344 Copy igh
©
2023 Ko ean Neu ological Associa ion
Risk o Cogni i e Impai men in Pa ien s
Wi h Pa kinson’s Disease Wi h Visual Hallucina ions and
Subjec i e Cogni i e Complain s
pISSN 1738-6586 / eISSN 2005-5013 / J Clin Neu ol 2023;19(4):344-357 / h ps://doi.o g/10.3988/jcn.2022.0186
Recei ed May 7, 2022 Re ised Augus 31, 2022 Accep ed Sep embe 1, 2022
Co espondence
Diego San os-Ga cía, PhD, Depa men o Neu ology, Hospi al Uni e si a io de A Co uña (HUAC), Complejo Hospi ala io Uni e si a io de A Co uña
(CHUAC), C/As Xubias 84, A Co uña 15006, Spain
Tel +34-646173341 E-mail diegosanga @yahoo.es
*De ails o COPPADIS S udy G oup is p esen ed in Supplemen a y Ma e ial.
cc This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion Non-Comme cial License (h ps://c ea i ecommons.o g/
licenses/by-nc/4.0) which pe mi s un es ic ed non-comme cial use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
JCN Open Access ORIGINAL ARTICLE
Diego San os-Ga cíaa, Te esa de Deus Fon icobab, Ca los Co es Ba oloméa, Ma ia J. Feal Paincei asa, Jose M. Paz Gonzáleza,
C is ina Ma ínez Mi óa, Sil ia Jesúsc,d, Miquel Aguila e, Pau Pas o e, Lluís Planellas , Ma ina Cosgayag, Juan Ga cía Calden eyh,
Nu ia Caballoli, Ines Lega daj, Jo ge He nández Va ad,k, I ia Cabol, Lydia López Manzana esm, Isabel González A ambu ud,n,
Ma ia A. Á ila Ri e ao, Víc o Gómez Mayo domop, Víc o Noguei aq, Víc o Puen e , Julio Do o Ga cía-So os, Ca men Bo ué ,
Be a Solano Vilau, Ma ía Ál a ez Sauco , Lydia Velaw, Sonia Escalan ex, Es he Cuboy, F ancisco Ca illo Padillaz,
Juan C. Ma ínez Cas illoA, Pila Sánchez AlonsoB, Ma ia G. Alonso LosadaC, Nu ia López A iz eguiD, I zia Gas ónE, Jaime Kulise skyd,F,
Ma a Blázquez Es adaG, Manuel Seijol, Ja ie Rúiz Ma ínezH, Ca idad Vale oI, Mónica Ku isJ, O iol de Fáb eguesk,
Jessica González A du aK, Ruben Alonso RedondoL, Ca los O dásM, Luis M. López Díaz LN, Da ian McA eeO, Pablo Ma inez-Ma ind,
Pablo Mi c,d, COPPADIS S udy G oup*
aCHUAC, Complejo Hospi ala io Uni e si a io de A Co uña, A Co uña, Spain
bCHUF, Complejo Hospi ala io Uni e si a io de Fe ol, A Co uña, Spain
cUnidad de T as o nos del Mo imien o, Se icio de Neu ología y Neu o isiología Clínica, Ins i u o de Biomedicina de Se illa, Hospi al Uni e si a io Vi gen del Rocío/CSIC/
Uni e sidad de Se illa, Se ille, Spain
dCIBERNED (Cen o de In es igación Biomédica en Red En e medades Neu odegene a i as), Mad id, Spain
eHospi al Uni e si a i Mu ua de Te assa, Te assa, Spain
Clínica del Pila , Ba celona, Spain
gHospi al Clínic de Ba celona, Ba celona, Spain
hCen o Neu ológico Oms 42, Palma de Mallo ca, Spain
iConso ci Sani a i In eg al, Hospi al Moisés B oggi, San Joan Despí, Spain
jHospi al Uni e si a io Son Espases, Palma de Mallo ca, Spain
kHospi al Uni e si a io Vall d´Heb on, Ba celona, Spain
lComplejo Hospi ala io Uni e si a io de Pon e ed a (CHOP), Pon e ed a, Spain
mHospi al Uni e si a io La P incesa, Mad id, Spain
nHospi al Uni e si a io Ma qués de Valdecilla, San ande , Spain
oConso ci Sani a i In eg al, Hospi al Gene al de L’Hospi ale , L’Hospi ale de Llob ega , Ba celona, Spain
pHospi al Uni e si a io Clínico San Ca los, Mad id, Spain
qHospi al Da Cos a, Bu ela, Lugo, Spain
Hospi al del Ma , Ba celona, Spain
sHospi al Uni e si a io Vi gen Maca ena, Se illa, Spain
Hospi al In an a So ía, Mad id, Spain
uIns i u d’Assis ència Sani à ia (IAS)-Ins i u Ca alà de la Salu , Gi ona, Spain
Hospi al Gene al Uni e si a io de Elche, Elche, Spain
wFundación Hospi al de Alco cón, Mad id, Spain
xHospi al de To osa Ve ge de la Cin a (HTVC), To osa, Spain
yComplejo Asis encial Uni e si a io de Bu gos, Bu gos, Spain
zHospi al Uni e si a io de Cana ias, San C is óbal de la Laguna, Spain
AHospi al Uni e si a io Ramón y Cajal, RYCIS, Mad id, Spain
BHospi al Uni e si a io Pue a de Hie o, Mad id, Spain
CHospi al Ál a o Cunquei o, Complejo Hospi ala io Uni e si a io de Vigo (CHUVI), Vigo, Spain
DComplejo Hospi ala io de Toledo, Toledo, Spain
EComplejo Hospi ala io de Na a a, Pamplona, Spain
FHospi al de San Pau, Ba celona, Spain
GHospi al Uni e si a io Cen al de As u ias, O iedo, Spain
HHospi al Uni e si a io Donos ia, San Sebas ián, Spain
IHospi al A nau de Vilano a, Valencia, Spain
JHospi al Rube In e nacional, Mad id, Spain
KHospi al de Cabueñes, Gijón, Spain
LUni e si a io Lucus Augus i (HULA), Lugo, Spain
MHospi al Rey Juan Ca los, Mad id, Spain
NComplejo Hospi ala io Uni e si a io de O ense (CHUO), O ense, Spain
OUni e si y o Ma yland School o Medicine, Bal imo e, MD, USA
www. hejcn.com 345
San os-Ga cía D e al. JCN
JCN Open Access
INTRODUCTION
Cogni i e impai men (CI) is one o he mos impo an non-
mo o symp oms ha can appea in pa ien s wi h Pa kinson’s
disease (PD).1 The ull spec um o cogni ion appea s in indi-
iduals wi h PD, anging om no mal cogni ion (NC) o mild
cogni i e impai men (MCI) o Pa kinson’s disease demen ia
(PDD).2 Abou 50% o pa ien s wi h Pa kinson’s disease and
no mal cogni ion (PD-NC) de elop MCI wi hin 6 yea s,3 and
