Staging Parkinson's disease according to the MNCD classification correlates with caregiver burden

Abstract Background and objective Recently, we demonstrated that staging Parkinson's disease (PD) with a novel simple classification called MNCD, based on four axes (motor, non‐motor, cognition, and dependency) and five stages, correlated with disease severity and patients’ quality of life. Here, we analyzed the correlation of MNCD staging with PD caregiver's status. Patients and methods Data from the baseline visit of PD patients and their principal caregiver recruited from 35 centers in Spain from the COPPADIS cohort from January 2016 to November 2017 were used to apply the MNCD total score (from 0 to 12) and MNCD stages (from 1 to 5) in this cross‐sectional analysis. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory‐II (BDI‐II), PQ‐10, and EUROHIS‐QOL 8‐item index (EUROHIS‐QOL8). Results Two hundred and twenty‐four PD patients (63 ± 9.6 years old; 61.2% males) and their caregivers (58.5 ± 12.1 years old; 67.9% females) were included. The frequency of MNCD stages was 1, 7.6%; 2, 58.9%; 3, 31.3%; and 4–5, 2.2%. A more advanced MNCD stage was associated with a higher score on the ZCBI (p < .0001) and CSI (p < .0001), and a lower score on the PQ‐10 (p = .001), but no significant differences were observed in the BDI‐II (p = .310) and EUROHIS‐QOL8 (p = .133). Moderate correlations were observed between the MNCD total score and the ZCBI (r = .496; p < .0001), CSI (r = .433; p < .0001), and BDI‐II (r = .306; p < .0001) in caregivers. Conclusion Staging PD according to the MNCD classification is correlated with caregivers’ strain and burden.


INTRODUCTION
Parkinson's disease (PD) is a complex and very heterogeneous progressive neurodegenerative disorder causing not only motor but also non-motor symptoms (NMSs) that result in loss of patient autonomy for activities of daily living (ADL) and worse quality of life (QoL) impairment, but second, caregiver's strain and burden as well (Greenland et al., 2019;Mosley et al., 2017;Zhao et al., 2021).Moreover, caregiver's status impacts on patient's status as well, which has been named the "vicious circle of illness" (Santos-García et al., 2023b).From a clinical point of view and with the aim of defining exhaustively the status of a patient with PD at each moment, a novel simple classification called "MNCD" has been proposed (Santos-García et al., 2021a).The MNCD is based on four major axes (M, motor; N, non-motor; C, cognition; D, dependency) and proposes five stages, from MNCD stage 1, no relevant symptoms, to MNCD stage 5, dementia and dependency for basic ADL, and a total score from 0 (0 + 0 + 0 + 0 = 0; the best possible status) to 12 (4 + 4 + 2 + 2 = 12; the worst possible status).Recently, we demonstrated using data from the COPPADIS cohort (Santos-García et al., 2016, 2019) that staging PD with the MNCD classification correlated with disease severity and patients' QoL (Santos-García et al., 2023a).Based on these findings and awaiting the results of an ongoing validation study of the MNCD classification and of its application in a prospective follow-up cohort, early observations suggest that the MNCD classification could be a useful tool to apply in PD patients to identify the main symptoms of the disease and to monitor the progression of the disorder.Neuropsychiatric symptoms, such as visual hallucinations, depression, cognitive impairment and/or dementia, falls, disability, and a more advanced stage disease, have been identified as patient factors associated with caregiver burden in PD (Aamodt et al., 2023).All these data are collected in the MNCD classification with also a proposed staging and scoring that indicates the degree of severity, from least to most.That is why we think that the MNCD classification can quickly provide us with information about the patient's condition that affects his/her QoL as well as the status of his/her principal caregiver.Importantly, with the aim to stop the vicious circle of illness in PD (Santos-García et al., 2023b), the detection of burden in the principal caregiver of the patient is important and should be acted on as earlier as possible.
The aim of this new analysis was to study the correlation of the MNCD staging with PD caregiver's status.Data from the COPPADIS cohort (Santos-García et al., 2021a) used in the previous publication (Santos-García et al., 2023a) were used in this analysis.Our hypothesis was that caregivers' status would be different between the different PD stages according to the MNCD classification, with a better QoL and mood when the patient has a low stage with a low score and vice versa, a worse mood and QoL with greater burden and stress when the patient has a higher stage and score (i.e., a more advanced MNCD stage, a worse caregiver's status).

