nins-15-708700 July 6, 2021 Time: 18:30 # 1
ORIGINAL RESEARCH
published: 12 July 2021
doi: 10.3389/ nins.2021.708700
Edi ed by:
Yuyi You,
Macqua ie Uni e si y, Aus alia
Re iewed by:
Alessand o A igo,
San Ra aele Hospi al (IRCCS), I aly
Dong Ho Pa k,
Kyungpook Na ional Uni e si y
Hospi al, Sou h Ko ea
*Co espondence:
Iñigo Gabilondo
[email p o ec ed]
Special y sec ion:
This a icle was submi ed o
Neu odegene a ion,
a sec ion o he jou nal
F on ie s in Neu oscience
Recei ed: 12 May 2021
Accep ed: 11 June 2021
Published: 12 July 2021
Ci a ion:
Mu ue a-Goyena A,
Ba enechea M, E amuzpe A,
Teijei a-Po as S, Pengo M, Ayala U,
Rome o-Bascones D, Ace a M,
Del Pino R, Gómez-Es eban JC and
Gabilondo I (2021) Fo eal Remodeling
o Re inal Mic o ascula u e
in Pa kinson’s Disease.
F on . Neu osci. 15:708700.
doi: 10.3389/ nins.2021.708700
Fo eal Remodeling o Re inal
Mic o ascula u e in Pa kinson’s
Disease
Ane Mu ue a-Goyena1,2, Mai ane Ba enechea3, Asie E amuzpe3, Sa a Teijei a-Po as1,
Ma a Pengo4, Unai Ayala3, Da id Rome o-Bascones3, Ma ian Ace a1, Rocío Del Pino1,
Juan Ca los Gómez-Es eban1,5,6 and Iñigo Gabilondo1,5,7*
1Neu odegene a i e Diseases G oup, Bioc uces Bizkaia Heal h Resea ch Ins i u e, Ba akaldo, Spain, 2Depa men
o P e en i e Medicine and Public Heal h, Uni e si y o he Basque Coun y (UPV/EHU), Leioa, Spain, 3Biomedical
Enginee ing Depa men , Facul y o Enginee ing, Mond agon Unibe si a ea (MU-ENG), Mond agon, Spain, 4Depa men
o Molecula and T ansla ional Medicine, Uni e si y o B escia, B escia, I aly, 5Neu ology Depa men , C uces Uni e si y
Hospi al, Ba akaldo, Spain, 6Depa men o Neu osciences, Uni e si y o he Basque Coun y (UPV/EHU), Leioa, Spain,
7Ike basque: The Basque Founda ion o Science, Bilbao, Spain
Backg ound: Re inal mic o ascula al e a ions ha e been p e iously desc ibed in
Pa kinson’s disease (PD) pa ien s using op ical cohe ence omog aphy angiog aphy
(OCT-A). Howe e , an ex ensi e desc ip ion o e inal ascula mo phological ea u es,
hei associa ion wi h PD- ela ed clinical a iables and hei po en ial use as diagnos ic
bioma ke s has no been explo ed.
Me hods: We pe o med a c oss-sec ional s udy including 49 PD pa ien s (87 eyes) and
40 con ols (73 eyes). Re inal mic o ascula u e was e alua ed wi h Spec alis OCT-A
and cogni i e s a us wi h Mon eal Cogni i e Assessmen . Uni ied PD Ra ing Scale and
disease du a ion we e eco ded in pa ien s. We ex ac ed mic o ascula pa ame e s
om supe icial and deep ascula plexuses o he macula, including he a ea and
ci cula i y o o eal a ascula zone (FAZ), skele on densi y, pe usion densi y, essel
pe ime e index, essel mean diame e , ac al dimension (FD) and lacuna i y using
Py hon and MATLAB. We compa ed he mic o ascula pa ame e s be ween g oups
and explo ed hei associa ion wi h hickness o macula laye s and clinical ou comes.
Da a we e analyzed wi h Gene al Es ima ing Equa ions (GEE) and adjus ed o age, sex,
and hype ension. Logis ic eg ession GEE models we e i ed o p edic diagnosis o PD
e sus con ols om mic o ascula , demog aphic, and clinical da a. The disc imina ion
abili y o models was es ed wi h ecei e ope a ing cha ac e is ic cu es.
Resul s: FAZ a ea was signi ican ly smalle in pa ien s compa ed o con ols in
supe icial and deep plexuses, whe eas pe usion densi y, skele on densi y, FD and
lacuna i y o capilla ies we e inc eased in he o eal zone o PD. In he pa a o ea,
mic o ascula pa ame e s o supe icial plexus we e associa ed wi h ganglion cell-
inne plexi o m laye hickness, bu his was mainly d i en by PD wi h mild cogni i e
impai men . No such associa ions we e obse ed in con ols. FAZ a ea was nega i ely
associa ed wi h cogni ion in PD (non-adjus ed models). Fo eal lacuna i y, combined
wi h demog aphic and clinical con ounding ac o s, yielded an ou s anding diagnos ic
accu acy o disc imina ing PD pa ien s om con ols.
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Mu ue a-Goyena e al. Re inal Mic o ascula u e in Pa kinson’s Disease
Conclusion: Pa kinson’s disease pa ien s displayed o eal mic o ascula al e a ions
causing an enla gemen o he ascula bed su ounding FAZ. Pa a o eal mic o ascula
al e a ions we e less p onounced bu we e ela ed o inne e inal laye hinning. Re inal
mic o ascula abno mali ies helped disc imina ing PD om con ols. All his suppo s
OCT-A as a po en ial non-in asi e bioma ke o e eal ascula pa hophysiology and
imp o e diagnos ic accu acy in PD.
Keywo ds: neu odegene a ion, angiog aphy, capilla y, densi y, Pa kinson’s disease, e ina, op ical cohe ence
omog aphy, bioma ke
INTRODUCTION
Pa kinson’s disease (PD) is a p og essi e neu odegene a i e
disease cha ac e ized by mo o impai men , including es
emo , muscle igidi y, b adykinesia, and pos u al imbalance.