almos 40% o pa ien s wi h Pa kinson’s disease and mild cog-
ni i e impai men (PD-MCI) subsequen ly de elop PDD.4 Al-
hough indings a y among s udies, he cumula i e p e a-
lence a es o PDD we e ound o be 17%, 46%, and 83% a 5,
10, and 20 yea s a e diagnosis, espec i ely.5 Since demen ia
is a equen and highly disabling complica ion in pa ien s
wi h PD, i is impo an o iden i y p edic i e ac o s o CI
de elopmen . The mos -es ablished isk ac o s o ea ly de-
men ia a e old age, mo o symp om se e i y (pa icula ly
pos u al and gai dis u bances), MCI, and isual hallucina-
ions (VH).6
VH a e a common symp om in PD, a ec ing up o 45% o
pa ien s wi hou demen ia and 65% o hose wi h PDD.7 Im-
po an ly, he ea ly p esence o VH is a s ong p edic o o
cogni i e decline,8 as well as inc eased mo ali y and educed
quali y o li e (QoL) o pa ien s and hei ca egi e s.9 Subjec-
i e cogni i e complain s (SCC) ha e mo e ecen ly been sug-
ges ed o be an independen p edic o o MCI de elopmen
in PD-NC.10,11 SCC is he subjec i e iden i ica ion o cogni i e
decline in people who may o may no ha e had impai men
de ec ed in neu opsychological es s.12 The p e alence o SCC
in PD epo edly a ies om 30% o 60%,10,13 and up o 70%
o pa ien s wi h PD-NC who de elop CI o e ime ha e SCC
a baseline.14 Howe e , he e iology o SCC can di e among
pa ien s, and hey can be ela ed o cogni i e decline as well
as o dep ession o o he psychia ic symp oms.13,15-17
In his con ex , he ela ionships among SCC, VH, and CI
a e unknown, and i is unclea how VH and SCC con ibu e
o CI de elopmen in pa ien s wi h PD-NC. We hypo hesized
ha he VH p e alence is highe in pa ien s wi h PD-NC wi h
SCC han in hose wi hou SCC and ha bo h VH and SCC
oge he could inc ease he isk o CI de elopmen in pa ien s
wi h PD-NC. Ou aims we e o de e mine he equencies o
VH and SCC in a PD-NC coho , o pe o m compa ison wi h
a con ol g oup, and o de e mine he ela ionship be ween
cogni i e unc ion and ac o s associa ed wi h VH and SCC
and he isk o CI de elopmen a a 2-yea ollow-up. Mo e-
o e , we analyzed he alues o di e en se um bioma ke s
(SB) ega ding he p esence o VH and SCC.
Backg ound and Pu pose Visual hallucina ions (VH) and subjec i e cogni i e complain s
(SCC) a e associa ed wi h cogni i e impai men (CI) in Pa kinson’s disease. Ou aims we e o
de e mine he associa ion be ween VH and SCC and he isk o CI de elopmen in a coho o
pa ien s wi h Pa kinson’s disease and no mal cogni ion (PD-NC).
Me hods Pa ien s wi h PD-NC ( o al sco e o >80 on he Pa kinson’s Disease Cogni i e Ra ing
Scale [PD-CRS]) ec ui ed om he Spanish COPPADIS coho om Janua y 2016 o No em-
be 2017 we e ollowed up a e 2 yea s. Subjec s wi h a sco e o ≥1 on domain 5 and i em 13 o
he Non-Mo o Symp oms Scale a baseline (V0) we e conside ed as “wi h SCC” and “wi h VH,”
espec i ely. CI a he 2-yea ollow-up (plus o minus 1 mon h) (V2) was de ined as a PD-CRS
o al sco e o <81.
Resul s A V0 (n=376, 58.2% males, age 61.14±8.73 yea s [mean±SD]), he equencies o VH
and SCC we e 13.6% and 62.2%, espec i ely. VH we e mo e equen in pa ien s wi h SCC
han in hose wi hou : 18.8% (44/234) s 4.9% (7/142), p<0.0001. A V2, 15.2% (57/376) o he
pa ien s had de eloped CI. VH p esen ing a V0 was associa ed wi h a highe isk o CI a V2
(odds a io [OR]=2.68, 95% con idence in e al=1.05–6.83, p=0.039) a e con olling o he
e ec s o age, disease du a ion, educa ion, medica ion, mo o and nonmo o s a us, mood, and
PD-CRS o al sco e a V0. Al hough SCC we e no associa ed wi h CI a V2, p esen ing bo h
VH and SCC a V0 inc eased he p obabili y o ha ing CI a V2 (OR=3.71, 95% con idence in-
e al=1.36–10.17, p=0.011).
Conclusions VH we e associa ed wi h he de elopmen o SCC and CI a he 2-yea ollow-up
in pa ien s wi h PD-NC.
Key Wo ds cogni i e impai men ; demen ia; pa kinson’s disease;
subjec i e cogni i e complain s; isual hallucina ions.
346 J Clin Neu ol 2023;19(4):344-357
Visual Hallucina ions and Subjec i e Cogni i e Complain s in PD
JCN
METHODS
Pa ien s diagnosed wi h PD om Janua y 2016 o No embe
2017 and con ols we e ec ui ed om he COPPADIS co-
ho o inclusion in his s udy, and we e e alua ed again a a
2-yea ollow-up in 35 cen e s in Spain.18 The me hodology o
he COPPADIS-2015 s udy can be ound a h ps://bmcneu-
ol.biomedcen al.com/a icles/10.1186/s12883-016-0548-
9.19 This was a mul icen e , obse a ional, longi udinal-p o-
spec i e, 5-yea ollow-up s udy designed o analyze disease
p og ession in a Spanish popula ion o pa ien s wi h PD. All
pa ien s included we e diagnosed acco ding o he UK PD
B ain Bank c i e ia.20 The same inclusion (excep PD diagno-
sis) and exclusion c i e ia we e applied o pa ien s and o he
con ols (subjec s wi h a disabling neu ological o nonneu-
ological condi ion we e excluded). Only subjec s om he
COPPADIS coho wi hou CI a baseline (i.e., PD-NC, co e-
sponding o a o al sco e on he Pa kinson’s Disease Cogni i e
Ra ing Scale [PD-CRS] o <81)21 we e analyzed in his s udy.
