Search Results (458)

Background: Amino acid tracer positron emission tomography–magnetic resonance imaging (PET-MRI) was shown to be superior to MRI alone for evaluating central nervous system (CNS) tumours in adults. This study aimed to investigate the utility of amino acid PET-MRI in children with CNS tumours. Methods: We reviewed the amino acid PET-MRI findings of children with suspected or confirmed CNS neoplasms managed in a territory-wide referral centre in Hong Kong from 2022 to 2025. Maximal standardized uptake values (SUVmax) were captured, and tumour-to-background SUVmax ratios (TBRmax) were measured with reference to adjacent or contralateral normal brain structures. Comparisons were made among patients with clinical high-grade and low-grade/non-neoplastic lesions. Results: Thirty-seven patients were included, with 63 PET-MRIs performed. PET-MRI was performed as part of initial diagnostics in 41% of the cases, for response assessment in 48%, and evaluation of residual/relapsed disease in 11%. High-grade lesions had a significantly higher SUVmax and TBRmax compared to low-grade/non-malignant lesions (median SUVmax 3.7 vs. 1.6, p = 0.00006; median TBRmax 2.06 vs. 0.91, p = 0.00002). Optimal SUVmax and TBRmax cut-offs by ROC analysis were 2.38 and 1.62, respectively. Similar performance was reproduced by focusing on the subset of patients with suspected CNS germ cell tumours (CNS-GCT). The impact of amino acid PET availability is considerable, as clinical management was modified in 65% of patients. Conclusions: Our study demonstrates the performance and clinical utility of amino acid PET-MRI in the management of children with CNS pathologies. Amino acid PET-MRI contributes to the diagnosis, monitoring, and treatment guidance of these patients, providing crucial information for decision-making. Full article

Alzheimer’s disease (AD) is the most common cause of dementia worldwide, and there are still no strategies to slow or prevent its clinical progression. Significant financial and research resources have been invested into studying the pathology of AD. However, its pathogenesis is not fully understood. This review provides a comprehensive analysis of current understanding of AD pathogenesis, including classical hypotheses (amyloid cascade, tau pathology, neuroinflammation, oxidative stress), emerging mechanisms (cellular senescence, endoplasmic reticulum stress, ubiquitin-proteasome system dysfunction), and alternative mechanisms (cholinergic dysfunction, glutamate excitotoxicity, disruption of the microbiota–gut–brain axis, and autophagy). Schematic illustrations summarize the relationships between the hypotheses and their role in the pathogenesis of AD. Particular attention is paid to the systematization of promising biological targets and the analysis of modern ligands of various nature, including small molecules, peptides, antibodies and their fragments, natural compounds, as well as innovative hybrid and multifunctional structures. A separate section is devoted to radiopharmaceuticals for PET imaging (Florbetaben, Flortaucipir, etc.) and promising therapeutic agents. Thus, in this review we (1) systematize modern concepts of AD pathogenesis, including classical, emerging mechanisms and alternative hypotheses; (2) conduct a comparative analysis of ligand classes (small molecules, peptides, antibodies, etc.) and their therapeutic potential; and (3) discuss the clinical prospects of radiopharmaceuticals for PET imaging and targeted therapy. The work provides a comprehensive analysis of modern approaches, which can help in the development of more effective drugs against AD. Full article

