RPS 1711 - Parkinson’s disease and amyotrophic lateral sclerosis (ALS): challenges and innovations

Author Block: S. Lee, J. Youn, E. Y. Kim, B. Sohn; Seoul/KR
Purpose: Susceptibility map-weighted imaging (SMwI) provides a reliable marker for the loss of nigral hyperintensity in Parkinson’s disease (PD), yet requires a dedicated high-resolution oblique-coronal acquisition. To improve feasibility and broader applicability, we investigated whether SMwI reconstructed from existing sequences—susceptibility-weighted imaging (SWI) and neuromelanin-sensitive imaging (NM)—could approximate the diagnostic performance of standard SMwI in differentiating early PD from disease controls (DC). Diagnostic performance was further evaluated with reference to 18F-FP-CIT PET as an independent standard.
Methods or Background: We retrospectively reviewed 187 early PD and 43 DC subjects imaged at Samsung Medical Center between 2021 and 2022. Source data for SMwI, SWI, and NM were acquired perpendicular to the midbrain, along the anterior commissure–posterior commissure plane, and perpendicular to the fourth ventricle, respectively, with resolutions of 0.5×0.5×1 mm³, 0.5×0.5×2 mm³, and 0.7×0.7×1.2 mm³. Standard SMwI, SWI-driven SMwI, and NM-driven SMwI were reconstructed in MATLAB. Two blinded neuroradiologists evaluated nigral hyperintensity, and diagnostic accuracy was assessed relative to both clinical diagnosis and PET.
Results or Findings: Standard SMwI demonstrated the highest accuracy against clinical diagnosis, significantly outperforming reconstructed alternatives, with the largest disparity observed for NM-driven SMwI. In both lesion- and patient-level analyses referenced to PET, standard SMwI consistently exceeded NM-driven SMwI, whereas its performance was not statistically distinguishable from SWI-driven reconstructions. These differences appear attributable to variations in spatial resolution, slice thickness, and acquisition geometry.
Conclusion: Standard SMwI outperformed reconstructed methods against clinical diagnosis, but SWI-driven SMwI showed comparable accuracy to the standard with PET, indicating its potential as a practical alternative when standard acquisition is not feasible.
Limitations: Because the compared methods varied simultaneously in in-plane resolution, slice thickness, and acquisition plane, the independent contribution of each factor could not be isolated.
Funding for this study: No funding was received for this study.
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: This study was approved by the Institutional Review Board of Samsung Medical Center.

Author Block: A. Silovs, N. Zdanovskis, G. K. Skuburs, S. Umbrasko, A. Sevcenko, J. Mednieks, A. Platkājis, J. Skilters, S. Bartusevica; Riga/LV
Purpose: Parkinson’s disease (PD) is characterised by progressive dopaminergic neuronal loss in the substantia nigra pars compacta. Neuromelanin-sensitive MRI (NM-MRI) allows in vivo assessment of this degeneration. We aimed to evaluate substantia nigra neuromelanin volume changes in PD patients and their association with motor symptoms using semi-automated volumetric analysis.
Methods or Background: This prospective case-control study enrolled 23 PD patients, mean age 64.9 ± 12.3 years; 23 controls, mean age 50.8 ± 11.1 years. High-resolution 3T NM-MRI was acquired using a T1-weighted spin-echo sequence. Semi-automated segmentation (Mango v3.5.1) with intracranial volume correction (FreeSurfer 7.3) was performed. Clinical severity was assessed with the Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn & Yahr (H&Y) staging.
Results or Findings: Corrected substantia nigra volume was significantly reduced in PD patients (0.0276 ± 0.0058 mm³) compared with controls (0.0337 ± 0.0102 mm³), representing an 18% reduction (p = 0.014, t-test; p = 0.039, Mann–Whitney U). ROC analysis demonstrated moderate diagnostic performance (AUC = 0.700; sensitivity = 68.4%; specificity = 74.1%). Progressive reduction was observed across disease stages: H&Y stage 1 (0.0285 ± 0.0054 mm³) and stage 2 (0.0279 ± 0.0064 mm³), both significantly lower than controls (p < 0.05). No significant correlation was found between corrected volumes and UPDRS-III motor scores. Semi-automated segmentation showed excellent agreement with manual measurements (ICC = 0.945).
Conclusion: Semi-automated NM-MRI reliably detects substantia nigra volume loss in early-stage PD with moderate diagnostic accuracy. While not strongly correlated with UPDRS-III, corrected NM volume reflects disease staging and may serve as a supportive biomarker for PD diagnosis and monitoring.
Limitations: The main limitation is age mismatch between groups (mean difference 14 years), representing a potential confounder. Additional limitations include modest sample size and cross-sectional design.
Funding for this study: This research was funded by the Latvian Council of Science, project No. lzp-2022/1-0100
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Ethics Committee of Paul Stradins University Hospital protocol code Nr 240423 - 211 24.04.2023

