Changes in Principal Caregiver Mood Affects the Mood of the Parkinson’s Disease Patient: The Vicious Cycle of Illness

Jou nal o Pa kinson’s Disease 13 (2023) 219–231 DOI 10.3233/JPD-225014 IOS P ess 219 Resea ch Repo Changes in P incipal Ca egi e Mood A ec s he Mood o he Pa kinson’s Disease Pa ien : The Vicious Cycle o Illness Diego San os-Ga c´ ıaa,∗, Te esa de Deus Fon icobab, Ca los Co es Ba olom´ ea, Ma ia J. Feal Paincei asa, Ma ia C is ina ´ I˜ niguez-Al a adoa, Iago Ga c´ ıa D´ ıaza, Sil ia Jes´ usc,d, Ma ia Te esa Buongio noe, Llu´ ıs Planellas , Ma ina Cosgayag, Juan Ga c´ ıa Calden eyh, Nu ia Caballoli, Ines Lega daj, Jo ge He n´ andez Va ad,k, I ia Cabol, Lydia L´ opez Manzana esm, Isabel Gonz´ alez A ambu ud,n, Ma ia A. ´ A ila Ri e ao,V ´ ıc o G´ omez Mayo domop,V ´ ıc o Noguei aq,V ´ ıc o Puen e , Julio Do o Ga c´ ıa-So os, Ca men Bo u´ e , Be a Solano Vilau, Ma ´ ıa ´ Al a ez Sauco , Lydia Velaw, Sonia Escalan ex, Es he Cuboy, F ancisco Ca illo Padillaz, Juan C. Ma ´ ınez Cas illoaa, Pila S´ anchez Alonsobb, Ma ia G. Alonso Losadacc, Nu ia L´ opez A iz eguidd, I zia Gas ´ onee, Jaime Kulise skyd, , Manuel Men´ endez Gonz´ alezgg, Manuel Seijol, Ja ie R´ uiz Ma ´ ınezhh, Ca idad Vale oii,M ´ onica Ku isjj, Jessica Gonz´ alez A du akk, Ruben Alonso Redondoll, Ca los O d´ asmm, Luis M. L´ opez D´ ıazcc, Da ian McA eenn, Pablo Ma inez-Ma ind, Pablo Mi d,cand COPPADIS S udy G oup1 aCHUAC, Complejo Hospi ala io Uni e si a io de A Co u˜na, A Co u˜na, Spain bCHUF, Complejo Hospi ala io Uni e si a io de Fe ol, A Co u˜na, Spain cUnidad de T as o nos del Mo imien o, Se icio de Neu olog´ıa y Neu ofisiolog´ıa Cl´ınica, Ins i u o de Biomedic- ina de Se illa, Hospi al Uni e si a io Vi gen del Roc´ıo/CSIC/Uni e sidad de Se illa, Se ille, Spain dCIBERNED (Cen o de In es igaci´on Biom´edica en Red En e medades Neu odegene a i as), Spain eHospi al Uni e si a i Mu ua de Te assa, Te assa, Ba celona, Spain Cl´ınica del Pila , Ba celona, Spain gHospi al Cl´ınic de Ba celona, Ba celona, Spain hCen o Neu ol´ogico Oms 42, Palma de Mallo ca, Spain iConso ci Sani a i In eg al, Hospi al Mois´es B oggi, San Joan Desp´ı, Ba celona, 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 qu´es 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 1See he Supplemen a y Ma e ial o ull de ails. ∗Co espondence o: D . Diego San os Ga c´ ıa, Depa men o Neu ology, Hospi al Uni e si a io de A Co u˜ na (HUAC), Com- plejo Hospi ala io Uni e si a io de A Co u˜ na (CHUAC), C/ As Xubias 84, 15006, A Co u˜ na, Spain. Tel.: +34 646173341; E-mail: [email p o ec ed]. ISSN 1877-7171 © 2023 – The au ho s. Published by IOS P ess. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion-NonComme cial License (CC BY-NC 4.0). 220 D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness pHospi al Uni e si a io Cl´ınico 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 ´ıa, Mad id, Spain uIns i u d’Assis `encia Sani `a ia (IAS) - Ins i u Ca al`a de la Salu , Gi ona, Spain Hospi al Gene al Uni e si a io de Elche, Elche, Spain wFundaci´on Hospi al de Alco c´on, Mad id, Spain xHospi al de To osa Ve ge de la Cin a (HTVC), To osa, Ta agona, 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 ´obal de la Laguna, San a C uz de Tene i e, Spain aaHospi al Uni e si a io Ram´on y Cajal, IRYCIS, Mad id, Spain bbHospi al Uni e si a io Pue a de Hie o, Mad id, Spain ccHospi al ´ Al a o Cunquei o, Complejo Hospi ala io Uni e si a io de Vigo (CHUVI), Vigo, Spain ddComplejo Hospi ala io de Toledo, Toledo, Spain eeComplejo Hospi ala io de Na a a, Pamplona, Spain Hospi al de San Pau, Ba celona, Spain ggHospi al Uni e si a io Cen al de As u ias, O iedo, Spain hhHospi al Uni e si a io Donos ia, San Sebas i´an, Spain iiHospi al A nau de Vilano a, Valencia, Spain jjHospi al Rube In e nacional, Mad id, Spain kkHospi al de Cabue˜nes, Gij´on, Spain llUni e si a io Lucus Augus i (HULA), Lugo, Spain mmHospi al Rey Juan Ca los, Mad id, Spain, Mad id, Spain nnUni e si y o Ma yland School o Medicine, Bal imo e, MD, USA Accep ed 19 Decembe 2022 P e-p ess 14 Janua y 2023 Published 14 Ma ch 2023 Abs ac . Backg ound: Al hough many s udies ha e analyzed wha ac o s con ibu e o ca egi e bu den in Pa kinson’s disease (PD), he e is cu en ly no knowledge abou how he s a us o he ca egi e could impac he pa ien . Objec i e: The aim o his s udy was o analyze how he change in he ca egi e ’s s a us in luences PD pa ien s. Me hods: PD pa ien s and hei ca egi e s who we e ec ui ed om Janua y/2016 o No embe /2017 om 35 cen e s in Spain om he COPPADIS coho we e included in he s udy (V0). They we e e alua ed again a 2-yea ollow-up (V2). Ca egi e s comple ed he Za i Ca egi e Bu den In en o y (ZCBI), Ca egi e S ain Index (CSI), Beck Dep es- sion In en o y-II (BDI-II), and EUROHIS-QOL 8-i em index (EUROHIS-QOL8) a V0 and V2. Mul i a ia e models we e used o analyze he impac o he change om V0 o V2 () on he ca egi e ’s s a us o e he change in he pa ien ’s s a us. Resul s: BDI-II and EUROHIS-QOL8 in he ca egi e p edic ed BDI-II (␤= 0.32; p< 0.0001; R2= 0.71) and EUROHIS-QOL8 (␤= 0.39; p< 0.0001; R2= 0.68) in he pa ien , espec i ely. Va iables ela ed o he ca egi e we e no associa ed wi h changes in he pa ien ´s heal h- ela ed QoL (PDQ-39 [39-i em Pa kinson’s disease Ques ionnai e]) o au onomy o ac i i ies o daily-li ing (ADLS [Schwab & England Ac i i ies o Daily Li ing Scale]). Conclusion: The change in he ca egi e ’s mood and global QoL was associa ed wi h he change in he pa ien ’s mood and global QoL, espec i ely, independen ly o o he a iables o he disease in luencing bo h pa ien ´s aspec s. Based on his inding, i could be o g ea impo ance o de ec dep ession in he p incipal ca egi e o a pa ien and ac on i as ea lie as possible. Keywo ds: Ca egi e , longi udinal, mood, Pa kinson’s disease, quali y o li e D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness 221 INTRODUCTION Pa kinson’s disease (PD) is a p og essi e neu ode- gene a i e diso de causing mo o and non-mo o symp oms (NMS) ha esul in loss o pa ien au on- omy o ac i i ies o daily-li ing (ADL) and quali y o li e (QoL) [1]. Gi en ha symp oms p og es- sion wi h longe disease du a ion leads o a loss o independence, he majo i y o pa ien s ha e a p in- cipal ca egi e esponsible o ca e h oughou he cou se o he disease. Howe e , PD symp oms impac no only he pa ien bu on he p incipal ca egi e oo and can cause s ess, bu den, dep ession, and a wo se QoL [2]. Pe sis en ca egi e bu den may lead o s ain, an endu ing change in he ca egi e ’s sense o well-being ha p edisposes o bu nou [3]. Symp oms associa ed wi h ca egi e bu den ha e been iden i ied in di e en s udies, such as cogni i e impai men , apa hy, i i abili y, sleep diso de s, alls, disabili y, and mo e ad anced s age disease, among o he s [2–15]. S ill, he e is no knowledge abou how he s a us o he ca egi e impac s on he pa ien . This is an impo an associa ion because an o e - wo ked ca egi e migh ake wo se ca e o he pa ien o ha e beha io changes (e.g., dep ession, i i abil- i y, e c.) ha could nega i ely in luence he pa ien di ec ly, es ablishing a icious cycle; he wo se he pa ien ’s condi ion, he wo se he ca egi e ’s con- di ion, and ice e sa. In his con ex , i would be especially use ul o analyze how he longi udinally changes expe ienced by he ca egi e can impac on he PD pa ien . Recen ly, we published he la ges (N = 192) and longes (2-yea ollow-up) p ospec i e s udy in which p edic o s o a change in bu den, s ain, mood, and QoL in he p incipal ca egi e o PD pa ien s we e iden i ied [16]. Mood changes in he pa ien we e he main ac o s a ec ing mood in he ca egi e and mood changes in he ca egi e was iden i ied as he main ac o impac ing on s ain, bu den and QoL o he ca egi e . We hypo hesized ha changes in he s a us o he ca egi e migh in luence he pa ien (Fig. 1). Unde his app oach, he aim o he p esen s udy was o analyze i a change in mood (BDI-II [Beck Dep ession In en o y-II]), bu den (ZCBI [Za i Ca egi e Bu den In en o y]), s ain (CSI [Ca egi e S ain Index]), and/o global QoL (EUROHIS-QOL8 [EUROHIS-QOL 8-i em index]) o he p incipal ca egi e o a pa ien wi h PD a e a 2-yea ollow-up was associa ed wi h changes in he pa ien ’s mood (BDI-II), au onomy