In o ma ion on sociodemog aphic aspec s, and ac o s e-
la ed o PD, como bidi ies, and ea men we e collec ed. The
e alua ions pe o med a V0 (baseline) and V2 (2-yea ollow-
up, plus o minus 1 mon h) included mo o assessmen s
(Hoehn and Yah , Uni ied Pa kinson’s Disease Ra ing Scale
[UPDRS] pa III and pa IV, F eezing o Gai Ques ionnai e
[FOGQ]), nonmo o symp oms (Non-Mo o Symp oms Scale
[NMSS], Pa kinson’s Disease Sleep Scale [PDSS], Visual An-
alog Scale–Pain [VAS-Pain], Visual Analog Scale–Fa igue
[VASF]), cogni ion (PD-CRS), mood and neu opsychia ic
symp oms (Beck Dep ession In en o y-II [BDI-II], Neu o-
psychia ic In en o y [NPI], Ques ionnai e o Impulsi e-
Compulsi e Diso de s in Pa kinson’s Disease Ra ing Scale
[QUIP-RS]), disabili y (Schwab and England Ac i i ies o Daily
Li ing Scale [ADLS]), and QoL (39-i em Pa kinson’s Disease
Ques ionnai e Summa y Index [PDQ-39SI], 8-i em EURO-
HIS-QOL index [EUROHIS-QOL8]).19 A highe sco e indi-
ca es a mo e-se e e inding on each scale/ques ionnai e excep
o PD-CRS, PDSS, ADLS, and EUROHIS-QOL8, o which
he opposi e holds. In pa ien s wi h mo o luc ua ions, mo o
assessmen s we e pe o med du ing he O s a e (wi hou
medica ion in he las 12 hou s) and On s a e. On he o he
hand, he assessmen was only pe o med wi hou medica-
ion in pa ien s wi hou mo o luc ua ions. The same e alu-
a ions (excep o he mo o assessmen ) we e pe o med on
he con ol subjec s a V0 and V2.19
Cogni i e assessmen and cogni i e s a us
classi ica ion
Cogni i e s a uses a V0 and V2 and he changes be ween
hese ime poin s we e assessed using he PD-CRS,22 which is a
cogni i e sc eening ba e y alida ed o assess he cogni i e
s a us o pa ien s wi h PD. The o al sco e is he sum o he
on al-subco ical (FS) subsco e (i em 1, immedia e ee e-
call e bal memo y; i em 3, sus ained a en ion; i em 4, wo k-
ing memo y; i em 5, unp omp ed d awing o a clock; i em 7,
delayed ee ecall e bal memo y; i em 8, al e na ing e bal
luency; and i em 9, ac ion e bal luency) and he pos e io -
co ical (PC) subsco e (i em 2, con on a ion naming; i em
6, copy d awing o a clock). Acco ding o he PD-CRS o al
sco e, each pa ien was classi ied as cogni i ely p ese ed (PD-
NC; sco e o >80) o CI (sco e o <81).23 All pa ien s had PD-
NC a baseline.
VH and SCC de ini ion
Subjec s we e classi ied as wi h o wi hou VH acco ding o
i em 13 o he NMSS a baseline (V0).24 This is 1 o 30 i ems in
his scale and is included in domain 4 (pe cep ion p oblems/
hallucina ions). The symp oms e e o he hose ha occu
du ing he 4 weeks p io o he assessmen . The ques ion ask-
ing abou VH was “Does he pa ien indica e ha he/she sees
hings ha a e no he e?” The sco e anges om 0 (wi hou
symp oms) o 12 (mos equen and se e e symp oms). Sub-
jec s wi h a sco e o 0 on i em 13 o he NMSS we e consid-
e ed as “wi hou VH” whe eas subjec s wi h a sco e o 1–12
we e conside ed as “wi h VH.” The same me hod was used a
V2, and pe sis en VH we e de ined as ha ing VH a bo h V0
and V2.
Rega ding SCC, subjec s we e classi ied as wi h o wi hou
SCC acco ding o domain 5 (a en ion/memo y) o he NMSS
a baseline. This domain includes h ee ques ions abou cogni-
ion pe cep ion: “Does he pa ien ha e p oblems sus aining
concen a ion du ing ac i i ies?” (i em 16), and “Does he pa-
ien o ge hings ha he/she has been old a sho ime ago
o e en s ha happened in he las ew yea s?” (i em 17), and
“Does he pa ien o ge o do hings?” (i em 18). The sco e
o each i em anges om 0 (wi hou symp oms) o 12 (mos
equen and se e e symp oms), wi h he o al sco e o do-
main 5 anging om 0 (wi hou symp oms) o 36 (sco e o 12
[mos equen and se e e symp oms] in all i ems). Subjec s
wi h a sco e o 0 in domain 5 o he NMSS we e conside ed as
“wi hou SCC” whe eas subjec s wi h a sco e o 1–36 we e
conside ed as “wi h SCC.” The same me hod was used a V2,
and pe sis en SCC was de ined as ha ing SCC a bo h V0
and V2.
SB de e mina ion
SB we e analyzed among a subg oup o he COPPADIS co-
ho .19 Collec ed blood samples we e used o de e mine di -
e en SB, and included S100B p o ein, umo nec osis ac o
(TNF)-α, in e leukin (IL)-1, IL-2, IL-6, i amin B12, me hyl-
www. hejcn.com 347
San os-Ga cía D e al. JCN
malonic acid, homocys eine, u ic acid, ul asensi i e CRP
(US-CRP), e i in, and i on. SB le els we e de e mined om
ozen blood samples ob ained om subjec s who pa icipa -
ed in he COPPADIS-2015 s udy om nine cen e s in Spain.
Sampling was ca ied ou no longe han 3 mon hs a e he
i s clinical assessmen (V0) in he absence o in ec ions and/
o e e . All analyses we e conduc ed a he same labo a o y:
REFERENCE LABORATORY (www. e e ence-labo a o y.
es).19 Di e en me hods we e used: isible spec opho om-
e y (i on), immunoluminescence (S100B p o ein, e i in,
i amin B12, and homocys eine), enzyme immunoassay (IL-
1, IL-2, and TNF-α), immunoassay (US-CRP), mass spec-
ome y (me hylmalonic acid), and an enzyma ic echnique
(u ic acid). Ou lie s we e excluded om he analysis.
Da a analysis
Da a we e p ocessed using SPSS so wa e ( e sion 20.0 o
Windows, IBM Co p, A monk, NY, USA). Compa isons be-
ween pa ien s and con ols and be ween pa ien s wi h and
wi hou VH and/o SCC we e pe o med using S uden ’s -
es , he Mann-Whi ney U es , he chi-squa e es , o Fishe ’s
es as app op ia e (dis ibu ions o a iables we e e i ied us-
ing he one-sample Kolmogo o -Smi no es ).
The gene al linea model epea ed-measu es p ocedu e was
used o es whe he he PD-CRS o al sco e, subsco es, and
i ems di e ed signi ican ly be ween he wo isi s (V0 and V2)
in pa ien s wi h PD ega ding he p esence o VH and SCC.
