Pub Date : 2025-12-15DOI: 10.1016/j.parkreldis.2025.108163
Audrey E. De Paepe , Linda Wang , David Zhang , Andrés Pascual-Leone , Kimberly Kwei , Sarah A. O'Shea , Guy M. McKhann , Gordon H. Baltuch , Marla Hamberger , Jeffrey Cole , Brett E. Youngerman
Introduction
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is effective for Parkinson's disease (PD) motor symptoms; however, effects on neuropsychiatric symptoms remain uncertain.
Methods
Baseline and post-operative neuropsychiatric outcomes were retrospectively reviewed among a cohort of patients with PD undergoing bilateral STN- or GPi-DBS, using the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Starkstein Apathy Scale (SAS). Absolute changes in psychiatric scores, rate of clinical meaningful score reduction (≥½ standard deviation below baseline scores), and number needed to treat (NNT) were calculated.
Results
Fifty-nine PD patients received either STN-DBS (n = 40) or GPi-DBS (n = 19). Clinically significant baseline anxiety (BAI ≥16) was present in 35.6 % of patients (STN-DBS = 13.50 ± 7.18; GPi-DBS = 17.47 ± 13.78). STN-DBS patients demonstrated a statistically significant reduction in anxiety (d = −4.75, P = 0.002) at 10.0 ± 7.4 months follow-up. Clinically meaningful anxiety improvement was observed in 52.5 % of STN-DBS patients (NNT = 1.9) compared to 26.3 % of GPi-DBS patients (NNT = 3.8). Longitudinal depression and apathy scores were stable for both groups.
Conclusions
STN-DBS was associated with a statistically and clinically significant reduction in anxiety, while GPi-DBS did not reach statistical significance but still yielded clinically meaningful improvement in one-quarter of patients. These findings highlight the potential anxiolytic benefits of STN-DBS and suggest that GPi-DBS may also offer benefit for some individuals, warranting further investigation.
{"title":"Short-term neuropsychiatric outcomes following deep brain stimulation for Parkinson's disease","authors":"Audrey E. De Paepe , Linda Wang , David Zhang , Andrés Pascual-Leone , Kimberly Kwei , Sarah A. O'Shea , Guy M. McKhann , Gordon H. Baltuch , Marla Hamberger , Jeffrey Cole , Brett E. Youngerman","doi":"10.1016/j.parkreldis.2025.108163","DOIUrl":"10.1016/j.parkreldis.2025.108163","url":null,"abstract":"<div><h3>Introduction</h3><div>Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is effective for Parkinson's disease (PD) motor symptoms; however, effects on neuropsychiatric symptoms remain uncertain.</div></div><div><h3>Methods</h3><div>Baseline and post-operative neuropsychiatric outcomes were retrospectively reviewed among a cohort of patients with PD undergoing bilateral STN- or GPi-DBS, using the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Starkstein Apathy Scale (SAS). Absolute changes in psychiatric scores, rate of clinical meaningful score reduction (≥½ standard deviation below baseline scores), and number needed to treat (NNT) were calculated.</div></div><div><h3>Results</h3><div>Fifty-nine PD patients received either STN-DBS (<em>n</em> = 40) or GPi-DBS (<em>n</em> = 19). Clinically significant baseline anxiety (BAI ≥16) was present in 35.6 % of patients (STN-DBS = 13.50 ± 7.18; GPi-DBS = 17.47 ± 13.78). STN-DBS patients demonstrated a statistically significant reduction in anxiety (<em>d</em> = −4.75, <em>P</em> = 0.002) at 10.0 ± 7.4 months follow-up. Clinically meaningful anxiety improvement was observed in 52.5 % of STN-DBS patients (NNT = 1.9) compared to 26.3 % of GPi-DBS patients (NNT = 3.8). Longitudinal depression and apathy scores were stable for both groups.</div></div><div><h3>Conclusions</h3><div>STN-DBS was associated with a statistically and clinically significant reduction in anxiety, while GPi-DBS did not reach statistical significance but still yielded clinically meaningful improvement in one-quarter of patients. These findings highlight the potential anxiolytic benefits of STN-DBS and suggest that GPi-DBS may also offer benefit for some individuals, warranting further investigation.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"143 ","pages":"Article 108163"},"PeriodicalIF":3.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-14DOI: 10.1016/j.parkreldis.2025.108155
Federica Veltri , Giulia Maria Sancesario , Marco Rosina , Davide Mascioli , Jacopo Bissacco , Matteo Conti , Henri Zenuni , Valentina Nesci , Daniela Maftei , Veronica Buttarazzi , Maria Mancini , Clara Simonetta , Ermanno Berlizzi , Aikaterini Andradi , Federica Todaro , Valerio Chiurchiù , Alberto Ferri , Cristiana Valle , Alessandro Stefani , Nicola Biagio Mercuri , Tommaso Schirinzi
Background
Serum and glucocorticoid-inducible kinase 1 (SGK1) is a ubiquitous kinase with cytoprotective and immune-specific functions. Parkinson's disease (PD) animal models disclosed interactions between SGK1 and the critical pathogenic pathways of the disease, whereas human-based evidence is lacking. We investigated the SGK1 contribution to the biological dynamics of PD ex vivo, at immune and systemic level.