o ADL (ADLS [Schwab & England Ac i i ies o Daily Li ing Scale]), heal h- ela ed QoL (PDQ-39 [39- i em Pa kinson’s disease Ques ionnai e], and global QoL (EUROHIS-QOL8), independen ly o o he PD ela ed ac o s. In o he wo ds, he goal was o de e - mine i a wo se s a us o he ca egi e impac s on he pa ien . Mo e impo an ly, his would jus i y he necessi y o iden i y and ea o e wo ked ca egi e s as soon as possible, as has been p e iously sugges ed [3]. MATERIALS AND METHODS PD pa ien s and hei ca egi e s, who we e ec ui ed om 35 cen e s in Spain om he COP- PADIS coho [17] om Janua y 2016 o No embe 2017 and e alua ed again a 2-yea ollow-up, we e included in he s udy. Me hodology abou COPPADIS-2015 s udy can be consul ed a h ps:// bmcneu ol.biomedcen al.com/a icles/10.1186/s128 83-016-0548-9 [18]. This is a mul i-cen e , obse - a ional, longi udinal-p ospec i e, 5-yea ollow-up s udy designed o analyze disease p og ession in a Spanish popula ion o PD pa ien s. All he pa ien s included we e diagnosed acco ding o UK PD B ain Bank c i e ia [19]. The p incipal ca egi e [20] o he pa ien was included i he pa ien had a ca egi e who olun a ily ag eed o pa icipa e and sign an in o med consen . Pa ien s had o ha e e ained he same p ima y ca egi e a bo h ime poin s o be included in his analysis. PD pa ien assessmen In PD subjec s, in o ma ion on sociodemog aphic aspec s, ac o s ela ed o PD, como bidi y, and ea - men was collec ed a baseline ( isi V0) and a 2 yea s ±1 mon h ( isi V2). V0 and V2 e alu- a ions included mo o assessmen (Hoenh & Yah [H&Y], Uni ied Pa kinson’s Disease Ra ing Scale [UPDRS] pa III and pa IV, F eezing o Gai Ques ionnai e [FOGQ]), NMS (Non-Mo o Symp- oms Scale [NMSS], Pa kinson’s Disease Sleep Scale [PDSS], Visual Analog Scale-Pain [VAS-Pain], Visual Analog Fa igue Scale [VAFS]), cogni ion (PD-CRS), mood and neu opsychia ic symp oms (BDI-II, Neu opsychia 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]), dis- abili y (ADLS), and heal h- ela ed (PDQ-39) and global QoL (EUROHIS-QOL8) [18]. In all he scales/ques ionnai es a highe sco e indica es a mo e 222 D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness Fig. 1. Hypo hesis p oposed in his s udy. Rega ding p e ious da a published om he COPPADIS coho [16], pa ien ’s mood is he main ac o in luencing ca egi e ’s mood and ca egi e ’s mood he main ac o in luencing ca egi e ’s bu den, s ain and QoL. The ques ion (ques ion ma k) is i he change in he long- e m o hese ca egi e ’s a iables can impac o e he change in pa ien ’s a iables (mood, QoL and au onomy o ADL). ADL, ac i i ies o daily li ing; ADLS, Schwab & England Ac i i ies o Daily Li ing Scale; CSI, Ca egi e S ain Index; EUROHIS-QOL8, EUROHIS-QOL 8-i em index; PD, Pa kinson’s disease; PDQ-39, 39-i em Pa kinson’s disease Ques ionnai e; QoL, quali y o li e; ZCBI, Za i Ca egi e Bu den In en o y. se e e a ec a ion apa om PD-CRS, PDSS, ADLS, and EUROHIS-QOL8, which we e he opposi e. In pa ien s wi h mo o luc ua ions, he mo o assess- men was made du ing he OFF s a e (wi hou medica ion in he las 12 hou s) and du ing he ON s a e. The assessmen was only pe o med wi hou medica ion in pa ien s wi hou mo o luc ua ions. Ca egi e assessmen In ca egi e s, sociodemog aphic da a we e col- lec ed a baseline [16]. Fou aspec s we e analyzed in he ca egi e a V0 and a V2: mood (BDI-II); bu den (ZCBI); s ain (CSI); and global QoL (EUROHIS- QOL8). ZCBI [21] con ains 22 i ems ha a e he impac o he disease on he ca egi e ’s physical, emo ional, and socioeconomic s a us. Responses a e sco ed on a scale om 0 (ne e ) o 4 (nea ly always). The maximum o al sco e, indica i e o he highes bu den, is 88. CSI [22] is a 13-i em ques ionnai e designed o assess he le el o s ess expe ienced by ca egi e s. The e a e wo possible esponses o each i em: “yes” o “no”. The o al sco e is he esul o adding all posi i e esponses ( om 0, no s ess, o 13, maximum le el o s ess). Mood was assessed wi h he BDI-II [23]. This is a sel -adminis e ed, 21 i em ins umen . I has been designed o assess he se e i y o dep ession symp oms in adul s and adolescen s wi h a minimum age o 13 