The effect of age and disease duration on the efficacy of subthalamic nuclei deep brain stimulation in Parkinson's disease patients

Abstract Background Previous studies have reported the effects of age and disease duration on the efficacy of subthalamic nuclei deep brain stimulation (STN‐DBS) of Parkinson's disease (PD) patients. However, available data involving these issues are not consistent. In particular, the effect of age and disease duration on the initial efficacy of STN‐DBS has not been established. Methods A total of 51 patients with PD treated with bilateral STN‐DBS were involved in the present study. They received clinical symptom evaluation during the preoperative, initial, and chronic stages of surgery. The correlations between age when undergoing surgery/age at disease onset/disease duration and outcomes of STN‐DBS were measured. Results The preoperative levodopa response was negatively associated with age. During the initial stage, the age when undergoing surgery and age at disease onset were negatively correlated with the effect on bradykinesia, with better symptom control of general symptoms in long‐term disease patients. Similarly, patients with an early time of surgery and disease onset and long‐term disease duration showed better control of bradykinesia and axial symptoms at the chronic stage. Furthermore, a long‐term disease duration and early disease onset benefited from an increase of therapeutic efficacy in general, rigid, and axial symptoms with STN‐DBS after a long period. Nevertheless, patients with late disease onset achieved a better relief of stigma. Conclusion Age and disease durations played a unique role in controlling the symptoms of PD patients treated with STN‐DBS. These results may contribute to patient selection and adjustments of expectations of surgery, based on the age, disease duration, and different symptoms.


| INTRODUC TI ON
Parkinson disease (PD) is one of the most common neurodegenerative diseases and is clinically characterized by a series of motor impairments, including tremor, rigidity, and bradykinesia. PD is also associated with non-motor symptoms, such as cognitive and emotional impairments. 1 Furthermore, subthalamic nuclei deep brain stimulation (STN-DBS) is a well-established therapy for relieving these symptoms of PD. 2,3 PD prevalence is increasing with age, with PD affecting 1% of the population greater than 60 years of age; however, more than 4% of the population greater than 85 years of age suffers from PD. 4 Compared with early-onset PD patients, significantly more severe motor impairments are observed in patients with a later onset but with similar disease durations. 5 A previous study showed that there was a significant negative correlation between age and the levodopa response. 6 Similarly, age has a great impact on the outcomes of STN-DBS when treating PD patients. After chronic stimulation, there is a significant negative correlation between age and the improvement of some parameters of health-related quality. 7 STN-DBS is typically used after the disease has been present for 11-13 years; however, recent studies reported that STN-DBS treatment was superior to medical therapy in patients with early PD, indicating that young patients and patients with short disease duration may undergo this surgery. 8,9 Some recent studies also found that elderly patients undergoing DBS did not have an increased risk of more serious complications. 10 However, the results of these studies were not consistent. To the best of our knowledge, no study has investigated the effects of age and disease duration on the efficacy of initial STN-DBS treatment of PD patients; therefore, these effects were investigated in the present study.

| Surgical procedures
Bilateral STN-DBS implantations were conducted using a Leksell were implanted and fixed, and the implanted pulse generator was then implanted.
After 4-5 weeks (1 month post-operation), the patients were asked to return to the hospital to start the program (in a stable off medication condition), to minimize micro-subthalamotomy effects. 13 Each patient underwent a regular adjustment of stimulation settings, achieving satisfactory clinical outcomes and avoiding intolerable side effects. The clinical symptoms were measured, and then each patient underwent a regular adjustment of stimulation settings and medications until optimal control of symptoms was established, followed by a chronic stage clinical evaluation (12 ± 1 months post-operation).

| Total electrical energy delivered (TEED) calculation
TEED, the total energy delivered by the DBS system over a specific period of time, was determined using the programmed parameters of stimulation and the measured system impedance, which was developed by a previous study and used to evaluate the stimulation intensity. 14 The formula was as follows: TEED (1 s) = [(voltage 2 × pulse width × frequency)/impedance].

