www.nature.com/npjparkd ARTICLE OPEN Non-motor predictors of 36-month quality of life after subthalamic stimulation in Parkinson disease Stefanie T. Jost1 ✉, Veerle Visser-Vandewalle2, Alexandra Rizos3, Philipp A. Loehrer 4, Monty Silverdale5, Julian Evans5, Michael Samuel3, Jan Niklas Petry-Schmelzer1, Anna Sauerbier1,6, Alexandra Gronostay1, Michael T. Barbe1, Gereon R. Fink 1,7 , 1✉ Keyoumars Ashkan3, Angelo Antonini8, Pablo Martinez-Martin9, K. Ray Chaudhuri 3,6, Lars Timmermann4, Haidar S. Dafsari and EUROPAR and the International Parkinson and Movement Disorders Society Non-Motor Parkinson’s Disease Study Group* To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperatively and at 6-month and 36-month follow-up: PD Questionnaire-8 (PDQ-8), NMSScale (NMSS), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). We analyzed factors associated with QoL improvement at 36-month follow-up based on (1) correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions and receiver operating characteristic curves using a dichotomized variable “QoL responders”/“non-responders”. At both follow-ups, 1234567890():,; NMSS total score, SCOPA-motor examination, and -complications improved and LEDD was reduced significantly. PDQ-8 improved at 6-month follow-up with subsequent decrements in gains at 36-month follow-up when 61.6% of patients were categorized as “QoL non-responders”. Correlations, linear, and logistic regression analyses found greater PDQ-8 improvements in patients with younger age, worse PDQ-8, and worse specific NMS at baseline, such as ‘difficulties experiencing pleasure’ and ‘problems sustaining concentration’. Baseline SCOPA scores were not associated with PDQ-8 changes. Our results provide evidence that 36-month QoL changes depend on baseline neuropsychological and neuropsychiatric non-motor symptoms burden. These findings highlight the need for an assessment of a wide range of non-motor and motor symptoms when advising and selecting individuals for DBS therapy. npj Parkinson’s Disease (2021)7:48 ; https://doi.org/10.1038/s41531-021-00174-x INTRODUCTION follow-up periods, hypothesized that QoL outcome depends on Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a demographic and non-motor predictors as well as baseline QoL. well-established therapy with long-term efficacy improving motor symptoms, quality of life (QoL), and non-motor symptoms (NMS) in patients with Parkinson’s disease (PD)1–5. Previous research also demonstrated beneficial effects of STN-DBS on QoL compared to RESULTS medical treatment6–8. However, on the individual level, 43–49% of Of 129 patients screened, 73 patients (43 male) were included in patients experience no clinically relevant improvement of QoL the final analysis (see Fig. 1). The mean age at baseline was 62.0 postoperatively at 6-month follow-up6,9,10. Furthermore, there is Class years (SD = 8.3) and disease duration 10.3 years (SD = 4.7). The I evidence that in 36% of pairs of patients treated either with best mean time to follow-up was 3.0 years (SD = 0.31). medical treatment alone or with STN-DBS, medical treatment alone results in better QoL outcomes than STN-DBS2. Identifying pre- operative factors that predict QoL outcome could support the Clinical outcomes at baseline, 6-month, and 36-month follow-up decision-making process for DBS eligibility and improve individual Friedman tests revealed significant differences between the three treatment results. Amongst other parameters younger age, worse visits for all outcome scores (see Table 1). In post hoc tests baseline QoL, and specific NMS have been identified as predictors of comparing baseline and 36-month follow-up, we observed more considerable QoL improvement at 6-month follow-up. How- significant longitudinal changes for the NMSS total score (P = ever, it is unclear which demographic and clinical parameters 0.037), SCOPA-motor examination (P = 0.001), and -motor com- influence the evolution of QoL beyond such a short-term follow-up. plications (P < 0.001), and significant sustained levodopa equiva- Therefore, we investigated predictors of QoL outcome after STN-DBS lent daily dose (LEDD) reduction (P < 0.001). No significant at 36-month follow-up and, based on previous studies with shorter changes at 36-month follow-up were found for the PDQ-8 SI 1 University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Neurology, Cologne, Germany. 2University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Stereotaxy and Functional Neurosurgery, Cologne, Germany. 3Parkinson Foundation International Centre of Excellence, King’s College Hospital, London, UK. 4Department of Neurology, University Hospital Giessen and Marburg, Campus Marburg, Marburg, Germany. 5Department of Neurology and Neurosurgery, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Greater Manchester, UK. 6Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK. 7Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Jülich, Jülich, Germany. 8 Department of Neurosciences (DNS), Padova University, Padova, Italy. 