Total Magnetic Resonance Imaging Burden of Small Vessel Disease in Cerebral Amyloid Angiopathy: An Imaging-Pathologic Study of Concept Validation | Radiology | JAMA Neurology | JAMA Network
[Skip to Navigation]
Sign In
Figure 1.  Cerebral Amyloid Angiopathy Total Small Vessel Disease Score: Magnetic Resonance Imaging (MRI) Signatures, Categories, and Points
Cerebral Amyloid Angiopathy Total Small Vessel Disease Score: Magnetic Resonance Imaging (MRI) Signatures, Categories, and Points

CMBs indicates cerebral microbleeds; CSF, cerebrospinal fluid; CSO-PVSs, centrum semiovale perivascular spaces; cSS, cortical superficial siderosis; SWI, susceptibility-weighted imaging; T2*-GRE, T2*-weighted gradient-recalled echo; and WMHs, white matter hyperintensities.

Figure 2.  Total Magnetic Resonance Imaging (MRI) Small Vessel Disease Score Distribution for All Patients With Cerebral Amyloid Angiopathy (CAA) and Separately for Patients Presenting With and Without Intracerebral Hemorrhage (ICH)
Total Magnetic Resonance Imaging (MRI) Small Vessel Disease Score Distribution for All Patients With Cerebral Amyloid Angiopathy (CAA) and Separately for Patients Presenting With and Without Intracerebral Hemorrhage (ICH)

P = .02 for Mann-Whitney test of CAA with ICH vs CAA without ICH.

