Ci a ion: Heim ich, K.G.; Mendo ,
S.; Schönenbe g, A.; San os-Ga cía,
D.; Mi , P.; COPPADIS S udy G oup;
P ell, T. Dep essi e Symp oms and
Thei Impac on Quali y o Li e in
Pa kinson’s Disease: An Explo a o y
Ne wo k Analysis App oach. J. Clin.
Med. 2023,12, 4616. h ps://
doi.o g/10.3390/jcm12144616
Academic Edi o s: Alejand o
Rod íguez-Moline o and Jussi Sipilä
Recei ed: 19 June 2023
Re ised: 4 July 2023
Accep ed: 8 July 2023
Published: 11 July 2023
Copy igh : © 2023 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
Jou nal o
Clinical Medicine
A icle
Dep essi e Symp oms and Thei Impac on Quali y o Li e in
Pa kinson’s Disease: An Explo a o y Ne wo k
Analysis App oach
Kons an in G. Heim ich 1,*,† , Sa ah Mendo 1,† , Aline Schönenbe g 2, Diego San os-Ga cía3, Pablo Mi 4,5,
COPPADIS S udy G oup 6,‡ and Tino P ell 2
1Depa men o Neu ology, Jena Uni e si y Hospi al, Am Klinikum 1, 07747 Jena, Ge many
2Depa men o Ge ia ics, Halle Uni e si y Hospi al, E ns -G ube-S aße 40, 06120 Halle, Ge many
3Depa men o Neu ology, CHUAC (Complejo Hospi ala io Uni e si a io de A Co uña), c/As Xubias 84,
15006 A Co uña, Spain
4Unidad 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,
41013 Se ille, Spain
5Cen o de In es igación Biomédica en Red Sob e En e medades Neu odegene a i as (CIBERNED),
28031 Mad id, Spain
6Fundación Española de Ayuda a la In es igación en En e medades Neu odegene a i as y/o de O igen
Gené ico, Calle An onio J de Suc e 1A, 15179 Olei os, Spain
*Co espondence: [email p o ec ed]
†These au ho s con ibu ed equally o his s udy.
‡Membe ship o he COPPADIS S udy G oup is p o ided in he Appendix A.
Abs ac :
The clinical p esen a ion o Pa kinson’s disease (PD) is o en domina ed by dep essi e
symp oms, which can signi ican ly impac he pa ien s’ quali y o li e (QoL). Howe e , i is no
clea how hese dep essi e symp oms a e in e connec ed, o i some symp oms a e mo e in luen ial
in a ec ing QoL. In he Coho o Pa ien s wi h Pa kinson’s Disease in Spain (COPPADIS) s udy,
686 pa ien s wi h PD we e analyzed using ne wo k analyses. The pa ien s comple ed he Beck
Dep ession In en o y II (BDI-II) and p o ided hei o e all QoL (EUROHIS-QOL) a he beginning
o he s udy. The s udy used cen ali y measu es such as Expec ed In luence and B idge Expec ed
In luence o iden i y dep essi e symp oms ha had he g ea es impac on o e all QoL. The esul s
o explo a o y ne wo k analyses indica e ha he BDI-II i ems ela ed o loss o ene gy,pas ailu e,
and i edness o a igue ha e he g ea es impac on o e all QoL as measu ed by he EUROHIS-QOL
8-i em index. The loss o ene gy and i edness o a igue BDI-II i ems a e also s ongly associa ed wi h a
numbe o di e en EUROHIS-QOL i ems, acco ding o B idge Expec ed In luences. Fo indi iduals
su e ing om PD, ne wo k analysis can aid in iden i ying signi ican non-mo o symp oms ha
impac hei QoL, hus pa ing he way o po en ial imp o emen s.
Keywo ds: Pa kinson’s disease; quali y o li e; BDI-II; dep ession; a igue; ne wo k analysis
1. In oduc ion
Pa kinson’s disease (PD) is one o he mos common p og essi e neu odegene a i e
diso de s and cha ac e ized by mo o and a ious non-mo o symp oms [
1
]. Dep ession is
a c ucial ac o ha de e mines he quali y o li e (QoL) in indi iduals wi h PD, and i is
a pa icula ly signi ican non-mo o symp om [
2
–
5
]. The o e all QoL and heal h- ela ed
QoL a e c i ical ou comes o heal hca e, and hey a e impo an p edic o s o mo bidi y
and mo ali y [
6
,
7
]. The e o e, iden i ying and ea ing dep ession is essen ial o main ain
QoL in indi iduals wi h PD. Howe e , jus a small numbe o indi iduals wi h PD who
epo dep essi e symp oms ul ill he diagnos ic c i e ia o a majo dep essi e diso de
as de ined by he Diagnos ic and S a is ical Manual o Men al Diso de s (DSM) [
8
,
9
].