Methods
Thirty-two well-phenotyped PD patients and 34 controls were enrolled. Peripheral blood mononuclear cells (PBMCs) and serum were obtained. PBMCs levels of SGK1, α-synuclein total and oligomeric forms (α-syntot, α-synolig) were measured by Western blot and ELISA, respectively. SGK1 levels were tested in the serum by ELISA. Group differences were assessed using age-adjusted, rank-based linear regression models; ROC analysis was performed using age-adjusted PBMC SGK1 residuals and a Youden-derived cutpoint; associations with clinical variables were tested using age-adjusted regressions.
Results
PD PBMCs exhibited lower SGK1 (p < 0.001) and higher α-synolig levels than controls (p = 0.026). SGK1 serum levels were also lower in PD patients (p = 0.040). ROC analysis showed that PBMC SGK1 significantly discriminated PD from controls (AUC = 0.85,[95 % CI 0.75–0.95],p < 0.001). The optimal cutpoint yielded a sensitivity of 1.00 and a specificity of 0.60. No significant correlations were found between biological and clinical parameters.
Conclusions
In PD patients, SGK1 was downregulated in both PBMCs and serum. Given the preliminary nature of these findings and the co-occurrence of α-synolig accumulation in leukocytes, common mechanistic pathways might be supposed, although pending confirmation. Nevertheless, SGK1 emerged as a potential target in PD, for both biomarker and therapeutic purposes.
{"title":"SGK1 downregulation co-occurs with leukocyte oligomeric α-synuclein accumulation in Parkinson's disease","authors":"Federica Veltri , Giulia Maria Sancesario , Marco Rosina , Davide Mascioli , Jacopo Bissacco , Matteo Conti , Henri Zenuni , Valentina Nesci , Daniela Maftei , Veronica Buttarazzi , Maria Mancini , Clara Simonetta , Ermanno Berlizzi , Aikaterini Andradi , Federica Todaro , Valerio Chiurchiù , Alberto Ferri , Cristiana Valle , Alessandro Stefani , Nicola Biagio Mercuri , Tommaso Schirinzi","doi":"10.1016/j.parkreldis.2025.108155","DOIUrl":"10.1016/j.parkreldis.2025.108155","url":null,"abstract":"<div><h3>Background</h3><div>Serum and glucocorticoid-inducible kinase 1 (SGK1) is a ubiquitous kinase with cytoprotective and immune-specific functions. Parkinson's disease (PD) animal models disclosed interactions between SGK1 and the critical pathogenic pathways of the disease, whereas human-based evidence is lacking. We investigated the SGK1 contribution to the biological dynamics of PD <em>ex vivo,</em> at immune and systemic level.</div></div><div><h3>Methods</h3><div>Thirty-two well-phenotyped PD patients and 34 controls were enrolled. Peripheral blood mononuclear cells (PBMCs) and serum were obtained. PBMCs levels of SGK1, α-synuclein total and oligomeric forms (α-syn<sup>tot</sup>, α-syn<sup>olig</sup>) were measured by Western blot and ELISA, respectively. SGK1 levels were tested in the serum by ELISA. Group differences were assessed using age-adjusted, rank-based linear regression models; ROC analysis was performed using age-adjusted PBMC SGK1 residuals and a Youden-derived cutpoint; associations with clinical variables were tested using age-adjusted regressions.</div></div><div><h3>Results</h3><div>PD PBMCs exhibited lower SGK1 (p < 0.001) and higher α-syn<sup>olig</sup> levels than controls (p = 0.026). SGK1 serum levels were also lower in PD patients (p = 0.040). ROC analysis showed that PBMC SGK1 significantly discriminated PD from controls (AUC = 0.85,[95 % CI 0.75–0.95],p < 0.001). The optimal cutpoint yielded a sensitivity of 1.00 and a specificity of 0.60. No significant correlations were found between biological and clinical parameters.</div></div><div><h3>Conclusions</h3><div>In PD patients, SGK1 was downregulated in both PBMCs and serum. Given the preliminary nature of these findings and the co-occurrence of α-syn<sup>olig</sup> accumulation in leukocytes, common mechanistic pathways might be supposed, although pending confirmation. Nevertheless, SGK1 emerged as a potential target in PD, for both biomarker and therapeutic purposes.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"143 ","pages":"Article 108155"},"PeriodicalIF":3.4,"publicationDate":"2025-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.parkreldis.2025.108152
Arunmozhimaran Elavarasi , Deepa Dash , Alfonso Fasano , Aparna Wagle Shukla , Renato P. Munhoz , Jonathan C. Lau , Heather Russell , Mandar Jog
Introduction
Deep brain stimulation (DBS) has become the standard of care in patients with Parkinson's Disease (PD) experiencing motor fluctuations. The existing literature suggests that deep-brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates levodopa-induced dyskinesias (LID), particularly those associated with high plasma levels of levodopa (peak dose), through medication reduction.