Table 1.  Clinical, Imaging, and Genetic Characteristics of the CAA Study Cohorta
Clinical, Imaging, and Genetic Characteristics of the CAA Study Cohorta
Table 2.  Multivariable Ordinal Logistic Regression Model for the Presence of Vasculopathic Changes and CAA Presentation With ICH
Multivariable Ordinal Logistic Regression Model  for the Presence of Vasculopathic Changes and CAA Presentation With ICH
Table 3.  Univariable and Multivariable Ordinal Regression Analyses of the Association Between Total Magnetic Resonance Imaging Small Vessel Disease Score and DWI Lesions and WMHs
Univariable and Multivariable Ordinal Regression Analyses of the Association Between Total Magnetic Resonance Imaging Small Vessel Disease Score and DWI Lesions and WMHs
1.
Charidimou  A, Gang  Q, Werring  DJ.  Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum.  J Neurol Neurosurg Psychiatry. 2012;83(2):124-137.PubMedGoogle ScholarCrossref
2.
Viswanathan  A, Greenberg  SM.  Cerebral amyloid angiopathy in the elderly.  Ann Neurol. 2011;70(6):871-880.PubMedGoogle ScholarCrossref
3.
Vinters  HV.  Cerebral amyloid angiopathy: a critical review.  Stroke. 1987;18(2):311-324.PubMedGoogle ScholarCrossref
4.
Mandybur  TI.  Cerebral amyloid angiopathy: the vascular pathology and complications.  J Neuropathol Exp Neurol. 1986;45(1):79-90.PubMedGoogle ScholarCrossref
5.
Arvanitakis  Z, Leurgans  SE, Wang  Z, Wilson  RS, Bennett  DA, Schneider  JA.  Cerebral amyloid angiopathy pathology and cognitive domains in older persons.  Ann Neurol. 2011;69(2):320-327.PubMedGoogle ScholarCrossref
6.
Reijmer  YD, van Veluw  SJ, Greenberg  SM.  Ischemic brain injury in cerebral amyloid angiopathy.  J Cereb Blood Flow Metab. 2016;36(1):40-54.PubMedGoogle Scholar
7.
Dierksen  GA, Skehan  ME, Khan  MA,  et al.  Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy.  Ann Neurol. 2010;68(4):545-548.PubMedGoogle ScholarCrossref
8.
Linn  J, Halpin  A, Demaerel  P,  et al.  Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy.  Neurology. 2010;74(17):1346-1350.PubMedGoogle ScholarCrossref
9.
Charidimou  A, Jaunmuktane  Z, Baron  JC,  et al.  White matter perivascular spaces: an MRI marker in pathology-proven cerebral amyloid angiopathy?  Neurology. 2014;82(1):57-62.PubMedGoogle ScholarCrossref
10.
Martinez-Ramirez  S, Pontes-Neto  OM, Dumas  AP,  et al.  Topography of dilated perivascular spaces in subjects from a memory clinic cohort.  Neurology. 2013;80(17):1551-1556.PubMedGoogle ScholarCrossref
11.
Greenberg  SM, Vernooij  MW, Cordonnier  C,  et al; Microbleed Study Group.  Cerebral microbleeds: a guide to detection and interpretation.  Lancet Neurol. 2009;8(2):165-174.PubMedGoogle ScholarCrossref
12.
Charidimou  A, Martinez-Ramirez  S, Shoamanesh  A,  et al.  Cerebral amyloid angiopathy with and without hemorrhage: evidence for different disease phenotypes.  Neurology. 2015;84(12):1206-1212.PubMedGoogle ScholarCrossref
13.
Greenberg  SM, Al-Shahi Salman  R, Biessels  GJ,  et al.  Outcome markers for clinical trials in cerebral amyloid angiopathy.  Lancet Neurol. 2014;13(4):419-428.PubMedGoogle ScholarCrossref
14.
Staals  J, Makin  SD, Doubal  FN, Dennis  MS, Wardlaw  JM.  Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden.  Neurology. 2014;83(14):1228-1234.PubMedGoogle ScholarCrossref
15.
Klarenbeek  P, van Oostenbrugge  RJ, Rouhl  RP, Knottnerus  IL, Staals  J.  Ambulatory blood pressure in patients with lacunar stroke: association with total MRI burden of cerebral small vessel disease.  Stroke. 2013;44(11):2995-2999.PubMedGoogle ScholarCrossref
16.
Huijts  M, Duits  A, van Oostenbrugge  RJ, Kroon  AA, de Leeuw  PW, Staals  J.  Accumulation of MRI markers of cerebral small vessel disease is associated with decreased cognitive function: a study in first-ever lacunar stroke and hypertensive patients.  Front Aging Neurosci. 2013;5:72.PubMedGoogle ScholarCrossref
17.
Staals  J, Booth  T, Morris  Z,  et al.  Total MRI load of cerebral small vessel disease and cognitive ability in older people.  Neurobiol Aging. 2015;36(10):2806-2811.PubMedGoogle ScholarCrossref
18.
Auriel  E, Gurol  ME, Ayres  A,  et al.  Characteristic distributions of intracerebral hemorrhage-associated diffusion-weighted lesions.  Neurology. 2012;79(24):2335-2341.PubMedGoogle ScholarCrossref
19.
Zhu  YC, Chabriat  H, Godin  O,  et al.  Distribution of white matter hyperintensity in cerebral hemorrhage and healthy aging.  J Neurol. 2012;259(3):530-536.PubMedGoogle ScholarCrossref
20.
Thanprasertsuk  S, Martinez-Ramirez  S, Pontes-Neto  OM,  et al.  Posterior white matter disease distribution as a predictor of amyloid angiopathy.  Neurology. 2014;83(9):794-800.PubMedGoogle ScholarCrossref
21.
Martinez-Ramirez  S, Romero  JR, Shoamanesh  A,  et al.  Diagnostic value of lobar microbleeds in individuals without intracerebral hemorrhage.  Alzheimers Dement. 2015;11(12):1480-1488.PubMedGoogle ScholarCrossref
22.
Vonsattel  JP, Myers  RH, Hedley-Whyte  ET, Ropper  AH, Bird  ED, Richardson  EP  Jr.  Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study.  Ann Neurol. 1991;30(5):637-649.PubMedGoogle ScholarCrossref
