Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment option for advanced Parkinson's Disease (PD) improving motor symptoms, quality of life and allowing to reduce dopaminergic medication (1). Aiming at a more symptom-specific, individualized DBS treatment there is a great interest to identify biomarkers that help to predict and monitor the individual DBS outcome. Moreover, personalized treatment decisions based on the individual status of the patient including genetics would be important not only for patients and their caregivers, but also for treating physicians when coucelling their patients. Studies like the EARLY STIM trial have proven that DBS in PD must not be limited to patients in advanced stages but rather ought to be offered to patients after the first years of motor fluctuations or dyskinesia with insufficient medical treatment adjustments (2). The significant beneficial impact of DBS on quality of life (QoL) in patients as well as the verification of long-term safety in different studies changed the clinical field toward an earlier approach in patients with motor fluctuations (2, 3). However, it is still difficult to predict patients' individual disease progression and potential functional DBS response. PD patients, per se, present heterogeneously in their clinical picture, their rate of disease progression and possible cognitive decline (4). While patients with dyskinesia and tremor, shorter disease duration, younger age, absence of dementia and stable psychiatric conditions seem to benefit particularly well from DBS, a predominance of axial symptoms and ON-Freezing correlates with presumably worse outcome (5–7).

Specific gene mutations seem to exert an individually different impact on disease progression, but also on DBS effects (8–10). PD patients with glucocerebrosidase (GBA) gene variants, e.g., present with faster progressing motor as well as cognitive deterioration (11, 12). Accordingly, although GBA patients benefit from DBS with regard to motor impairment and QoL (13, 14) they also experience faster worsening of cognitive decline and non-motor symptoms after DBS when compared to e.g., mutation-negative DBS patients (13–15). Parkin gene (PRKN) mutation has clinically been associated with a higher frequency and severity of impulse control behaviors (ICB) (16), but PRKN carriers seem to be good responders to DBS needing intervention later than GBA-gene mutation carriers (8). A more variable picture has been reported for LRRK2 mutation carriers where LRRK2-G2019S variant carriers show excellent STN-DBS responses (8, 17, 18), but stimulation effects in patients with LRRRK2-R1441G mutations was poor (8, 17).

At least 5–10% of the so-called Early-onset PD patients (EOPD) are estimated to carry genetic mutations (19, 20). With slight variability in literature, EOPD present first PD motor symptoms between the 21^st and 40–55^th year of age (21–23). Due to the comparably young age of onset (AOO) in EOPD, patients are more likely to still work for a living and take care of children. Several studies report on a correlation between younger age of onset and poor QoL in EOPD due to, e.g., difficulties with family and spouse, role expectations, a higher level of stigma, social isolation and job loss next to mere physical limitations (24–27). EOPD with DBS exhibit a higher percentage of PD gene mutations than their older counterparts (13, 28, 29). Besides, EOPD with proven gene mutations often show additional clinical features that differ from sporadic late onset PD (19, 30). Genetic factors, e.g., have been suggested to play a role in the development of early and/or severe dyskinesia with marked levodopa sensitivity as well as dystonia, painful cramps and dysautonomia (9, 10, 31–35). Furthermore, psychiatric symptoms such as depression, impulsive- or obsessive-compulsive behavior, increased intake of dopamine agonists (DA) or levodopa as well as substance abuse or dependence and paranoid symptoms is more common in EOPD (26, 35–37). Given the variable clinical presentation and levodopa response in EOPD with and without gene mutation (Mut+ and Mut-), treatment response to DBS might differ due to gene-specific effects. How much and in what way genetic status impacts the outcome of STN-DBS in PD is yet to be elucidated. Some studies indicate more durable results in patients with EOPD and certain PD gene mutations (38). A more recent review on DBS effects in monogenic PD patients, however, reported on rather variable cognitive and neuropsychiatric DBS benefits depending on the respective mutated gene (8) but no difference in DBS motor effects in monogenetic PD patients in comparison to the general PD population (8, 39). Especially beyond the most common LRRK2-, PRKN- and GBA-gene mutation, detailed knowledge and literature on the influence of individual monogenetic mutations on motor as well as non-motor DBS effects is limited. EOPD present with a highly complex clinical as well as psychosocial profile of requirement. Comprehensive data on DBS effects in this PD sub-cohort will be needed increasingly in order to offer individualized counseling and to weigh possible clinical benefits and risks of a highly elective surgical intervention in young patients with multi-layered treatment expectations.

Here, we retrospectively analyse DBS effects in a mere EOPD-cohort with 15% of proven PD-gene mutation carrier by means of standardized comprehensive clinical assessment and documentation of clinical outcome, socioeconomic aspects, non-motor symptoms as well as QoL data.

The present results demonstrate that EOPD with and without known genetic background benefit from STN-DBS with about 53% motor improvement measured by UPDRS III accompanied by a ~59% LEDD-reduction 12 months after implantation. In line with this, patients experienced a meaningful reduction of additional motor as well as non-motor neuropsychiatric symptoms corroborated by significant improvements in the UPDRS IV with regard to motor fluctuations and a significant reduction in the QUIP-Score examining impulsivity in PD. Furthermore, patients experienced significant 30% improvements of QoL measured by the PDQ-39.