The Bon e oni me hod was used as a pos -hoc es a e ANO-
VA. In e ac ions o isi and g oup we e hen es ed be o e
es ing o g oup di e ences o e ime. Cohen’s d o mula
was applied o measu e he e ec size (in pa ien s wi h PD),
which was ca ego ized in o a small e ec (=0.2), medium
e ec (=0.5), o la ge e ec (=0.8). Age, disease du a ion,
educa ion, and le odopa equi alen daily dose (LEDD)25 a
V0 we e included as co a ia es.
To explo e he associa ion be ween VH and/o SCC and he
isk o CI, bina y eg ession models we e used wi h he p es-
ence o CI (PD-CRS sco e <81) as a dependen a iable. The
e ec was con olled o age, sex, disease du a ion, educa-
ion, LEDD, mo o (UPDRS-III and UPDRS-IV) and nonmo-
o (NMSS) s a us, mood (BDI-II), cogni i e unc ion (PD-
CRS o al sco e), REM beha io diso de (RBD), and aking a
dopamine agonis a V0, which we e included as co a ia es in
he model. Ou analysis was based on a clea ly speci ied a-p i-
o i hypo hesis and a well-planned eg ession model, as ecom-
mended by bes -p ac ice me hods.26
All alues we e quo ed o wo decimal places, wi h he ex-
cep ion o pe cen age alues o which a single decimal place
was used (in he case o ze o, i was omi ed). A p obabili y
alue o p<0.05 was conside ed signi ican .
S anda d p o ocol app o als, egis a ions, and
pa ien consen s
We ecei ed app o al o his s udy om he Comi é de É ica
de la In es igación Clínica de Galicia in Spain (2014/534; De-
cembe 2, 2014). W i en in o med consen s we e ob ained
om all pa icipan s in his s udy. COPPADIS-2015 was clas-
si ied by he Agencia Española del Medicamen o y P oduc os
Sani a ios (AEMPS) as a pos au ho iza ion p ospec i e ol-
low-up s udy wi h he code COH-PAK-2014-01.
Da a a ailabili y
The p o ocol and s a is ical analysis plan a e a ailable on e-
ques . Deiden i ied pa icipan da a a e no a ailable o legal
and e hical easons.
RESULTS
VH and SCC in pa ien s wi h PD s con ols
A V0, VH and SCC we e mo e equen in pa ien s wi h
PD (n=376, 58.2% males, age 61.14±8.73 yea s) han in he
con ols (n=116, 48.3% males, age 62.40±8.46 yea s): 13.6%
(51/376) s 0% (0/116) (p<0.001) and 62.2% (234/376) s.
50.9% (59/116) (p=0.019), espec i ely. SCC we e signi i-
can ly mo e equen in pa ien s wi h PD han in con ols ac-
co ding o NMSS i em 16 (44.4% s. 21.6%, p<0.001) and i em
17 (39.6% s. 29.3%, p=0.028), bu no in i em 18 (29.5% s.
25%, p=0.205).
No VH cases we e de ec ed in he con ol g oup. In he PD-
NC g oup, SCC we e p esen in 86.3% (44/51) o pa ien s
wi h VH compa ed wi h 58.5% (190/325) o pa ien s wi hou
VH (p<0.001) (Fig. 1A). In he PD-NC subg oup wi h SCC,
VH we e mo e equen han in he PD-NC g oup wi hou
SCC (18.8% [44/234] s. 4.9% [7/142], p<0.001) (Fig. 1B).
A he 2-yea ollow-up, 66 ou o 376 pa ien s wi h PD-NC
(17.6%) p esen ed VH, o which 35 we e new cases (10.8% o
he pa ien s wi hou VH a V0). Only ou cases (3.4%) wi h
VH a V2 we e ound in he con ol g oup. SCC we e de ec ed
a V2 in 65.7% and 44% o he pa ien s and con ols, espec-
i ely. The equencies o SCC a V2 in he PD-NC and con ol
g oups ha did no epo SCC a V0 we e 42.3% (60/142) and
15.8% (9/57), espec i ely.
Pa ien s wi h PD-NC wi h s wi hou VH a baseline
VH p esen ing a baseline we e associa ed wi h a highe LEDD
(661.49±390.14 s. 529.51±395.02, p=0.011), highe sco es on
he UPDRS-III (24.57±11.45 s. 20.51±9.78, p=0.022), UP-
DRS-IV (2.63±2.67 s. 1.74±2.26, p=0.009), FOGQ (4.41±
4.45 s. 3.14±4.41, p=0.005), NMSS (73.55±46.58 s. 36.55±
29.28, p<0.001), NPI (7.95±9.01 s. 4.70±6.88, p=0.010),
VASF–men al (2.82±2.43 s. 1.87±2.4, p=0.004), and PDQ-
348 J Clin Neu ol 2023;19(4):344-357
Visual Hallucina ions and Subjec i e Cogni i e Complain s in PD
JCN
Fig. 1. SCCs and VH a baseline. A: F equency a baseline (V0) o subjec i e cogni i e complain s (SCC) in pa ien s wi h Pa kinson’s disease wi h
no mal cogni ion (PD-NC, de ined as o al sco e on he Pa kinson’s Disease Cogni i e Ra ing Scale [PD-CRS] o >80) wi h isual hallucina ions (VH)
(n=51) s. wi hou VH (n=325). B: F equency a V0 o VH in pa ien s wi h PD-NC wi h SCC (n=234) s wi hou SCC (n=142).
39SI (26.92±15.87 s. 13.72±10.75, p<0.001), and lowe sco es
on he PDSS (110.76±29.91 s. 119.67±23.42, p=0.035), ADLS
(86.86±9.05 s. 90.31±8.49, p=0.004), and EUROHIS-QOL8
(3.67±0.55 s. 3.86±0.52, p=0.026) (Table 1). Speci ically, mo-
o luc ua ions (49.0% s. 28.3%, p=0.003), FOGQ (41.2%
s. 28.1%, p=0.044), alls (21.6% s. 8.0%, p=0.005), se e e o
e y se e e nonmo o symp oms bu den (66.7% s. 33.8%,
p<0.001), and majo dep ession (21.6% s. 10.8%, p=0.031)
we e mo e equen in pa ien s wi h PD-NC wi h VH han
in hose wi hou VH (Table 1). No di e ences we e obse ed
be ween pa ien s wi h s wi hou VH in global cogni ion (PD-
CRS o al sco e) o FS unc ions (PD-CRS FS subsco e), bu
he PD-CRS PC subsco es we e signi ican ly lowe in he sub-
g oup wi h VH (26.16±4.58 s. 28.97±1.46, p=0.001). The e
we e no di e ences be ween pa ien s wi h and wi hou VH in
he d ugs ha hey we e aking: le odopa (72.5% s. 67.4%,
p=0.286), dopamine agonis (76.5% s. 71.1%, p=0.269), MAO-
B inhibi o (86.3% s. 74.5%, p=0.053), COMT inhibi o
(23.5% s. 16.6%, p=0.156), aman adine (5.9% s. 8%, p=
0.426), o an icholine gic d ugs (2% s. 3.1%, p=0.547).