J. Clin. Med. 2023,12, 4616. h ps://doi.o g/10.3390/jcm12144616 h ps://www.mdpi.com/jou nal/jcm
J. Clin. Med. 2023,12, 4616 2 o 13
None heless, e en sub h eshold dep essi e symp oms can nega i ely a ec he QoL o
indi iduals wi h PD [
10
]. To p o ide ailo ed ea men o indi iduals wi h PD and
dep essi e symp oms, i is impo an o de e mine which dep essi e symp oms ha e he
g ea es impac on gene al QoL and di e en domains o QoL.
To add ess his inqui y, one mus con on a ious me hodological challenges. Measu -
ing and diagnosing dep ession in PD p esen s di icul ies since he e a e mul iple dis inc
measu es a ailable. Diagnosis and hus p e alence may a y depending on he de ini ion
o dep essi e diso de s, e.g., majo dep ession acco ding o DSM c i e ia o dep essi e episode
acco ding o he In e na ional Classi ica ion o Diseases (ICD), as well as a ious sel - epo
o clinician- a ed psychia ic symp om a ing scales [
9
,
11
]. In addi ion, he e is signi ican
o e lap be ween dep ession and o he non-mo o symp oms o PD [
7
,
12
,
13
]. Addi ionally,
di e en dep essi e symp oms may ha e he same o opposi e e ec on QoL, making
i challenging o de e mine he one-di ec ional e ec o hese symp oms. Consequen ly,
con en ional s a is ical me hods may no cap u e he in ica e in e play be ween dep essi e
symp oms and QoL measu es. This p esen s an exci ing scien i ic challenge ha equi es
ca e ul conside a ion.
The me hod o ne wo k analysis is a p omising way o model in e ac ions be ween
a la ge numbe o a iables, which is pa icula ly impo an o he s udy o men al
heal h p oblems [
14
]. Unlike classical eg ession modeling, which educes he s uc u e o
a iables o hei sha ed in o ma ion, ne wo k analysis di ec ly es ima es he associa ions
be ween all a iables [
15
,
16
]. This explo a o y app oach allows o he isualiza ion o he
ela ionships be ween mul iple a iables wi hou he assump ion o a di ec ion o e ec s. In
his s udy, we implemen ed ne wo k analysis o e eal he complex in e ac i e ela ionship
be ween dep essi e symp oms and QoL in people wi h PD (PwPD).
2. Ma e ials and Me hods
2.1. S udy Design and Pa icipan s
We used da a om he na ional, mul icen e , and longi udinal Coho o Pa ien s
wi h Pa kinson’s Disease in Spain (COPPADIS) s udy [
17
]. Non-demen ed PwPD be ween
30 and 75 yea s we e ec ui ed om Janua y 2016 o No embe 2017. Mo e de ailed
in o ma ion ega ding he s udy design, con en , and exclusion c i e ia can be ound in he
COPPADIS s udy p o ocol [
17
]. We selec ed PwPD o whom measu es o dep ession and
QoL we e a ailable a baseline (N = 686).
2.2. Ex ac ed Va iables
Fo measu emen o dep essi e symp oms, he Beck Dep ession In en o y II (BDI-II)
was used. The BDI-II consis s o 21 i ems (each a ed on a 4-poin Like scale anging
om ze o o h ee). The summed o al sco e anges om 0 o 63 poin s, wi h highe alues
indica ing mo e dep essi e symp oms [
18
]. In ou ne wo k analysis, we e ained om
classi ying pa ien s in o wo ca ego ies o ha ing o no ha ing dep ession. We el ha
e en he p esence o subsynd omal dep ession o some dep essi e symp oms could impac
he QoL. Howe e , o desc ip i e s a is ics, we elied on he es ablished BDI h eshold o
iden i y pa ien s wi h dep ession.