MATERIALS AND METHODS
Data collected at the baseline visit from PD patients and their principal caregiver recruited from 35 hospitals in Spain from the COPPADIS cohort (Santos-García et al., 2016) from January 2016 to November 2017 were used in this cross-sectional transversal study.Methodology about COPPADIS-2015 study has been published and can be consulted (Santos-García et al., 2019).All patients included were diagnosed according to UK PD Brain Bank criteria (Hughes et al., 1992).
Exclusion criteria were: non-PD parkinsonism; a mini-mental state examination <26; age <18 or >75 years; inability to read or understand the questionnaires; to be receiving any advanced therapy (continuous infusion of levodopa or apomorphine, and/or with deep brain stimulation); and the presence of comorbidity, sequelae, or any disorder that could interfere with the assessment.

PD patient assessment
Information on sociodemographic aspects, factors related to PD, comorbidity, and treatment, including levodopa equivalent daily dose (Schade et al., 2020), were collected at baseline.As this analysis was focused on the caregiver status and the results about the relationship between the MNCD staging and patients' symptoms have been already published (Santos-García et al., 2023a), all the information collected about motor, NMS, QoL, and autonomy for ADL in PD patients (Santos-García et al., 2019) were not provided on this occasion.

Caregiver assessment
A person who, without being a professional and/or receiving money in exchange for services, lived with the patient and was responsible for his/her was included as a primary caregiver (Santos-García et al., 2016).His/her participation was voluntary, and a written informed consent was collected for all participants.In caregivers, four aspects were analyzed using validated specific scales: burden (Zarit Caregiver Burden Inventory [ZCBI]), strain (Caregiver Strain Index [CSI]), mood (Beck Depression Inventory-II [BDI-II]), and global QoL (PQ-10 and EUROHIS-QOL 8-item index [EUROHIS-QOL8]).The ZCBI (Novak & Guest, 1989) contains 22 items that rate the impact of the disease on the caregiver's physical, emotional, and socioeconomic status.
Responses are scored on a scale from 0 (never) to 4 (nearly always).
The maximum total score, indicative of the highest burden, is 88.The CSI (Robinson, 1983) is a 13-item questionnaire designed to assess the level of stress experienced by caregivers.There are two possible responses for each item: "yes" or "no".The total score is the result of adding all positive responses (from 0, no stress, to 13, maximum level of stress).Mood was assessed with the BDI-II (Beck et al., 1996).This is a self-administered, 21-item instrument.the WHOQOL-100 and the WHOQOL-BREF.For each item, the score ranges from 0 (not at all) to 5 (completely).The total score is expressed as the mean of the individual scores.A higher score indicates a higher QoL.Sociodemographic data about the principal caregiver of the PD patient was also collected.

MNCD classification
The MNCD classification was applied using the same criteria recently reported in the COPPADIS cohort (Santos-García et al., 2023) (there is dementia and/or dependency for basic ADL).Moreover, the MNCD total score (from 0 to 12) was calculated according to the sum of the score of all axes of the MNCD classification: M (from 0 to 4) + N (from 0 to 4) + C (from 0 to 2) + D (from 0 to 2).
For comparison of caregivers' burden (ZCBI), strain (CSI), mood ates.With the aim of having a very strong evidence against the null hypothesis, the p-value was considered significant (highly significant) when it was ≤.001 (Krikwood & Sterne, 2003).

Standard protocol approvals, registrations, and patient consents
Approval from the Comité de Ética de la Investigación Clínica de Galicia

Data availability
The protocol and the statistical analysis plan are available on request.
Deidentified participant data are not available for legal and ethical reasons.

