Subjective cognitive decline (SCD) may represent a special cognitive stage distinct from mild cognitive impairment (MCI) in Parkinson's disease (PD), but its microstructural correlates are underexplored. We aimed to investigate microstructural alterations in PD-SCD compared to PD with normal cognition (PD-NC) and PD-MCI, and to explore their association with cognitive status. 68 PD patients (PD-NC: n = 23; PD-SCD: n = 20; PD-MCI: n = 25) and 27 healthy controls (HC) underwent multimodal MRI. Analyses included tract-based spatial statistics (TBSS), calculation of the peak width of skeletonized mean diffusivity (PSMD), and hippocampal subfield segmentation. PSMD showed significant differences across subgroups and negatively correlated with MoCA scores, suggesting its utility as a metric that differentiated cognitive stage. TBSS revealed reduced fractional anisotropy (FA) in multiple tracts in PD-MCI, while PD-SCD exhibited reduced FA only in FMajor relative to HC. Hippocampal subfield segmentation revealed atrophy in subregions such as CA1 and HATA in PD-SCD and PD-MCI compared to PD-NC. This study provides evidence that microstructural alterations are already detectable at the PD-SCD stage. PSMD emerges as a sensitive cross-sectional biomarker of PD cognitive staging. These findings highlight the potential role of white‑matter changes in PD‑related cognitive complaints.
主观认知衰退（SCD）可能代表了帕金森病（PD）中不同于轻度认知障碍（MCI）的特殊认知阶段，但其微观结构相关性尚未得到充分探讨。我们的目的是研究PD- scd与正常认知的PD （PD- nc）和PD- mci相比的微观结构改变，并探讨它们与认知状态的关系。68例PD患者（PD- nc: n = 23; PD- scd: n = 20; PD- mci: n = 25）和27例健康对照（HC）接受了多模态MRI检查。分析包括基于束的空间统计（TBSS）、骨架化平均扩散率（PSMD）的峰宽计算和海马子区分割。PSMD在各亚组间存在显著差异，且与MoCA得分呈负相关，表明其作为区分认知阶段的指标的效用。TBSS在PD-MCI的多个束中显示分数各向异性（FA）降低，而PD-SCD相对于HC仅在FMajor中显示FA降低。海马亚区分割显示，与PD-NC相比，PD-SCD和PD-MCI的CA1和HATA等亚区萎缩。本研究提供的证据表明，在PD-SCD阶段已经可以检测到微观结构的改变。PSMD作为PD认知分期的敏感横断面生物标志物出现。这些发现强调了白质变化在PD相关认知疾患中的潜在作用。
{"title":"Neuroimaging evidence of microstructural alteration in Parkinson's disease with subjective cognitive decline.","authors":"Kaidong Chen,Ruixuan Zhang,Yi Ji,Liujia Lu,Bin He,Yao Lu,Qin Wen,Leikun Wang,Feng Wang,Li Zhang,Xiangming Fang","doi":"10.1038/s41531-026-01313-y","DOIUrl":"https://doi.org/10.1038/s41531-026-01313-y","url":null,"abstract":"Subjective cognitive decline (SCD) may represent a special cognitive stage distinct from mild cognitive impairment (MCI) in Parkinson's disease (PD), but its microstructural correlates are underexplored. We aimed to investigate microstructural alterations in PD-SCD compared to PD with normal cognition (PD-NC) and PD-MCI, and to explore their association with cognitive status. 68 PD patients (PD-NC: n = 23; PD-SCD: n = 20; PD-MCI: n = 25) and 27 healthy controls (HC) underwent multimodal MRI. Analyses included tract-based spatial statistics (TBSS), calculation of the peak width of skeletonized mean diffusivity (PSMD), and hippocampal subfield segmentation. PSMD showed significant differences across subgroups and negatively correlated with MoCA scores, suggesting its utility as a metric that differentiated cognitive stage. TBSS revealed reduced fractional anisotropy (FA) in multiple tracts in PD-MCI, while PD-SCD exhibited reduced FA only in FMajor relative to HC. Hippocampal subfield segmentation revealed atrophy in subregions such as CA1 and HATA in PD-SCD and PD-MCI compared to PD-NC. This study provides evidence that microstructural alterations are already detectable at the PD-SCD stage. PSMD emerges as a sensitive cross-sectional biomarker of PD cognitive staging. These findings highlight the potential role of white‑matter changes in PD‑related cognitive complaints.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"317 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-13DOI: 10.1038/s41531-026-01285-z
Jessica Pei, Nathalia L Oliveira, Sherilyn J Recinto, Alexandra Kazanova, Celso M Queiroz-Junior, Ziyi Li, Katalina Couto, Susan Westfall, Ahmed M Fahmy, Camila Tiefensee-Ribeiro, Irah L King, Austen J Milnerwood, Michel Desjardins, Ajitha Thanabalasuriar, Jo Anne Stratton, Samantha Gruenheid