QoL was assessed wi h he EUROHIS-QOL [
19
]. The EUROHIS-QOL was de i ed
om he Wo ld Heal h O ganiza ion Quali y o Li e assessmen [
20
]. I consis s o eigh
i ems gi en on a 5-poin Like scale and co e s psychological, physical, social, and en i-
onmen al domains o QoL [
19
]: How would you a e you quali y o li e? (QOL); How
sa is ied a e you wi h you heal h? (HEA); Do you ha e enough ene gy o e e yday li e?
(ENE); How sa is ied a e you wi h you abili y o pe o m you daily li ing ac i i ies?
(ACT); How sa is ied a e you wi h you sel ? (YOU); How sa is ied a e you wi h you
pe sonal ela ionships? (REL); Ha e you enough money o mee you needs? (MON); How
sa is ied a e you wi h he condi ions o you li ing place? (LIV).
An index o o e all QoL (EUROHIS-QOL 8-i em index) is calcula ed by summa ion o
he sco es o e e y i em, whe eby highe alues indica e a be e QoL [21].
J. Clin. Med. 2023,12, 4616 3 o 13
Fu he mo e, he ollowing a iables we e ob ained o desc ibe he coho : age, sex,
Hoehn and Yah s age [
22
], Uni ied Pa kinson’s Disease Ra ing Scale (UPDRS) pa s III and
IV [
23
], o al sco es o he Non-Mo o Symp oms Scale in Pa kinson’s disease (NMSS) [
24
],
and he Mini-Men al S a e Examina ion (MMSE) [25].
2.3. S a is ical Analyses
Fo s a is ical analyses, we used R ( e sion 4.2.1, R Founda ion o S a is ical Com-
pu ing, Vienna, Aus ia), SPSS (IBM SPSS S a is ics 27, IBM, A monk, NY, USA), and
JASP ( e sion 0.15, JASP Team, Ams e dam, The Ne he lands). Fo he cha ac e iza ion
o he coho , desc ip i e s a is ics we e applied. Da a we e es ed o no mali y by using
he Shapi o–Wilk es . Fo non-no mally dis ibu ed da a, he median and in e qua ile
ange we e de e mined. The le el o s a is ical signi icance o all es s was se a p< 0.05
( wo- ailed).
Explo a o y ne wo k analyses we e conduc ed o explo e he associa ions be ween he
21 BDI-II i ems and he EUROHIS-QOL. In a ne wo k, he whole complex in e ac ing sys em
be ween a ious symp oms is used o unde s and hei connec ions. A egula iza ion
echnique was used o p e en o e i ing he s uc u e o he ne wo k [
26
], called he
ex ended Bayesian in o ma ion c i e ion (EBIC) [
27
,
28
] wi h he leas absolu e sh inkage
and selec ion ope a o (LASSO) [
29
]. Due o he o dinal s uc u e o he da a, polycho ic
co ela ions we e es ima ed [
30
]. The uning pa ame e o EBICglasso was se o 0.5 o allow
mo e sensi i e and speci ic ne wo k analysis. The i ems o he ques ionnai es a e displayed
by he nodes o he ne wo k and posi ioned by he F uch e man–Reingold algo i hm [
31
].
The connec ions be ween nodes a e called edges and hei hickness indica es he s eng h
o he co ela ions. Co ela ions we e classi ied as low (| |= 0.1), mode a e (| | = 0.3),
o s ong (| | = 0.5) [
32
]. Blue edges e e o a posi i e co ela ion, and ed edges o a
nega i e one.
To desc ibe he ne wo k, he cen ali y measu e Expec ed In luence was de e mined by
ela i e alues. The Expec ed In luence o a node is de ined as he sum o he absolu e
edge weigh s ha a e connec ed o ha node, aking in o accoun posi i e and nega i e
edges [
33
]. Addi ionally, he cen ali y measu e B idge Expec ed In luence (1-s ep) was
de e mined using ela i e alues. B idge Expec ed In luence e e s o he sum o he alue
o all edges ha exis be ween a node o one communi y (i.e., a dep essi e symp om) and
all nodes o ano he communi y (i.e., he eigh i ems o he EUROHIS-QOL) [34].
Mo eo e , we de e mined nodewise p edic abili y o de e mine how well a gi en node
o a ne wo k (i.e., he EUROHIS-QOL 8-i em index) is p edic able by all nodes di ec ly
connec ed o i (i.e., associa ed dep essi e symp oms) [
35
]. The ob ained explained a iance
R
2
can be be ween 0 and 1, and alues
≥
0.13 a e de ined as mode a e and
≥
0.26 as high [
32
].
