Exploring the neuroprotective potential of immunosuppressants in Parkinson’s disease
(2025) Parkinsonism and Related Disorders, 132, art. no. 107294, .
Mubarak, H.M.a , Racette, B.A.a b c , Killion, J.A.a , Faust, I.M.a , Laurido-Soto, O.J.b , Doddamreddy, S.A.a , Searles Nielsen, S.b
a Department of Neurology, Barrow Neurological Institute, 240 W Thomas Rd, Phoenix, AZ 85013, United States
b Department of Neurology, Washington University School of Medicine in St. Louis, 660 S Euclid Ave, St. Louis, MO 63110, United States
c School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, 27 St Andrews Rd, Parktown2193, South Africa
Abstract
Introduction: Neuroprotective therapy to slow Parkinson’s disease (PD) progression is a critical unmet need. Neuroinflammation likely represents an important pathophysiologic mechanism for disease progression. Medications that target this inflammation, such as immunosuppressants, represent potential disease-modifying therapies for PD. The relation between these medications and PD risk might inform candidate selection. Methods: We conducted a population-based case-control study using Medicare data from the United States. The study included 207,532 incident PD cases and 975,177 controls from 2016 to 2018, age 67–110. We examined the association between PD risk and immunosuppressant use before PD diagnosis/control selection. We considered 37 immunosuppressants, representing >10 medication classes, in Part D prescription claims. We used logistic regression to estimate the relative risk (RR) and 95 % confidence interval (CI) between each medication and PD, while accounting for age, sex, race/ethnicity, smoking, and healthcare utilization. In sensitivity analyses we applied exposure lagging, restricted to immunosuppressant users, and corrected for multiple comparisons. Results: Medicare beneficiaries using the calcineurin inhibitor tacrolimus (RR 0.49, CI 0.40–0.60) and mTOR inhibitors everolimus (RR 0.38, CI 0.26–0.56) and sirolimus (RR 0.59, CI 0.37–0.93) had a lower risk of PD compared to those not taking the medication. The TNF inhibitor certolizumab was also associated with lower PD risk (RR 0.54, CI 0.34–0.84). Tacrolimus and everolimus remained significant after Bonferroni correction. Sensitivity analyses otherwise confirmed results for all four medications. Conclusion: Calcineurin or mTOR inhibition might reduce PD risk. Future studies should examine whether these medications or structurally similar agents might have potential as disease-modifying therapies for PD. © 2025 Elsevier Ltd
Author Keywords
Disease modifying therapy; Immunosuppressant; Neurodegenerative; Neuroprotective; Parkinson’s disease
Document Type: Article
Publication Stage: Final
Source: Scopus
Female mice lacking GluA3 show early onset of hearing loss, cochlear synaptopathy, and afferent terminal swellings in ambient sound levels
(2025) iScience, 28 (2), art. no. 111799, .
Pal, I.a , Bhattacharyya, A.b , V-Ghaffari, B.b , Williams, E.D.a , Xiao, M.b , Rutherford, M.A.b , Rubio, M.E.a c
a Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States
b Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States
Abstract
AMPA-type glutamate receptors (AMPARs) mediate excitatory cochlear transmission. However, unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 (Gria3KO) in male mice reduced cochlear output by 8 postnatal weeks. Here, we studied the role of X-linked Gria3 in cochlear function and synapse anatomy in females. Auditory brainstem responses (ABRs) were similar in 3-week-old female Gria3WT and Gria3KO mice raised in quiet. However, after switching to ambient sound, ABR thresholds were elevated and wave-1 amplitudes were diminished at 5-week and older in Gria3KO. A quiet vivarium precluded this effect. Paired synapses were similar in number, but lone ribbons and ribbonless synapses were more frequent, and swollen afferent terminals were observed only in female Gria3KO mice in ambient sound. Synaptic GluA4:GluA2 ratios increased relative to Gria3WT, particularly in ambient sound, suggesting an activity-dependent increase in calcium-permeable AMPARs in Gria3KO. We propose that lack of GluA3 induces a sex-dependent vulnerability to AMPAR-mediated excitotoxicity. © 2025 The Author(s)
Author Keywords
Cellular neuroscience; Neuroscience; Sensory neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Planned Surgical Trajectory Affects Clinical Motor Outcome in Deep Brain Stimulation Targeted at Subthalamic Nucleus for Parkinson’s Disease
(2024) Operative Neurosurgery, art. no. 10.1227/ons.0000000000001355, .
Wang, L.S.a , Younce, J.R.b , Milchenko, M.c , Ushe, M.a , Alfradique-Dunham, I.a , Tabbal, S.D.d , Dowling, J.L.e , Perlmutter, J.S.a c f g h , Norris, S.A.a c
a Department of Neurology, Washington University in St Louis, St Louis, MO, United States
b Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Neurology, Penn State University, Hershey, PA, United States
e Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
f Department of Neuroscience, Washington University in St Louis, St Louis, MO, United States
g Program in Physical Therapy, Washington University in St Louis, St Louis, MO, United States
h Program in Occupational Therapy, Washington University in St Louis, St Louis, MO, United States
Abstract
BACKGROUND AND OBJECTIVES:Surgical planning is critical to achieve optimal outcome in deep brain stimulation (DBS). The relationship between clinical outcomes and DBS electrode position relative to subthalamic nucleus (STN) is well investigated, but the role of surgical trajectory remains unclear. We sought to determine whether preoperatively planned DBS lead trajectory relates to adequate motor outcome in STN-DBS for Parkinson’s disease (PD).METHODS:In 49 participants who underwent bilateral STN-DBS for PD using a Leksell® frame, we coregistered the frame and participant MRI images to obtain participant-specific anatomical planes. We evaluated relationships between clinical data and planned trajectories relative to their midsagittal and axial planes. We computed percent change in Unified PD Rating Scale subsection 3 (Unified Parkinson’s Disease Rating Scale, part III) scores before and after DBS, and performed binary logistic regression to determine whether planned trajectories affect adequate (>30% Unified Parkinson’s Disease Rating Scale, part III improvement) motor outcome.RESULTS:Preoperatively planned left lead trajectory relative to midsagittal plane predicted likelihood of adequate right body motor outcomes (odds ratio = 0.69, P =.024), even when controlling for ventricular width through Evans index. This effect reflects that increasingly lateral angle of approach reduced odds of adequate motor outcome. Right lead trajectory lacked a similar trend.CONCLUSION:Left DBS lead trajectory predicts adequate right-body motor outcome after bilateral STN-DBS. Greater planned trajectory angle relative to midsagittal plane reduces motor outcomes, independent of patients’ ventricular width. These data may guide patient selection, inform risk/benefit discussions, optimize surgical planning, or support evidence-based evaluation of the methodologies used to select the approach trajectory, with careful consideration of the angle of approach relative to target. © Congress of Neurological Surgeons 2024. Unauthorized reproduction of this article is prohibited.
Author Keywords
Deep brain stimulation; Parkinson’s disease; Stereotactic technique
Document Type: Article
Publication Stage: Article in Press
Source: Scopus