{"title":"Author Correction: Lrrk2 G2019S mutation incites increased cell-intrinsic neutrophil effector functions and intestinal inflammation in a model of infectious colitis.","authors":"Jessica Pei, Nathalia L Oliveira, Sherilyn J Recinto, Alexandra Kazanova, Celso M Queiroz-Junior, Ziyi Li, Katalina Couto, Susan Westfall, Ahmed M Fahmy, Camila Tiefensee-Ribeiro, Irah L King, Austen J Milnerwood, Michel Desjardins, Ajitha Thanabalasuriar, Jo Anne Stratton, Samantha Gruenheid","doi":"10.1038/s41531-026-01285-z","DOIUrl":"10.1038/s41531-026-01285-z","url":null,"abstract":"","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"12 1","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12988035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147459387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study investigated the genetic and phenotypic associations of the glymphatic system and brain characteristics with Parkinson's disease (PD) and developed an imaging-derived early prediction model. In a case-control analysis of 118 PD patients and 58 matched controls, a lower analysis along the perivascular space (ALPS) index (odds ratio [OR] = 0.049, 95% confidence interval [CI]: 0.013-0.181) and elevated free water content, particularly in the temporal lobe (OR = 5.603, 95% CI: 3.093-10.150), were both associated with PD. Their combination provided the highest predictive accuracy for PD (area under the curve (AUC) = 0.818, 95% CI: 0.750-0.886). Furthermore, Mendelian randomization analysis demonstrated positive causal effects of frontal, occipital, parietal, and temporal lobes on PD risk (OR > 1, p ≤ 0.05). These findings indicate that glymphatic dysfunction and specific brain alterations are associated with PD, and that combining them may improve early prediction strategies.
{"title":"Imaging and genome-supported association of glymphatic system function and multiregional brain characteristics with Parkinson's disease.","authors":"Zhinan Ye,Yuchen Lin,Yangguang Lu,Zihao Wu,Baoyi Zhu,Qiaoqiao Jin,Yang Zhang,Zhuoyu Chen,Xinyi Yuan,Zihan Yuan,Ziyu Yang,Suwen Huang,Yiyun Weng,Dehao Yang","doi":"10.1038/s41531-026-01314-x","DOIUrl":"https://doi.org/10.1038/s41531-026-01314-x","url":null,"abstract":"This study investigated the genetic and phenotypic associations of the glymphatic system and brain characteristics with Parkinson's disease (PD) and developed an imaging-derived early prediction model. In a case-control analysis of 118 PD patients and 58 matched controls, a lower analysis along the perivascular space (ALPS) index (odds ratio [OR] = 0.049, 95% confidence interval [CI]: 0.013-0.181) and elevated free water content, particularly in the temporal lobe (OR = 5.603, 95% CI: 3.093-10.150), were both associated with PD. Their combination provided the highest predictive accuracy for PD (area under the curve (AUC) = 0.818, 95% CI: 0.750-0.886). Furthermore, Mendelian randomization analysis demonstrated positive causal effects of frontal, occipital, parietal, and temporal lobes on PD risk (OR > 1, p ≤ 0.05). These findings indicate that glymphatic dysfunction and specific brain alterations are associated with PD, and that combining them may improve early prediction strategies.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"15 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Homozygous (Q789X) DNAJC6 mutation causes PARK19. Q787 of Dnajc6 corresponds to Q789 of DNAJC6. Dnajc6Q787X/Q787X mouse was utilized to elucidate pathomechanisms underlying (Q789X) DNAJC6-induced PARK19. Dnajc6Q787X/Q787X mice displayed PARK19 motor deficits and degeneration of substantia nigra (SN) dopaminergic neurons. (Q787X) Dnajc6 decreased clathrin heavy chain and lysosomal number, leading to downregulation of lysosomal cathepsin D and upregulation of α-synuclein or α-synuclein oligomers in SN dopaminergic neurons. Lysosomal biogenesis activator rapamycin precluded (Q787X) Dnajc6-induced downregulation of cathepsin D, upregulation of α-synuclein, and PARK19 phenotypes. (Q787X) Dnajc6-induced elevation of ER and mitochondrial α-synuclein excited ER stress and mitochondrial pro-apoptotic cascades. (Q787X) Dnajc6-evoked α-synuclein oligomer overexpression activated SN microglia and NLRP3 inflammasome and upregulated IL-1β, IL-18, and TNF-α, which stimulated MKK4-JNK -c-Jun/ATF-2 and RIPK1-RIPK3-MLKL death cascades. Our results suggest that PARK19 (Q789X) DNAJC6 mutation causes lysosomal deficiency and impairs cathepsin D-mediated degradation of α-synuclein, resulting in upregulated α-synuclein-induced neurodegeneration of SN dopaminergic cells.