RESULTS
Two hundred and twenty-four PD patients (63 ± 9.6 years old; 61.2% males) and their caregivers (58.5 ± 12.1 years old; 67.9% females) were ).Nearly 70% of the caregivers were females (67.9%) and up to 92.4% were living with the patient and 21.9% taking care of the patient full time (33.5% of the patients had cognitive impairment and/or needed some help for some ADL).No significant differences were observed in sociodemographic aspects between caregivers of PD patients in the different stages except in age (p = .002),being younger the caregivers of those patients in stages 4-5 (in this group, 40% of the caregivers were the son or the daughter) (Table 1).
Regarding mood, no significant differences were detected between different stages neither in the BDI-II total score (p = .310)nor groups according to depressive symptoms (p = .330)(Table 1 and Figure 2).
However, the correlation between the MNCD stage and the BDI-II total score was moderate (r = .306;p < .0001).Moderate correlations were observed between the BDI-II and the ZCBI (r = .541;p < .0001) and the BDI-II and the CSI (r = .599;p < .0001).Global QoL was related to MNCD stage when the PQ-10 was used, with a lower score at a higher stage (from 8.4 ± 1.4 at stage 1 to 5.6 ± 2.5 at stage 4; p = .001) (Table 1 and Figure 2).However, no significance was detected when the EUROHIS-QOL8 was used (p = .133)(Table 1).By domains, significant differences were observed in "quality of life" and "economic capacity" between groups (from MNCD stage 1 to stages 4-5), with a lower score at a higher stage (Table 1 and Figure 2).Correlations between the MNCD total score and the PQ-10 and between the MNCD total score and the EUROHIS-QOL8 were weak (Table 2).As the proof of the utility of the PQ-10, the correlation between the PQ-10 and the EUROHIS-QOL8 was strong (r = .735;p < .0001).