Case presentation
We report a case of early-onset PD with motor fluctuations and levodopa-induced peak-dose dyskinesias, who developed an interesting phenomenon of diphasic dyskinesias during the monopolar review of DBS. These dyskinesias resolved when the stimulation amplitude was increased to achieve a more stable 'ON' phase.
Conclusion
This rare phenomenon suggests that when predominantly lower-limb dyskinesias occur at low current stimulation, increasing stimulation amplitude might improve the excessive movements. Diphasic dyskinesias are often misdiagnosed and under-reported. Future studies should clarify the frequency.
{"title":"Subthalamic DBS-induced diphasic dyskinesias: An overlooked complication?","authors":"Arunmozhimaran Elavarasi , Deepa Dash , Alfonso Fasano , Aparna Wagle Shukla , Renato P. Munhoz , Jonathan C. Lau , Heather Russell , Mandar Jog","doi":"10.1016/j.parkreldis.2025.108152","DOIUrl":"10.1016/j.parkreldis.2025.108152","url":null,"abstract":"<div><h3>Introduction</h3><div>Deep brain stimulation (DBS) has become the standard of care in patients with Parkinson's Disease (PD) experiencing motor fluctuations. The existing literature suggests that deep-brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates levodopa-induced dyskinesias (LID), particularly those associated with high plasma levels of levodopa (peak dose), through medication reduction.</div></div><div><h3>Case presentation</h3><div>We report a case of early-onset PD with motor fluctuations and levodopa-induced peak-dose dyskinesias, who developed an interesting phenomenon of diphasic dyskinesias during the monopolar review of DBS. These dyskinesias resolved when the stimulation amplitude was increased to achieve a more stable 'ON' phase.</div></div><div><h3>Conclusion</h3><div>This rare phenomenon suggests that when predominantly lower-limb dyskinesias occur at low current stimulation, increasing stimulation amplitude might improve the excessive movements. Diphasic dyskinesias are often misdiagnosed and under-reported. Future studies should clarify the frequency.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"143 ","pages":"Article 108152"},"PeriodicalIF":3.4,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145774889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.parkreldis.2025.108153
Yueh-Feng Sung , Shang-Yih Yen , Jiu-Haw Yin , Chih-Wei Wang , Yu-Ching Chou , Fu-Chi Yang , Jiunn-Tay Lee , Kuo-Sheng Hung , Chung-Hsing Chou
{"title":"Corrigendum to “NOTCH3 p.R544C variant in vascular Parkinsonism: Clinical and imaging correlates in a Taiwanese cohort” [Parkinsonism & Related Disorders 139 (2025) 6 6 107997]","authors":"Yueh-Feng Sung , Shang-Yih Yen , Jiu-Haw Yin , Chih-Wei Wang , Yu-Ching Chou , Fu-Chi Yang , Jiunn-Tay Lee , Kuo-Sheng Hung , Chung-Hsing Chou","doi":"10.1016/j.parkreldis.2025.108153","DOIUrl":"10.1016/j.parkreldis.2025.108153","url":null,"abstract":"","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"143 ","pages":"Article 108153"},"PeriodicalIF":3.4,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1016/j.parkreldis.2025.108144
Carlos Augusto Kalva-Filho , Vinícius Cavassano Zampier , Diego Orcioli-Silva , Murilo Henrique Faria , Marcelo Papoti , Fabio Augusto Barbieri
Introduction
Hypoxia exposure has been suggested as a complementary strategy for gait rehabilitation in Parkinson's disease (PD). However, due to the significant decrease in oxygen availability, the practical use of hypoxia may mitigate the positive effects of other interventions on gait in people with PD, such as treadmill-based exercise. Therefore, this study investigated the effects of inter-effort recovery hypoxia (IEH) during treadmill sessions on gait in people with PD.
Methods
Nineteen individuals with PD underwent this randomized, double-blind, controlled trial. The experimental session consisted of two periods of hypoxia or placebo exposure (2 × 10 min), interspersed with treadmill exercise at participant's self-selected gait velocity (2 × 10 min). The hypoxia generator (Everest Summit II) was set to deliver either 13.6 % O2 during IEH or 20.9 % O2 during the control condition (CON). Gait was assessed at a self-selected speed before and immediately after the session (GAITRite).