Pa ien s wi h PD-NC wi h s wi hou SCC a baseline
SCC p esen ing a baseline we e associa ed wi h highe sco es
on he UPDRS-III (22.25±10.57 s. 19.2±9.05, p=0.008), UP-
DRS-IV (2.08±2.47 s. 1.5±2.05, p=0.006), FOGQ (3.77±4.6
s. 2.54±4.02, p=0.002), NMSS (51.94±37.05 s. 24.49±20.64,
p<0.001), BDI-II (9.00±6.92 s. 4.85±4.42, p<0.001), NPI
(5.93±7.81 s. 3.68±5.94, p=0.002), QUIP-RS (5.55±9.80 s.
2.79±6.99, p<0.001), VAS-Pain (2.72±2.86 s. 2.12±2.79, p=
0.019), VASF–physical (3.19±2.67 s. 2.00±2.45, p<0.001),
VASF–men al (2.44±2.50 s. 1.27±2.09, p<0.001), and PDQ-
39SI (18.80±13.36 s. 10.09±8.18, p<0.001), and lowe sco es
on he PD-CRS (97.44±11.15 s. 99.92±11.45, p=0.026), PD-
CRS CP subscale (28.30±2.79 s. 29.07±1.25, p=0.029), PDSS
(113.38±27.12 s. 126.85±16.54, p<0.001), ADLS (86.76±
9.20 s. 91.62±7.30, p=0.004), and EUROHIS-QOL8 (3.74±
0.54 s. 3.98±0.45, p<0.001) (Table 2). Speci ically, FOGQ
(34.6% s. 22.0%, p=0.006), alls (12.8% s. 4.9%, p=0.008),
se e e o e y se e e nonmo o symp oms bu den (51.7% s.
16.2%, p<0.001), majo dep ession (17.1% s 4.2%, p<0.001),
pain (63.7% s 47.9%, p=0.002), and unc ional dependency
(6.8% s 2.1%, p=0.032) we e mo e equen in pa ien s wi h
PD-NC wi h SCC han in hose wi hou SCC (Table 2).
SB ela ed o VH and SCC
No signi ican di e ences we e de ec ed in SB le els be ween
pa ien s wi h PD-NC wi h (n=64) and wi hou (n=68) SCC
(da a no shown). The e we e also no di e ences in SB le els
44/51
(86.3)
44/234
(18.8)
190/325
(58.5)
190/234
(81.2)
135/325
(41.5)
135/142
(95.1)
350
300
250
200
150
100
50
0
250
200
150
100
50
0
Numbe
Numbe
PD-NC pa ien s wi h VH PD-NC pa ien s wi hou VH PD-NC pa ien s wi h SCCs PD-NC pa ien s wi hou SCCs
SCCs in PD-NC pa ien s wi h s. wi hou VH a baseline VH in PD-NC pa ien s wi h s. wi hou SCCs a baseline
Wi h SCCs
Wi hou SCCs
Wi h VH
Wi hou VH
n=376
p<0.001
n=376
p<0.001
7/51 (13.7)
7/142 (4.9)
A B

www. hejcn.com 349
San os-Ga cía D e al. JCN
be ween pa ien s wi h PD-NC wi h VH (n=14) and wi hou
VH (n=118) (da a no shown).
VH and SCC de elopmen a he 2-yea ollow-up
ela ed o baseline symp oms
In he subg oup o pa ien s wi h PD-NC wi hou VH a base-
Table 1. Disease- ela ed cha ac e is ics, mo o and nonmo o symp oms, au onomy in pe o ming he ac i i ies o daily li ing, and quali y o li e
in pa ien s wi h PD-NC (de ined as o al sco e on he PD-CRS o >80) wi h and wi hou VH a baseline (n=376)
En i e sample
(
n
=376)
Pa ien s wi h
PD-NC wi h VH
(
n
=51)
Pa ien s wi h
PD-NC wi hou VH
(
n
=325)
p
Age (y ) 61.14±8.73 62.16±8.26 60.98±8.8 0.396
Sex, male (%) 58.2 56.9 58.5 0.473
Disease du a ion (y ) 5.29±3.9 5.86±3.74 5.19±3.92 0.176
Le odopa equi alen daily dose (mg) 547.61±396.44 661.49±390.14 529.51±395.02 0.011
Mo o pheno ype (%) 0.129
T emo dominan 49.5 58.8 48.0
PIGD 34.0 21.6 36.0
Inde e mina e 16.5 19.6 16.0
Hoehn and Yah s age 2 [1.5–2] 2 [1.5–2] 2 [1.5–2] 0.680
F om 3 o 5 (%) 7.8 4.7 8.2 0.323
UPDRS-III sco e 21.09±10.11 24.57±11.45 20.51±9.78 0.022
UPDRS-IV sco e 1.86±2.33 2.63±2.67 1.74±2.26 0.009
Mo o luc ua ions (%) 31.1 49.0 28.3 0.003
Dyskinesia (%) 17.4 21.6 16.7 0.253
FOGQ sco e 3.31±4.34 4.41±4.45 3.14±4.41 0.005
Pa ien s wi h eezing o gai (%) 29.9 41.2 28.1 0.044
Pa ien s wi h alls (%) 9.8 21.6 8.0 0.005
PD-CRS o al sco e 98.38±11.33 96.82±10.76 98.62±11.41 0.268
PD-CRS FS subsco e 69.79±10.83 70.67±9.07 69.65±11.09 0.319
PD-CRS PC subsco e 28.59±2.36 26.16±4.58 28.97±1.46 0.001
SCC (%) 62.2 86.3 58.5 <0.001
NMSS sco e 41.57±34.51 73.55±46.58 36.55±29.28 <0.001
Se e e o e y se e e nonmo o symp oms bu den (NMSS sco e >40) (%) 38.3 66.7 33.8 <0.001
BDI-II sco e 7.43±6.41 8.71±7.17 7.23±6.28 0.148
Majo dep ession (%) 12.2 21.6 10.8 0.031
NPI sco e 5.14±7.28 7.95±9.01 4.7±6.88 0.010
QUIP-RS sco e 4.3±8.1 4.5±83.47±6.88 0.119
PDSS sco e 118.46±24.55 110.76±29.91 119.67±23.42 0.035
VAS-Pain sco e 2.49±2.84 2.64±2.9 2.47±2.84 0.791
Pa ien s wi h pain (%) 57.7 60.8 57.2 0.375
VASF–physical sco e 2.74±2.65 3.35±2.57 2.65±2.65 0.072
VASF–men al sco e 2±2.42 2.82±2.43 1.87±2.4 0.004
ADLS sco e 89.84±8.64 86.86±9.05 90.31±8.49 0.004
Pa ien s wi h unc ional dependency (%) 5.1 9.8 4.3 0.099
PDQ-39SI sco e 15.51±12.41 26.92±15.87 13.72±10.75 <0.001
EUROHIS-QOL8 sco e 3.83±0.53 3.67±0.55 3.86±0.52 0.026
Da a a e pe cen age, mean±SD, o median [in e qua ile ange] alues. Chi-squa e and Mann-Whi ney-Wilcoxon es s we e used o compa e pa ien s
wi h and wi hou SCC a baseline. Da a on Hoehn and Yah s ages and UPDRS sco es we e ob ained du ing he O s a e ( i s hou in he mo ning
wi hou aking medica ion in he p e ious 12 hou s).