23.
Greenberg  SM, Vonsattel  JP.  Diagnosis of cerebral amyloid angiopathy: sensitivity and specificity of cortical biopsy.  Stroke. 1997;28(7):1418-1422.PubMedGoogle ScholarCrossref
24.
Wardlaw  JM, Smith  EE, Biessels  GJ,  et al; STandards for ReportIng Vascular changes on nEuroimaging (STRIVE v1).  Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration.  Lancet Neurol. 2013;12(8):822-838.PubMedGoogle ScholarCrossref
25.
Kidwell  CS, Greenberg  SM.  Red meets white: do microbleeds link hemorrhagic and ischemic cerebrovascular disease?  Neurology. 2009;73(20):1614-1615.PubMedGoogle ScholarCrossref
26.
Charidimou  A, Jäger  RH, Fox  Z,  et al.  Prevalence and mechanisms of cortical superficial siderosis in cerebral amyloid angiopathy.  Neurology. 2013;81(7):626-632.PubMedGoogle ScholarCrossref
27.
Doubal  FN, MacLullich  AM, Ferguson  KJ, Dennis  MS, Wardlaw  JM.  Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease.  Stroke. 2010;41(3):450-454.PubMedGoogle ScholarCrossref
28.
Fazekas  F, Chawluk  JB, Alavi  A, Hurtig  HI, Zimmerman  RA.  MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging.  AJR Am J Roentgenol. 1987;149(2):351-356.PubMedGoogle ScholarCrossref
29.
Kimberly  WT, Gilson  A, Rost  NS,  et al.  Silent ischemic infarcts are associated with hemorrhage burden in cerebral amyloid angiopathy.  Neurology. 2009;72(14):1230-1235.PubMedGoogle ScholarCrossref
30.
Charidimou  A, Linn  J, Vernooij  MW,  et al.  Cortical superficial siderosis: detection and clinical significance in cerebral amyloid angiopathy and related conditions.  Brain. 2015;138(pt 8):2126-2139.PubMedGoogle ScholarCrossref
31.
Knudsen  KA, Rosand  J, Karluk  D, Greenberg  SM.  Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria.  Neurology. 2001;56(4):537-539.PubMedGoogle ScholarCrossref
32.
Greenberg  SM, Eng  JA, Ning  M, Smith  EE, Rosand  J.  Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage.  Stroke. 2004;35(6):1415-1420.PubMedGoogle ScholarCrossref
33.
Charidimou  A, Peeters  AP, Jäger  R,  et al.  Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy.  Neurology. 2013;81(19):1666-1673.PubMedGoogle ScholarCrossref
34.
Charidimou  A, Hong  YT, Jäger  HR,  et al.  White matter perivascular spaces on magnetic resonance imaging: marker of cerebrovascular amyloid burden?  Stroke. 2015;46(6):1707-1709.PubMedGoogle ScholarCrossref
35.
Fazekas  F, Kleinert  R, Offenbacher  H,  et al.  Pathologic correlates of incidental MRI white matter signal hyperintensities.  Neurology. 1993;43(9):1683-1689.PubMedGoogle ScholarCrossref
36.
von Elm  E, Altman  DG, Egger  M, Pocock  SJ, Gøtzsche  PC, Vandenbroucke  JP; STROBE Initiative.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.  Lancet. 2007;370(9596):1453-1457.PubMedGoogle ScholarCrossref
37.
Deramecourt  V, Slade  JY, Oakley  AE,  et al.  Staging and natural history of cerebrovascular pathology in dementia.  Neurology. 2012;78(14):1043-1050.PubMedGoogle ScholarCrossref
38.
Smallwood  A, Oulhaj  A, Joachim  C,  et al.  Cerebral subcortical small vessel disease and its relation to cognition in elderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort.  Neuropathol Appl Neurobiol. 2012;38(4):337-343.PubMedGoogle ScholarCrossref
39.
Charidimou  A, Meegahage  R, Fox  Z,  et al.  Enlarged perivascular spaces as a marker of underlying arteriopathy in intracerebral haemorrhage: a multicentre MRI cohort study.  J Neurol Neurosurg Psychiatry. 2013;84(6):624-629.PubMedGoogle ScholarCrossref
40.
van Veluw  SJ, Biessels  GJ, Bouvy  WH,  et al.  Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces.  J Cereb Blood Flow Metab (Nihongoban). 2016;36(3):576-580.PubMedGoogle Scholar
41.
Gurol  ME, Viswanathan  A, Gidicsin  C,  et al.  Cerebral amyloid angiopathy burden associated with leukoaraiosis: a positron emission tomography/magnetic resonance imaging study.  Ann Neurol. 2013;73(4):529-536.PubMedGoogle ScholarCrossref
42.
van Veluw  SJ, Biessels  GJ, Klijn  CJ, Rozemuller  AJ.  Heterogeneous histopathology of cortical microbleeds in cerebral amyloid angiopathy.  Neurology. 2016;86(9):867-871.PubMedGoogle ScholarCrossref
43.
Fisher  M.  Cerebral microbleeds: where are we now?  Neurology. 2014;83(15):1304-1305.PubMedGoogle ScholarCrossref
44.
Charidimou  A, Pantoni  L, Love  S.  The concept of sporadic cerebral small vessel disease: A road map on key definitions and current concepts.  Int J Stroke. 2016;11(1):6-18.PubMedGoogle ScholarCrossref
45.
Batool  S, O’Donnell  M, Sharma  M,  et al; PURE Study Investigators.  Incidental magnetic resonance diffusion-weighted imaging-positive lesions are rare in neurologically asymptomatic community-dwelling adults.  Stroke. 2014;45(7):2115-2117.PubMedGoogle ScholarCrossref
46.
Biffi  A, Halpin  A, Towfighi  A,  et al.  Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy.  Neurology. 2010;75(8):693-698.PubMedGoogle ScholarCrossref
47.
Jickling  GC, Chen  C.  Rating total cerebral small-vessel disease: does it add up?  Neurology. 2014;83(14):1224-1225.PubMedGoogle ScholarCrossref
Original Investigation
August 2016

