In recent years, the incidence of neurodegenerative diseases has increased rapidly worldwide due to the aggravation of the aging population and the increase in life expectancy. This issue has become a significant one in the field of international public health.1 Neurodegenerative diseases are a category of severe neurological conditions that include conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The distinguishing characteristic of these diseases is the progressive degeneration and death of neurons, clinically presenting as motor dysfunction, cognitive impairment, and other neurological symptoms.2 Neuroinflammation and oxidative stress are two significant characteristics of neurodegenerative diseases and are closely related to their occurrence and progression.3,4 It has been determined that oxidative stress and neuroinflammation are two independent pathological processes, yet they are closely related and mutually reinforcing. Oxidative stress, in particular, has been shown to induce mitochondrial dysfunction and inflammation, while inflammation can exacerbate oxidative stress and trigger negative feedback mechanisms.5

Neuroinflammation is defined as the adaptive response of neural tissue to various stimuli or damage, including infections, toxins, misfolded proteins, and autoantigens. This process is characterized by the abnormal activation of glial cells, particularly microglia and astrocytes, and the high expression of pro-inflammatory cytokines. The duration of the inflammatory response influences the outcome of neuroinflammation. Short-lived acute inflammation helps to remove toxins, repair damaged tissue, and prevent further damage.6 The persistent state of chronic neuroinflammation is characterized by the sustained activation of glial cells, which in turn secrete excessive amounts of pro-inflammatory cytokines, chemokines, and other inflammatory mediators. This pathological state is not only associated with neurotoxic effects but also with the promotion of abnormal pathological protein aggregation, which in turn can lead to progressive damage to neurons, synaptic dysfunction, and structural brain damage.7 It is important to acknowledge the observation that protein aggregates and endogenous danger-associated molecular patterns (DAMPs) released by damaged neurons can establish a detrimental cycle that perpetuates the neuroinflammatory process. Furthermore, certain abnormal proteins, including TDP-43 and α-synuclein, possess the capacity to invade mitochondria and can directly induce the programmed death of neurons.8 In Alzheimer's disease (AD), for instance, cytokines play a role in the expression and processing of β-amyloid precursors, as well as the phosphorylation of tau protein in neurons. The deposition of β-amyloid and the phosphorylation of tau protein in neurons are pathological features of AD, suggesting that neuroinflammation is involved in the development and progression of the disease.9

Oxidative stress is a pathological process that functions as an independent entity. However, it is also a product of neuroinflammation and can promote the occurrence and development of neuroinflammation. Consequently, it is a significant research topic in the field of neurodegenerative diseases.3 A variety of factors may contribute to an imbalance in copper homeostasis, including but not limited to neuroinflammation, mitochondrial dysfunction, the accumulation of misfolded proteins, the overactivation of oxidases, and the inactivation of antioxidant enzymes within the nervous system.10 In the event of a disruption in the homeostasis between oxides and antioxidants, the interaction of oxygen with redox-active metal ions can result in the production of excessive amounts of reactive substances, including free radicals and reactive oxygen species (ROS), hydrogen peroxide, and superoxide anions. These reactive substances can oxidize and modify lipids, proteins, and DNA in neural tissue, leading to neuronal dysfunction, degeneration, and death.11 At the same time, in neurodegenerative diseases, the excessive accumulation of free radicals and reactive oxygen species (ROS) can lead to the accumulation of misfolded proteins, such as the Aβ protein, lipofuscin, ferritin, the Huntington protein, and α-synuclein oligomers (Lewy bodies), which can contribute to disease progression.3,10,12

These pathophysiological cascades are intimately linked to mitochondrial dysfunction. Electron transport chain inefficiency drives the excessive generation of mitochondrial reactive oxygen species (mROS), which directly induces oxidative modifications to mitochondrial DNA (mtDNA) and lipid membrane peroxidation. This redox imbalance reciprocally impairs cristae architecture through the disassembly of respiratory supercomplexes, resulting in bioenergetic failure (reduced ATP synthesis), collapse of the proton motive force (ΔΨm), and destabilization of mitochondrial permeability transition pore (MPTP) gating kinetics. Furthermore, disrupted calcium buffering capacity synergistically enhances excitotoxic stress, culminating in cytochrome c-mediated activation of intrinsic apoptotic pathways characteristic of neurodegenerative pathology.

