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Learn more: PMC Disclaimer | PMC Copyright Notice Mov Disord Clin Pract . 2025 Nov 13;13(4):973–984. doi: 10.1002/mdc3.70411 Search in PMC Search in PubMed View in NLM Catalog Add to search Motor and Cognitive Outcome After Subthalamic Nucleus Deep Brain Stimulation in Patients with Parkinson's Disease Harboring GBA1 Variant Hikaru Kamo Hikaru Kamo , MD, PhD 1 Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan 2 Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida, USA Find articles by Hikaru Kamo 1, 2 , Genko Oyama Genko Oyama , MD, PhD 1 Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan 3 Department of Neurology, Saitama Medical University, Saitama, Japan Find articles by Genko Oyama 1, 3, ✉ , Mai Shimizu Mai Shimizu , MD 1 Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan Find articles by Mai Shimizu 1 , Haruka Takeshige‐Amano Haruka Takeshige‐Amano , MD, PhD 1 Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan Find articles by Haruka Takeshige‐Amano 1 , Takashi Ogawa Takashi Ogawa , MD, PhD 4 Department of Neurology, Juntendo Urayasu Hospital, Urayasu, Japan Find articles by Takashi Ogawa 4 , Wataru Sako Wataru Sako , MD, PhD 1 Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan Find articles by Wataru Sako 1 , Noriko Nishikawa Noriko Nishikawa , MD, PhD 1 Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan Find articles by Noriko Nishikawa 1 , Taku Hatano Taku Hatano , MD, PhD 1 Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan Find articles by Taku Hatano 1 , Yuanzhe Li Yuanzhe Li , PhD 1 Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan Find articles by Yuanzhe Li 1 , Hiroyo Yoshino Hiroyo Yoshino , PhD 1 Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan Find articles by Hiroyo Yoshino 1 , Manabu Funayama Manabu Funayama , PhD 1 Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan Find articles by Manabu Funayama 1 , Masanobu Ito Masanobu Ito , MD, PhD 5 Department of Psychiatry, Faculty of Medicine, Juntendo University, Tokyo, Japan Find articles by Masanobu Ito 5 , Hirokazu Iwamuro Hirokazu Iwamuro , MD, PhD 6 Department of Neurosurgery, Faculty of Medicine, Juntendo University, Tokyo, Japan Find articles by Hirokazu Iwamuro 6 , Atsushi Umemura Atsushi Umemura , MD, PhD 6 Department of Neurosurgery, Faculty of Medicine, Juntendo University, Tokyo, Japan Find articles by Atsushi Umemura 6 , Nobutaka Hattori Nobutaka Hattori , MD, PhD 1 Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan Find articles by Nobutaka Hattori 1, ✉ Author information Article notes Copyright and License information 1 Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan 2 Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Gainesville, Florida, USA 3 Department of Neurology, Saitama Medical University, Saitama, Japan 4 Department of Neurology, Juntendo Urayasu Hospital, Urayasu, Japan 5 Department of Psychiatry, Faculty of Medicine, Juntendo University, Tokyo, Japan 6 Department of Neurosurgery, Faculty of Medicine, Juntendo University, Tokyo, Japan * Correspondence to: Drs. Genko Oyama and Nobutaka Hattori, Department of Neurology, Faculty of Medicine, Juntendo University, 21‐1 Hongo, Bunkyo‐ku, Tokyo 113‐8421, Japan. E‐mail: [email protected] and [email protected] ✉ Corresponding author. Revised 2025 Sep 22; Received 2025 Jul 10; Accepted 2025 Oct 13; Collection date 2026 Apr. © 2025 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. PMC Copyright notice PMCID: PMC13071310 PMID: 41230957 Abstract Background Deep brain stimulation (DBS) is effective for Parkinson's disease (PD); however, its efficacy varies with genetic background, such as the GBA1 variant—the causative gene of Gaucher disease—associated with increased PD risk and cognitive decline after subthalamic nucleus (STN)‐DBS. Objectives The aim of the study was to examine the relationship between outcomes after STN‐DBS and GBA1 variants in PD patients undergoing bilateral STN‐DBS. Methods Patients were retrospectively analyzed over 5 years, with clinical and genetic assessments, including GBA1 variant status performed at baseline and at 1‐, 3‐, and 5‐years post‐DBS. Longitudinal changes in motor, cognitive, and medication outcomes were evaluated using propensity score matching and linear mixed‐effects models. Results A total of 371 PD patients undergoing bilateral STN‐DBS were analyzed, including 54 GBA1 variant carriers and 253 noncarriers, after excluding other genetic variants. Propensity score matching yielded 2 groups with balanced baseline characteristics, with 50 patients each. Over time, no significant differences were observed in motor, cognitive, or neuropsychiatric assessments between groups. GBA1 carriers exhibited worsened medication OFF‐DBS off state motor symptoms at 5 years postoperatively, whereas cognitive function, assessed by the Mini‐Mental State Examination, remained stable in both groups. Levodopa‐equivalent daily dose (LEDD) significantly decreased in both groups. Linear mixed‐effects models showed progressive motor and cognitive decline and reduced medication use over 5 years, with no significant impact on GBA1 variant status. Conclusions Findings from Japan's largest genetic cohort suggest that GBA1 variants may not significantly affect postoperative motor or cognitive trajectories following STN‐DBS. Further validation through large‐scale multinational and multicenter studies is warranted. Keywords: deep brain stimulation, Parkinson's disease, glucocerebrosidase, genetic, cognition Deep brain stimulation (DBS) is a well‐established treatment for advanced Parkinson's disease (PD), 1 , 2 with evident motor benefits that last over a decade. 3 , 4 However, the impact of DBS varies, and some patients experience cognitive and psychiatric side effects. 