Citations

Freezing of gait (FOG) is a complex and highly disabling motor symptom that frequently affects patients with Parkinson’s disease (PD), especially in the middle and late stages. Although traditionally associated with motor deficits, accumulating evidence suggests that FOG is also strongly influenced by non-motor domains, including cognitive dysfunction and emotional disturbances. The prefrontal cortex (PFC), a key hub for executive functions, attention, and emotional regulation, has been increasingly implicated in the pathophysiology of FOG. Structural and functional abnormalities in the PFC, particularly in the dorsolateral prefrontal cortex (DLPFC) and medial prefrontal cortex (MPFC), have been reported in PD patients with FOG. This narrative review aims to summarize current evidence on the role of the prefrontal cortex in the development and modulation of freezing episodes, focusing on neuroimaging findings. Clarifying the contribution of frontal lobe dysfunction to FOG may inform therapeutic strategies targeting frontostriatal circuits to improve mobility and quality of life in PD patients. This is a narrative review and does not employ formal systematic review methodology.

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

Neutrophils and neutrophil extracellular traps (NETs) contribute to early neuromyelitis optica (NMO) histopathology initiated by IgG targeting astrocytic aquaporin-4 (AQP4) water channels. Yet, the mechanisms underlying neutrophil recruitment and their pathogenic roles in disease progression remain unclear. To investigate molecular-cellular events preceding classical complement cascade activation in a mouse NMO model, we continuously infused, via spinal subarachnoid route, a non-complement-activating mouse monoclonal AQP4-IgG. Parenchymal infiltration of netting neutrophils containing C5a ensued with microglial activation and motor impairment but no blood-brain barrier leakage. Motor impairment and neuronal dysfunction both reversed when AQP4-IgG infusion stopped. Two-photon microscopy and electron microscopy–based reconstructions revealed physical interaction of infiltrating neutrophils with microglia. Ablation of either peripheral neutrophils or microglia attenuated the motor deficit, highlighting their synergistic pathogenic roles. Of note, mice lacking complement receptor C5aR1 exhibited reduction in neutrophil infiltration, microglial lysosomal activation, neuronal lipid droplet burden, and motor impairment. Pharmacological inhibition of C5aR1 recapitulated this protection. Immunohistochemical analysis of an NMO patient’s spinal cord revealed disease-associated microglia surrounding motor neurons in nondestructive lesions. Our study identifies neutrophil-derived C5a signaling through microglial C5aR1 as a key early driver of reversible motor neuron dysfunction in the precytolytic phase of NMO.

Abstract: AIM: The purpose of this study is to investigate the safety and effectiveness of remote ischemic conditioning (RIC) as a therapeutic intervention for cerebral ischemia in patients with Takayasu arteritis (TA). METHODS: TARIC-1 is a randomized, double-blind, parallel-group pilot trial conducted at Xuanwu Hospital, Capital Medical University. Participants with TA and reduced cerebral blood perfusion are randomly allocated to either the RIC or sham-RIC groups. Both the groups receive conventional medical care, with the RIC group receiving twice-daily sessions of 200 mmHg inflation pressure and the sham-RIC group receiving 60 mmHg inflation pressure, for 24 consecutive weeks. OUTCOMES: The primary outcome is the change in mean cerebral blood flow across the entire brain and regions of interest following the 24-week RIC treatment. Secondary outcomes include clinical assessments using the Indian Takayasu Clinical Activity Score 2010, Vasculitis Damage Index, and Birmingham Vasculitis Activity Score at 24 weeks postintervention. Changes in arterial transit time and the incidence of major adverse cerebrovascular events are additional secondary outcomes. Safety outcomes include mortality and any adverse events, including skin changes and pain ratings, within the 24-week period. SAMPLE SIZE ESTIMATES: This pilot study plans to enroll 22 patients per group, totaling 44 participants. CONCLUSIONS: In individuals with TA, RIC may be a well-tolerated treatment that enhances cerebral perfusion and lowers the risk of ischemic cerebrovascular episodes. TRIAL REGISTRATION: http://www.clinicaltrials.gov (identifier: NCT06178419).