Objective: The high expression of prostate-specific membrane antigen (PSMA) associated with neovascularization in non-prostatic malignant tumors and metastatic lesions has been documented in many studies. By taking advantage of the absence of PSMA-related background activity in brain tissue, in recent years, PSMA has been used for the imaging of glial tumors, especially for postoperative follow-up. The aim of this prospective study was to investigate the diagnostic value of ⁶⁸Ga-PSMA-11 PET/CT by comparing ⁶⁸Ga-PSMA-11 PET/CT, ¹⁸F-FDG PET/CT, and MRI findings in patients with brain metastases (BM). Materials and Method: In this prospective study, 27 cases, 11 female and 16 male, with a mean age of 59.48 ± 12.21 years, were included. Patients diagnosed with BM on ¹⁸F-FDG PET/CT or CT/MRI at initial diagnosis or in the follow-up period were included in the study. PET findings of BM lesions obtained from ¹⁸F-FDG and ⁶⁸Ga-PSMA-11 PET/CT imaging, demographic characteristics, histopathological data of the primary foci, and other clinical features were evaluated together. Results: Twenty-four (89%) patients were included in the study for restaging, two (7%) patients for local recurrence assessment, and one (4%) patient for local recurrence and suspicion of additional lesions. The indications for ¹⁸F-FDG PET/CT were breast carcinoma for 37% (n:10), followed by lung carcinoma for 26% (n:7), colorectal adenocarcinoma for 14% (n:4), squamous cell larynx carcinoma for 7% (n:2), gastric signet ring cell carcinoma for 4% (n:1), pancreatic NET3 for 4% (n:1), thyroid papillary carcinoma for 4% (n:1), and malignant melanoma for 4% (n:1). In total, 26/27 included patients had PSMA-positive brain metastases but only one patient had PSMA-negative brain metastases with ⁶⁸Ga-PSMA-11 PET/CT imaging. This patient was followed with a diagnosis of primary larynx squamous carcinoma and had a mass suspected of brain metastases. Further tests and an MRI revealed that the lesion in this patient was a hemorrhagic metastasis. The smallest metastatic focus on ⁶⁸Ga-PSMA-11 PET/CT imaging was 0.22 cm, also confirmed by MRI (range: 0.22–2.81 cm). The mean ± SD SUVmax of the BM lesions was 17.9 ± 8.6 and 6.8 ± 5.2 on ¹⁸F-FDG PET/CT and ⁶⁸Ga-PSMA-11 PET/CT imaging, respectively. Metastatic foci that could not be detected by ¹⁸F-FDG PET/CT imaging were successfully detected with ⁶⁸Ga-PSMA-11 PET/CT imaging in 11 cases (42%). The distribution and number of metastatic lesions observed on cranial MRI and ⁶⁸Ga-PSMA-11 PET/CT were compatible with each other for all patients. Immunohistochemical staining was performed in the primary tumor of 10 (38%) cases, and positive IHC staining with PSMA was detected in 5 patients. In addition, positive IHC staining with PSMA was detected in all of the four surgically excised brain metastatic tumor foci. Conclusions: In this study,⁶⁸Ga-PSMA-11 PET/CT appears to be superior to ¹⁸F-FDG in detecting BM from various tumors, largely due to its high expression associated with neovascularization and the absence of PSMA expression in normal brain parenchyma. This lack of physiological uptake in healthy brain tissue provides excellent tumor-to-background contrast, further supporting the advantage of ⁶⁸Ga-PSMA-11 over ¹⁸F-FDG for BM imaging. However, larger studies are required to confirm these findings, particularly through comparisons across tumor types and histopathological subgroups, integrating PSMA immunohistochemistry (IHC) scores with ⁶⁸Ga-PSMA-11 uptake levels. Beyond its diagnostic potential, our results may also inform PSMA-targeted therapeutic strategies, offering new perspectives for the management of patients with brain metastases from diverse primary tumors. Full article