yea s. The e alua ed subjec mus choose one o ou al e na- i es (o de ed om lesse o g ea e se e i y), in each i em, ha bes desc ibes his/he s a us o e he p e i- ous wo weeks. The sco e anges om 0 (minimum) o 63 (maximum). Highe sco es will e lec , a p io i, a wo se mood. Finally, global QoL was measu ed wi h he EUROHIS-QOL8 [24]. This is an 8-i em QoL ques ionnai e (QoL, heal h s a us, ene gy, au on- omy in ac i i ies o daily li ing [ADL], sel -es eem, social ela ionships, economic capaci y, and habi a ) de i ed om he WHOQOL-100 and he WHOQOL- BREF. Fo each i em, he sco e anges om 0 (no a all) o 5 (comple ely). The o al sco e is exp essed as he mean o he indi idual sco es. A highe sco e indica es a highe QoL. D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness 223 Table 1 Co ela ion be ween he change in he s age o he p incipal ca egi e (mood, bu den, s ain and QoL) and he change in he s age o he pa ien (mood, au onomy o ADL, and QoL) om baseline isi (V0) o 2-yea ollow-up isi (V2) V2 – V0 BDI-IIcZCBIcCSIcEUROSHIS-QOL8c BDI-IIcN. A 0.42 (p< 0.0001) 0.39 (p< 0.0001) –0.35 (p< 0.0001) ZCBIc0.42 (p< 0.0001) N. A. 0.55 (p< 0.0001) –0.34 (p< 0.0001) CSIc0.39 (p< 0.0001) 0.55 (p< 0.0001) N. A. –0.31 (p< 0.0001) EUROHIS-QOL8c–0.35 (p< 0.0001) –0.34 (p< 0.0001) –0.31 (p< 0.0001) N. A. BDIp0.39 (p< 0.0001) 0.19 (p= 0.007) 0.18 (p= 0.010) –0.23 (p= 0.001) ADLSp–0.08 (p= 0.271) –0.18 (p= 0.012) –0.14 (p= 0.042) 0.09 (p= 0.184) PDQ-39p0.15 (p= 0.037) 0.13 (p= 0.065) 0.10 (p= 0.163) 0.02 (p= 0.740) EUROHIS-QOL8p–0.08 (p= 0.231) –0.03 (p= 0.629) –0.10 (p= 0.156) 0.39 (p< 0.0001) Spea man co ela ion coe icien was applied ( and p alue a e shown). ADLS, Schwab & England Ac i i ies o Daily Li ing Scale; BDI-II, Beck Dep ession In en o y-II; CSI, Ca egi e S ain Index; PDQ-39, he ZCBI, Za i Ca egi e Bu den In en o y; QoL, quali y o li e. C in subsc ip , ca egi e (i.e., BDI-IIc, change om V0 o V2 in he BDI-II sco e, e c.); P in subsc ip , pa ien . Da a analysis Da a we e p ocessed using SPSS 20.0 o Win- dows. Only PD pa ien s and hei ca egi e s ( he same ca egi e a e he 2-yea ollow-up) om he COP- PADIS coho wi h da a o he BDI-II, ZCBI, CSI, and EUROHIS-QOL8 collec ed a bo h isi s, V0 and V2, we e included in he analysis [16]. Wi h he aim o know he in luence o he change om V0 o V2 o ca egi e ’s a iables o e he change in mood, QoL, and au onomy o ADL in he PD pa ien , linea eg ession models we e conduc ed. The change in each a iable om he pa ien and he ca egi e was calcula ed as he di e ence be ween he alue a V2 and a V0 (i.e., BDI-II = BDI-IIV2 – BDI-IIV0). In all he models, he ou ca egi e ’s a iables we e included (BDI-II; ZCBI; CSI; EUROHIS-QOL8). Fou models we e de ined as ha ing an aspec o he pa ien o analyze as a dependen a iable: 1) Model 1, change in mood (BDI-II); 2) Model 2, change in heal h- ela ed QoL (PDQ-39); 3) Model 3, change in global QoL (EUROHIS-QOL8); 4) Model 4, change in au on- omy o ADL (ADLS). Co a ia es om he pa ien included in he models we e he change om V0 o V2 () in LEDD [25], UPDRS-III-OFF, UPDRS-IV, FOGQ, PD-CRS, NMSS, BDI-II (excep in Model 1 o being he dependen a iable), PDSS, QUIP-RS, NPI, VAS-PAIN, VAFS, ADLS (excep in Model 4 o being he dependen a iable), PDQ-39 (excep in Model 2 o being he dependen a iable), and EUROHIS-QOL8 (excep in Model 3 o being he dependen a iable). Each model was adjus ed o he alue o he dependen a iable a baseline oo. Tol- e ance and a iance in la ion ac o (VIF) we e used o de ec mul icollinea i y. Mul icollinea i y was con- side ed p oblema ic when ole ance was less han 0.2 and, simul aneously, he alue o VIF was 10 and abo e. Spea man’s o Pea son’s co ela ion coe i- cien we e also used as app op ia e (dis ibu ion o a iables was e i ied by a one-sample Kolmogo o - Smi no es ). Co ela ions we e conside ed weak o coe icien alues ≤0.29, mode a e o alues be ween 0.30 and 0.59, and s ong o alues ≥0.60. The p- alue was conside ed signi ican (highly sig- ni ican ) when i was <0.001. S anda d p o ocol app o als, egis a ions, and pa ien consen s Fo his s udy, we ecei ed app o al om he Comi ´ede ´ E ica de