Total Magnetic Resonance Imaging Burden of Small Vessel Disease in Cerebral Amyloid Angiopathy: An Imaging-Pathologic Study of Concept Validation

Author Affiliations
  • 1Hemorrhagic Stroke Research Program, Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston
  • 2C. S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 3Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 4Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston
JAMA Neurol. 2016;73(8):994-1001. doi:10.1001/jamaneurol.2016.0832
Abstract

Importance  Cerebral amyloid angiopathy (CAA) is characteristically associated with magnetic resonance imaging (MRI) biomarkers of small vessel brain injury, including strictly lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. Although these neuroimaging markers reflect distinct pathophysiologic aspects in CAA, no studies to date have combined these structural imaging features to gauge total brain small vessel disease burden in CAA.

Objectives  To investigate whether a composite score can be developed to capture the total brain MRI burden of small vessel disease in CAA and to explore whether this score contributes independent and complementary information about CAA severity, defined as intracerebral hemorrhage during life or bleeding-related neuropathologic changes.

Design, Setting, and Participants  This retrospective, cross-sectional study examined a single-center neuropathologic CAA cohort of eligible patients from the Massachusetts General Hospital from January 1, 1997, through December 31, 2012. Data analysis was performed from January 2, 2015, to January 9, 2016. Patients with pathologic evidence of CAA (ie, any presence of CAA from routinely collected brain biopsy specimen, biopsy specimen at hematoma evacuation, or autopsy) and available brain MRI sequences of adequate quality, including T2-weighted, T2*-weighted gradient-recalled echo, and/or susceptibility-weighted imaging and fluid-attenuated inversion recovery sequences, were considered for the study.

Main Outcomes and Measures  Brain MRIs were rated for lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. All 4 MRI lesions were incorporated into a prespecified ordinal total small vessel disease score, ranging from 0 to 6 points. Associations with severity of CAA-associated vasculopathic changes (fibrinoid necrosis and concentric splitting of the wall), clinical presentation, number of intracerebral hemorrhages, and other imaging markers not included in the score were explored using logistic and ordinal regression.

Results  In total, 105 patients with pathologically defined CAA were included: 52 with autopsies, 22 with brain biopsy specimens, and 31 with pathologic samples from hematoma evacuations. The mean (range) age of the patients was 73 (71-74) years, and 55 (52.4%) were women. In multivariable ordinal regression analysis, severity of CAA-associated vasculopathic changes (odds ratio, 2.40; 95% CI, 1.06-5.45; P = .04) and CAA presentation with symptomatic intracerebral hemorrhage (odds ratio, 2.23; 95% CI, 1.07-4.64; P = .03) were independently associated with the total MRI small vessel disease score. The score was associated with small, acute, diffusion-weighted imaging lesions and posterior white matter hyperintensities in adjusted analyses.

Conclusions and Relevance  This study provides evidence of concept validity of a total MRI small vessel disease score in CAA. After further validation, this approach can be potentially used in prospective clinical studies.

Introduction

Sporadic cerebral amyloid angiopathy (CAA) is the most common cause of symptomatic lobar intracerebral hemorrhage (ICH) in elderly people and results from cerebrovascular amyloid-β deposition, preferentially involving cortical and leptomeningeal small vessels.1-4 Frequently, CAA is present in the brain of patients with Alzheimer disease, but it can also have an independent contribution in age-related cognitive decline.5,6

Cerebral amyloid angiopathy is characteristically associated with magnetic resonance imaging (MRI) biomarkers of small vessel brain injury, including multiple, strictly lobar cerebral microbleeds (CMBs),7 cortical superficial siderosis (cSS),8 centrum semiovale perivascular spaces (CSO-PVSs),9,10 and white matter hyperintensities (WMHs).1,11 Although these neuroimaging markers probably reflect distinct pathophysiologic aspects or steps in CAA,4,12 they are often closely related. No studies to date have combined these structural imaging features to gauge total brain small vessel disease burden in CAA. A comprehensive approach might have potential advantages over individual markers, providing a practical framework to better assess the effect of CAA-related damage on clinical outcomes.13