2 Recently, genetic background has been reported to affect DBS outcomes. Patients with LRRK2 (p.G2019S), PRKN , and CHCHD2 variants generally show favorable outcomes; however, poor prognosis has been reported in patients with LRRK2 variants (p.R1441G and p.T2031S), and the outcomes of DBS on SNCA variants remain controversial. 5 , 6 , 7 , 8 Glucocerebrosidase 1 ( GBA1 ) is the most frequent variant in PD patients; however, cognitive decline after subthalamic nucleus (STN)‐DBS has been reported. 9 The responsiveness of GBA1 ‐PD to DBS remains controversial. 9 , 10 , 11 , 12 Additionally, the characteristics of variants differ between regions and countries. 13 , 14 , 15 , 16 We conducted a retrospective analysis to evaluate the impact of GBA1 variants after STN‐DBS in a monoethnic Japanese cohort. Methods Patients In this study, we retrospectively analyzed patients with PD who underwent bilateral STN‐DBS at the Juntendo University Hospital between April 2015 and March 2024. The patients were diagnosed according to the diagnostic criteria for PD and advanced PD. 17 , 18 Selection criteria for DBS were as follows: age ≤ 75, levodopa responsiveness (≥ 30%), and no severe cognitive or psychiatric issues. 19 , 20 We did not perform a standardized sample size calculation because we included all post‐DBS patients with PD who underwent clinical evaluation and genetic analyses during the study period. A total of 54 patients with GBA1 variant carriers and 253 noncarriers were identified. Clinical Assessments Clinical assessments were conducted preoperatively (T 0 ) and at 1‐ (T 1 ), 3‐ (T 3 ), and 5‐years (T 5 ) postoperatively. A preoperative evaluation was performed within 6 months before surgery (Fig. S1 ). Preoperative assessments included genetic testing and clinical evaluation, including sex, age at onset, and age at DBS. Motor symptoms were assessed using the Movement Disorders Society‐Sponsored Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) Part III in medication‐off and ‐on states. 21 The UPDRS Part III score was converted to the MDS‐UPDRS Part III score as previously reported. 22 Additional assessments included the MDS‐UPDRS Parts I, II, and IV; cognitive evaluations using the Mini‐Mental State Examination (MMSE), frontal assessment battery (FAB), and Montreal Cognitive Assessment (MoCA); and neuropsychiatric evaluations using the Neuropsychiatric Inventory (NPI), Hamilton Depression Rating Scale (HAM‐D), Beck Depression Inventory (BDI), Dementia Rating Scale (DRS), and the Questionnaire for Impulsive‐Compulsive Disorders in Parkinson's Disease (QUIP). Olfactory function was assessed using the odor stick identification test (OSIT). Radioisotope imaging included dopamine transporter single‐photon emission computed tomography (DaT‐SPECT) and 123 I‐metaiodobenzylguanidine (MIBG) scintigraphy. DaT‐SPECT was analyzed with DaT‐View TM (MediPhysics, Japan); regions of interest (ROIs) were placed on the putamen and caudate, and mean bilateral specific binding ratios (SBRs) were used for analysis. 23 In 123 I‐MIBG scintigraphy, early and delayed images were acquired, and heart‐to‐mediastinum (H/M) ratios and washout rates were calculated from ROIs on the heart and mediastinum. 24 The levodopa‐equivalent daily dose (LEDD) was calculated as previously reported. 25 At T 1 and T 5 , motor symptoms were assessed using the MDS‐UPDRS Part III under 4 conditions: medication off/DBS off (OFF‐med/OFF‐DBS), medication on/DBS off (ON‐med/OFF‐DBS), medication off/DBS on (OFF‐med/ON‐DBS), and medication on/DBS on (ON‐med/ON‐DBS). In addition, data for the MDS‐UPDRS Parts I, II, and IV, MMSE, and LEDD were collected at these time points. At the 3‐year time point after DBS, the MDS‐UPDRS Part III score, MMSE score, and LEDD were evaluated in the ON‐med/ON‐DBS condition. Genetic Analysis Genomic DNA was extracted from peripheral blood using the QIAamp DNA Blood Maxi Kit (Qiagen) according to standard protocols. All exons and exon–intron boundaries of GBA1 ( NM_000157.4 ) were analyzed using direct sequencing. Long‐range polymerase chain reaction (PCR) was performed using previously reported primers to prevent the amplification of pseudogenes. 26 The purified PCR product obtained using ExoSAP‐IT (Thermo Fisher Scientific) was subsequently subjected to Sanger sequencing (Azenta, Tokyo, Japan). GBA1 variants were classified into 5 classes (mild, risk, severe, complex, and unknown) in accordance with the literature. 27 , 28 Severe and complex variants were merged in the severe group for statistical analysis. 11 Statistical Analyses All data are expressed as median (interquartile range [IQR]). Analyses were performed using Python (version 3.10). Normality was tested using the Shapiro–Wilk test. Baseline characteristics of GBA1 variant carriers and noncarriers were compared using Fisher's exact test for categorical variables and the Mann‐Whitney U test for continuous variables, with multiple testing corrected using the Benjamini–Hochberg false discovery rate (FDR). Propensity score matching (PSM) was performed using logistic regression based on sex, disease duration, age at surgery, MDS‐UPDRS Part III (OFF‐med and ON‐med), MMSE, and LEDD, with one‐to‐one nearest‐neighbor matching without replacement. Matching quality was assessed by pre‐ and post‐matching comparisons. 