la In es igaci´on Cl´ınica de Galicia om Spain (2014/534; 02/DEC/2014). W i - en in o med consen s om all pa icipan s in his s udy we e ob ained. COPPADIS-2015 was classi ied by he AEMPS (Agencia Espa˜ nola del Medica- men o y P oduc os Sani a ios) as a Pos -au ho iza ion P ospec i e Follow-up s udy wi h he code COH- PAK-2014-01. Da a a ailabili y The p o ocol and he s a is ical analysis plan a e a ailable on eques . Deiden i ied pa icipan da a a e no a ailable o legal and e hical easons. RESULTS The s udy included one hund ed and nine y- wo PD pa ien s (63.96 ±8.74 yea s old; 63% males) and hei p incipal ca egi e . The mean age o he ca e- gi e s was 58.82 ±11.71 yea s old, and 69.3% we e emales. Clinical and sociodemog aphic de ails o pa ien s and ca egi e s ha e been ecen ly published [16] and a e shown in Supplemen a y Table 1. 224 D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness Table 2 E ec o changes in he ca egi e o e he change in mood in PD pa ien s om he COPPADIS coho a e 2-yea ollow-up (N = 192) Uni a ia e analysis Mul i a ia e analysis ␤95% CI p␤95% CI p Ca egi e BDI-II 0.42 0.40 – 0.77 <0.0001 0.32 0.27 – 0.67 <0.0001 ZCBI 0.19 0.05 – 0.28 0.006 0.10 –0.02–0.22 0.125 CSI 0.14 0.03 – 1.33 0.039 –0.03 –0.89–0.50 0.576 EUROHIS-QOL8 –0.21 –7.97––1.67 0.003 0.20 1.74–8.13 0.003 Pa ien EUROHIS-QOL8 0.22 0.07–0.40 0.006 –0.56 –9.34––5.95 <0.0001 BDI-II a baseline 0.19 –0.14––0.01 0.035 –0.36 –0.64––0.32 <0.0001 Dependen a iable: change in he PD pa ien om V0 o V2 () in he BDI-II o al sco e. ␤s anda dized coe icien and 95% IC a e shown. a, uni a ia e analysis; b, mul i a ia e analysis (Du bin-Wa son es = 2.11; R2= 0.71). Only signi ican a iables (p< 0.01) om he pa ien in he mul i a ia e analysis a e shown. Co a ia es om he pa ien included we e he change om V0 o V2 () in LEDD, UPDRS-III-OFF, UPDRS-IV, FOGQ, PD-CRS, NMSS, PDSS, QUIP-RS, NPI, VAS-PAIN, VAFS, ADLS, PDQ-39SI, EUROHIS-QOL8, and he sco e on he BDI-II a baseline. ADLS, Schwab & England Ac i i ies o Daily Li ing Scale; BDI-II, Beck Dep ession In en o y-II; CSI, Ca egi e S ain Index; FOGQ, F eezing O Gai Ques ionnai e; LEDD, le odopa equi alen daily dose; Non-Mo o Symp oms Scale; NPI, Neu opsychia ic In en o y; PD-CRS, Pa kinson’s Disease Cogni i e Ra ing Scale; PDQ-39, he 39-i em Pa kinson’s disease Ques ionnai e Summa y Index; PDSS, Pa kinson’s Disease Sleep Scale; QUIP-RS, Ques ionnai e o Impulsi e-Compulsi e Diso de s in Pa kinson’s Disease-Ra ing Scale; UPDRS, Uni ied Pa kinson’s Disease Ra ing Scale; VAS, Visual Analogue Scale; ZCBI, Za i Ca egi e Bu den In en o y. A signi ican mode a e co ela ion was obse ed be ween he ou ca egi e ’s a iables (p< 0.0001 in all analyses): BDI-II and ZCBI, = 0.42; BDI- II and CSI, = 0.39; BDI-II and EUROHIS- QOL8, = –0.35; ZCBI and CSI, = 0.55; ZCBI and EUROHIS-QOL8, = –0.34; CSI and EUROHIS-QOL8, = –0.31. Rega ding PD- ela ed a iables, he s onges co ela ion was obse ed o he change om V0 o V2 in mood (BDI-II) in he pa ien and he ca egi e ( = 0.39; p< 0.0001) and in he global QoL (EUROSHIS- QOL8) in he pa ien and he ca egi e ( = 0.39; p< 0.0001) (Table 1). The change in he ca egi e om V0 o V2 in mood was associa ed wi h he change in he pa ien om V0 o V2 in mood (BDI-II) a e he adjus men o co a ia es (Model 1; R2= 0.71): ␤= 0.32; p< 0.0001 (Table 2). The o he ac o associa ed wi h BDI-II in he pa ien was he change in global QoL in he pa ien (␤= –0.56; p< 0.0001). No ca egi e ’s a iables we e associa ed wi h he change in he pa ien om V0 o V2 in his/he heal h- ela ed QoL (Table 3A), as he change in he pa ien om V0 o V2 in he NMSS o al sco e he ac o signi ican ly associ- a ed wi h PDQ-39 (␤= 0.29; p< 0.0001) (Model 2; R2= 0.51). Howe e , ega ding he pa ien ’s change in global QoL, he change in he ca egi e om V0 o V2 in he global QoL was iden i ied as an associa ed ac o (␤= 0.39; p< 0.0001) oge he wi h he change in he own ca egi e in mood (␤= 0.55; p< 0.0001) (Model 3; R2= 0.68; Table 3B). Finally, and again, no ca egi e ’s a iables we e associa ed wi h he change in he pa ien om V0 o V2 in he au on- omy o ADL, being he change in he