The absence of effective treatment for neurodegenerative diseases remains a significant unmet medical need, with current treatment options proving ineffective and limited in their ability to combat the underlying pathologies. In the contemporary research landscape, there has been a marked shift towards a greater emphasis on neuroinflammation and oxidative stress as key research domains aimed at addressing neurodegenerative diseases. The integration of diagnostic and evaluative approaches targeting neuroinflammation and oxidative stress has emerged as a critical facet in clinical management, providing clinicians with a more comprehensive understanding of the underlying pathobiological mechanisms of neurodegenerative diseases, as well as crucial insights into disease progression and prognosis. Positron emission tomography (PET) is a diagnostic imaging tool frequently used in medicine to obtain more meaningful information on neurological diseases through noninvasive visualization and quantitative analysis of specific biological targets and metabolic levels. The prevailing emphasis of contemporary positron emission tomography (PET) imaging of neuroinflammation is directed towards a specific biological target of glial cells,13 with a particular focus on the transporter protein (TSPO),14 Monoamine oxidase B (MAO-B),15 cyclooxygenase (COX),16 Colony-stimulating factor-1 receptor (CSF1R),17 Adenosine diphosphate (ADP) / adenosine triphosphate (ATP) receptors P2 × 7 and P2Y12.18,19 Corresponding radioactive tracers have been developed for these targets for preclinical and clinical translational research. The application of these targets and related tracers in clinical settings remains limited due to their inherent shortcomings, underscoring the necessity for the development of more suitable tracers and imaging methods for both preclinical research and clinical translation of neuroinflammation. An alternative approach involves assessing neuroinflammation and oxidative stress in neurodegenerative diseases from the perspective of hypoxia and oxidative stress. The subsequent discussion will focus on the mechanism of action and research progress of the hypoxia imaging agent Cu-ATSM, particularly in relation to neuroinflammation and oxidative stress, providing guidance for the development and application of future probes.

Cu-ATSM is a neutral, low-molecular-weight (322 Da) copper(II) complex characterized by a central copper atom coordinated through bis(thiosemicarbazone) ligands (Fig. 1). This compound exhibits robust thermodynamic stability with a formation constant (Ka =1018) while maintaining the lipophilic character that facilitates efficient transmembrane diffusion. The charge-neutral nature of the complex at physiological pH, coupled with its compact molecular architecture, contributes to its favorable pharmacokinetic properties in biological systems.20 Cu-ATSM represents one of the bis(aminothiourea) coordination complexes initially developed as a hypoxia-selective imaging agent. Emerging evidence suggests that this radiopharmaceutical also exhibits retention in normoxic tissues with mitochondrial respiratory chain dysfunction, particularly under conditions of elevated electron transport chain activity, such as redox imbalance. This aberrant biodistribution pattern suggests a mechanism involving redox-dependent ligand dissociation kinetics, wherein impaired oxidative phosphorylation perturbs copper(II) reduction, leading to metabolic trapping within pathological microenvironments.21 Consequently, the level of Cu-ATSM intake can also serve as an indicator of the redox state.22

Cu-ATSM is a neutral lipophilic complex that passively diffuses into cells via its high membrane permeability and low reduction potential. Intracellularly, it undergoes bioreduction to generate a charged Cu(I)-ATSM⁻ intermediate. In normoxic cells and tissues with functional electron transport chains (ETC), the Cu(I)-ATSM⁻ species undergoes rapid reoxidation to its neutral lipophilic form, enabling efficient efflux from the cellular compartment. Conversely, under hypoxic conditions or in tissues with mitochondrial dysfunction, impaired ETC activity induces an electron surplus relative to oxygen availability. This disequilibrium drives the accumulation of reducing equivalents (e.g., NADPH, NADH), thereby establishing a hyper-reductive microenvironment.23 Following reduction by nicotinamide adenine dinucleotide (NADH), the Cu(II)-ATSM complex is converted to a Cu(I)-ATSM⁻ intermediate that accumulates within the cells. Pathological elevations in NADH concentration amplify the reductive capacity of the mitochondrial matrix,24 ultimately driving the irreversible reduction of Cu(I)-ATSM⁻ to uncomplexed Cu(I) species, which are retained intracellularly through thiol-mediated sequestration. Furthermore, the acidic intracellular microenvironment characteristic of hypoxic cells facilitates acid-induced dissociation of the Cu-ATSM complex via protonation of its thioureide ligands.25 Distinct from tumor hypoxia, neurodegeneration represents a normoxic pathological process wherein mitochondrial electron transport chain (ETC) impairment—secondary to neuroinflammatory processes or genetic defects—induces a compensatory hyper-reductive state. This redox dysregulation synergizes with oxidative stress cascades to potentiate aberrant Cu-ATSM retention in diseased neural tissues.26 The proposed mechanisms are shown in Figure 2.