Results
Higher hypoxia doses were observed throughout the IEH (median [IQR]: 4.4 [1.7]%.h) compared to CON (0.2 [0.3]%.h) (p = 0.001; large effect size). Gait velocity and step length improved following the experimental sessions (p < 0.005; moderate to large effect sizes), with no significant differences between IEH and CON (p > 0.302; small effect sizes).
Conclusion
IEH did not negatively affect the acute impact of treadmill exercise on gait in people with PD. These findings address the existing literature, demonstrating that the hypoxia exposure approach can be used during exercise sessions without adverse effects on gait in people with PD.
{"title":"Inter-effort recovery hypoxia did not mitigate acute treadmill effects in people with Parkinson’s disease","authors":"Carlos Augusto Kalva-Filho , Vinícius Cavassano Zampier , Diego Orcioli-Silva , Murilo Henrique Faria , Marcelo Papoti , Fabio Augusto Barbieri","doi":"10.1016/j.parkreldis.2025.108144","DOIUrl":"10.1016/j.parkreldis.2025.108144","url":null,"abstract":"<div><h3>Introduction</h3><div>Hypoxia exposure has been suggested as a complementary strategy for gait rehabilitation in Parkinson's disease (PD). However, due to the significant decrease in oxygen availability, the practical use of hypoxia may mitigate the positive effects of other interventions on gait in people with PD, such as treadmill-based exercise. Therefore, this study investigated the effects of inter-effort recovery hypoxia (IEH) during treadmill sessions on gait in people with PD.</div></div><div><h3>Methods</h3><div>Nineteen individuals with PD underwent this randomized, double-blind, controlled trial. The experimental session consisted of two periods of hypoxia or placebo exposure (2 × 10 min), interspersed with treadmill exercise at participant's self-selected gait velocity (2 × 10 min). The hypoxia generator (Everest Summit II) was set to deliver either 13.6 % O<sub>2</sub> during IEH or 20.9 % O<sub>2</sub> during the control condition (CON). Gait was assessed at a self-selected speed before and immediately after the session (GAITRite).</div></div><div><h3>Results</h3><div>Higher hypoxia doses were observed throughout the IEH (median [IQR]: 4.4 [1.7]%.h) compared to CON (0.2 [0.3]%.h) (p = 0.001; large effect size). Gait velocity and step length improved following the experimental sessions (p < 0.005; moderate to large effect sizes), with no significant differences between IEH and CON (p > 0.302; small effect sizes).</div></div><div><h3>Conclusion</h3><div>IEH did not negatively affect the acute impact of treadmill exercise on gait in people with PD. These findings address the existing literature, demonstrating that the hypoxia exposure approach can be used during exercise sessions without adverse effects on gait in people with PD.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"143 ","pages":"Article 108144"},"PeriodicalIF":3.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.parkreldis.2025.108147
Nils M. Tangedal , Ole-Bjørn Tysnes
The association between impulse control disorders (ICDs) and dopamine agonist (DA) treatment in Parkinson's disease (PD) has been well known and extensively researched since the early 2000s. The most common behaviors included in ICDs are compulsive shopping, pathological gambling and hypersexuality which confer substantial burdens to patients and families. DAs show a more stable effect on motor control and confer lower risk of dyskinesia than levodopa, however due to the burden of ICDs, DAs in PD treatment are approached with increasing caution. Mechanisms and risk factors for ICD development in PD patients treated with DAs have been linked to D3 receptor agonism, premorbid traits and genetic predispositions. In this review we sought to examine the relevance of the degree of dopamine receptor subtype selectivity and risk of ICD, and implications for clinical practice. In line with current views, we found D3 receptor agonism to be more consistently associated with increased ICD risk compared to agents with wider receptor agonism profiles. However, this may also be explained by the difference in extended release (ER) and immediate release (IR) formulations. These findings provide the possibility that both ER formulations and agonists with wider dopamine receptor profiles may be preferred in order to reduce ICD risk in DA therapy. However, DAs confer significantly increased risk nonetheless, and as such it may be advisable to limit the use of these DAs to clinical contexts in which their administration is strongly indicated.