9Center for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED), Carlos III Institute of Health, Madrid, Spain. *A list of authors and their affiliations appears at the end of the paper. ✉email: stefanie.jost@uk-koeln.de; haidar.dafsari@uk-koeln.de Published in partnership with the Parkinson’s Foundation S.T. Jost et al. 2 Fig. 1 Enrollment. The flow chart describes the enrollment of patients. DBS deep brain stimulation. Table 1. Outcome parameters at preoperative baseline and postoperative 6-month and 36-month follow-up. 1234567890():,; Baseline 6-month follow-up 36-month follow-up n M SD n M SD n M SD pa Post hoc tests PDQ-8 Summary Index 73 32.8 16.8 69 23.6 14.9 73 31.1 20.2 <0.001 a NMSS-total score 73 57.3 34.9 69 39.1 24.6 73 47.6 31.4 <0.001 ab SCOPA Motor examination 73 11.3 5.5 66 8.1 5.0 64 8.7 4.8 <0.001 ab Activities of daily living 73 7.2 3.4 69 5.3 2.9 72 6.7 3.6 <0.001 a Motor complications 73 4.9 3.0 69 2.2 2.5 71 2.3 2.4 <0.001 ab LEDD 73 1146.2 508.2 69 550.1 339.0 72 722.7 469.4 <0.001 ab MMSE 73 29.0 1.1 69 28.9 3.7 65 28.9 1.4 0.128 LEDD levodopa equivalent daily dose, MMSE Mini-Mental State Examination, NMSS Non-Motor Symptom Scale, PDQ-8 8-item Parkinson’s Disease Questionnaire, SCOPA Scales for Outcomes in Parkinson’s Disease. a Friedman test or repeated-measures ANOVA when parametric test criteria were fulfilled. Benjamini-Hochberg correction was applied to account for multiple testing and all presented P-values were adjusted to the significance threshold P < 0.05. Baseline assessments were conducted in the medication ON state (MedON) and postoperative assessments in the medication ON/stimulation ON state (MedON/StimON). Post hoc comparisons (Wilcoxon signed rank or t test): a = significant difference between baseline vs 6-month follow-up (P < 0.05) b = significant difference between baseline vs 36-month follow-up (P < 0.05) (P = 0.296) and SCOPA-activities of daily living (P = 0.161). PDQ-8 Linear regression analysis domains are reported in supplementary Table e-1. Univariate regression analyses were performed using the variables with a P < 0.2 in the correlation analyses as candidate predictors. Correlation analyses This additionally included the items “fainting” (NMSS-2baseline, r = Table 2 shows correlations between PDQ-8 SI change score (baseline −0.17, P = 0.157), “hallucinations” (NMSS-13baseline, r = 0.18, P = 0.131), “forget things or events” (NMSS-17baseline, r = 0.17, P = 0.157), vs. 36-month follow-up) and demographic variables and preopera- “interest in sex” (NMSS-25baseline, r = 0.21, P = 0.082), and “pain” tive clinical scores. Significant correlations were found between PDQ- (NMSS-27baseline, r = 0.22, P = 0.063). Univariate regression analyses 8 SI changes and PDQ-8 SIbaseline (moderate strength) and agebaseline with change in PDQ-8 SI at 36-month follow-up as the criterion (weak). Correlations between improvement in PDQ-8 SI and NMSS variable was significant for the following independent variables: totalbaseline trended. Explorative Spearman correlations between PDQ-8 SIbaseline (β = 0.42, P < 0.001), agebaseline (β = –0.29, P = 0.012), PDQ-8 SI changes at 36-month follow-up and NMSS items at NMSS totalbaseline (β = 0.26, P = 0.025), NMSS-2baseline (β = −0.25, baseline showed significant associations with the items “difficulty P = 0.034), NMSS-12baseline (β = 0.48, P < 0.001), NMSS-16baseline (β = experiencing pleasure” (NMSS-12baseline, r = 0.24, P = 0.041), “con- 0.37, P = 0.001), and NMSS 23baseline (β = 0.25, P = 0.032). For the centration” (NMSS-16baseline, r = 0.34, P = 0.003), and “urinary fre- multivariate regression analysis, we excluded the variable NMSS quency” (NMSS 23baseline, r = 0.27, P = 0.022). We observed no totalbaseline due to high intercorrelation with PDQ-8 SIbaseline (r = significant correlation between these NMSS items at baseline. A 0.65, P = <0.001). In the stepwise multivariate regression analysis, partial correlation between PDQ-8 SI change score and NMSS- the variables agebaseline, NMSS item 2baseline, NMSS item 12baseline, 16baseline was still significant after controlling for NMSS-12baseline and NMSS item 16baseline remained significant. The multivariate (r = 0.31, P = 0.007). model accounted for 36% of the variance (R2 = 0.40) in PDQ-8 SI npj Parkinson’s Disease (2021) 48 Published in partnership with the Parkinson’s Foundation S.T. Jost et al. 3 Table 2. Correlations between preoperative baseline test scores or demographic variables and 36-month change scores of quality of life. PDQ-8 SI change score n r P Age 73 −0.29* 0.012 Sexa 73 −0.14 0.215 Disease duration 73 −0.02 0.860 PDQ-8 Summary Index 73 0.42*** <0.001 NMSS-total score 73 0.20 0.083 SCOPA Motor examination 73 0.01 0.938 Activities of daily living 73 0.14 0.233 Motor complications 73 −0.04 0.751 LEDD 73 0.04 0.713 MMSE 73 −0.06 0.599 Spearman correlations, respectively Pearson correlations for normally distributed variables were calculated between PDQ-8 SI change scores from preoperative baseline to postoperative 36-month follow-up and preoperative baseline test scores, respectively for demographic variables. Fig. 2 Receiver operating characteristic curve. The receiver LEDD Levodopa equivalent daily dose, MMSE Mini-Mental State Examina- operating characteristic curve (blue) illustrates the classification tion, NMSS Non-motor Symptom Scale, PDQ-8 8-item Parkinson’s Disease accuracy of the fitted logistic regression model (dependent variable: Questionnaire, SCOPA Scales for Outcomes in Parkinson’s Disease. PDQ-8 SI “Responder”/”Non-Responder”, independent variables: *P < 0.050, **P < 0.010, ***P < 0.001. agebaseline, PDQ-8 SIbaseline, NMSS-total scorebaseline, NMSS item a Rank-biserial correlation. 