Background: Malignant melanoma remains an oncological challenge, with advanced-stage five-year survival rates under 20%. Precise molecular imaging has become indispensable for accurate staging, selection of targeted or immunotherapies, treatment response assessment, and early detection of immune-related adverse events. This review examines the roles of PET/CT, PET/MRI, and SPECT/CT radiopharmaceuticals in melanoma management and highlights novel tracers and theranostic strategies poised to enhance precision nuclear medicine in this disease. Methods: We performed a review of English-language literature from January 2000 through June 2025, querying PubMed, Scopus, and clinical-trial registries for original research articles, meta-analyses, clinical guidelines, and illustrative case reports. Eligible studies investigated PET/CT, PET/MRI, or SPECT/CT applications in melanoma diagnosis, nodal and distant staging, therapy monitoring, irAE (immune-related adverse events) detection, and the development of emerging radiotracers or theranostic radiopharmaceutical pairs. Results:¹⁸F-FDG PET/CT demonstrated a high detection rate for distant metastases, outperforming conventional CT and MRI in advanced disease, despite limited resolution for infracentimetric nodal deposits. PET/MRI offers comparable diagnostic accuracy with superior soft-tissue contrast and improved brain lesion detection, while SPECT/CT enhanced sentinel lymph node localization prior to surgical biopsy. Also, FDG PET/CT identified visceral irAEs with great sensitivities, revealing asymptomatic toxicities in up to one-third of patients. Emerging radiotracers targeting melanin, fibroblast activation protein, PD-1 (programmed cell death protein 1)/PD-L1 (programmed cell death-ligand 1), and CD8⁺ T cells have demonstrated enhanced tumor specificity and are on their way to forming novel theranostic pairs. Conclusions: While ¹⁸F-FDG PET/CT remains the cornerstone of melanoma imaging, complementary advantages of PET/MRI and SPECT/CT imaging refine melanoma management. The advent of highly specific radiotracers and integrated theranostic approaches heralds a new era of tailored nuclear-medicine strategies, promising improved patient stratification, therapy guidance, and clinical outcomes in melanoma. Full article

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, has a poor prognosis due to rapid recurrence and treatment resistance. This review examines the evolution of radiotherapy (RT) for GBM management, from whole-brain RT to modern techniques like intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), guided by 2023 European Society for Radiotherapy and Oncology (ESTRO)-European Association of Neuro-Oncology (EANO) and 2025 American Society for Radiation Oncology (ASTRO) recommendations. The standard Stupp protocol (60 Gy/30 fractions with temozolomide [TMZ]) improves overall survival (OS) to 14.6 months, with greater benefits in O6-methylguanine-DNA methyltransferase (MGMT)-methylated tumors (21.7 months). Tumor Treating Fields (TTFields) extend median overall survival (mOS) to 31.6 months in MGMT-methylated patients and 20.9 months overall in supratentorial GBM (EF-14 trial). However, 80–90% of recurrences occur within 2 cm of the irradiated field due to tumor infiltration and radioresistance driven by epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) mutations, cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions, tumor hypoxia, and tumor stem cells. Pseudoprogression, distinguished using Response Assessment in Neuro-Oncology (RANO) criteria and positron emission tomography (PET), complicates response evaluation. Targeted therapies (e.g., bevacizumab; PARP inhibitors) and immunotherapies (e.g., pembrolizumab; oncolytic viruses), alongside advanced imaging (multiparametric magnetic resonance imaging [MRI], amino acid PET), support personalized RT. Ongoing trials evaluating reirradiation, hypofractionation, stereotactic radiosurgery, neoadjuvant therapies, proton therapy (PT), boron neutron capture therapy (BNCT), and AI-driven planning aim to enhance efficacy for GBM IDH-wildtype, but phase III trials are needed to improve survival and quality of life. Full article

This paper presents the development of two mobile brain Positron Emission Tomography (PET) scanners under the PETITION project, designed for Intensive Care Units (ICUs) and Proton Beam Therapy (PBT) applications. The ICU scanner facilitates bedside imaging for critically ill patients, while the PBT scanner enables undisturbed proton beam irradiation during imaging. Key aspects of the hardware design, including modular detectors and electromagnetic interference considerations, are discussed along with preliminary performance evaluations. Operational testing, employing a ²²Na source and a hot-rod phantom, was conducted to determine the timing resolution (548 $\mathrm{p}$$\mathrm{s}$), energy resolution (11.4%) and a qualitative spatial resolution (around 2.2 $\mathrm{m}$$\mathrm{m}$). Our study presents findings on the ICU PET scanner’s electromagnetic emissions measured in a controlled EMC testing facility, where all the emissions tests performed comply with the standard EN 60601-1-2 (radiated emissions 15 dB below regulatory limits in the frequency range of 30 $\mathrm{M}$$\mathrm{Hz}$ to 1 G$\mathrm{Hz}$). Full article