Ne wo k s abili y was assessed by means o he co ela ion s abili y (CS) coe icien
(numbe o case-d opping boo s aps = 1000). The CS coe icien quan i ies he p opo ion
o cases which can be omi ed o s ill main ain a co ela ion wi h he o iginal cen ali y
measu e ha is a minimum 0.7 in a leas 95% o samples [
16
]. The CS coe icien should
be in gene al abo e 0.25 and p e e able abo e 0.5 [16].
3. Resul s
3.1. Desc ip i e Analyses
Desc ip i e s a is ics o he s udy popula ion a e shown in Table 1. O he 686 PwPD,
274 (39.9%) we e emale and 412 (60.1%) we e male. Pa ien s had a median age o 64 yea s
(IQR = 57–70 yea s), and a median du a ion o he disease o i e yea s (IQR = 2–8 yea s).
Mos pa ien s had a disease s age wi h bila e al in ol emen (Hoehn and Yah s age
≥
2),
and mode a e mo o impai men (median UPDRS III: 21 poin s; IQR = 14–30). F equen ly,
hey expe ienced one mo o complica ion (median UPDRS IV: 1 poin ; IQR = 0–3). Pa ien s
p esen ed non-mo o symp oms acco ding o he NMSS wi h a median o al sco e o
35 poin s
(IQR = 19–61). The median BDI-II o al sco e was 7 poin s (IQR = 3–13). Using
J. Clin. Med. 2023,12, 4616 4 o 13
he p e iously desc ibed BDI-II cu -o s, 16.2% (N = 111) had dep ession, 27.0% (N = 185)
had sub h eshold dep ession, and 56.9% (N = 390) had no dep ession [36].
Table 1. Desc ip i e s a is ics (N = 686).
Va iable
Age 64 (57–70)
Disease du a ion 5 (2–8)
HY o 2 (2–2)
UPDRS III o 21 (14–30)
UPDRS IV o 1 (0–3)
NMSS, o al sco e 35 (19–61)
MMSE, o al sco e 30 (29–30)
BDI-II, o al sco e 7 (3–13)
1. Sadness 0 (0–1)
2. Pessimism 0 (0–1)
3. Pas ailu e 0 (0–0)
4. Loss o pleasu e 0 (0–1)
5. Guil y eelings 0 (0–0)
6. Punishmen eelings 0 (0–0)
7. Sel -dislike 0 (0–0)
8. Sel -c i icalness 0 (0–1)
9. Suicidal hough s o wishes 0 (0–0)
10. C ying 0 (0–1)
11. Agi a ion 0 (0–1)
12. Loss o in e es 0 (0–1)
13. Indecisi eness 0 (0–1)
14. Wo hlessness 0 (0–1)
15. Loss o ene gy 1 (0–1)
16. Changes in sleeping pa e n 1 (0–2)
17. I i abili y 0 (0–1)
18. Changes in appe i e 0 (0–1)
19. Concen a ion di icul y 1 (0–1)
20. Ti edness o a igue 1 (0–1)
21. Loss o in e es in sex 0 (0–1)
EUROHIS-QOL 8-i em index 31 (28–33)
1. QOL, quali y 4 (3–4)
2. HEA, heal h 3 (3–4)
3. ENE, ene gy 4 (3–4)
4. ACT, ac i i ies 4 (3–4)
5. YOU, you sel 4 (3–4)
6. REL, ela ionships 4 (4–4)
7. MON, money 4 (3–4)
8. LIV, li ing 4 (4–5)
Values a e gi en as he medians and in e qua ile anges. BDI-II: e ised Beck Dep ession In en o y; EUROHIS-
QOL: Eu opean Union Heal h In e iew Su ey o Quali y O Li e (QOL: How would you a e you quali y
o li e?; HEA: How sa is ied a e you wi h you heal h?; ENE: Do you ha e enough ene gy o e e yday li e?;
ACT: How sa is ied a e you wi h you abili y o pe o m you daily li ing ac i i ies?; YOU: How sa is ied a e you
wi h you sel ?; REL: How sa is ied a e you wi h you pe sonal ela ionships?; MON: Ha e you enough money o
mee you needs?; LIV: How sa is ied a e you wi h he condi ions o you li ing place?); HY: Hoehn and Yah
s age; MMSE: Mini-Men al S a e Examina ion; N: numbe o pa icipan s; NMSS: Non-Mo o Symp oms Scale in
Pa kinson’s Disease; UPDRS: Uni ied Pa kinson’s Disease Ra ing Scale.