Decision making on the right timing of an elective surgical procedure such as DBS ought to be done in a highly individualized manner and under careful weighting of motor complications, motor subtype, putative disease progression, gender, genetics, presence of specific symptoms at diagnosis, lifestyle and treatment preferences (50). In their review, Kleiner-Fisman et al. (51) described greater improvements after subthalamic DBS in PD-patients with higher baseline motor deficits, longer disease duration and a higher baseline levodopa responsiveness prior to surgery (52). Correspondingly, responsiveness to DBS in our EOPD-cohort correlated significantly with presurgical responsiveness of motor symptoms to levodopa. Additionally, our EOPD cohort has an overall high motor improvement compared to recent STN-DBS trials (53) and motor as well as non-motor benefits of our cohort are at least comparable if not better than those in advanced later onset PD-patients with regard to previous trials (51, 53–55). Accordingly, several studies describe a profound and persistent improvement of disability and motor features as well as relatively better axial and cognitive outcomes of operated patients with younger age (6, 56–59) which, to some extend, might derive from more efficient compensatory mechanisms in younger patients (60). Hitherto publication landscape on DBS in genetic and early onset PD puts a main emphasis on motor outcome. Although motor improvements self-evidently are important in PD-patients and we also found a correlation between motor improvements and changes in BDI in our cohort (p = 0.03), mood and hypo- as well as hyperdopaminergic behavior exert greater effects on QoL in PD than do motor complications (61). With regard to impulsivity, we realized a statistically significant reduction of impulsivity in the QUIP-score together with a meaningfully reduced declaration of additional neuropsychiatric symptoms under subthalamic stimulation and after significant overall LEDD-reduction at 12 MFU (see Tables 1, 3). This is in line with data on STN-DBS-induced alleviation of neuropsychiatric non-motor fluctuations and hyperdopaminergic behaviors that could also be seen in comparison to best medical PD treatment in the EARLYSTIM cohort (62, 63). ICB is observed under higher dosages of pulsatile L-Dopa monotherapy (64). In allowing the reduction of dopaminergics, STN-DBS can help to reduce not only dyskinesia that is frequent in EOPD but also to improve psychiatric side effects based on dopaminergic overtreatment (57, 62, 63, 65). Hassan et al. found that men were more likely to develop DA-induced ICBs (66). Due to a higher D3-receptor-affinity, especially DA dose reduction is reported to significantly diminish hyperdopaminergic behaviors (62, 67). Mere DA component reduction of the total LEDD alone did not explain the beneficial neuropsychiatric benefits, in our cohort. However, one patient of our cohort without known gene mutation and a tendency for ICB became hypomanic after re-initiation of DA-therapy 9 months after STN-DBS and attempted suicide 8 weeks later in association to a marital dispute. DA-withdrawal resolved ICB and suicidal tendencies in this patient so that DBS was not considered responsible for the suicide attempt. Another of our patients had attempted suicide before DBS due to DA-associated hypersexuality and severe motor fluctuations. After STN-DBS with significantly reduced LEDD and relevant motor benefits this patient never complained of suicidal ideation again to date. Additionally, the PDQ39-subitem “cognition” had improved significantly after LEDD reduction in our EOPD cohort at 12 MFU. While neuropsychiatric off-drug fluctuations are associated with e.g. reduced motivation, empty mind and cognitive slowing, on-drug effects might induce racing of thought (67). Studies comparing EOPD and older-onset PD-patients found that PD-patients with younger AOO show worse QoL as well as depression scores and perceive more stigmatization than older patients with comparable disease severity or disability (27). With regard to this, not only “cognition” but also the QoL subdivisions “mobility,” “activities of daily living,” “stigma,” and “bodily discomfort,” each representing a potential prerequisite of participation in social and professional life, improved significantly under STN-DBS in our cohort. Moreover, improvements of mood correlated significantly with lower apathy and impulsivity scores (p = 0.01 and p < 0.01, respectively) and higher QoL (p < 0.01).

61% of our cohort were already retired aged 51 ± 9 years at baseline and showed significantly worse initial QoL scores than those still working. Having said that, the initial 32% of fully employed patients were still working 12 months after DBS, so that one might speculate on potential benefits of earlier DBS on coping strategies in question of professional abilities. Additionally, QoL subdivisions “social support,” “communication,” and “emotional well-being” possibly affecting working abilities as well, have not been improved significantly after 12 months of DBS in our cohort. EOPD are confronted with a variety of additional challenges such as disruption of family life, depression, social isolation, greater perceived stigmatization and disability-related loss of income (27, 68). Preliminary studies on employment in EOPD found a mean time to loss of employment of 4.9 years. 46% of young PD-patients had stopped working after a disease duration of 5 years and 82% after 10 years of PD (23). Reversal of retirement is not to be expected so that early medical as well as social support and possibly earlier intervention might help to improve the rate of full occupation in EOPD patients.