29 , 30 , 31 For sensitivity analysis, we also performed PSM including all baseline variables with <20% missing data. These analyses were planned to assess the robustness of the primary findings. To compare baseline characteristics between patients with and without GBA1 variants after PSM, sex, disease duration, age at onset, age at surgery, clinical rating scales (MDS‐UPDRS Parts I–IV, MMSE, FAB, MoCA), Neuropsychiatric Inventory (NPI, HAM‐D, BDI, DRS, and QUIP), OSIT, and imaging scores (DaT‐SPECT and 123 I‐MIBG scintigraphy) were compared using Fisher's exact test and the Mann‐Whitney U test with FDR correction. Motor, cognitive, and LEDD outcomes were assessed at each time point (T 0 , MDS‐UPDRS Part III (OFF‐med, ON‐med); T 1 and T 5 , 4‐condition MDS‐UPDRS Part III (OFF‐med/ON‐DBS, OFF‐med/OFF‐DBS, ON‐med/OFF‐DBS, ON‐med/ON‐DBS); T 3 , ON‐med/ON‐DBS (plus MMSE and LEDD at all time points). Attrition bias was evaluated by comparing follow‐up rates (Fisher's exact test). Cognitive status at 5‐years (normal, mild cognitive impairment (MCI), dementia) was compared using Fisher's exact test. 32 Longitudinal changes were assessed using Wilcoxon signed‐rank tests (baseline vs. later time points, FDR‐adjusted), including analyses limited to severe variants such as L444P, R120W, RecNciI, D409H, and G202R. Linear mixed‐effects models (LMMs) evaluated effects of time, GBA1 variant status, and their interaction on MDS‐UPDRS Part III (ON‐med/ON‐DBS, OFF‐med/OFF‐DBS), MMSE, and LEDD, adjusted for sex, ages at onset and surgery, and baseline scores, excluding the baseline measure of the same outcome, with subject‐specific random intercepts (restricted maximum likelihood). Three‐year time point was excluded for missing OFF‐med/OFF‐DBS data. Sensitivity models replaced baseline ON‐med and OFF‐med scores with levodopa responsiveness. Post hoc power analysis after PSM ( α = 0.05) showed 80% power to detect standardized mean differences (SMD) of 0.566 for continuous outcomes and odds ratios of 3.15–4.25 for binary outcomes (baseline rates 10%–30%). Statistical significance was set at P < 0.05. Patient Consents and Data Availability Written informed consent was obtained from all patients who agreed to participate in the study. This study was approved by the Ethics Committee of the Juntendo University School of Medicine (approval number: M08‐0477). Anonymized data not published in this article will be made available upon request from a qualified investigator. Results Characteristics of the Patients and Changes in Clinical Symptoms A total of 371 patients were enrolled in the study. Patients carrying known PD‐related variants, including PRKN , PINK1 , LRRK2 , GCH1 , CHCHD2 , and VPS35 , were excluded (n = 64). Fifty‐four patients were carriers of GBA1 variants and 253 patients were noncarriers of known genetic variants (Fig. S2 ). Significant differences in baseline characteristics were observed between the GBA1 variant carriers and noncarriers. Specifically, the age at surgery was significantly higher in GBA1 variant carriers (Mann‐Whitney U test, FDR correction, P = 0.0003). No significant differences were found in sex (Fisher's exact test, FDR correction, P = 0.55) or other clinical variables after correction for multiple comparisons (Table S1 ). Fifty patients were included in each group after PSM. Among the 50 PD patients with GBA1 variants, 14 carried L444P, 13 had R120W, and 9 carried the RecNciI recombinant allele. Based on established classifications, 39 patients had severe variants, 8 had variants of unknown significance, and 2 were classified as complex (Table 1 ). Follow‐up data were available for 40, 24, and 19 GBA1 variant carriers and 39, 29, and 17 noncarriers at T 1 , T 3 , and T 5 , respectively. Follow‐up rates were comparable between groups (Fisher's exact test, T 1 : P = 1.00; T 3 : P = 0.42; T 5 : P = 0.83), suggesting minimal risk of attrition bias (Table S2 ). The matched cohorts exhibited an improved balance in baseline covariates, effectively minimizing confounding effects and enabling more accurate comparisons between groups. No significant differences were found in motor symptom severity as assessed by the MDS‐UPDRS Parts I, II, III (ON‐med/ON‐DBS and OFF‐med/OFF‐DBS), and IV scores. Similarly, cognitive function tests and neuropsychiatric evaluations showed no significant group differences. OSIT and nuclear imaging parameters also did not differ significantly between the groups (Table 2 ). In the sensitivity analysis, including all baseline variables with <20% missing data, the balance between groups after matching was poorer, with SMDs exceeding 0.1 for multiple variables, and the matched sample size decreased from 50 versus 50 to 23 versus 23. Therefore, these results were not adopted as the primary analysis. TABLE 1. Frequency of each GBA1 variant in this study Variant Allele name Frequency of the variant (n = 52) Class of variant p.Leu483Pro L444P 14 Severe p.Arg159Trp R120W 13 Severe p.Leu483Pro, p.Ala495Pro, p.Val499= RecNciI 9 Severe p.Ile528Val I489V 2 Unknown p.Asp419Asn D380N 2 Unknown p.Asp448His D409H 2 Severe p.Gln286Arg Q247R 1 Unknown p.Asn431Ser N392S 1 Unknown p.Val499Ala V460A 1 Unknown p.Asn227Ser N188S 1 Unknown p.Arg202Gln R163Q 1 Unknown p.Arg398Ter R359* 1 Unknown p.Phe252Ile F213I 1 Unknown p.Phe298Tyr F259Y 1 Unknown p.Gly241Arg G202R 1 Severe p.Tyr343Asp Y304D 1 Unknown Open in a new tab Note : This table lists each variant by protein change together with the corresponding allele name. Counts refer to alleles, not unique individuals. In some cases, recombinant/complex cis alleles (eg, RecNciI) harbor multiple substitutions on the same chromosome; therefore, a single individual may contribute to more than one entry. All GBA1 ‐positive subjects were heterozygous; no biallelic pathogenic configurations (compound heterozygotes or homozygotes) were identified, and no cases met genetic criteria for Gaucher disease. TABLE 2. Comparison of baseline demographic and clinical characteristics between patients with and without GBA1 variants after propensity score matching Variable GBA1 noncarriers GBA1 carriers FDR‐adjusted P ‐value Sex M = 31, F = 19 M = 26, F = 24 0.6689 Disease duration 10.5 (2.0–17.0) 9.0 (4.0–20.0) 0.1698 Age at onset 41.0 (26.0–61.0) 45.5 (26.0–65.0) 0.1111 Age at surgery 49.5 (37.0–70.0) 54.5 (36.0–74.0) 