Recently, the approach of assessing total MRI small vessel disease burden has been developed and applied in patients at high risk for ischemic small vessel damage, including lacunar or nondisabling cortical stroke.14-16 By summing different MRI features of ischemic small vessel disease in one measure (with 1 point assigned for each of the following: lacunar infarct, CMBs, basal ganglia PVSs, and WMHs), Staals et al14 demonstrated that a higher score is independently related to lacunar stroke subtype and certain vascular risk factors (eg, age, hypertension, or smoking). In patients with lacunar stroke, this score was associated with blood pressure15 and cognition.16 Furthermore, the score was associated with lower general cognitive ability in 680 older participants.17

In this study, we prespecified and developed a total MRI small vessel disease score specifically tailored for patients with CAA based on the 4 major imaging signatures of the disease as described in a consensus report on CAA neuroimaging biomarkers. In a cohort with pathologic evidence of CAA, we investigated whether this is a valid construct by examining (1) whether the total MRI CAA score is associated with symptomatic CAA-related intraparenchymal bleeding events during life and severe CAA on neuropathologic examination and (2) the association between the total MRI CAA score and other characteristic imaging findings in CAA, including small positive lesions on diffusion-weighted imaging (DWI)18 and occipital-predominant WMHs.19,20

Box Section Ref ID

Key Points

  • Question Can a composite score be developed to capture the total brain magnetic resonance imaging (MRI) burden of small vessel disease in cerebral amyloid angiopathy (CAA)?

  • Findings In this cross-sectional study, a prespecified total MRI small vessel disease score was specifically tailored for patients with CAA based on 4 major imaging signatures of the disease. In a neuropathologically defined CAA cohort, this score was independently associated with CAA-related vasculopathic changes on pathologic and clinical presentations with symptomatic hemorrhage.

  • Meaning This study provides evidence of concept validity of a total MRI small vessel disease score in CAA, but further validation of this approach is warranted.

Methods
Case Selection and Clinical Data Collection

In this retrospective, cross-sectional study, we used data from a neuropathologically defined CAA cohort based on eligible patients from the Massachusetts General Hospital from January 1, 1997, through December 31, 2012, who were systematically identified using overlapping methods as described.12,21 Data analysis was performed from January 2, 2015, to January 9, 2016. Patients with pathologic evidence of CAA (ie, any presence of CAA from routinely collected brain biopsy specimen, biopsy specimen at hematoma evacuation, or autopsy) and available in vivo brain MRI sequences of adequate quality, including T2-weighted, T2*-weighted gradient-recalled echo, and/or susceptibility-weighted imaging and fluid-attenuated inversion recovery sequences, were considered for the study, as previously described.12,21 The clinical presentation of included patients was ascertained based on all available data and was classified as (1) symptomatic lobar ICH (confirmed on neuroimaging) or (2) presentation without ICH (including cognitive impairment, transient focal neurologic episodes, or other neurologic symptoms) at the time of the MRI.12

Standard Protocol Approvals, Registrations, and Patient Consents

The study received ethical approval by the institutional review board of Massachusetts General Hospital. All patients provided written informed consent, and all data were deidentified for statistical analysis but not for imaging analysis.

Collection of Pathologic Data

Morphologic assessment was performed in routine hematoxylin-eosin staining, and the presence or absence and severity of vascular amyloid-β deposition were confirmed by immunohistochemical detection (anti–antibody 6E10; 1:200; Signet Laboratories) and Congo red staining. Cases were considered positive for CAA when they had at least 1 leptomeningeal or cortical vessel with amyloid-β reported by an experienced neuropathologist, providing enough information to reliably classify CAA severity according to the modified Vonsattel grading system.22,23 We systematically extracted information on the presence of CAA-related vasculopathic changes, defined as vessel-within-vessel appearance (sometimes called double-barreling) and fibrinoid necrosis, corresponding to modified Vonsattel grade 3 and grade 4, respectively, and hence severe CAA.23

Neuroimaging Data and Analysis

Imaging for all patients included T2-weighted, fluid-attenuated inversion recovery, T2*-weighted gradient-recalled echo (field strength, 1.5 T; section thickness, 5 mm; section gap, 1 mm; and echo time, 24 milliseconds), and/or susceptibility-weighted imaging (field strength, 3 T; section thickness, 1.2 mm; section gap, 0 mm; and echo time, 21 milliseconds).21 Two different MRI scanners were used during the study period: a Siemens Trio at 3 T (used in 25% of the patients) and a GE Signa at 1.5 T. Review of the MRIs were masked to all clinical and histopathologic findings by trained observers, according to Standards for Reporting Vascular Changes on Neuroimaging (STRIVE).24 For patients with multiple MRIs available, the MRI closest to the neuropathologic assessment was examined.

The presence and number of CMBs were evaluated according to current consensus criteria.11 The presence and number of macro-ICHs (>5 mm in diameter)25 were also noted. Cortical superficial siderosis was defined as linear residues of blood products in the superficial layers of the cerebral cortex showing a characteristic gyriform pattern of low signal on blood-sensitive sequences as previously described.26 The distribution and severity of cSS were classified as focal (restricted to ≤3 sulci) or disseminated (≥4 sulci).8 Contiguous or potentially anatomically connected cSS with any lobar ICH was not included in the aforementioned categories.

Perivascular spaces were assessed in line with STRIVE definitions24 and rated on axial T2-weighted MRIs using a previously described, validated 4-point visual rating scale (0 indicating no PVS; 1, ≤10 PVSs; 2, 11-20 PVSs; 3, 21-40 PVSs; and 4, >40 PVSs) in the basal ganglia and CSO.9,27 Deep and periventricular WMHs were assessed according to the 4-point Fazekas rating scale.28 The WMHs in the frontal and occipital lobe were further evaluated separately on axial fluid-attenuated inversion recovery as described by Zhu et al.19 The frontal-occipital gradient (the WMH score in the frontal lobe minus that in the occipital lobe) was calculated (range, −6 to 6; >0 implies frontal dominance and <0 implies occipital dominance).19 All available DWIs were reviewed for the presence of small (generally <4 mm) hyperintensities by trained raters.29

Total MRI Burden of Small Vessel Disease in CAA

We prespecified an ordinal scale that represented the total burden of small vessel disease in CAA by incorporating the 4 most characteristic MRI markers of the disease (lobar CMBs, cSS, CSO-PVSs, and WMHs) (Figure 1). For lobar CMBs, a point was awarded if 2 to 4 CMBs were present and 2 points for 5 or more CMBs. The presence of cSS was awarded with 1 point if focal and 2 points if disseminated. The presence of CSO-PVSs was counted if there were moderate to severe (grade 3–4, ie, >20) PVSs (1 point if present). The presence of WMHs was defined as (early) confluent deep (ie, the region between juxtacortical and ventricular areas) WMHs (Fazekas score ≥2) or irregular periventricular WMHs extending into the deep white matter (Fazekas score of 3) (1 point if either present), as previously described.14 Hence, the score ranged from a minimum of 0 to a maximum of 6 points, creating an ordinal scale.