| Statistical analysis
All data are expressed as the mean ± standard deviation or as a median (Q1, Q3). The influence of age when undergoing surgery, age at disease onset, and disease duration on the efficacy of STN-DBS (and symptoms of PD and efficacies of medications) were investigated using Pearson's correlations between age when undergoing surgery/age at disease onset/disease duration and the efficacy/symptom severity, for each continuous variable. The changes of symptoms at different time points were measured using paired t-test or Wilcoxon signed-rank test. All statistical analyses were conducted using MATLAB (2019b; Mathworks). The medication, stimulation and optimal (stimulation + medication) effects on UPDRS III were calculated as follows: Medication response (rate) = The therapeutic outcome differences between the initial and chronic stages were further measured using the following: . . The subscores of UPDRS III, including tremor, rigidity, bradykinesia, and axial symptoms, were only measured for changes in values, instead of the rates, because some subscores were zero, which could not be used as a denominator. Other scales, such as PDQ-39, HAMA, and HDRS were measured in a similar manner. A value of p < 0.05 was considered to indicate statistical significance.

| Patient demographics
A total of 51 PD patients (30 males and 21 females) with bilateral STN-DBS were involved in the present study. The mean age when undergoing surgery was 62.47 ± 7.73 years. The mean age at disease onset was 52.23 ± 9.07 years. The mean disease duration was 10.24 ± 4.31 years, and the median H-Y stage was 3.0 (3.0, 3.0).
The patients showed significant motor improvements after being treated with medications (p < 0.0001). Importantly, the initial and chronic optimal therapeutic efficacies (stimulation + medication) were both better than preoperative medication efficacies (initial: p < 0.0001; chronic: p = 0.0002); however, there was no significant difference of motor impairment between the initial and chronic stages (medication on: p = 0.3610; medication off: p = 0.3103).

| The effect of age and disease duration on motor impairments
Similar with a previous study, 6 there was a negative correlation between age when undergoing surgery and preoperative medication response. This association might have been mainly attributed to bradykinesia and axial subscores of UPDRS III. Similar results were obtained between age at disease onset and preoperative medication response ( Figure 1) (general, bradykinesia, and axial) ( Table 2).
For the initial stage of STN-DBS, the stimulation effect on rigidity was positively associated with age at disease onset, whereas the stimulation effect on bradykinesia was negatively associated with the age when undergoing surgery. The optimal therapeutic efficacy (stimulation + medication) on bradykinesia was negatively correlated with age when undergoing surgery and age at disease onset.
Moreover, the changes in optimal therapeutic efficacy (at the initial stage) and medication efficacy (preoperative) were positively associated with disease duration ( Table 2).
For chronic stages of STN-DBS, the age at disease onset was associated with the stimulation effect. Furthermore, stimulation and optimal therapeutic efficacy on bradykinesia and axial symptoms was both negatively correlated with age when undergoing surgery and age at disease onset. Notably, the disease duration was positively associated with the stimulation effect on axial symptoms and change in optimal therapeutic efficacies (axial symptoms during the chronic stage) and medication efficacies.
We further investigated the difference between the initial and chronic stages. The disease duration was positively associated with the stronger optimal therapeutic efficacies of general and axial symptoms, and the stimulation effects of general, rigid, and axial symptoms. The age at disease onset had a negative impact on stronger optimal therapeutic efficacies for axial symptoms, and stimulation effects on general, rigid, and axial symptoms ( Figure 2, Table 2).
Up to 50% of patients with PD experience sudden and transient motor blocks (freezing) while initiating or performing activities. 15 Giladi et al. 16 developed the FOGQ, which is a clinician/interview administered patient-reported rating scale, with higher scores denoting more severe FOG symptoms. However, we did not find a significant correlation between age/disease duration and the severity of FOG. Furthermore, we found that older patients showed a better amelioration of stigma ( Figure 3, Table 3).

| The effect of age and disease duration on cognition and emotion
MoCA was used to evaluate cognitive impairments in PD patients, with a low score indicating a worse cognition performance. The age when undergoing surgery and age at disease onset were positively

F I G U R E 1
The relationship between medication response and age. The preoperative medication response (total Unified Parkinson Disease Rating Scale III score) was negatively correlated with the age when undergoing surgery (A) and age at disease onset (B) TA B L E 2 The effect of age and disease duration on the motor efficacy of subthalamic nuclei deep brain stimulation