own pa ien in he heal h- ela ed QoL he ac o associa ed wi h ADLS (␤= –0.42; p< 0.0001) (Model 4; R2= 0.33; Table 4). Figu e 2 shows he in luence o ca egi e ’s a iables (BDI-II; ZCBI; CSI; EUROHIS- QOL8) o e pa ien ’s a iables (BDI-II; PDQ-39; EUROHIS-QOL8; ADLS) and he associa ions be ween pa ien ’s a iables. In all models, ole ance was less han 0.2 o all a iables included. DISCUSSION Unlike p e iously published s udies [2–15] ha analyze which ac o s o PD in luence he s a us o he p incipal ca egi e , he p esen s udy ana- lyzes whe he he p og essi e changes in he s a us o he ca egi e ha e epe cussions on he s a us o he pa ien . We ound ha he change in he ca e- gi e ’s mood p edic ed he change in he pa ien ’s mood independen ly o o he a iables o he dis- ease in luencing he pa ien ’s mood. We also ound an associa ion be ween he change in he global QoL in bo h he pa ien and he ca egi e . This inding is no el and ag ees wi h he idea o he icious cycle o illness. Dep essi e symp oms in he pa ien impac he ca egi e ’s mood, and dep essi e symp oms in D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness 225 Table 3 E ec o changes in he ca egi e o e he change in heal h- ela ed and global QoL in PD pa ien s om he COPPADIS coho a e 2-yea ollow-up (N = 192) Uni a ia e analysis Mul i a ia e analysis ␤95% CI p␤95% CI p A) PDQ-39SI Ca egi e BDI-II 0.19 0.10–0.62 0.006 0.16 0.01–0.54 0.047 ZCBI 0.28 0.16–0.46 <0.0001 0.03 –0.13–0.20 0.671 CSI 0.20 0.41–2.15 0.004 0.04 –0.72–1.20 0.818 EUROHIS-QOL8 0.01 –3.89–4.64 0.863 0.13 –0.33–7.74 0.072 Pa ien UPDRS-III 0.41 0.37–0.73 <0.0001 0.20 0.06–0.43 0.008 NMSS 0.57 0.16–0.25 <0.0001 0.29 0.05–0.15 <0.0001 ADLS –0.48 –0.62––0.36 <0.0001 –0.25 –0.39––0.10 0.001 PDQ-39 a baseline –0.20 –0.32––0.05 0.005 –0.20 –0.29––0.06 0.002 B) EUROSHIS-QOL8 Ca egi e BDI-II –0.14 –0.029––0.001 0.039 0.24 0.01–0.04 0.001 ZCBI –0.04 –0.011–0.006 0.530 0.02 -0.00–0.01 0.679 CSI –0.09 –0.078–0.016 0.201 –0.03 –0.06–0.03 0.604 EUROHIS-QOL8 0.41 0.454–0.878 <0.0001 0.39 0.49–0.89 <0.0001 Pa ien BDI-II –0.63 –0.053––0.037 <0.0001 –0.55 –0.03––0.66 <0.0001 EUROHIS-QOL8 a baseline 0.39 0.024–0.049 <0.0001 –0.37 –0.65––0.36 <0.0001 Dependen a iable: change in he PD pa ien om V0 o V2 () in he PDQ-39 (A) and EROHIS-QOL8 (B). ␤ s anda dized coe icien and 95% IC a e shown. a, uni a ia e analysis; b, mul i a ia e analysis: A) Du bin-Wa son es = 2.07; R2= 0.51; B) Du bin-Wa son es = 2.02; R2= 0.68. Only signi ican a iables (p< 0.01) om he pa ien in he mul i a ia e analysis a e shown. Co a ia es om he pa ien included we e he change om V0 o V2 ()in LEDD, UPDRS-III-OFF, UPDRS-IV, FOGQ, PD-CRS, NMSS, PDSS, QUIP-RS, NPI, VAS-PAIN, VAFS, ADLS, and he sco e on he PDQ-39SI (A) and EUROHIS-QOL8 (B) a baseline. ADLS, Schwab & England Ac i i- ies o Daily Li ing Scale; BDI-II, Beck Dep ession In en o y-II; CSI, Ca egi e S ain Index; FOGQ, F eezing O Gai Ques ionnai e; LEDD, le odopa equi alen daily dose; Non-Mo o Symp oms Scale; NPI, Neu opsychi- a ic In en o y; PD-CRS, Pa kinson’s Disease Cogni i e Ra ing Scale; PDQ-39, he 39-i em Pa kinson’s disease Ques ionnai e Summa y Index; PDSS, Pa kinson’s Disease Sleep Scale; QUIP-RS, Ques ionnai e o Impulsi e- Compulsi e Diso de s in Pa kinson’s Disease-Ra ing Scale; UPDRS, Uni ied Pa kinson’s Disease Ra ing Scale; VAS, Visual Analogue Scale; ZCBI, Za i Ca egi e Bu den In en o y. Table 4 E ec o changes in he ca egi e o e he change in au onomy o ADL in PD pa ien s om he COPPADIS coho a e 2-yea ollow-up (N = 192) Uni a ia e analysis Mul i a ia e analysis ␤95% CI p␤95% CI p Ca egi e BDI-II –0.05 –0.35–0.16 0.465 0.25 0.07–0.81 0.018 ZCBI -0.23 -0.40––0.10 0.001 –0.14 –0.38–0.04 0.112 CSI –0.18 –1.99––0.28 0.009 –0.05 –1.55–0.79 0.526 EUROHIS-QOL8 0.05 –2.60–5.72 0.461 0.06 –3.62–7.61 0.484 Pa ien FOGQ –0.38 –1.55––0.75 <0.0001 –0.25 –1.28––0.33 0.001 PDQ39SI –0.48 –0.59––0.34 <0.0001 –0.42 –0.62––0.24 <0.0001 Dependen a iable: change in he PD pa ien om V0 o V2 () in he ADLS sco e. ␤s anda dized coe icien and 95% IC a e shown. a, uni a ia e analysis; b, mul i a ia e analysis (Du bin-Wa son es = 1.956; R2= 