Positron emission tomography (PET) has become a powerful tool in Alzheimer’s disease (AD) research by enabling in vivo visualization of pathological biomarkers. Recent efforts have aimed to integrate PET-derived imaging phenotypes with genome-wide association studies (GWASs) to better elucidate the genetic architecture underlying AD. This systematic review examines studies that leverage PET imaging in the context of GWASs (PET-GWASs) to identify genetic variants associated with disease risk, progression, and brain region-specific pathology. A comprehensive search of PubMed and Embase databases was performed on 18 February 2025, yielding 210 articles, of which 10 met pre-defined inclusion criteria and were included in the final synthesis. Studies were eligible if they included AD populations, employed PET imaging alongside GWASs, and reported original full-text findings in English. No formal protocol was registered, and the risk of bias was not independently assessed. The included studies consistently identified APOE as the strongest genetic determinant of amyloid burden, while revealing additional significant loci including ABCA7 (involved in lipid metabolism and amyloid clearance), FERMT2 (cell adhesion), CR1 (immune response), TOMM40 (mitochondrial function), and FGL2 (protective against amyloid deposition in Korean populations). The included studies suggest that PET-GWAS approaches can uncover genetic loci involved in processes such as lipid metabolism, immune response, and synaptic regulation. Despite limitations including modest cohort sizes and methodological variability, this integrated approach offers valuable insight into the biological pathways driving AD pathology. Expanding PET-genomic datasets, improving study power, and applying advanced computational tools may further clarify genetic mechanisms and contribute to precision medicine efforts in AD. Full article

Background/Objectives: Quantitative analysis of amyloid PET imaging plays a crucial role in diagnosing Alzheimer’s disease (AD), particularly in cases where visual interpretation is equivocal. Multiple commercial software tools are available for this purpose, yet differences in their quantification and diagnostic performance remain understudied, especially for Neurophet SCALE PET. Methods: We retrospectively analyzed ¹⁸F-florbetaben PET/CT scans from 129 patients with cognitive impairment, comprising 39 patients with AD and 90 with non-AD diagnoses, using three software tools: MIMneuro, CortexID Suite, and Neurophet SCALE PET. Standardized uptake value ratios (SUVRs) were obtained for six brain regions known for amyloid accumulation. Diagnostic accuracy was evaluated using ROC curve analysis, while inter-software correlations and reliability were assessed via Pearson correlation coefficients and intraclass correlation coefficients (ICC). Results: All three software programs significantly distinguished AD from non-AD patients in most brain regions. MIMneuro and Neurophet SCALE PET demonstrated the highest diagnostic performance, with MIMneuro achieving an AUC of 1.000 in the anterior cingulate gyrus. While MIMneuro and Neurophet SCALE PET showed moderate-to-strong SUVR correlations (r = 0.715–0.865), CortexID Suite showed limited correlation with the other tools. Inter-software reliability was moderate only in selected regions (ICC ≈ 0.5), indicating potential variability in SUVR measurements across platforms. Conclusions: MIMneuro, CortexID Suite, and Neurophet SCALE PET are effective for the semi-quantitative analysis of amyloid PET and can aid in the diagnosis of AD. However, clinicians should be cautious when interpreting SUVRs across different software tools due to limited inter-software consistency. Standardization efforts or consistent use of a single platform are recommended to avoid diagnostic discrepancies. Full article