3.2. Ne wo k Analyses
To explo e he links be ween dep essi e symp oms (21 BDI-II i ems) and EUROHIS-
QOL, ne wo k analyses we e conduc ed. The s udy examined wo models: he i s model
included he EUROHIS-QOL 8-i em index, while he second model included all eigh i ems
o he EUROHIS-QOL.
J. Clin. Med. 2023,12, 4616 5 o 13
3.2.1. Ne wo k Model 1: Associa ion be ween BDI-II I ems and O e all QoL
(EUROHIS-QOL 8-I em Index)
The ne wo k plo o model 1 is shown in Figu e 1. The blue nodes display he i ems o
he BDI-II (b1–b21), and he o ange node displays he EUROHIS-QOL 8-i em index (QOL8)
as a measu e o o e all QoL.
Figu e 1.
Ne wo k s uc u e BDI-II i ems and EUROHIS-QOL 8-i em index (model 1). The blue nodes
display he i ems o he BDI-II (b1–b21), and he o ange node displays he summed EUROHIS-QOL
8-i em index (QOL8). The edges display he co ela ions be ween he nodes. Blue edges ep esen
posi i e associa ions, and ed edges ep esen nega i e associa ions. The hickness o he edges
indica e how s ong hese connec ions a e. BDI-II: e ised Beck Dep ession In en o y (b1: Sadness;
b2: Pessimism; b3: Pas ailu e; b4: Loss o pleasu e; b5: Guil y eelings; b6: Punishmen eelings;
b7: Sel -dislike; b8: Sel -c i icalness; b9: Suicidal hough s o wishes; b10: C ying; b11: Agi a ion;
b12: Loss o in e es ; b13: Indecisi eness; b14: Wo hlessness; b15: Loss o ene gy; b16: Changes in
sleeping pa e n; b17: I i abili y; b18: Changes in appe i e; b19: Concen a ion di icul y; b20: Ti ed-
ness o a igue; b21: Loss o in e es in sex); EUROHIS-QOL: Eu opean Union Heal h In e iew
Su ey o Quali y O Li e.
On a global le el, he ne wo k was well-connec ed (137 o 231 non-ze o edges) wi hou
isola ed nodes. The BDI-II and QOL8 nodes had nume ous in e ac ions, p ima ily nega i e
ones (indica ed by ed edges). This means ha dep essi e symp oms we e linked o poo e
QoL. The s onges nega i e connec ions we e obse ed be ween QOL8–loss o ene gy (b15),
QOL8–pas ailu e (b3), and QOL8– i edness o a igue (b20), wi h edge weigh s de ailed in
Table S1.
Expec ed In luence was de e mined o each node (see Figu e 2, and Table S1). A
high Expec ed In luence means ha changing he alue o his node can ha e a apid
e ec on o he nodes wi hin he ne wo k. He e, QOL8 had he s onges nega i e Expec ed
In luence. Acco dingly, QOL8 had he highes nega i e inpu weigh s om o he nodes
ha a e di ec ly connec ed. The 13 nodes ha we e di ec ly connec ed o QOL8 (sadness,
pessimism,pas ailu e,loss o pleasu e,sel -dislike,suicidal hough s o wishes,c ying,agi a ion,
loss o in e es ,indecisi eness,loss o ene gy,changes in appe i e, i edness o a igue) explained
42.8% o QOL8 a iance, as e ealed by nodewise p edic abili y analysis (see Table S1).

J. Clin. Med. 2023,12, 4616 6 o 13
Figu e 2.
Expec ed In luence BDI-II i ems and EUROHIS-QOL 8-i em index (model 1). Expec ed
In luence cen ali y measu es o he i ems o he BDI-II (b1–b21) and he EUROHIS-QOL 8-i em
index (QOL8) a e gi en in ela i e alues. BDI-II: e ised Beck Dep ession In en o y (b1: Sadness;
b2: Pessimism; b3: Pas ailu e; b4: Loss o pleasu e; b5: Guil y eelings; b6: Punishmen eelings;
b7: Sel -dislike; b8: Sel -c i icalness; b9: Suicidal hough s o wishes; b10: C ying; b11: Agi a ion;
b12: Loss o in e es ; b13: Indecisi eness; b14: Wo hlessness; b15: Loss o ene gy; b16: Changes in
sleeping pa e n; b17: I i abili y; b18: Changes in appe i e; b19: Concen a ion di icul y; b20: Ti ed-
ness o a igue; b21: Loss o in e es in sex); EUROHIS-QOL: Eu opean Union Heal h In e iew
Su ey o Quali y O Li e.