{"title":"PARK19 truncation mutant Dnajc6 causes lysosomal deficiency-induced upregulation of pathologic α-synuclein and neurodegeneration of substantia nigra dopaminergic cells in PARK19 knockin mice.","authors":"Hung-Li Wang,Ying-Ling Chen,Tai-Ju Chiu,Ching-Chi Chiu,Yi-Hsin Weng,Shu-Yu Liu,Allen Hon-Lun Li,Tu-Hsueh Yeh","doi":"10.1038/s41531-026-01317-8","DOIUrl":"https://doi.org/10.1038/s41531-026-01317-8","url":null,"abstract":"Homozygous (Q789X) DNAJC6 mutation causes PARK19. Q787 of Dnajc6 corresponds to Q789 of DNAJC6. Dnajc6Q787X/Q787X mouse was utilized to elucidate pathomechanisms underlying (Q789X) DNAJC6-induced PARK19. Dnajc6Q787X/Q787X mice displayed PARK19 motor deficits and degeneration of substantia nigra (SN) dopaminergic neurons. (Q787X) Dnajc6 decreased clathrin heavy chain and lysosomal number, leading to downregulation of lysosomal cathepsin D and upregulation of α-synuclein or α-synuclein oligomers in SN dopaminergic neurons. Lysosomal biogenesis activator rapamycin precluded (Q787X) Dnajc6-induced downregulation of cathepsin D, upregulation of α-synuclein, and PARK19 phenotypes. (Q787X) Dnajc6-induced elevation of ER and mitochondrial α-synuclein excited ER stress and mitochondrial pro-apoptotic cascades. (Q787X) Dnajc6-evoked α-synuclein oligomer overexpression activated SN microglia and NLRP3 inflammasome and upregulated IL-1β, IL-18, and TNF-α, which stimulated MKK4-JNK -c-Jun/ATF-2 and RIPK1-RIPK3-MLKL death cascades. Our results suggest that PARK19 (Q789X) DNAJC6 mutation causes lysosomal deficiency and impairs cathepsin D-mediated degradation of α-synuclein, resulting in upregulated α-synuclein-induced neurodegeneration of SN dopaminergic cells.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"127 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-08DOI: 10.1038/s41531-026-01307-w
Tahereh Zarrat Ehsan, Michael Tangermann, Yağmur Güçlütürk, SooYoon Shin, King Chung Ho, Bastiaan R. Bloem, Luc J. W. Evers
Accurately quantifying motor characteristics in Parkinson’s disease is crucial for monitoring disease progression and optimizing treatment strategies. The finger-tapping test is a standard motor assessment. Clinicians visually evaluate a patient’s tapping performance and assign an overall severity score based on tapping amplitude, speed, and irregularity. Simultaneous video recording during the standard test enables a more objective, continuous quantification of detailed motor characteristics, thereby reducing the subjectivity and inter-rater variability inherent in clinical evaluations. This paper introduces a computer vision-based method for quantifying granular PD motor characteristics from video recordings. Four sets of clinically relevant features are proposed to characterize hypokinesia, bradykinesia, sequence effect, and hesitation-halts. We evaluate our approach on video recordings and clinical evaluations of 446 people with PD from the Personalized Parkinson Project. Using principal component analysis with varimax rotation, we show that the extracted features largely align with the four clinically defined motor deficits, while additionally revealing finer-grained substructures within the sequence effect and hesitation-halts domains. In addition, we have used these features to train machine learning classifiers to estimate the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) finger-tapping severity score. Compared to state-of-the-art approaches, our method achieves a higher accuracy in MDS-UPDRS score prediction, while still providing an interpretable quantification of individual finger-tapping motor characteristics. In addition, we present the first large-scale dataset of finger-tapping, comprising 4073 video recordings. In summary, the proposed framework provides a practical solution for the objective assessment of PD motor characteristics, that can potentially be applied in both clinical and remote settings. Future work is needed to assess its responsiveness to symptomatic treatment and disease progression.
