Parkinson’s disease (PD) is a common neurodegenerative movement disorder. Overactive bladder symptoms (OAB) are the most common clinical manifestation of neurogenic lower urinary dysfunction (NLUTD) in patients with PD. Antimuscarinic agents are the first-line treatment for OAB symptoms in those patients. However, it is important to balance the therapeutic benefits of these drugs with their potential adverse effects. Cognitive adverse events by anticholinergics are a concern, particularly in elderly patients with PD[1]. Intradetrusor injections of botulinum toxin are effective but associated with an increased risk of urinary retention. Neuromodulation can be used to treat PD-related OAB symptoms but is considered with limited efficacy[2]. Stem cell therapy is a promising treatment for many urological conditions. Intradetrusor injections of  ADSCs may have a role in treating PD-related OAB symptoms.  The objective of this study was to assess the safety of intradetrusor adipose stem cells (ADSC) injections and their effect on PD-related OAB symptoms.

Between January 2019 and December 2020, we performed a prospective trial that enrolled male and female PD patients with symptoms of OAB (urgency, urinary frequency, and/or urgency incontinence). A total of 12 patients were randomized in 1 of 2 groups: treatment group (received a single injection into the detrusor muscle of 10ml of ADSC solution), or placebo group (single injection into the detrusor muscle of 10ml of normal saline). ADSCs were injected using a template showing 20 injections (0.5 ml/injection) throughout the posterior and lateral walls of the bladder sparing the trigone and dome. Injections were delivered with a rigid scope under general anesthesia using bladder injection needle 22Gauge  (tip length 4mm, working length 35cm). ADSCs solution was reconstituted in 5 ml of sterile saline. Liposuction was performed from the treatment group to isolate ADSCs. Briefly, the lipoaspirate was digested with collagenase, at 37 °C. Then it was washed 3 times with cold phosphate-buffered saline (PBS). The Stromal vascular fraction was plated into a culture flask. The medium was replaced every 3 days and cultured in expansion. The cells are used after confluence in the first passage. 
Inclusion criteria were: patients with a clinical diagnosis of PD according to UK Brain Bank Criteria[3], patients age between 40 and 70 years, have a stable dose of antiparkinsonian drugs 8 weeks before study entry,  stage 1 to 3 on modified Hoehn and Yahr scale, patients had an urgency score ≥ of 2 and a total score ≥ of 3 of the OAB symptom score (OABSS).
Exclusion criteria were: patients with secondary parkinsonism syndromes,  patients with polyuria with a daily urine volume >3000 mL, patients taking anticholinergic medications for  OAB symptoms, history of benign prostatic hypertrophy, patients with stress urinary incontinence or urinary tract infection.
Eligible participants were randomly assigned to one of the 2 groups by a computer-generated lottery. Both the urologists and the patients were blinded to the treatment assignments.
The primary outcomes of our study were the change from baseline in OAB symptom score (OABSS) and the overactive bladder questionnaire short form (OAB-q SF) score. The secondary outcomes were the change from baseline in the mean number of micturitions/24 h, the mean number of urgency episodes/24 h, the mean number of urgency incontinence episodes/24 h, and the mean number of nocturia episodes/night as recorded on a 3-day bladder diary at baseline and 6 months later. Safety assessments included any reported adverse events.

A total of 12 patients were included in the study. Most of the patients in both groups had an age between 60 and 70 years, had PD for more than 5 years, Hoehn and Yahr stage 2 and 2.5, duration of the OAB symptoms  > 12 months (table 1).
Significant improvements from baseline were seen in the OABSS total score in the treatment group compared to placebo at the end of the study (6 months). The mean OABSS total score decreased from 10.33  to 6.83 in the treatment group. A reduction of ≥3 points from total OABSS  was estimated as a minimal clinically important change.  In the placebo group, the OABSS remain almost the same between baseline and at 6 months. Significant improvements were observed from baseline to the end of study in the mean number of micturition/24 h (baseline 10.66 to 7.50); the mean number of micturition/night (baseline 1.33 to 0.33); the mean number of urgency episodes/24 (baseline 2.83 to 1.66); the mean number of leaks/24 h (baseline  2.66 to 0.66). In the placebo group, there were no significant changes in all bladder diary measures from baseline to the end of the study. Significant improvements from baseline were noted for the mean of OAB-q SF symptom bother score and the mean of OAB-q SF total HRQL score in the treatment group. In the placebo group, the mean of OAB-q SF symptom bother score and the mean of OAB-q SF total HRQL score remain almost the same till the end of the study. The outcomes of the study are summarized in table 2.
There were no serious adverse events reported in the treatment or placebo group.

For the first time in the literature our study report that intradetrusor ADSCs could control OAB symptoms in patients with PD. In this study, patients who received a single intradetrusor ADSCs injection experienced significant improvements in all bladder diary measures and a reduction of OABSS. Patients' satisfaction with treatment, assessed by the mean of OAB-q SF total HRQL score significantly improved and symptom bothers significantly decreased.
The main limitation of our study is the small sample size.

Findings from this study provide preliminary evidence in support of the safety and potential clinical utility of intradetrusor ADSCs injections for the treatment of PD-related OAB symptoms

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