0.1686 MDS‐UPDRS Part I 11.0 (0.0–24.0) 9.0 (0.0–30.0) 0.6689 MDS‐UPDRS Part II 19.0 (5.0–35.0) 17.0 (0.0–33.0) 0.6689 MDS‐UPDRS Part III (OFF‐med) 46.0 (16.0–75.0) 41.0 (16.0–70.0) 0.6484 MDS‐UPDRS Part III (ON‐med) 12.0 (1.0–37.0) 14.5 (1.0–32.0) 0.7845 Washout rate ( 123 I‐MIBG) 48.5 (20.0–62.5) 47.1 (11.8–62.8) 0.7845 MDS‐UPDRS Part IV 8.0 (4.0–11.0) 10.0 (0.0–19.0) 0.2538 SBR average (bilateral putamen, DaT‐SPECT) 2.4 (0.6–7.9) 2.0 (0.0–5.3) 0.2575 OSIT 4.0 (0.0–12.0) 4.0 (0.0–9.0) 0.6689 MMSE 30.0 (25.0–30.0) 29.0 (25.0–30.0) 0.5112 FAB 17.0 (11.0–18.0) 17.0 (11.0–18.0) 0.8815 MoCA 26.0 (18.0–30.0) 27.0 (19.0–30.0) 0.9371 NPI 4.0 (0.0–20.0) 4.0 (0.0–20.0) 0.9223 HAM‐D 2.5 (0.0–30.0) 3.0 (0.0–23.0) 0.5112 BDI 10.0 (0.0–33.0) 15.0 (3.0–36.0) 0.5112 DRS 1.0 (1.0–5.0) 1.0 (1.0–5.0) 0.2538 QUIP 1.0 (0.0–10.0) 1.0 (0.0–7.0) 0.9223 LEDD 1269.2 (600.0–2199.2) 1151.9 (0.0–2240.0) 0.6689 Open in a new tab Note: Values for continuous variables are presented as median (range). Abbreviations: MDS‐UPDRS, Movement Disorder Society‐Sponsored Unified Parkinson's Disease Rating Scale; 123 I‐MIBG, iodine‐123 metaiodobenzylguanidine; SBR, specific binding ratio; DaT‐SPECT, dopamine transporter single‐photon emission computed tomography; OSIT, odor stick identification test; MMSE, Mini‐Mental State Examination; FAB, frontal assessment battery; MoCA, Montreal Cognitive Assessment; NPI, Neuropsychiatric Inventory; HAM‐D, Hamilton Depression Rating Scale; BDI, Beck Depression Inventory; DRS, Dementia Rating Scale; QUIP, Questionnaire for Impulsive‐Compulsive Disorders in Parkinson's Disease; LEDD, levodopa‐equivalent daily dose. Longitudinal Clinical Comparison Between GBA1 Variant Carriers and Noncarriers We compared the motor symptoms, cognitive function, and LEDD at T 0 , T 1 , T 3 , and T 5 between GBA1 variant carriers and noncarriers after PSM (Fig. 1 ). No significant group differences were observed at any time point. Although the MMSE scores at 3 years postoperatively tended to be lower in GBA1 variant carriers, the difference was not significant after FDR correction. Also, in the analysis restricted to patients with severe variant, no between‐group differences were significant at any time point. Fig. 1. Open in a new tab Longitudinal comparison of motor symptoms, Mini‐Mental State Examination (MMSE) scores, and levodopa‐equivalent daily dose (LEDD) between GBA1 variant carriers and noncarriers at baseline and postoperative time points. Boxplots illustrate the distribution of clinical measures by GBA1 variant status at each time point: T 0 (preoperative), T 1 (1 year), T 3 (3 years), and T 5 (5 years) post‐deep brain stimulation (DBS). Blue boxes represent noncarriers, and red boxes represent GBA1 carriers. No statistically significant differences were observed after false discovery rate (FDR) correction (Mann‐Whitney U test, FDR‐adjusted, P = 0.4939). We evaluated the longitudinal changes in clinical measures by comparing each follow‐up time point (T 1 , T 3 , and T 5 ) with the baseline (T 0 ) within each genetic group. For MDS‐UPDRS Part III OFF‐med/OFF‐DBS scores, no statistically significant differences were observed at T 1 and T 3 in either group. However, a significant increase was observed at T 5 in the GBA1 variant carriers from 41 (36–48) to 63 (46–78), indicating worsening motor symptoms in the OFF‐med/OFF‐DBS state. No significant change was observed at T 5 in the GBA1 variant noncarriers (Fig. 2 ). MDS‐UPDRS Part III ON‐med/ON‐DBS scores showed no significant changes at any follow‐up time point in either group, suggesting stable motor function when medicated. MMSE scores remained stable over time in both groups, with no significant differences from the baseline at any time point (Fig. 2 ), indicating preserved cognitive function. LEDD demonstrated a significant reduction over time in both groups. In GBA1 variant noncarriers, LEDD was significantly reduced, but not at T 5 . In GBA1 variant carriers, LEDD remained significantly lower than baseline at all follow‐up time points (Fig. 2 ). Fig. 2. Open in a new tab Longitudinal changes in clinical outcomes across genetic groups. Line plots depicting the median values and 95% confidence intervals of ( A ) Movement Disorder Society‐Sponsored Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) Part III (OFF‐med/OFF‐DBS), ( B ) MDS‐UPDRS Part III (ON‐med/ON‐DBS), ( C ) Mini‐Mental State Examination (MMSE), and ( D ) levodopa‐equivalent daily dose (LEDD) from baseline (T 0 ) to 5 years (T 5 ) in individuals with GBA1 variant noncarriers (blue) and GBA1 variant carriers (orange). Each subplot shows the temporal trend within each group. Asterisks (*) indicate statistical significance at P < 0.05, and (**) indicate statistical significance at P < 0.01. Within severe carriers, LEDD was significantly reduced from baseline at T 1 and T 3 , whereas the reduction at T 5 did not remain significant. Motor scores (MDS‐UPDRS Part III ON‐med/ON‐DBS and OFF‐med/OFF‐DBS score) and MMSE did not show significant within‐group changes. Baseline‐to‐follow‐up changes focused on severe variants are visualized in Figure S3 . Preoperatively, 90% of patients in both the GBA1 variant carrier and noncarrier groups were classified as normal and 10% as mild cognitive impairment (MCI), with no dementia cases; the distribution did not differ between groups (Fisher's exact test, P = 1.0). At 5 years postoperatively, the proportions of normal cognition, MCI, and dementia were 86.7%, 6.7%, and 6.7% in carriers and 66.7%, 33.3%, and 0% in noncarriers, respectively, with no significant difference observed between groups (Fisher's exact test, P = 0.430). Mixed‐Effects Model Analysis of Motor, Cognitive, and Medication Changes After STN‐DBS over 5 Years LMM analyses were performed on the PSM cohort and demonstrated significant