{"title":"Interpretable and granular video-based quantification of motor characteristics from the finger-tapping test in Parkinson’s disease","authors":"Tahereh Zarrat Ehsan, Michael Tangermann, Yağmur Güçlütürk, SooYoon Shin, King Chung Ho, Bastiaan R. Bloem, Luc J. W. Evers","doi":"10.1038/s41531-026-01307-w","DOIUrl":"https://doi.org/10.1038/s41531-026-01307-w","url":null,"abstract":"Accurately quantifying motor characteristics in Parkinson’s disease is crucial for monitoring disease progression and optimizing treatment strategies. The finger-tapping test is a standard motor assessment. Clinicians visually evaluate a patient’s tapping performance and assign an overall severity score based on tapping amplitude, speed, and irregularity. Simultaneous video recording during the standard test enables a more objective, continuous quantification of detailed motor characteristics, thereby reducing the subjectivity and inter-rater variability inherent in clinical evaluations. This paper introduces a computer vision-based method for quantifying granular PD motor characteristics from video recordings. Four sets of clinically relevant features are proposed to characterize hypokinesia, bradykinesia, sequence effect, and hesitation-halts. We evaluate our approach on video recordings and clinical evaluations of 446 people with PD from the Personalized Parkinson Project. Using principal component analysis with varimax rotation, we show that the extracted features largely align with the four clinically defined motor deficits, while additionally revealing finer-grained substructures within the sequence effect and hesitation-halts domains. In addition, we have used these features to train machine learning classifiers to estimate the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) finger-tapping severity score. Compared to state-of-the-art approaches, our method achieves a higher accuracy in MDS-UPDRS score prediction, while still providing an interpretable quantification of individual finger-tapping motor characteristics. In addition, we present the first large-scale dataset of finger-tapping, comprising 4073 video recordings. In summary, the proposed framework provides a practical solution for the objective assessment of PD motor characteristics, that can potentially be applied in both clinical and remote settings. Future work is needed to assess its responsiveness to symptomatic treatment and disease progression.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"124 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147371109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-06DOI: 10.1038/s41531-026-01310-1
Emma J MacDougall,Carol X-Q Chen,Eric Deneault,Zhipeng You,David Kalaydjian,Narges Abdian,Thomas M Durcan,Konstantin Senkevich,Ziv Gan-Or,Edward A Fon
Variants in the LRRK2 and GBA1 genes are among the most common risk factors associated with Parkinson's disease (PD). Both patients carrying PD-associated variants in GBA1, encoding lysosomal enzyme glucocerebrosidase (GCase), and a subset of non-carrier patients have been shown to have reduced GCase enzymatic activity, suggesting that reduced GCase activity may be a feature of both genetic and a subset of sporadic PD. However, the effect of PD-associated variants in LRRK2, encoding a serine/threonine kinase, on GCase activity remains controversial, with conflicting results in various tissues and cell types. Moreover, rare patients carrying both GBA1 and LRRK2 risk alleles seem to have a more benign disease course than carriers of GBA1 variants alone, suggesting a complex interplay between these two genes in PD. Here, we evaluate the effect of LRRK2 kinase activity on GCase activity in human induced pluripotent stem cell (iPSC)-derived microglia (iMGs), a PD-relevant brain cell type expressing high levels of LRRK2. Using CRISPR editing, isogenic control iPSC lines were generated to match PD patient-derived iPSC lines harbouring the LRRK2 p.G2019S, p.M1646T, or p.N551K-p.R1398H protective haplotype variants. Whereas iMGs harbouring the p.M1646T variant, and the protective haplotype, respectively increased and decreased phosphorylation of canonical LRRK2 substrate, Rab10, GCase protein levels and activity were not altered in any of the LRRK2 variant lines. Additionally, whereas pharmacological inhibition of LRRK2 kinase activity had no impact on GCase activity in iMGs under basal conditions, it attenuated the increase in GCase activity elicited in response to interferon γ (IFNγ) treatment. Moreover, GCase activity induced by IFNγ was reduced in PD risk LRRK2 p.M1646T iMGs and increased in p.N551K-p.R1398H protective haplotype iMGs compared to their isogenic corrected controls, congruent with their respective effects on LRRK2 kinase activity and PD risk. Thus, our data suggest a role for LRRK2 kinase activity in regulation of GCase activity in response to neuroinflammation.