F I G U R E 2
The relationship between alleviation of motor impairment and disease duration. The disease duration had a positive effect on elevation of stimulation (A) and optimal (B) effect on motor impairment between the initial and chronic stages associated with preoperative and chronic stage cognitive impairments; however, the age or disease duration did not show any effect on changes of cognitive impairments. HAMA and HDRS can measure the severity of anxiety and depression, respectively. However, disease duration was only found to be negatively associated with anxiety symptoms during the chronic stage ( Table 3).

| The effect of age and disease duration on the LEDD and programming setting
The stimulation parameters during the chronic stage were collected and used to calculate the TEED. However, there was no correlation between TEED and age or disease duration. Similarly, although STN-DBS could significantly decrease the LEDD, as previously mentioned ( Table 1), age and disease duration did not influence or change the LEDD during the preoperative and chronic stage.

| DISCUSS ION
Age and disease duration had a great impact on the symptoms and progression of PD; however, studies of these parameters did not obtain consistent results. 6,7,17,18 Therefore, we conducted the present study, which provided results concerning these issues based on our cohort of patients. To the best of our knowledge, this study was the first to investigate the influences of age and disease duration on the initial outcomes of STN-DBS treatment of PD patients. Previously, patients older than 65 years were not traditionally con- Overall, patients with an early time of surgery and disease onset, and long-term disease duration may receive better motor improvements in general symptoms or some specific symptoms.

| The age and disease duration influence the outcomes of DBS
Health-related quality could be divided into different classes.
The results of our study on chronic outcomes indicated that late sur-

| The potential mechanisms related with age and disease duration effects
There is no doubt that the age and disease duration had a great impact on the symptoms of PD and outcomes of STN-DBS, so specific mechanisms may contribute to these observations. Morphology The morbidity of PD increases with aging, and both processes share similar cellular and other alterations in the dopaminergic pathways and other systems. 26,27 Healthy aging is accompanied by loss of dopaminergic neurons, 28 and it is assumed that the symptoms of PD appear when dopaminergic neurons in the substantia nigra are lost by up to 60%-70%. 29 A previous study found the right dorsal premotor area, precentral, parietal lobule, and bilateral precuneus were more activated in PD patients, when compared with old control subjects, when imagining stepping over obstacles. In a similar manner, the premotor area, precentral and parietal lobes, and visual association areas were activated in older subjects, when compared with younger subjects. 30 Another study investigated electroencephalographic changes during an auditory oddball task while walking in young adults, older adults, and patients with PD, and found that old adults and patients with PD showed prolonged P300 latency, when compared with young adults. Furthermore, the authors found that better motor and cognitive performances were correlated with shorter P300 latencies. 31 Aging may therefore be an extra border to PD pathology. Phaseamplitude coupling (PAC) between beta and gamma oscillations as well as beta burst features can be identified as electrophysiological biomarkers for PD, and an additional study confirmed that PAC between beta and gamma activity was elevated in elderly subjects, when compared to younger subjects without PD. 26 Elevated beta oscillatory activity in the STN is considered as the most pronounced abnormal electrophysiological signature of PD, 32 with a correlation found between beta power and bradykinesia. 33 However, it could be relieved by levodopa and DBS 34,35 ; moreover, an incidence of longer beta bursts in the STN has been confirmed to be positively correlated with clinical impairments. 36  than that of the loss in young men; however, the opposite effect was discovered in young women, indicating a neurobiological basis for known behavioral sex differences in reward and punishment processing. 38 Chandra et al. revealed major sex disparities (young male and female rats) in gene expression and canonical pathways of microvessels and these differences provided a foundation to study neurological diseases. 39 Meanwhile, a previous study showed that young women had significantly higher cerebral blood flow than men in the frontal and temporal lobes, but these differences disappeared at age 65 years. 17 PD mainly affects elderly people and the sample size in our study was limited to investigate the effect of different sexes on the PD symptoms.
Our study emphasized and illustrated the effect of age and disease duration on the outcomes of STN-DBS; however, multicenter studies with a larger cohort of patients should be conducted in the future to strengthen and confirm our observations.

| CON CLUS ION
The present study investigated the effects of age and disease dura-

CO N FLI C T O F I NTE R E S T
None declared.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.