12baseline, NMSS item 16baseline). The discriminatory power of the test with these parameters is demonstrated by C-statistic = 0.78. The diagonal line (red) represents chance classification accuracy. The change (F4,68 = 11.1, P < 0.001). In this model, NMSS item 12baseline cross of black reference lines indicates the optimal trade-off point in had the highest predictive value (β = 0.35, P = 0.001), followed by which the model reached 75.0% sensitivity and 73.3% specificity. agebaseline (β = −0.28, P = 0.004), NMSS item 16baseline (β = 0.26, P = NMSS Non-Motor Symptom Scale, PDQ-8 SI8-item Parkinson’s 0.011), and NMSS item 2baseline (β = −0.22, P = 0.025). Disease Questionnaire Summary Index. Logistic regression analysis The cut-off for a clinically relevant change in PDQ-8 SI at 36-month Linear and logistic regression analyses were confirmed by follow-up was 8.4 points (12 SD of PDQ-8 SIbaseline). Out of 73 Mann–Whitney U tests comparing baseline parameters between patients in our cohort, 28 patients (38.4%) were classified as 36- long-term QoL responders and non-responders. Significant differ- month QoL “responders”, 29 patients (39.7%) reported unchanged ences were found for PDQ-8 SI (responders: 40.1 ± 20.4, non- QoL, and 16 patients (21.9%) indicated a clinically relevant responders 28.3 ± 12.5, P = 0.021), NMSS-12baseline (responders: 1.7 ± 3.0, non-responders 0.4 ± 1.0, P = 0.015), NMSS-16baseline worsening of long-term QoL. For binary logistic regression analyses, patients reporting (responders: 3.1 ± 2.9, non-responders 1.5 ± 2.1, P = 0.009), NMSS- 23baseline (responders: 3.1 ± 4.0, non-responders 1.6 ± 3.0, P = 0.017), unchanged and worsened QoL were grouped as QoL “non- and NMSS-27baseline (responders: 3.5 ± 3.7, non-responders 2.0 ± 3.5, responders” (n = 45, 61.6%). In explorative logistic regression P = 0.027). analyses, every additional year of age at baseline decreased the odds of 36-month QoL improvement by ~5% (odds ratio [OR]= 0.949, confidence interval [CI]=0.895–1.007, P = 0.082). Furthermore, DISCUSSION the odds of QoL improvement were increased by ~5% with every In the present study, we report the 36-month effects of STN-DBS additional point of baseline QoL impairment in the PDQ-8 SIbaseline on QoL in a cohort of 73 patients with PD. We observed significant (OR = 1.048, CI = 1.012–1.086, P = 0.008) and by ~14% for every improvements in QoL following STN-DBS at a short-term, i.e., 6- additional 10 points of baseline non-motor burden in the NMSS-total month follow-up with subsequent decrements in gains at 36- scorebaseline (OR = 1.014, CI = 0.999–1.029, P = 0.074). Moreover, month follow-up when only 38% of the patients experienced a specific NMSS items had a predictive value: one additional point in sustained clinically relevant QoL improvement compared to NMSS-12baseline (“difficulties experiencing pleasure”) increased the preoperative baseline. Our results provide evidence that clinically odds of QoL improvement by 46% (OR = 1.462, CI = 1.054–2.028, P relevant QoL improvement three years after preoperative baseline = 0.023) and in NMSS-16baseline (“concentration”) by 30% (OR = assessment can be predicted with 75% accuracy. Greater QoL 1.302, CI = 1.064–1.593, P = 0.010). improvement was observed for patients with younger age at A logistic regression model using the aforementioned parameters intervention, worse baseline QoL, and a higher burden of specific (agebaseline, PDQ-8 SIbaseline, NMSS-totalbaseline, NMSS-12baseline, and NMS, such as anhedonia and concentration impairments. In NMSS-16baseline) correctly classified 75.3% of patients into groups of contrast, patients more severely affected by fainting at baseline long-term QoL “responders/non-responders” (Nagelkerke’s R2 = experienced less QoL improvement. 0.338, χ2 = 0.9, P = 0.001, n = 73) as opposed to only 61.6% without To our knowledge, the present study is the first to report an predictors. The model reached 75.0% sensitivity and 73.3% specificity association between younger age at intervention and greater QoL at the optimal trade-off point (C-statistic = 0.779, P < 0.001, CI = improvement at 36-month follow-up. The association between these 0.667–0.892, see Fig. 2)11. parameters was previously described for a 12-month period by Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2021) 48 S.T. Jost et al. 4 Soulas et al.12. However, other studies found no association between month follow-up. The relationship between baseline concentration age and changes in QoL6,13. This inconsistency might be explained and QoL changes remained significant after controlling for by the fact that calendar age may not predict QoL. Instead, QoL after anhedonia. Floden et al. and Witt et al. have reported that higher STN-DBS may be associated with ‘physiological age’. For example, preoperative verbal memory deficits (Rey Auditory Verbal Learning frailty and co-morbidities may impact QoL post STN-DBS more than Test single-trial memory and Dementia Rating Scale-2) are predictors calendar age14. In line with previous research, other sociodemo- of more unsatisfactory postoperative QoL outcome at 6- and 8- graphic parameters, such as sex and disease duration were not month follow-up10,19. Concentration/attention deficits are often significantly correlated with long-term change of QoL6,15. accompanied by global cognition impairment in patients with PD. Confirming results of earlier studies with shorter follow-up However, in our cohort, multi-disciplinary team assessments included periods, the dosage of dopaminergic medication at preoperative expert neuropsychological assessments with formal testing of global baseline was not associated with QoL outcome6,13. In line with cognition scores, psychiatric interviews, and neurological examina- previous studies with follow-up periods up to 5 years, motor tions to identify risks of adverse outcomes in patients with poor examination did not predict QoL changes13,16. In