ADLS, Schwab and England Ac i i ies o Daily Li ing Scale; BDI-II, Beck Dep ession In en o y-II; EUROHIS-QOL8, 8-i em EUROHIS-QOL index; FS, on-
al-subco ical; NMSS, Non-Mo o Symp oms Scale; NPI, Neu opsychia ic In en o y; PC, pos e io -co ical; PD-CRS, Pa kinson’s Disease Cogni i e
Ra ing Scale; PD-NC, Pa kinson’s disease wi h no mal cogni ion; PDQ-39SI, 39-i em Pa kinson’s Disease Quali y o Li e Ques ionnai e Summa y Index;
PDSS, Pa kinson’s Disease Sleep Scale; PIGD, Pos u al Ins abili y Gai Di icul y; QUIP-RS, Ques ionnai e o Impulsi e Compulsi e Diso de s in Pa kin-
son’s Disease Ra ing Scale; SCC, subjec i e cogni i e complain s; UPDRS, Uni ied Pa kinson’s Disease Ra ing Scale; VASF, Visual Analog Scale–Fa igue;
VAS-Pain, Visual Analog Scale–Pain; VH, isual hallucina ions.
350 J Clin Neu ol 2023;19(4):344-357
Visual Hallucina ions and Subjec i e Cogni i e Complain s in PD
JCN
line (n=325), 13.7% o he g oup wi h SCC a baseline (26/190)
and 6.7% o he g oup wi hou SCC a baseline (9/135) had
de eloped VH a V2 (p=0.032). In con as , in he subg oup o
pa ien s wi hou SCC a baseline (n=142), 42.7% o he g oup
wi h VH a baseline (3/7) and 42.2% o he g oup wi hou VH
a baseline (57/135) had de eloped SCC a V2 (p=0.632). Like
Table 2. Disease- ela ed cha ac e is ics, mo o and nonmo o symp oms, au onomy in pe o ming he ac i i ies o daily li ing, and quali y o li e
in pa ien s wi h PD wi h and wi hou SCC a baseline (n=499)
En i e sample
(
n
=376)
Pa ien s wi h
PD-NC wi h SCC
(
n
=234)
Pa ien s wi h
PD-NC wi hou SCC
(
n
=142)
p
Age (y ) 61.14±8.73 62.31±8.40 60.86±9.26 0.791
Sex, male (%) 58.2 60.3 54.9 0.182
Disease du a ion (y ) 5.29±3.9 5.53±3.99 4.91±3.72 0.144
Le odopa equi alen daily dose (mg) 547.61±396.44 569.35±390.69 512.39±404.5 0.099
Mo o pheno ype (%) 0.363
T emo dominan 49.5 47.4 52.8
PIGD 34.0 36.8 29.6
Inde e mina e 16.5 15.8 17.6
Hoehn and Yah s age 2 [1.5–2] 2 [1.5–2] 2 [1.5–2] 0.412
F om 3 o 5 (%) 7.8 8.6 6 .5 0.319
UPDRS-III sco e 21.09±10.11 22.25±10.57 19.2±9.05 0.008
UPDRS-IV sco e 1.86±2.33 2.08±2.47 1.5±2.05 0.006
Mo o luc ua ions (%) 31.1 33.3 27.5 0.141
Dyskinesia (%) 17.4 18.1 16.3 0.391
FOGQ sco e 3.31±4.34 3.77±4.6 2.54±4.02 0.002
Pa ien s wi h FOG (%) 29.9 34.6 22.0 0.006
Pa ien s wi h alls (%) 9.8 12.8 4.9 0.008
PD-CRS o al sco e 98.38±11.33 97.44±11.15 99.92±11.45 0.026
PD-CRS FS subsco e 69.79±10.83 69.15±10.6 70.85±11.16 0.112
PD-CRS PC subsco e 28.59±2.36 28.3±2.79 29.07±1.25 0.029
VH (%) 13.6 18.8 4.9 <0.001
NMSS sco e 41.57±34.51 51.94±37.05 24.49±20.64 <0.001
Se e e o e y se e e nonmo o symp oms bu den (NMSS sco e >40) (%) 38.3 51.7 16.2 <0.001
BDI-II sco e 7.43±6.41 9±6.92 4.85±4.42 <0.001
Majo dep ession (%) 12.2 17.1 4.2 <0.001
NPI sco e 5.14±7.28 5.93±7.81 3.68±5.94 0.002
QUIP-RS sco e 4.30±8.10 5.55±9.80 2.79±6.99 <0.001
PDSS sco e 118.46±24.55 113.38±27.12 126.85±16.54 <0.001
VAS-Pain sco e 2.49±2.84 2.72±2.86 2.12±2.79 0.019
Pa ien s wi h pain (%) 57.7 63.7 47.9 0.002
VASF–physical sco e 2.74±2.65 3.19±2.67 2.00±2.45 <0.001
VASF–men al sco e 2.00±2.42 2.44±2.50 1.27±2.09 <0.001
ADLS sco e 89.84±8.64 86.76±9.20 91.62±7.30 0.004
Pa ien s wi h unc ional dependency (%) 5.1 6.8 2.1 0.032
PDQ-39SI sco e 15.51±12.41 18.8±13.36 10.09±8.18 <0.001
EUROHIS-QOL8 sco e 3.83±0.53 3.74±0.54 3.98±0.45 <0.001
Da a a e pe cen age, mean±SD o median [in e qua ile ange] alues. Chi-squa e and Mann-Whi ney-Wilcoxon es s we e applied o compa e pa-
ien s wi h and wi hou SCC a baseline. Da a on Hoehn and Yah s ages and UPDRS-III sco es we e ob ained om du ing he O s a e.
