Title: Neuroimaging standards for research into small vessel disease and

its contribution to ageing and neurodegeneration: A united approach

STandards for ReportIng Vascular Changes on NEuroimaging

(STRIVE) v1

Authors:

*Joanna M Wardlaw MDa,b, Neuroimaging Sciences, Centre for Clinical Brain Sciences

and Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh,

Bramwell Dott Building, Western General Hospital, Crewe Road, Edinburgh EH4 2XU,

UK

*Eric E Smith MDc, Departments of Clinical Neurosciences and Radiology, Hotchkiss

Brain Institute, University of Calgary and Seaman Family MR Research Centre, Foothills

Medical Centre, Alberta Health Services, 1403 29th Street NW, Calgary, Alberta, T2N

2T9, Canada

Geert J Biessels MDd, Department of Neurology, G03.232, Rudolf Magnus Institute of

Neuroscience, UMC Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands

Charlotte Cordonnier MDe, Univ Lille Nord de France, EA1046, Department of

Neurology, Lille University Hospital. Lille, France

1

Franz Fazekas MDf, Department of Neurology, Medical University of Graz,

Auenbruggerplatz 22, A-8036 Graz, Austria

Richard Frayne PhDg, Departments of Radiology, and Clinical Neurosciences, Hotchkiss

Brain Institute, University of Calgary and Seaman Family MR Research Centre, Foothills

Medical Centre, Alberta Health Services, 1403 29th Street NW, Calgary, Alberta, T2N

2T9, Canada

Richard I. Lindley MDh, University of Sydney and George Institute for Global Health,

Level 2 Clinical Sciences, Westmead Hospital C24, University of Sydney, Sydney, NSW

2006, Australia

John T O'Brien DMi, Department of Psychiatry, University of Cambridge, Box 189,

Addenbrooke's Hospital, Cambridge CB2 0QQ, UK

Frederik Barkhof MDj, Department of Radiology & Nuclear Medicine, VU University

Medical Centre, PO Box 7057 1007 MB Amsterdam The Netherlands

Oscar R Benavente MDk, Department of Medicine, Division of Neurology, Brain

Research Centre, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC

V6T 2B5, Canada

Sandra Black MDl, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Room

A 421, Toronto, Ontario M4N 3M5, Canada

2

Carol Brayne PhDm, Cambridge Institute of Public Health, School of Clinical Medicine,

Forvie Site, Robinson Way, Cambridge CB2 0SR, UK

Monique Breteler MDn, German Center for Neurodegenerative diseases (DZNE),

Holbeinstrasse 13-15, 53175 Bonn, Germany

Hugues Chabriat MDo, Service de Neurologie, Hopital Lariboisiere, APHP; INSERM

U740; Université Denis Diderot Paris 7, France

Charles DeCarli MDp, University of California at Davis, Department of Neurology, 4860 Y

Street, Suite 3700, Sacramento, CA 95817, USA

Frank-Erik de Leeuw MDq, Radboud University Nijmegen Medical Center Donders

Institute for Brain Cognition & Behaviour, Center for Neuroscience Department of

Neurology PO Box 9101 6500HB Nijmegen, The Netherlands

Fergus Doubal PhDr, Brain Research Imaging Centre, University of Edinburgh, Bramwell

Dott Building, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK

Marco Duering MDs , Institute for Stroke and Dementia Research, Klinikum der

Universität München, Marchioninistr. 15, 81377 München, Germany

3

Nick C Fox MDt, Department of Neurodegeneration, Institute of Neurology, University

College London, Dementia Research Centre, Box 16, Queen Square, London, WC1N

3BG, UK

Steven Greenberg MDu, Neurology, Massachusetts General Hospital, MGH Stroke

Research Center, 175 Cambridge Street, Suite 300, Boston, MA, USA

Vladimir Hachinski MDv, Department of Clinical Neurological Sciences, Western

University, 339 Windermere Road, London, Ontario N6A 5A5, Canada

Ingo Kilimann MDw, DZNE Rostock/Greifswald, Gehlsheimer Straße 20, 18147 Rostock,

Germany

Vincent Mok MDx, Division of Neurology, Department of Medicine and Therapeutics,

Prince of Wales Hospital, The Chinese University of Hong Kong

Robert van Oostenbrugge MDy, Department of Neurology, School of Mental Health and

Neuroscience and the Cardiovascular Research Institute Maastricht, Maastricht

University Medical Center, PO Box 5800, 6202 AZ, Maastricht, The Netherlands

Leonardo Pantoni MDz, Azienda Universitario Ospedaliera Careggi and NeuroFarBa

Department, University of Florence, Piazza di San Marco, 4 50121 Florence, Italy

4

Oliver Speck PhDaa, Department of Biomedical Magnetic Resonance, Faculty for Natural

Sciences, Institute for Experimental Physics, Otto-von-Guericke University Magdeburg,

Leipziger Str. 44, Haus 65, 39120 Magdeburg, Germany

Blossom CM Stephan PhDbb, Newcastle University, The Baddiley-Clark Building,

Richardson Road, Newcastle upon Tyne NE2 4AX, UK

Stefan Teipel MDcc, Department of Psychosomatic Medicine, University Medicine

Rostock, and DZNE Rostock, Gehlsheimer Str. 20, 18471 Rostock, Germany

Anand Viswanathan MDu, Massachusetts General Hospital Stroke Research Center,

Harvard Medical School, 175 Cambridge Street, Suite 300, Boston, MA 02114, USA

David Werring PhDdd, Stroke Research Group, Dept Brain Repair and Rehabilitation,

UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK

Christopher Chen BM BChee, Yong Loo Lin School of Medicine, National University of

Singapore

Colin Smith MDff, Centre for Clinical Brain Sciences, University of Edinburgh,

Chancellor's Building, Edinburgh, EH16 4SB, UK

Mark van Buchem MDgg, Department of Radiology, Leiden University Medical Center,

PO Box 9600, 2300RC Leiden, The Netherlands

5

Bo Norrving MDhh, Department of Clinical Sciences, Section of Neurology Skåne

University Hospital, S-221 85 Lund, Sweden

Philp B Gorelick MDii, Saint Mary's Health Care, Hauenstein Neuroscience Center, 220

Cherry Street SE, Room H 3037, Grand Rapids, MI 49503, USA

*Martin Dichgans MDs, 1. Institute for Stroke and Dementia Research, Klinikum der

Universität München, Ludwig-Maximilians-University, Marchioninistr. 15, 81377

München, Germany; 2. German Center for Neurodegenerative Diseases (DZNE,

Munich), Schillerstraße 44, 80336 Munich, Germany; 3. Munich Cluster for Systems

Neurology (SyNergy), Munich, Germany

Correspondence: JM Wardlaw, Division of Neuroimaging Sciences, Western General

Hospital, Crewe Rd, Edinburgh, EH4 2XU, UK, tel +44 131 537 2943, fax +44 131 332

5150, email Joanna.wardlaw@ed.ac.uk

6

Abstract:

Cerebral small vessel disease (SVD) is a common accompaniment of ageing, whose

visible neuroimaging features include recent small subcortical infarcts, lacunes, white

matter hyperintensities, perivascular spaces, microbleeds and brain atrophy. SVD may

present as a stroke or cognitive decline, or may be asymptomatic or minimally

symptomatic, and frequently coexists with neurodegenerative disease where it may

exacerbate cognitive deficits, physical disabilities, and other symptoms arising from

neurodegeneration. The terminology and definitions used to describe imaging features

of SVD vary widely as do protocols for image acquisition and image analysis. This lack

of consistency obstructs progress in determining the contribution that SVD makes to the

pathophysiology and clinical expression of common neurodegenerative diseases.

Against this background, an International working group of the Centres of Excellence in

Neurodegeneration completed a structured process to develop definitions and imaging

standards for specific markers and consequences of SVD. The group was charged with

the following tasks: to i) provide a common advisory terminology and definitions for

imaging features of SVD visible on magnetic resonance (MR) imaging (MRI), ii) suggest

minimum standards for their image acquisition and analysis, iii) agree on standards for

scientific reporting of small-vessel-related changes on neuroimaging, iv) review

emerging imaging methods for detecting and quantifying preclinical manifestations of

SVD. Our findings apply to research studies and in addition can be used in the clinical

setting to standardise image interpretation, acquisition, and reporting.

This manuscript summarises the main outcomes of this international effort to provide the

STandards for ReportIng Vascular Changes on NEuroimaging (STRIVE).

7

Funding: Centres of Excellence in Neurodegeneration (COEN) concordat (United

Kingdom Medical Research Council, the German Center for Neurodegenerative Disease

[Deutsches Zentrum für Neurodegenerative Erkrankungen, DZNE], Germany) and the

Canadian Institutes of Health Research [CIHR, Canada]) reference COEN017; Royal

Society of Edinburgh; Scottish Imaging Network, a Platform for Scientific Excellence

(SINAPSE) Collaboration; UK Cross-Council Centre for Cognitive Ageing and Cognitive

Epidemiology, Edinburgh; Carl Friedrich von Siemens Foundation; Vascular Dementia

Research Foundation; NIHR Biomedical Research Unit in Dementia awarded to

Cambridge University Hospitals NHS Trust and the University of Cambridge; NIHR

Biomedical Research Unit in Dementia awarded to UCL Hospitals NHS Trust and UCL; 

FP6 ERA-NET NEURON grant (01 EW1207); and Canadian Stroke Network.