{"title":"LRRK2 kinase mediates increased GCase activity in microglia in response to IFNγ-induced proinflammatory stimulation.","authors":"Emma J MacDougall,Carol X-Q Chen,Eric Deneault,Zhipeng You,David Kalaydjian,Narges Abdian,Thomas M Durcan,Konstantin Senkevich,Ziv Gan-Or,Edward A Fon","doi":"10.1038/s41531-026-01310-1","DOIUrl":"https://doi.org/10.1038/s41531-026-01310-1","url":null,"abstract":"Variants in the LRRK2 and GBA1 genes are among the most common risk factors associated with Parkinson's disease (PD). Both patients carrying PD-associated variants in GBA1, encoding lysosomal enzyme glucocerebrosidase (GCase), and a subset of non-carrier patients have been shown to have reduced GCase enzymatic activity, suggesting that reduced GCase activity may be a feature of both genetic and a subset of sporadic PD. However, the effect of PD-associated variants in LRRK2, encoding a serine/threonine kinase, on GCase activity remains controversial, with conflicting results in various tissues and cell types. Moreover, rare patients carrying both GBA1 and LRRK2 risk alleles seem to have a more benign disease course than carriers of GBA1 variants alone, suggesting a complex interplay between these two genes in PD. Here, we evaluate the effect of LRRK2 kinase activity on GCase activity in human induced pluripotent stem cell (iPSC)-derived microglia (iMGs), a PD-relevant brain cell type expressing high levels of LRRK2. Using CRISPR editing, isogenic control iPSC lines were generated to match PD patient-derived iPSC lines harbouring the LRRK2 p.G2019S, p.M1646T, or p.N551K-p.R1398H protective haplotype variants. Whereas iMGs harbouring the p.M1646T variant, and the protective haplotype, respectively increased and decreased phosphorylation of canonical LRRK2 substrate, Rab10, GCase protein levels and activity were not altered in any of the LRRK2 variant lines. Additionally, whereas pharmacological inhibition of LRRK2 kinase activity had no impact on GCase activity in iMGs under basal conditions, it attenuated the increase in GCase activity elicited in response to interferon γ (IFNγ) treatment. Moreover, GCase activity induced by IFNγ was reduced in PD risk LRRK2 p.M1646T iMGs and increased in p.N551K-p.R1398H protective haplotype iMGs compared to their isogenic corrected controls, congruent with their respective effects on LRRK2 kinase activity and PD risk. Thus, our data suggest a role for LRRK2 kinase activity in regulation of GCase activity in response to neuroinflammation.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"13 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-06DOI: 10.1038/s41531-026-01311-0
Julia Schumacher,Stefan Teipel,Alexander Storch,Wiebke Hermann
Cholinergic system degeneration is a hallmark of Lewy body disease, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), but its involvement in prodromal stages, particularly regarding pedunculopontine-thalamic projections, remains unclear. This study investigated cholinergic pathway integrity in isolated REM sleep behaviour disorder (iRBD) and its relation to phenoconversion risk. We analyzed data from 146 iRBD patients and 102 controls from the Parkinson's Progression Markers Initiative using T1-weighted MRI for basal forebrain volume and diffusion-weighted imaging for three cholinergic pathways: lateral and medial nucleus basalis of Meynert (NBM)-cortical pathways and pedunculopontine nucleus (PPN)-thalamic pathways. Bayesian mixed models and Cox proportional hazards models assessed group differences, cognitive associations, and phenoconversion risk. Fractional anisotropy along PPN-thalamic pathways was reduced in iRBD, particularly in the left hemisphere. Within iRBD patients, medial NBM pathway integrity correlated with baseline cognitive performance. Reduced PPN-thalamic integrity predicted increased phenoconversion risk (hazard ratio=2.08). No group differences or associations with phenoconversion were found for NBM-cortical pathways or basal forebrain volume. These findings suggest that brainstem-thalamic cholinergic projections may be affected earlier than the basal forebrain system in Lewy body disease, potentially serving as a sensitive marker for phenoconversion risk in iRBD pending validation in longer follow-up studies.