longitudinal changes in motor symptoms, cognitive function, and medication dosage over a 5‐year follow‐up period. Specifically, the MDS‐UPDRS Part III OFF‐med/OFF‐DBS scores showed a significant increase over time ( β = 3.12 per year; LMM; FDR‐adjusted P = 0.00038 at T 1 and 0.0035 at T 5 ), reflecting progressive worsening of motor symptoms despite DBS surgery. Furthermore, baseline MDS‐UPDRS Part III ON‐med scores were strongly associated with changes in postoperative OFF‐med/OFF‐DBS scores ( β = 0.63; LMM; FDR‐adjusted P = 0.002), suggesting that preoperative motor function in the ON‐med state may serve as a valuable predictor of postoperative motor outcomes in the OFF‐med/OFF‐DBS. No significant effects of sex, GBA1 variant status, age at onset, or age at surgery were observed on the trajectory of the OFF‐med scores. For MDS‐UPDRS Part III ON‐med/ON‐DBS scores, time‐related changes were not statistically significant; however, baseline OFF‐med scores remained a significant predictor ( β = 0.28; LMM; FDR‐adjusted P = 0.009), indicating that motor symptom severity in the OFF‐med state influences symptom management in the ON‐med/ON‐DBS state postoperatively. Cognitive function, as measured by the MMSE, declined significantly over the 5‐year period ( β = −0.29 per year; LMM; FDR‐adjusted P = 0.014), indicating that despite DBS intervention, cognitive deterioration persists. Neither sex nor GBA1 variant status had a significant influence on cognitive trajectories. Regarding medication management, LEDD decreased significantly over time ( β = −111.9 per year; LMM; FDR‐adjusted P = 0.0001), confirming the sustained medication‐sparing effect of DBS surgery. However, the GBA1 variant status showed no significant impact on the LEDD trajectory. Neither GBA1 variant status nor the time × GBA1 interaction was significant for any endpoint, indicating no differential 5‐year trajectories (Table 3 ). TABLE 3. Linear mixed‐effects model results for longitudinal changes in motor, cognitive, and medication Outcome Variable Coefficient ( β ) Standard error z ‐value FDR‐adjusted P ‐value MDS‐UPDRS Part III (OFF‐med/OFF‐DBS) Time (years) 3.12 0.56 5.57 <0.001* Sex 2.54 2.78 0.91 0.65 GBA1 variant 0.04 2.62 0.01 0.99 Age at onset −0.38 0.39 −0.98 0.65 Age at surgery 0 0.38 −0.01 0.99 Baseline MDS‐UPDRS Part III (ON‐med) 0.63 0.17 3.7 0.002* Baseline MMSE −0.57 0.84 −0.67 0.71 Baseline LEDD 0 0 1.16 0.65 GBA1 variant carrier × time −0.17 1.16 −0.15 0.97 MDS‐UPDRS Part III (ON‐med/ON‐DBS) Time (years) 0.39 0.33 1.17 0.65 Sex 2.94 1.9 1.55 0.49 GBA1 variant −1.32 1.78 −0.74 0.71 Age at onset 0.21 0.27 0.77 0.65 Age at surgery −0.15 0.26 −0.55 0.71 Baseline MDS‐UPDRS Part III (OFF‐med) 0.28 0.07 3.86 0.009* Baseline MMSE 0.21 0.58 0.37 0.85 Baseline LEDD 0 0 −0.88 0.71 GBA1 variant carrier × time −0.96 0.68 −1.41 0.65 MMSE Time (years) −0.29 0.1 −3.03 0.014* Sex 0.38 0.39 0.98 0.65 GBA1 variant −0.23 0.36 −0.62 0.71 Age at onset −0.05 0.05 −0.99 0.65 Age at surgery 0.04 0.05 0.7 0.71 Baseline MDS‐UPDRS Part III (OFF‐med) −0.02 0.02 −0.94 0.65 Baseline MDS‐UPDRS Part III (ON‐med) 0 0.03 0.02 0.99 Baseline LEDD 0 0 0.15 0.99 GBA1 variant carrier × time −0.04 0.20 −0.18 0.97 LEDD Time (years) −111.9 23.94 −4.68 <0.001* Sex −218.44 92.87 −2.35 0.07 GBA1 variant 56.89 91.16 0.62 0.71 Age at onset −17.5 13.52 −1.3 0.65 Age at surgery 12.79 13.27 0.96 0.71 Baseline MDS‐UPDRS Part III (OFF‐med) −0.19 4.07 −0.05 0.99 Baseline MDS‐UPDRS Part III (ON‐med) 0.43 4.94 0.09 0.99 Baseline MMSE 22.57 24.18 0.93 0.71 GBA1 variant carrier × time 48.58 40.29 1.21 0.65 Open in a new tab Note : P ‐values are FDR‐adjusted. Asterisks (*) indicate statistical significance at P < 0.05. Abbreviation: FDR, false discovery rate; DBS, deep brain stimulation; MDS‐UPDRS, Movement Disorder Society‐Sponsored Unified Parkinson's Disease Rating Scale; MMSE, Mini‐Mental State Examination; LEDD, levodopa‐equivalent daily dose. Sensitivity analyses yielded the same result that responsiveness was strongly associated with ON‐med/ON‐DBS severity ( β = −0.33; LMM; FDR‐adjusted P = 3.29 × 10 −9 ) but not OFF‐med/OFF‐DBS change or LEDD. The time effect on MMSE was nonsignificant. Full results are provided in Table S3 . Discussion This study comprehensively evaluated the effect of GBA1 variants on long‐term motor and cognitive outcomes following bilateral STN‐DBS in a well‐characterized Japanese cohort. After excluding other PD‐related variants and adjusting for confounders, GBA1 variant carriers and noncarriers showed no significant differences in motor progression, cognitive decline as measured by MMSE, or medication reduction. LMM identified baseline motor severity and sex as significant predictors of postoperative motor and medication outcomes, respectively, whereas GBA1 variant status showed no significant effect. These results suggest that factors other than GBA1 variants predominantly influence the clinical trajectories after STN‐DBS. Outcomes and Predictors After STN‐DBS in GBA1 ‐Associated PD Over long‐term follow‐up, carriers and noncarriers showed similar motor, cognitive, and LEDD trajectories, consistent with prior reports of sustained motor benefit from STN‐DBS regardless of GBA1 variant status. 33 , 34 However, a significant worsening of motor symptoms in the OFF‐med/OFF‐DBS was detected only in GBA1 variant carriers 5 years postoperatively, suggesting that progressive neurodegeneration may eventually surpass the motor symptom control effects of DBS. 35 , 36 Interestingly, no significant difference in ON‐med/ON‐DBS motor scores was observed between the groups at any time point, indicating that both cohorts maintained effective symptom control with medication and DBS stimulation. Furthermore, GBA1 variant carriers exhibited a significant reduction in LEDD over the 5‐year follow‐up period, suggesting that medication dosages were successfully lowered while maintaining motor function during the ON‐med/ON‐DBS state. This reduction may reflect differences in medication responsiveness or a more cautious approach to dopaminergic therapy in GBA1 variant carriers, who are known to have a higher risk of cognitive decline and psychiatric complications. 