ADLS, Schwab and England Ac i i ies o Daily Li ing Scale; BDI-II, Beck Dep ession In en o y-II; EUROHIS-QOL8, 8-i em EUROHIS-QOL index; FS,
on al-subco ical; NMSS, Non-Mo o Symp oms Scale; NPI, Neu opsychia ic In en o y; PC, pos e io -co ical; PD-CRS, Pa kinson’s Disease Cogni-
i e Ra ing Scale; PD-NC, Pa kinson’s disease wi h no mal cogni ion; PDQ-39SI, 39-i em Pa kinson’s Disease Quali y o Li e Ques ionnai e Summa y
Index; PDSS, Pa kinson’s Disease Sleep Scale; PIGD, Pos u al Ins abili y Gai Di icul y; QUIP-RS, Ques ionnai e o Impulsi e Compulsi e Diso de s in
Pa kinson’s Disease Ra ing Scale; SCC, subjec i e cogni i e complain s; UPDRS, Uni ied Pa kinson’s Disease Ra ing Scale; VASF, Visual Analog Scale–
Fa igue; VAS-Pain, Visual Analog Scale–Pain; VH, isual hallucina ions.
www. hejcn.com 351
San os-Ga cía D e al. JCN
a baseline, no ela ionship was obse ed be ween d ug ea -
men and VH a V2 in pa ien s wi h and wi hou VH: le odo-
pa (89.4% s. 87.4%, p=0.378), dopamine agonis (71.2% s.
75.8%, p=0.393), MAO-B inhibi o (78.8% s. 77.1%, p=0.432),
COMT inhibi o (33.3% s. 26.8%, p=0.253), aman adine
(12.1% s. 10%, p=0.668), o an icholine gic d ugs (4.5% s.
2.6%, p=0.328).
Change in cogni ion ela ed o VH and SCC
A he 2-yea ollow-up, he PD-CRS o al sco e had signi i-
can ly dec eased in bo h pa ien s wi h PD-NC wi h VH (n=51,
om 96.82±10.76 o 91.08±17.85, Cohen’s d=-0.71, p=0.001)
and wi h PD-NC bu wi hou VH (n=325, om 98.62±11.41
o 96.26±14.6, Cohen’s d=-0.31, p<0.001). The FS and PC
subsco es o PD-CRS also dec eased signi ican ly in bo h
g oups (Table 3). Compa ing bo h g oups, in pa ien s wi h
PD-NC wi h VH, he sco e on he PD-CRS PC subscale de-
c eased signi ican ly mo e han ha in pa ien s wi h PD-NC
wi hou VH (Cohen’s d=-0.41 s. -0.23, p<0.001). A signi i-
can end was obse ed in he educ ion o he PD-CRS o al
sco e in he g oup wi h VH compa ed wi h he g oup wi hou
VH (Cohen’s d=-0.71 s. -0.31, p=0.061), bu no di e ences
we e de ec ed in he PD-CRS FS subsco e (Table 3). A V2,
he equency o CI was signi ican ly highe in pa ien s wi h
han wi hou VH a V0: 33.3% (17/51) s. 12.3% (40/325), p<
0.001 (Fig. 2A). Mo eo e , CI was signi ican ly mo e equen
a V2 in pa ien s wi h PD wi h VH a V2 compa ed wi h hose
wi hou VH a V2 (38.6% s. 13.8%, p<0.001), and in hose pa-
ien s wi h pe sis en VH (i.e., a bo h V0 and V2) han in hose
wi h no VH o wi h VH a only one o he wo isi s (24.6%
s. 5.3%, p<0.001).
Rega ding SCC, global cogni i e unc ion (PD-CRS o al
sco e, Cohen’s d=-0.43 s. -0.27, p=0.008) and FS unc ion
(PD-CRS FS subsco e, Cohen’s d=-0.53 s. -0.23, p=0.035)
we e signi ican ly impai ed in pa ien s wi h PD-NC wi h SCC
compa ed wi h hose wi hou SCC (Table 4). Howe e , pa-
ien s wi h PD-NC wi hou SCC exhibi ed a signi ican ly la g-
e dec ease in PD-CRS PC subsco e compa ed wi h pa ien s
wi h PD-NC and SCC (Cohen’s d=-0.31 s. -0.23, p=0.003). A
signi ican end (p=0.066) was obse ed in he highe equen-
cy o CI a V2 in pa ien s wi h PD-NC wi h SCC compa ed
wi h hose wi hou SCC (17.5% [41/234] s. 11.3% [16/142])
(Fig. 2B). Simila esul s we e obse ed when SCC a V2 we e
conside ed (17.4% [43/247] s. 10.9% [14/129], p=0.061).
When pa ien s wi h pe sis en SCC (a V0 and V2) we e
compa ed wi h pa ien s wi hou pe sis en SCC, CI was mo e
equen in he o me (19.3% [36/187] s. 11.1% [21/189],
p=0.020).
VH and SCC as p edic o s o CI a he 2-yea
ollow-up
In pa ien s wi h PD-NC (n=376), VH p esen ing a V0 was as-
socia ed wi h CI a he 2-yea ollow-up (odds a io [OR]=
3.56, 95% con idence in e al=1.82–6.96, p<0.001). A e ad-
Table 3. Changes in cogni ion in pa ien s wi h PD-NC wi h s wi hou VH a V0 (baseline) om V0 o V2 (2-yea ollow-up, plus o minus 1 mon h)
Pa ien s
wi h PD wi h
VH a V0
(
n
=51)
Pa ien s
wi h PD wi h
VH a V2
(
n
=51)
Cohen’s
d
p
*
Pa ien s wi h
PD wi hou
VH V0
(
n
=325)
Pa ien s wi h
PD wi hou
VH V2
(
n
=325)
Cohen’s
d
p
†
p
‡
p
§
PD-CRS o al sco e 96.82±10.76 91.08±17.85 -0.71 0.001 98.62±11.41 96.26±14.6 -0.31 <0.001 0.100 0.061
PD-CRS FS subsco e 70.67±9.07 66.61±14.32 -0.69 0.001 69.65±11.09 67.67±13.8 -0.28 <0.001 0.114 0.927
Immedia e e bal memo y 8.96±1.80 8.53±1.94 -0.32 0.103 8.45±1.86 8.64±2.75 0.10 0.179 0.153 0.324
Sus ained a en ion 9.33±1.03 8.65±1.36 -0.69 0.001 9.03±1.21 8.66±1.70 -0.29 <0.001 0.310 0.218
Wo king memo y 8.41±1.75 7.57±1.70 -0.62 0.003 7.65±1.90 7.24±1.93 -0.29 <0.001 0.180 0.013
Clock d awing 9.65±0.62 8.86±1.45 -0.79 <0.001 9.33±1.51 9.18±1.32 -0.11 0.154 0.022 N.A.