The main hallma k o PD is he accumula ion o anomalous
α-synuclein deposi s wi hin neu onal cy oplasm, p esumably
esul ing in p o ound loss o neu ons, mainly o dopamine gic
neu ons (Lo ha ius and B undin, 2002). The pa hological
ea u es o PD ha e also been obse ed in pos mo em e inas
(O uno-Liza an e al., 2018), and se e al in i o c oss-sec ional
s udies ha e epo ed educed e inal hickness in PD by
means o op ical cohe ence omog aphy (OCT) (Ch ysou e al.,
2019). Re inal a ophy seems o be speci ic o he inne e inal
laye s, conc e ely, o macula ganglion cell-inne plexi o m
complex (GCIPL) a ound he o ea (Mu ue a-Goyena e al.,
2019), whe e he la ges amoun o e inal dopamine gic cells
is ound (O uño-Liza án e al., 2020). The GCIPL hinning
is signi ican ly mo e p onounced in PD pa ien s o e ime
compa ed o con ols (Mu ue a-Goyena e al., 2021), bu i is
p esen om p od omal s ages (Lee e al., 2019a,b), sugges ing
ha an ea ly bu ac i e neu odegene a ion akes place in PD
e ina (Mu ue a-Goyena e al., 2021).
P e ious publica ions ha e indica ed ha , in addi ion o
neu odegene a ion, he ascula componen migh be a key
con ibu ing ac o o he pa hogenesis and p og ession o PD
(B ada ic e al., 2012;Guan e al., 2013;Yang e al., 2015).
In ac , b ain au opsies o PD pa ien s ha e e ealed capilla y
dis up ion (Guan e al., 2013), angiogenesis (B ada ic e al.,
2012), and small essel degene a ion in subs an ia nig a, middle
on al co ex and b ains em nuclei (Yang e al., 2015). I
has been sugges ed ha e inal ascula u e shows simila i ies
wi h ce eb al mic oci cula ion and can be he e o e used as a
su oga e ma ke o ce eb al mic o ascula pa hology (Pa on
e al., 2005). Wi hin he e ina, blood low o inne e inal
laye s comes om capilla ies de i ed om he cen al e inal
a e y, whe eas ou e e inal laye s a e supplied by cho oidal
ascula u e. Recen ad ances in OCT echnology allow he
isualiza ion o e inal ascula u e using non-in asi e, dep h-
selec i e, and high- esolu ion images. OCT angiog aphy (OCT-
A) de ec s blood low down o he capilla y le el by measu ing
changes in OCT signal in consecu i e c oss-sec ional images
aken a he same loca ion and allows a h ee-dimensional
mapping o e inal mic o ascula u e. S udying he mo phome ic
a ia ions o capilla y ne wo ks in PD migh p o ide key
in o ma ion abou he egional neu onal s uc u e, and he
basis o in es iga ing e inal ascula mo phological ea u es
as po en ial bioma ke s o ce eb al mic oci cula ion in PD.
Al hough o da e ew s udies ha e explo ed e inal ascula
al e a ions in PD using OCT-A, he obse a ions so a suppo
he iew ha e inal ascula al e a ions a e p esen in PD
(K ome e al., 2016;Kwapong e al., 2018;Rascunà e al.,
2020;Shi e al., 2020;Zou e al., 2020;Robbins e al.,
2021).
On he o he hand, he ela ionship be ween ce eb al small
essel disease and cogni i e decline is well-es ablished (Zanon
Zo in e al., 2021). In PD, cogni i e impai men is p esen in
15 o 40% o pa ien s a diagnosis o ea ly s ages o he disease
(Aa sland e al., 2009;P ei e e al., 2014), and abou 80% o
PD pa ien s will p og ess o demen ia, bu he a e o disease
p og ession is no uni o m ac oss pa ien s (Aa sland e al.,
2017). Recen e idence shows ha subjec s wi h mild cogni i e
impai men (MCI) display e inal ascula ne wo k impai men
(Chua e al., 2020;C iscuolo e al., 2020;Shin e al., 2021).
Simila ly, i seems ha PD pa ien s wi h GCIPL a ophy migh
cons i u e a clinical endopheno ype wi h mo e p onounced
cogni i e impai men and wo se p ognosis (Mu ue a-Goyena
e al., 2019, 2021). Howe e , he ela ionship be ween he
cogni i e s a us, e inal mic o ascula pa ame e s and e inal
laye hicknesses has no been ully explo ed in PD pa ien s.
In his s udy, we aimed o ex ensi ely desc ibe e inal ascula
mo phome ic pa ame e s in PD pa ien s using high- esolu ion
Spec alis OCT-A images, in o de o e i y he p esence o
mic o ascula abno mali ies in PD compa ed o con ols o
speci ic al e a ions in PD-MCI compa ed o PD pa ien s wi h
no mal cogni ion. We also e alua ed he associa ion o e inal
mic o ascula pa ame e s wi h e inal hickness measu emen s
and disease- ela ed clinical a iables. Finally, we assessed he
diagnos ic accu acy o e inal mic o ascula pa ame e s alone o
in combina ion wi h he hickness o e inal laye s o di e en ia e
PD pa ien s om con ols.
MATERIALS AND METHODS
Design and Pa icipan s
55 pa ien s wi h Pa kinson’s disease (105 eyes) and 48 con ols
(95 eyes) we e ini ially ec ui ed o he p esen c oss-sec ional
s udy om June 2020 o Ma ch 2021. We included indi iduals
aged 40 yea s o olde . PD pa ien s we e ec ui ed h ough he
ou pa ien neu ology depa men a C uces Uni e si y Hospi al
and ul illed PD Pa kinson’s UK B ain Bank c i e ia o he
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diagnosis o PD be o e en ollmen . Demog aphic da a, disease
onse , disease se e i y and ype and dosage o dopamine gic
ea men we e collec ed. One expe ienced neu ologis in he
ield o mo emen diso de s eco ded disease onse , Uni ied
Pa kinson’s Disease Ra ing Scale (UPDRS) sco e, and calcula ed
Le odopa Equi alen Daily Dose (LEDD). All pa ien s we e
s udied in an on-s a e o medica ion. Con ol indi iduals wi hou
PD o a his o y o symp oms o o he neu ological condi ions
we e also en olled in he s udy. Mon eal Cogni i e Assessmen
(MoCA) was adminis e ed o all pa icipan s o e alua e gene al
cogni ion. A cu o o 24 was es ablished o de e mining MCI in
his Spanish popula ion (Milani e al., 2018).