8

Introduction

Neurodegenerative diseases such as Alzheimer’s disease (AD) commonly co-exist with

cerebrovascular disease in older people. Cerebral small vessel disease (SVD) is the

commonest vascular cause of dementia, the major contributor to mixed dementia, and is

the cause of at least a fifth of all strokes.1,2 AD and SVD share risk factors,3,4 both lead to

cognitive decline and dementia,5-7 and the clinical differentiation of AD from “vascular

cognitive impairment” or “vascular dementia” is recognised increasingly to be blurred.8

Visible manifestations of SVD on conventional MR imaging (MRI) include recent small

subcortical infarcts, white matter MR hyperintensities (WMH), lacunes, prominent

perivascular spaces (PVS), cerebral microbleeds (CMB) and atrophy.2 However, the

terms and definitions of these lesions have varied hugely across studies.9,10 For

example, our systematic review of terms for WMH identified 1,144 instances of 50

different terms used to describe WMH among 940 publications; in some cases two

different terms were used within the same publication (table 1 and appendix). This

degree of variation in terms inhibits cross-study comparisons, and is a barrier to

research on the risk factors, pathophysiology, pathological correlations and clinical

consequences of these lesions. Indeed, the same lesions may be classified differently

across studies—for example, small cavities have been variably classified as either

perivascular spaces or lacunes by different definitions.9 Variable fates of acute SVD-

related lesions and convergence of aetiologically different lesions into similar

appearances on MRI (figure 1) adds to the difficulties in interpreting data from many

research reports. More standard terminology, definitions, image acquisition and analysis

methods across research centres would remove a major barrier to progress in the field.

9

Furthermore, such standardization could be adopted in clinical practice to improve our

ability to diagnose and understanding the cause of cognitive impairment in the elderly

Neuroimaging consensus standards for SVD classification were first proposed by the

U.S. National Institute of Neurological Disorders and Stroke (NINDS) and Canadian

Stroke Network (CSN) as part of standards for vascular cognitive impairment (VCI)

research.11 Subsequently, a scientific statement from the American Heart Association

incorporated neuroimaging evidence of SVD or stroke as part of “probable” criteria for

vascular mild cognitive impairment and dementia, and included a class II

recommendation for neuroimaging as part of the work-up for vascular cognitive

impairment.12 However, neither of these guidelines provide comprehensive

recommendations for the many neuroimaging manifestations of SVD, and neither reflect

recent advances in understanding the pathophysiology and measurement of SVD, a

rapidly changing field.

This international effort builds on prior initiatives to provide clear, scientifically rigorous,

evidence based, easy to apply definitions and terminologies for structural neuroimaging

features of SVD that avoid presuming mechanisms of pathogenesis, with examples to

facilitate improved standard use; minimum advisory standards for image acquisition;

standards for analysis of neuroimaging SVD and related features; and scientific

reporting standards to improve clarity of publications on SVD. The present standard

focuses on SVD. However other vascular lesions, including non-SVD-related ischemic

or haemorrhagic stroke, subarachnoid haemorrhage, subdural hematoma and vascular

malformations, can also contribute to cognitive impairment and dementia, especially

10

after stroke. These, and neuroimaging recommendations, are discussed in the

appendix.

This manuscript summarises the resulting STandards for ReportIng Vascular Changes

on NEuroimaging (STRIVE). Our primary aim is to recommend standards for research

using MRI; however, many of the principles also apply to research using CT, and the

standards may also facilitate a more consistent approach to identifying neuroimaging

manifestations of SVD in clinical practice.

Methods

In 2011, the United Kingdom Medical Research Council, the German Center for

Neurodegenerative Disease (DZNE, Germany) and the Canadian Institutes of Health

Research (CIHR, Canada) issued a call for proposals under a funding concordat the

Centres of Excellence in Neurodegeneration (COEN) which aimed to accelerate

progress in understanding the pathogenesis of neurodegeneration (www.coen.org).13

This provided funding for a working group of experts to establish standards for

neuroimaging in SVD.

The core group of experts was convened in Edinburgh in March 2012. These experts

were identified by three study co-chairs (JW, MD and EES) based on location in a

COEN-affiliated Centre, supplemented by representatives from active research groups

in SVD neuroimaging in non-COEN participant countries. The group included experts in

neurology, neuroradiology, neuroepidemiology, psychiatry, geriatrics, stroke, medical

imaging physics and neuropathology. The working method was based on the Delphi

11

principle, with workshops at the beginning and end of the project and interim work

packages (details in appendix). A template focused the discussion on achieving a

consensus in key areas: terminology, definitions, image acquisition, image analysis, and

reporting standards. The group endorsed a key principle that terms and definitions

should reflect imaging characteristics as descriptively as possible, avoiding unfounded

presumptions of mechanism or pathological correlation not well supported by the

scientific literature, so as not to inhibit future studies of the pathophysiology of SVD.

Subsequently, working groups were assigned to develop standards for each of six key

lesion types, following established principles for guideline development published by the

equator network (http://www.equator-network.org/). Systematic searches were

conducted to identify relevant literature (appendix). The entire group reconvened in

Munich in November 2012 to present draft standards from each working group for

discussion and revision, with additional review and comment from six external advisors

newly invited to the process. This consensus document was drafted and revised with

input from all workshop members. The final manuscript document was reviewed and

endorsed by all participants.

For each of six key SVD lesion types, we describe the context, terminology and

definitions. Image acquisition, image analysis and reporting standards for SVD-related

lesions are described thereafter. We also comment on haemorrhage as a component of

SVD and other vascular lesions as these may contribute to dementia (appendix). We

discussed size limits for perforating arteries and arterioles to determine the correct term,

but found these to be highly variable in the literature and not well translated to their

appearance on imaging. We therefore decided to use the term ‘arteriole’ to refer to small

12

perforating arteries/arterioles that are affected in SVD. Example images of the key SVD

lesion types are given in figure 2, with further details in the appendix. These standards

are expected to reliably classify most neuroimaging manifestations of SVD; however, we

acknowledge that individual investigator judgment may be required to classify

ambiguous lesions on the borderline between clear cut categories (appendix), and that

clinical judgment may be even more necessary when using these standards in clinical

practice.

Context, terminology and definitions of individual imaging features of SVD

Recent small subcortical infarcts

Context: Clinically evident recent small subcortical infarcts (SSI), frequently referred to

clinically as “lacunar stroke” or “lacunar syndrome”, cause about 25% of all ischaemic

strokes (figure 2). Occasionally, a recent asymptomatic SSI may be identified

serendipitously on imaging,14,15 and referred to as a ‘silent cerebral infarct’. Conversely,

for as yet unexplained reasons, symptomatic lacunar stroke syndromes may not be

accompanied by visible SSI in up to 30% of cases,16 indicating that MRI is not perfectly

sensitive for recent SSI. Additionally, more recent work demonstrates that SSI may have

variable fates, evolving into either a lacunar cavity, a T2 hyperintensity without apparent

cavitation, or may disappear leaving little visible consequence on conventional MRI

(figure 1). Estimates of the proportion of recent SSI that cavitate range from 28% 17 to

94%.18

Limited pathological correlation studies suggest that SSI may be associated with small

artery occlusion, although the aetiopathogenesis of SSI is unclear. SSI occur in the

13

perfusion territory of a small artery or arteriole penetrating into the internal part of the

brain. MRI studies suggest that recent SSI may exceed 15 mm axial diameter (the usual

size limit for lacunes of presumed vascular origin, see below) in the acute phase and

can range up to approximately 20 mm on axial sections. MRI also shows that SSI and

lacunes may exceed 20 mm in length when measured in the coronal or sagittal plane

(appendix).

Terminology: A sampling of 641 abstracts and a prior systematic review9 identified 159

different terms for recent SSI; the commonest terms included lacunar infarcts, lacunar

infarctions and lacunar strokes (appendix). We propose the new consensus term recent

small subcortical infarct (rSSI), dropping the term “lacunar” because of emerging

evidence that not all small subcortical infarcts become lacunes (i.e. cavities).17,18

Definition: We propose that recent small subcortical infarct should refer to neuroimaging

evidence of recent infarction in the territory of a single perforating arteriole with imaging

features or correlating clinical symptoms consistent with a lesion occurring in the last

few weeks (table 2). “Recent” should refer to lesions with symptoms or imaging features

suggesting that they occurred within the last few weeks and is used instead of ‘acute’ to

reflect the first few weeks not just the hyperacute stage. “Small” indicates a lesion that

should generally be less than 20 mm maximum diameter in the axial plane, although it is

acknowledged that some lesions that appear to represent infarction in the territory of a

single vessel could be somewhat larger in the coronal plane (appendix).19 Additional

research is required to determine the upper size limits more precisely. Lesions in the

basal ganglia and internal capsule that are larger and appear to represent infarction in

14

multiple penetrating arteries simultaneously should not be classified as SSI, rather as

the aetiologically distinct subtype of infarction, striatocapsular infarct.20 Similarly, anterior

choroidal artery infarcts are also aetiologically distinct, identifiable by their location (in

the caudate nucleus head) and shape (usually ‘comma’ shaped) so should not be

classified as SSI. There is no lower size limit for SSI, in contrast to lacunes of presumed

vascular origin, because positive diffusion-weighted images (DWI) allow discrimination

of small recent infarcts from perivascular spaces. MR signal characteristics of rSSI are

given in figure 2.