9 , 37 In the severe variant subgroup, LEDD significantly decreased at T 1 and T 3 , with a similar but nonsignificant trend at T 5 . MDS‐UPDRS Part III and MMSE showed no significant changes. These patterns were consistent with the main analysis, and the loss of significance at T 5 likely reflects reduced sample size and statistical power. LMM showed that preoperative motor function significantly influenced postoperative outcomes after DBS. Higher baseline ON‐med scores predicted slower deterioration of OFF‐med/OFF‐DBS scores, whereas baseline OFF‐med scores predicted postoperative ON‐med/ON‐DBS scores, indicating a bidirectional relationship. These results highlight the prognostic value of dopaminergic responsiveness for motor outcomes after DBS, aligning with prior reports on its role in long‐term efficacy. 38 Furthermore, sensitivity analyses incorporating preoperative levodopa responsiveness, an established predictor of postoperative outcomes, 39 supported the same conclusions as the main models, showing no GBA1 ‐related differences and robust time trends. In addition, levodopa responsiveness was strongly associated with ON‐med/ON‐DBS severity but not with changes in OFF‐med/OFF‐DBS scores, suggesting that it mainly reflects dopaminergic treatment effects rather than disease progression. In summary, although GBA1 variant carriers may show gradual motor decline in the OFF‐med/OFF‐DBS state due to disease progression, STN‐DBS with optimized medication can maintain motor benefits and reduce dopaminergic load in the midterm. In patients with severe variants, similar trends were observed, underscoring the need for individualized treatment, given their higher susceptibility to nonmotor symptoms and medication side effects. Is the GBA1 Variant Type a Key Determinant of DBS Outcomes in PD? Genetic background is increasingly recognized as influencing DBS outcomes. Although standard preoperative assessments include levodopa responsiveness, imaging, and cognition, 40 , 41 genetic factors such as GBA1 variants are notable for links to longer disease duration, greater motor complications, earlier onset, and more severe cognitive/nonmotor symptoms, with severe variants carrying higher cognitive risk, likely via greater cortical Lewy body pathology. 28 , 42 , 43 , 44 , 45 , 46 , 47 These factors underscore the significance of GBA1 variants in assessing DBS outcomes. STN‐DBS in GBA1 ‐PD generally provides sustained motor benefit, 46 , 48 , 49 , 50 , 51 but cognitive outcomes are mixed. 46 , 50 , 51 , 52 Our findings parallel large multicenter studies showing durable benefit, 11 with 5‐year off‐state worsening similar to prior cohorts. 33 Unlike a previous 4‐group study reporting DBS‐related cognitive decline, 9 we found no MMSE difference, possibly due to less‐sensitive testing, selection of cognitively preserved candidates, or center‐level factors; globus pallidus internus (GPi) data remain limited. 49 Racial and ethnic variation in GBA1 frequency and phenotype may also shape DBS outcomes. 53 , 54 , 55 In East Asians, severe variants are relatively common, potentially influenced by genetic background, environmental factors, and ascertainment differences. These may affect candidacy timing and cognitive trajectories, possibly explaining why some series, including ours, show no between‐group differences on screening tools despite prior risk signals. 11 , 34 , 56 Frequency of GBA1 Variants in Our Cohort The frequency of GBA1 variants in our Japanese cohort was within the range previously reported for Asian PD populations (1.8%–8.7%) and was higher among patients undergoing DBS. 53 , 57 This enrichment may reflect referral and eligibility criteria favoring preserved cognition and psychiatric stability. 58 , 59 Variant prevalence differs across ethnicities, with East Asian cohorts showing higher rates of severe variants such as L444P/RecNciI and distinct distributions of E365K/T408M/N409S compared to European cohorts. 53 , 54 A Japanese study reported a frequency of 18.8%, with L444P, R120W, and D409H most common, and rates even higher in DBS patients. 16 , 60 The pathogenic role of GBA1 variants in PD remains incompletely understood, as not all carriers develop PD, and effects may vary by age, ethnicity, and variant type. 9 , 14 Some Asian series report that despite more severe variants, clinical expression can be milder, potentially due to genetic background, environmental modifiers, or ascertainment differences. 53 , 54 , 55 These factors, along with study design, likely influence both reported frequencies and phenotypic expression. In our cohort, frequent variants included L444P, R120W, and RecNciI, all associated with neuropathic Gaucher disease. 42 , 61 Despite this, postoperative motor and cognitive outcomes did not differ significantly between carriers and noncarriers. Possible explanations include the selection of carriers with slower nonmotor progression, population‐specific spectra influencing DBS timing, and center‐level decision thresholds or unmeasured confounders. 