0.33). Only signi ican a iables (p< 0.01) om he pa ien in he mul i a ia e analysis a e shown. Co a ia es om he pa ien included we e he change om V0 o V2 () in LEDD, UPDRS-III-OFF, UPDRS-IV, FOGQ, PD-CRS, NMSS, PDSS, QUIP-RS, NPI, VAS-PAIN, VAFS, ADLS, PDQ-39SI, EUROHIS-QOL8, and he sco e on he ADLS a baseline. ADLS, Schwab & England Ac i i ies o Daily Li ing Scale; BDI-II, Beck Dep ession In en o y-II; CSI, Ca egi e S ain Index; FOGQ, F eezing O Gai Ques ionnai e; LEDD, le odopa equi alen daily dose; Non-Mo o Symp oms Scale; NPI, Neu opsychia ic In en o y; PD-CRS, Pa kinson’s Disease Cogni i e Ra ing Scale; PDQ-39, he 39-i em Pa kinson’s disease Ques ionnai e Summa y Index; PDSS, Pa kinson’s Disease Sleep Scale; QUIP-RS, Ques ionnai e o Impulsi e-Compulsi e Diso de s in Pa kinson’s Disease-Ra ing Scale; UPDRS, Uni ied Pa kinson’s Disease Ra ing Scale; VAS, Visual Analogue Scale; ZCBI, Za i Ca egi e Bu den In en o y. 226 D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness Fig. 2. The associa ions be ween he change om baseline isi (V0) o 2-yea ollow-up isi (V2) in ca egi e ’s and pa ien ’s a iables a e shown. The change in ca egi e ’s mood in luences he change in pa ien ’s mood (BDI-II; in b igh g een) whe eas he change in ca egi e ’s global QoL is associa ed o he change in pa ien ’s global QoL (EUROHIS-QOL8; in b igh yellow). Mo eo e , he change in pa ien ’s mood in luences he change in pa ien ’s global QoL whe eas he change in pa ien ’s global QoL and heal h- ela ed QoL is associa ed wi h he change in pa ien ’s mood and au onomy o ADL, espec i ely ( ed a ows). ADL, ac i i ies o daily li ing; ADLS, Schwab & England Ac i i ies o Daily Li ing Scale; CSI, Ca egi e S ain Index; EUROHIS-QOL8, EUROHIS-QOL 8-i em index; PD, Pa kinson’s disease; PDQ-39, 39-i em Pa kinson’s disease Ques ionnai e; QoL, quali y o li e; ZCBI, Za i Ca egi e Bu den In en o y. he ca egi e ha e a nega i e impac on he pa ien ’s mood as well. This could jus i y he necessi y o ea ly iden i ica ion and p ope managemen o dep ession and bu den in he p incipal ca egi e o a PD pa ien [2, 26]. Ca egi ing may ha e ewa ding consequences, such as s eng hening emo ional ies, imp o ing sel - es eem, gene a ing al uism, and making inancial sa ings [27]. Howe e , ca ing o ill amily membe s, especially wi h a ch onic degene a i e disease in he long- e m, can ha e nega i e impac s on ca egi e s’ men al heal h [28]. Ca egi ing bu den, in e ms o physical s ain, has been ound o p edic ca egi e s’ heal h [29]. On he o he hand, men al heal h, in e ms o dep ession, could p edic bu den [30]. In ac , dep ession is one o he mos common nega i e e ec s o ca egi ing [31], being majo dep ession de ec ed in his coho in 13% and 15.1% o he ca egi e s a baseline and a e he 2-yea ollow- up, espec i ely [16]. In his con ex , an impo an ques ion a ises: does he wo sening o he ca egi e ’s condi ion wo sen he ca e o he pa ien and sec- onda ily pe pe ua e he p oblem since bo h ac o s eed o each o he ? Su p isingly, in PD and o he pa hologies including cance , he li e a u e ocuses on iden i ying he causes o ca egi e o e load and he consequences on he ca egi e bu no on he pa ien [32, 33]. E en hough he e is li e a u e abou he apies aimed o ea ca egi e bu den, again he bene i s o he ca egi e a e analyzed bu no he posi i e consequences ha hey could ha e on he pa ien [2, 34, 35]. This is impo an because one o he consequences o ca egi e bu den is a educ ion in ca e p o ision and in he quali y o ca e p o ided [36]. A s udy by Gi en e al. [37] claims ha he quali y o ca e is educed when a ca egi e expe- iences bu den, and i may be mani es ed due o a dec eased coping abili y and lack o emo ional sup- po o he ca e- ecipien . Ou s udy analyzes o he i s ime how sho - e m de e io a ion in he s a us o he ca egi e can nega i ely in luence he pa ien . I also de ec s ha he wo sening o he ca egi e ’s D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness 227 mood is a key ac o ha impac s on he pa ien ’s mood a e adjus ing o he changes expe ienced in many o he a iables o he pa ien ’s disease. Impo - an ly, he model p