Glioblastoma multiforme (GBM) remains one of the most aggressive and treatment-resistant brain tumors, with poor prognosis and limited therapeutic options. Background/Objectives: Integrin α_vβ₃, a cell surface receptor overexpressed in GBM, specifically binds to cyclic arginine-glycine-aspartate-D-phenylalanine-lysine (c(RGDfK)) motif, making it a valuable target for tumor-specific delivery and PET imaging. This study explores a novel radiotheranostic agent, [⁶⁴Cu]Cu-NOTA-TP-c(RGDfK), which combines the imaging and therapeutic capabilities of copper-64 (⁶⁴Cu) and the cytotoxic activity of a terpyridine-platinum (TP) complex, conjugated to c(RGDfK). Methods: A robust protocol was developed for the small-scale preparation of NOTA-TP-c(RGDfK). Comparative cellular studies were conducted using U87 MG glioblastoma (GBM) cells and SVG p12 human astrocytes to evaluate the performance of [⁶⁴Cu]Cu-NOTA-TP-c(RGDfK) relative to [⁶⁴Cu]Cu-NOTA-c(RGDfK), [⁶⁴Cu]Cu-NOTA-TP, ^natCu-NOTA-TP-c(RGDfK), cisplatin, and temozolomide. Results: ⁶⁴Cu-radiolabeling of NOTA-TP-c(RGDfK) was achieved with >99% radiochemical purity, and competition assays confirmed high binding affinity to integrin α_vβ₃ (IC₅₀ = 16 ± 8 nM). Cellular uptake, internalization, and retention studies demonstrated significantly higher accumulation of [⁶⁴Cu]Cu-NOTA-TP-c(RGDfK) in U87 MG cells compared to control compounds, with 38.8 ± 1.8% uptake and 28.0 ± 1.0% internalization at 24 h. Nuclear localization (6.0 ± 0.5%) and stable intracellular retention further support its therapeutic potential for inducing localized DNA damage. Importantly, [⁶⁴Cu]Cu-NOTA-TP-c(RGDfK) exhibited the highest cytotoxicity in U87 MG cells (IC₅₀ = 10 ± 2 nM at 48 h), while maintaining minimal toxicity in normal SVG p12 astrocytes. Conclusions: These results highlight [⁶⁴Cu]Cu-NOTA-TP-c(RGDfK) as a promising targeted radiotheranostic agent for GBM, warranting further preclinical development Full article

Background/Objectives: This study aims to evaluate the additional value of [¹⁸F]F-fluorocholine ([¹⁸F]F-FCH) PET/CT over contrast-enhanced magnetic resonance imaging (CE-MRI) in detecting the recurrence of brain metastases (BMs) after stereotactic radiosurgery (SRS) in patients with lung cancer brain metastases (LCBMs). Methods: Thirty-one patients with suspected recurrence of BM in LCBM after SRS were enrolled in this retrospective study. They underwent both [¹⁸F]F-FCH PET/CT and CE-MRI within 2 weeks. The tumor imaging parameters and clinical features were analyzed. The results of histopathology or radiographic follow-up served as the reference standard for the final diagnosis. Results: In these 31 patients, there were 54 lesions, of which 27 lesions were proven to be BM recurrence, while 27 lesions were non-recurrence. [¹⁸F]F-FCH PET/CT showed high radiotracer uptake in recurrent lesions of BM and identified 24 positive lesions (88.89% of sensitivity), while CE-MRI indicated 23 positive lesions (85.19% of sensitivity). [¹⁸F]F-FCH PET/CT indicated higher specificity (81.48%) and accuracy (85.19%) in detecting recurrence of BM than CE-MRI (40.74% and 62.96%, both p < 0.05), particularly in frontal lobes and cerebella. For lesion sizes, the accuracy of [¹⁸F]F-FCH PET/CT in detecting recurrent lesions was higher than that of CE-MRI for lesions over 1.0 cm but below 2.0 cm (p = 0.016). The detective performance of [¹⁸F]F-FCH PET/CT combined with CE-MRI was higher than [¹⁸F]F-FCH PET/CT or CE-MRI alone (all p < 0.05). Interestingly, TLC (≥4.11) was significantly correlated with poor intracranial PFS (iPFS), meaning it was a significant prognostic factor for iPFS. Conclusions: This study identified that compared with CE-MRI, [¹⁸F]F-FCH PET/CT demonstrated higher specificity and accuracy in diagnosing recurrence of BM in LCBM after SRS. Combining [¹⁸F]F-FCH PET/CT with CE-MRI has the potential to improve diagnostic performance for recurrence of BM and management of patient treatment. TLC was an independent risk factor for iPFS. Full article