{"title":"Impulse control disorders and dopamine receptor agonism in Parkinson's disease patients: Clinical implications","authors":"Nils M. Tangedal , Ole-Bjørn Tysnes","doi":"10.1016/j.parkreldis.2025.108147","DOIUrl":"10.1016/j.parkreldis.2025.108147","url":null,"abstract":"<div><div>The association between impulse control disorders (ICDs) and dopamine agonist (DA) treatment in Parkinson's disease (PD) has been well known and extensively researched since the early 2000s. The most common behaviors included in ICDs are compulsive shopping, pathological gambling and hypersexuality which confer substantial burdens to patients and families. DAs show a more stable effect on motor control and confer lower risk of dyskinesia than levodopa, however due to the burden of ICDs, DAs in PD treatment are approached with increasing caution. Mechanisms and risk factors for ICD development in PD patients treated with DAs have been linked to D3 receptor agonism, premorbid traits and genetic predispositions. In this review we sought to examine the relevance of the degree of dopamine receptor subtype selectivity and risk of ICD, and implications for clinical practice. In line with current views, we found D3 receptor agonism to be more consistently associated with increased ICD risk compared to agents with wider receptor agonism profiles. However, this may also be explained by the difference in extended release (ER) and immediate release (IR) formulations. These findings provide the possibility that both ER formulations and agonists with wider dopamine receptor profiles may be preferred in order to reduce ICD risk in DA therapy. However, DAs confer significantly increased risk nonetheless, and as such it may be advisable to limit the use of these DAs to clinical contexts in which their administration is strongly indicated.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"143 ","pages":"Article 108147"},"PeriodicalIF":3.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.parkreldis.2025.108150
Anto P. Rajkumar , Abdul Hye , Sue Fen Tan , Holly Green , Richard Killick , Zubair Nizamudeen , Fatma Busra Isik , Grazziela Figueredo , Clive Ballard , Per Svenningsson , Dag Aarsland
Introduction
Blood-based biomarkers that can aid diagnosis of Parkinson's Disease (PD) dementia (PDD), and predict PDD onset in people with PD are urgently needed. Plasma small extracellular vesicles (SEV) reflect molecular changes in living human brain. Next-generation RNA-sequencing (RNA-Seq) of PDD plasma SEV can advance our understanding of PDD molecular pathology, and identify blood-based biomarkers. Hence, we conducted the first comprehensive transcriptomic analysis of PDD plasma SEV.
Methods
We investigated plasma SEV RNA of PDD, PD, and people without PD or dementia (Controls) using RNA-Seq (n = 15/group; N = 45). SEV were separated by ultracentrifugation, and characterized by cryo-transmission electron microscopy. We identified differentially expressed genes (DEGs) in PDD plasma SEV using an edgeR-based data analysis pipeline and verified them by high-throughput qPCR. We assessed functional implications of identified DEGs using Ingenuity Pathway and causal network analyses.
Results
We identified 51 transcriptome-wide significant (edgeR q < 0.05) DEGs, compared to controls, and 26 transcriptome-wide significant DEGs, compared to PD, in PDD plasma SEV. The identified DEGs, which included WNT5A, MAPT, FOSB, MIR324, MIR574, MIR3161, and MIR6821 were significantly enriched among Tetrahydrofolate salvage, Reelin signalling, tRNA splicing, Wnt signalling, and ERBB signalling pathways. We identified eight potential multiplex plasma SEV RNA biomarker assays that can distinguish PDD from PD with at least 80 % sensitivity and specificity using an artificial intelligence-based algorithm.
Conclusion
Future research on the identified dysfunctional molecular pathways may facilitate discovery of novel therapeutic targets for PDD. Diagnostic biomarker potential of the derived multiplex RNA biomarker assays should be investigated by larger clinical studies.
{"title":"Transcriptomic analysis of plasma small extracellular vesicles identifies potential diagnostic biomarkers for Parkinson's disease dementia","authors":"Anto P. Rajkumar , Abdul Hye , Sue Fen Tan , Holly Green , Richard Killick , Zubair Nizamudeen , Fatma Busra Isik , Grazziela Figueredo , Clive Ballard , Per Svenningsson , Dag Aarsland","doi":"10.1016/j.parkreldis.2025.108150","DOIUrl":"10.1016/j.parkreldis.2025.108150","url":null,"abstract":"<div><h3>Introduction</h3><div>Blood-based biomarkers that can aid diagnosis of Parkinson's Disease (PD) dementia (PDD), and predict PDD onset in people with PD are urgently needed. Plasma small extracellular vesicles (SEV) reflect molecular changes in living human brain. Next-generation RNA-sequencing (RNA-Seq) of PDD plasma SEV can advance our understanding of PDD molecular pathology, and identify blood-based biomarkers. Hence, we conducted the first comprehensive transcriptomic analysis of PDD plasma SEV.