Acco ding o he case-d opping boo s apped p ocedu e, he ne wo k can be consid-
e ed s able as he CS coe icien o Expec ed In luence emained high (CS(co = 0.7) = 0.67)
(see Figu e S1).
3.2.2. Ne wo k Model 2: Associa ion be ween BDI-II I ems and he Eigh
EUROHIS-QOL I ems
In he second ne wo k, we analyzed he associa ion be ween BDI-II i ems and he
dis inc EUROHIS-QOL i ems. The ne wo k plo o model 2 is shown in Figu e 3. The blue
nodes ep esen he BDI-II i ems (b1–b21) and he o ange nodes ep esen he eigh i ems o
he EUROHIS-QOL.
Again, ne wo k analysis demons a ed a well-connec ed ne wo k (183 o 406 non-ze o
edges) wi hou isola ed nodes. One can dis inguish wo pa s e lec ing he wo di e en
ques ionnai es. Howe e , he e we e many in e ac ions be ween he nodes o he BDI-II
and he EUROHIS-QOL. These in e ac ions we e p ima ily nega i e, as depic ed by he
ed edges. This implies ha a lowe in ensi y o dep essi e symp oms is associa ed wi h a
highe QoL. The s onges nega i e connec ion be ween he wo pa s was obse ed be-
ween “ i edness o a igue” and “Do you ha e enough ene gy o e e yday li e?” (b20 and
ENE), which is no su p ising as bo h a e simila cons uc s. Howe e , iden i ying he de-
p essi e symp oms ha a e linked wi h all eigh i ems on he EUROHIS-QOL ques ionnai e
is a ma e o g ea in e es . This is why B idge Expec ed In luences we e de e mined. The
B idge Expec ed In luence cen ali y measu es a e shown in Figu e 4(and also abula ed
in Table S2). The nodes b15 (loss o ene gy) and b20 ( i edness o a igue) we e ound o
ha e he highes B idge Expec ed In luences, sugges ing ha hey a e he mos s ongly
J. Clin. Med. 2023,12, 4616 7 o 13
associa ed dep essi e symp oms wi h all eigh i ems on he EUROHIS-QOL ques ionnai e.
The eby, node b15 is associa ed in pa icula wi h ACT (How sa is ied a e you wi h you
abili y o pe o m you daily li ing ac i i ies?) (edge weigh :
−
0.102). This means ha
eeling loss o ene gy has g ea es in luence on he abili y o pe o m daily li ing ac i i ies
among he QoL domains. Mo eo e , node b20 showed an associa ion wi h ENE (Do you
ha e enough ene gy o e e yday li e?) o he quali y-o -li e domain (edge weigh :
−
0.236).
Respec i ely, pa ien s who epo ed i edness o a igue had less ene gy o e e yday li e.
As e ealed by he ne wo k plo o model 2 (Figu e 3), hese wo dep essi e symp oms wi h
he highes B idge Expec ed In luence (loss o ene gy and i edness o a igue) we e closely
connec ed o each o he . Loss o pleasu e (b4) was he hi d in luen ial dep essi e symp om,
which is especially associa ed wi h QOL (How would you a e you quali y o li e?; edge
weigh :
−
0.063) and REL (How sa is ied a e you wi h you pe sonal ela ionships?; edge
weigh : −0.053).
Figu e 3.
Ne wo k s uc u e BDI-II i ems and EUROHIS-QOL i ems (model 2). The blue nodes display
he i ems o he BDI-II (b1–b21), and he o ange nodes display he eigh i ems o he EUROHIS-QOL.