Background: Despite its central role in pediatric pre-surgical evaluation of drug-resistant focal epilepsy, conventional analog ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT (aPET) systems often yield modest epileptogenic zone (EZ) detection rates (~50–60%). Silicon photomultiplier–based digital PET/CT (dPET) promises enhanced image quality, but its performance in pediatric epilepsy remains untested. Methods: We retrospectively analyzed 22 children (mean age 11.5 ± 2.6 years) who underwent interictal brain ¹⁸F-FDG PET/CT: 11 on an analog system (Discovery ST, 2018–2019) and 11 on a digital system (Biograph Vision 450, 2020–2021). Three blinded nuclear medicine physicians independently scored EZ localization and image quality (4-point scale); post-surgical histology and ≥1-year clinical follow-up served as reference. Results: The EZ was correctly identified in 8/11 analog scans (72.7%) versus 10/11 digital scans (90.9%). Average image quality was significantly higher with dPET (3.0 ± 0.9 vs. 2.1 ± 0.9; p < 0.05), and inter-reader agreement improved from good (ICC = 0.63) to excellent (ICC = 0.91). Conclusions: Our preliminary findings suggest that dPET enhances image clarity and reader consistency, potentially improving localization accuracy in pediatric epilepsy presurgical workups. Full article

Hydrogen-rich water (HRW) has shown neuroprotective effects in acute brain injury, but its role in chronic radiation-induced brain injury (RIBI) remains unclear. This study investigated the long-term efficacy of HRW in mitigating cognitive impairment and neuronal damage caused by chronic RIBI. Fifty male Sprague Dawley rats were randomly divided into five groups: control, irradiation (IR), IR with memantine, IR with HRW, and IR with combined treatment. All but the control group received 20 Gy whole-brain X-ray irradiation, followed by daily interventions for 60 days. Behavioral assessments, histopathological analyses, oxidative stress measurements, ¹⁸F-FDG PET/CT imaging, transcriptomic sequencing, RT-qPCR, Western blot, and serum ELISA were performed. HRW significantly improved anxiety-like behavior, memory, and learning performance compared to the IR group. Histological results revealed that HRW reduced neuronal swelling, degeneration, and loss and enhanced dendritic spine density and neurogenesis. PET/CT imaging showed increased hippocampal glucose uptake in the IR group, which was alleviated by HRW treatment. Transcriptomic and molecular analyses indicated that HRW modulated key genes and proteins, including CD44, CD74, SPP1, and Wnt1, potentially through the MIF, Wnt, and SPP1 signaling pathways. Serum CD44 levels were also lower in treated rats, suggesting its potential as a biomarker for chronic RIBI. These findings demonstrate that HRW can alleviate chronic RIBI by preserving neuronal structure, reducing inflammation, and enhancing neuroplasticity, supporting its potential as a therapeutic strategy for radiation-induced cognitive impairment. Full article