All pa icipan s comple ed a comp ehensi e ques ionnai e
on cu en como bidi ies o check o he ollowing sys emic
exclusion c i e ia: se e e smoking (>20 ciga e es/day), hea y
alcohol use (>4 d inks/day o men o >3 d inks/day o
women), diagnosis o any ype o g ade o diabe es, uncon olled
o esis an ele a ed blood p essu e, his o y o consump ion
o d ugs o medica ions known o induce e inal oxici y o
cogni i e impai men , ch onic in lamma o y sys emic diseases
(e.g., lupus e y hema osus, sa coid, Beche disease), his o y
o b ain auma o cen al ne ous sys em diseases di e en
om PD. Pa icipan s wi h well-con olled hype ension wi hou
complica ions we e included in he s udy.
PD pa ien s and con ols unde wen a comple e
oph halmologic examina ion including pupilla y e lexes,
e ac ion, isual acui y, colo disc imina ion, sli lamp
examina ion, and spec al domain OCT. Sphe ical equi alen
e ac i e e o abo e 4.00 diop e s o mo e han 3.00 diop e s
o as igma ism o any ocula o sys emic pa hological condi ion,
excep PD, in luencing e inal OCT measu es we e conside ed
exclusion c i e ia. OCT-A images wi h isually iden i iable
mo ion a i ac s o incomple e acquisi ions we e excluded
om he analyses.
The s udy p o ocol was app o ed by he egional Basque
Clinical Resea ch E hics Commi ee. All pa icipan s ga e w i en
in o med consen p io o hei pa icipa ion in he s udy, in
acco dance wi h he ene s o he Decla a ion o Helsinki.
Spec al Domain Op ical Cohe ence
Tomog aphy (OCT)
Macula e inal hickness was assessed using he Spec alis
spec al-domain OCT sys em (HRA2 Acquisi ion Module
e sion 6.16.6.0, Heidelbe g Enginee ing, Heidelbe g, Ge many).
Macula olume ic scans consis ed o 25 single ho izon al axial
scans (B-scans) co e ing a 20◦×20◦a ea, wi h 512 A-scans pe
B-scan and 49 ames a e aged pe B-scan. Laye segmen a ion
o he OCT da a was pe o med wi h he buil -in so wa e.
All OCT images ul illed quali y con ol c i e ia om OSCAR-
IB consensus (Tewa ie e al., 2012), accoun ing o Ob ious
p oblems (O), poo Signal s eng h (S), Cen a ion o scan (C),
Algo i hm ailu e (A), Re inal pa hology o he han PD- ela ed
(R), Illumina ion (I), and Beam placemen (B).
Macula olume ic scans we e expo ed in aw o ma (∗. ol)
and impo ed in o MATLAB 2018b and 2019b (Ma hwo ks,
Na ick, MA, Uni ed S a es) using he openVolFas .m unc ion
o he AURA ools so wa e (Lang e al., 2013). The cen al
poin o he macula was de e mined as he poin o minimum
hickness a e smoo hing he hickness map wi h a ci cula
ke nel o 0.05 mm adius ( o eaFinde .m unc ion o AURA
ools). The hickness alues de i ed om he acqui ed as e
pa e n we e esampled o a egula g id using cubic in e pola ion
and 0.02 mm spacing be ween adjacen poin s. Then, he a e age
hickness wi hin he o eal zone (cen al 1-mm diame e disc)
and pa a o eal a ea (2.5-mm diame e ing adjacen o he
o eal zone) we e compu ed by a e aging he poin -by-poin
hicknesses in each sec o .
The o eal and pa a o eal hicknesses we e calcula ed
o he ollowing laye complexes: o al e inal hickness
(Re ina), macula ne e ibe laye (mRNFL), ganglion cell-
inne plexi o m complex (GCIPL), inne nuclea laye (INL),
ou e plexi o m-Henle ibe -ou e nuclea laye (OPL-ONL),
and he complex including ex e nal limi ing memb ane
and pho o ecep o inne and ou e segmen s (ELM-IS/OS)
(Figu e 1).
Spec al Domain Op ical Cohe ence
Tomog aphy Angiog aphy (OCT-A)
High- esolu ion acquisi ion was pe o med wi h Spec alis OCT
Angiog aphy Module (Heidelbe g Enginee ing, Ge many) which
o e s a la e al esolu ion o 5.7 µm and an axial esolu ion
o 3.9 µm pe pixel, using a scanning a ea o 10◦×10◦and
512 A-scans pe B-scan. T uT ack Ac i e Eye T acking was
used o a oid mo ion a i ac s. Supe icial and deep ascula
plexus complexes o he macula we e in es iga ed [supe icial
ascula complex (SVC) loca ed be ween he ganglion cell laye
and he inne mid-pa o inne plexi o m laye and deep
ascula complex (DVC) loca ed be ween he ou e mid-pa
o inne plexi o m laye and ou e plexi o m laye ]. En ace
images we e expo ed om Spec alis and s o ed as 768 ×768
pixels jpeg images.
OCT-A Image P ocessing
MATLAB 2018b and 2019b and Py hon ( 3.8.5) we e used o
de elop image analysis and pa ame e ex ac ion algo i hms. Fo
ascula and o eal ea u e ex ac ion, en ace OCT-A images
we e i s c opped o emo e he SLO unduscopic image o he
pe iphe y. Then, OCT-A images we e scaled using X and Y axis
scaling pa ame e s om Spec alis OCT-A o ob ain images o
1:1 pixel:µm co espondence. We de ined he o eal zone as he
cen al 1-mm disc, and he pa a o ea as he ing su ounding he
o eal zone, wi h an ou e diame e o 2.5 mm. The cen e o he
inne 1-mm diame e ci cle and ou e 2.5 mm diame e ing was
he cen oid o he FAZ in DVC, i.e., he same cen e loca ion was
used in SVC and DVC o calcula ing mic o ascula pa ame e s
in di e en concen ic egions (Figu e 1).