o ided abou 70% o he a iance o he p incipal a iable (pa ien ’s mood change). This is a c i ical poin gi en ha he change in he pa ien ’s mood is he mos in luen ial ac o in he ca egi e ’s mood, and his, a he same ime, gene - a es o e load, s ess, and a wo se QoL in he ca egi e him/he sel [16], which is associa ed wi h a wo se QoL o he pa ien . Howe e , he s a us o he ca e- gi e did no in luence he pa ien ’s heal h- ela ed QoL, which is mo e condi ioned (PDQ-39) by he symp oms o he disease [38, 39], especially NMS as i has been ound in he model. We also ailed o demons a e he impac o ca egi e s a us on pa ien au onomy. Ou indings a e no el, and he nex s ep should be o demons a e i ea ing ca egi e bu den and dep ession can imp o e no only he s a us o he ca egi e bu also he pa ien indi ec ly as well. Di - e en s a egies could be es ed, such as educa ion and psycho he apy [40], ehabili a ion [41], o mul- idisciplina y in e en ions [42]. Again, ea men o pa ien ’s symp oms o imp o e he ca egi e ’s s a us has been analyzed [43] bu he opposi e has no . Ou s udy has some limi a ions, some o hem p e- iously epo ed in a ecen publica ion [16], such as a loss o ollow-up o nea ly 30% o he subjec s (pa ien and his/he ca egi e ) wi h espec o he baseline sample and he ac ha ca egi e ’s ea men o o he possible in e en ions we e no collec ed. In he models, he ela ionship be ween some a iables changed he sign a e adjus ing o he co a ia es, such as he ela ion be ween BDI-II in he pa ien (dependen a iable) and EUROHIS-QOL8 in he ca egi e in Model 1 ( om nega i e o posi i e) and EUROHIS-QOL8 in he pa ien (dependen a i- able) and BDI-II in he ca egi e in Model 3 ( om nega i e o posi i e), con a y o expec a ion. This could be explained by he e ec o including many co a ia es and he in luence o al oge he o e he dependen a iable. Howe e , in all models he R2 was high, collinea i y was excluded, and only esul s wi h e y high signi icance (p< 0.001) we e consid- e ed alid. In conclusion, his is he i s ime ha he change in he ca egi e ’s s a us demons a ed an in luence on he change in pa ien ’s s a us. So, dep essi e symp- oms in he pa ien a ec he ca egi e bu also ice e sa. Mo eo e , he change in he ca egi e ’s global QoL seems o p edic he change in he pa ien ’s global QoL. Wi h he aim o s op he icious ci cle o illness in PD, de ec ion o dep ession and bu den in he p incipal ca egi e o he pa ien is impo an and should be ac ed on as ea lie as possible. In addi ion, mo e s udies o eplica e hese indings and es his hypo hesis a e needed. ACKNOWLEDGMENTS We would like o hank all pa ien s and hei ca egi e s who collabo a ed in his s udy. Many hanks also o Fundaci´ on Espa˜ nola de Ayuda a la In es igaci´ on en En e medades Neu odegene a i as y/o de O igen Gen´ e ico (h ps:// undaciondegen.o g/) and Alpha Bio esea ch (h ps://www.alphabio esea ch.com) and o he ins i u ions helping us. FUNDING COPPADIS and he p esen s udy we e de el- oped wi h he help o Fundaci´ on Espa˜ nola de Ayuda a la In es igaci´ on en En e medades Neu odegene a i as y/o de O igen Gen´ e ico (h ps:// undaciondegen.o g/) and Alpha Bio esea ch (www.alphabio esea ch.com). Also, we ecei ed g an s om he Spanish Minis y o Economy and Compe i i eness [PI16/01575] co- ounded by ISCIII (Concesi´ on de sub enciones de P oyec os de In es igaci´ on en Salud de la con oca o ia 2020 de la Acci´ on Es a ´ egica en Salud 2017-2020 po el P oyec o “PROGRESI ´ ON NO MOTORA E IMPACTO EN LA CALIDAD DE VIDA EN LA ENFERMEDAD DE PARKINSON”) o de elop a pa o he COPPADIS p ojec . CONFLICT OF INTEREST San os Ga c´ ıa D. has ecei ed hono a ia o edu- ca ional p esen a ions and ad ice se ice by Abb ie, UCB Pha ma, Lundbeck, KRKA, Zambon, Bial, I al- a maco, Te a, A ch´ ımedes, Es e e, S ada, Me z, and g an s om he Spanish Minis y o Economy and Compe i i eness [PI16/01575] co- ounded by ISCIII (Concesi´ on de sub enciones de P oyec os de In es i- gaci´ on en Salud de la con oca o ia 2020 de la Acci´ on Es a ´ egica en Salud 2017-2020 po el p oyec o “PROGRESI ´ ON NO MOTORA E IMPACTO EN LA CALIDAD DE VIDA EN LA ENFERMEDAD DE PARKINSON”).