lesion evolution and neurodegeneration in rvcl-s · 10/6/2020 · retinal vasculopathy with...

ARTICLE OPEN ACCESS

Lesion evolution and neurodegenerationin RVCL-SA monogenic microvasculopathy

Andria L Ford MD MSCI Victoria W Chin BS Slim Fellah PhD Michael M Binkley PhD Allie M Bodin BS

Vamshi Balasetti MD Yewande Taiwo MS Peter Kang MD Doris Lin MD Joanna C Jen MD PhD

M Gilbert Grand MD Madonna Bogacki AA M Kathryn Liszewski BA Dennis Hourcade PhD

Yasheng Chen DSc Jason Hassenstab PhD Jin-Moo Lee MD PhD Hongyu An DSc

Jonathan J Miner MD PhD and John P Atkinson MD

Neurologyreg 202095e1918-e1931 doi101212WNL0000000000010659

Correspondence

Dr Ford

fordawustledu

AbstractObjectiveTo characterize lesion evolution and neurodegeneration in retinal vasculopathy with cerebralleukoencephalopathy and systemic manifestations (RVCL-S) using multimodal MRI

MethodsWe prospectively performedMRI and cognitive testing in RVCL-S and healthy control cohortsGray and white matter volume and disruption of white matter microstructure were quantifiedAsymmetric spin echo acquisition permitted voxel-wise oxygen extraction fraction (OEF)calculation as an in vivo marker of microvascular ischemia The RVCL-S cohort was included ina longitudinal analysis of lesion subtypes in which hyperintense lesions on fluid-attenuatedinversion recovery (FLAIR) T1-postgadolinium and diffusion-weighted imaging were de-lineated and quantified volumetrically

ResultsTwenty individuals with RVCL-S and 26 controls were enrolled White matter volume andmicrostructure declined faster in those with RVCLndashS compared to controls White matteratrophy in RVCL-S was highly linear (ρ = minus0908 p lt 00001) Normalized OEFwas elevated inRVCL-S and increased with disease duration Multiple cognitive domains specifically thosemeasuring working memory and processing speed were impaired in RVCL-S Lesion volumesregardless of subtype progressedregressed with high variability as a function of age whileFLAIR lesion burden increased near time to death (p lt 0001)

ConclusionRVCL-S is a monogenic microvasculopathy affecting predominantly the white matter withregard to atrophy and cognitive impairment White matter volumes in RVCL-S declinedlinearly providing a potential metric against which to test the efficacy of future therapiesProgressive elevation of white matter OEF suggests that microvascular ischemia may underlieneurodegeneration in RVCL-S

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EditorialNeuroimaging andcognitive profile inRVCL-S Possible newinsights into pathogenesis

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From the Department of Neurology (ALF VWC SF MBM AMB VB YT PK YC JH J-ML) Mallinckrodt Institute of Radiology (ALF J-ML HA) Department ofOphthalmology (MGG) and Department of Medicine (MB MKL DH JJM JPA) Division of Rheumatology Washington University School of Medicine St Louis MODepartment of Radiology (DL) The Johns Hopkins University School of Medicine Baltimore MD and Department of Neurology (JCJ) Icahn School of Medicine at Mount Sinai NewYork NY

Go to NeurologyorgN for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

The Article Processing Charge was funded by NIH

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

e1918 Copyright copy 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology

Retinal vasculopathy with cerebral leukoencephalopathy andsystemic manifestations (RVCL-S) is a familial micro-vasculopathy leading to early vision loss and progressive neu-rocognitive deterioration in the fourth to sixth decadesultimately fatal within asymp10 years of symptom onset1 The au-tosomal dominant disease is caused by a C-terminal frameshiftmutation in TREX1 (a 39ndash59 repair exonuclease 1)2 with 40families identified worldwide (MKL and JPA unpublished2018-2020) In 2016 a multicenter study defined the geneticand clinicopathologic spectra of the disease on the basis ofaggregate data in 78TREX1mutation carriers from 11 unrelatedfamilies proposing diagnostic criteria to increase recognitionand to facilitate future studies3

Despite recent progress disease mechanisms in RVCL-S remainpoorly defined The TREX1 frameshift mutations produce a trun-cated TREX1 protein that lacks its anchor to the endoplasmic re-ticulum2 A recent study described interactions between the TREX1carboxy-terminal region and oligosaccharide transferase at the en-doplasmic reticulum (organelle that promotes normal N-linked gly-cosylation)4 Experiments with knock-in mice and human cell linesdemonstrated that expression of the truncated TREX1 protein dys-regulated the oligosaccharide transferase complex resulting in freeglycan release immune activation and autoantibody production45

Alternatively the relatively small nuclear proportion of the truncatedTREX1 protein which harbors a functional 39 DNase is increasedafter apoptotic or genotoxic stress6 thus genome stability may becompromised by unregulated activity of the misplaced DNase in itsuntethered state Despite these potential disease mechanisms it isunclear why the microvasculature is most markedly affected inRVCL-S Immunohistochemistry studies in postmortem brain tissuefrom patients with RVCL-S and patients with stroke without RVCL-S demonstrated thatTREX1 localizes predominantly towhitematterIba1+ microglia in association with the microvasculature near ische-mic lesions suggesting a role for TREX1 in response to ischemia7

Due to the rarity of RVCL-S it has been challenging to evaluatetherapeutic efficacy when only a few patients can be tested andwithout a contemporaneous placebo arm From the aggregate dataabove3 cognitive and psychological impairments have been definedas present or absent by history and examination MRI findingsdemonstrated (1) smallmedium T2 hyperintense white matterlesions in all but 1 patient (97) noting that some were associatedwith diffusion restriction or postcontrast enhancement and (2) ring-enhancing pseudotumor lesions in 84 which are frequently ob-served with advanced disease and may cause life-threatening mass

effect due to vasogenic edema Imaging studies in RVCL-S havebeen limited to small case series without controls8ndash12 including arecent study of pseudotumor lesions in 6 patients that quantified theduration of diffusion restriction and ring enhancement across serialMRI scans11

Defining pathogenesis in RVCL-S has been challenged by theinability of animal models to recapitulate the human disease phe-notype5 Brain MRI findings give some insight into mechanismspunctate diffusion-restricting lesions support a role for microvas-cular ischemia while nodular and ring-enhancing lesions suggestdisruption of the blood-brain barrier In support of ischemia brainpathology in RVCL-S demonstrates a microvasculopathy associ-ated with multilaminated basement membranes mural thickeningand hyalinization luminal stenosis and fibrinoid necrosis whichcan resemble radiation necrosis13 Chronic inflammatory cells maybe seen near the microvasculature or rarely in the parenchyma313

In postmortem brain tissue of patients with RVCL-S TREX1 isreadily detectable within microglia surrounding the white mattermicrovasculature suggesting that TREX1mislocalizationmay playa role in white matter vulnerability7 While immune serologies arenormal in patients mouse models of RVCL-S induced a non-nuclear autoimmunity that was suppressed by a chemotherapeuticagent suggesting that immune activation may contribute to path-ogenesis or progression45

In this study we evaluated the temporal-spatial dynamics ofneuroimaging features and cognitive performance from a pro-spective cohort of patients with RVCL-S compared to healthycontrols We sought to characterize neurodegeneration and lesionevolution to enable testing of future treatments against this naturalhistory to quantify domain-specific cognitive impairment and toapply advanced MRI methods to reveal pathogenic mechanismshypothesizing that decreased cerebral blood flow (CBF) and in-creased oxygen extraction fraction (OEF) in RVCL-S wouldsupport the role of chronic microvascular ischemia

MethodsStandard protocol approvals registrationsand patient consentsThe studies were approved by the institutional review board

Study participantsThe studies included a prospective cohort with a standardimaging protocol and an older prospective cohort without

GlossaryCADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CBF = cerebralblood flow cSVD = cerebral small vessel diseaseDSST = Digit Symbol Substitution TestDWI = diffusion-weighted imagingFA = fractional anisotropy FCSRT = Free and Cued Selective Reminding Test FLAIR = fluid-attenuated inversion recoveryMD = mean diffusivity MoCA = Montreal Cognitive Assessment NAWM = normal-appearing white matter nCBF = CBFnormalized to gray matter nOEF = OEF normalized to gray matter OEF = oxygen extraction fraction RVCL-S = retinalvasculopathy with cerebral leukoencephalopathy and systemic manifestations

NeurologyorgN Neurology | Volume 95 Number 14 | October 6 2020 e1919

standard imaging (figure 1 shows enrollment overview) Forthe recent cohort with standard imaging we enrolled adultswith genetically confirmed RVCL-S and age-matched con-trols Exclusion criteria included contraindications to MRIand pregnancy Controls were also excluded for history ofneurologic or chronic illness While controls had a single MRIscan individuals with RVCL-S had 1 to 5 MRI scans duringthe study period typically at 6- to 12-month intervals Vitalsigns and laboratory samples history of medications and in-terim illness were obtained with each scan Image analyses tomeasure atrophy white matter microstructure and metrics ofblood flow and oxygen metabolism were performed only onscans acquired with the standard imaging protocol describedbelow The older cohort without standard imaging includedindividuals with RVCL-S who had been followed up at theWashington University RVCL Research Center (rvcl-re-searchwustledu) over the past 2 decades in whom MRIswere obtained as part of standard clinical care Longitudinalanalyses evaluating lesion subtypes over time included all MRIscans in patients with RVCL-S (those performed with andwithout standard imaging)

Common disease features in patients with RVCL-S wereassessed by review of the patientrsquos medical record and werepresent if documented by the treating physician at the Wash-ington University RVCL Research Center Common neuro-radiologic features were present if described in the radiologyreport Systemic features of RVCL-S were defined as (1) liverdisease if alanine transaminase aspartate transaminase or al-kaline phosphatase was elevated beyond the laboratory refer-ence range (2) anemia if hemoglobin fell below the laboratoryreference range (3) nephropathy if serum creatinine or urineprotein was elevated (4) hypertension if the patient requireddaily antihypertensive medications (5) hypothyroidism if thepatient required thyroid replacement and (6) Reynaud phe-nomenon if listed as a chart diagnosis