</div></div><div><h3>Methods</h3><div>We investigated plasma SEV RNA of PDD, PD, and people without PD or dementia (Controls) using RNA-Seq (n = 15/group; N = 45). SEV were separated by ultracentrifugation, and characterized by cryo-transmission electron microscopy. We identified differentially expressed genes (DEGs) in PDD plasma SEV using an <em>edgeR</em>-based data analysis pipeline and verified them by high-throughput qPCR. We assessed functional implications of identified DEGs using Ingenuity Pathway and causal network analyses.</div></div><div><h3>Results</h3><div>We identified 51 transcriptome-wide significant (<em>edgeR</em> q < 0.05) DEGs, compared to controls, and 26 transcriptome-wide significant DEGs, compared to PD, in PDD plasma SEV. The identified DEGs, which included <em>WNT5A</em>, <em>MAPT</em>, <em>FOSB</em>, <em>MIR324</em>, <em>MIR574, MIR3161</em>, and <em>MIR6821</em> were significantly enriched among Tetrahydrofolate salvage, Reelin signalling, tRNA splicing, Wnt signalling, and ERBB signalling pathways. We identified eight potential multiplex plasma SEV RNA biomarker assays that can distinguish PDD from PD with at least 80 % sensitivity and specificity using an artificial intelligence-based algorithm.</div></div><div><h3>Conclusion</h3><div>Future research on the identified dysfunctional molecular pathways may facilitate discovery of novel therapeutic targets for PDD. Diagnostic biomarker potential of the derived multiplex RNA biomarker assays should be investigated by larger clinical studies.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"143 ","pages":"Article 108150"},"PeriodicalIF":3.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.parkreldis.2025.108145
Yao Chen , Chunyu Li , Ke Chen , Huifang Shang
Background
While Omega-3 and Omega-6 fatty acids have been implicated in neurodegenerative disorders (NDDs), existing epidemiological evidence remains inconclusive. We aim to clarify these relationships in a large population-based cohort from the UK Biobank.
Methods
We conducted Cox proportional hazards regression analyses to assess the association between baseline serum Omega-3 and Omega-6 levels and incident NDDs, adjusting for sociodemographic and lifestyle factors.
Results
Over a mean follow-up of 13.3 years, higher Omega-6 level at baseline was associated with a lower risk of incident Parkinson's disease (PD) (HR = 0.76, P = 1.11E-06, 95 % CI = 0.68–0.85) and dementia (HR = 0.83, P = 8.79E-08, 95 % CI = 0.78–0.89). Elevated Omega-3 level at baseline was linked to a lower risk of incident multiple sclerosis (MS) (HR = 0.17, P = 0.001, 95 % CI = 0.06–0.48). Nominally significant associations were also observed between Omega-3 level and reduced risk of PD (HR = 0.67, P = 0.03, 95 % CI = 0.46–0.97) and dementia (HR = 0.79, P = 0.04, 95 % CI = 0.63–0.99), as well as Omega-6 and lower risk of MS (HR = 0.73, P = 0.03, 95 % CI = 0.55–0.97).
Conclusions
The large prospective study demonstrates distinct neuroprotective profiles for Omega-3 and Omega-6 fatty acids in NDDs. These subtype-specific associations advance our understanding of nutritional factors in neurodegeneration and highlight potential avenues for targeted prevention strategies.
背景：虽然Omega-3和Omega-6脂肪酸与神经退行性疾病（ndd）有关，但现有的流行病学证据仍不确定。我们的目标是在英国生物银行的大型人群队列中澄清这些关系。方法：我们进行了Cox比例风险回归分析，评估基线血清Omega-3和Omega-6水平与ndd发生率之间的关系，并调整了社会人口统计学和生活方式因素。结果：在平均13.3年的随访中，基线时较高的Omega-6水平与较低的帕金森病（PD） （HR = 0.76, P = 1.11E-06, 95% CI = 0.68-0.85）和痴呆（HR = 0.83, P = 8.79E-08, 95% CI = 0.78-0.89）发生风险相关。基线时Omega-3水平升高与多发性硬化症（MS）发生风险降低相关（HR = 0.17, P = 0.001, 95% CI = 0.06-0.48）。名义上，Omega-3水平与PD （HR = 0.67, P = 0.03, 95% CI = 0.46-0.97）、痴呆（HR = 0.79, P = 0.04, 95% CI = 0.63-0.99）、MS （HR = 0.73, P = 0.03, 95% CI = 0.55-0.97）风险降低之间也存在显著关联。结论：这项大型前瞻性研究表明，Omega-3和Omega-6脂肪酸在ndd中具有明显的神经保护作用。这些亚型特异性关联促进了我们对神经变性中营养因素的理解，并强调了有针对性预防策略的潜在途径。
{"title":"Association of Omega-3 and Omega-6 with neurodegenerative disorders: a UK biobank prospective cohort study","authors":"Yao Chen , Chunyu Li , Ke Chen , Huifang Shang","doi":"10.1016/j.parkreldis.2025.108145","DOIUrl":"10.1016/j.parkreldis.2025.108145","url":null,"abstract":"<div><h3>Background</h3><div>While Omega-3 and Omega-6 fatty acids have been implicated in neurodegenerative disorders (NDDs), existing epidemiological evidence remains inconclusive. We aim to clarify these relationships in a large population-based cohort from the UK Biobank.</div></div><div><h3>Methods</h3><div>We conducted Cox proportional hazards regression analyses to assess the association between baseline serum Omega-3 and Omega-6 levels and incident NDDs, adjusting for sociodemographic and lifestyle factors.</div></div><div><h3>Results</h3><div>Over a mean follow-up of 13.3 years, higher Omega-6 level at baseline was associated with a lower risk of incident Parkinson's disease (PD) (HR = 0.76, P = 1.11E-06, 95 % CI = 0.68–0.85) and dementia (HR = 0.83, P = 8.79E-08, 95 % CI = 0.78–0.89). Elevated Omega-3 level at baseline was linked to a lower risk of incident multiple sclerosis (MS) (HR = 0.17, P = 0.001, 95 % CI = 0.06–0.48). Nominally significant associations were also observed between Omega-3 level and reduced risk of PD (HR = 0.67, P = 0.03, 95 % CI = 0.46–0.97) and dementia (HR = 0.79, P = 0.04, 95 % CI = 0.63–0.99), as well as Omega-6 and lower risk of MS (HR = 0.73, P = 0.03, 95 % CI = 0.55–0.97).</div></div><div><h3>Conclusions</h3><div>The large prospective study demonstrates distinct neuroprotective profiles for Omega-3 and Omega-6 fatty acids in NDDs. These subtype-specific associations advance our understanding of nutritional factors in neurodegeneration and highlight potential avenues for targeted prevention strategies.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"143 ","pages":"Article 108145"},"PeriodicalIF":3.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.parkreldis.2025.108149