line with preoperative global cognition as these patients have a higher risk to previous studies with follow-up periods up to 5 years, motor progress to dementia. Strict indication assessments resulted in examinations did not predict QoL changes. Daniels et al.6 reported normal global cognition at baseline which remained stable at 6- and that the cumulative daily OFF time is the strongest predictor for 36-month follow-up. Therefore, in this highly selected cohort, a improvement in disease-related QoL after DBS at 6-month follow- higher burden of isolated concentration deficits constituted a up. Further studies including cumulative OFF time with a longer predictor of greater QoL improvement. Future studies in larger follow-up are needed. cohorts including formal testing of concentration are warranted to To our knowledge, this is the first report of a significant confirm this finding. relationship between more severe preoperative QoL impairment To our knowledge, our study is the first to report an association and greater postoperative QoL improvement at 36-month follow- between the presence of preoperative fainting and worse QoL up3. This is in line with previous studies, that reported a outcome at 36-month follow-up. This finding is in line with the relationship between these parameters at 6-month and 24- observation that cardiovascular symptoms, such as fainting/ month follow-up3,9. Every additional point in the PDQ-8 SI at syncopes, worsen at 36-month follow-up8 and have a marked baseline increased the odds of favorable long-term QoL outcome negative impact on QoL20. by 5%. The strength of the association is in line with the results of Some limitations of our study should be acknowledged. One our previous study at short-term follow-up9 and the Cleveland important limiting factor is the underrepresentation of patients Clinic cohort results10, emphasizing the essential role of baseline with severe NMS, such as clinically relevant psychiatric disorders QoL for the prediction of even long-term QoL outcome and also or cognitive impairment, as these patients were not eligible for demonstrating the validity of our results. Our results are in line DBS. Although the cohort size of the present study (n = 73) is with several previous studies which have demonstrated that limited, it is still one of the largest beyond short-term follow-up. higher baseline QoL impairments predict greater postoperative Furthermore, the multicenter design of our study increases QoL improvement at short-term follow-up3,6,10. In contrast, a study external validity by reducing bias caused by single-center studies. by Lezcano et al.16 has observed that lower less severe QoL We did not systematically assess apathy, which could have impairments could predict greater QoL improvement at 1- and 5- improved our prediction model, as patients with negative QoL year follow-up. These differences could be explained by demo- outcome showed higher preoperative apathy scores in previous graphic and clinical parameters in the study by Lezcano et al., such research21. QoL was assessed with the PDQ-8, which may be less as a longer mean disease duration (13.2 years) and higher mean sensitive to small QoL changes than the PDQ-39 due to a reduced baseline PDQ impairments (41.1 points), than in the present study scale gradation resulting from fewer items22. Due to the focus on (10.3 years and 32.8 points)3,6,10,16. In the multivariate model, QoL and non-motor aspects of PD, we did not conduct anhedonia, age, concentration problems and fainting contributed assessments of motor examination in pre- or postoperative toward explaining QoL outcome at 36-month follow-up, whereas medication or stimulation OFF states and we did not assess other baseline QoL did not add to the predictive value of this model. motor aspects, such as the cumulative daily OFF time or severity of This means that, although baseline QoL was a significant predictor dyskinesia. Future studies are needed to further explore a possible of QoL change at 36-month follow-up in the univariate analysis, its predictive potential of these parameters. Another limitation is that contribution in the multivariate model was dominated by the severe disease progression can result in patients being lost to other four variables mentioned earlier. follow-up which could introduce a systematic bias in studies with In the present study, specific preoperative NMS, namely more longer follow-up periods23. severe anhedonia and problems with sustaining concentration, Also, the variability of the exact location of stimulation in the were predictors for greater QoL improvement. target area might be relevant for postoperative QoL improve- The predictive potential of depressive symptoms is in line with ment24, but was not investigated in the present study as we the results at 6-month follow-up in a previous study of our group9 focused on preoperative predictors of QoL outcome. A recent and 8-month follow-up in the Cleveland Clinic cohort10. The study by Petry-Schmelzer et al. reported that non-motor out- present study results also extend the time frame of a 24-month comes, such as mood/apathy and attention/memory, depend on follow-up study by Schuepbach et al. which reported greater QoL the location of neurostimulation and are correlated with QoL improvement in patients with worse baseline scores in two outcome24–26. These results and the predictive value of baseline depression scales (Beck Depression Inventory and Montgomery- anhedonia and concentration deficits observed in the present Åsberg Depression Rating