Cognitive and psychological assessmentOn the same day as the MRI scan cognitive assessment wasperformed in participants undergoing the standard MRIprotocol Tests were selected on the basis of demonstratedreliability and sensitivity to decline in neurodegenerativediseases and included the Montreal Cognitive Assessment(MoCA) a global cognitive screening measure sensitive toexecutive impairment14 the Wechsler Adult IntelligenceScalendashRevised Digit Symbol Substitution Test (DSST)1516

for working memory and processing speed categoryfluency17ndash19 (animal and vegetable naming) and the Bushckeand Grober Free and Cued Selective Reminding Test(FCSRT)2021 for semantic and episodic memory re-spectively and Gait Speed22 a measure of global cognitiveand motor processing Levels of depression and anxiety wereassessed with the Geriatric Depression Scale23 and the State-Trait Anxiety Inventory24 respectively

Image protocol and processing

MRI acquisition segmentation and coregistrationFor the standard imaging protocol controls and participantswith RVCL-S underwent brain MRI on a Siemens 3T TimTrio or 3T Biograph mMR scanner (Erlangen Germany)with a 12-channel head coil Standard 3D magnetization-prepared rapid gradient-echo T1 (echo timerepetition time2951800 milliseconds inversion time 1000 millisecondsflip angle 8deg 10 times 10 times 10 mm) fluid-attenuated inversionrecovery (FLAIR) (echo timerepetition time 939000 mil-liseconds inversion time 2500 milliseconds 10 times 09 times3 mm) Magnetization-prepared rapid gradient-echo imageswere segmented into gray and white matter with StatisticalParametric Mapping version 1225 Using FMRIB SoftwareLibrary (FSL Oxford University Oxford UK) we segmentedsubcortical nuclei with the FMRIB Integrated Registrationand Segmentation Tool26 and coregistered images obtained

Figure 1 Participant enrollment scheme

Participants with retinal vasculopathy with cere-bral leukoencephalopathy and systemic mani-festations (RVCL-S) and healthy controls wereprospectively enrolled with a standard imagingprotocol These participants had advanced MRIanalyses to evaluate atrophy white matter mi-crostructure and metrics of tissue ischemia(CBF OEF) This RVCL-S cohort was enlarged toinclude patients with scans dating farther back(without standard imaging) who had been fol-lowed over many years Given that these scansdid not have a standard imaging protocol onlythe lesion segmentation analysis was performedin the larger cohort FA = fractional anisotropyMD = mean diffusivity

e1920 Neurology | Volume 95 Number 14 | October 6 2020 NeurologyorgN

within a scan session with the FMRIB Linear Image Regis-tration Tool2728 with accuracy confirmed by visual in-spection Segmented brain volumes were normalized to totalintracranial volume to adjust for head size defined as the sumof gray matter white matter and CSF volumes29

Diffusion tensor imagingDiffusion tensor imaging was acquired as follows echo timerepetition time 8910100 milliseconds and isotropic 20 times 20 times20 mm Twenty-five directions were acquired b = 0 smm2 andb = 1400 smm2 (field of view 224 mm) Diffusion tensor para-metric maps including fractional anisotropy (FA) and mean dif-fusivity (MD) were calculated with the FSL diffusion toolbox(Oxford University)30 Individual mean FA and MD were mea-sured in normal-appearing white matter (NAWM) after exclusionof voxels within the manually delineated FLAIR lesion mask (de-scribed below) such that only nonlesioned tissue was included

CBF and OEF image acquisition and processingWe used a pseudocontinuous arterial spin labeling sequence(echo timerepetition time 123780 milliseconds 30 times 30 times50 mm 22 slices number of averages 80 labeling duration 2000milliseconds postlabel delay 1500 milliseconds) to measureCBF31 Blood T1 for CBF calculation was measured in the su-perior sagittal sinus of each participant as previously described3233

An asymmetric spin echo sequence measured tissue deoxy-hemoglobin permitting OEF quantification3435 CBF and OEFwere calculated as previously described36 Individual mean CBFandOEFwithin graymatter and whitematter were calculated Tolimit partial volume effects voxels with lt07 probability of beingclassified correctly as gray or white matter after T1 segmentationwere removed and a 1-voxel morphologic erosion between tissuetypes was applied To account for participant-related systemiceffects onwhole-brainCBF andOEF such as anemia or age whitematter CBF andOEFwere normalized to graymatter (nCBF andnOEF respectively)

Lesion subtype segmentationFive lesion subtypes were evaluated for hyperintensity (1) allFLAIR lesions (2) FLAIR lesions excluding pseudotumors (3)FLAIR lesions including only pseudotumors (4) all T1 post-gadolinium lesions and (5) all diffusion-weighted imaging (DWI)lesions Hyperintense lesions weremanually outlined by a vascularneurology fellow and board-certified neurologist (VB) andmedical student (VWC) and then reviewed and edited by aboard-certified vascular neurologist (ALF) using Medical ImageProcessing Analysis and Visualization software (mipavcitnihgov) Pseudotumors were defined as a central T1 ring-enhancinglesion located near the lateral ventricles that was associated withsurrounding vasogenic edema on FLAIR While FLAIR lesionswere separated into 2 lesion subtypes based on being a pseudo-tumor or not (to separate out the effect of vasogenic edema onlesion volume) T1 postgadolinium lesions also referred to asnodular contrast-enhancing lesions were all included as a singlelesion group because the volumes between the ring-enhancingcentral lesion of a pseudotumor and other enhancing lesionsthroughout the white matter do not differ significantly

Statistical analysisStatistical analyses were performed with SAS version 94 (SASInstitute Inc Cary NC) Data are described with median(interquartile range) A Wilcoxon rank-sum test comparedRVCL-S and control cohorts for several neuroimaging out-comes gray matter volume white matter volume FA MDnCBF and nOEF For all imaging analyses except lesionsubtype analysis (described below) in which patients con-tributed multiple scan time points the median imaging valueand the corresponding median age from the scan time pointswere used Raw p values were reported with significance notedafter adjustment with the Benjamini-Hochberg procedure tomaintain a family-wise error rate lt005 To evaluate the in-dependent effects of age disease and their interaction onneuroimaging outcomes linear regression was performedWhen criteria for normality were not met data underwentnatural logarithmic transformation and multivariate normal-ity was retested The interaction term was included if signif-icant at p lt 005 otherwise the interaction termwas removed

For cognitive and psychological analyses a Wilcoxon rank-sum test compared the RVCL-S and control cohorts Age attesting and years of education were compared For partici-pants with RVCL-S with multiple cognitive assessments(performed before eachMRI scan) the most recent test resultwas used Because underlying depression and anxiety mayaffect cognitive performance37ndash39 we evaluated whetherRVCL-S predicted cognitive performance after adjusting forthe Geriatric Depression Scale and State-Trait Anxiety In-ventory scores Two linear regression models one adjustingfor depression and one adjusting for anxiety as predictors ofeach cognitive domain were performed separately (maximum2 covariates per model) to avoid model overfitting

Only the participants with RVCL-S with at least 3 scan timepoints over at least 30 months were included for the lesionsubtype analysis Of these 7 patients 5 had known age atdeath and 2 were still alive with age at death imputed as themedian value from all patients with RVCL-S who had diedRepeated patient data were included as a random effect in allmodels For models not meeting normality assumptions dataunderwent transformation before regression with the naturallogarithmic function or nonlinear fits as needed Across allstudy analyses results were presented only if valid withoutcollinearity and with normal residuals

Data availabilityData are available on request to the corresponding author

ResultsCohort characteristicsFor the prospective study with the standard MRI protocol 14individuals with RVCL-S and 26 age-matched healthy con-trols were enrolled An additional 6 patients with RVCL-S didnot have any standard imaging and this larger cohort (n = 20)


Table 1 Participant characteristics

Prospective cohort with standard imagingprotocol

Prospective cohort with andwithout standard imaging

Healthy controls(n = 26)

Patients with RVCL-S(n = 14)

Patients withRVCL-S (n = 20)

Age at baseline scan ya 50 (38 54) 48 (37 54) 46 (40 54)

Age at last scan y mdash mdash 50 (42 55)

Age at death y mdash 59 (59 59) 56 (53 60)

Female sex n () 18 (69) 9 (64) 14 (70)

White n ()b 16 (62) 14 (100) 20 (100)

No of scansb 10 (10 10) 20 (10 28) 2 (10 42)

Duration between baseline and last scan y mdash 14 (10 19) 31 (26 57)

Common disease features n ()c

Retinopathy (retinal examination not performed in one) 9 (69) 15 (79)

Focal neurologic deficitsd 5 (36) 10 (50)

Cognitive impairment 7 (50) 13 (65)

Psychiatric disturbance 9 (64) 15 (75)

Seizures 1 (7) 3 (15)

Migraine headache 7 (50) 12 (60)

Common neuroradiologic features n ()e

All FLAIR lesions 11 (79) 17 (85)

Punctate white matter lesions on FLAIR 11 (79) 17 (85)

Pseudotumor ring-enhancing lesions with vasogenic edema on FLAIR 4 (29) 10 (50)

Contrast-enhancing lesions 11 (79) 17 (85)

DWI lesions 8 (57) 14 (70)

Other systemic manifestations n ()f

Liver disease 511 (45) 916 (56)

Anemia 414 (29) 719 (37)

Nephropathy 614 (43) 1019 (53)

Hypertension requiring medications 714 (50) 1020 (50)

Hypothyroidism requiring medication 414 (29) 419 (21)

Raynaud phenomenon 314 (21) 320 (15)

Abbreviations DWI = diffusion-weighted imaging FLAIR = fluid-attenuated inversion recovery RVCL-S = retinal vasculopathy with cerebral leukoencephal-opathy and systemic manifestationsData are shown as median (25th 75th percentile) as appropriatea For controls there was a single scan thus only baseline scan age is reported For patients with RVCL-S with standard imaging there could be single ormultiple scans and themedian imaging values were used Thus themedian age across scan time points is reported as the age at baseline scan For the largerRVCL-S cohort with and without standard imaging that was used for the longitudinal lesion analysis individual scan data were used so both the age atbaseline and age at last scans are reportedb There were no significant differences between patients with RVCL-S and healthy controls except for more Whites (p = 0002) and a larger number of MRIscans in the RVCL-S group (p lt 0001)c Common disease features were present if documented within the medical record by the treating physician at the Washington University RVCL ResearchCenterd Focal neurologic deficits included any report of language visual-spatial motor sensory cranial nerve coordination balance or gait deficits in the chart Theexception was that any vision deficits were not included in this category but were included only in the retinopathy categorye Common neuroradiologic features were present if described in the radiology report or identified on image review by a board-certified vascular neurologist(ALF)f Other systemicmanifestationswere present as follows liver disease if alanine transaminase aspartate transaminase or alkaline phosphatasewas elevatedbeyond the laboratory reference range anemia if either hemoglobin or hematocrit was low nephropathy if either serum creatinine or urine protein waselevated hypertension if the patient required daily home antihypertensive medications hypothyroidism if the patient was taking thyroid replacementmedication and Raynaud phenomenon if listed as a clinical diagnosis Smaller denominators are due to unavailability of laboratory values in someparticipants


was used for the longitudinal lesion analysis Baseline char-acteristics for the study cohorts are shown in table 1 Indi-viduals from 6 unrelated families with RVCL-S wererepresented with 18 of 20 individuals carrying the mostcommonTREX1mutation V235fs while 2 individuals carriedthe T250Nfs mutation3 There were no differences in age orsex between the controls and participants with RVCL-Showever there was a greater percentage ofWhites (p = 0002)and more MRI scans performed (p lt 0001) in the RVCL-Scohort