Author Block: F. De Rosa¹, R. Franciosi², D. Vo¹, G. Greco¹, M. Fusina¹, C. C. Quattrocchi¹; ¹Trento/IT, ²Rovereto (TN)/IT
Purpose: To evaluate the effects of Quadrato Motor Training (QMT) on resting-state FC in PD patients.
Methods or Background: Parkinson’s disease (PD) is characterized by motor and cognitive impairments, associated with alterations in functional connectivity (FC) across brain networks. Motor interventions with cognitive engagement may foster neuroplasticity and compensatory mechanisms.
Results or Findings: Out of 50 randomized PD patients, 48 completed the trial (QMT n=23, control n=25). Independent component analysis identified 11 major resting-state networks (RSNs).
Control group showed significant FC decrease (p<0.01 FDR-corrected) across multiple RSNs including default mode (Tmax=5.03, L frontal pole), dorsal attention (Tmax=5.03, R occipital cortex), executive control (Tmax=3.72, paracingulate gyrus), sensorimotor (Tmax=4.80, precuneus; Tmax=4.38, R postcentral gyrus) and cerebellar networks (Tmax=4.89, L Crus II).
QMT group exhibited increased FC in the right frontoparietal network (T=3.99, R angular gyrus) and in the sensorimotor II network (T=3.62, R postcentral gyrus), with no significant reductions in any RSN.
Between-group comparisons (ΔFC): QMT preserved connectivity in the left postcentral gyrus (T=4.41), supplementary motor area (T=3.72), and cerebellar Crus II (T=3.83), while controls showed significant decline.
Conclusion: By combining motor and cognitive stimulation,QMT may prevent FC decline and enhance connectivity within key motor and cognitive networks in PD. Brain functional connectivity measures are suitable to measure the effect of rehabilitation strategies in PD.
Limitations: The study was limited to 4 weeks; pre- and post-intervention assessments of motor and cognitive functions (beyond fMRI) were not included; control groups: only a sham motor control was used, without an active cognitive control group.
Funding for this study: Brain functional connectivity (FC) emerged as a sensitive marker to capture the neural effects of rehabilitation strategies in Parkinson’s disease (PD). Resting-state fMRI revealed that controls (sham exercise) exhibited a widespread decline in FC across default mode, executive, dorsal attention, sensorimotor, and cerebellar networks, confirming the progressive disconnection typical of PD.
QMT group: showed preserved or increased FC, with significant gains in the right frontoparietal and sensorimotor networks.
Between-group comparison: highlighted that QMT protected connectivity in regions critical for motor control and compensation, including the supplementary motor area and cerebellar Crus II, which were selectively impaired in controls.
These findings demonstrate that resting-state FC is not only suitable but highly informative to assess the impact of motor-cognitive rehabilitation in PD. The ability of QMT to enhance or stabilize FC in key brain networks supports its potential role as a neuroplastic and neuroprotective intervention, measurable with functional imaging biomarkers.
Has your study been approved by an ethics committee? Not applicable
Ethics committee - additional information:

Author Block: G. Di Cerbo, G. Saltarelli, A. Innocenzi, C. De Felici, S. Di Terlizzi, A. Catalucci, F. Bruno, E. Di Cesare, A. Splendiani; L'Aquila/IT
Purpose: To evaluate long-term clinical and radiological outcomes of unilateral MR-guided focused ultrasound (MRgFUS) Vim thalamotomy for essential tremor over five years, assessing durability of tremor control and lesion evolution on MRI.
Methods or Background: Retrospective single-centre cohort of 28 right-handed, medication-refractory essential tremor patients who underwent unilateral (left) Vim MRgFUS thalamotomy between February 2018 and December 2019 (San Salvatore Hospital, L’Aquila). Clinical evaluations used the Fahn–Tolosa–Marin Tremor Rating Scale (FTM-TRS) at baseline, 24 h, 1 month, 1, 2, and 5 years. Brain MRI (T1, T2, FLAIR, DWI, SWI, DTI) was acquired at the same time points. Lesion presence and volume were assessed on all sequences, and whole-brain volumetry was performed with dedicated software. DTI tractography reconstructed the dentato-rubro-thalamic tract (DRTT) in the treated hemisphere using ROIs in the dentate nucleus, red nucleus, and Vim.
Results or Findings: Tremor severity improved and remained stable (FTM-TRS 5.1 ± 0.79 baseline vs 1.3 ± 0.61 at 5 years; −74.5%). Recurrence occurred in 2 patients. No adverse events at 5-year follow-up. MRI showed progressive lesion shrinkage. At 5 years, lesions were visible in 56% on fluid-sensitive sequences, 73% on T1-weighted, and 100% on SWI. No lesion was visible on DWI after 6 months. Only the treated thalamus showed significant long-term volume reduction (7.36 ± 0.79 mL at 1 year vs 7.15 ± 0.71 mL at 5 years; p = 0.001).
Conclusion: MRgFUS thalamotomy provides sustained tremor control with a favorable safety profile and durable imaging signatures of thalamic ablation.
Limitations: The main limitation is the small sample size, which may reduce statistical power.
Funding for this study: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Has your study been approved by an ethics committee? Not applicable
Ethics committee - additional information:

Author Block: Y. Yang, H. Lyu, Y. Lu; Shanghai/CN
Purpose: The locus coeruleus (LC), brain’s principal noradrenergic nucleus, contributes to cognitive and non-motor symptoms in Parkinson’s disease (PD), yet its role in multiple system atrophy (MSA) and its subtypes—cerebellar (MSA-C) and parkinsonian (MSA-P)—remains unclear. This study quantified LC relative contrast ratios (rCR) on neuromelanin-sensitive MRI (NM-MRI), compared LC integrity among PD, MSA subtypes, and healthy controls (HC), and examined associations with motor, autonomic, cognitive, and sleep functions.
Methods or Background: A total of 147 participants (42 PD, 82 MSA, 23 HC) underwent 2D NM-MRI. LC signal intensity was normalized to pontine white matter (rCR-LC-Pons). Group differences were assessed using Kruskal–Wallis with Bonferroni correction; clinical associations were examined via Spearman correlations and age-, sex-, and education-adjusted GLMs. Receiver operating characteristic (ROC) analyses evaluated the diagnostic performance of rCR-LC-Pons across groups.
Results or Findings: rCR-LC-Pons showed strong group differences (p < 0.001), indicating a progressive LC signal decline from HC to PD to MSA and MSA subtypes. rCR-LC-Pons correlated negatively with disease duration in both PD and MSA, reflecting ongoing neuro degeneration. Adjusted models showed rCR-LC-Pons 5.44 units lower in MSA than PD at matched duration, independent of age or sex. Diagnostic accuracy was high for distinguishing MSA from HC (AUC = 0.93) and PD from HC (AUC = 0.82). In PD, LC integrity predicted cognitive performance (MoCA: β = 0.46, p < 0.01; R² ≈ 0.20), supporting its value as a marker of cognitive vulnerability and disease stratification.
Conclusion: NM-MRI reliably detects LC degeneration across PD and MSA spectra. Pons-referenced normalization provides superior discrimination, and LC integrity partly explains cognitive variance in PD, supporting its utility as a clinical imaging biomarker.
Limitations: Cross-sectional design and modest model fits limit causal inference; longitudinal and multimodal validation is needed.
Funding for this study: This work was supported by Shanghai Jiao Tong University Trans-med Awards Research (YG2023LC02), Shanghai Science and Technology Commission of China (SHDC2022CRD017)
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: Our study has been approved by the ethics committee of Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital

Author Block: J. Qin, M. Zhang; Hangzhou/CN
Purpose: Parkinson’s disease (PD) is increasingly recognized to involve cortical regions. Quantitative susceptibility mapping (QSM), a marker of iron accumulation, may sensitively capture such changes. We sought to characterize whole-brain susceptibility alterations in PD and evaluate their structural and molecular correlates.
Methods or Background: We studied 355 PD patients and 206 healthy controls with 3T MRI, including QSM and T1-weighted imaging. Cortical QSM values were extracted using Desikan–Killiany parcellation with multiscale vessel filter to minimize venous contamination, while cortical thickness and subcortical volumes were derived from FreeSurfer. Group comparisons used general linear models adjusting for age, sex, and intracranial volume. Spatial correlations were tested against ENIGMA PD cortical atrophy maps (3092 PD patients and 1262 healthy controls), intrinsic functional networks, cytoarchitectonic classes, and neurotransmitter receptor distributions, with spin-test spatial null models. Regional gene expression from the Allen Human Brain Atlas was analyzed using partial least squares (PLS), followed by gene set enrichment analysis to identify underlying biological pathways.
Results or Findings: QSM revealed widespread cortical and subcortical susceptibility increases, already evident in early-stage PD, while morphometric measures showed limited changes. Cortical QSM abnormalities show strong spatially overlapped with ENIGMA PD atrophy patterns, and were centered in frontoparietal and association cortices. This susceptibility abnormalities pattern correlated with serotonin (5-HT6, 5-HT2A), dopamine transporters, and cholinergic systems. PLS analysis revealed gene expression profiles associated with cortical QSM alterations, highlighting pathways related to mitochondrial dysfunction, impaired synaptic signaling, and immune–glial processes.
Conclusion: QSM detects early cortical iron-related abnormalities in PD, aligning with large-scale atrophy patterns and linking to neurotransmitter and molecular pathways. These findings support cortical susceptibility as a potential biomarker and implicate neuronal vulnerability in disease mechanisms.
Limitations: Longitudinal imaging and multi-cohort replication will be needed to validate and extend these findings.
Funding for this study: This work was supported by the National Natural Science Foundation of China (Grant Nos. 82271935, 82171888, 82202091, 82001767 and 82302132), the China Postdoctoral Science Foundation (Grant Nos. 2023M733085), and the 13th Five-year Plan for National Key Research and Development Program of China (Grant No. 2016YFC1306600).
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: This research was conducted in accordance with the ethical standards of the Declaration of Helsinki and was approved by the Ethics Committee of The Second Affiliated Hospital of Zhejiang University School of Medicine.

Author Block: Z. Chen, S. Huang, Y. Liang, D. Cai, X. Zhou, W. He, J. Xia; Shenzhen/CN
Purpose: Inter-individual variability in levodopa responsiveness complicates personalized treatment of Parkinson's disease (PD). Previous studies have suggested that magnetic resonance imaging (MRI)-based indices of the perivascular space (PVS) and choroid plexus (CP) volume may be related to levodopa responsiveness. This study integrated multiple MRI indices, including CP volume, free water (FW) fraction, PVS volume fraction (PVSVF), and diffusion tensor imaging along the PVS (DTI-ALPS), to investigate their associations with levodopa responsiveness.
Methods or Background: This retrospective study included 100 participants with PD (median age, 63.5 years; 53% females) who underwent 3T MRI between March 2023 and December 2024 and were grouped into good (n=54) and poor (n=46) responders based on the results of an acute levodopa challenge test. CP volume, FW fraction, PVSVF, and DTI-ALPS index were calculated. The Mann–Whitney U test and binary logistic regression were used for analysis.
Results or Findings: Participants in the poor responder group had a higher CP volume (p = 0.048) and FW fraction (p < 0.01) than those in the good responder group. Higher CP volume (odds ratio [OR], 0.986; p = 0.038) and FW fraction (odds ratio [OR], 0.883; p < 0.01) were significantly associated with poor levodopa responsiveness, while higher PVS volume fraction, higher PVSVF-BG, higher PVSVF-WM and lower DTI-ALPS were not.
Conclusion: Higher CP volume and FW fraction were independently associated with poor levodopa responsiveness. CP volume and FW fraction measurements may be valuable imaging biomarkers for predicting levodopa responsiveness.
Limitations: Glymphatic and choroid plexus metrics were indirect or structural, not fully capturing function or regional variations. Future work should employ direct imaging tracers, dynamic techniques, and spatially refined analyses for validation.
Funding for this study: This study has received funding by the National Natural Science Foundation of China (82171913), the Key Clinical Research Program of
Shenzhen Second People's Hospital (20243357010) and the Shenzhen Science and Technology Program (JCYJ 20220818101816036).
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: This study was approved by our hospital’s Ethics Committee. All participants provided written informed consent.