The edges display he co ela ions be ween he nodes., Blue edges ep esen posi i e associa ions,
and ed edges ep esen nega i e associa ions. The hickness o he edges indica e how s ong hese
connec ions a e. BDI-II: e ised Beck Dep ession In en o y (b1: Sadness; b2: Pessimism; b3: Pas ailu e;
b4: Loss o pleasu e; b5: Guil y eelings; b6: Punishmen eelings; b7: Sel -dislike; b8: Sel -c i icalness;
b9: Suicidal hough s o wishes; b10: C ying; b11: Agi a ion; b12: Loss o in e es ; b13: Indecisi eness;
b14: Wo hlessness; b15: Loss o ene gy; b16: Changes in sleeping pa e n; b17: I i abili y; b18: Changes
in appe i e; b19: Concen a ion di icul y; b20: Ti edness o a igue; b21: Loss o in e es in sex);
EUROHIS-QOL: Eu opean Union Heal h In e iew Su ey o Quali y O Li e (QOL: How would you
a e you quali y o li e?; HEA: How sa is ied a e you wi h you heal h?; ENE: Do you ha e enough
ene gy o e e yday li e?; ACT: How sa is ied a e you wi h you abili y o pe o m you daily li ing
ac i i ies?; YOU: How sa is ied a e you wi h you sel ?; REL: How sa is ied a e you wi h you pe sonal
ela ionships?; MON: Ha e you enough money o mee you needs?; LIV: How sa is ied a e you wi h
he condi ions o you li ing place?).
J. Clin. Med. 2023,12, 4616 8 o 13
Figu e 4.
B idge Expec ed In luence BDI-II i ems and EUROHIS-QOL i ems (model 2). B idge Expec ed
In luence cen ali y measu es o he i ems o he BDI-II (b1–b21) and he eigh i ems o he EUROHIS-
QOL a e gi en in ela i e alues. BDI-II: e ised Beck Dep ession In en o y (b1: Sadness; b2: Pessimism;
b3: Pas ailu e; b4: Loss o pleasu e; b5: Guil y eelings; b6: Punishmen eelings; b7: Sel -dislike;
b8: Sel -c i icalness; b9: Suicidal hough s o wishes; b10: C ying; b11: Agi a ion; b12: Loss o in e -
es ; b13: Indecisi eness; b14: Wo hlessness; b15: Loss o ene gy; b16: Changes in sleeping pa e n;
b17: I i abili y; b18: Changes in appe i e; b19: Concen a ion di icul y; b20: Ti edness o a igue;
b21: Loss o in e es in sex); EUROHIS-QOL: Eu opean Union Heal h In e iew Su ey o Quali y O
Li e (QOL: How would you a e you quali y o li e?; HEA: How sa is ied a e you wi h you heal h?;
ENE: Do you ha e enough ene gy o e e yday li e?; ACT: How sa is ied a e you wi h you abili y o
pe o m you daily li ing ac i i ies?; YOU: How sa is ied a e you wi h you sel ?; REL: How sa is ied a e
you wi h you pe sonal ela ionships?; MON: Ha e you enough money o mee you needs?; LIV: How
sa is ied a e you wi h he condi ions o you li ing place?).
Acco ding o he case-d opping boo s apped p ocedu e, he ne wo k can be conside ed
s able as he CS coe icien o B idge Expec ed In luence emained high (
CS(co = 0.7) = 0.60
)
(see Figu e S2).
4. Discussion
Ou esea ch u ilized ne wo k analysis o unco e in ica e ela ionships be ween
dep essi e symp oms and QoL in PwPD. Ou indings con i med ha he e is a s ong
co ela ion be ween he 21 i ems o he BDI-II and EUROHIS-QOL, whe he we conside ed
he EUROHIS-QOL 8-i em index (model 1) o all eigh i ems oge he (model 2). These
co ela ions a e la gely nega i e, indica ing ha lowe le els o dep essi e symp oms a e
associa ed wi h highe QoL. Speci ically, he wo BDI-II i ems ela ed o loss o ene gy (b15)
and i edness o a igue (b20) had he mos signi ican impac on QoL. Fu he mo e, ou
ne wo k analysis e ealed ha hese wo BDI-II i ems (b15 and b20) we e closely linked o
each o he .
J. Clin. Med. 2023,12, 4616 9 o 13
When e alua ing he impac o dep essi e symp oms on QoL using he EUROHIS-
QOL 8-i em index, ou ne wo k analysis (model 1) ound ha eelings o loss o ene gy (b15),
pas ailu e (b3), and i edness o a igue (b20) we e in luen ial symp oms. Conside ing he
impac o dep essi e symp oms on all eigh i ems o he EUROHIS-QOL (model 2), ne wo k
analysis e ealed nega i e associa ions be ween QoL and especially loss o ene gy (b15)
and i edness o a igue (b20). Taking in o accoun he complex in e ac ions o all 21 BDI-II
i ems and he eigh QoL measu es, ne wo k analysis demons a ed ha bo h symp oms a e
closely connec ed o each o he . In addi ion, loss o pleasu e (b4) was iden i ied as he hi d
in luen ial dep essi e symp om as e ealed by B idge Expec ed In luence.