{"title":"Pedunculopontine-thalamic cholinergic projections in rapid eye movement sleep behaviour disorder.","authors":"Julia Schumacher,Stefan Teipel,Alexander Storch,Wiebke Hermann","doi":"10.1038/s41531-026-01311-0","DOIUrl":"https://doi.org/10.1038/s41531-026-01311-0","url":null,"abstract":"Cholinergic system degeneration is a hallmark of Lewy body disease, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), but its involvement in prodromal stages, particularly regarding pedunculopontine-thalamic projections, remains unclear. This study investigated cholinergic pathway integrity in isolated REM sleep behaviour disorder (iRBD) and its relation to phenoconversion risk. We analyzed data from 146 iRBD patients and 102 controls from the Parkinson's Progression Markers Initiative using T1-weighted MRI for basal forebrain volume and diffusion-weighted imaging for three cholinergic pathways: lateral and medial nucleus basalis of Meynert (NBM)-cortical pathways and pedunculopontine nucleus (PPN)-thalamic pathways. Bayesian mixed models and Cox proportional hazards models assessed group differences, cognitive associations, and phenoconversion risk. Fractional anisotropy along PPN-thalamic pathways was reduced in iRBD, particularly in the left hemisphere. Within iRBD patients, medial NBM pathway integrity correlated with baseline cognitive performance. Reduced PPN-thalamic integrity predicted increased phenoconversion risk (hazard ratio=2.08). No group differences or associations with phenoconversion were found for NBM-cortical pathways or basal forebrain volume. These findings suggest that brainstem-thalamic cholinergic projections may be affected earlier than the basal forebrain system in Lewy body disease, potentially serving as a sensitive marker for phenoconversion risk in iRBD pending validation in longer follow-up studies.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"47 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-05DOI: 10.1038/s41531-026-01287-x
Anastasiya Moiseyenko, Giacomo Antonello, Aubrey M. Schonhoff, Joseph C. Boktor, Kaelyn Long, Blake Dirks, Anastasiya D. Oguienko, Alexander Viloria Winnett, Patrick Simpson, Dorsa Daeizadeh, Rustem F. Ismagilov, Rosa Krajmalnik-Brown, Nicola Segata, Levi D. Waldron, Sarkis K. Mazmanian
Gut microbiome composition is altered in Parkinson’s disease (PD), the fastest-growing neurological condition, that is characterized by neurodegeneration, motor dysfunction, and is frequently accompanied by gastrointestinal (GI) symptoms. Notably, microbial taxa with anti-inflammatory properties are consistently depleted in PD patients compared to controls. To explore whether specific gut bacteria may be disease-protective, we assembled a microbial consortium of 8 human-associated taxa that are reduced in individuals with PD. Treatment of α-synuclein overexpressing (Thy1-ASO) mice, an animal model of PD, with this consortium improved motor and GI deficits. A single bacterial species from this consortium, Faecalibacterium prausnitzii, was sufficient to correct gut microbiome deviations in Thy1-ASO mice, induce anti-inflammatory immune responses, and promote protective colonic gene expression profiles. Accordingly, oral treatment with F. prausnitzii robustly ameliorated motor and GI deficits and reduced α-synuclein aggregates in the brain. These findings support the emerging hypothesis of functional contributions by the microbiome to PD outcomes, and embolden the development of potential probiotic therapies to treat motor and non-motor symptoms.