Abstract Iron-deficiency anemia (IDA) affects nearly one-third of women globally, with heavy menstrual bleeding (HMB) being a significant risk factor among those of reproductive age. Despite the substantial burden of HMB-related IDA, patients often face delays in receiving effective treatment. Oral iron is typically used as first-line therapy, despite frequent gastrointestinal side effects and challenges in treatment adherence. This study evaluated the reproductive life span cost-effectiveness of first-line intravenous (IV) vs oral iron therapy for women with HMB and IDA. We developed a Markov model simulating a cohort of women aged 18 to 51 years, comparing first-line treatment with IV iron dextran, IV ferumoxytol, IV iron sucrose, or oral ferrous sulfate. Costs and quality-adjusted life years (QALYs) were estimated from the societal perspective. IV iron dextran was the cost-effective treatment, yielding 19.26 QALYs at a cost of $157 500, compared with 19.10 QALYs at $152 900 for oral ferrous sulfate. The incremental cost-effectiveness ratio for IV iron dextran was $28 600 per QALY. Treatment with IV ferumoxytol and iron sucrose cost $158 300 and $163 500, respectively, and did not provide additional QALY benefit compared with IV iron dextran, which remained the cost-effective treatment across a range of scenarios and sensitivity analyses. Our findings indicate that first-line treatment with IV iron dextran is the cost-effective strategy for managing IDA in women with HMB at commonly accepted willingness-to-pay thresholds. These results support expanding access to IV iron as a first-line option, and highlight the need to reduce treatment delays and insurance-related barriers.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) for brain arteriovenous malformations (AVMs) can cause radiation-induced changes (RIC), but its interactions with AVM embolization are not well established. The aim of this study was to assess the effect of previous embolization on RIC in SRS-treated AVM patients. METHODS: Data of AVM patients treated with single-session SRS from 1987 to 2018 were retrieved from the International Radiosurgery Research Foundation. Univariable and stepwise backward logistic regression models were used to identify RIC predictors. Patients were stratified into those who received pre-SRS embolization (E + SRS) vs those who did not (SRS-only). Radiologic RIC (rRIC) was the primary end point. Secondary outcomes included symptomatic RIC (sRIC) and permanent symptomatic RIC (pRIC). RESULTS: Among 1187 AVM patients, the mean age was 36.4 years (SD 16.8), with 50.4% female patients. AVMs had a mean untreated AVM volume of 5.2 cm 3 . A total of 130 patients (11%) underwent neoadjuvant embolization (E + SRS). The overall rRIC and sRIC rates were 32.8% and 12.1%, respectively, with time to rRIC and sRIC being significantly longer in the E + SRS vs SRS-only cohorts (103.6 ± 339.4 vs 11.3 ± 12.5 and 60.4 ± 262.9 vs 9.5 ± 9.0 months, respectively). Seizures at presentation and ≥3-cm untreated AVM volume significantly correlated with a higher likelihood of rRIC (adjusted odds ratio [aOR] 2.32 [1.25-4.30] and aOR 2.77 [1.24-6.16], respectively). Age and pre-SRS embolization were associated with a significantly lower risk of rRIC (aOR 0.97 [0.96-0.99] and aOR 0.32 [0.13-0.74], respectively). The E + SRS cohort had significantly reduced odds of rRIC (aOR = 0.37 [0.15-0.89]) and pRIC (aOR = 0.04 [0.00-0.30]) after adjusting for significant covariates. CONCLUSION: Seizures at presentation and larger untreated AVM volume were independently associated with an increased risk of rRIC, whereas older age and pre-SRS embolization were protective. Notably, patients who underwent embolization before SRS had lower odds of rRIC and pRIC, with delayed onset of complications compared with SRS-only.

Background Animal models are essential for evaluating endovascular device safety and efficacy. Rats offer advantages, such as genetic manipulability, lower cost, and shorter healing and breeding cycles, compared to large animals. These features support studying aneurysm healing mechanisms and enable high-throughput testing. We developed an optimal rat aneurysm model for device evaluation. Methods Saccular aneurysms were created at the origins of the left renal artery (LRA) with acetylsalicylic acid (ASA) (LRA/ASA group, n = 7); the right common iliac artery (RCIA) with ASA alone (RCIA/ASA group, n = 6) or ASA plus clopidogrel (CLP) (RCIA/ASA + CLP group, n = 7); and the left common iliac artery (LCIA) with ASA + CLP (LCIA/ASA + CLP group, n = 7). The origins of these arteries were surgically exposed. During temporary ligation of the vessel origin, the vessel was bisected and endoluminal elastase was incubated in the proximal stump for 10 min, followed by release of the proximal ligation and permanent ligation of the stump. Angiographical and histological analysis were performed 4 weeks post-procedure. Results Follow-up digital subtraction angiography revealed mean ± standard deviation aneurysm height/neck dimensions of 1.2 ± 0.4/1.2 ± 0.1, 2.9/3.1, 2.3 ± 0.6/1.9 ± 0.3, and 2.1 ± 0.6/2.0 ± 0.4 mm for the LRA/ASA, RCIA/ASA, RCIA/ASA + CLP, and LCIA/ASA + CLP groups, respectively. The survival rate was 29%, 17%, 71%, and 86% in the LRA/ASA, RCIA/ASA, RCIA/ASA + CLP, and LCIA/ASA + CLP groups, respectively. Histopathological analysis of these aneurysms confirmed the absence of the internal elastic lamina and revealed aneurysmal changes in the arterial wall, resembling the pathological findings observed in human aneurysm specimens. Conclusions Common iliac aneurysm models with ASA + CLP can be used to evaluate the safety and efficacy of endovascular devices.