Lacunes of presumed vascular origin

Context: Miller Fisher wrote concerning pathology: “Historically, the original small vessel

disease feature was the ’lacune‘ (hole) which derived from French for a small fluid-filled

cavity that was thought to mark the healed stage of a small deep brain infarct. The term

was adopted into English. By a process of medico-linguistic evolution, the precavitary

phase became the lacunar infarct, the associated clinical entity became the lacunar

stroke and the neurological features became the lacunar syndrome”.21 Lacunes are

commonly seen on imaging in asymptomatic elderly and are associated with an

increased risk of stroke, gait impairment and dementia.22-25 Most lacunes are presumed

to result from SSI, symptomatic or silent; however, some may represent the sequelae of

small deep haemorrhages (figure 1).26

Terminology: A systematic review identified more than 100 terms that have been used to

describe lacunes of presumed vascular origin (appendix); commonly used terms

included “lacune”, “lacunar stroke” and “silent brain infarct”. We propose the new term

15

lacune of presumed vascular origin, which discriminates small cavitated lesions of

presumed vascular origin from other small brain cavities, and accommodates the fact

that there may be some uncertainty regarding ischemic or hemorrhagic origin of the

lesion when imaging in the acute phase is unavailable, as is commonly the case.

Definitions: We define a lacune of presumed vascular origin as a round or ovoid,

subcortical, fluid filled (similar signal to CSF) cavity between 3 and about 15 mm in

diameter, compatible with a previous acute small deep brain infarct or haemorrhage in

the territory of a single perforating arteriole (table 2). MRI signal characteristics are given

in figure 2. On fluid-attenuated inversion recovery (FLAIR) images, lacunes of presumed

vascular origin usually have central CSF-like hypointensity with a surrounding rim of

hyperintensity although the rim is not universal and a hyperintense rim may also

surround PVS when passing through a WMH. In some cases the central cavity fluid may

not be suppressed on FLAIR, such that the lesion appears entirely hyperintense on

FLAIR despite clearly showing CSF-like intensity on other sequences such as T1-

weighted (T1-w) and T2-weighted (T2-w).18 Lacunes of presumed vascular origin should

be distinguished from perivascular spaces (PVS). Although pathological studies show

that there is no absolute size cut-off, lesions <3 mm in diameter are more likely to be

PVS than lacunes (appendix) and therefore we recommend the continued use of this

size criterion to discriminate the two lesion types, consistent with prior studies.27,28 The

maximum size of 15 mm was chosen to reflect the generally smaller size of old versus

recent infarcts due to tissue loss and ex-vacuo effect in the former and swelling in the

latter, but we recognise that there is little objective data to support this size boundary

and that more research is required.

16

White matter hyperintensities of presumed vascular origin

Context: White matter lesions marked by usually bilateral and largely symmetrical

hyperintensities on T2-w images are common in older subjects. They are strongly

associated with cerebrovascular disease and vascular risk factors,29 although their

pathogenesis is poorly understood and may be multifactorial.30 WMH are associated with

covert neurological and cognitive symptoms and physical difficulties such as gait

disturbance.31-35 Hyperintensities may be present in subcortical gray matter structures,

such as the basal ganglia as well, and have sometimes been analyzed together with

WMH. They may also be present in the brainstem. Some studies have distinguished

between perivascular and deep WMH (appendix) in analysis, with the suggestion, as yet

the subject of debate, that they may have different pathogenesis, risk factors and clinical

consequences. Many studies analyze total WMH.

Terminology: A systematic review of 940 abstracts identified 50 different terms for WMH;

the commonest terms were leukoaraiosis, white matter lesions, white matter

hyperintensities, leukoencephalopathy (usually in the context of CADASIL) and white

matter disease (table 1; appendix). Leukoaraiosis is a descriptive term for reduced x-ray

attenuation seen on CT,36 subsequently adopted to denote hyperintensity on T2-w and

FLAIR, sometimes also hypointensity on T1-w MR images (appendix), reflecting a

situation in which radiological preceded pathological description. We propose the term

white matter hyperintensity of presumed vascular origin (WMH) to exclude white

matter lesions from other diseases such as multiple sclerosis or leukodystrophies.

17

Definitions: MRI signal characteristics of white matter hyperintensities of presumed

vascular origin (WMH) are provided in figure 2. On T1-w sequences WMH may appear

iso- or hypointense depending on the sequence (and severity of pathology), although

the hypointensity should not approach that of CSF (table 2; appendix). Opinion was

divided regarding whether gray matter hyperintensities or brainstem hyperintensities

should be classified routinely as “WMH”, as some studies have done. The consensus

opinion was that lesions in the subcortical gray matter or brainstem are not included into

the WMH category unless explicitly stated; the use of the term “subcortical

hyperintensities” was endorsed as an acceptable alternative collective term to refer to

any non-cortical hyperintensities including those in white matter, deep gray matter and

brainstem. In the context of CT scanning, the term ‘white matter hypoattenuation’ or

‘white matter hypodensities’ can be substituted, reflecting their appearance on CT

Perivascular spaces

Context: Perivascular spaces (PVS) constitute an extension of the extracerebral fluid

spaces around arteries, arterioles, veins and venules as they course from the brain

surface into and through the brain parenchyma and are variably followed by sheets of

leptomeninges (figure 2).37 PVS are most often microscopic and thus not visible by

conventional neuroimaging, but larger ones tend to become increasingly apparent with

increasing age especially at the base of the brain.38 A more general enlargement of PVS

has been associated with other morphologic features of small vessel disease such as

white matter hyperintensities39 and lacunes,40 but not atrophy.41 The clinical significance

of having numerous visible PVS is still controversial and they should therefore not be

18

termed “lesions”; however, emerging evidence associates more prominent PVS with

worse cognitive function.42

Terminology: Synonymous terms for PVS include “Virchow-Robin Space” (VRS),40 “type

3 lacune”,43 or (when predominantly in the basal ganglia) état crible.38 Numerous terms

such as large’, ‘dilated’, ‘large dilated’ or ‘enlarged’ ‘VRS’ or ‘PVS' have also been used

to describe visible PVS.38,41,42,44-48 These were not considered appropriate because the

relationship between PVS size and clinical consequences is not well understood, and

because the visibility of PVS depends on MR sequence characteristics which vary

across studies, therefore visibility alone cannot be a uniform criterion for pathologically

enlarged PVS. We therefore recommend the consensus term perivascular space

(PVS).

Definitions: Perivascular spaces (PVS) are defined as fluid-filled spaces, which follow

the typical course of a vessel penetrating/traversing the brain through gray or white

matter; with signal intensity similar to CSF on all sequences (figure 2); because they

follow the course of penetrating vessels, they will appear linear when imaged parallel to

the course of the vessel and round or sometimes ovoid shape with a diameter

commonly not exceeding 2 mm when imaged perpendicular to the course of the vessel

(table 2; appendix). At high resolution, a central vessel may occasionally be seen

coursing through the centre of the PVS, possibly differentiating them from lacunes. PVS

tend to be most prominent in the inferior basal ganglia, may also be seen coursing

centripetally through the hemispheric white matter and in the midbrain, but are rarely if

19

ever seen in the cerebellum. They may exhibit focal enlargement, and can be

particularly enlarged (up to 10-20 mm even with mass effect) in the inferior basal

ganglia. PVS must be discriminated from small lacunes of presumed vascular origin

(appendix). In contrast to lacunes, PVS usually do not exceed a diameter of 2 mm as

confirmed pathologically,49,50 and do not have a T2 hyperintense rim around the fluid

filled space on T2w or FLAIR imaging, unless they happen to be coursing through an

area of WMH.51

Cerebral Microbleeds

Context: Microbleeds are small hypointense lesions on paramagnetic sensitive MR

sequences such as T2*-weighted gradient-recalled echo (GRE) or susceptibility-

weighted sequences, and are most frequently located in the cortico-subcortical junction,

deep grey or white matter in the cerebral hemispheres, brainstem and cerebellum (figure

2). Pathologically, the few correlative studies30,52,53 suggest that the MR-visible lesions

correspond to haemosiderin-laden macrophages in perivascular tissue consistent with

vascular leakage of blood cells.52,54-56 Cerebral microbleeds are associated with SVD and

Alzheimer’s disease.57,58 The presence or absence of strictly lobar microbleeds has been

incorporated into research criteria for cerebral amyloid angiopathy (CAA).59 Originally

thought to be asymptomatic markers of SVD, emerging studies demonstrate

associations with cognitive impairment although the mechanisms of the association,

including whether microbleeds directly damage the brain and cause dysfunction, are not

well understood. Recommendations for microbleed imaging and reporting have been

recently published, and we endorse the use of these standards.60 When microbleeds

occur in the context of AD or beta-amyloid immunotherapies they have been termed

20

amyloid-related imaging abnormalities-haemorrhage (ARIA-H). A consensus group

convened by the Alzheimer’s Association has recently published standards for

assessing microbleeds in this specific clinical context,61 and we endorse the use of these

guidelines as well.