In defining these cutoffs, we took into account current evidence from cross-sectional and longitudinal studies in CAA. We aimed to distinguish the weights of hemorrhagic imaging markers of CAA (lobar CMBs, cSS) from other nonhemorrhagic markers (CSO-PVSs, WMHs), which might also occur with high frequency in other diseases. For example, multiple (≥2) strictly lobar CMBs are the most common and characteristic imaging feature of CAA and are part of the Boston criteria8,31; the presence of 5 or more CMBs is associated with recurrent lobar ICH.34 Cortical superficial siderosis, particularly disseminated, is a common hemorrhagic marker of CAA26 associated with future lobar ICH risk.33 The prespecified definition of CSO-PVS (ie, >20, grade 3) was found to be more strongly related to CAA.9,10,34 The WMH cutoffs chosen are also in line with the scores used in the suggested total MRI scale for ischemic small vessel disease14-17 based on those Fazekas scores related to small vessel disease in a histopathologic study.35

As an exploratory analysis, we tested the effect of using 2 alternative scores: (1) an expanded score that also included the presence of occipital predominant WMHs19 as another element (1 extra point; hence, a total score ranging from 0-7) and (2) a simplified version of the CAA score in line with the original MRI score suggested for ischemic small vessel disease.14-16 For this simplified score, we rated the presence (yes vs no) of each of the 4 MRI features above and assigned 1 point for each (ie, presence of any lobar CMBs, any cSS, moderate to severe CSO-PVSs, and extensive WMHs), resulting in an ordinal scale of 0 to 4.

Statistical Analysis

To investigate the construct validity of this score, our statistical approach was to use the total MRI score as the dependent variable against clinical and neuropathologic markers of CAA severity. We performed univariable ordinal logistic regression to investigate the association between the MRI small vessel disease score with clinical characteristics, presence of CAA-associated vasculopathic changes, and CAA clinical presentation with ICH. We performed multivariable ordinal logistic regression that explored the independent association between the presence of vasculopathic changes and CAA clinical presentation with the small vessel disease score (as dependent variable), controlling for age, sex, and hypertension. To further account for potential biases based on the size of the pathologic specimen (biopsy vs autopsy specimen), with full autopsy being more likely to reveal some CAA and severe CAA pathologic findings than biopsy, we adjusted for this factor in a sensitivity analysis.

Separate univariable and multivariable ordinal regression analyses were used to assess the association between the small vessel disease score and DWI lesions, occipital predominant WMH presence, and symptomatic ICH number, adjusting for age and sex and additionally for CAA-related vasculopathic changes and clinical presentation. We tested the effect of the occipital predominant WMH as an additional score element and the alternative simplified total MRI small vessel disease score using a similar approach.

Significance level was set at P < .05. We used STATA software, version 11.2 (StataCorp). In the ordinal regression models, the proportional odds assumption was checked using relevant tests (omodel command). Colinearity was tested using the variance inflation factor (<10 for all variables). The article was prepared with reference to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.35

Results

In total, 105 patients with pathologically defined CAA were included: 52 with autopsies, 22 with brain biopsy specimens, and 31 with pathologic samples from hematoma evacuations. Fifty-four patients presented with symptomatic, spontaneous lobar ICH, whereas 51 patients presented without any symptomatic ICH at baseline. Patients without ICH presented with cognitive impairment (n = 42; median Clinical Dementia Rating score, 1; interquartile range [IQR], 0.5–2), transient focal neurologic episodes (n = 3), or a combination of other symptoms (n = 6; including altered mental status or seizures consistent with inflammatory CAA). Clinical and imaging characteristics are given in Table 1. As previously reported, mild CAA (Vonsattel grade 1) and moderate to severe CAA (Vonsattel grades 2–4) were equally represented in the groups (P = .43).12 Among the 52 patients with autopsy data, 39 (75%) had evidence of arteriolosclerosis (ie, concentric hyaline thickening of small arteries) in deep (basal ganglia or deep white matter) perforating arterioles, which was moderate to severe in 31 cases.

Eighteen patients (17.3%) had none of the MRI markers of small vessel disease included in the score. Most patients (15 of 18 [83.3%]) had only mild CAA. The distribution of total small vessel disease score severity is shown in Figure 2. Patients with CAA and ICH had higher ratings of small vessel disease burden compared with those presenting without ICH (median score, 3 [IQR, 1-5] vs 2 [IQR, 1-4], respectively; P = .02). In univariable analysis, total small vessel disease score was associated with the presence of CAA-related vasculopathic changes on pathologic analysis (odds ratio [OR], 2.21; 95% CI, 1.02-4.78; P = .04) and CAA presentation with ICH (OR, 2.37; 95% CI, 1.19-4.72; P = .02) but not with age, hypertension, sex, or antithrombotic drug use. None of the different MRI markers comprising the score were individually associated with vasculopathic changes in univariable or multivariable logistic regression analyses, including all 4 markers.

In multivariable ordinal regression, the total score was associated with the presence of vasculopathic changes and CAA presentation with ICH (Table 2). The results remained consistent and of similar effect size when hypertension was not included in the model and when the size of the pathologic specimen (biopsy vs autopsy), time from MRI to pathologic analysis and whether different blood-sensitive MRI sequences were included in sensitivity analyses. There was an increasing MRI score with increasing macrobleed count on MRI (median, 1; range, 1-6) in the patient group with symptomatic ICH (coefficient, 1.77; 95% CI, 0.08-3.45; P = .04). Small acute DWI lesions and occipital predominant WMHs were associated with small vessel disease score in unadjusted ordinal regression and remained so in fully adjusted models (Table 3).