Fo mic o ascula pa ame e ex ac ion, OCT-A images we e
i s enhanced using median il e ing and la e p ocessed wi h
a op-ha il e o imp o e he con as in he image. The
images we e bina ized using adap i e h esholding. In SVC, a
sepa a e bina iza ion algo i hm was applied based on O su’s
h eshold o segmen la ge blood essels. By sub ac ing la ge
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FIGURE 1 | OCT-A image p ocessing pipeline and e alua ed e inal laye s and egions o OCT and OCT-A images. The analysis p o ocol o he OCT-A images
(A) was di e en o he supe icial ascula complex (SVC) and o he deep ascula complex (DVC) (see “Ma e ials and Me hods” o mo e de ails). Bo h SVC and
DVC images we e c opped & escaled (1) and bina ized wi h an adap i e h eshold (“adap . hld.”) (2). In SVC images, a e being bina ized, he la ge essels we e
segmen ed (3) and he mic o essels we e bina ized (4). Wi h bina ized SVC mic o essel and bina ized DVC images, images o essel skele on (5) and pe ime e s (6)
we e ob ained. F om he essel skele on images, he “skele on densi y” was quan i ied, om essel pe ime e images he “ essel pe ime e index” was compu ed
and om he combina ion o essel skele on and pe ime e images, he “mean diame e o blood essels” was compu ed. F om he bina ized images o SVC and
DVC, he pa ame e s “Lacuna i y,” “Pe usion densi y,” and “F ac al dimension” we e calcula ed. Finally, he c opped & escaled DVC images we e p e-p ocessed
wi h whi e op-ha and opening/closing o segmen he o eal a ascula zone (FAZ) mask, om which “FAZ a ea” and “FAZ ci cula i y” we e compu ed. The laye s o
he e ina ha we e segmen ed om he OCT images (B) we e macula e inal ne e ibe laye (mRNFL), ganglion cell-inne plexi o m laye complex (GCIPL), inne
nuclea laye (INL), ou e plexi o m laye , Henle ibe s, and ou e nuclea laye complex (OPL-ONL) and he complex including ex e nal limi ing memb ane and in e nal
andou e segmen s o pho o ecep o s (ELM-IS/OS). The mean hickness o he men ioned laye s was ob ained o wo macula egions (B,C): he o eal egion
(cen al ci cle o 1 mm in diame e ) and he pa a o eal ing (cen e ed in he o ea and delimi ed by ci cles wi h an inne diame e o 1-mm and ou e diame e o
2.5 mm). Fo bo h egions, he mean hicknesses o he men ioned e inal laye s and he desc ibed OCT-A pa ame e s we e calcula ed.
essel segmen a ion o he bina ized OCT-A images, we ob ained
SVC mic o ascula u e. As he OCT-A de ec s blood low down
o he capilla y le el by measu ing he changes in OCT signal in
consecu i e c oss-sec ional images, he whi eness o he bina ized
images e lec s he p obabili y o pe usion. This allowed us o
calcula e mic o ascula pe usion densi y as he a io be ween
he numbe o whi e pixels o he bina ized image and he o al
numbe o pixels in he egion o in e es . The bina ized images
o he mic o ascula u e we e u he p ocessed o ex ac he
skele on o he ascula u e using a buil -in unc ion in MATLAB.
Fu he mo e, a Canny edge de ec o was implemen ed o de ec
he bo de s o he ascula u e. F om hese images, we compu ed
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Mu ue a-Goyena e al. Re inal Mic o ascula u e in Pa kinson’s Disease
he ollowing mic o ascula pa ame e s: skele on densi y as he
numbe o pixels o he skele on di ided by he numbe o pixels
in he egion, he essel pe ime e index (Alam e al., 2017), mean
essel diame e (Alam e al., 2017), he ac al dimension (FD)
es ima ed wi h Hausdo (Box-coun ing) me hod (Ha a and
Hamami, 2007) and lacuna i y wi h gliding box me hod (Tolle
e al., 2008). The lacuna i y pa ame e used he ein e e s o he
calcula ion o lacuna i y using a box-size o 512 pixels, which
ep esen s a ela i e box-size o 0.1741 wi h espec o he escaled
bina ized image. These pa ame e s we e ex ac ed in he o eal
zone and he pa a o ea. FD, lacuna i y and pe usion densi y
we e dimensionless, skele on densi y and essel pe ime e index
we e measu ed in 1/mm (leng h pe uni o a ea) and mean essel
diame e in µm.
Fo o eal a ascula zone (FAZ) pa ame e ex ac ion, FAZ
was i s segmen ed using a pa ame e ized e sion o Díaz e al.
(2019). The p ocess consis ed o a op ha ans o m o image
enhancemen , Canny edge de ec ion p ocessing (including a
Gaussian il e ), and he applica ion o opening and closing
mo phological ope a ions o emo e noise and ill holes. The FAZ
a ea (mm2) was measu ed, and he ci cula i y was calcula ed wi h
he ollowing o mula: 4π(a ea/pe ime e 2).
S a is ical Analysis
S a is ical analysis was done in R ( e sion 3.6.1) and RS udio
( e sion 1.2.1335). G oup di e ences o demog aphic ca ego ical
a iables we e es ed using Chi squa e es . Quan i a i e a iables
we e desc ibed using mean and s anda d de ia ion. No mali y o
da a was isually inspec ed and es ed wi h Shapi o-Wilks. G oup
compa isons o no mally dis ibu ed a iables we e done wi h
T- es and non-no mally dis ibu ed da a assessed wi h Mann
Whi ney U- es . The analyses o OCT and OCT-A pa ame e s
we e conduc ed using gene alized es ima ing equa ion (GEE)
models wi h an exchangeable wo king co ela ion s uc u e o
accoun o co ela ion be ween he wo eyes om a single
pa icipan . E ec sizes we e calcula ed wi h Cohen’s d. To es he
diagnos ic abili y o OCT-A pa ame e s alone o in combina ion
wi h demog aphic o e inal hickness a iables, we i ed logis ic
GEE models and hei p edic i e abili y was es ed in ROC
cu es, using i ed alues as p edic o s. Fo his, we i s i ed
he null model including age, sex, and hype ension as a p io i
con ounde s, and hen added e inal a iables o he ull model.
The di e ences in goodness-o - i be ween models we e es ed
wi h Wald es . All GEE analyses we e pe o med wi h geepack
package and ROC cu es calcula ed wi h pROC package. p- alues
lowe han 0.05 we e conside ed s a is ically signi ican .
RESULTS
A o al o 87 eyes om 49 PD pa ien s and 73 eyes om 40
con ols we e analyzed a e emo ing he acquisi ions wi h
isually iden i iable mo ion a i ac s, incomple e acquisi ions o
eyes p esen ing ocula exclusion c i e ia.
The demog aphics and clinical cha ac e is ics o pa icipan s
a e lis ed in Table 1. The e we e no s a is ically signi ican
di e ences in age, bu he p opo ion o emales was la ge in
he con ol g oup. The mean disease du a ion was 7.1 ±4.1
yea s ( ange 0.4 o 19.4 yea s), and he mean UPDRS mo o
sco e was 27.7 ±7.7 ( ange, 9 o 54). The cogni i e s a us was
simila be ween PD and con ols, bu he p opo ion o subjec s
wi h MCI was la ge in PD g oup. In PD pa ien s, MoCA sco e
p esen ed a mild co ela ion wi h mo o de ici s ( = −0.292,
p=0.04). The equency o well-con olled hype ension was
compa able in bo h g oups.