Scale)3. One must acknowledge, that study highlight the importance of assessments of a wide range of preoperative psychological interviews and strict formal testing NMS which may have implications for DBS programming to resulted in a highly selected cohort with low baseline depression achieve optimal long-term QoL outcomes. similar to other cohorts2,3,17. Therefore, the observation that worse The observation of greater QoL improvements at 36-month baseline depression results in greater QoL improvements is only follow-up in patients with younger age at intervention, worse valid for patients with minimal or subclinical depression. More preoperative QoL, worse preoperative anhedonia and concentra- severe preoperative depression is a known risk factor for tion problems, and less autonomic dysfunction, such as fainting, postoperative attempted or completed suicide18. highlight the importance of preoperative assessments of a wide Furthermore, we observed that patients with greater baseline range of motor and nonmotor symptoms. Our results, therefore, concentration deficits experienced greater QoL improvements at 36- contribute to the long-term goal of identifying patients who npj Parkinson’s Disease (2021) 48 Published in partnership with the Parkinson’s Foundation S.T. Jost et al. 5 experience more considerable postoperative QoL improvement we calculated Wilcoxon signed-rank and t-tests, respectively, to compare and optimizing patient selection for STN-DBS. outcome changes between pairs of visits. Benjamini-Hochberg correction was applied to account for multiple testing. The presented P-values were adjusted to the significance threshold P < 0.05 unless stated otherwise. METHODS Correlation analyses. The relationship between changes in QoL scores Study design and preoperative demographic and clinical parameters was explored using In this ongoing, prospective, observational, multicenter international study Spearman correlations, respectively Pearson correlations for normally (Cologne, London, Manchester), we examined patients with PD undergoing distributed variables. PDQ-8 SI change score (mean Testbaseline – mean STN-DBS as part of the DBS arm of the NILS study at preoperative baseline, Test36-month follow-up) was correlated with the following variables: agebaseline, 6-month, and 36-month follow-up postoperatively27,28. Patients were sex, disease duration since diagnosis, NMSS total scorebaseline, PDQ-8 screened between 06/2011 and 07/2017. The study was conducted under SIbaseline, SCOPA-motor examinationbaseline, -activities of daily livingbaseline, the Declaration of Helsinki. Study protocols had been approved by the local -motor complicationsbaseline, MMSEbaseline, and LEDDbaseline. In addition, we ethics committees (Cologne, study no.: 12-145; German Clinical Trials explored if PDQ-8 SI change score correlated to specific NMSS itemsbaseline Register: DRKS00006735; United Kingdom: NIHR portfolio, number: 10084; and, when appropriate, if these results remained significant after National Research Ethics Service South East London REC 3, 10/H0808/141). controlling for changes in other NMSS items in partial correlations. All patients gave written informed consent before study procedures. Linear regression analysis. In a second step, we aimed to identify Participants preoperative predictors of long-term QoL outcome using stepwise linear PD diagnosis was based on the UK Brain Bank criteria and patients were regression analysis. We included parameters from the correlation analyses screened for DBS treatment according to the guidelines of the Interna- (P < 0.2)40 as candidate predictor variables and PDQ-8 SI change score as tional PD and Movement Disorders Society29. A sufficient levodopa criterion variable. Multi-collinearity was checked using intercorrelations responsiveness (>30% improvement in the Unified Parkinson’s Disease between candidate predictor variables (r > 0.6) and Variance Inflation Rating Scale-III) was required for each patient. Furthermore, eligibility for Factors, which should not exceed 1041. STN-DBS was based on multi-disciplinary assessments including move- ment disorders specialists, stereotactic neurosurgeons, neuropsychologists, Logistic regression analyses and receiver operating characteristics. Further- psychiatrists, and when necessary, speech therapists and physiotherapists. more, the cohort was divided into groups of patients with clinically This led to the exclusion of patients with clinically relevant cognitive relevant QoL improvement and patients reporting stable/worsened QoL at impairment and psychiatric diseases30. 36 months. Each patient was classified as a long-term QoL “responder” or “non-responder” based on a preassigned threshold (½ SD of PDQ-8 SIbaseline) to report clinically important differences42. We employed Clinical assessment exploratory logistic regression models and receiver operating characteristic Clinical assessments were carried out under medication ON (MedON) at analyses with dichotomized QoL outcome as criterion variable and preoperative baseline and with neurostimulation ON and medication ON demographic and preoperative clinical parameters as predictor variables (MedON/StimON) at 6-month and 36-month follow-up. to evaluate the utility of linear regression models to predict patients’ The following scales and questionnaires were assessed: postoperative long-term QoL changes. Moreover, we analyzed differences of baseline characteristics between “responders”/“non-responders” using (1) QoL was investigated with the PD Questionnaire-8 (PDQ-8) reported