White matter volume and microstructuredecline faster in RVCL-SWhile atrophy in RVCL-S has been noted qualitatively onbrain imaging tissue-type atrophy and disruption in whitematter microstructure have not previously been quantified inRVCL-S Because lesions occur most commonly yet not ex-clusively in white matter we hypothesized that white matterwould demonstrate greater atrophy in RVCL-S even afteraccounting for lesion volume and that rate of decline would begreater than that in age-matched controls White matter vol-umes normalized to intracranial volume were reduced inpatients with RVCL-S compared to controls (0281 vs 0316respectively p lt 00001) whereas normalized gray mattervolumes did not differ between the 2 cohorts (0466 in pa-tients vs 0480 in controls p = 0340) (figure 2 A and B)Because tissue segmentation techniques are based on T1imaging and may misclassify lesioned tissue within whitematter as gray matter we compared white matter volumesbetween patients with RVCL-S and controls after adding the

lesion volume for each participantrsquos scan to the white mattervolume to account for this potential misclassification (patientexample of misclassification is shown in figure S1 data avail-able from Dryad dryadorg105061dryadstqjq2c0j) Thiswas performed in participants with RVCL-S and controlsalike although the control participants were free of riskfactors and were not elderly and therefore had very smalllesion burden (median white matter lesion volume 00[00ndash005] cm3) After doing so we continued to find re-duced normalized white matter volumes in participants withRVCL-S compared to controls (0283 vs 0316 respectivelyp lt 00001)

We next evaluated the relationship of tissue-type atrophy as afunction of age and disease status The rate of decline in whitematter volume was faster in participants with RVCL-S com-pared to controls (p = 00002 for the interaction of age andRVCL-S status) while rate of gray matter atrophy did notdiffer between the 2 cohorts (figure 2 C and D and table 2)Furthermore the decline in normalized white matter volumein the RVCL-S cohort (n = 14) was highly linear (Spearmanρ = minus0908 p lt 00001) compared to controls (ρ = minus0051 p =0806) In figure 3 3 patient examples with sequential imagesspanning 5 to 10 years demonstrate cerebral atrophy quali-tatively however by visual inspection it is unclear whetheratrophy affects gray matter white matter or both For these 3patients quantitative white matter volumes decreased overtime (relative decrease 235ndash296 from baseline) com-pared to gray matter (relative decrease minus44 to 64 frombaseline)

Figure 2 White matter but not gray matter atrophy is accelerated in RVCL-S

(A) Normalized gray matter (GM) vol-umes did not differ between healthycontrols (CTLs) and individuals withretinal vasculopathy with cerebralleukoencephalopathy and systemicmanifestations (RVCL-S) (B) Normal-ized white matter (WM) volumes weresignificantly lower in those with RVCL-S compared to CTLs (p lt 00001) (C)Rate of GM atrophy did not differ be-tween CTLs and individuals with RVCL-S (D) Rate ofWMatrophy was faster inindividuals with RVCL-S compared toCTLs (p = 00002 for interaction of ageand RVCL-S status)


Next we evaluated the decrease in FA and increase in MD withage as metrics of disrupted white matter microstructure and thathave been found to precede the development of white matterhyperintensities in sporadic cerebral small vessel disease(cSVD)4041 We measured the effect of RVCL-S disease statuson FA andMD inNAWMafter adjusting for age The reductionin FA (p = 00060) and increase in MD (p = 00011) were fasterin participants with RVCL-S compared to controls (p valuesgiven for interaction of age and disease status) (table 2)

White matter OEF is elevated in RVCL-S andincreases with disease durationWhile the mechanisms underlying retinal and neuro-degeneration in RVCL-S are unclear pathologic findings con-sistently demonstrate a small vessel vasculopathy associatedwith multilaminated basement membranes mural thickeningand hyalinization luminal stenosis and fibrinoid necrosis313

To investigate in vivo signs of small vessel ischemia in RVCL-Swe measured voxel-wise CBF and OEF We hypothesized that

white matter CBF may be decreased while OEF would beincreased in patients with RVCL-S compared to healthy con-trols Representative CBF and OEF maps in a patient withRVCL-S are shown in figure 4A While nCBF in NAWM didnot differ between the 2 cohorts nOEF in NAWM was higherin patients with RVCL-S compared to controls (p = 0009figure 4B) We further evaluated whether nCBF decreased andnOEF increased over time suggestive of progressive whitematter ischemia with disease duration The interaction of ageand RVCL-S status predicted increasing OEF in NAWM (p =00103) while the interaction did not predict change in CBF(figure 4 C and D and table 2) The progressive elevation inwhite matter OEF with disease duration may indicate chronicsmall vessel ischemia as an underlying disease mechanism

Cognitive and psychological assessmentin RVCL-SWhile individuals with RVCL-S may develop lacunarstroke with acute focal neurologic deficits more

Table 2 Whitematter atrophy disruption of white matter microstructure and white matter OEF are increased in RVCL-S

Dependent variable Predictor β Coefficient (standard error) p Value Log-transformeda Normala

Atrophy

nGM volume RVCL-S status minus0002 (0012) 08385 No Yes

Age minus00023 (0000) lt00001

nWM volume RVCL-S status minus0213 (0081) 00126 Yes Yes

Age minus0006 (0001) 00001

Interaction 0007 (0002) 00002

WM microstructure (DTI metrics)

FA_NAWM RVCL-S status minus00095 (0030) 00036 No Yes

Age minus0001 (0000) 00138

Interactionb 0002 (0001) 00060

MD_NAWM RVCL-S status 0153 (0042) 00009 No Yes

Age 0002 (0001) 00228

Interactionb minus0003 (0001) 00011

CBF

nCBF_NAWM RVCL-S status 00009 (0024) 0707 No Yes

Age 0002 (0001) 0041

OEF

nOEF_NAWM RVCL-S status 0078 (0038) 00468 Yes Yes

Age 0003 (0001) 00003


Abbreviations CBF = cerebral blood flow DTI = diffusion tensor imaging FA = fractional anisotropy MD =mean diffusivity NAWM = normal-appearing whitematter nCBF = normalized CBF nGM = normalized gray matter nOEF = normalized OEF nWM = normalized WM OEF = oxygen extraction fraction RVCL-S =retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations WM = white matterLinear regression evaluated age RVCL-S disease status and their interaction as predictors of brain volume WM microstructure CBF and OEFa Data transformation was performed when normality assumptions were not met After transformation normality assumptions were retestedb Interaction term was included as the product of age and RVCL-S status If the interaction term was nonsignificant then it was removed from the model


commonly individuals experience subclinical cognitive decline3

It has been unclear which cognitive domains are most affected inRVCL-S and how underlying depression and anxiety affect cog-nitive performance A standard cognitive assessment was per-formed in 12 and 11 participants in the RVCL-S and controlcohorts respectively (table 3) There were no differences in age attesting (p = 0740) and years of education (p = 0379) in thecohorts undergoing cognitive testing Of the items tested se-mantic memory (tested as category fluency or the number ofanimals and vegetables named in 2 minutes) demonstrated thegreatest difference between cohorts with a median of 27 words inparticipants with RVCL-S and 42 words in controls (p = 00009)Participants with RVCL-S scored lower on processing speedmeasured by DSST (p = 0005) and gait speed (p = 0006) Onpsychological evaluation the Geriatric Depression Scale score washigher (p = 0008) with a nonsignificant increase in State-TraitAnxiety Inventory scores (p = 0056) in those with RVCL-SGiven that increased depression and anxiety affect cognitive

performance we evaluated whether RVCL-S was an independentpredictor of cognitive impairment after adjusting for the GeriatricDepression Scale and State-Trait Anxiety Inventory scores inseparate models When adjusted for depression RVCL-Sremained an independent predictor of semantic fluency (β[95 confidence intervals] = minus123 [minus53 to minus193] p = 0002)and processing speed (DSST score) (β = minus131 [minus14 tominus248] p= 0030) but did not independently predictMoCA score FCSRTscore or gait speedWhen adjusted for anxiety RVCL-S remainedindependently predictive of semanticmemory (β = minus129 [minus64 tominus194] p = 00006) DSST score (β = minus164 [minus51 to minus278] p =0007) and gait speed (β = minus0266 [minus0025 tominus0506] p= 0032)but did not independently predict MoCA or FCSRT score

Burden of FLAIR lesions in RVCL-S increasesnear time to deathTo evaluate the temporal evolution of lesion subtypes inRVCL-S MRI scans from participants with RVCL-S (n = 20)

Figure 3 Progression in cerebral atrophy and evolution of lesion subtypes in RVCL-S

Top row shows fluid-attenuated inversion recovery (FLAIR) images middle row shows diffusion-weighted imaging (DWI) images bottom row shows T1postgadolinium images (A) A 45-year-old woman with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)demonstrated a pseudotumor adjacent to the right frontal horn The pseudotumor demonstrates an underlying ring-enhancing lesion on T1 postgadoliniumwith central hyperintensity on DWI and surrounding vasogenic edema on FLAIR MRI scan a decade later demonstrates that the previous pseudotumor isinactive without central diffusion restriction contrast enhancement or significant vasogenic edema on FLAIR Diffuse central gt peripheral atrophy isprominent and additional white matter lesions have developed a decade after the baseline MRI (B) MRI scan of a 54-year-old woman with RVCL-S showsmultiple subcortical and periventricular white matter lesions several which are hyperintense on DWI and a few of which show nodular enhancement on T1postgadolinium Five years later her MRI scan just before death demonstrates a relative decreaseregression in number and overall burden of white matterlesions on FLAIR DWI and T1 postgadolinium with greater lesion burden near the ventricles and less within the subcortical white matter howeversubstantial atrophy (central and peripheral) has progressed over the 5 years before death Sequential neuroimaging on this patient never revealed anypseudotumors (C) A 43-year-old womanwith RVCL-S demonstrates periventricular and subcortical whitematter lesions on FLAIR imaging several but not allof which are bright on DWI and show nodular enhancement on T1 postgadolinium Follow-upMRI scan 7 years later near the time of death shows substantialprogression in FLAIR lesion burden with overall decrease in DWI hyperintense lesions Furthermore nodular enhancement of white matter lesions hasdiminished but a ring-enhancing pseudotumor lesion has appeared adjacent to the right frontal horn Notably there is substantial progression of atrophy(central gt peripheral) over the 7-year interval


were evaluated for hyperintensity across 5 lesion types (1) allFLAIR lesions (2) FLAIR lesions excluding pseudotumors(3) FLAIR pseudotumor lesions only (4) T1 postgadoliniumlesions and (5) DWI lesions Figure 3 shows 3 individualswith RVCL-S and MRIs spanning 5 to 10 years includingrepresentative maps for FLAIR (row 1) DWI (row 2) and T1postgadolinium (row 3) The examples qualitatively demon-strate how FLAIR DWI and T1 gadolinium-enhancing le-sions progress and regress over time