PD pa ien s we e u he di ided in o wo g oups: PD pa ien s
wi h MCI (PD-MCI) (n=18) and PD pa ien s wi h no mal
cogni ion (PD-NC) (n=31). The mean age o PD-MCI was
67.1 ±8.9 yea s and in PD-NC i was 63.1 ±6.9 yea s (p=0.11).
Disease du a ion was compa able among bo h g oups (PD-MCI
6.3 ±4.4 s. PD-NC 7.5 ±4.0, p=0.3). The p opo ion o
emales was also simila in bo h g oups (PD-MCI 38.9% and PD-
NC 32.2%, p=0.9), as well as he p opo ion o pa ien s wi h
well-con olled hype ension (PD-MCI 16.6% and PD-NC 22.2%,
p=0.7).
Compa ison o Mic o ascula
Pa ame e s Be ween PD Pa ien s and
Con ols
Compa ing PD pa ien s and con ols, signi ican di e ences we e
ound in FAZ a ea in SVC (p=0.004) and DVC (p<0.001)
wi h a medium o la ge e ec size, bu no in FAZ ci cula i y.
A e con olling o a p io i con ounde s (i.e., age, sex, and
hype ension), FAZ a ea emained signi ican ly smalle in PD
pa ien s compa ed o con ols in bo h SVC and DVC (es ima e
−0.1 µm, adjus ed p=0.004 in SVC and p=0.014 in
DVC) (Table 2).
When analyzing di e ences in mic o ascula pa ame e s
be ween PD pa ien s and con ols, skele on densi y, pe usion
densi y and essel pe ime e o PD pa ien s we e inc eased in
he o eal zone, wi h s a is ically signi ican di e ences compa ed
TABLE 1 | Demog aphics and clinical cha ac e is ics o pa icipan s.
PD Con ol p- alue
n 49 40
Age (yea s) 64.6 (7.9) 62.1 (8.0) 0.2
Sex ( emale n, %) 16 (34.7%) 27 (67.5%) <0.001
MoCA 24.4 (4.1) 25.7 (2.5) 0.3
MCI (n, %) 18 (36.7%) 6 (15%) 0.03
Hype ension (n, %) 12 (24.5%) 7 (17.5%) 0.59
Disease Du a ion (yea s) 7.1 (4.1) –
UPDRS I 2.0 (1.5) –
UPDRS II 10.8 (4.0) –
UPDRS III 27.7 (7.7) –
UPDRS IV 4.0 (2.9) –
LEDD (mg) 647.5 (364.6) –
Ca ego ical da a a e exp essed as numbe and pe cen age, whe eas quan i a i e
da a is exp essed as mean (s anda d de ia ion). The p opo ion o pa icipan s wi h
well-con olled o benign hype ension is p o ided o each g oup. LEDD, Le odopa
Equi alen Daily Dose; MCI, Mild Cogni i e Impai men ; MoCA, Mon eal Cogni i e
Assessmen ; n, sample size; PD, Pa kinson’s disease; UPDRS, Uni ied Pa kinson’s
disease Ra ing Scale.
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Mu ue a-Goyena e al. Re inal Mic o ascula u e in Pa kinson’s Disease
o con ols (Figu e 2). Mo eo e , PD eyes showed inc eased FD
and lacuna i y o bo h complexes in he o eal zone. Adjus ed
GEE models showed ha he SVC lacuna i y and FD, and
DVC lacuna i y, skele on densi y and pe usion densi y we e
signi ican ly di e en be ween g oups (Table 2), being he e ec
size pa icula ly la ge o lacuna i y. On he o he hand, he
pa a o eal lacuna i y in he e ina o PD pa ien s was signi ican ly
dec eased in SVC and signi ican ly inc eased in DVC (GEE,
p<0.001), bu no di e ences we e obse ed in he emaining
pa a o eal mic o ascula pa ame e s.
Re inal Thicknesses and I s Associa ion
Wi h Mic o ascula Pa ame e s
Mul i a ia e GEE adjus ed o age, sex and hype ension showed
no signi ican di e ences in e inal hickness o i s laye s be ween
PD pa ien s and con ols.
In he o eal zone, FAZ a ea was nega i ely associa ed wi h
GCIPL and INL hickness in bo h PD pa ien s and con ols
(p<0.001), and no signi ican associa ions we e ound wi h
ELM-IS/OS hickness in any g oup. These esul s sugges ha
he o eal mic o ascula u e signi ican ly con ibu es o OCT
hickness measu emen o inne e inal laye s in no mal and
pa hological condi ions. In a simila ashion, in bo h g oups,
skele on densi y, pe usion densi y, FD, and essel pe ime e o
bo h plexuses we e posi i ely associa ed wi h he hickness o
inne e inal laye s (GCIPL and INL), bu no wi h ELM-IS/OS.
Howe e , a unique posi i e associa ion was ound in PD
pa ien s be ween mic o ascula pa ame e s and OPL-ONL in he
o ea. Conc e ely, FAZ a eas in SVC and DVC we e nega i ely
associa ed, and skele on densi y, pe usion densi y, and essel
pe ime e o bo h plexuses we e posi i ely associa ed wi h OPL-
ONL hickness, indica ing ha inc eased capilla y bed in he
o ea was ela ed o OPL-ONL hickening. Also, o eal lacuna i y
o DVC was associa ed wi h GCIPL, INL and OPL-ONL hinning
in PD pa ien s, bu no in con ols.
In he pa a o ea o PD pa ien s, a posi i e associa ion was
ound be ween some mic o ascula pa ame e s o he SVC,
including skele on densi y, pe usion densi y, FD and essel
pe ime e wi h pa a o eal GCIPL hickness (GEE, adjus ed
p- alues: 0.014, 0.006, <0.001, and 0.013, espec i ely), bu no
wi h he hickness o he emaining e inal laye complexes. No
such signi ican associa ions we e ound in con ol pa icipan s.
None o he mic o ascula pa ame e s o DVC we e associa ed
wi h e inal hicknesses in he pa a o ea.
Re inal Pa ame e s in PD Pa ien s Wi h
Mild Cogni i e Impai men
We also es ed whe he di e ences in mic o ascula pa ame e s
could be de ec ed be ween PD pa ien s wi h and wi hou MCI.