In the same multivariable regression model as above, the alternative score, including occipital predominant WMHs, was associated with CAA-related vasculopathic changes (OR, 2.64; 95% CI, 1.13-6.14; P = .02) and symptomatic ICH presentation (OR, 2.28; 95% CI, 1.09-4.79; P = .03). However, although the simplified total MRI small vessel disease score was associated with CAA presentation with ICH (OR, 2.51; 95% CI, 1.19-5.30; P = .02), there was only a trend for an association with the presence of vasculopathic changes (OR, 1.99; 95% CI, 0.88-4.48; P = .10).

Discussion

In this study, we developed an MRI small vessel disease score based on the 4 most characteristic neuroimaging signatures of sporadic CAA to compile the overall brain burden of the disease. Using a neuropathologically defined CAA cohort of patients presenting with and without ICH, we provide evidence of the construct validity of our approach. The total small vessel disease score was found to be independently associated with CAA-related vasculopathic changes on pathologic analysis (a marker of CAA-related microangiopathy severity) and clinical presentation with symptomatic lobar ICH.

Studies37,38 have suggested staging schemes based on pathologic analysis for the extent of cerebral small vessel disease in aging brains. In the Oxford Project to Investigate Memory and Ageing cohort, small vessel disease severity assessed using 1 of these pathology schemes was correlated with cognitive impairment.38 Approaches to integrate a range of imaging manifestations of small vessel disease into 1 score have been recently advocated by an international working group (STRIVE).24 Some studies14-17 have presented a first attempt to capture the total MRI burden in ischemic small vessel disease, validating this approach mainly in populations with lacunar stroke. An assessment of total small vessel disease load on MRI has several potential advantages because it avoids overreliance on any 1 individual marker of small vessel disease. Hence, a more complete evaluation of the total burden may be important to understand the effect of small vessel disease on clinical outcomes, such as disability and cognition.

In CAA, studies8,9 have found that the combination of 2 different MRI markers of the disease (lobar CMBs and cSS, lobar CMBs and high-grade CSO-PVSs) increase diagnostic sensitivity. Our score provides a practical and easily applied structural MRI visual tool to comprehensively evaluate small vessel disease in CAA using validated rating systems for each feature.24 We acknowledge that the assessment of the total MRI small vessel disease burden is complex, and different imaging features probably reflect distinct pathophysiologic mechanisms in CAA.4,12 For example, cSS likely represents blood-leaking episodes into the subarachnoid space from CAA-affected leptomeningeal vessels30 (as opposed to lobar CMBs, which may arise from CAA-laden parenchymal vessels), whereas CSO-PVSs might be related to cerebrovascular amyloid burden and drainage impairment10,39,40 and WMHs to chronic ischemia.41 The pathologic substrates of small vessel disease imaging markers are, however, heterogenenous,42,43 and direct histopathologic imaging correlation studies are notably underused in the field.44 Despite different mechanisms, these features are often related and co-occur in patients with CAA.6 We also note that the chosen cutoffs and weightings in our CAA score might not be optimal and to a certain extent are arbitrary, although we did take into account the totality of current clinical, neuroimaging, and neuropathologic evidence from cross-sectional and longitudinal studies1,9,14,31,32 in defining different weights for these markers. In support of our approach, none of the individual MRI lesions included in the score seem to be significantly driving the associations with CAA severity in isolation.

Clinically silent small areas of restricted diffusion on DWI MRI, thought to represent acute microinfarcts, are sometimes considered an additional marker of CAA.18 Their transient nature, combined with the lack of neuropathologic confirmation and their occurrence in patients with hypertensive arteriopathy and healthy individuals,45 may render it difficult to reliably use them as a specific biomarker of the disease. On the basis of these considerations, we did not include DWI lesions in the MRI small vessel disease score. We did, however, find an association between DWI lesions and total MRI score, indicating that they may be an additional marker of disease severity. Similarly, a more posterior distribution of WMHs may be an additional promising marker for CAA,19,20 potentially associated with more severe disease.46

Our study has limitations. The fact that our score was tested on a clinical pathologic series of patients with CAA, including patients with the most salient clinical manifestations of the disease, makes the current analysis powerful and informative for construct validity. However, this approach could also represent a constraint because of selection bias because only symptomatic patients with pathologic evaluation and brain MRI were included, likely representing patients at the more severe end of the disease spectrum. The differences in pathologic sampling between autopsied brains and biopsy specimens may have contributed to bias in that some patients with CAA who had negative brain biopsy results may have been excluded. Another limitation of the current study is the retrospective (which means that not all MRI sequence parameters were standardized) and cross-sectional design, which precludes any analysis on the prognostic significance of the small vessel disease scores. T1 sequences were not systematically obtained as part of the MRI protocol, precluding any assessment of lacunes and atrophy. Finally, the tacit implication of the current and previous scores is that there are only 2 major types of cerebral microvascular disease in the brain, CAA and everything else (so-called hypertensive arteriopathy, including arteriolosclerosis, lipohyalinosis, fibrinoid necrosis, and microaneurysm), which is an oversimplification.44

Conclusions

This study provides evidence of the concept validity of a total MRI small vessel disease score in CAA. Despite limitations, the suggested scale for CAA performed reasonably well in the current study and raises several questions and opportunities for further testing and development in large-scale studies. Longitudinal cohorts should investigate whether this system, with or without modifications, can be used to assess the effect of CAA on clinical outcomes in different settings, including cognitive impairment, ICH risk, and disability.13,47

Back to top
Article Information

Accepted for Publication: March 1, 2016.

Corresponding Author: Andreas Charidimou, MD, PhD, Hemorrhagic Stroke Research Program, Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, 175 Cambridge St, Ste 300, Boston, MA 02114 (andreas.charidimou.09@ucl.ac.uk).

Published Online: June 27, 2016. doi:10.1001/jamaneurol.2016.0832.