To evaluate whether total lesion volume changed with age ornear time to death individuals with ge3 scan time points acrossa minimum of 30 months were included in linear regression

analysis with repeated patient data included as a random effectSeven participants and 60 MRI scans were included with amedian (interquartile range) between scans of 05 (04ndash10)years and total duration of imaging follow-up of 5 (3ndash65)years Age as a predictor of lesion volume did not produce validmodels with or without data transformation or nonlinearmethods (data available from Dryad figure S2 dryadorg105061dryadstqjq2c0j) However time to death was a signifi-cant predictor of lesion volume for all FLAIR lesions and forFLAIR lesions excluding pseudotumors (figure 5) FLAIR le-sions including pseudotumors increased at a rate of 22ycloser to death (p lt 00001) Similarly FLAIR lesions excludingpseudotumors increased at a rate of 15y closer to death (p lt

Figure 4 White matter OEF increases with disease duration and may indicate progressive microvascular ischemia

(A) Representative cerebral blood flow(CBF) oxygen extraction fraction(OEF) and fluid-attenuated inversionrecovery (FLAIR) maps in an individualwith retinal vasculopathy with cere-bral leukoencephalopathy and sys-temic manifestations (RVCL-S) (B)Normalized white matter OEF (nOEF_NAWM) but not normalized whitematter CBF (nCBF_NAWM) was sig-nificantly elevated in patients withRVCL-S compared to healthy controls(CTLs) (C) nOEF_NAWM progressivelyincreased in participants with RVCL-Scompared to CTLs (p = 00103) how-ever rate of change in nCBF_NAWMwas not different in those with RVCL-Scompared to CTLs


00001) Models including time to death as a predictor ofpseudotumors only contrast-enhancing lesions or DWI lesionburden were invalid without meeting normality assumptionseven after data transformation Of all lesion subtypes DWI andcontrast-enhancing lesions were the most common to regress

To evaluate the onset of lesion appearance in RVCL-Slesion volumes were plotted across lesion subtypes as afunction of age for the entire RVCL-S cohort (data avail-able from Dryad figure S3 dryadorg105061dryadstqjq2c0j) Individuals were more likely to have brain le-sions after 40 years of age regardless of lesion subtypehowever data are limited at younger ages Five patients(including 9 MRI scans) at lt40 years of age showed min-imal FLAIR lesion burden (median [interquartile range]016 [002ndash037] cm3) with 2 individuals having no brainlesions Lesions were common after 40 years of age (me-dian [interquartile range] 49 [15ndash183] cm3) 67 scansdemonstrated ge1 FLAIR lesions

DiscussionRVCL-S is devastating and untreatable Identifying effectivetherapies will likely require an in-depth understanding ofmolecular mechanisms The current study provides the earlystages of a neuroradiologic natural history of RVCL-S Byprofiling participants across a wide age range we modeled therate of change in key neuroradiologic features such as cerebralatrophy disruption of white matter microstructure and lesionsubtypes Furthermore we obtained a standard cognitivebattery in patients with RVCL-S and controls to determinewhich domains are affected most by the disease

Prior studies have focused on lesion characterization inRVCL-S without attention to tissue-type atrophy Our workreveals that white matter atrophy is a prominent feature inRVCL-S Indeed the decline in white matter volumes oc-curred earlier than expected appearing to diverge from con-trols between 30 and 40 years of age before substantial lesiondevelopment (figure 2 and table 2) suggesting earlier onset ofmicrostructural disease than previously knownMoreover thedecline in white matter volume with age was highly linearsuggesting that normalized white matter volume could pro-vide a metric to demonstrate slowed neurodegeneration infuture clinical trials Such a neuroimaging outcome has pre-viously been unavailable for the therapies that have beensuggested or tried3442

Prior studies have reported the prevalence of cognitive (56)and psychological (42) impairment by chart review3 Ourfindings demonstrate impairment in specific cognitive do-mains with the largest impairments identified for timed testsof working memory and processing speed (table 3) It is likelythat the white matter injury observed in RVCL-S may becontributing to deterioration in processing and psychomotorspeed as has been shown in other neurodegenerative diseasescharacterized by white matter changes43ndash46 The GeriatricDepression Scale score was significantly higher in RVCL-Swhich negatively affects processing speed although semanticfluency and processing speed continued to be affected byRVCL-S even after adjustment for underlying depression andanxiety

The largest cohort of RVCL-S has previously been describedwith a high prevalence of both smallmedium FLAIR hyper-intensities and ring-enhancing pseudotumors3 We in

Table 3 Cognitive and psychological testing in patients with RVCL-S compared to healthy controls

Healthy controls (n = 11) Patients with RVCL-Sa (n = 12) p Valueb

Age at testing y 54 (50 56) 52 (42 58) 0740

Education y 16 (15 16) 15 (12 16) 0379

MoCA score 29 (26 29) 25 (24 27) 0055

DSST No of symbols completed in 90 s 52 (47 54) 32 (21 48) 0005abc

Category fluency No of words in 2 min 42 (39 45) 27 (24 32) 00009abc

FCSRT free recall score 37 (34 39) 33 (28 34) 0032b

Gait speed ms 132 (123 140) 115 (090 12) 0006ab

Geriatric Depression Scale score 2 (0 4) 16 (5 18) 0008b

State-Trait Anxiety Inventory score 54 (47 64) 78 (59 92) 0056

Abbreviations DSST = Digit Symbol Substitution Test FCSRT = Bushcke and Grober Free and Cued Selective Reminding Test MoCA = Montreal CognitiveAssessment RVCL-S = retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestationsData are shown as median (25th 75th percentile)a RVCL-S disease status remained a significant predictor of cognitive test score after adjustment for State-Trait Anxiety Inventory score using multivariablelinear regression modelingb Significance after adjustment with the Benjamini-Hochberg procedure to maintain a family-wise error rate lt005c RVCL-S disease status remained a significant predictor of cognitive test score after adjustment for Geriatric Depression Scale score usingmultivariable linearregression modeling


addition found that regardless of pseudotumors patientsdemonstrate nodular contrast-enhancing lesions in 84 andDWI hyperintense lesions in 68 The appearance of smallsubcortical DWI hyperintense and contrast-enhancing lesionsthat appear and regress over time may suggest chronic pro-gressive microvascular ischemia While the contrast-enhancing and DWI lesion burden fluctuated over time andwas not predicted by age or time to death the FLAIR lesionsaccumulated significantly and nonlinearly as time to deathdecreased (figure 5) Assessing the rate of FLAIR lesionprogression may assist in determining the prognosis or ap-propriate treatments targeting later stages of disease Finallywe found that FLAIR lesion volumes were very low before 40years of age (data available from Dryad figure S3 dryadorg105061dryadstqjq2c0j) This finding is limited by havingonly 5 patients imaged before 40 years of age however lowlesion volumes were also identified in a cohort of 33 mutationcarriers from the Netherlands in whom FLAIR lesion volumein individuals lt40 years of age (n = 11) was 019 cm3 similarto our median volume of 016 cm347

White matter OEF was elevated in the RVCL-S cohort whichincreased over time (figure 4) suggesting chronic ischemia as

a likely pathogenic mechanism Regional elevation in ce-rebral OEF measured by brain MRI or PET has provided abiomarker of ischemic vulnerability in several clinical set-tings such as carotid occlusive disease48 acute ischemicstroke49 and sickle cell anemia3650 Along with other ad-vanced MRI methods that provide biomarkers of in vivopathophysiology such as quantifying cerebrovascular re-activity and white matter microstructure we propose thatregional OEF may provide a metric of microvascular healthin RVCL-S and other forms of cSVD In support of ourfindings implicating chronic microvascular ischemiapathologic studies have described a small vessel vascul-opathy in RVCL-S associated with multilaminated base-ment membranes mural thickening and hyalinizationluminal stenosis and fibrinoid necrosis Consistent with aselective vulnerability of white matter in RVCL-S Kothariet al7 demonstrated numerous TREX1-expressing micro-glia in association with the microvasculature in both le-sioned white matter and NAWM but much less so in graymatter In support of an endothelial activation phenotypein RVCL-S von Willebrand factor antigen and propeptideand angiopoietin-2 were elevated in 3 Dutch families withRVCL-Se51 Another study evaluated vascular reactivity by

Figure 5 Lesions in RVCL-S regardless of subtype progressregress with high interparticipant variability

Each line represents an individualpatient As time to death decreasesfluid-attenuated inversion recovery(FLAIR) lesion burden accelerates Toevaluate the temporal evolution oflesion subtypes in retinal vasculop-athy with cerebral leukoencephalop-athy and systemic manifestations(RVCL-S) MRI scans from 7 patientswith RVCL-S who contributed ge3 timepoints over at least 30 months wereevaluated across 5 lesion subtypesTime to death was evaluated as apredictor of lesion volume in linearregression analysis with repeatedpatient data included as a randomeffect As time to death decreasedFLAIR lesion volumes increased in-cluding (A) a 22 increase in lesionvolumeper year closer to death for allFLAIR lesions (p lt 00001) and (B) a15 increase in lesion volume peryear closer to death for FLAIR lesionsexcluding pseudotumors Time todeath as a predictor of (C) pseudotu-mor lesion volume on FLAIR (D)contrast-enhancing lesion volumeand (E) diffusion-weighted imaging(DWI) hyperintense lesion volumeproduced invalid models Significantfluctuation in lesion burden for theselast 3 lesion subtypes is evidentsuggesting high interparticipant vari-ability and limited sample size


measuring flow-mediated dilation of the brachial arteryfinding a reduction in percent change in arterial diameterin patients with RVCL-Se52 Therefore increasing evi-dence suggests endothelial damage and ischemia as un-derlying pathogenic mechanisms with a potential role forTREX1-expressing microglia or macrophages7