So far, knowledge on the genetic background of PD-patients leads to no specific recommendations in the clinical evaluation procedure for DBS. In our cohort, 7 patients presented with known PD-gene mutations. In direct comparison to the Mut- patients, our Mut+ cohort tended to have a shorter disease duration at time of surgery. Angelini et al. found significantly differing disease durations between genetic subgroups in PD-DBS patients (13). While in our subanalysis comparison of Mut+ and Mut- EOPD revealed no significant difference in motor outcome, mean UPDRS III motor improvement in the Mut+ EOPD reached only ~35% most likely due to the more variable motor response in this small patient cohort. Additionally, the two PARK2+ patients deteriorated with regard QoL at last follow-up due to residual OFF-dystonia, development of severe apathy in one patient (see suppl. fig. 1; yellow line) and worsening of the PDQ39 subdivisions “activities of daily living,” “social support,” and “communication.” One additional complicating factor in this context might have been the immigrant status with severe language barrier in both patients.

Several studies found that patients with PD-associated mutations benefit from STN-DBS as well as patients without known PD gene-mutation (69, 70). Moro et al. found a reduced DBS effect in the mutation carrier group after 12 months of stimulation. However, this difference vanished after 3–6 years of continuous stimulation due to a more pronounced clinical decline of the non-mutation carriers after 3-5 years (71). Apathy changed significantly in-between the Mut+ and Mut-cohort in our study but worsened in the Mut+ and improved in the Mut- patients after DBS (see Table 2) with a tendency to worsening in the Mut+. A correlation with DA-reduction as an explanation for this in-between subgroup-trend could not be found. For the two patients with less favorable outcome (see Supplementary Figure 1) case 6 had a GBA mutation and case 7 was identified as a LRRK2-(p.G2019S-variant) mutation carrier. The latter variant has been associated with favorable outcome in previous study (8). Kuusimäki et al. (8) summarize previous study results reporting on poor DBS-outcome in LRRK2-patients with p.R1441G mutations compared to excellent results in p.G2019S-mutation carriers, development of neuropsychiatric problems 5–7 years after DBS in two p.T2031S-mutation carriers, inhomogeneous clinical benefits with regard to GBA-gene mutation and development of cognitive and/or neuropsychiatric problems some years after implantation in 3/5 SNCA-mutation carriers. Thus, certain genetic isoforms might have an impact on DBS effect.

Adverse events associated with DBS are of crucial importance in consideration for early DBS that needs weighing up of possible clinical benefits against individualized risks, requirements of the surgical procedure with IPG changes, possible lead fractures or malfunctioning and the lifelong need for follow ups by an experienced multidisciplinary team: SAE frequency in our cohort with overall 6.5% (n = 3) patients with postoperative confusion, 2.2% with wound healing difficulties and 2.2% intracranial bleeding (n = 1, respectively) did not outnumber previously published DBS risks (72).

We here present a single center EOPD-cohort treated with the same standardized procedures by the same team. The main strength of this study lies in the detailed information on motor and non-motor symptom evaluation by means of the UPDRS I-IV, documentation of additional neurological as well as neuropsychiatric features and information on occupation, mood, cognition, QoL, genetic status, stimulation parameters and (S)AES in 46 patients with EOPD and STN-DBS. The panels used here are convenient for use in the routine outpatient clinic allowing standardization and easy implementation in the clinical setting. Although our cohort size is one of the largest in studies of this kind, it is still small in terms of absolute numbers. Further limitations of the study lie in the rather short follow-up period up to now, the isolated use of STN as a target, the retrospective design, the monocentric study, the small number of mutation carriers, the unequal distribution of Mut+ and Mut- patients as well as in the fact that not all patients underwent genetic testing for PD mutations. A better understanding of the genetic background and associated clinical features might have an impact on decision making in DBS and the eventual individual outcome. Proper patient characterization is becoming increasingly relevant. Longitudinal monitoring of DBS-EOPD-cohorts over long-term periods with standardized comprehensive clinical assessment, accurate phenotypic characterization and documentation of clinical outcome might help to gain insights into disease etiology, to contextualize genomic information and to identify predictors of optimal EOPD-DBS candidates as well as those in danger of deterioration and/or non-response in future. Therefor our cohort encouraged us to establish the so-called EOPS-DBS-Registry (DRKS00028134) in order to gain knowledge on patients' progression and long-term outcome that might enable clinicians to improve the counseling of EOPD-patients.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Local Ethics Committee, Charité [EA4/263/21]. All patients gave their written informed consent.

AK, PK, JR, JK, FB, G-HS, and KF: conception and design of the study, or acquisition of data, or analysis and interpretation of data. PK, JR, JK, G-HS, KF, and AK: drafting the article or revising it critically for important intellectual content. PK and AK: final approval of the version to be submitted. All authors contributed to the article and approved the submitted version.

This study was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 424778381 – TRR 295. KF is supported by the BIH Clinical Fellow Programm, Charité.

Author AK received speaker's honoraria and consultancies from Medtronic and Boston Scientific. Author PK received speaker's honoraria from Medtronic and is in the Advisory Board of Abbott, outside the submitted work. Author G-HS received speaker's honoraria from Medtronic, Boston Scientific and Abbott. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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