Author Contributions: Drs Charidimou and Viswanathan had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Charidimou, Greenberg, Viswanathan.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscripts: Charidimou, Viswanathan.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Charidimou.

Obtained funding: Greenberg, Viswanathan.

Administrative, technical, or material support: Charidimou, Oliveira-Filho, Lauer.

Study supervision: Rosand, Gurol, Greenberg, Viswanathan.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grants 5R01AG047975, 5P50AG005134, 5K23AG028726 (Dr Viswanathan), and R01AG26484 (Dr Greenberg) from the National Institutes of Health.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

References
1.
Charidimou  A, Gang  Q, Werring  DJ.  Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum.  J Neurol Neurosurg Psychiatry. 2012;83(2):124-137.PubMedGoogle ScholarCrossref
2.
Viswanathan  A, Greenberg  SM.  Cerebral amyloid angiopathy in the elderly.  Ann Neurol. 2011;70(6):871-880.PubMedGoogle ScholarCrossref
3.
Vinters  HV.  Cerebral amyloid angiopathy: a critical review.  Stroke. 1987;18(2):311-324.PubMedGoogle ScholarCrossref
4.
Mandybur  TI.  Cerebral amyloid angiopathy: the vascular pathology and complications.  J Neuropathol Exp Neurol. 1986;45(1):79-90.PubMedGoogle ScholarCrossref
5.
Arvanitakis  Z, Leurgans  SE, Wang  Z, Wilson  RS, Bennett  DA, Schneider  JA.  Cerebral amyloid angiopathy pathology and cognitive domains in older persons.  Ann Neurol. 2011;69(2):320-327.PubMedGoogle ScholarCrossref
6.
Reijmer  YD, van Veluw  SJ, Greenberg  SM.  Ischemic brain injury in cerebral amyloid angiopathy.  J Cereb Blood Flow Metab. 2016;36(1):40-54.PubMedGoogle Scholar
7.
Dierksen  GA, Skehan  ME, Khan  MA,  et al.  Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy.  Ann Neurol. 2010;68(4):545-548.PubMedGoogle ScholarCrossref
8.
Linn  J, Halpin  A, Demaerel  P,  et al.  Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy.  Neurology. 2010;74(17):1346-1350.PubMedGoogle ScholarCrossref
9.
Charidimou  A, Jaunmuktane  Z, Baron  JC,  et al.  White matter perivascular spaces: an MRI marker in pathology-proven cerebral amyloid angiopathy?  Neurology. 2014;82(1):57-62.PubMedGoogle ScholarCrossref
10.
Martinez-Ramirez  S, Pontes-Neto  OM, Dumas  AP,  et al.  Topography of dilated perivascular spaces in subjects from a memory clinic cohort.  Neurology. 2013;80(17):1551-1556.PubMedGoogle ScholarCrossref
11.
Greenberg  SM, Vernooij  MW, Cordonnier  C,  et al; Microbleed Study Group.  Cerebral microbleeds: a guide to detection and interpretation.  Lancet Neurol. 2009;8(2):165-174.PubMedGoogle ScholarCrossref
12.
Charidimou  A, Martinez-Ramirez  S, Shoamanesh  A,  et al.  Cerebral amyloid angiopathy with and without hemorrhage: evidence for different disease phenotypes.  Neurology. 2015;84(12):1206-1212.PubMedGoogle ScholarCrossref
13.
Greenberg  SM, Al-Shahi Salman  R, Biessels  GJ,  et al.  Outcome markers for clinical trials in cerebral amyloid angiopathy.  Lancet Neurol. 2014;13(4):419-428.PubMedGoogle ScholarCrossref
14.
Staals  J, Makin  SD, Doubal  FN, Dennis  MS, Wardlaw  JM.  Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden.  Neurology. 2014;83(14):1228-1234.PubMedGoogle ScholarCrossref
15.
Klarenbeek  P, van Oostenbrugge  RJ, Rouhl  RP, Knottnerus  IL, Staals  J.  Ambulatory blood pressure in patients with lacunar stroke: association with total MRI burden of cerebral small vessel disease.  Stroke. 2013;44(11):2995-2999.PubMedGoogle ScholarCrossref
16.
Huijts  M, Duits  A, van Oostenbrugge  RJ, Kroon  AA, de Leeuw  PW, Staals  J.  Accumulation of MRI markers of cerebral small vessel disease is associated with decreased cognitive function: a study in first-ever lacunar stroke and hypertensive patients.  Front Aging Neurosci. 2013;5:72.PubMedGoogle ScholarCrossref
17.
Staals  J, Booth  T, Morris  Z,  et al.  Total MRI load of cerebral small vessel disease and cognitive ability in older people.  Neurobiol Aging. 2015;36(10):2806-2811.PubMedGoogle ScholarCrossref
18.
Auriel  E, Gurol  ME, Ayres  A,  et al.  Characteristic distributions of intracerebral hemorrhage-associated diffusion-weighted lesions.  Neurology. 2012;79(24):2335-2341.PubMedGoogle ScholarCrossref
19.
Zhu  YC, Chabriat  H, Godin  O,  et al.  Distribution of white matter hyperintensity in cerebral hemorrhage and healthy aging.  J Neurol. 2012;259(3):530-536.PubMedGoogle ScholarCrossref
20.
Thanprasertsuk  S, Martinez-Ramirez  S, Pontes-Neto  OM,  et al.  Posterior white matter disease distribution as a predictor of amyloid angiopathy.  Neurology. 2014;83(9):794-800.PubMedGoogle ScholarCrossref
21.
Martinez-Ramirez  S, Romero  JR, Shoamanesh  A,  et al.  Diagnostic value of lobar microbleeds in individuals without intracerebral hemorrhage.  Alzheimers Dement. 2015;11(12):1480-1488.PubMedGoogle ScholarCrossref
22.
Vonsattel  JP, Myers  RH, Hedley-Whyte  ET, Ropper  AH, Bird  ED, Richardson  EP  Jr.  Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study.  Ann Neurol. 1991;30(5):637-649.PubMedGoogle ScholarCrossref
23.
Greenberg  SM, Vonsattel  JP.  Diagnosis of cerebral amyloid angiopathy: sensitivity and specificity of cortical biopsy.  Stroke. 1997;28(7):1418-1422.PubMedGoogle ScholarCrossref
24.
Wardlaw  JM, Smith  EE, Biessels  GJ,  et al; STandards for ReportIng Vascular changes on nEuroimaging (STRIVE v1).  Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration.  Lancet Neurol. 2013;12(8):822-838.PubMedGoogle ScholarCrossref
25.
Kidwell  CS, Greenberg  SM.  Red meets white: do microbleeds link hemorrhagic and ischemic cerebrovascular disease?  Neurology. 2009;73(20):1614-1615.PubMedGoogle ScholarCrossref
26.
Charidimou  A, Jäger  RH, Fox  Z,  et al.  Prevalence and mechanisms of cortical superficial siderosis in cerebral amyloid angiopathy.  Neurology. 2013;81(7):626-632.PubMedGoogle ScholarCrossref
27.
Doubal  FN, MacLullich  AM, Ferguson  KJ, Dennis  MS, Wardlaw  JM.  Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease.  Stroke. 2010;41(3):450-454.PubMedGoogle ScholarCrossref
28.
Fazekas  F, Chawluk  JB, Alavi  A, Hurtig  HI, Zimmerman  RA.  MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging.  AJR Am J Roentgenol. 1987;149(2):351-356.PubMedGoogle ScholarCrossref
29.
Kimberly  WT, Gilson  A, Rost  NS,  et al.  Silent ischemic infarcts are associated with hemorrhage burden in cerebral amyloid angiopathy.  Neurology. 2009;72(14):1230-1235.PubMedGoogle ScholarCrossref
30.
Charidimou  A, Linn  J, Vernooij  MW,  et al.  Cortical superficial siderosis: detection and clinical significance in cerebral amyloid angiopathy and related conditions.  Brain. 2015;138(pt 8):2126-2139.PubMedGoogle ScholarCrossref
31.
Knudsen  KA, Rosand  J, Karluk  D, Greenberg  SM.  Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria.  Neurology. 2001;56(4):537-539.PubMedGoogle ScholarCrossref
32.
Greenberg  SM, Eng  JA, Ning  M, Smith  EE, Rosand  J.  Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage.  Stroke. 2004;35(6):1415-1420.PubMedGoogle ScholarCrossref
33.
Charidimou  A, Peeters  AP, Jäger  R,  et al.  Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy.  Neurology. 2013;81(19):1666-1673.PubMedGoogle ScholarCrossref
34.
Charidimou  A, Hong  YT, Jäger  HR,  et al.  White matter perivascular spaces on magnetic resonance imaging: marker of cerebrovascular amyloid burden?  Stroke. 2015;46(6):1707-1709.PubMedGoogle ScholarCrossref
35.
Fazekas  F, Kleinert  R, Offenbacher  H,  et al.  Pathologic correlates of incidental MRI white matter signal hyperintensities.  Neurology. 1993;43(9):1683-1689.PubMedGoogle ScholarCrossref
36.
von Elm  E, Altman  DG, Egger  M, Pocock  SJ, Gøtzsche  PC, Vandenbroucke  JP; STROBE Initiative.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.  Lancet. 2007;370(9596):1453-1457.PubMedGoogle ScholarCrossref
37.
Deramecourt  V, Slade  JY, Oakley  AE,  et al.  Staging and natural history of cerebrovascular pathology in dementia.  Neurology. 2012;78(14):1043-1050.PubMedGoogle ScholarCrossref
38.
Smallwood  A, Oulhaj  A, Joachim  C,  et al.  Cerebral subcortical small vessel disease and its relation to cognition in elderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort.  Neuropathol Appl Neurobiol. 2012;38(4):337-343.PubMedGoogle ScholarCrossref
39.
Charidimou  A, Meegahage  R, Fox  Z,  et al.  Enlarged perivascular spaces as a marker of underlying arteriopathy in intracerebral haemorrhage: a multicentre MRI cohort study.  J Neurol Neurosurg Psychiatry. 2013;84(6):624-629.PubMedGoogle ScholarCrossref
40.
van Veluw  SJ, Biessels  GJ, Bouvy  WH,  et al.  Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces.  J Cereb Blood Flow Metab (Nihongoban). 2016;36(3):576-580.PubMedGoogle Scholar
41.
Gurol  ME, Viswanathan  A, Gidicsin  C,  et al.  Cerebral amyloid angiopathy burden associated with leukoaraiosis: a positron emission tomography/magnetic resonance imaging study.  Ann Neurol. 2013;73(4):529-536.PubMedGoogle ScholarCrossref
42.
van Veluw  SJ, Biessels  GJ, Klijn  CJ, Rozemuller  AJ.  Heterogeneous histopathology of cortical microbleeds in cerebral amyloid angiopathy.  Neurology. 2016;86(9):867-871.PubMedGoogle ScholarCrossref
43.
Fisher  M.  Cerebral microbleeds: where are we now?  Neurology. 2014;83(15):1304-1305.PubMedGoogle ScholarCrossref
44.
Charidimou  A, Pantoni  L, Love  S.  The concept of sporadic cerebral small vessel disease: A road map on key definitions and current concepts.  Int J Stroke. 2016;11(1):6-18.PubMedGoogle ScholarCrossref
45.
Batool  S, O’Donnell  M, Sharma  M,  et al; PURE Study Investigators.  Incidental magnetic resonance diffusion-weighted imaging-positive lesions are rare in neurologically asymptomatic community-dwelling adults.  Stroke. 2014;45(7):2115-2117.PubMedGoogle ScholarCrossref
46.
Biffi  A, Halpin  A, Towfighi  A,  et al.  Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy.  Neurology. 2010;75(8):693-698.PubMedGoogle ScholarCrossref
47.
Jickling  GC, Chen  C.  Rating total cerebral small-vessel disease: does it add up?  Neurology. 2014;83(14):1224-1225.PubMedGoogle ScholarCrossref
×