Unexpectedly we found that whitematter CBFwas not lower inpatients with RVCL-S compared to controls We postulate thatischemia early in disease leads to regions of impaired vascularautoregulation that prevent the tissue from finely regulatingCBF leading to greater fluctuations in CBF but not a net lowerCBF Local inability to regulate CBF may lead to intermittentischemia when systemic blood pressure fluctuations drop localCBF leading to a compensatory elevation in regional OEF andeventually tissue infarction Similar to our findings in sporadiccSVD CBF in NAWM has typically not been low compared tocontrolse53e54 Measures of degree of impairment in cerebralvasoreactivity but not baseline CBF have been predictive ofdisease progression in sporadic and in another inherited cSVDcerebral autosomal dominant arteriopathy with subcortical in-farcts and leukoencephalopathy (CADASIL)e55minuse57

As one of several monogenic microvasculopathies RVCL-Smay provide an additional cSVD model to study vascularcontributions to dementia as the second leading cause ofdementia and a key contributor to Alzheimer dementiae58

Rapid neurodegeneration in RVCL-S may facilitate studies ofthe mechanisms and treatments for sporadic cSVD whichprogresses later in life and over a longer duration Microvas-cular pathology in genetic forms of cSVD such as RVCL-S andCADASIL has demonstrated findings qualitatively similar tothose seen in sporadic cSVD but with more severe pathologyseen in the hereditary formse59 suggesting that cSVD of di-verse origins may have a common final pathway towardmicrovasculopathy and white matter degeneration

Given the rarity of RVCL-S with lt200 individuals identifiedworldwide our work provides a relatively large cohort scan-ned with standard imaging at multiple time points Howeverthere are limitations to consider First rates of white mattervolume DTI CBF and OEF change were obtained byregressing median values per individual by age and diseasestatus This analysis was chosen (1) to reduce the noise thatoccurs in the setting of sequential imaging over a short du-ration and (2) because only single imaging sessions wereobtained in the control cohort We plan to acquire more datain both cohorts over a longer duration to confirm and improvethe accuracy of our findings Another limitation is that voxel-wise measurements of CBF using pseudocontinuous arterialspin labeling have low signal-to-noise ratio in the deep whitematter which may limit our ability to detect differences inwhite matter CBF between the 2 cohorts Previous work hasinvestigated this limitation finding that the signal remainsadequate for the majority of white mattere60 Moreover weused the recommended parameters that resulted from thiswork to optimize white matter signal Future efforts to

standardize neuroimaging protocols across RVCL-S centersworldwide may help expand and refine our findings For ex-ample in addition to white matter atrophy there may be anincrease in the rate of gray matter atrophy that may be de-tectable in larger cohorts Furthermore larger longitudinalimaging studies in RVCL-S cohorts will allow evaluation ofthe phenotypic variability such as how sex kindred mutationand other vascular comorbid conditions affect the onset andprogression of neurodegeneration and lesion evolution

AcknowledgmentThe authors thank the patients and families with RVCL-S andhealthy controls who have participated in this research

Study fundingThis work was supported by Clayco Foundation Energy 4 ACureFoundation CureCRVResearchNIHNationalHeart Lung andBlood Institute (R01HL129241 ALF and HA) NIH NationalInstitute of Neurological Disorders and Stroke (R01NS116565ALF andHA) andWashingtonUniversity St LouisClinical andTranslational Science Award (UL1 TR000448 ALF)

DisclosureThe authors report no disclosures relevant to the manuscriptGo to NeurologyorgN for full disclosures

Publication historyReceived by Neurology October 10 2019 Accepted in final formApril 10 2020

Appendix Authors

Name Location Contribution

Andria LFord MDMSCI

Washington UniversitySchool of Medicine StLouis MO

Conceived and designed thestudy acquired the dataperformed the analysis anddrafted the manuscript

Victoria WChin BS


Acquired the data andperformed the analysis

Slim FellahPhD


Acquired the data performedthe analysis and edited themanuscript

Michael MBinkley PhD


Acquired the data andperformed the statisticalanalysis

Allie MBodin BS



VamshiBalasettiMD

University of MissouriSchool of MedicineColumbia MO


YewandeTaiwo MS



Peter KangMD



Continued


References1 Grand MG Kaine J Fulling K et al Cerebroretinal vasculopathy a new hereditary

syndrome Ophthalmology 198895649ndash6592 Richards A van denMaagdenberg AM Jen JC et al C-terminal truncations in human

39-59 DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy withcerebral leukodystrophy Nat Genet 2007391068ndash1070

3 Stam AH Kothari PH Shaikh A et al Retinal vasculopathy with cerebral leu-koencephalopathy and systemic manifestations Brain 20161392909ndash2922

4 Hasan M Fermaintt CS Gao N et al Cytosolic nuclease TREX1 regulates oligo-saccharyltransferase activity independent of nuclease activity to suppress immuneactivation Immunity 201543463ndash474

5 Sakai T Miyazaki T Shin DM et al DNase-active TREX1 frame-shift mutants induceserologic autoimmunity in mice J Autoimmun 20178113ndash23

6 Lindahl T Barnes DE Yang YG Robins P Biochemical properties of mammalianTREX1 and its association with DNA replication and inherited inflammatory diseaseBiochem Soc Trans 200937535ndash538

7 Kothari PH Kolar GR Jen JC et al TREX1 is expressed by microglia in normalhuman brain and increases in regions affected by ischemia Brain Pathol 201828806ndash821

8 Mateen FJ Krecke K Younge BR et al Evolution of a tumor-like lesion in cere-broretinal vasculopathy and TREX1 mutation Neurology 2010751211ndash1213

9 Raynowska J Miskin DP Pramanik B et al Retinal vasculopathy with cerebral leu-koencephalopathy (RVCL) a rare mimic of tumefactive MS Neurology 201891e1423ndashe1428

10 Vodopivec I Oakley DH Perugino CA Venna N Hedley-Whyte ET Stone JH A 44-year-old man with eye kidney and brain dysfunction Ann Neurol 201679507ndash519

11 Hedderich DM Lummel N Deschauer M et al Magnetic resonance imaging char-acteristics of retinal vasculopathy with cerebral leukoencephalopathy and systemicmanifestations Clin Neuroradiol 202030229ndash236

12 Dhamija R Schiff D Lopes MB Jen JC Lin DD Worrall BB Evolution of brainlesions in a patient with TREX1 cerebroretinal vasculopathy Neurology 2015851633ndash1634

13 Kolar GR Kothari PH Khanlou N Jen JC Schmidt RE Vinters HV Neuropathologyand genetics of cerebroretinal vasculopathies Brain Pathol 201424510ndash518

14 Dong Y Xu J Chan BP et al The Montreal Cognitive Assessment is superior toNational Institute of Neurological Disease and Stroke-Canadian Stroke Network5-minute protocol in predicting vascular cognitive impairment at 1 year BMCNeurol20161646

15 Gutierrez J Marshall RS Lazar RM Indirect measures of arterial stiffness and cog-nitive performance in individuals without traditional vascular risk factors or diseaseJAMA Neurol 201572309ndash315

16 Rosano C Perera S Inzitari M Newman AB Longstreth WT Studenski S DigitSymbol Substitution Test and future clinical and subclinical disorders of cognitionmobility and mood in older adults Age Ageing 201645688ndash695

17 Andriuta D Roussel M Barbay M et al Differentiating between Alzheimerrsquos diseaseand vascular cognitive impairment is the memory versus executive function contraststill relevant J Alzheimers Dis 201863625ndash633

18 Takeda JRT Matos TM de Souza-Talarico JN Cardiovascular risk factors and cog-nitive performance in aging Dement Neuropsychol 201711442ndash448

19 Zeki Al Hazzouri A Vittinghoff E Sidney S Reis JP Jacobs DR Jr Yaffe K Intima-media thickness and cognitive function in stroke-free middle-aged adults findingsfrom the Coronary Artery Risk Development in Young Adults Study Stroke 2015462190ndash2196

20 Epelbaum S Benisty S Reyes S et al Verbal memory impairment in subcorticalischemic vascular disease a descriptive analysis in CADASIL Neurobiol Aging 2011322172ndash2182

21 Grober E Gitlin HL Bang S Buschke H Implicit and explicit memory in young oldand demented adults J Clin Exp Neuropsychol 199214298ndash316

22 Fritz S Lusardi M White paper walking speed the sixth vital sign J Geriatr PhysTher 20093246ndash49

23 Yesavage JA Brink TL Rose TL et al Development and validation of a GeriatricDepression Screening Scale a preliminary report J Psychiatr Res 19821737ndash49

24 Gaudry E Vagg P Spielberger CD Validation of the state-trait distinction in anxietyresearch Multivariate Behav Res 197510331ndash341

25 DellrsquoOglio E Ceccarelli A Glanz BI et al Quantification of global cerebral atrophy inmultiple sclerosis from 3T MRI using SPM the role of misclassification errorsJ Neuroimaging 201525191ndash199

26 Patenaude B Smith SM Kennedy DN Jenkinson M A Bayesian model of shape andappearance for subcortical brain segmentation NeuroImage 201156907ndash922

27 Jenkinson M Smith S A global optimisation method for robust affine registration ofbrain images Med Image Anal 20015143ndash156

28 Jenkinson M Bannister P Brady M Smith S Improved optimization for the robustand accurate linear registration and motion correction of brain images Neuroimage200217825ndash841

29 Wardlaw JM Smith EE Biessels GJ et al Neuroimaging standards for research intosmall vessel disease and its contribution to ageing and neurodegeneration LancetNeurol 201312822ndash838

30 Behrens TE Woolrich MW Jenkinson M et al Characterization and propagation ofuncertainty in diffusion-weighted MR imaging Magn Reson Med 2003501077ndash1088

31 Wu WC Fernandez-Seara M Detre JA Wehrli FW Wang J A theoretical andexperimental investigation of the tagging efficiency of pseudocontinuous arterial spinlabeling Magn Reson Med 2007581020ndash1027

32 Jain V Duda J Avants B et al Longitudinal reproducibility and accuracy of pseudo-continuous arterial spin-labeled perfusion MR imaging in typically developing chil-dren Radiology 2012263527ndash536