Mann–Whitney U tests or t-tests, respectively. To explore the relationship as PDQ-8 Summary Index (PDQ-8 SI) ranging from 0 (no impairment) between QoL outcome changes and specific NMS, all analyses were to 100 (maximum impairment)31,32. The PDQ-8 assesses eight aspects explored for NMSS item scores. of QoL (mobility, activities of daily living, emotional wellbeing, stigma, social support, cognition, communication, bodily discomfort) and has been commonly used in PD33 and STN-DBS28,34,35. Reporting summary (2) The clinician-rated NMS Scale (NMSS) contains 30 items covering Further information on research design is available in the Nature Research nine domains of NMS: cardiovascular, sleep/fatigue, mood/apathy, Reporting Summary linked to this article. perceptual problems/hallucinations, attention/memory, gastrointest- inal tract, urinary, sexual function, and miscellaneous (including pain, inability to smell/taste, weight changes, and sweating). Symptoms DATA AVAILABILITY are surveyed over the last four weeks and therefore reflect ON and The data included in this study are available on request to the corresponding author. OFF states. The NMSS total score ranges from 0 (no impairment) to The data are not publicly available due to their containing information that could 360 (maximum impairment)36. compromise the privacy of the participants. (3) Motor examination, activities of daily living, and motor complications were assessed with the Scales for Outcomes in PD (SCOPA) -motor examination, -activities of daily living, and -motor complications37. The SCOPA is an abbreviated version of the Unified PD Rating Scale. CODE AVAILABILITY It strongly correlates with the corresponding parts of the Unified PD Statistical analyses were performed using SPSS Statistics 26. 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(Grant KFO 219). 14. DeLong, M. R. et al. Effect of advancing age on outcomes of deep brain stimu- lation for Parkinson disease. JAMA Neurol. 71, 1290–1295 (2014). 15. Chandran, S. et al. Gender influence on selection and outcome of deep brain AUTHOR CONTRIBUTIONS stimulation for Parkinson’s disease. Ann. Indian Acad. Neurol. 17, 66–70 (2014). 16. Lezcano, E. et al. Long-term impact on quality of life of subthalamic nucleus S.T.J.—data acquisition, data analysis, drafting of the manuscript, tables and figures. stimulation in Parkinson’s disease. J. Neurol. 263, 895–905 (2016). V.V.-V.—surgical intervention, critical revision of the manuscript. A.R.—data acquisi- 17. Dafsari, H. S. et al. EuroInf 2: Subthalamic stimulation, apomorphine, and levo- tion, critical revision of the manuscript. P.A.L.—data acquisition, critical revision of the dopa infusion in Parkinson’s disease. Mov. Disord. 34, 353–365 (2019). manuscript. M.S.—data acquisition, critical revision of the manuscript. J.E.—surgical 18. Giannini, G. et al. Suicide and suicide attempts after subthalamic nucleus sti- intervention, critical revision of the manuscript. M.S.—critical revision of the mulation in Parkinson disease. Neurology 93, e97–e105 (2019). manuscript. J.N.P.-S.—data acquisition, critical revision of the manuscript. A.S.—data 19. Witt, K. et al. Negative impact of borderline global cognitive scores on quality of acquisition, critical revision of the manuscript. A.G.—critical revision of the manu- life after subthalamic nucleus stimulation in Parkinson’s disease. J. Neurol. Sci. script. M.T.B.—data acquisition, critical revision of the manuscript. G.R.F.—data 310, 261–266 (2011). acquisition, critical revision of the manuscript. K.A.—surgical intervention, critical 20. McCarthy, K., Ward, M., Romero Ortuno, R. & Kenny, R. A. Syncope, fear of falling revision of the manuscript. A.A.—data acquisition, critical revision of the manuscript. and quality of life among older adults: findings from the irish longitudinal study P.M.-M.—study concept and design, critical revision of the manuscript. K.R.-C.—study on aging (TILDA). Front. Cardiovasc. Med. 7, 7 (2020). concept and design, data acquisition, critical revision of the manuscript. L.T.—data 21. Maier, F. et al. Patients’ expectations of deep brain stimulation, and subjective acquisition, critical revision of the manuscript. H.S.D.—study concept and design, perceived outcome related to clinical measures in Parkinson’s disease: a mixed- data acquisition, critical revision of the manuscript. method approach. J. Neurol. Neurosurg. Psychiatry 84, 1273–1281 (2013). 22. Luo, N. et al. Determination of the longitudinal validity and minimally important difference of the 8-item Parkinson’s Disease Questionnaire (PDQ-8). Mov. Disord. FUNDING 24, 183–187 (2009). Open Access funding enabled and organized by Projekt DEAL. 23. Limousin, P. & Foltynie, T. Long-term outcomes of deep brain stimulation in Parkinson disease. Nat. Rev. Neurol. 15, 234–242 (2019). 24. Petry-Schmelzer, J. N. et al. Non-motor outcomes depend on location of neuro- COMPETING INTERESTS stimulation in Parkinson’s disease. Brain 142, 3592–3604 (2019). S.T.J. reports no financial disclosures. Veerle Visser-Vandewalle is a member of the 25. Irmen, F. et al. Left prefrontal connectivity links subthalamic stimulation with advisory boards and reports consultancies for Medtronic, Boston Scientific and St. depressive symptoms. Ann. Neurol. 87, 962–975 (2020). Jude Medical. She received a grant from SAPIENS Steering Brain Stimulation. A.R. has 26. Dafsari, H. S. et al. Non-motor outcomes of subthalamic stimulation in Parkin- received honorarium from UCB and was supported by a grant from Medtronic. P.A.L. son’s disease depend on location of active contacts. Brain Stimul. 