D. Guévremont , J. Roy , A. Garvey , C. McLean , N. Cutfield , J. Williams
Background
Parkinson's disease (PD), the second most common neurodegenerative disease, is currently diagnosed clinically by impairments in motor control. PD, however, includes a diversity of non-motor symptoms, such as cognitive decline. Thus, it is imperative to establish a diagnostic framework for PD which reflects this heterogeneous phenotype. While misfolded α-synuclein is a cellular hallmark of PD and candidate biofluid marker, microRNA are an important class of biomarkers that are stable and easily detectable in blood, and are dysregulated at post-mortem in PD patients. This study aimed to establish PD plasma microRNA biomarkers that reflect cognitive abilities, as determined by the Montreal Cognitive Assessment (MoCA).
Methods
Using custom-designed low-density TaqMan arrays we assessed plasma levels of 187 neurodegeneration-related microRNA, in cross-sectional (n = 102), and longitudinal cohorts (n = 26) as well as in post-mortem brain tissue (n = 16).
Results
We found numerous microRNA were altered with increasing cognitive decline in PD and that the overall direction of change moved towards downregulation. A notable exception was miR-192-5p which was consistently upregulated in plasma and was found to be downregulated at postmortem in the superior frontal gyrus. Overall, microRNA identified were largely distinct from those known to be regulated in Alzheimer's disease. Focusing on a longitudinal cohort, controlled for disease progression and age we showed that miR-151-3p and miR-192-5p provided the best predictive model for separating cognitively normal PD patients from those who decline cognitively.
Conclusion
Plasma microRNA are altered in PD patients, can predict cognitive decline and therefore may be clinically useful biomarkers.
{"title":"Plasma microRNA predict cognitive decline in Parkinson's disease","authors":"D. Guévremont , J. Roy , A. Garvey , C. McLean , N. Cutfield , J. Williams","doi":"10.1016/j.parkreldis.2025.108149","DOIUrl":"10.1016/j.parkreldis.2025.108149","url":null,"abstract":"<div><h3>Background</h3><div>Parkinson's disease (PD), the second most common neurodegenerative disease, is currently diagnosed clinically by impairments in motor control. PD, however, includes a diversity of non-motor symptoms, such as cognitive decline. Thus, it is imperative to establish a diagnostic framework for PD which reflects this heterogeneous phenotype. While misfolded α-synuclein is a cellular hallmark of PD and candidate biofluid marker, microRNA are an important class of biomarkers that are stable and easily detectable in blood, and are dysregulated at post-mortem in PD patients. This study aimed to establish PD plasma microRNA biomarkers that reflect cognitive abilities, as determined by the Montreal Cognitive Assessment (MoCA).</div></div><div><h3>Methods</h3><div>Using custom-designed low-density TaqMan arrays we assessed plasma levels of 187 neurodegeneration-related microRNA, in cross-sectional (n = 102), and longitudinal cohorts (n = 26) as well as in post-mortem brain tissue (n = 16).</div></div><div><h3>Results</h3><div>We found numerous microRNA were altered with increasing cognitive decline in PD and that the overall direction of change moved towards downregulation. A notable exception was miR-192-5p which was consistently upregulated in plasma and was found to be downregulated at postmortem in the superior frontal gyrus. Overall, microRNA identified were largely distinct from those known to be regulated in Alzheimer's disease. Focusing on a longitudinal cohort, controlled for disease progression and age we showed that miR-151-3p and miR-192-5p provided the best predictive model for separating cognitively normal PD patients from those who decline cognitively.</div></div><div><h3>Conclusion</h3><div>Plasma microRNA are altered in PD patients, can predict cognitive decline and therefore may be clinically useful biomarkers.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"143 ","pages":"Article 108149"},"PeriodicalIF":3.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-08DOI: 10.1016/j.parkreldis.2025.108143
Paulo Bugalho , Vítor Mendes Ferreira
Introduction
The effects of sleep disordered breathing (SDB) in Parkinson's Disease (PD) are poorly understood. Data is uncertain regarding correlation with REM sleep behavior disorder (RBD) and the effects on non-motor symptoms. Markers of hypoxic burden other than the Apnea-Hypopnea Index (AHI) have been overlooked. We aimed to assess the relation between SDB, RBD and non-motor symptoms in PD patients.