53 , 54 , 55 , 57 , 58 , 59 As this study included only Japanese patients, further research comparing across populations is needed to clarify whether severe variants have differential DBS effects. Limitations and Future Directions Reliance on the MMSE likely limits the detection of subtle cognitive changes, and the lack of comprehensive nonmotor and psychiatric assessments restricts the interpretation of its results. In our cohort, FAB and MoCA‐J were administered only at baseline as part of the DBS evaluation. Given that MMSE is not specifically designed for PD and may fail to detect executive and visuospatial deficits, the absence of group differences should be interpreted with caution. Ethnic and environmental modifiers may also influence the phenotypic expression and generalizability. Future studies should stratify patients by variant severity, include detailed nonmotor assessments, and integrate genetic and biomarker data to optimize personalized DBS strategies. Importantly, our cohort of GBA1 variant carriers was derived from a single tertiary center and had a relatively higher age at surgery compared to noncarriers. Together with the stable MMSE performance observed over 5 years, this suggests that the included GBA1 variant carriers may represent a subgroup with a more benign disease course than typically reported. Possible explanations for these cohort characteristics include ethnic or racial differences in phenotypic expression, as well as selection bias inherent to the referral process and surgical eligibility criteria. These factors may, in part, explain why our findings contrast with previous literature that has reported earlier cognitive decline in GBA1 variant carriers, but further investigations, particularly large‐scale international multicenter studies, are needed to validate these hypotheses. Additionally, because follow‐up completeness varied over time, there is potential for attrition bias. However, dropout rates were similar between groups, and time point‐specific analyses were conducted using available data. This study suggests that even among GBA1 variant carriers, appropriately managed STN‐DBS therapy combined with tailored medication adjustment can achieve sustained motor symptom control and medication reduction over the mid‐ to long‐term. However, the progression of OFF‐med/OFF‐DBS motor symptoms and the risk of cognitive decline underscore the need for individualized treatment approaches that account for each patient's unique disease profile and nonmotor symptom burden, regardless of GBA1 variant status. Future investigations should include stratification by variant severity, comprehensive assessments of nonmotor and psychiatric symptoms, and integrative approaches combining genetic, biomarker, and imaging data to optimize patient selection and maximize therapeutic outcomes, thereby advancing precision medicine tailored to the heterogeneous pathophysiology of PD. Author Roles (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript preparation: A. Writing of the first draft, B. Review and critique. H.K.: 1A, 1B, 1C, 2A, 2B, 3A, 3B G.O.: 1A, 1C, 2C, 3C M.S.: 1C, 3C H.T.A.: 1A, 1C, 2C, 3C T.O.: 1C, 2C, 3C T.H.: 1C, 2C, 3C Y.L.: 1C, 2C, 3C H.Y.: 1C, 2C, 3C M.F.: 1C, 2C, 3C M.I.: 1C, 2C, 3C H.I.: 1C, 2C, 3C A.U.: 1C, 2C, 3C N.H.: 1C, 2C, 3C Disclosures Ethical Compliance Statement: This study was approved by the institutional review board of Ethics Committee of the Juntendo University School of Medicine (approval number: M08‐0477). Written informed consent was obtained from all participants prior to their inclusion in the study. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: This work was supported by JSPS KAKENHI (grant numbers: 23K19409). The authors declare that there are no funding sources or conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: GO received speaker honorarium from Medtronic Japan Co., Ltd., Boston Scientific Japan K.K., Abbott Japan Co., Ltd., Sumitomo Pharma Co., Ltd., Kyowa Kirin Co., Ltd., FP Pharmaceutical Corporation, Takeda Pharmaceutical Company Ltd., Eisai Co., Ltd., EA Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Biogen Japan Ltd., Nihon Mediphysics Co., Ltd., Benesse Style Care Co., Ltd., Viatris INC, Eli Lilly Japan K.K, and Abbvie GK, and received consultation fees from Teijin Pharma Ltd., NysnoBio, and Lundbeck Japan K.K." to Financial disclosures for previous 12 month. Dr. Kamo declares no conflicts of interest. Employment: Fixel Institute for Neurological Diseases, University of Florida. Supporting information Figure S1. Study protocol. Timeline of clinical assessments. Clinical evaluations were conducted at 4 time points: preoperatively (T 0 ), at 1 year (T 1 ), 3 years (T 3 ), and 5 years (T 5 ) after subthalamic nucleus deep brain stimulation (STN‐DBS). Preoperative assessments were performed within 6 months before surgery. MDC3-13-973-s004.pdf (164.6KB, pdf) Figure S2. Flowchart. Study participant flow diagram. A total of 371 patients who underwent bilateral subthalamic nucleus deep brain stimulation (STN‐DBS) were enrolled. Patients carrying other known Parkinson's disease (PD)‐related genetic variants ( PRKN , PINK1 , LRRK2 , GCH1 , CHCHD2 , and VPS35 ) were excluded (n = 64). The final cohort included 54 GBA1 variant carriers and 253 noncarriers. MDC3-13-973-s003.pdf (105.5KB, pdf) Figure S3. Longitudinal changes in clinical outcomes across genetic groups focused on severe variant. Line plots depicting the median values and 95% confidence intervals of ( A ) Movement Disorder Society‐Sponsored Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) Part III (OFF‐med/OFF‐DBS), ( B ) MDS‐UPDRS Part III (ON‐med/ON‐DBS), ( C ) Mini‐Mental State Examination (MMSE), and ( D ) levodopa‐equivalent daily dose (LEDD) from baseline (T 0 ) to 5 years (T 5 ) in individuals with GBA1 variant noncarriers (blue) and GBA1 variant carriers (orange). Each subplot shows the temporal trend within each group. Asterisks (*) indicate statistical significance at P < 0.05, and (**) indicate statistical significance at P < 0.01. MDC3-13-973-s002.pdf (38.1KB, pdf) Table S1. Comparison of baseline demographic and clinical characteristics between patients with and without GBA1 variants before propensity score matching. Values for continuous variables are presented as median (range). 