In summa y, he mos in luen ial dep essi e symp oms a ec ing bo h he EUROHIS-
QOL 8-i em index and all eigh EUROHIS-QOL i ems oge he we e loss o ene gy (b15) and
eelings o i edness o a igue (b20). O e all, his s udy sheds ligh on he impo ance o
conside ing he complex in e play be ween dep essi e symp oms and QoL measu es.
Fa igue is gene ally desc ibed as an all-encompassing eeling o i edness, dec eased
ene gy, and o en a sense o comple e deple ion. I should no be con used wi h symp oms
o dep ession, such as eelings o wo hlessness, despai , o hopelessness, al hough i can be
a sign o dep ession. Addi ionally, i is no equi alen o limb weakness o any isible sign
o physical weakness [
37
]. The de ini ion indica es ha loss o ene gy may be pa o he
clinical pic u e o a igue. Howe e , hese symp oms a e conside ed sepa a e componen s
o he BDI-II since no all indi iduals wi h loss o ene gy expe ience es ablished a igue.
Ne e heless, ou esea ch has e ealed ha bo h aspec s a e closely linked o one ano he .
One o he mos p e alen and disabling non-mo o symp oms in PwPD is a igue [
38
],
which can mani es e en in he ea ly s ages o he disease [
39
] and o en pe sis s o wo sens
o e ime [
40
,
41
]. This can lead o dec eased pa icipa ion in social and ec ea ional ac i i-
ies [
42
,
43
], nega i ely impac ing he pa ien s’ QoL [
38
,
44
]. This was also demons a ed in
his s udy, in which bo h BDI-II i ems (loss o ene gy and i edness o a igue) had a s ong
in luence on QoL. The e o e, iden i ica ion and ea men o a igue in PD appea s o be
p omising o imp o e pa ien s’ QoL. Howe e , he e a e cu en ly no speci ic guidelines o
managing PD- ela ed a igue, and esea ch has no p o ided enough e idence o suppo
he use o pha maceu ical o non-pha maceu ical ea men s [
45
,
46
]. The p ima y and
essen ial s ep in managing a igue in PD is o educa e pa ien s and hei amilies abou i s
common occu ence.
Ano he BDI-II i em ha has g ea in luence on QoL was pas ailu e (b3). The ex-
pe ience o pas ailu es can a ec QoL [
47
,
48
], leading o nega i e psychological ou -
comes [
49
,
50
]. Indi iduals who ha e expe ienced se backs, ailu es, o nega i e li e e en s
such as di o ce o job loss, may a ibu e blame o hemsel es and expe ience shame due
o hei inabili y o mee hei own o o he s’ expec a ions in a ious aspec s o li e [
51
,
52
].
These eelings o shame can also con ibu e o a lowe QoL and inc eased suscep ibili y o
psychopa hological symp oms [53,54].
Mo eo e , he p esence o loss o pleasu e (b4), also known as anhedonia, is o cen al
impo ance wi hin he ne wo k. Anhedonia is seen as he inabili y o eel pleasu e om ac-
i i ies o expe iences ha a e no mally enjoyable o ewa ding [
55
]. The e o e, anhedonia
can ha e a signi ican impac on QoL [56,57].
Using ne wo k analyses, ou p e ious s udy e ealed he impac o dep essi e symp-
oms in PwPD [
58
,
59
]. I was demons a ed ha in pa icula eelings o sadness a e
impo an wi hin he complex in e ac ing ne wo k o non-mo o symp oms in PD, as as-
sessed by he NMSS [
58
]. Fu he mo e, a igue was iden i ied as non-mo o symp om ha
is mos s ongly associa ed wi h heal h- ela ed QoL, as assessed by he Pa kinson’s Disease
Ques ionnai e 39 (PDQ-39) summa y index and in pa icula he mobili y and ac i i ies o
daily li ing subscales o he PDQ-39 [
59
]. These indings demons a e ha dep ession is
a he e ogenous cons uc , and dep essi e symp oms o en o e lap wi h o he non-mo o
symp oms in PD [60].
Ou s udy has shown ha he loss o ene gy and cons an a igue a e c ucial ac o s in
he ne wo k o dep essi e symp oms and QoL measu es. These symp oms a e ca ego ized