Some o such pa ame e s ended o be lowe in PD-MCI
compa ed o PD-NC pa ien s, like DVC lacuna i y in he o eal
zone o SVC skele on densi y in he pa a o ea, bu he di e ences
did no each s a is ical signi icance (Table 3). FAZ a ea was
la ge and FAZ ci cula i y was dec eased in PD-MCI pa ien s, and
bo h pa ame e s we e signi ican ly di e en in SVC compa ed
o PD-NC pa ien s.
On he o he hand, we obse ed ha in PD-MCI e inal
hickness was 6 µm lowe in he pa a o ea and 9 µm lowe
in he o eal zone compa ed o PD-NC pa ien s. Mos o he
pa a o eal e inal hickness dec ease in PD-MCI was accoun ed
o changes in GCIPL (absolu e di e ence o 4 µm). Con a ily,
in he o eal zone, he GCIPL only accoun ed o a hi d pa o
he o al e inal hinning (3 µm hinne ), whe eas o eal OPL-
ONL hickness accoun ed o he es (6 µm lowe in PD-MCI
s. PD-NC, GEE, p=0.047). Howe e , none o hese di e ences
TABLE 2 | Fo eal mic o ascula changes in PD.
PD Con ol Cohen’s dUni a ia ep- alue Mul i a ia e p- alue
FAZ a ea (mm2) SVC 0.669 ±0.214 0.824 ±0.292 0.61 0.004 0.004
DVC 0.401 ±0.181 0.544 ±0.198 0.75 <0.001 0.014
FAZ ci cula i y SVC 0.187 ±0.038 0.194 ±0.029 0.21 0.280 0.686
DVC 0.257 ±0.045 0.271 ±0.043 0.32 0.067 0.210
Lacuna i y SVC 6.0 ±0.4 5.7 ±0.4 0.75 <0.001 <0.001
DVC 12.8 ±0.7 9.8 ±3.2 1.30 <0.001 <0.001
F ac al Dimension SVC 1.42 ±0.05 1.37 ±0.09 0.69 0.008 0.027
DVC 1.49 ±0.04 1.47 ±0.04 0.50 0.030 0.127
Pe usion Densi y SVC 0.14 ±0.04 0.11 ±0.05 0.66 0.009 0.112
DVC 0.22 ±0.04 0.20 ±0.05 0.44 0.020 <0.001
Skele on Densi y (1/mm) SVC 6.0 ±1.9 4.8 ±2.2 0.58 0.052 0.650
DVC 8.6 ±1.9 7.6 ±1.8 0.54 0.034 0.002
Vessel Pe ime e Index (1/mm) SVC 17.1 ±4.8 13.6 ±5.6 0.67 0.006 0.210
DVC 27.6 ±5.2 23.6 ±5.6 0.74 0.003 0.541
Vessel Diame e (µm) SVC 23.3 ±1.6 23.7 ±2.1 0.21 0.160 0.056
DVC 26.1 ±2.1 25.8 ±2.0 0.15 0.320 0.944
Mic o ascula pa ame e s a e exp essed as mean ±s anda d de ia ion o each g oup. Cohen’s d ep esen s he e ec size. p- alues we e ob ained wi h GEE. Mul i a ia e
p- alues a e adjus ed o age, sex, and hype ension. Signi ican esul s a e highligh ed in bold. Mic o ascula pa ame e s wi hou uni s a e dimensionless. DVC, deep
ascula complex; FAZ, o eal a ascula zone; PD, Pa kinson’s disease; SVC, supe icial ascula complex.
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FIGURE 2 | Rep esen a i e images o he mic o ascula iza ion in he o eal zone in con ols and PD pa ien s. Top panel igu es show bina ized images o he Deep
Vascula Complex o he e ina, cen e ed in he cen oid o he Fo eal A ascula Zone (FAZ), in a ci cle wi h a adius o 500 µm. The scaling ac o was 5.60 in bo h
subjec s, so he di e ences in FAZ size canno be a ibu ed o ocula biome ic di e ences o magni ica ion e ec s. G aphs co espond o he esul s in he Deep
Vascula Complex. Signi icance le els o unadjus ed GEE models a e ep esen ed wi h an as e isk: *p<0.05, ** p<0.01, *** p<0.001.
eached s a is ical signi icance a e con olling o he e ec o
age, sex, and hype ension (Table 3).
In e es ingly, we obse ed ha pa a o eal GCIPL hickness
was signi ican ly associa ed wi h pa a o eal mic o ascula
pa ame e s in SVC, including skele on densi y, pe usion densi y,
ac al dimension, lacuna i y and essel pe ime e , bu only in
PD-MCI and no in PD-NC.
Associa ion Be ween Mic o ascula
Pa ame e s and Clinical Ou comes
In PD pa ien s, FAZ a ea and ci cula i y o SVC we e signi ican ly
associa ed wi h MoCA sco es (GEE, p=0.028, p=0.036,
espec i ely), bu no wi h disease du a ion o UPDRS III sco es.
Howe e , he ela ionship be ween supe icial FAZ pa ame e s
and cogni i e unc ion los signi icance when con olling o he
e ec o co a ia es. None o he emaining o eal o pa a o eal
mic o ascula pa ame e s yielded signi ican associa ions wi h
disease du a ion, mo o impai men o cogni i e ou comes.
Diagnos ic Accu acy o Macula
Pa ame e s
To es he diagnos ic abili y o OCT-A pa ame e s alone o
in combina ion wi h demog aphic, clinical, o e inal hickness
a iables, we i ed mul i a iable logis ic GEE models and hei
p edic i e abili y was es ed in ROC cu es. We i s i ed
he null model including age, sex, and hype ension as he
a p io i con ounde s. This yielded an a ea unde he cu e
(AUC) o 0.691 (95% CI, 0.601 – 0.772). Then, we included
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Mu ue a-Goyena e al. Re inal Mic o ascula u e in Pa kinson’s Disease
TABLE 3 | Mic o ascula and hickness pa ame e s in PD pa ien s wi h and
wi hou MCI.