123 I‐MIBG, iodine‐123 metaiodobenzylguanidine; BDI, Beck Depression Inventory; DaT‐SPECT, dopamine transporter single‐photon emission computed tomography; DRS, Dementia Rating Scale; FAB, frontal assessment battery; HAM‐D, Hamilton Depression Rating Scale; LEDD, levodopa‐equivalent daily dose; MDS‐UPDRS, Movement Disorder Society‐Sponsored Unified Parkinson's Disease Rating Scale; MMSE, Mini‐Mental State Examination; MoCA, Montreal Cognitive Assessment; NPI, Neuropsychiatric Inventory; OSIT, odor stick identification test; QUIP, Questionnaire for Impulsive‐Compulsive Disorders in Parkinson's Disease; SBR, specific binding ratio. MDC3-13-973-s005.docx (17.1KB, docx) Table S2. Follow‐up data availability and group comparisons at each time point post‐STN‐DBS. Follow‐up data availability and comparison between GBA1 variant carriers and noncarriers. The table shows the number of patients with available follow‐up data at 1 year (T 1 ), 3 years (T 3 ), and 5 years (T 5 ) postoperatively. Follow‐up rates were similar between GBA1 variant carriers (n = 40, 24, and 19 at T 1 , T 3 , and T 5 , respectively) and noncarriers (n = 39, 29, and 17), with no significant differences at any time point (Fisher's exact test, T 1 : P = 1.00; T 3 : P = 0.42; T 5 : P = 0.83), indicating a minimal risk of attrition bias. MDC3-13-973-s006.docx (15KB, docx) Table S3. Sensitivity linear mixed‐effects models using baseline levodopa responsiveness. P ‐values are FDR‐adjusted. Asterisks (*) indicate statistical significance at P < 0.05. DBS, deep brain stimulation; FDR, false discovery rate; LEDD, levodopa‐equivalent daily dose; MDS‐UPDRS, Movement Disorder Society‐Sponsored Unified Parkinson's Disease Rating Scale; MMSE, Mini‐Mental State Examination. MDC3-13-973-s001.docx (18.6KB, docx) Contributor Information Genko Oyama, Email: [email protected]. 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Ann Neurol 2016;80(5):674–685. 10.1002/ana.24781. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Supplementary Materials Figure S1. Study protocol. Timeline of clinical assessments. Clinical evaluations were conducted at 4 time points: preoperatively (T 0 ), at 1 year (T 1 ), 3 years (T 3 ), and 5 years (T 5 ) after subthalamic nucleus deep brain stimulation (STN‐DBS). Preoperative assessments were performed within 6 months before surgery. MDC3-13-973-s004.pdf (164.6KB, pdf) Figure S2. Flowchart. Study participant flow diagram. A total of 371 patients who underwent bilateral subthalamic nucleus deep brain stimulation (STN‐DBS) were enrolled. Patients carrying other known Parkinson's disease (PD)‐related genetic variants ( PRKN , PINK1 , LRRK2 , GCH1 , CHCHD2 , and VPS35 ) were excluded (n = 64). The final cohort included 54 GBA1 variant carriers and 253 noncarriers. MDC3-13-973-s003.pdf (105.5KB, pdf) Figure S3. Longitudinal changes in clinical outcomes across genetic groups focused on severe variant. Line plots depicting the median values and 95% confidence intervals of ( A ) Movement Disorder Society‐Sponsored Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) Part III (OFF‐med/OFF‐DBS), ( B ) MDS‐UPDRS Part III (ON‐med/ON‐DBS), ( C ) Mini‐Mental State Examination (MMSE), and ( D ) levodopa‐equivalent daily dose (LEDD) from baseline (T 0 ) to 5 years (T 5 ) in individuals with GBA1 variant noncarriers (blue) and GBA1 variant carriers (orange). Each subplot shows the temporal trend within each group. Asterisks (*) indicate statistical significance at P < 0.05, and (**) indicate statistical significance at P < 0.01. MDC3-13-973-s002.pdf (38.1KB, pdf) Table S1. Comparison of baseline demographic and clinical characteristics between patients with and without GBA1 variants before propensity score matching. Values for continuous variables are presented as median (range). 123 I‐MIBG, iodine‐123 metaiodobenzylguanidine; BDI, Beck Depression Inventory; DaT‐SPECT, dopamine transporter single‐photon emission computed tomography; DRS, Dementia Rating Scale; FAB, frontal assessment battery; HAM‐D, Hamilton Depression Rating Scale; LEDD, levodopa‐equivalent daily dose; MDS‐UPDRS, Movement Disorder Society‐Sponsored Unified Parkinson's Disease Rating Scale; MMSE, Mini‐Mental State Examination; MoCA, Montreal Cognitive Assessment; NPI, Neuropsychiatric Inventory; OSIT, odor stick identification test; QUIP, Questionnaire for Impulsive‐Compulsive Disorders in Parkinson's Disease; SBR, specific binding ratio. MDC3-13-973-s005.docx (17.1KB, docx) Table S2. Follow‐up data availability and group comparisons at each time point post‐STN‐DBS. Follow‐up data availability and comparison between GBA1 variant carriers and noncarriers. The table shows the number of patients with available follow‐up data at 1 year (T 1 ), 3 years (T 3 ), and 5 years (T 5 ) postoperatively. Follow‐up rates were similar between GBA1 variant carriers (n = 40, 24, and 19 at T 1 , T 3 , and T 5 , respectively) and noncarriers (n = 39, 29, and 17), with no significant differences at any time point (Fisher's exact test, T 1 : P = 1.00; T 3 : P = 0.42; T 5 : P = 0.83), indicating a minimal risk of attrition bias. MDC3-13-973-s006.docx (15KB, docx) Table S3. Sensitivity linear mixed‐effects models using baseline levodopa responsiveness. P ‐values are FDR‐adjusted. Asterisks (*) indicate statistical significance at P < 0.05. DBS, deep brain stimulation; FDR, false discovery rate; LEDD, levodopa‐equivalent daily dose; MDS‐UPDRS, Movement Disorder Society‐Sponsored Unified Parkinson's Disease Rating Scale; MMSE, Mini‐Mental State Examination. MDC3-13-973-s001.docx (18.6KB, docx) Data Availability Statement H.K. had full access to all study data and takes responsibility for data integrity and accuracy of analysis. 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