11, 904–912 was funded by the SUCCESS-Program of the University of Marburg, the Parkinson’s (2018). Foundation, and the Stiftung zur Förderung junger Neurowissenschaftler. M.S. has 27. Dafsari, H. S. et al. Beneficial nonmotor effects of subthalamic and pallidal neu- received honoraria from Bial, Britannia and Medtronic as well as grants from rostimulation in Parkinson’s disease. Brain Stimul. 13, 1697–1705 (2020). Parkinson’s UK, Michael J Fox Foundation, NIHR, BBSRC, Dystonia society and 28. Jost, S. T. et al. Subthalamic stimulation improves quality of sleep in Parkinson Innovate UK. Julian Evans reports no financial disclosures. M.S. has received honoraria disease: A 36-month controlled study. J. Parkinsons. Dis. 11, 323–335 (2021). for educational meetings/travel/accommodation from Medtronic, Abbott, and UCB, 29. Lang, A. E. et al. Deep brain stimulation: preoperative issues. Mov. Disord. 21 grants from Parkinson’s UK and Ipsen, and has acted as a consultant for Medtronic (Suppl 14), S171–S196 (2006). and Abbott. J.N.P.-S. has received travel grants from Boston Scientific. Anna Sauerbier 30. Florin, E. et al. Modulation of local field potential power of the subthalamic reports no financial disclosures. Alexandra Gronostay reports no financial disclosures. nucleus during isometric force generation in patients with Parkinson’s disease. M.T.B. received speaker’s honoraria from Medtronic, Boston Scientific, Abbott Neuroscience 240, 106–116 (2013). (formerly St. Jude), GE Medical, UCB, Apothekerverband Köln e.V. and Bial as well 31. Jenkinson, C., Fitzpatrick, R., Peto, V., Greenhall, R. & Hyman, N. The PDQ-8: as research funding from the Felgenhauer-Stiftung, Forschungspool Klinische Studien Development and validation of a short-form Parkinson’s Disease Questionnaire. (University of Cologne), Horizon 2020 (Gondola), Medtronic (ODIS), and Boston Psychol. Health 12, 805–814 (1997). Scientific and advisory honoraria for the IQWIG. G.R.F. reports no financial disclosures. 32. Dafsari, H. S. et al. Subthalamic stimulation improves quality of life of patients K.A. has received honoraria for educational meetings, travel and consultancy from aged 61 years or older with short duration of Parkinson’s disease. Neuromodu- Medtronic, St Jude Medical and Boston Scientific. A.A. reports personal consultancy lation 21, 532–540 (2018). fees from Zambon, AbbVie, Boehringer Ingelheim, GE, Neuroderm, Biogen, Bial, EVER 33. Sauerbier, A. et al. Non-motor phenotyping of black and asian minority ethnic Neuro Pharma, Therevance, Vectura grants from Chiesi Pharmaceuticals, Lundbeck, compared to white individuals with Parkinson’s disease living in the United Horizon 2020 - PD_Pal Grant 825785, Ministry of Education University and Research Kingdom. J. Parkinsons. Dis. 11, 299–307 (2021). (MIUR) Grant ARS01_01081, owns Patent WO2015110261-A1, owns shares from PD 34. Dafsari, H. S. et al. Beneficial effect of 24-month bilateral subthalamic stimulation Neurotechnology Limited. P.M.-M. has received honoraria from Editorial Viguera and on quality of sleep in Parkinson’s disease. J. Neurol. 267, 1830–1841 (2020). Movement Disorder Society for lecturing in courses; from AbbVie for speaking in npj Parkinson’s Disease (2021) 48 Published in partnership with the Parkinson’s Foundation S.T. Jost et al. 7 experts’ meetings and from AbbVie and Zambon for participating in the Advisory Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims Board of epidemiological studies. License fee payments for the King’s Parkinson’s in published maps and institutional affiliations. Disease Pain Scale, and grants from the International Parkinson and Movement Disorder Society for development and validation of the MDS-Non-Motor Symptoms Scale. K.R.C. has received funding from Parkinson’s UK, NIHR, UCB, and the European Union; he received honoraria from UCB, Abbott, Britannia, US Worldmeds, and Otsuka Pharmaceuticals; and acted as a consultant for AbbVie, UCB, and Britannia. L.T. Open Access This article is licensed under a Creative Commons reports grants, personal fees and non-financial support from SAPIENS Steering Brain Attribution 4.0 International License, which permits use, sharing, Stimulation, Medtronic, Boston Scientific and St. Jude Medical. H.S.D.’s work was adaptation, distribution and reproduction in any medium or format, as long as you give funded by the Prof. Klaus Thiemann Foundation and the Felgenhauer Foundation appropriate credit to the original author(s) and the source, provide a link to the Creative and has received honoraria by Boston Scientific and Medtronic. Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the ADDITIONAL INFORMATION article’s Creative Commons license and your intended use is not permitted by statutory Supplementary information The online version contains supplementary material regulation or exceeds the permitted use, you will need to obtain permission directly available at https://doi.org/10.1038/s41531-021-00174-x. from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. Correspondence and requests for materials should be addressed to S.T.J. or H.S.D. © The Author(s) 2021 Reprints and permission information is available at http://www.nature.com/ reprints EUROPAR AND THE INTERNATIONAL PARKINSON AND MOVEMENT DISORDERS SOCIETY NON-MOTOR PARKINSON’S DISEASE STUDY GROUP Roongroj Bhidayasiri10, Cristian Falup-Pecurariu11, Beomseok Jeon12, Valentina Leta13, Per Borghammer14, Per Odin15, Anette Schrag16, Alexander Storch17,18,19, Mayela Rodriguez Violante20, Daniel