{"title":"Faecalibacterium prausnitzii, depleted in the Parkinson’s disease microbiome, improves motor deficits in α-synuclein overexpressing mice","authors":"Anastasiya Moiseyenko, Giacomo Antonello, Aubrey M. Schonhoff, Joseph C. Boktor, Kaelyn Long, Blake Dirks, Anastasiya D. Oguienko, Alexander Viloria Winnett, Patrick Simpson, Dorsa Daeizadeh, Rustem F. Ismagilov, Rosa Krajmalnik-Brown, Nicola Segata, Levi D. Waldron, Sarkis K. Mazmanian","doi":"10.1038/s41531-026-01287-x","DOIUrl":"https://doi.org/10.1038/s41531-026-01287-x","url":null,"abstract":"Gut microbiome composition is altered in Parkinson’s disease (PD), the fastest-growing neurological condition, that is characterized by neurodegeneration, motor dysfunction, and is frequently accompanied by gastrointestinal (GI) symptoms. Notably, microbial taxa with anti-inflammatory properties are consistently depleted in PD patients compared to controls. To explore whether specific gut bacteria may be disease-protective, we assembled a microbial consortium of 8 human-associated taxa that are reduced in individuals with PD. Treatment of α-synuclein overexpressing (Thy1-ASO) mice, an animal model of PD, with this consortium improved motor and GI deficits. A single bacterial species from this consortium, Faecalibacterium prausnitzii, was sufficient to correct gut microbiome deviations in Thy1-ASO mice, induce anti-inflammatory immune responses, and promote protective colonic gene expression profiles. Accordingly, oral treatment with F. prausnitzii robustly ameliorated motor and GI deficits and reduced α-synuclein aggregates in the brain. These findings support the emerging hypothesis of functional contributions by the microbiome to PD outcomes, and embolden the development of potential probiotic therapies to treat motor and non-motor symptoms.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"19 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Previous metabolomic studies have reported significant alterations in circulating amino acids in Parkinson's disease (PD). However, it remains unclear whether these changes reflect central nervous system pathology or are restricted to peripheral metabolism. To address this issue, here we measured the levels of a panel of amino acids in post-mortem brain samples from MPTP-intoxicated monkeys, with and without L-DOPA treatment, and from PD patients at different Braak Lewy body (LB) stages through targeted UPLC-MS. In untreated MPTP monkeys, the putamen showed significant increases in glutamate, aspartate, GABA, phenylalanine, branched-chain amino acids, and serine. L-DOPA treatment further altered this profile, increasing glycine, threonine, and citrulline levels. In contrast, no amino acid changes were detected in the superior frontal gyrus (SFG) of MPTP monkeys, regardless of treatment. In PD patients, caudate-putamen analysis revealed consistent serine upregulation at Braak LB stages 3-4 and 6, with stage 6 additionally showing increased proline and reduced phosphoethanolamine. No amino acid changes were observed in the PD SFG, whereas Alzheimer's disease SFG samples showed marked amino acid increases. Together, these findings demonstrate region-specific amino acid dysregulation in PD, preferentially affecting nigrostriatal targets and supporting disease-specific metabolic signatures across neurodegenerative disorders.
{"title":"Ultra-performance liquid chromatography-mass spectrometry analysis of post-mortem brain tissue reveals specific amino acid profile dysregulation in Parkinson's disease and Alzheimer's disease patients.","authors":"Jacopo Gervasoni,Anna Di Maio,Marcello Serra,Michela Cicchinelli,Lavinia Santucci,Gabriele Ciasca,Tommaso Nuzzo,Qin Li,Marie-Laure Thiolat,Micaela Morelli,Andrea Urbani,Francesco Errico,Erwan Bezard,Alessandro Usiello","doi":"10.1038/s41531-026-01306-x","DOIUrl":"https://doi.org/10.1038/s41531-026-01306-x","url":null,"abstract":"Previous metabolomic studies have reported significant alterations in circulating amino acids in Parkinson's disease (PD). However, it remains unclear whether these changes reflect central nervous system pathology or are restricted to peripheral metabolism. To address this issue, here we measured the levels of a panel of amino acids in post-mortem brain samples from MPTP-intoxicated monkeys, with and without L-DOPA treatment, and from PD patients at different Braak Lewy body (LB) stages through targeted UPLC-MS. In untreated MPTP monkeys, the putamen showed significant increases in glutamate, aspartate, GABA, phenylalanine, branched-chain amino acids, and serine. L-DOPA treatment further altered this profile, increasing glycine, threonine, and citrulline levels. In contrast, no amino acid changes were detected in the superior frontal gyrus (SFG) of MPTP monkeys, regardless of treatment. In PD patients, caudate-putamen analysis revealed consistent serine upregulation at Braak LB stages 3-4 and 6, with stage 6 additionally showing increased proline and reduced phosphoethanolamine. No amino acid changes were observed in the PD SFG, whereas Alzheimer's disease SFG samples showed marked amino acid increases. Together, these findings demonstrate region-specific amino acid dysregulation in PD, preferentially affecting nigrostriatal targets and supporting disease-specific metabolic signatures across neurodegenerative disorders.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"42 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Several studies have investigated the prodromal factors for early diagnosis of Parkinson's disease (PD). Instrumental activities of daily living (IADL) involve both motor and non-motor functions, and has been used as a screening tool for dementia. This study aimed to examine the association between IADL dependency and PD incidence and identify specific IADL items linked to an increased likelihood of developing PD. This population-based cohort study used data from the Korean National Health Insurance Service database, that contains information on long-term care services. Individuals who underwent at least one health screening and completed the geriatric assessment sheet between 2009 and 2021 were included in this study. Information on IADL was extracted from the geriatric assessment sheet. The Fine-Gray subdistribution hazard model was used to assess the association between IADL dependency and PD incidence. During a mean follow-up period of 3.78 ± 3.34 years, 308 of the 21,662 participants developed PD. The highest IADL dependency was significantly associated with an increased incidence of PD (adjusted hazard ratio [aHR] = 1.458, 95% confidence interval [CI] 1.037-2.050), particularly among women or ≥75 years. Among the 10 IADL items, dependency in financial management (aHR 1.420, 95% CI 1.057-1.909, p = 0.0201) or telephone use was significantly associated with an increased incidence of PD (aHR 1.536, 95% CI 1.204-1.961, p = 0.0006). Our results suggests that IADL dependency is a potential prodromal indicator of PD. Further research on other ethnicities that considers sociocultural differences is required to confirm this association.