PD-MCI PD-NC Cohen’s
d
GEE
p- alue
n 18 31
FAZ a ea (mm2) SVC 0.73 ±0.20 0.63 ±0.21 0.49 0.049
DVC 0.43 ±0.17 0.38 ±0.18 0.29 –
FAZ ci cula i y SVC 0.17 ±0.02 0.20 ±0.04 0.95 0.001
DVC 0.25 ±0.05 0.26 ±0.04 0.22 –
Mic o ascula
pa ame e s
Fo ea
F ac al Dimension SVC 1.40 ±0.05 1.42 ±0.05 0.40 –
DVC 1.49 ±0.04 1.50 ±0.04 0.25 –
Lacuna i y SVC 6.02 ±0.32 6.03 ±0.48 0.02 –
DVC 12.59 ±0.63 12.91 ±0.66 0.50 –
Skele on Densi y
(1/mm)
SVC 11.8 ±1.5 11.7 ±1.2 0.07 –
DVC 12.0 ±1.2 12.1 ±1.3 0.08 –
Pe usion Densi y SVC 0.28 ±0.04 0.27 ±0.03 0.28 –
DVC 0.31 ±0.02 0.32 ±0.02 0.50 –
Pa a o ea
F ac al Dimension SVC 1.63 ±0.02 1.63 ±0.01 0 –
DVC 1.69 ±0.01 1.69 ±0.01 0 –
Lacuna i y SVC 1.04 ±0.01 1.04 ±0.01 0 –
DVC 10.98 ±0.24 11.14 ±0.24 0.67 –
Skele on Densi y
(1/mm)
SVC 11.4 ±1.4 11.8 ±1.3 0.30 –
DVC 13.4 ±1.2 13.5 ±1.2 0.08 –
Pe usion Densi y SVC 0.24 ±0.02 0.24 ±0.02 0.00 –
DVC 0.35 ±0.01 0.35 ±0.01 0.00 –
Thickness (µm)
Fo ea
Re ina 277.1 ±19.1 286.3 ±18.2 0.49 0.045
GCIPL 36.0 ±7.7 39.4 ±7.9 0.44 –
INL 19.4 ±6.1 21.0 ±5.9 0.27 –
OPL-ONL 117.2 ±13.7 123.3 ±8.4 0.54 0.047
ELM-IS/OS 49.6 ±6.2 49.1 ±4.9 0.09 –
Pa a o ea
Re ina 339.4 ±14.8 345.9 ±13.3 0.46 –
GCIPL 92.0 ±8.5 96.3 ±7.2 0.55 0.039
INL 40.7 ±2.8 40.7 ±4.3 0 –
OPL-ONL 104.7 ±8.1 106.1 ±6.6 0.19 –
ELM-IS/OS 44.2 ±3.5 44.0 ±3.0 0.06 –
Da a a e exp essed as mean ±s anda d de ia ion o each g oup. Cohen’s d
ep esen s he e ec size. p- alues we e ob ained wi h uni a ia e GEE. P- alues
a e only p o ided o signi ican esul s. DVC, deep ascula complex; ELM-
IS/OS, macula complex including ex e nal limi ing memb ane and inne and ou e
segmen s o pho o ecep o s; FAZ, o eal a ascula zone; GCIPL, ganglion cell-
inne plexi o m complex; INL, inne nuclea laye ; OPL-ONL, complex including
he ou e plexi o m and ou e nuclea laye s; PD-MCI, Pa ien s wi h Pa kinson’s
disease and Mild Cogni i e Impai men ; PD-NC, pa ien s wi h Pa kinson’s disease
and no mal cogni ion; SVC, supe icial ascula complex.
single mic o ascula pa ame e s ha di e ed mos be ween
PD pa ien s and con ols, including FAZ a ea, o eal skele on
densi y, pe usion densi y and lacuna i y (bo h plexuses), o eal
FD in SVC and pa a o eal lacuna i y (bo h plexuses). Each
model was hen compa ed o he null wi h Wald es o es
whe he mic o ascula pa ame e s signi ican ly con ibu ed o
diagnos ic accu acy. F om his, we obse ed ha 3 pa ame e s
signi ican ly con ibu ed o he model, p o iding excellen
diagnos ic accu acies (AUC >0.8). These pa ame e s we e he
lacuna i y in DVC o ea (AUC =0.852, 95% CI 0.79 – 0.92),
lacuna i y in DVC pa a o ea (AUC =0.838, 95% CI 0.77 –
0.90) and lacuna i y in SVC pa a o ea (AUC =0.835, 95%
CI 0.77 – 0.90) (Figu e 3). Fu he adding e inal hicknesses
o he pa a o ea o cen al macula o combining di e en
mic o ascula pa ame e s did no signi ican ly imp o e he
classi ica ion pe o mance.
DISCUSSION
In he p esen s udy, we obse ed e inal capilla y al e a ions
in he cen al macula o PD pa ien s. The a ea o he FAZ in
bo h supe icial and deep ascula plexuses was signi ican ly
smalle in PD pa ien s compa ed o con ols. In line wi h his
inding, he pe usion and densi y o capilla ies in he o eal
zone was g ea e in PD pa ien s, mainly in deep ascula plexus,
sugges ing an enla ged ascula bed su ounding FAZ. Mo eo e ,
ac al dimension and lacuna i y o capilla ies we e g ea e in
his egion e lec ing he inc eased ascula complexi y and
he e ogenei y in PD o ea. Remodeling o o eal capilla y bed was
associa ed wi h inc eased OPL-ONL hickness in PD pa ien s.
E en hough we ailed o ind di e ences in mic o ascula densi y
o pe usion in he pa a o ea, pa a o eal lacuna i y signi ican ly
di e ed be ween pa ien s and con ols. In e es ingly, pa a o eal
mic o ascula pa ame e s on he supe icial ascula complex
we e associa ed wi h GCIPL hickness in PD pa ien s, bu no in
con ols, and hese associa ions we e mainly d i en by PD-MCI.
Ou esul s demons a e ha e inal mic o ascula al e a ions in
PD a e mainly es ic ed o he o ea, and ha he pa a o eal
GCIPL a ophy in PD-MCI is associa ed wi h he supe icial
ascula supply.
P e ious s udies ha e explo ed e inal ascula al e a ions in
PD. The i s s udy analyzing e inal ascula changes in PD was
conduc ed using luo escein angiog aphy (FA) (Mi i e al., 2015).