Weintraub21,22, Charles Adler23, Paolo Barone24, David J. Brooks25,26, Richard Brown27, Marc Cantillon28, Camille Carroll29, Miguel Coelho30, Tove Henriksen31, Michele Hu32,33, Peter Jenner34, Milica Kramberger35,36, Padma Kumar37, Mónica Kurtis38, Simon Lewis39, Irene Litvan40, Kelly Lyons41, Davide Martino42, Mario Masellis43, Hideki Mochizuki44, James F. Morley45,46, Melissa Nirenberg47, Javier Pagonabarraga48, Jalesh Panicker49, Nicola Pavese50, Eero Pekkonen51, Ron Postuma52, Raymond Rosales53,54,55, Anthony Schapira56, Tanya Simuni57, Fabrizio Stocchi58, Indu Subramanian59, Michele Tagliati60, Michele Tinazzi61, Jon Toledo62,63, Yoshio Tsuboi64 and Richard Walker65 10 Chulalongkorn Centre of Excellence for Parkinson’s Disease & Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand. 11Faculty of Medicine, Transilvania University of Brașov, Brașov, Romania. 12Department of Neurology, Seoul National University College of Medicine, Seoul, South Korea. 13King’s College London, Institute of Psychiatry, Psychology & Neuroscience, London, UK. 14Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark. 15University of Lund, Faculty of Medicine, Lund, Sweden. 16UCL Institute of Neurology, London, UK. 17Division of Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, Dresden, Germany. 18Department of Neurology, Dresden University of Technology, Dresden, Germany. 19German Center for Neurodegenerative Diseases (DZNE), Research Site Dresden, Dresden, Germany. 20Movement Disorders Clinic, National Institute of Neurology and Neurosurgery, Mexico City, Mexico. 21Department of Psychiatry and Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. 22Parkinson’s Disease and Mental Illness Research, Education and Clinical Centers, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA. 23The Parkinson’s Disease and Movement Disorders Center, Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA. 24Center for Neurodegenerative Diseases (CEMAND), Neuroscience Section, University of Salerno, Salerno, Italy. 25Institute of Neuroscience, Newcastle University, Newcastle, UK. 26Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark. 27Department of Medicine, University of Birmingham Institute of Cardiovascular Sciences, City Hospital, Birmingham, UK. 28Reviva Pharmaceuticals, Inc, Santa Clara, CA, USA. 29Faculty of Medicine and Dentistry, University of Plymouth, Plymouth, UK. 30FAS Center for Systems Biology, Harvard University, Cambridge, MA, USA. 31 Movement Disorder Clinic, University Hospital of Bispebjerg, Copenhagen, NV, Denmark. 32Oxford Parkinson’s Disease Centre, University of Oxford, Oxford, UK. 33Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. 34Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK. 35Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden. 36Department of Neurology, University Medical Centre Ljubljana, Ljubljana, Slovenia. 37Parkinson’s Disease Service for the Older Person, Rankin Park Centre, John Hunter Hospital, HNELHD, Newcastle, NSW, Australia. 38Functional Movement Disorders Unit, Movement Disorders Program, Neurology Department, Hospital Ruber Internacional, Madrid, Spain. 39Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia. 40Department of Neurosciences Movement Disorders Center, University of California, San Diego, USA. 41University of Kansas Medical Center, Kansas City, KS, USA. 42Department of Clinical Neurosciences, University of Calgary & Hotchkiss Brain Institute, Calgary, Canada. 43Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada. 44Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan. 45Parkinson Disease Research, Education, and Clinical Center, Philadelphia Veteran Affairs Medical Center, Philadelphia, PA, USA. 46Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA. 47Department of Neurology, NYU School of Medicine, New York, NY, USA. 48Movement Disorders Unit, Sant Pau Hospital and Biomedical Research Institute (IIB-Sant Pau), Barcelona, Spain. 49Neurology, National Hospital for Neurology & Neurosurgery, London, UK. 50 Newcastle Magnetic Resonance Centre & Positron Emission Tomography Centre, Newcastle University, Campus for Ageing & Vitality, Newcastle upon Tyne, UK. 51Department of Neurology, Helsinki University Hospital, and Department of Neurological Sciences (Neurology), University of Helsinki, Helsinki, Finland. 52Research Institute of McGill University Health Centre, Montréal, Canada. 53Department of Neurology and Psychiatry, University of Santo Tomas Hospital, Manila, Philippines. 54International Institute of Neuroscience, Saint Luke’s Medical Center, Manila, Philippines. 55Center for Neurodiagnostic and Therapeutic Services, Metropolitan Medical Center, Manila, Philippines. 56Department of Clinical Neurosciences, University College London (UCL) Institute of Neurology, Royal Free Campus, Rowland Hill Street, London, UK. 57Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. 58University and Institute for Research and Medical Care, IRCCS San Raffaele, Rome, Italy. 59UCLA/West LA VA, Los Angeles, CA, USA. 60Cedars-Sinai Medical Center, Los Angeles, CA, USA. 61Department of Neuroscience, Biomedicine, and Movement, University of Verona, Verona, Italy. 62 Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. 63Department of Neurology, Houston Methodist Hospital, Houston, TX, USA. 64 Department of Neurology, Fukuoka University, Fukuoka, Japan. 65Northumbria Healthcare NHS Foundation Trust, North Tyneside General Hospital, Rake Lane, North Shields, Tyne and Wear, UK. Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2021) 48