33 Hales PW Kirkham FJ Clark CA A general model to calculate the spin-lattice (T1)relaxation time of blood accounting for haematocrit oxygen saturation and magneticfield strength J Cereb Blood Flow Metab 201636370ndash374

34 An H Lin W Impact of intravascular signal on quantitative measures of cerebraloxygen extraction and blood volume under normo- and hypercapnic conditions usingan asymmetric spin echo approach Magn Reson Med 200350708ndash716

35 Lee JM Vo KD An H et al Magnetic resonance cerebral metabolic rate of oxygenutilization in hyperacute stroke patients Ann Neurol 200353227ndash232

36 Guilliams KP Fields ME Ragan DK et al Red cell exchange transfusions lowercerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemiaBlood 20181311012ndash1021

37 EhgoetzMartens KA Silveira CRA Intzandt BN AlmeidaQJ State anxiety predicts cognitiveperformance in patients with Parkinsonrsquos disease Neuropsychology 201832950ndash957

38 Hashem AH Nasreldin M Gomaa MA Khalaf OO Late versus early onset de-pression in elderly patients vascular risk and cognitive impairment Curr Aging Sci201710211ndash216

39 Mortamais M Abdennour M Bergua V et al Anxiety and 10-year risk of incidentdementia-an association shaped by depressive symptoms results of the prospectivethree-city study Front Neurosci 201812248

40 Promjunyakul NO Dodge HH Lahna D et al Baseline NAWM structural integrity andCBF predict periventricularWMHexpansion over time Neurology 201890e2119ndashe2126

41 van Leijsen EMC Bergkamp MI van Uden IWM et al Progression of white matterhyperintensities preceded by heterogeneous decline of microstructural integrityStroke 2018491386ndash1393

Appendix (continued)


Doris LinMD

Johns HopkinsUniversity BaltimoreMD


Joanna CJen MD PhD

Mount Sinai School ofMedicine New York NY


M GilbertGrand MD



MadonnaBogacki AA



M KathrynLiszewskiBA



DennisHourcadePhD



YashengChen DSc



JasonHassenstabPhD


Performed the analysisinterpreted the data anddrafted the manuscript

Jin-Moo LeeMD PhD


Conceived and designed thestudy and drafted themanuscript

Hongyu AnDSc



JonathanMiner MDPhD



John PAtkinsonMD




42 Kernt M Gschwendtner A Neubauer AS Dichgans M Haritoglou C Effects ofintravitreal bevacizumab treatment on proliferative retinopathy in a patient withcerebroretinal vasculopathy J Neurol 20102571213ndash1214

43 DeLuca J Chelune GJ Tulsky DS Lengenfelder J Chiaravalloti ND Is speed ofprocessing or working memory the primary information processing deficit in multiplesclerosis J Clin Exp Neuropsychol 200426550ndash562

44 Hsu YH Huang CF Lo CP Wang TL Yang CC Tu MC Frontal assessment batteryas a useful tool to differentiate mild cognitive impairment due to subcortical ischemicvascular disease from Alzheimer disease Dement Geriatr Cogn Disord 201642331ndash341

45 Jacobs HI Leritz EC Williams VJ et al Association between white matter micro-structure executive functions and processing speed in older adults the impact ofvascular health Hum Brain Mapp 20133477ndash95

46 Turken A Whitfield-Gabrieli S Bammer R Baldo JV Dronkers NF Gabrieli JDCognitive processing speed and the structure of white matter pathways convergent

evidence from normal variation and lesion studies Neuroimage 2008421032ndash1044

47 Pelzer N Hoogeveen ES Haan J et al Systemic features of retinal vasculopathy withcerebral leukoencephalopathy and systemic manifestations a monogenic small vesseldisease J Intern Med 2019285317ndash332

48 Derdeyn CP Videen TO Yundt KD et al Variability of cerebral blood volume andoxygen extraction stages of cerebral haemodynamic impairment revisited Brain2002125595ndash607

49 Liu Z Li Y Cortical cerebral blood flow oxygen extraction fraction and metabolicrate in patients with middle cerebral artery stenosis or acute stroke AJNR Am JNeuroradiol 201637607ndash614

50 Fields ME Guilliams KP Ragan DK et al Regional oxygen extraction predicts borderzone vulnerability to stroke in sickle cell disease Neurology 201890e1134ndashe1142

References e51-e60 are available at Dryad httpsdoiorg105061dryadstqjq2c0j


DOI 101212WNL0000000000010659202095e1918-e1931 Published Online before print September 4 2020Neurology

Andria L Ford Victoria W Chin Slim Fellah et al Lesion evolution and neurodegeneration in RVCL-S A monogenic microvasculopathy

This information is current as of September 4 2020

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ISSN 0028-3878 Online ISSN 1526-632XWolters Kluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2020 The Author(s) Published by

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

Disputes amp Debates Editorsrsquo ChoiceSteven Galetta MD FAAN EditorAravind Ganesh MD DPhil FRCPC Deputy EditorAriane Lewis MD Deputy EditorJames E Siegler IIIMD Deputy Editor

Reader Response Association of Initial ImagingModality and FutileRecanalization After ThrombectomyJames E Siegler (Camden NJ) and Jesse M Thon (Camden NJ)

Neurologyreg 202196915ndash916 doi101212WNL0000000000011898

We read with interest the results of the BEYOND-SWIFT retrospective observational registry byMeinel et al1 Determination of candidacy for acute stroke intervention is a rapidly evolving andhighly controversial field because we have seen in recently published trials which are expandingeligibility criteria

We would respectfully caution the authors to avoid using language such as ldquothere is a need toreduce [futile recanalization]rdquo in the opening of their article and to reiterate it verbatim in theDiscussion because these aremisleading proclamations Certainly it remains a priority among allclinicians to provide cost-effective care with the aim of improving functional outcomes andorsatisfying end-of-life preferences However to leverage ldquofutile recanalizationrdquo to justify whetherCT or MRI-based modalities be used in selecting thrombectomy candidates will undoubtedlybias clinicians in their imaging recommendations (leading to delays in care as the investigatorshave shown) It may also falsely influence a clinicianrsquos determination of thrombectomy eligibilityTo conclude that CT-based selection of thrombectomy candidates results in a higher rate of futile

Editorsrsquo Note Association of Initial Imaging Modality and FutileRecanalization After ThrombectomyIn ldquoAssociation of Initial Imaging Modality and Futile Recanalization After Thrombec-tomyrdquo Meinel et al reported that the rate of futile recanalization (defined as 90-daymodified Rankin Scale (mRS) score 4ndash6 despite successful recanalization) among patientsenrolled in the BEYOND-SWIFT multicenter retrospective observational registry wassignificantly higher in patients selected for thrombectomy based on a CT scan as comparedwith patients selected for thrombectomy based on anMRI Siegler andThon cautioned thatthese findings should not dissuade against (1) use of a CT scan to determine eligibility forthrombectomy because this could lead to unnecessary delays in care or (2) performance ofthrombectomy after CT scans because the imaging modality itself does not directly affectoutcome and 40 of patients selected for thrombectomy based on a CT scan had a good90-day mRS score (which represents a 22ndash27 absolute increase compared with patientstreatedwithmedicalmanagement in theDAWNandDEFUSE-3 trials)Meinel et al agreedthat it is imperative to avoid delays before thrombectomy and reinforced that their findingsshould not influence the selection of imaging modality for potential thrombectomy can-didates They also pointed out that implementation of high-speedMRI protocols should beconsidered to obtain more detailed information than a CT scan can provide while avoidinglengthy delays between imaging and groin puncture

Ariane Lewis MD and Steven Galetta MD

Neurologyreg 202196915 doi101212WNL0000000000011904

NeurologyorgN Neurology | Volume 96 Number 19 | May 11 2021 915

Author disclosures are available upon request (journalneurologyorg)

Copyright copy 2021 American Academy of Neurology Unauthorized reproduction of this article is prohibited

thrombectomy when compared with MRI-based methods (although accurate) is inherentlymisleading We do not question the effect of imaging modality on treatment-related outcomeHowever even among CT-based selection of patients from BEYOND-SWIFT 40 of patientsachieved functional independence by 90 days This is a marginal 5ndash9 decrement from whatwas observed in DAWN2 and DEFUSE-33 and (more importantly) a 22ndash27 absoluteincrease in the rate of functional achievement of these patients when compared to medicallymanaged controls from these trials

To suggest that these patients are ldquofutile recanalizersrdquo is a misrepresentation and decontextu-alization of the data Such claims could impede the care of many treatment responders po-tentially growing the number of disabled stroke survivors or even resulting in medicolegalconsequences for clinicians who justify treatment deferral based on these findings It is worth-while to consider CT versus MRI in predicting the long-term outcome after thrombectomy butknowing that time is a critical determinant of functional outcomes in treated large vessel oc-clusion4 should encourage clinicians to rely on the quickest imaging assessmentmdashin thiscase CT

1 Meinel TR Kaesmacher J Mosimann PJ et al Association of initial imaging modality and futile recanalization after thrombectomyNeurology 202095e2331ndashe2342

2 Nogueira RG Jadhav AP Haussen DC et al Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarctN Engl J Med 201837811ndash21

3 Albers GW Marks MP Kemp S et al Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging N Engl J Med2018378708ndash718

4 Jahan R Saver JL Schwamm LH et al Association between time to treatment with endovascular reperfusion therapy and outcomes inpatients with acute ischemic stroke treated in clinical practice JAMA 2019322252ndash263

Copyright copy 2021 American Academy of Neurology

Author Response Association of Initial ImagingModality and FutileRecanalization After ThrombectomyThomas Raphael Meinel (Bern Switzerland) Johannes Kaesmacher (Bern Switzerland)

and Urs Fischer (Bern Switzerland)


We thank the authors for their comment in response to our article1 In their letter they pointout an important issue namely the questionable term ldquofutile interventionrdquo This term has beenused as successful recanalization despite an unfavorable outcome at 3 months23 However thedefinition of an unfavorable outcome has varied and patient and caregiver perspectives arequite heterogeneous regarding what to consider an unfavorable outcome

We fully agree with the authors that time delays seen in MR imaging are to be avoided andfurther efforts are necessary to close the gap in the onset-to-groin time between CT and MRIpatients Given the vast amount of high-speed MRI protocols published this seems feasibleHowever we do not agree that our article suggests that we generally favor MRI over CT forsuspected thrombectomy candidates In fact we did question the effect of the imaging modalityon the overall outcome stating that ldquothe main aim of this study was to sensitize strokephysicians that apparently the imaging modality influences their decisions regarding whichpatients to treat by MT Whether this results in an overall better worse or equal outcome canonly be judged by upcoming RCTs on this issuerdquo