Terminology: A literature search revealed 387 instances of 20 different terms for

microbleeds in 370 abstracts (appendix). Microbleed was by far the commonest term,

followed by ‘cerebral microbleed’ and then ‘brain microbleed’. We propose the

consensus term cerebral microbleed.

Definitions: Cerebral microbleeds (CMB) are visualised as small (usually 2-5 mm or

sometimes 10 mm in diameter) areas of signal void with associated “blooming” on T2* or

other MR sequences sensitive to susceptibility effects,57,60 (table 2) that are generally not

visualised on CT or on FLAIR, T1-w- or T2-w MR sequences. On T2*-weighted (T2*-w)

gradient-recalled echo (GRE) images, they are well defined, of homogeneous low

signal, either round or oval, in shape (figure 2). Because the blooming artifact, and

therefore the visualized size, depends on MR field strength and sequence we do not

recommend an absolute criteria for size. On 1.5 and 3T GRE, CMB are usually 2-5 mm,

but can range up to 10 mm in diameter. Hypointensities less than 2 mm, which could

represent signal loss over only a single voxel, should be regarded as questionable on

MRI at 1.5T because such small hypointensities could be artifactual. Susceptibility-

weighted imaging (SWI) may also be used to assess CMBs. Emerging quantitative

based methodologies (i.e., quantitative susceptibility mapping, QSM) require more

evaluation, but may provide improved methods for CMB assessment. Several lesions or

21

structures may mimic cerebral microbleeds and should be considered, including

calcification, normal vessels seen in cross-section, iron deposits from other causes,

haemorrhagic metastases (e.g. melanoma), and diffuse axonal injury (e.g. after head

trauma).60 CMB may be differentiated from old small deep spontaneous intracerebral

haemorrhage because, in general, the latter may be larger, irregular with a cystic cavity

(figure 1), and will be usually be visualised on T1-w, and T2-w or FLAIR imaging.

Other haemorrhagic lesions

The consensus group discussed two other haemorrhagic manifestations of SVD worthy

of mention: intracerebral haemorrhage and superficial cortical siderosis (appendix).

Intracerebral haemorrhage (ICH) may be a manifestation of SVD62 or may be secondary

to other causes such as vascular malformations. The consensus term spontaneous

ICH presumed due to SVD was suggested, as opposed to secondary ICH from other

causes or traumatic ICH. Comprehensive guidelines for the diagnosis and management

of ICH have been published previously. In the context of studying SVD, we promote

research to disentangle the contribution of different vascular diseases to ICH; in the

meantime, we recommend that lobar ICHs, which may be caused by CAA, should be

distinguished from non-lobar ICHs, which are thought generally not to be caused by

CAA and are mostly attributed to perforating arteriolar vasculopathy.63,64 A small study

suggested good, but not perfect, inter-rater agreement on the site of origin of ICH. 65 The

Boston criteria for CAA should be considered for use in assigning the likelihood of

underlying CAA in patients with lobar ICH.59

22

We propose the consensus term superficial cortical siderosis to refer to neuroimaging

evidence of chronic blood products in the superficial cortex just below the pia.

Superficial cortical siderosis may be a chronic consequence of subarachnoid bleeding or

may result from other causes of very superficial cortical bleeding, including vascular

malformations, CAA,66 spinal dural defects, or may be idiopathic.66,67 It is visible as linear

hypointensity overlying the cortex on T2* GRE or other blood-sensitive sequences. It

may be mimicked by petechial cortical haemorrhagic transformation of an infarct.

Revised research criteria for CAA incorporate the presence of superficial cortical

siderosis as another haemorrhagic manifestation of CAA, equivalent to a lobar ICH. 66

The location of the siderosis (the number of sulci involved66 and in which lobes) should

be described.

Brain Atrophy

Context: Brain atrophy can be generalized or focal (affecting only particular lobes or

specific brain regions, e.g. the hippocampus), symmetrical or asymmetrical or tissue

selective (affecting a certain tissue class, e.g. white matter) and occurs in many

conditions. The pathological changes that underlie atrophy are heterogeneous and do

not necessarily reflect neuronal loss.68-70 Brain atrophy accompanies normal ageing to a

varying extent. In the context of vascular disease and dementia, the neuropathological

substrate of atrophy includes neuronal loss,71 cortical thinning, subcortical vascular

pathology with white matter rarefaction and shrinkage, arteriolosclerosis, venous

collagenosis and secondary neurodegenerative changes.72,73 Many imaging studies have

observed an association between presence and severity of SVD and brain atrophy,

including global atrophy as well as atrophy of the corpus callosum, central atrophy (with

23

increased ventricular size and atrophy of the basal ganglia), mesencephalic atrophy,

hippocampal atrophy, and focal cortical thinning in brain regions connected to

subcortical infarcts (figure 3).74,75 Vascular lesions should therefore be considered in

studies that focus on atrophy and conversely, atrophy is an important measure in

imaging studies that assess the burden of vascular damage in the brain and mediates at

least partially the effects of vascular lesions on cognition.76-78

Terminology: A systematic review of literature on SVD and atrophy revealed use of

multiple synonymous terms including “atrophy”, “brain volume”, “volume loss” and

others. We propose the consensus term brain atrophy. We also propose that studies

should use unambiguous terms regarding whether the atrophy assessment was cross-

sectional or longitudinal, and avoid the use of terms such as “accelerated atrophy” or

“brain volume loss” in cross-sectional studies, in favour of “more atrophy” or “lower brain

volume”. When discussing atrophy, investigators should be clear regarding which brain

volumes have been measured and should consider including the brain subregion in their

description- e.g. hippocampal atrophy.

Definitions (table 2): We define ‘brain atrophy’ in the context of SVD, operationalised

through imaging, as lower brain volume, not related to a specific macroscopic focal

injury such as trauma or infarction. Tissue loss is often inferred from enlargement of

peripheral (sulcal) and central (ventricular) cerebrospinal fluid (CSF) spaces in relation

to the intracranial volume and other measures (figure 3). However, in the strict sense

such assumption would require longitudinal observation. Tissue loss resulting from

discrete focal lesions, such as cortical infarcts, is more easy to substantiate cross-

24

sectionally and should not be confused with generalised global or regional brain atrophy

likely secondary to a diffuse process.

Other vascular lesions

These consensus standards are focused on SVD. However, there are other vascular

lesions that may be seen particularly in the elderly subjects and in subjects with

cognitive impairment. They include non-SVD-related ischemic stroke, ICH from non-

SVD causes, subarachnoid haemorrhage, subdural hematoma, vascular malformations

and larger arterial ischaemic disease. These are described in detail in the online

appendix.

Advisory minimum standards for imaging of SVD

Image acquisition standards and parameters (table 3)

For both routine clinical and research uses, if there are no contraindications then MR is

preferred to CT as MR has higher sensitivity and specificity for detecting most

manifestations of SVD. Field strength of 3T may be preferred, but modern 1.5T is often

of as high definition,79 is acceptable and may be more widely available, an important

consideration for multicenter studies. Regardless, imaging sequences should be

optimized for field strength and scanner configuration. If CT is used in SVD, then a thin

section volume sequence without contrast covering the whole brain on a brain

parenchymal algorithm and axial 5 mm reconstructions should be obtained. However, in

general, CT is no longer recommended except possibly in large scale epidemiological

studies or where MR imaging is not available or too expensive.

25

For MR imaging, the minimum acceptable MR examination should include axial DWI

(and ADC map), FLAIR, T2-w, GRE/T2*-w or SWI, and T1-w images. The DWI

sequence is vital for identifying recent infarcts, e.g. in symptomatic patients. MRI with

DWI should be considered the reference standard for recent SSI, although it may be

negative in some cases.16 Clinical syndrome plus MR without DWI, or clinical syndrome

plus CT, is suboptimal, and clinical syndrome alone is least reliable.80 Acquiring one of

these sequences (T1-w usually) in the coronal or sagittal plane instead of axial facilitates

visualisation of the true lesion dimensions (appendix). Slice thickness should be 5 mm

or less, ideally with no gap; in-plane resolution should be 1 mm by 1 mm or better.

Whole-brain coverage is recommended for all sequences for optimum image analysis. A

3D T1-w thin section isotropic sequence is now commonly available, quick and can be

reformatted on thicker slices for ease of viewing in multiple planes: this sequence also

allows anatomical co-registration and quantification of brain volume. 3D MT T1-w

sequence protocols for the major scanner types at 1.5 and 3T have been validated in

the Alzheimer’s Disease Neuroimaging Initiative (ADNI); sequence protocols are freely

available on the web (www.adni-info.org).

A comprehensive SVD-intensive research MR protocol should consider acquiring the

MR data at higher resolution than the sequences specified above, using volume

acquisitions to allow for volumetric whole brain imaging with near- isotropic resolution.