一些研究探讨了帕金森病（PD）早期诊断的前驱因素。工具性日常生活活动（IADL）包括运动和非运动功能，并已被用作痴呆症的筛查工具。本研究旨在研究IADL依赖与PD发病率之间的关系，并确定与PD发病可能性增加相关的IADL特定项目。这项基于人群的队列研究使用了韩国国民健康保险服务数据库的数据，该数据库包含长期护理服务的信息。在2009年至2021年期间接受至少一次健康筛查并完成老年评估表的个人被纳入本研究。IADL的信息摘自老年评估表。采用Fine-Gray亚分布风险模型评估IADL依赖与PD发病率之间的关系。在平均3.78±3.34年的随访期间，21,662名参与者中有308人患上了帕金森病。最高的IADL依赖性与PD发病率增加显著相关（校正风险比[aHR] = 1.458, 95%可信区间[CI] 1.037-2.050），尤其是女性或≥75岁。在10个IADL项目中，财务管理依赖（aHR 1.420, 95% CI 1.057-1.909, p = 0.0201）或电话使用与PD发病率增加显著相关（aHR 1.536, 95% CI 1.204-1.961, p = 0.0006）。我们的结果表明，IADL依赖是PD的潜在前驱指标。需要对考虑社会文化差异的其他种族进行进一步研究，以证实这种联系。
{"title":"Association between instrumental activities of daily living and incidence of Parkinson's disease: a nationwide population-based cohort study.","authors":"You Hyun Park,Hyo Jeong Lee,Yong Wook Kim,Sang Chul Lee,Seo Yeon Yoon","doi":"10.1038/s41531-026-01293-z","DOIUrl":"https://doi.org/10.1038/s41531-026-01293-z","url":null,"abstract":"Several studies have investigated the prodromal factors for early diagnosis of Parkinson's disease (PD). Instrumental activities of daily living (IADL) involve both motor and non-motor functions, and has been used as a screening tool for dementia. This study aimed to examine the association between IADL dependency and PD incidence and identify specific IADL items linked to an increased likelihood of developing PD. This population-based cohort study used data from the Korean National Health Insurance Service database, that contains information on long-term care services. Individuals who underwent at least one health screening and completed the geriatric assessment sheet between 2009 and 2021 were included in this study. Information on IADL was extracted from the geriatric assessment sheet. The Fine-Gray subdistribution hazard model was used to assess the association between IADL dependency and PD incidence. During a mean follow-up period of 3.78 ± 3.34 years, 308 of the 21,662 participants developed PD. The highest IADL dependency was significantly associated with an increased incidence of PD (adjusted hazard ratio [aHR] = 1.458, 95% confidence interval [CI] 1.037-2.050), particularly among women or ≥75 years. Among the 10 IADL items, dependency in financial management (aHR 1.420, 95% CI 1.057-1.909, p = 0.0201) or telephone use was significantly associated with an increased incidence of PD (aHR 1.536, 95% CI 1.204-1.961, p = 0.0006). Our results suggests that IADL dependency is a potential prodromal indicator of PD. Further research on other ethnicities that considers sociocultural differences is required to confirm this association.","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":"1 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：