This narrative review explores the integration of theranostics and artificial intelligence (AI) in neuro-oncology, addressing the urgent need for improved diagnostic and treatment strategies for brain tumors, including gliomas, meningiomas, and pediatric central nervous system neoplasms. A comprehensive literature search was conducted through PubMed, Scopus, and Embase for articles published between January 2020 and May 2025, focusing on recent clinical and preclinical advancements in personalized neuro-oncology. The review synthesizes evidence on novel theranostic agents—such as Lu-177-based radiopharmaceuticals, CXCR4-targeted PET tracers, and multifunctional nanoparticles—and highlights the role of AI in enhancing tumor detection, segmentation, and treatment planning through advanced imaging analysis, radiogenomics, and predictive modeling. Key findings include the emergence of nanotheranostics for targeted drug delivery and real-time monitoring, the application of AI-driven algorithms for improved image interpretation and therapy guidance, and the identification of current limitations such as data standardization, regulatory challenges, and limited multicenter validation. The review concludes that the convergence of AI and theranostic technologies holds significant promise for advancing precision medicine in neuro-oncology, but emphasizes the need for collaborative, multidisciplinary research to overcome existing barriers and enable widespread clinical adoption. Full article

A novel brain positron emission tomography (PET) radioligand, [¹¹C]HY-2-15, has potential for imaging alpha-synuclein aggregations in multiple system atrophy and misfolded tau proteins in tauopathies, based on its high binding affinity in disease brain tissue homogenates. Here, we demonstrate that [³H]HY-2-15 has the capability to bind to aggregated alpha-synuclein in multiple system atrophy brain and tau aggregations in progressive supranuclear palsy and corticobasal degeneration brain tissues via in vitro autoradiography study. A first-in-human pilot multicenter clinical study recruited a total of 10 subjects including healthy controls and patients with Parkinson’s disease, multiple system atrophy, or progressive supranuclear palsy. The study revealed that [¹¹C]HY-2-15 has a relatively higher specific uptake in the pallidum and midbrain of patients with progressive supranuclear palsy. Total-body scans performed on the PennPET Explorer showed the radiotracer was cleared by renal excretion. However, the rapid metabolism and low brain uptake resulted in a limited signal of [¹¹C]HY-2-15 in brain. Full article

The intranasal delivery of exogenous mitochondria is a potential therapy for Parkinson’s disease (PD). The regulatory mechanisms and effectiveness in genetic models remains uncertain, as well as the impact of modulating the mitochondrial permeability transition pore (mPTP) in grafts. Utilizing UQCRC1 (p.Tyr314Ser) knock-in mice, and a cellular model, this study validated the transplantation of mitochondria with or without cyclosporin A (CsA) preloading as a method to treat mitochondrial dysfunction and improve disease progression through intranasal delivery. Liver-derived mitochondria were labeled with bromodeoxyuridine (BrdU), incubated with CsA to inhibit mPTP opening, and were administered weekly via the nasal route to 6-month-old mice for six months. Both treatment groups showed significant locomotor improvements in open-field tests. PET imaging showed increased striatal tracer uptake, indicating enhanced dopamine synthesis capacity. The immunohistochemical analysis revealed increased neuron survival in the dentate gyrus, a higher number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) and striatum (ST), and a thicker granule cell layer. In SN neurons, the function of mitochondrial complex III was reinstated. Additionally, the CsA-accumulated mitochondria reduced more proinflammatory cytokine levels, yet their therapeutic effectiveness was similar to that of unmodified mitochondria. External mitochondria were detected in multiple brain areas through BrdU tracking, showing a 3.6-fold increase in the ST compared to the SN. In the ST, about 47% of TH-positive neurons incorporated exogenous mitochondria compared to 8% in the SN. Notably, GFAP-labeled striatal astrocytes (ASTs) also displayed external mitochondria, while MBP-labeled striatal oligodendrocytes (OLs) did not. On the other hand, fewer ASTs and increased OLs were noted, along with lower S100β levels, indicating reduced reactive gliosis and a more supportive environment for OLs. Intranasally, mitochondrial transplantation showed neuroprotective effects in genetic PD, validating a noninvasive therapeutic approach. This supports mitochondrial recovery and is linked to anti-inflammatory responses and glial modulation. Full article