These 3D acquisitions are now possible on most scanners for T1-w, T2-w, T2* GRE,

SWI and/or FLAIR techniques. Alternative high resolution sequences sensitive to

paramagnetic content such as SWI and equivalents should be considered, although

these also generate more artefacts. Diffusion tensor imaging (DTI) extends DWI and

26

should be used in research protocols. DTI is useful for assessing surrogates of

microarchitectual integrity of normal-appearing and lesional white matter, to determine

structural connectivity of white matter and in tractography. For quantitative volumetric

assessments of atrophy, a high resolution (1 to 1.5 mm isotropic voxels) T1w sequence

with good gray-white matter differentiation is advised. Other MR measurements show

great promise for SVD in research applications including measurements of perfusion,

magnetisation transfer, blood-brain barrier permeability, vascular reactivity, metabolites,

and microatheroma in perforating arterioles (see Future Directions).

Image analysis standards (table 4; appendix)

For all lesion types, qualitative (visual rating) and quantitative (computational analysis)

methods are established or emerging. For at least some lesion types, these two

approaches are highly correlated;81,82 both have advantages and disadvantages that

should be considered in the design of any SVD study. Full details of image processing

are given in the appendix.

For all lesion types, observers should be trained in brain imaging interpretation and

specifically how to recognize SVD lesions. If possible, particularly in trials or large

observational studies, images should be rated centrally by a single or small number of

experienced raters. If more than one rater is used, inter-rater reliability should be

assessed. To measure global and regional atrophy, observers should have good

knowledge of normal neuroanatomy. Observers should train on established training sets

and should aim for high observer agreement before undertaking actual measurements.

27

Regular ‘recalibration’ against standard examples is useful to maintain consistency

when rating large numbers of scans or when rating scans in different sessions.

When using automated computational methods for analysis, we emphasize that the

accuracy of each subject’s output should be visually confirmed by a trained observer.

This validation step is critical for studies of SVD because many automated methods

have not been developed for SVD specifically and there is a high risk of misclassification

of SVD lesions as other lesions or tissue classes, especially when unfamiliar pulse-

sequences are used or scanners are upgraded. Known examples to avoid include

misclassification of WMH as normal gray matter, of lacunes as ventricle or WMH, or of

SSI as WMH.83 Several of these misclassifications will require manual correction.77,84

For small discrete lesions of limited number, such as rSSI, lacunes, and microbleeds,

we recommend recording the location of each lesion and the total number of lesions. At

minimum, we recommend recording the number of lesions in each of the following brain

subregions, on the right and left side: cerebral cortex (divided by lobe), corona

radiata/centrum semiovale, putamen, globus pallidus, thalamus, internal capsule,

external capsule, brainstem, and cerebellum. Detailed recommendations for analysis of

different lesion types are summarized in table 4 and in the appendix.

Reporting standards for vascular findings on neuroimaging (table 5)

Conduct and reporting of vascular findings on neuroimaging should follow standards

already established for observational, epidemiological, diagnostic test assessment or

randomised clinical trials (www.equator-network.org). In addition to these, we suggest

28

some specific points that will aid progress in and standardize future research using

imaging (table 5). We encourage future reports to use the terms and definitions for SVD-

related imaging findings proposed above. Wherever possible studies using visual rating

scales should employ established broadly used rating scales to secure comparability of

studies and facilitate meta-analyses.

Future Developments and Challenges (table 6)

Advances in imaging technologies as well as novel protocols for image acquisition and

image post-processing have improved options for imaging the various manifestations of

SVD, with the potential to better clarify their role in neurodegenerative disease and to

identify new mechanisms of disease. Examples include advances in small arterial

imaging using ultra high-field strength MRI (>3T), DTI measures of detailed structural

connectivity, magnetization transfer imaging assessment of white matter myelination,

imaging of blood-brain barrier permeability and of vascular reactivity, perfusion imaging,

imaging of retinal vessels, QSM and others. The advantages of multi-modal imaging

should be exploited for advancing understanding of pathophysiology. For example,

combining DTI and atrophy measures allows the study of the effects of vascular lesions

on distantly connected brain regions.85

Importantly, there is increasing interest in the clinical relevance of further small brain

infarct subtype, microinfarcts, which are very small ischaemic lesions found mostly in the

cortex at autopsy in older people and visible in occasional subjects on high field MRI. 86,87

Their true vascular pathological relationship to SVD is yet to be determined. Although

yet to be confirmed, it is possible that some tiny cortical DWI acute lesions are

29

microinfarcts.86 Microinfarcts appear to be highly clinically relevant, so neuroimaging

methods to measure microinfarcts or a validated close surrogate is required. Larger

cortical microinfarcts have been visualized on 7T MRI, which were sometimes visible on

conventional 3T MRI as well.88

Comprehensive studies are now required that account for both vascular and

neurodegenerative pathologies in patients followed over longer time periods from

younger ages. These studies should include (amongst others) multimodal MRI, amyloid

imaging with positron emission tomography (PET), detailed clinical testing, and

biomarkers from serum and CSF to allow disentangling of the crosstalk between

vascular and neurodegenerative pathologies and how these interact to cause clinical

symptoms in particular cognitive decline, gait impairment, physical disability and

depression. There is considerable need for more imaging-pathology correlation.30,52

Additionally, carefully conducted imaging studies with repeat short-term (e.g. monthly)

follow-up are required to study the progression of SVD-related imaging features and

their impact on brain tissue loss.

Conclusions

These neuroimaging standards for SVD are intended to harmonize current disparate

terminology and analysis methods. We encourage other researchers to adopt these

standards. They may serve as a useful introduction to the principles of SVD

neuroimaging, that may assist investigators seeking to incorporate measurement of SVD

into their own studies focused on neurodegenerative diseases or, even more broadly,

the pathological basis of ageing. These standards should facilitate across-study

30

comparisons of findings, accelerating translation of new findings into practice.

Additionally, standardised approaches could enable formal between-study meta-

analyses, which are increasingly required to obtain the sample sizes needed for some

types of research such as genetic association studies. We suggest that our reporting

standards may prove a useful guide to authors, peer reviewers and editors, and may

elevate the methodological quality of neuroimaging studies of SVD just as analogous

reporting standards (e.g. the CONSORT guidelines) have elevated the quality of other

types of research. Finally, although the primary purpose of our standards was for

research we hope that these standards will positively influence clinical diagnosis and the

reporting of SVD lesions in routine clinical practice.

These standards were developed based on consensus among a relatively large group of

experts using rigorous methods. However, we acknowledge that in some aspects of this

rapidly evolving field, our recommendations are based on small studies, unvalidated

findings or expert opinion without a strong body of supporting evidence. It is clear that

future work is essential to validate these standards. In particular, the dearth of

radiological-pathological correlation studies is a key limitation to our understanding of

the neuroimaging of SVD. Additionally, it was recognized that best standards for SVD

neuroimaging will change over time and therefore periodic revision of these standards

will be required.

31

The Centres of Excellence in Neurodegeneration Vascular Imaging Standards

Work Group membership:

Coordinators: J. Wardlaw, M. Dichgans, E. Smith

External advisors: P. Gorelick (Chair), C. Chen, B. Norrving, M. van Buchem, C. Smith.

Recent small subcortical infarcts: JM. Wardlaw (chair), R. van Oostenbrugge, V.

Hachinski, B. Stephan, V. Mok, L. Pantoni, F Doubal.

Lacunes of presumed vascular origin: R. Lindley (chair), H. Chabriat, M. Breteler, C.

Brayne, V. Mok, O. Benavente

WMH of presumed vascular origin: C. Cordonnier (chair), SE. Black, C. De Carli, FE. de

Leeuw, F. Fazekas, J. O’Brien, L. Pantoni

PVS: F. Fazekas (chair), V. Hachinski, A. Viswanathan, GJ. Biessels, R. van

Oostenbrugge, F Barkhof.

Cerebral microbleeds: JT. O’Brien (chair), D. Werring, M. Breteler, C.Cordonnier, R.

Lindley, R. Frayne,

Brain atrophy: GJ. Biessels (chair), N. Fox, I Kilimann, S. Greenberg, S. Teipel, SE.

Black, F. Barkof,

Image acquisition and analysis: R. Frayne, O. Speck, SE Black, M Duering, JM Wardlaw

Clinical relevance: O. Benavente, L. Pantoni

Other lesions: E. Smith (chair), D. Werring, A. Viswanathan

Future directions: M. Dichgans, M Duering,

We are grateful to M. Henderson, K. Shuler, L Thomas, I Wittko-Schneider, and Anna

Charlton for administrative support.

32

Author Contributions

All authors contributed through attendance at the two workshops, participation in specific

workgroups as listed, drafting and editing of the manuscript and approval for final

submission. JM Wardlaw, M. Dichgans, E. Smith co-ordinated the overall process,

obtained funding, organized the two workshops, co-ordinated the manuscript

preparation and finalized the manuscript for submission. External advisers were: P.

Gorelick, C. Chen, B Norrving, M van Buchem, C Smith, who attended the second

workshop, read the draft standards in detail, provided in depth critique, and approved

the final manuscript for submission. E Smith, F Doubal, M Dichgans, JM Wardlaw, A

Viswanathan, JT O’Brien, SE Black, RI Lindley performed literature searches.

Workgroup participants were: Recent small subcortical infarcts (JM. Wardlaw (chair), R.

van Oostenbrugge, V. Hachinski, B. Stephan, V. Mok, L. Pantoni, F Doubal), Lacunes of

presumed vascular origin (R. Lindley (chair), H. Chabriat, M. Breteler, C. Brayne, V.