Al hough he esolu ion o ine capilla y essels o e inal FA
is somewha limi ed, hese au ho s ound a sh inking o FAZ
in PD pa ien s compa ed o con ols, which is in line wi h he
esul s o he cu en s udy using OCT-A images and imp o ed
algo i hms o enhance he isualiza ion o capilla ies a ound he
FAZ. Fu he mo e, we ound ha he dec ease in FAZ a ea was
accompanied by an inc ease in mic o ascula pa ame e s in he
o eal zone, like skele on and pe usion densi y, ac al dimension
o lacuna i y. This con as s wi h he esul s o Zou e al. who
ound less essel leng h and pe usion in he cen al macula o
PD pa ien s and no changes in FAZ a ea (Zou e al., 2020), and
wi h he esul s o Rascunà e al. who did no ind ascula densi y
changes in he o eal zone o ea ly PD pa ien s (Rascunà e al.,
2020). Some o hese di e ences migh be a ibu ed o smalle
sample sizes, di e ences in disease s age o pa ien s and s udy
design laws o p e ious s udies.
The i s s udy using OCT-A in PD was published in 2018,
whe e Kwapong e al. (2018) nicely desc ibed a dec ease in
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FIGURE 3 | Recei e ope a ing cha ac e is ic (ROC) cu es o es ing he diagnos ic accu acy o mic o ascula pa ame e s. Fi ed alues esul ing om logis ic
eg ession we e used as classi ie s. ROC cu e o he null model is shown in ed, in which con ounding demog aphical and clinical a iables we e used as
independen ac o s, including age, sex, and hype ension. In blue, ROC cu es o eg ession models ha we e signi ican ly di e en om null (Wald es ) a e adding
single mic o ascula pa ame e s o he model. AUC, a ea unde he cu e; DVC, deep ascula complex; SVC, supe icial ascula complex.
pa a o eal mic o ascula densi y o supe icial ascula complex
in PD and i s ela ionship wi h GCIPL hickness dec ease. Simila
esul s we e epo ed by Shi e al. (2020). None heless, none o
hese au ho s explo ed mic o ascula al e a ions in he o eal
zone, whe e he undamen al mic o ascula al e a ions occu
acco ding o he p esen s udy. They did nei he con ol o he
in e -eye co ela ion in s a is ical analyses, possibly inc easing
he a e o alse posi i e indings in he pa a o ea. In ou
s udy, we used GEE models o con ol o his e ec , and
did no ind signi ican changes in he pa a o eal skele on o
pe usion densi y. None heless, pa o hei esul s coincides
wi h ou s, as we also ound an associa ion be ween he
pa a o eal mic o ascula densi y and GCIPL hickness, e en a e
adjus ing o con ounding a iables. Simila ly, Rascunà e al.
(2020), did no obse e signi ican di e ences in he pa a o eal
mic o ascula densi y be ween ea ly PD pa ien s and con ols
bu did ind a co ela ion o inne e inal laye hickness and
mic o ascula densi y. Howe e , hese co ela ions we e mos ly
es ic ed o he o eal zone, and in he p esen s udy, we
showed ha such associa ions we e no speci ic o PD, as hey
we e also obse ed in con ols. Mo e ecen ly, Robbins e al.
(2021) used la ge sample sizes, including 124 eyes o 69 PD
pa ien s and 248 eyes o 137 con ols, concluding ha e inal
supe icial capilla y essel densi y and pe usion densi y a ound
he o eal zone a e dec eased in PD compa ed o age and
sex-ma ched con ol pa icipan s, bu no co ela ion analyses
wi h e inal hickness we e pe o med. In iguingly, we obse ed
ha he associa ion be ween pa a o eal GCIPL hickness and
mic o ascula pa ame e s in PD was mainly d i en by PD-
MCI pa ien s, whose pa a o eal GCIPL was signi ican ly educed
compa ed o PD-NC pa ien s. As a as we know, his is he i s
s udy ha classi ies PD pa ien s in o subg oups in an a emp
o un a el OCT-A di e ences be ween clinical endopheno ypes.
E en hough ew signi ican di e ences we e ound, PD-MCI
ended o display la ge FAZ a eas and less FAZ ci cula i y
han PD-NC. Fu u e s udies wi h la ge sample sizes migh
con i m his end.
To da e, ew s udies ha e assessed e inal ascula desc ip o s
beyond densi y ha can be use ul o inc easing he in o ma ion
ob ainable om OCT-A images. F ac al dimension is a widely
known pa ame e o desc ibing shape o ex u e, and de e mines
he complexi y o an image. Two s udies calcula ed FD o he
e inal ascula u e o PD pa ien s inding con adic o y esul s.
Mi i e al. (2015) did no ind di e ences using FA, whe eas Shi
e al. (2020) epo ed dec eased FD in he pa a o eal supe icial
and deep ascula plexuses using OCT-A. This con as s wi h ou
esul s, as we did no ind di e ences in FD in he pa a o eal
egion, bu he FD wi hin he o eal zone was signi ican ly
inc eased in PD pa ien s. On he o he hand, lacuna i y is
a ea u e desc ip o ha de e mines he he e ogenei y o an
image and complemen s FD. Lacuna i y exp esses pa chiness
o inhomogenei y o an image, and since i is no p edica ed
on ac ali y, i may be pa icula ly use ul o cha ac e izing
he ex u e o e inal mic o ascula u e. Indeed, in ou s udy
lacuna i y was he pa ame e ha di e ed mos be ween pa ien s
and con ols. The lacuna i y wi hin he o eal zone was
signi ican ly highe in PD pa ien s compa ed o con ols, e en
a e adjus ing o age, sex, and hype ension, sugges ing ha he
dis ibu ion o capilla ies was mo e he e ogeneous in his egion,
wi h la ge dispe sion o gap sizes. The pa a o eal lacuna i y
was g ea e in DVC in bo h PD pa ien s and con ols, as
his plexus con ains i egula ly dis ibu ed ascula loops and
ascula b anches ex ending om a cen al seed poin , no ably
inc easing image he e ogenei y (Hi ano e al., 2018). S ill, in he
p esen wo k his pa ame e was also ound o be signi ican ly
highe in PD pa ien s compa ed o con ols.
Mo eo e , lacuna i y yielded he bes diagnos ic accu acy.
Many e o s a e being de o ed o he iden i ica ion and
cha ac e iza ion o PD bioma ke s. No wi hs anding he p og ess
made so a , eliable bioma ke s a e s ill lacking. In his wo k, we
showed ha o eal lacuna i y could be a p omising bioma ke
o di e en ia ing pa ien s om con ols, as a signi ican ly
g ea e AUC was achie ed a e adding his pa ame e o
he null model ha con olled o con ounding a iables
F on ie s in Neu oscience | www. on ie sin.o g 9July 2021 | Volume 15 | A icle 708700