DISCUSSION
The present study observed that a more advanced stage in PD patients according to the MNCD classification was associated with greater strain and burden (ZCBI; CSI) and a worse QoL (PQ-10) in the principal caregiver.This finding, combined with previous reports (Santos-García et al., 2023), supports that the MNCD classification could be a useful tool to monitor the progression of PD.
PD is a complex and very heterogeneous disorder with a variable prognosis between patients.From a clinical point of view and looking at the disease as a whole, four cardinal aspects in the patient linked to outcome are motor symptoms, NMS, cognition, and the abil-ity to perform day-to-day activities.Throughout the evolution of the disease, motor and NMS burden increase, and progressive cognitive impairment and dependency for ADL appear.However, many phenotypes in PD have been reported, and disability can appear very early in some patients or late in the disease course in others (Lawton et al., 2018;Fereshtehnejad et al., 2015;De Pablo-Fernández et al., 2019).
In this context, a classification to monitor PD is required.Although the Hoehn and Yahr (1967) stage is used very frequently in clinical practice because it is very simple, it provides information only about the motor stage.As NMS or cognitive dysfunction can be present at the first steps of the disease or even before motor symptoms development and they impact on QoL (Santos-García et al., 2021c;Goldman & Postuma, 2014), they should be identified and monitored from the first moment (i.e., at diagnosis) (Zis et al., 2015).In fact, NMSs have gained in importance in the latest proposed diagnostic criteria of PD (Postuma et al., 2015;Berg et al., 2015;Heinzel et al., 2019).Note: Spearman correlation test were applied.Correlations between all variables are also shown.
motor fluctuations, NMS, cognitive problems, and their impact on disability.
Although it is necessary to apply the MNCD in clinical practice and demonstrate good inter-and intra-variability, a very recent application of this tool using retrospectively the database of the baseline visits from the Spanish Cohort COPPADIS found that the MNCD staging was associated with disease severity and patient's QoL (Santos-García et al., 2023).That is, a more advanced MNCD stage corresponded to a greater disease severity in terms of motor symptoms and NMS and a worse QoL and autonomy for ADL.On the other hand, the MNCD total score (from 0 to 12) correlated strongly with health-related (PDQ-39) and global (EUROHIS-QOL8) QoL in PD patients (Santos-García et al., 2023).In this new analysis using the same database and with the aim of gathering more information about the potential role of the MNCD classification in PD, we wanted to know what the status of the principal caregiver of a PD patient with respect to the MNCD classification was.
Many studies have identified symptoms related to caregiver burden, such as depression, visual hallucinations, sleep disturbances, cognitive impairment, falls, a more advanced stage disease, and a greater disability (Santos-García & de la Fuente-Fernández, 2015;Schrag et al., 2006;Martinez-Martin et al., 2007;D'Amelio et al., 2009;Martinez Martin et al., 2012;Smith et al., 2019;Peters et al., 2011;Santos-García et al., 2022).Based on this, our hypothesis was that caregivers' status would be different between the different MNCD stages, with a better mood and QoL in stage 1 and a worse QoL and mood and a greater strain and burden in caregivers at a more advanced stage (i.e., a more advanced MNCD stage, a worse caregiver's status).We found differences for caregiver burden (ZCBI), strain (CSI), and QoL (PQ-10) but not for mood (BDI-II).All caregivers of PD patients in stages 4-5 had some degrees of burden compared to only 11.8% at stage 1.Additionally, up to 40% of caregivers of PD patients in stages 4-5 reported a high level of stress compared to none of the caregivers of stage 1 PD patients.However, it is important to be cautious because although the sample size was 224 caregivers, only 5 were of PD patients in the most advanced stage (stages 4 and 5).The very small sample size of the group with MNCD stages 4-5 (N = 5) suggests that these findings need to be replicated and are not entirely reliable.On the other hand, some of the non-statistically significant differences (EUROHIS-QOL8; BDI-II) may be due to a small sample size (e.g., 60% of caregivers of patients at stages 4-5 had depressive symptoms compared to 35.3% at stage 1).Of note, a moderate correlation was observed between the caregiver's BDI-II total score and the MNCD total score (from 0 to 12), and between mood and burden and mood and strain in the caregiver, suggesting the necessity of being alert about depressive symptoms due to its important implications (Santos-García et al., 2023) in the principal caregiver of a patient with a greater disease burden according to the MNCD classification.An ideal scenario could be to apply the MNCD classification in clinical practice to the patient at the first visit (i.e., a naïve patient) and to monitor its changes in each visit in the short-, medium-, and long-term (i.e., >15 years) in a big cohort of PD patients and caregivers (i.e., >500) in a prospective follow-up study.As an alternative, applying the MNCD classification in a big cohort (i.e., >1,000) in only one visit (cross-sectional study) with many PD patients in all stages (i.e., from 1 to 5 of Hoehn & Yahr, 1967) would avoid the frequent bias of not including very advanced PD patients (e.g., with dementia and institutionalized).Finally, and regarding QoL, the PQ-10 was a good marker of global QoL related to the MNCD staging.It is a simple question about the global QoL perception (from 0, the worst, to 10, the best), and in-line with many previous observations in the COPPADIS cohort (Santos-García et al., 2019;Santos-García et al., 2021b), we recommend using it as a very simple and quick marker of global QoL for PD patients and their caregivers as an alternative to others.Indeed, the correlation between the PQ-10 and the EUROHIS-QOL8 was strong (r > .7).
This study has important limitations; many of them commented in the recent report about the correlation between disease severity and QoL in PD patients from the COPPADIS cohort and the MNCD  Gossweiler Foundation, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña.
Zarit Caregiver Burden Inventory (ZCBI) total score (on the left) and frequency of caregivers with different burden degree (on the right) regarding to the motor, non-motor, cognition, and dependency (MNCD) stage, from stage 0 to stages 4-5.(b) Caregiver Strain Index (CSI) total score (on the left) and frequency of caregivers with high level (CSI > 6) versus no high level of stress (on the left) regarding to the MNCD stage, from stage 0 to stages 4-5.included.The mean disease duration was 5.6 ± 4.1 years.Regarding MNCD stages, the distribution was stage 1, 7.6% (N = 17); stage 2, 58.9% (N = 132); stage 3, 31.3%(N = 70); stages 4-5, 2.2% (N = 5; four patients in stage 4 and only one patient in stage 5 from the MNCD classification according to the original description [Santos-García et al., 2021a]
These four capitals' aspects commented are the basement of a new proposed classification for PD called MNCD (Santos-García et al., 2023).The MNCD classification includes four major axes (M, motor symptoms; N, NMS; C, cognition; D, dependency for ADL) and five stages with the aim to categorize and differentiate patients in a different evolutionary stage, being the first PD classification taking into account key aspects of the disease, such as axial symptoms, TA B L E 2 Correlations between the motor, non-motor, cognition, and dependency (MNCD) total score (from 0 to 12) and the other variables about the status of the caregiver (Zarit Caregiver Burden Inventory [ZCBI], Caregiver Strain Index [CSI], Beck Depression Inventory-II [BDI-II], PQ-10, EUROHIS-QOL 8-item index [EUROHIS-QOL8]).