Mok, O. Benavente), WMH of presumed vascular origin (C. Cordonnier (Chair), SE.

Black, C. De Carli, FE. de Leeuw, F. Fazekas, J.T. O’Brien, L. Pantoni), PVS (F.

Fazekas (Chair), V. Hachinski, A. Viswanathan, GJ. Biessels, R. van Oostenbrugge, F

Barkhof) Cerebral microbleeds (JT. O’Brien (chair), D. Werring, M. Breteler,

C.Cordonnier, R. Lindley, R. Frayne), Brain atrophy (GJ. Biessels (chair), N. Fox, I

Kilimann, S. Greenberg, S. Teipel, SE. Black, F. Barkof), Image acquisition and

analysis: R. Frayne, O. Speck, SE Black, M Duering, JM Wardlaw), Clinical relevance

(O. Benavente, L. Pantoni), Other lesions (E. Smith (chair), D. Werring, A.

Viswanathan), Future directions (M. Dichgans, M Duering).

33

Conflicts of Interest

GJB consults for and receives research support from Boehringer Ingelheim. FF serves

on scientific advisory boards for Bayer-Schering, Biogen Idec, Genzyme, Merck Serono,

Pfizer, Novartis and Teva Pharmaceutical Industries Ltd. and as scientific advisor for

Perceptive Informatics; serves on the editorial boards of Cerebrovascular Diseases,

Multiple Sclerosis, the Polish Journal of Neurology and Neurosurgery, Stroke, and the

Swiss Archives of Neurology and Psychiatry; and has received speaker honoraria and

support from Biogen Idec, Bayer Schering, Merck Serono, Novartis, Sanofi-Aventis and

Teva Pharmaceutical Industries Ltd. He declares no specific conflict of interest with

submitted mansucript. RF receives related operating research funding from the CIHR,

the Alberta/Pfizer Translational Research Program , the Hotchkiss Brain Institute, and

the University of Calgary to support work in imaging small vessel disease. JTO has been

a consultant for GE Healthcare, Lilly, Bayer Healthcare and TauRx and has received

honoraria for talks from Pfizer, GE Healthcare, Eisai, Shire, Lundbeck, Lilly and

Novartis. SEB has had a financial relationship in the last two years in the form of:

Contract research funds to the Cognitive Neurology Research and Stroke Research

Units: Pfizer (Wyeth Research), GlaxoSmithKline, Lundbeck, Roche and Novartis. She

has received Speaker’s honoraria for CME: Pfizer, Eisai and Novartis and honoraria for

ad hoc consulting: Pfizer, Novartis, GlaxoSmithKline, Roche, Elan and Bristol Myers

Squibb. She holds no stocks or bonds. HC has received honoraria related to

consultancy for Servier, Lundbeck and Janssen Research and development. FEdL is

supported by a VIDI grant from ZonMW, The Netherlands Organisation for Health

34

Research and Development (grantnumber 016.126.351). LP is a member of the Editorial

boards of: Acta Neurologica Scandinavica, International Journal of Alzheimer Disease,

and Cerebrovascular Diseases and editor of the Vascular Cognitive Impairment section

of Stroke. ST served as a Member of the Advisory Board for Lilly Deutschland GmbH.

MD is a consultant for Bayer Vital GmbH; Boehringer Ingelheim Pharma GmbH & Co.

KG; Biologische Heilmittel Heel GmbH; Bristol-Myers Squibb GmbH & Co. KGaA; Ever

Neuro Pharma GmbH. He has received honoraria from Bayer Vital GmbH; Boehringer

Ingelheim Pharma GmbH & Co. KG; Biologische Heilmittel Heel GmbH; Bristol-Myers

Squibb GmbH & Co. KGaA; Lundbeck GmbH; Sanofi-Aventis Deutschland GmbH;

Shire Deutschland GmbH; Deutsches Zentrum für Neurodegenerative Erkrankungen

e.V. (DZNE); Georg Thieme Verlag KG, UpToDate, W. Kohlhammer GmbH. He has

received Principal Investigator/Research Funding (industry) from Bayer Vital GmbH;

Eisai Medical Research Inc.; Eisai Ltd.; Essex Pharma GmbH; Ferrer Internacional,

S.A.; ICON Clinical Research GmbH. All other authors declare that they have no

conflicts of interest.

35

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52

53

Table 1: Terms used previously to describe white matter hyperintensities of presumed vascular origin

Term Variants of use of termUse of term

in titles and abstractsTotal No.* %

leukoaraiosis ischemic leukoaraiosis, subcortical leukoaraiosis 350 31

white matter lesionsMRI white matter lesions (WML), cerebral WML, T2 WML/WMLs, cerebrovascular WML, subcortical WML, WML of Binswanger's disease, cerebral WML of Binswanger's disease, confluent WML, intracranial WML

275 24

white matter hyperintensity cerebral WMH, age-related WMH, brain WMH, MRI WMH 217 19

white matter changes age-related cerebral white matter changes (WMC); age-related WMC, cerebral WMC, changes in white matter, age-related changes in WM 136 12

leukoencephalopathy subcortical ischemic leukoencephalopathy 76 7

white matter disease age-related white matter disease (WMD), cerebral WMD, subcortical WMD 45 4

white matter damage age-related WMD, 5 0ischemic/ ischaemic white matter disease

ischemic subcortical WMD, chronic ischemic cerebral WMD, subcortical ischemic WMD 4 0

other terms (N=9) 17 1Data were derived from structured literature search; for methodology see Supplemental material*Number of instances term was mentioned at least once in the abstract or in the title. The total number of instances was N=1144

54

Table 2: Glossary of proposed terms and definitions for neuroimaging features of SVD

Proposed term Definition

Recent small subcortical infarct neuroimaging evidence of infarction in the territory of a single perforating arteriole with imaging features or correlating clinical symptoms consistent with a lesion occurring in the last few weeks

Lacuneof presumed vascular origin

round or ovoid, subcortical, fluid filled (similar signal to CSF) cavity between 3 mm and 15 mm in diameter, compatible with a previous acute small small subcortical infarct or haemorrhage in the territory of a single perforating arteriole

White matter hyperintensityof presumed vascular origin

signal abnormality of variable size in the white matter showing the following characteristics: hyperintense on T2-weighted images like FLAIR without cavitation (signal different from CSF). Lesions in the subcortical gray matter or brain stem are not included into this category unless explicitly stated – where deep grey matter and brainstem hyperintensities are included as well, the collective name should be “subcortical hyperintensities”

Perivascular spacefluid filled space, which follows the typical course of a vessel penetrating / traversing the brain through gray or white matter; has signal intensity similar to CSF on all sequences; has a round or ovoid shape with a diameter commonly not exceeding 2 mm when imaged perpendicular to the course of the vessel

Cerebral microbleed small (usually 2 mm – 5 mm or sometimes 10 mm in size) areas of signal void with associated “blooming” on T2* or other MR sequences sensitive to susceptibility effects

Brain atrophy brain volume loss, not related to a specific macroscopic focal injury such as trauma or infarction . Thus, the latter is not included in this measure unless explicitly stated

55

Table 3: Proposed image acquisition standards for neuroimaging features of SVD

Sequence Purpose* OrientationTarget slice

thickness/ in-plane resolution

Comment

Minimum essential sequences, e.g. for clinical or large scale epidemiological studies, generally available on most MR scannersT1-weighted important for discriminating lacunes from dilated

PVS; for discriminating gray from white matter and for studying brain atrophy

2D axial, sagittal, or

coronal

3-5 mm/1 mm x 1 mm

at least one sequence acquired in sagittal or coronal plane is helpful in visualizing full extent and orientation of lesions

Diffusion-weighted imaging (DWI)

most sensitive sequences for acute ischaemic lesions; positive up to several weeks after event 2D axial

3-5 mm/2 mm x 2 mm

reduced signal on apparent diffusion co-efficient map helps identifying recent from old lesions

T2-weighted Brain structure; differentiate lacunes from WMH and PVS; identify old infarcts 2D axial

3-5mm/1 mm x 1 mm

Fluid Attenuated Inversion Recovery (FLAIR)

identify WMH and established cortical or large subcortical infarcts; differentiate WML from PVS and lacunes

2D axial3-5 mm/

1 mm x 1 mm

T2*-weighted gradient echo recalled (T2*-w GRE)

detect haemorrhage, cerebral microbleeds, siderosis; measurement of intracranial volume

2D axial3-5 mm/

1 mm x 1 mm

only reliable routine sequence for detection of haemorrhage

Other commonly available routine sequences, generally available on most MR scannersProton Density-weighted

detect WMH, infarcts, perivascular spaces(with T2w dual echo),other pathologies 2D axial

3-5 mm/2 mm x 2 mm

now largely replaced by FLAIR

Magnetic resonance angiography (MRA)

ICA, vertebral, basilar or MCA/ACA/PCA stenosis or other pathology post contrast or

3D time of flight for intracranial

3D, axial, coronal, sagittal

reconstruction; 1 mm isotropic voxels

only large vessels visible at 1.5 or 3T; see below for perforating arterioles.