Abstract Background Standardizing beam modeling in the treatment planning system is challenging due to machine‐specific configuration variations. Because of the proton therapy system (PTS) complexity and continuous development, there is no vendor's representative (“golden”) beam data like in LINACs at this stage. Purpose The primary goal of this study is to create a PTS‐specific repository of source model parameters and beam commissioning data for scanning proton therapy treatment planning systems and establish a set of reference values with associated bands of variations for this data. Methods We conducted a survey of 31 PTSs at 27 proton therapy centers to gather beam commissioning source model parameters used in their treatment planning system, ensuring a diverse selection of PTSs from major vendors: Hitachi, IBA, Varian, and Mevion. For each proton therapy center, we collected (i) beam meterset calibration in protons per MU, (ii) in‐air spot size at isocenter in terms of standard deviation in x‐ (crossline, σ x ) and y‐ (inline, σ y ) directions, (iii) in‐air angular spread at isocenter in x‐direction (θ x ) and y‐direction (θ y ) and (iv) distal falloff. For each PTS, we plotted each parameter as a function of nominal energy and performed polynomial regression analysis with optimal model selection based on Akaike Information Criterion. We calculated intraclass correlation coefficients (ICC) to quantify inter‐PTS variability and generated uncertainty bands representing standard deviations across PTSs for each parameter. Additionally, we computed percentage deviations of each individual PTS from the overall multi‐vendor mean to identify systematic vendor‐specific patterns and outliers across the 31 total PTSs analyzed. Results Multi‐vendor beam parameter analysis across 31 PTSs revealed systematic vendor‐specific patterns in inter‐PTS consistency and energy dependencies. Beam meterset calibration demonstrated excellent inter‐PTS consistency across most vendors (ICC: Varian ProBeam ≈ 0, IBA Proteus ONE = 0.006, Mevion S250i with HYPERSCAN = 0.015), with IBA Proteus PLUS systems showing moderate variation (ICC = 0.156 for the dedicated nozzle, ICC = 0.248, for the universal nozzle). Spot size and angular spread variability were highly vendor‐dependent, ranging from excellent consistency in IBA Proteus ONE to substantial variation in IBA Proteus PLUS with the universal nozzle (angular spread ICC = 0.566). Distal falloff maintained excellent consistency across all vendors (ICC < 0.023), indicating reliable energy spread characteristics. Uncertainty band analysis revealed characteristic energy‐dependent patterns, with most systems showing larger uncertainties at lower energies for spot size and angular spread, while IBA Proteus PLUS with the universal nozzle exhibited the largest uncertainty bands overall. Percentage deviation analysis demonstrated vendor‐specific clustering patterns, with some systems showing systematic positive or negative deviations from the multi‐vendor mean. Conclusions The reference data provided in this work will help to cross‐check the beam model during treatment planning system commissioning. Furthermore, this information is useful for Monte Carlo applications and research, where beam characteristics are required to set up phase space parameters, thereby avoiding the need to model the entire PTS. Finally, the results of this study will have indispensable educational value by providing valuable insights into the characteristics and capabilities of different PTSs.

Abstract Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e−4). At disease progression, multiple myeloma cells upregulated cancer–testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune–tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression. Significance: Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune–tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.

To improve synthetic CT (sCT) generation from cone-beam CT (CBCT) in radiotherapy, we propose a multiscale segmentation-guided diffusion framework. The proposed model integrates anatomical priors across multiple spatial resolutions through a segmentation mask pyramid and introduces a scale-specific loss function to guide learning at each level. When evaluated on the SynthRAD2023 brain dataset, our model achieves a mean absolute error (MAE) of 61.82 HU, a peak signal-to-noise ratio (PSNR) of 32.05 dB, and a structural similarity index (SSIM) of 0.90, outperforming baseline models. These results suggest that multiscale anatomical guidance can improve the fidelity and anatomical consistency of sCT images, thus facilitating high-quality CBCT-to-CT translation in radiotherapy applications.