Manuel
Menéndez-González: Investigation; writing-review and editing; methodology.Darrian McAfee: Writing-review and editing.Pablo Martinez-Martin: Writing-review and editing; supervision.Pablo Mir: Investigation; conceptualization; writing-review and editing; methodology; supervision.Pablo Martinez-Martin has received honoraria from Bial for lecturing in course and from the Parkinson and Movement Disorder Society (MDS) for management of the COA International Program of the Society.Pablo Mir has received honoraria from AbbVie, Abbott, Allergan, Bial, Merz, UCB, and Zambon and have received grants from the Spanish Ministry of Economy and Competitiveness [ PI16/01575] cofounded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [ PI-0437-2012, PI-0471-2013], the Sociedad Andaluza de Neurología, the Jacques and Gloria Sociodemographic details and data about the status of the principal caregiver of patients with Parkinson's disease (PD) according to the motor, non-motor, cognition, and dependency (MNCD) stage (N controlling for covariates mentioned in methods (age; gender; disease duration; caregiver's sociodemographic variables), the MNCD TA B L E 1 Abbreviations: ADL, activities of daily living scale; BDI-II, Beck Depression Inventory-II; EUROHIS-QOL8, EUROHIS-QOL 8-item index; PD, Parkinson's disease.
trary, the results of this study are again novel and support the idea to consider the MNCD classification as a simple tool to use in PD patients for identifying the main symptoms and monitor the progression of PD.In conclusion, we observed in this study that staging PD according to the MNCD classification correlates with caregiver burden.More studies are needed to demonstrate the potential value of this new simple proposed tool.The backing of a scientific society may be key to its prosperous use by the scientific community.; methodology; writing-review and editing.Carlos Cores Bartolomé: Investigation; writing-review and editing.María J. Feal Painceiras: Investigation; writing-review and editing.Iago García Díaz: Investigation; writing-review and editing.María Cristina Íñiguez Alvarado: Investigation; writing-review and editing.Jose Manuel Paz: Investigation; writing-review and editing.Silvia Jesús: writing-review and editing; methodology.Isabel González Aramburu: Investigation; writing-review and editing; methodology.Maria A. Ávila Rivera: Investigation; writing-review and editing; methodology.Víctor Gómez Mayordomo: Investigation; writing-review and editing; methodology.Víctor Nogueira: Investigation; writing-review and editing; methodology.Julio Dotor García-Soto: Investigation; writing-review and editing; methodology.Carmen Borrué: writing-review and editing; methodology.Maria Teresa Buongiorno: Investigation; writing-review and editing; methodology.Carlos Ordás: Investigation; writing-review and editing; methodology.