Sequences often available on commercial clinical MR scanners; used more for research studies at present but some techniques have rapidly emerging use in clinical protocolsDiffusion tensor imaging (DTI) with 6 gradient direction diffusion encoding

diagnose recent infarct; allows measurement of mean diffusivity and fractional anisotropy 2D axial

3-5 mm2 mm x 2 mm

more detailed characterisation than DWI; acquisition time doubled

Susceptibility-weighted imaging (SWI) or equivalent

very sensitive to haemosiderin, measurement of intracranial volume

2D or 3D axial

2D: 3-5 mm/2 mm x 2 mm

3D: 1 mm isotropic voxels

visualises more CMBs than T2* GRE imaging and more sensitive to artifacts including motion.

56

Research only sequences (i.e. require research expertise)Isotropic volumetric T2-w

display fine detail of PVS3D axial 1 mm isotropic

voxels

allows post-acquisition reformatting, potentially could replace 2D T2-w imaging if signal-to-noise is judged adequate.

Isotropic volumetric 3D T1-w (eg using MP-RAGE)

Improved volumetric brain measurements – global and regional 3D axial 1 mm isotropic

voxels

allows post-acquisition reformatting, potentially could replace 2D T1-w imaging if signal-to-noise is judged adequate

Isotropic volumetric FLAIR

identification of WMH; cortical or subcortical infarcts 3D axial 1 mm isotropic

voxels

allows post-acquisition reformatting, potentially could replace 2D FLAIR imaging if signal-to-noise is judged adequate; more homogeneous CSF suppression

Advanced DTI with >6 direction diffusion encoding (e.g. 32 or more diffusion encoding directions)

provides refined/superior quantitative measure of microscopic tissue changes

2D axial3-5 mm/

2 mm x 2 mm

allows for tractography, connectome, and more accurate measure of mean diffusivity and fractional anisotropy

Magnetisation Transfer Ratio (MTR)

sensitive to demyelination and axonal loss2D axial

3-5 mm/1 mm x 1 mm

requires experience in acquisition and interpretation; two measurements (with and without MT-pulse)

T1 mapping determine water content of tissueaxial

3-5 mm/2 mm x 2 mm

requires experience in acquisition and interpretation;

Permeability imaging estimate permeability of the blood-brain barrier axial; sequential pre- and post-

contrast

3-5 mm/2 mm x 2 mm

requires intravenous contrast injection; complex image processing; methods improving rapidly at present

Arterial spin labeling (ASL) perfusion imaging

measure tissue perfusion – quantitative, with assumptions

2D axial3-5 mm/

2 mm x 2 mm

complex to set up and run accurately; requires post processing; optimum processing strategies not yet confirmed; does not require contrast injection.

Perfusion imaging (dynamic contrast enhancement, DCE, or dynamic susceptibility contrast, DSC)

provides semi-quantitative measures of blood perfusion in tissue perfusion

2D axial3-5 mm/

2 mm x 2 mm

requires intravenous injection of contrast agent and post processing; optimum acquisition and/or processing not yet confirmed for T1 (dynamic contrast enhancement, DCE) or T2* (dynamic susceptibility contrast, DSC) approaches

functional MRI (fMRI) measure brain function in response to task or stimulus or at rest of default mode networks 2D axial

3-5 mm/2 mm x 2 mm

complex set up, acquisition and processing

57

Quantitative susceptibility mapping (QSM)

provides quantitation of susceptibility changes independent of scanner or acquisition parameters

2D or 3D axial 2D: 3 mm – 5 mm/2 mm x 2 mm

or3D: 1 mm isotropic

voxels

uses an SWI-like acquisition but requires very complex post-processing methodology required; post processing strategies currently under investigation

Micro-atheroma- / arteriolar imaging

for visualizing perforating arteriolar anatomy and atheroma

uncertain, emerging method

uncertain, emerging method

promising experimental approach that requires >3 T scanner

*Note that MR at 3 Tesla (T) is preferred to 1.5T; although these standards are listed as minimum essential through to research only applications, these categories are not absolute, the purposes are variable, and will vary with investigator interest, expertise and available technology. 2D: two-dimensional, 3D: three-dimensional; ACA = anterior cerebral artery, CMB = cerebral microbleeds, ICA = internal carotid artery, MCA = middle cerebral artery, MP-RAGE = magnetization-prepared rapid acquisition with gradient echo, PCA = posterior cerebral artery, PVS = perivascular spaces, WMH = white matter hyperintensities.

58

Table 4: Proposed analysis standards for neuroimaging features of SVD

Measures of interest Qualitative Quantitative Study design Accuracy, reliability,feasibility

Generalcomment

Recent small subcortical infarctsnumber (multiplicity may indicate causes other than SVD)89,90

size (max. diameter)

volume

location (anatomical region; vascular territory)

shape (round, ovoid, tubular)

swelling (indicates recent not old)

various coding schemes available for location:

anatomical: e.g. centrum semiovale, corona radiata, basal ganglia, thalamus, internal capsule, external capsule, optic radiation, cerebellum, brain stem

vascular territory: e.g. middle cerebral artery, posterior cerebral artery, internal carotid artery, basilar artery

possible but impractical for size and volume

cross-sectional and longitudinal: recent small subcortical infarcts are typically detected in the setting of an acute clinical event but may also be an incidental finding

easy to identify on DWI, reliability depends on time between infarct occurrence and imaging

more difficult on other sequences or on CT without longitudinal data

mimics include acute inflammatory MS plaques

acute lesions usually have increased signal on DWI and reduced signal on apparent diffusion coefficient images

Lacune of presumed vascular originnumber (single or multiple)

size (max. diameter)

shape (round, ovoid, tubular, other)

location (anatomical region)

evidence of previous hemorrhage

ex vacuo effect

various coding schemes available for shape and for location:

anatomical: e.g. lentiform nucleus, thalamus, internal capsule, centrum semiovale, brain stem

prominent ex-vacuo effect indicates lesion was originally larger (e.g. striatocapsular infarct)20

protocols for quantitative measurements available, require manual correction

cross-sectional and longitudinal: particular care is required to differentiate lacunes from PVS

longitudinal:difference imaging helps identifying incident lacunes

differentiation from PVS may be difficult

aim for high observer agreement before undertaking actual ratings

hypointense rim on T2* suggests previous small deep haemorrhage

White matter hyperintensitiesvolume

location (anatomical region) number

various coding schemes available for location:

anatomical: e.g. perivascular, deep, subcortical, brain stem;

or centrum semiovale, corona radiata, internal capsule, external capsule, optic radiation, brain stem;

or frontal, temporal, parietal, occipital

various visual rating scores91-96 and protocols for quantitative measurements84,97-100 available, the two approaches are complementary81,82

outputs should be visually reviewed by an experienced rater for mimics, artifacts, focal infarcts and

cross-sectional and longitudinal: consider masking recent small subcortical lesions, lacunes, and PVS when measuring WMH volume to avoid inflating WMH volumes

longitudinal:difference imaging may help identifying new white matter lesions

inter and Intra-rater reliability for both qualitative and quantitative analysis of WMH quite high if performed by trained raters, with ICCs generally above 0.90

visual rating scores may have ceiling or floor effects, so performance may differ with more or less disease

careful visual checking at all stages of computational analysis required to avoid problems from excess lesion distortion by e g bias field correction

consider regular ‘recalibration’ against standard examples when rating large numbers of scans

59

Measures of interest Qualitative Quantitative Study design Accuracy, reliability,feasibility

Generalcomment

mislabelingPerivascular spacesnumber (multiplicity)

location (anatomical region)

size (max. diameter)

shape (see text)

anatomical: midbrain, hippocampus, basal ganglia, centrum semiovale

visual scores rate number of lesions in basal ganglia, centrum semiovale, midbrain etc.42,45,46

various threshold-based methods are in development

cross-sectional: consider masking PVS when measuring WMH volume, although this may be difficult

longitudinal:little experience

difficult to determine, especially when numerous and in the presence of WMH

can be difficult to distinguish from lacunes

giant PVS may reach size >2cm, most commonly located below putamen

Cerebral microbleedsnumber (few or multiple)

location (lobar, deep, or infratentorial; anatomical region)

size

semi-automated approaches, which segment cerebral microbleeds as an extra tissue class or radial symmetry and mask out areas of mineralization are being described101,102 but are experimental at the present time and require validation

several visual scores available60,60,103,103,104,104

currently, there are no methods for automated detection

cross-sectional and longitudinal: consider using visual scores

longitudinal:no specific scores for longitudinal studies

there is some variability in inter-rater agreement on presence/absence of one or two microbleeds, but reasonable agreement (i.e. 0.8) between the numbers of microbleeds, reliability can be improved through the use of standardized scales60,103,104

lobar and deep cerebral microbleeds may have different risk factors and causes (e.g. lobar cerebral microbleeds are associated with cerebral amyloid angiopathy)

Brain atrophywhole brain (should be adjusted for intracranial volume, ICV)

regional (hippocampus, specific gyri, lobes. should be adjusted for whole brain volume)

cortical or subcortical

superficial or deep (sulcal or ventricular enlargement; ditto adjustment)

If scans are not suited for volumetric techniques or if such techniques are not available, qualitative rating scales may provide an alternative105,106