Delayed e bal memo y 7.06±2.90 6.69±2.50 -0.25 0.210 5.97±2.63 6.3±2.88 0.17 0.026 0.105 0.016
Al e na ing e bal luency 11.41±4.45 11.08±4.06 -0.43 0.032 12.9±3.96 12.1±4.47 -0.27 0.001 0.857 0.148
Ac ion e bal luency 12.2±3.17 14.24±7.04 0.28 0.160 16.33±5.18 15.56±5.50 -0.22 0.004 0.698 0.054
PD-CRS PC subsco e 26.16±4.58 25.47±5.23 -0.41 0.046 28.97±1.46 28.59±2.19 -0.23 0.003 0.412 <0.001
Con on a ion naming 16.27±4.57 16.12±4.81 -0.13 0.485 19.19±1.20 18.95±1.96 -0.17 0.030 0.787 <0.001
Clock copying 9.59±1.19 9.35±1.38 -0.60 0.004 9.78±0.81 9.64±0.95 -0.16 0.033 0.041 N.A.
Da a a e mean±SD alues. p alues we e compu ed using he GLM epea ed-measu es p ocedu e.
*p, change o e ime (V2 s. V0) in pa ien s wi h PD-NC wi h VH a V0; †p, change o e ime (V2 s. V0) in pa ien s wi h PD-NC wi hou VH a V0; ‡p,
g oup– isi in e ac ion; §p, pa ien s wi h PD-NC wi h VH s pa ien s wi h PD-NC wi hou VH. Age, disease du a ion, educa ion, and LEDD a V0 we e in-
cluded as co a ia es. Pa ien s wi h PD-NC wi h VH s. pa ien s wi h PD-NC wi hou VH we e no applicable i he in e ac ion es was signi ican (indica -
ing ha he a es o change o e ime di e be ween he wo g oups).
GLM; gene al linea model; LEDD, le odopa equi alen daily dose; N.A., no applicable; PC, pos e io -co ical; PD, Pa kinson’s disease; PD-CRS, Pa kinson’s
Disease Cogni i e Ra ing Scale; PD-NC, Pa kinson’s disease wi h no mal cogni ion; PIGD, Pos u al Ins abili y Gai Di icul y; VH, isual hallucina ions.
352 J Clin Neu ol 2023;19(4):344-357
Visual Hallucina ions and Subjec i e Cogni i e Complain s in PD
JCN
17/57 (29.8)
41/234
(17.5)
34/319
(10.7) 16/142 (11.3)
40/57
(70.2)
193/234
(82.5)
285/319
(89.3) 126/142
(98.7)
350
300
250
200
150
100
50
0
250
200
150
100
50
0
Numbe
Numbe
PD-NC pa ien s wi h VH PD-NC pa ien s wi hou VH PD-NC pa ien s wi h SCCs PD-NC pa ien s wi hou SCCs
CI a V2 in PD-NC pa ien s wi h s. wi hou VH a V0 CI a V2 in PD-NC pa ien s wi h s. wi hou SCCs a V0
Wi h CI
Wi hou CI
Wi h CI
Wi hou CI
n=376
p<0.001
n=376
p<0.001
A B
Fig. 2. CI a V2 ega ding VH and SCCs. A: F equency o cogni i e impai men (CI, de ined as Pa kinson’s Disease Cogni i e Ra ing Scale [PD-CRS]
o al sco e o <81) in pa ien s wi h Pa kinson’s disease wi h no mal cogni ion (PD-NC) wi h s wi hou isual hallucina ions (VH) a he 2-yea ol-
low-up (V2). B: F equency o CI in pa ien s wi h PD-NC wi h s wi hou subjec i e cogni i e complain s (SCC) a V2.
Table 4. Changes in cogni ion in pa ien s wi h PD-NC wi h s wi hou SCC a V0 om V0 o V2
Pa ien s wi h
PD wi h
SCC V0
(
n
=234)
Pa ien s wi h
PD wi h
SCC V2
(
n
=234)
Cohen’s
d
p
*
Pa ien s wi h
PD wi hou
SCC V0
(
n
=142)
Pa ien s wi h
PD wi hou
SCC V2
(
n
=142)
Cohen’s
d
p
†
p
‡
p
§
PD-CRS o al sco e 97.44±11.15 94.18±15.39 -0.43 <0.001 99.92±11.45 97.83±14.52 -0.27 0.023 0.434 0.008
PD-CRS FS subsco e 69.15±10.6 66.31±13.81 -0.53 <0.001 70.85±11.16 69.16±13.84 -0.23 0.050 0.391 0.035
Immedia e e bal memo y 8.44±1.91 8.41±2.23 -0.02 0.785 8.64±1.76 8.99±3.21 0.16 0.163 0.106 0.022
Sus ained a en ion 9.14±1.17 8.57±1.72 -0.46 <0.001 8.96±1.22 8.81±1.55 -0.12 0.287 0.026 N.A.
Wo king memo y 7.73±1.83 7.18±1.78 -0.42 <0.001 7.78±2.02 7.45±2.09 -0.22 0.064 0.305 0.645
Clock d awing 9.38±1.48 9.51±1.19 0.25 0.007 9.36±1.33 9.32±1.08 -0.03 0.754 0.111 0.432
Delayed e bal memo y 6.06±2.80 6.22±2.82 0.09 0.310 6.21±2.50 6.56±2.86 0.17 0.149 0.729 0.233
Al e na ing e bal luency 12.49±3.70 11.74±4.53 -0.26 0.004 13.32±4.08 12.31±4.26 -0.33 0.006 0.362 0.078
Ac ion e bal luency 15.90±5.57 15.16±5.81 -0.22 0.016 16.58±4.92 15.73±5.62 -0.24 0.045 0.718 0.177
PD-CRS PC subsco e 28.30±2.79 27.86±3.44 -0.23 0.010 29.07±1.25 28.67±1.94 -0.31 0.010 0.976 0.003
Con on a ion naming 18.50±2.69 18.35±3.12 -0.09 0.284 19.29±1.03 18.92±1.80 -0.30 0.010 0.199 0.007
Clock copying 9.80±0.88 9.51±1.19 -0.29 0.002 9.78±0.52 9.75±0.64 -0.06 0.571 0.041 N.A.
Da a a e mean±SD alues.
p alues we e compu ed using a GLM epea ed-measu es p ocedu e. *p, change o e ime (V2 s V0) in pa ien s wi h PD-NC wi h SCC a V0; †p,
change o e ime (V2 s V0) in pa ien s wi h PD-NC wi hou SCC a V0; ‡p, g oup– isi in e ac ion; §p, pa ien s wi h PD-NC wi h SCC s pa ien s wi h
PD-NC wi hou SCC. Age, disease du a ion, educa ion, and LEDD a V0 we e included as co a ia es. Pa ien s wi h PD-NC wi h SCC s pa ien s wi h PD-
NC wi hou SCC we e no applicable i he in e ac ion es was signi ican .
FS, on al-subco ical; GLM; gene al linea model; LEDD, le odopa equi alen daily dose; N.A., no applicable; PD, Pa kinson’s disease; PD-CRS, Pa kin-
son’s Disease Cogni i e Ra ing Scale; PD-NC, Pa kinson’s disease wi h no mal cogni ion.