academy of Sciences of the United States of America. 2021 Apr 27;118(17)

PMID: 33875602    Open Access: PMC8092380

Authors: Malik R, Georgakis MK, Vujkovic M, Damrauer SM, Elliott P, Karhunen V, Giontella A, Fava C, Hellwege JN, Shuey MM, Edwards TL, Rogne T, Åsvold BO, Brumpton BM, Burgess S, Dichgans M, Gill D

Hypertension (Dallas, Tex. : 1979). 2021 Jun;77(6):2004-2013

PMID: 33813844    Open Access: PMC8115430

Authors: Clancy U, Garcia DJ, Stringer MS, Thrippleton MJ, Valdés-Hernández MC, Wiseman S, Hamilton OK, Chappell FM, Brown R, Blair GW, Hewins W, Sleight E, Ballerini L, Bastin ME, Maniega SM, MacGillivray T, Hetherington K, Hamid C, Arteaga C, Morgan AG, Manning C, Backhouse E, Hamilton I, Job D, Marshall I, Doubal FN, Wardlaw JM

European stroke journal. 2021 Mar;6(1):81-88

PMID: 33817338    Open Access: PMC7995323

Authors: Kerkhofs D, Wong SM, Zhang E, Staals J, Jansen JFA, van Oostenbrugge RJ, Backes WH

Neurology. 2021 Apr 27;96(17):e2192-e2200

PMID: 33762423    Open Access: PMC8166427

Authors: Sleight E, Stringer MS, Marshall I, Wardlaw JM, Thrippleton MJ

Frontiers in physiology. 2021;12:643468

PMID: 33716793    Open Access: PMC7947694

Authors: Valdés Hernández MDC, Grimsley-Moore T, Chappell FM, Thrippleton MJ, Armitage PA, Sakka E, Makin S, Wardlaw JM

Frontiers in neurology. 2021;12:634460

PMID: 33732208    Open Access: PMC7956970

Authors: Webb AJS, Lawson A, Mazzucco S, Li L, Rothwell PM, Oxford Vascular Study Phenotyped Cohort.

Stroke. 2021 Apr;52(4):1330-1338

PMID: 33588593    Open Access: PMC7610951

Authors: Harshfield EL, Georgakis MK, Malik R, Dichgans M, Markus HS

Stroke. 2021 Mar;52(3):931-936

PMID: 33535786    Open Access: PMC7903981

Authors: Liu G, Mestre H, Sweeney AM, Sun Q, Weikop P, Du T, Nedergaard M

Cell reports. 2020 Dec 22;33(12):108524

PMID: 33357428    Open Access: PMC8186543

Authors: van den Brink H, Weaver NA, Biessels GJ

Case reports in neurology. 2020 Sep-Dec;12(3):416-421

PMID: 33362520    Open Access: PMC7747080

Authors: Valdés Hernández MDC, Smith K, Bastin ME, Nicole Amft E, Ralston SH, Wardlaw JM, Wiseman SJ

Lupus. 2021 Feb;30(2):285-298

PMID: 33307988    Open Access: PMC7854491

Authors: Webb AJS, Lawson A, Wartolowska K, Mazzucco S, Rothwell PM

Hypertension (Dallas, Tex. : 1979). 2021 Jan;77(1):193-201

PMID: 33249860    Open Access: PMC7720874

Authors: Biessels GJ

Stroke. 2020 Dec;51(12):3487-3488

PMID: 33148147

Authors: Hamilton OKL, Backhouse EV, Janssen E, Jochems ACC, Maher C, Ritakari TE, Stevenson AJ, Xia L, Deary IJ, Wardlaw JM

Alzheimer's & dementia : the journal of the Alzheimer's Association. 2021 Apr;17(4):665-685

PMID: 33185327

Authors: Webb AJ, Lawson A, Mazzucco S, Li L, Rothwell PM

International journal of stroke : official journal of the International Stroke Society. 2020 Nov 9;:1747493020971905

PMID: 33167788

Authors: Webb AJ, Lawson A, Li L, Mazzucco S, Rothwell PM, Oxford Vascular Study Phenotyped Cohort.

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2021 Jun;41(6):1463-1471

PMID: 33153374    Open Access: PMC8138338

Authors: Clancy U, Appleton JP, Arteaga C, Doubal FN, Bath PM, Wardlaw JM

Chinese medical journal. 2020 Oct 6;134(2):127-142

PMID: 33118960    Open Access: PMC7817338

Authors: Giannetto M, Xia M, Stæger FF, Metcalfe T, Vinitsky HS, Dang JAML, Xavier ALR, Kress BT, Nedergaard M, Hablitz LM

Scientific reports. 2020 Sep 30;10(1):16073

PMID: 32999319    Open Access: PMC7528110

Authors: Cleary CM, Moreira TS, Takakura AC, Nelson MT, Longden TA, Mulkey DK

eLife. 2020 Sep 14;9

PMID: 32924935    Open Access: PMC7521922

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. 2021 Feb;12(1):15-30

PMID: 32936435    Open Access: PMC7803876

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

Investigative radiology. 2021 Jan;56(1):10-19

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 Oct 6;41(9):095002

PMID: 32764198    Open Access: PMC7116588

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    Open Access: PMC7660704

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, Al-Shahi Salman R, 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