Furthermore we do not think that it is appropriate to compare the results of this cohortincluding early time-window patients to the DAWN and DEFUSE-3 population Neither didwe call only CT patients as ldquofutile recanalizersrdquo Rather we considered both MRI and CTpatients that had a modified Rankin Scale of 4ndash6 at 3 months with a sensitivity analysis

916 Neurology | Volume 96 Number 19 | May 11 2021 NeurologyorgN



considering only mRS 5ndash6 at 3 months as futile This was done because there may be a higherconsensus among physicians and also patients that mRS 5ndash6 despite successful reperfusionconstitutes a futile treatment (5-Year QUALE 005)4 Given the fact that current guidelinesjudge MRI and CT equivalent5 we doubt that an established MRI workflow will lead tomedicolegal consequences

We fully agree that time delays should be avoided and a potentially life-saving treatment shouldbe offered to any patient fulfilling criteria for endovascular stroke treatment Clinicians shouldbe aware that the initial imaging modality might affect their treatment decisions Whether MRimaging as compared with CT imaging leads to over-selection and time delays or that it harborsthe potential to reduce futile interventions without over-excluding patients can only be eval-uated in upcoming randomized controlled trials Until then our study should not influenceclinicians to change the imaging modality for suspected thrombectomy candidates


2 Espinosa de RuedaM Parrilla GManzano-Fernandez S et al Combined multimodal computed tomography score correlates with futilerecanalization after thrombectomy in patients with acute stroke Stroke 2015462517ndash2522

3 Hussein HM Georgiadis AL Vazquez G et al Occurrence and predictors of futile recanalization following endovascular treatmentamong patients with acute ischemic stroke a multicenter study AJNR Am J Neuroradiol 201031454ndash458

4 Ganesh A Luengo-Fernandez R Pendlebury ST Rothwell PM Weights for ordinal analyses of the modified Rankin Scale in stroketrials a population-based cohort study EClinicalMedicine 202023100415

5 Powers WJ Rabinstein AA Ackerson T et al Guidelines for the early management of patients with acute ischemic stroke 2019 updateto the 2018 guidelines for the early management of acute ischemic stroke a guideline for Healthcare Professionals from the AmericanHeart AssociationAmerican Stroke Association Stroke 201950e344ndashe418


Editorsrsquo Note Comparison of Ice Pack Test and Single-Fiber EMGDiagnostic Accuracy in Patients Referred for Myasthenic PtosisIn ldquoComparison of Ice Pack Test and Single-Fiber EMG Diagnostic Accuracy in PatientsReferred for Myasthenic Ptosisrdquo Giannoccaro et al compared the diagnostic accuracy ofthe ice pack test (IPT) with single-fiber EMG (SF-EMG) on the orbicularis oculi muscle in155 patients with ptosis being evaluated for ocular myasthenia defined as a positive re-sponse to the edrophonium test presence of acetylcholine-receptor antibodies a decre-ment of gt10 of the third to fifth compound muscle action potential after repetitive nervestimulation or unequivocal response to oral steroids or acetylcholinesterase inhibitors forat least 3 months They found that the IPT and SF-EMG had similar diagnostic accuracy inthis patient population Silvestri noted interest that (1) the IPT a simple and cheap bedsideassessment is comparable with a complicated test like the SF-EMG (2) the results of theIPT and SF-EMG were discordant for 10 of subjects (mostly in the setting of mild orisolated ptosis) and (3) the utility of the IPT was not evaluated in patients with isolateddiplopia Giannoccaro and Liguori responded that the discordance in results generallyoccurred in the setting of a negative IPT which may be related to the lack of repetition ofthe test They also cited previously published data that the IPT is useful in patients withisolated diplopia particularly because SF-EMG may be negative in these patients






Reader Response Comparison of Ice Pack Test and Single-FiberEMG Diagnostic Accuracy in Patients Referred forMyasthenic PtosisNicholas Silvestri (Buffalo)


Giannoccaro et al1 reported their findings on the sensitivity and specificity of the ice pack testand single-fiber electromyography (SF-EMG) in the diagnosis of ocular myasthenia gravis It isinterestingmdashand perhaps humblingmdashthat such a straightforward test as cooling muscle withice has very similar diagnostic accuracy compared with a technically complex and sophisticatedtest as SF-EMG in patients presenting with eyelid ptosis These findings are largely in line withprevious research evaluating the positive and negative predictive values of the ice pack test inocular myasthenia gravis2-5

One concern is the discordance in the results of the 2 tests in 10 of the study participantsalthough this occurred more often in cases of mild and isolated ptosis Another limitation is thatthe authors did not assess the utility of the ice pack test in patients with isolated diplopia a fairlycommon clinical manifestation in those ultimately diagnosed with ocular myasthenia

Overall the results of this study are encouraging given the simplicity of the ice pack test anda relatively limited availability of SF-EMG and they highlight the continued importance of thephysical examination in neurologic diagnosis in an age of extensive and often ldquoshotgunrdquo ap-proach to diagnostic testing

1 Giannoccaro MP Paolucci M Zenesini C et al Comparison of ice pack test and single-fiber EMG diagnostic accuracy in patientsreferred for myasthenic ptosis Neurology 202095e1800ndashe1806

2 Ellis FD Hoyt CS Ellis FJ Jeffery AR Sondhi N Extraocular muscle responses to orbital cooling (ice test) for ocular myasthenia gravisdiagnosis J AAPOS 20004271ndash281

3 Ertas M Arac N Kumral K Tuncbay T Ice test as a simple diagnostic aid for myasthenia gravis Acta Neurol Scand 199489227ndash2294 Lertchavanakul A Gamnerdsiri P Hirunwiwatkul P Ice test for ocular myasthenia gravis J Med Assoc Thai 200184(suppl 1)

S131ndashS1365 Fakiri MO Tavy DLJ Hama-Amin AD Wirtz PW Accuracy of the ice test in the diagnosis of myasthenia gravis in patients with ptosis

Muscle Nerve 201348902ndash904


Author Response Comparison of Ice Pack Test and Single-FiberEMG Diagnostic Accuracy in Patients Referred forMyasthenic PtosisMaria Pia Giannoccaro (Bologna Italy) and Rocco Liguori (Bologna Italy)


We thank Dr Silvestri for the comment on our article1 and agree that a relatively highproportion of patients showed discordant results between the ice pack test and single-fiberelectromyography (SF-EMG) because they were observed in 15 of patients with a finaldiagnosis of ocular myasthenia (OM) Most of discordant cases were related to the negativity ofthe ice pack test in the presence of an altered SF-EMG result One explanation could be the lackof repetition of the ice pack test as we outlined in the discussion Indeed a previous studyshowed that repeated ice pack tests improved sensitivity by 346 compared with a single test2

We also found that the repetition of the ice pack test in some patients increased its sensitivityand therefore the number of patients showing concordant results (unpublished data)




We also acknowledged that we did not investigate the usefulness of the ice pack test inpatients with isolated diplopia Nevertheless Chatzistefanou et al3 reported a sensitivity of769 and a specificity of 983 suggesting that the ice pack test is similarly useful in theassessment of myasthenic diplopia This could be particularly relevant because we showedthat diagnostic tests for OMmdashincluding SF-EMGmdashare frequently negative in patients withthis clinical presentation4


2 Park JY Yang HK Hwang JM Diagnostic value of repeated ice tests in the evaluation of ptosis in myasthenia gravis PLoS One 201712e0177078

3 Chatzistefanou KI Kouris T Iliakis E et al The ice pack test in the differential diagnosis of myasthenic diplopia Ophthalmology20091162236ndash2243

4 Giannoccaro MP Di Stasi V Zanesini C et al Sensitivity and specificity of single-fibre EMG in the diagnosis of ocular myasthenia variesaccordingly to clinical presentation J Neurol 2020267739ndash745


CORRECTIONS

Lesion Evolution and Neurodegeneration in RVCL-SAMonogenicMicrovasculopathyNeurologyreg 202196919 doi101212WNL0000000000011323

In the article ldquoLesion Evolution and Neurodegeneration in RVCL-S A Monogenic Micro-vasculopathyrdquo by Ford et al1 the following sentence was omitted from the Study Fundingstatement ldquoThis work was supported by Clayco Foundation Energy 4A Cure FoundationCure CRV Research and The Foundation for Barnes Jewish Hospital (MB MKL DH JJMJPA)rdquo The authors regret the omission

Reference1 Ford AL Chin VW Fellah S et al Lesion evolution and neurodegeneration in RVCL-S a monogenic microvasculopathy Neurology

202095e1918ndashe1931

Apathy and Risk of Probable Incident Dementia AmongCommunity-Dwelling Older AdultsNeurologyreg 202196919 doi101212WNL0000000000011756

In the article ldquoApathy and Risk of Probable Incident Dementia Among Community-DwellingOlder Adultsrdquo by Bock et al1 the Study Funding should read ldquoThis research was supported byNational Institute on Aging (NIA) Contracts N01-AG-6-2101 N01-AG-6-2103 N01-AG-6-2106 NIA grant R01-AG028050 and NINR grant R01-NR012459 This research was funded inpart by the Intramural Research Program of the NIH National Institute on Aging It is alsosupported through NIA K24 AG-31155rdquo The authors regret the omission

Reference1 Bock MA Bahorik A Brenowitz WD Yaffe K Apathy and risk of probable incident dementia among community-dwelling older adults

Neurology 202095e3280ndashe3287




Retinal vasculopathy with cerebral leukoencephalopathy andsystemic manifestations (RVCL-S) is a familial micro-vasculopathy leading to early vision loss and progressive neu-rocognitive deterioration in the fourth to sixth decadesultimately fatal within asymp10 years of symptom onset1 The au-tosomal dominant disease is caused by a C-terminal frameshiftmutation in TREX1 (a 39ndash59 repair exonuclease 1)2 with 40families identified worldwide (MKL and JPA unpublished2018-2020) In 2016 a multicenter study defined the geneticand clinicopathologic spectra of the disease on the basis ofaggregate data in 78TREX1mutation carriers from 11 unrelatedfamilies proposing diagnostic criteria to increase recognitionand to facilitate future studies3

Despite recent progress disease mechanisms in RVCL-S remainpoorly defined The TREX1 frameshift mutations produce a trun-cated TREX1 protein that lacks its anchor to the endoplasmic re-ticulum2 A recent study described interactions between the TREX1carboxy-terminal region and oligosaccharide transferase at the en-doplasmic reticulum (organelle that promotes normal N-linked gly-cosylation)4 Experiments with knock-in mice and human cell linesdemonstrated that expression of the truncated TREX1 protein dys-regulated the oligosaccharide transferase complex resulting in freeglycan release immune activation and autoantibody production45