Methods
71 PD patients (29 with RBD) were compared with healthy controls matched for sex, age and AHI, regarding video-PSG data, including obstructive AHI (total, REM and NREM), Mean O2 Saturation %, number of O2 desaturations >4 % (NuO2des), Minimal O2 desaturation (MinO2des), O2 Desaturation Index and % of time with O2 Saturation <90 %. 32 patients were also assessed for non-motor symptoms.
Results
PD patients presented significantly lower sleep efficiency (SE), REM sleep duration and AHI in REM and higher MinO2des. These findings were replicated on RBD patients when compared with their respective controls but not on non-RBD patients (except for lower SE). There was a very significant association between the NuO2des and cardiovascular symptoms; hallucinations were significantly associated with NREM AHI and very significantly associated with MinO2des.
Conclusion
Compared to subjects with same AHI, PD patients showed lower SE, lower AHI during REM sleep and less O2 desaturation. These differences were related to the presence of RBD, suggesting a protective role of REM sleep without atonia. SDB, and particularly O2 desaturation markers, bear a significant association with cardiovascular symptoms and hallucinations.
{"title":"Sleep disordered breathing in Parkinson's disease: Assessing the relevance of REM behavior sleep disorder and hypoxic burden","authors":"Paulo Bugalho , Vítor Mendes Ferreira","doi":"10.1016/j.parkreldis.2025.108143","DOIUrl":"10.1016/j.parkreldis.2025.108143","url":null,"abstract":"<div><h3>Introduction</h3><div>The effects of sleep disordered breathing (SDB) in Parkinson's Disease (PD) are poorly understood. Data is uncertain regarding correlation with REM sleep behavior disorder (RBD) and the effects on non-motor symptoms. Markers of hypoxic burden other than the Apnea-Hypopnea Index (AHI) have been overlooked. We aimed to assess the relation between SDB, RBD and non-motor symptoms in PD patients.</div></div><div><h3>Methods</h3><div>71 PD patients (29 with RBD) were compared with healthy controls matched for sex, age and AHI, regarding video-PSG data, including obstructive AHI (total, REM and NREM), Mean O<sub>2</sub> Saturation %, number of O<sup>2</sup> desaturations >4 % (NuO<sub>2</sub>des), Minimal O<sub>2</sub> desaturation (MinO<sub>2</sub>des), O<sub>2</sub> Desaturation Index and % of time with O<sub>2</sub> Saturation <90 %. 32 patients were also assessed for non-motor symptoms.</div></div><div><h3>Results</h3><div>PD patients presented significantly lower sleep efficiency (SE), REM sleep duration and AHI in REM and higher MinO<sub>2</sub>des. These findings were replicated on RBD patients when compared with their respective controls but not on non-RBD patients (except for lower SE). There was a very significant association between the NuO<sub>2</sub>des and cardiovascular symptoms; hallucinations were significantly associated with NREM AHI and very significantly associated with MinO<sub>2</sub>des.</div></div><div><h3>Conclusion</h3><div>Compared to subjects with same AHI, PD patients showed lower SE, lower AHI during REM sleep and less O<sub>2</sub> desaturation. These differences were related to the presence of RBD, suggesting a protective role of REM sleep without atonia. SDB, and particularly O<sub>2</sub> desaturation markers, bear a significant association with cardiovascular symptoms and hallucinations.</div></div>","PeriodicalId":19970,"journal":{"name":"Parkinsonism & related disorders","volume":"143 ","pages":"Article 108143"},"PeriodicalIF":3.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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