(semi-) automated quantitative methods preferred but visual checking and manual editing is commonly needed to avoid including the orbits and excluding the brain stem from the whole brain volume68,84,107

(sub-)regional brain volume computational methods are in development but their reliability, especially in diseased populations, has yet to be determined77,77,108,108

cross-sectional: brain atrophy can be estimated by comparison with the inner skull volume (an estimate of maximum brain size in youth); all intracranial contents must be included in the ICV measure including veins and meninges which expand to take up space left by a shrinking brain75

longitudinal:Serial brain volumes can be measured; a registration-based approach is currently preferred although the field is rapidly advancing109

computational approaches have high reliability

visual rating is more varied but can be improved with reference to a standard visual template106

subcortical and cortical vascular lesions affect the reliability of automated volumetric techniques,78 particularly in subjects with a high lesion load

consider masking recent small subcortical lesions, lacunes, and PVS when measuring brain volume.77,108 Specific standards are emerging for hippocampal volume measurement110

60

Table 5: Proposed reporting standards for neuroimaging features of SVD

Aspect Studies should report on:

Study sample

- demographic details of the research subjects and reference population from which they were drawn

- proportions with vascular risk factors and how measured

- stroke and its subtype(s) as well as other vascular disease

- timing of imaging and clinical assessments in relation to disease presentation (if relevant)

- any clinical or imaging follow-up with time intervals

- for studies on cognition or specific physical functions: details of test versions used, who administered them, their training

- for cognitive studies: assessment of premorbid cognitive ability and of depression

Image acquisition

- scanner characteristics (type and manufacturer, field strength, coils, high order shim and use of shimming routines, quality assurance (QA) protocol for scanner and frequency of QA assessment), high order shim and use of shimming routines, quality assurance (QA) protocol for scanner and frequency of QA assessment)

- use of multiple scanners

- change of scanners or change to a scanner system during study

- MRI sequences, acquisition parameters ( including as appropriate: repetition time, echo time, inversion time, echo train length), acquisition and reconstruction matrices, field-of-view), slice thickness including gaps and scanning plane, details of selected options (tailored excitation pulses, parallel imaging, flow compensation, preparation pulses, etc.), total acquisition time. If a work in progress package is used, as much information as possible should be provided

Image analysis / postprocessing

- use and qualification of a central analysis facility, or training procedure across multiple analysis centres

- whether analyses were done blinded to initial presentation or other data (specify) that might bias interpretation

- details of qualitative visual rating and quantitative computational methods including web-address if available for download, or appendix describing the method in detail

- for visual rating scales: whether images were rated centrally by a single or small number of readers; the raters’ background (e.g. neurology, psychiatry, neuroradiology, radiology) and experience; rater reliability (intra and inter-rater)

- for studies using computational image analysis programs: training of the analyst(s), any expert supervision and the background of the expert; repeatability

- statistical methods used in data analysis

- ideally: sample size estimation

61

SVD-specific aspects

- for recent small subcortical infarcts (rSSI): specify whether infarcts are symptomatic or not, location, size, shape, and number; the delay from stroke to imaging, and the proportion with visible acute lesion on DWI and/or FLAIR/T2

- for lacunes of presumed vascular origin: location, size, shape and number; distinguish haemorrhagic lesions from lacunes; for volumetric methods state whether lacunes are counted as part of the CSF volume, as part of the WMH volume or as separate ‘lacune volume’

- for white matter hyperintensities (WMH) of presumed vascular origin: specify if grey matter and brain stem hyperintensities are included (and if so refer to all hyperintensities collectively as ‘; rating scale or volume measurement software used, observer reliability; whether the WMH volume was adjusted for intracranial or brain volume and how this was done; whether lacunes were included into WMH or measured separately, and whether acute lesions were masked

- for perivascular spaces: separate between PVS of the basal ganglia and white matter; describe how qualitative aspects considered (number, location,size etc.) are defined; observer reliability of the rating scale

- for cerebral microbleeds: number and distribution as divided into lobar, deep and infratentorial (brain stem and cerebellum); full details of image acquisition parameters; standardized rating scales applied

- for atrophy: rating scale or method of volume measurement and whether corrected for intracranial volume and if so how

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Table 6: Future Challenges in imaging SVD-related changes

Aspect Questions to be addressed:

Recent small subcortical infarcts (rSSI)

- how can different aetiological subtypes (e.g. embolic, parent or branch artery atheroma, intrinsic SVD), be better differentiated by neuroimaging?

- what proportion of infarcts cavitate, become WMH, or subsequently disappear on conventional MR scans and what are the factors determining conversion in one or the other direction.

Lacunes of presumed vascular origin

- how can the methods for distinguishing lacunes from PVS be improved?

- how do secondary degenerative changes in the vicinity of lacunes influence their size and shape over longer time periods?

- how important is the presence of a hyperintense rim for differentiating lacunes from other small cystic structures, e.g. PVS?

White matter hyperintensities (WMH) of presumed vascular origin

- to what extent do perivascular and deep WMH differ in terms of mechanisms and clinical consequences? to address this clear definitions and standardized protocols for distinguishing perivascular from deep WMH are needed

- how can newer imaging techniques such as measurements of T1 water content aid in better characterizing WMH and determining their impact on connected brain regions (e.g. cortex) and clinical symptoms?

- Is there pathological or epidemiological justification for distinguishing between hyperintensities in grey matter and those in white matter?

Perivascular spaces (PVS)

- what are the mechanisms underlying (multiple) PVS?- what is the relationship between PVS diameter, risk factors and potential clinical consequences? Can a PVS diameter be

identified such that PVS of greater diameter can be considered to be pathologically enlarged?- how do PVS relate to SVD-related vascular and parenchymal lesions?

- how do PVS relate to brain atrophy and neurodegenerative pathology?

- how can the protocols for detecting and quantifying PVS be improved?

- what are the clinical consequences of PVS?

- what is the clinical utility of rating PVSCerebral Microbleeds (CMB)

- how do different neurodegenerative or vascular pathologies influence the pathology, spatial distribution and imaging appearance of microbleeds?how reliable, sensitive or specific is the distribution of CMB to amyloid angiopathy or hypertension?

- what is their predictive value with respect to cognitive and functional decline?

- what is their clinical utility with respect to guiding treatment decisions (e.g. use of thrombolysis and antithrombotic therapy)?- how do different protocols for imaging and quantifying microbleeds compare and how can findings obtained through

different protocols be integrated into a common read-out?

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Brain atrophy

- to what extent do SVD-related vascular lesions affect measures of brain atrophy (cortical, subcortical, gray versus white matter?)

- to what extent does brain atrophy (cortical, subcortical, gray and white matter) impact on volumetric measures of vascular lesions?

- what are the mechanisms underlying secondary brain atrophy mediated by vascular lesions?

- what are the clinical consequences of secondary brain atrophy mediated by vascular lesions?

Other vascular lesions

Microinfarcts

- what is their frequency in neurodegenerative disease?

- what are their clinical consequences?

- what are the imaging signatures of acute microinfarcts on clinical scanning at 1.5 and 3.0 Tesla?

Superficial siderosis

- what is the frequency in Alzheimer’s disease?

- how frequently does acute sulcal subarachnoid hemorrhage lead to siderosis?

- to what extent do these lesions affect cortical neuronal function?- what are their clinical consequences, including the frequency of subsequent symptomatic subarachnoid or intracerebral

hemorrhage?

General

- how can direct imaging of small intracerebral arteries be improved?- how can subtle changes of vascular origin be differentiated from changes mediated by other pathologies e.g.

neurodegeneration and what are the exact histopathological substrates?- to what extent do SVD-related lesions cause secondary neurodegeneration and what are the underlying mechanisms?- how do vascular lesions interact with neurodegenerative pathology in causing cognitive decline and other clinical

manifestations, in particular, physical disability, gait disturbance, and depression?- is there any suitable imaging scale that allows integrating multiple SVD-related imaging findings and what is the utility of this

scale for research and for clinical practice (e.g. for risk prediction and treatment stratification)?- how can imaging of vascular manifestations be used to improve the selection of patients included into future clinical trials

and in measuring their outcome?- how can the protocols for measuring BBB integrity be improved and how do SVD-related and neurodegenerative pathology

interact in influencing BBB integrity?

- what is the relationship between alterations in cerebral blood flow and volume with ischemic brain pathology?

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Figure 1: Variable fates of SVD-related lesions and convergence of aetiologically different acute lesions to result in similar late appearances on MRI: arrows indicate possible late fates of acute MR imaging findings; black arrows indicate common fates of recent small subcortical infarcts; solid grey arrows indicate less common and grey dashed arrows indicate least common late fates, according to best available current knowledge.

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Figure 2: Characteristics of SVD-related MR imaging findings: illustrative examples (upper panel) and schematic representation (middle panel) of MR features of different SVD-related changes on typical scans are shown together with a summary of imaging characteristics (lower panel) for individual lesions; = increased signal; = decreased signal; = isointense signal

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Figure 3: Secondary brain atrophy in a 55 year old patient with documented SVD. The follow-up scan (T1-weighted image) shows marked sulcal widening (white arrowheads) particularly in occipital brain regions as well as ventricular enlargement (black arrowheads) in the absence of new infarctions during follow-up. The FLAIR image (left panel) shows marked WMH.

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