Alternatively the relatively small nuclear proportion of the truncatedTREX1 protein which harbors a functional 39 DNase is increasedafter apoptotic or genotoxic stress6 thus genome stability may becompromised by unregulated activity of the misplaced DNase in itsuntethered state Despite these potential disease mechanisms it isunclear why the microvasculature is most markedly affected inRVCL-S Immunohistochemistry studies in postmortem brain tissuefrom patients with RVCL-S and patients with stroke without RVCL-S demonstrated thatTREX1 localizes predominantly towhitematterIba1+ microglia in association with the microvasculature near ische-mic lesions suggesting a role for TREX1 in response to ischemia7

Due to the rarity of RVCL-S it has been challenging to evaluatetherapeutic efficacy when only a few patients can be tested andwithout a contemporaneous placebo arm From the aggregate dataabove3 cognitive and psychological impairments have been definedas present or absent by history and examination MRI findingsdemonstrated (1) smallmedium T2 hyperintense white matterlesions in all but 1 patient (97) noting that some were associatedwith diffusion restriction or postcontrast enhancement and (2) ring-enhancing pseudotumor lesions in 84 which are frequently ob-served with advanced disease and may cause life-threatening mass

effect due to vasogenic edema Imaging studies in RVCL-S havebeen limited to small case series without controls8ndash12 including arecent study of pseudotumor lesions in 6 patients that quantified theduration of diffusion restriction and ring enhancement across serialMRI scans11

Defining pathogenesis in RVCL-S has been challenged by theinability of animal models to recapitulate the human disease phe-notype5 Brain MRI findings give some insight into mechanismspunctate diffusion-restricting lesions support a role for microvas-cular ischemia while nodular and ring-enhancing lesions suggestdisruption of the blood-brain barrier In support of ischemia brainpathology in RVCL-S demonstrates a microvasculopathy associ-ated with multilaminated basement membranes mural thickeningand hyalinization luminal stenosis and fibrinoid necrosis whichcan resemble radiation necrosis13 Chronic inflammatory cells maybe seen near the microvasculature or rarely in the parenchyma313

In postmortem brain tissue of patients with RVCL-S TREX1 isreadily detectable within microglia surrounding the white mattermicrovasculature suggesting that TREX1mislocalizationmay playa role in white matter vulnerability7 While immune serologies arenormal in patients mouse models of RVCL-S induced a non-nuclear autoimmunity that was suppressed by a chemotherapeuticagent suggesting that immune activation may contribute to path-ogenesis or progression45

In this study we evaluated the temporal-spatial dynamics ofneuroimaging features and cognitive performance from a pro-spective cohort of patients with RVCL-S compared to healthycontrols We sought to characterize neurodegeneration and lesionevolution to enable testing of future treatments against this naturalhistory to quantify domain-specific cognitive impairment and toapply advanced MRI methods to reveal pathogenic mechanismshypothesizing that decreased cerebral blood flow (CBF) and in-creased oxygen extraction fraction (OEF) in RVCL-S wouldsupport the role of chronic microvascular ischemia

MethodsStandard protocol approvals registrationsand patient consentsThe studies were approved by the institutional review board

Study participantsThe studies included a prospective cohort with a standardimaging protocol and an older prospective cohort without

GlossaryCADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CBF = cerebralblood flow cSVD = cerebral small vessel diseaseDSST = Digit Symbol Substitution TestDWI = diffusion-weighted imagingFA = fractional anisotropy FCSRT = Free and Cued Selective Reminding Test FLAIR = fluid-attenuated inversion recoveryMD = mean diffusivity MoCA = Montreal Cognitive Assessment NAWM = normal-appearing white matter nCBF = CBFnormalized to gray matter nOEF = OEF normalized to gray matter OEF = oxygen extraction fraction RVCL-S = retinalvasculopathy with cerebral leukoencephalopathy and systemic manifestations































Female sex n () 18 (69) 9 (64) 14 (70)

White n ()b 16 (62) 14 (100) 20 (100)

No of scansb 10 (10 10) 20 (10 28) 2 (10 42)







Seizures 1 (7) 3 (15)







DWI lesions 8 (57) 14 (70)


Liver disease 511 (45) 916 (56)

Anemia 414 (29) 719 (37)

Nephropathy 614 (43) 1019 (53)




















Atrophy


Age minus00023 (0000) lt00001


Age minus0006 (0001) 00001

Interaction 0007 (0002) 00002



Age minus0001 (0000) 00138



Age 0002 (0001) 00228


CBF


Age 0002 (0001) 0041

OEF


Age 0003 (0001) 00003

























Age at testing y 54 (50 56) 52 (42 58) 0740

Education y 16 (15 16) 15 (12 16) 0379

MoCA score 29 (26 29) 25 (24 27) 0055




Gait speed ms 132 (123 140) 115 (090 12) 0006ab





















Appendix Authors


Andria LFord MDMSCI



Victoria WChin BS



Slim FellahPhD






Allie MBodin BS



VamshiBalasettiMD



YewandeTaiwo MS



Peter KangMD



Continued














































Doris LinMD



Joanna CJen MD PhD



M GilbertGrand MD



MadonnaBogacki AA






DennisHourcadePhD



YashengChen DSc



JasonHassenstabPhD



Jin-Moo LeeMD PhD



Hongyu AnDSc



JonathanMiner MDPhD



John PAtkinsonMD





























Errata





Reprints





































































CORRECTIONS




202095e1918ndashe1931





































Female sex n () 18 (69) 9 (64) 14 (70)

White n ()b 16 (62) 14 (100) 20 (100)

No of scansb 10 (10 10) 20 (10 28) 2 (10 42)







Seizures 1 (7) 3 (15)







DWI lesions 8 (57) 14 (70)


Liver disease 511 (45) 916 (56)

Anemia 414 (29) 719 (37)

Nephropathy 614 (43) 1019 (53)




















Atrophy


Age minus00023 (0000) lt00001


Age minus0006 (0001) 00001

Interaction 0007 (0002) 00002



Age minus0001 (0000) 00138



Age 0002 (0001) 00228


CBF


Age 0002 (0001) 0041

OEF


Age 0003 (0001) 00003

























Age at testing y 54 (50 56) 52 (42 58) 0740

Education y 16 (15 16) 15 (12 16) 0379

MoCA score 29 (26 29) 25 (24 27) 0055




Gait speed ms 132 (123 140) 115 (090 12) 0006ab





















Appendix Authors


Andria LFord MDMSCI



Victoria WChin BS



Slim FellahPhD






Allie MBodin BS



VamshiBalasettiMD



YewandeTaiwo MS



Peter KangMD



Continued














































Doris LinMD



Joanna CJen MD PhD



M GilbertGrand MD



MadonnaBogacki AA






DennisHourcadePhD



YashengChen DSc



JasonHassenstabPhD



Jin-Moo LeeMD PhD



Hongyu AnDSc



JonathanMiner MDPhD



John PAtkinsonMD





























Errata





Reprints





































































CORRECTIONS




202095e1918ndashe1931






















Atrophy


Age minus00023 (0000) lt00001


Age minus0006 (0001) 00001

Interaction 0007 (0002) 00002



Age minus0001 (0000) 00138



Age 0002 (0001) 00228


CBF


Age 0002 (0001) 0041

OEF


Age 0003 (0001) 00003

























Age at testing y 54 (50 56) 52 (42 58) 0740

Education y 16 (15 16) 15 (12 16) 0379

MoCA score 29 (26 29) 25 (24 27) 0055




Gait speed ms 132 (123 140) 115 (090 12) 0006ab





















Appendix Authors


Andria LFord MDMSCI



Victoria WChin BS



Slim FellahPhD






Allie MBodin BS



VamshiBalasettiMD



YewandeTaiwo MS



Peter KangMD



Continued














































Doris LinMD



Joanna CJen MD PhD



M GilbertGrand MD



MadonnaBogacki AA






DennisHourcadePhD



YashengChen DSc



JasonHassenstabPhD



Jin-Moo LeeMD PhD



Hongyu AnDSc



JonathanMiner MDPhD



John PAtkinsonMD





























Errata





Reprints





































































CORRECTIONS




202095e1918ndashe1931





























Age at testing y 54 (50 56) 52 (42 58) 0740

Education y 16 (15 16) 15 (12 16) 0379

MoCA score 29 (26 29) 25 (24 27) 0055




Gait speed ms 132 (123 140) 115 (090 12) 0006ab





















Appendix Authors


Andria LFord MDMSCI



Victoria WChin BS



Slim FellahPhD






Allie MBodin BS



VamshiBalasettiMD



YewandeTaiwo MS



Peter KangMD



Continued














































Doris LinMD



Joanna CJen MD PhD



M GilbertGrand MD



MadonnaBogacki AA






DennisHourcadePhD



YashengChen DSc



JasonHassenstabPhD



Jin-Moo LeeMD PhD



Hongyu AnDSc



JonathanMiner MDPhD



John PAtkinsonMD





























Errata





Reprints





































































CORRECTIONS




202095e1918ndashe1931
























Appendix Authors


Andria LFord MDMSCI



Victoria WChin BS



Slim FellahPhD






Allie MBodin BS



VamshiBalasettiMD



YewandeTaiwo MS



Peter KangMD



Continued














































Doris LinMD



Joanna CJen MD PhD



M GilbertGrand MD



MadonnaBogacki AA






DennisHourcadePhD



YashengChen DSc



JasonHassenstabPhD



Jin-Moo LeeMD PhD



Hongyu AnDSc



JonathanMiner MDPhD



John PAtkinsonMD





























Errata





Reprints





































































CORRECTIONS




202095e1918ndashe1931




















































Doris LinMD



Joanna CJen MD PhD



M GilbertGrand MD



MadonnaBogacki AA






DennisHourcadePhD



YashengChen DSc



JasonHassenstabPhD



Jin-Moo LeeMD PhD



Hongyu AnDSc



JonathanMiner MDPhD



John PAtkinsonMD





























Errata





Reprints





































































CORRECTIONS




202095e1918ndashe1931

































Errata





Reprints





































































CORRECTIONS




202095e1918ndashe1931









































































CORRECTIONS




202095e1918ndashe1931








lesion evolution and neurodegeneration in rvcl-s · 10/6/2020 · retinal vasculopathy with...

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