Author Block: J. Luan, S. Liu, F. Liu; Jinan/CN
Purpose: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by cortical thinning and surface area reduction, though its molecular basis remains poorly understood. This study combined multi-level data to explore regional vulnerability in ALS.
Methods or Background: We analyzed T1-MRI from 73 ALS patients and 70 healthy controls to assess cortical surface area (SA) and thickness (TH). Two-sample Mendelian randomization (MR) evaluated causal effects of structural phenotypes on ALS risk. Regional gene expression from the Allen Human Brain Atlas was integrated via partial least squares regression and differential expression analysis to identify SA- and TH-associated genes. Functional annotation, cell-type enrichment, and summary-data-based MR (SMR) incorporating eQTL/mQTL were performed. Candidate genes were validated using single-cell RNA sequencing and cell-cell communication analysis.
Results or Findings: ALS patients exhibited reduced SA in the left precentral gyrus and decreased TH in the left frontal pole. MR analysis confirmed a causal influence of reduced SA in the paracentral lobule and diminished TH in the frontal pole regions on ALS risk. Integrated imaging-transcriptomic analysis identified 215 SA-intersect and 979 TH-intersect genes, which were enriched in synaptic processes, neuroactive ligand-receptor interactions, and glycosphingolipid metabolism. SA-intersect genes were primarily expressed in oligodendrocytes (ODC), while TH-intersect genes showed expression in astrocytes (ASC). SMR nominated myelin-associated MOBP and ZNHIT3 as potential causal genes. Single-cell analyses confirmed downregulation of MOBP in ODC and reduced expression of ZNHIT3 in ASC. Cell-cell communication analysis revealed enhanced signaling involving neuregulin (NRG) and pleiotrophin (PTN) pathways in ALS.
Conclusion: We demonstrate a causal influence of cortical structural changes on ALS risk, implicate synaptic and glial dysregulation in regional vulnerability, and nominate MOBP and ZNHIT3 as potential therapeutic targets.
Limitations: Limited sample size, cross-sectional design, and regional focus constrain causal and generalizable conclusions.
Funding for this study: This work was supported by Natural Science Foundation of Shandong Province (2601010520249H).
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: the Research Ethics Committee of the School of Medicine, Shandong University

Author Block: X. Yi¹, B. T. Chen²; ¹Chongqing/CN, ²Duarte, CA/US
Purpose: Beyond well-established gray and white matter pathology, alterations in cortical gyrification have recently been observed in Amyotrophic lateral sclerosis (ALS) , yet their clinical relevance and molecular underpinnings remain to be understood. We aimed to perform an in-depth investigation of the cortical gyrification changes and their microstructural and transcriptional correlates in symptomatic patients with ALS.
Methods or Background: Here, we investigated this premise by examining its microstructural and transcriptional basis in 60 patients with ALS (median age = 55, range = 25-72 years) and 60 matched controls (median age = 56, range = 27-72 years) using structural and diffusion MRI.
Results or Findings: Patients exhibited a significant reduction in local gyrification index (LGI) within bilateral precentral and postcentral gyri, left middle frontal gyrus, and left superior parietal lobule. This was accompanied by reduced fractional anisotropy (FA) in the white matter tracts, primarily involving the corticospinal tract and corpus callosum. Higher LGI and FA values were associated with better motor function as measured by the ALS Functional Rating Scale-Revised, and LGI also showed positive associations with global cognitive status. A mediation analysis indicated that FA partially accounted for the relationship between LGI and functional disability, suggesting that disrupted white matter pathways contribute to the clinical impact of gyrification changes. Regions of reduced LGI showed spatial convergence with cortical expression of ALS-related genes such as TARDBP and C9orf72, enriched for biological processes related to protein aggregation, axon guidance, and synaptic signaling.
Conclusion: These findings suggest that cortical gyrification abnormalities in ALS are closely linked to white matter degeneration, functional impairment, and genetic vulnerability, thereby offering an integrative window into the multiscale pathology of ALS.
Limitations: The sample size was relatively small, and this was a cross-sectional study.
Funding for this study: None
Has your study been approved by an ethics committee? Yes
Ethics committee - additional information: The study was approved by the Ethics Committee and the Expert Committee of Xiangya Hospital, Central South University , and written informed consent was obtained from all participants.