Cu-ATSM demonstrates rapid systemic biodistribution characterized by high blood-brain barrier permeability and favorable clearance kinetics, coupled with hypoxia-selective retention mediated by aberrant electron transport chain activity. These pharmacodynamic properties, arising from its redox-activated copper dissociation mechanism, establish this bis(thiosemicarbazone) radiopharmaceutical as the most extensively investigated ligand in its class across both preclinical and clinical neuroscience research paradigms.27 Multiple radiocopper isotopes, including 60Cu, 61Cu, 64Cu, and 67Cu, have been successfully complexed with Cu-ATSM while preserving its intrinsic biodistribution profile. These isotopes exhibit distinct radionuclidic properties—varying physical half-lives (T1/2≥0.39-61.9h), decay modes (β+, β-, γ), and associated background radiation levels—yet demonstrate remarkable ligand-specific pharmacokinetic consistency. Crucially, the hypoxia-targeting specificity and tissue penetration kinetics remain isotope-independent, enabling strategic selection based on clinical objectives: β+-emitting isotopes (60/61/64Cu) for positron emission tomography (PET) temporal resolution optimization versus β- Auger electron-emitting 67Cu for theranostic radiation dosimetry.28 As a radiotracer, the substance has been found to exhibit a low radiation dose, with the liver identified as the primary organ limiting the dose. A safe clinical dose of 500−800 MBq has been established, supporting its widespread clinical use in PET imaging.29 The radiochemical synthesis of 62/64Cu-ATSM has been standardized using established chelation protocols. Liu et al. demonstrated automated radiosynthesis on a modified GE TRACERlab FX2N synthesis module, achieving batch-to-batch consistency with radiochemical purity exceeding 99% as determined by radio-HPLC. The resulting radiopharmaceutical exhibits high specific activity and shelf-life stability, providing robust technical support for translational neuroscience research spanning preclinical studies to clinical trial-grade production.30

Although Cu(II)-ATSM has been predominantly utilized in clinical research and practice for tumor hypoxia imaging and prognostic evaluation, its high blood-brain barrier permeability and unique uptake mechanisms suggest potential applications in assessing oxidative stress and neuroinflammation in neurodegenerative diseases. Preliminary studies have reported that Cu-ATSM and its derivatives may serve as promising tools for detecting redox imbalances and inflammatory cascades associated with conditions such as Alzheimer’s and Parkinson’s diseases, leveraging its ability to penetrate the blood-brain barrier and selectively accumulate in pathologically altered microenvironments. In a comparative PET imaging study conducted by Ikawa et al., 62Cu-ATSM exhibited significantly elevated striatal-to-cerebellar standardized uptake value ratios (S/C ratios) in Parkinson’s disease (PD) patients relative to healthy controls (Fig. 3). And bilateral striatal S/C ratios demonstrated a positive correlation with Unified Parkinson’s Disease Rating Scale (UPDRS-III) motor scores. These findings not only validate 62Cu-ATSM as a quantitative biomarker of regional oxidative stress intensity within the nigrostriatal pathway but also provide in vivo evidence supporting redox dyshomeostasis as a critical driver of dopaminergic neurodegeneration.31 Nevertheless, in patients with advanced Parkinson's disease, the density of the remaining nigrostriatal dopaminergic neurons may be significantly diminished.32 This reduction may consequently modify the uptake of 62Cu-ATSM by the striatum in patients with Parkinson's disease. Therefore, the author subsequently used 123I-FP-CIT SPECT scans of PD patients to estimate the density of remaining striatal presynaptic dopaminergic neurons, obtained the striatal-specific binding rate (SBR) of 123I-FP-CIT, and used the delayed phase of 62Cu-ATSM PET to obtain standardized uptake values (SUV) and calculate the striatum-to-cerebellum SUV ratio (SUVR). Finally, the author used SUVR/SBR to assess the degree of oxidative stress in remaining striatal dopaminergic neurons, finding a positive correlation with disease severity.33 These findings position 62Cu-ATSM PET as an emerging quantitative biomarker for noninvasive stratification of region-specific oxidative stress burden within nigrostriatal dopaminergic neurons in Parkinson's disease.

Similarly, 62Cu-ATSM demonstrated significantly higher radioactivity uptake in the bilateral cortex, including the motor cortex and the right supramarginal gyrus, surrounding the central sulcus in ALS patients compared to controls. The increased radioactivity uptake in these areas was associated with a decrease in the revised ALS Functional Rating Scale score, indicating a good correlation with the severity of ALS.34

In a preliminary clinical study, researchers performed dynamic ¹¹C-PiB and ⁶⁴Cu-ATSM PET/MRI scans on 10 patients with Alzheimer’s disease (AD) and 10 healthy controls (HCs). The subsequent analysis compared three 64Cu-ATSM PET parameters reflecting oxidative stress intensity: standardized uptake value (SUV), tracer influx rate (Kin), and rate constant k3. All early-stage AD (eAD) patients exhibited PiB-positive uptake, whereas the HC group showed PiB-negative uptake, with significantly divergent Mini-Mental State Examination (MMSE) scores between the cohorts. Both SUV and Kin values of 64Cu-ATSM demonstrated a tendency toward higher values in the eAD group compared to HCs. Specifically, eAD patients displayed elevated Kin in the posterior cingulate cortex and increased k3 in the hippocampus (Fig. 4). These findings indicate that combined ⁶⁴Cu-ATSM PET/MRI and tracer kinetic analysis can detect alterations in cerebral oxidative stress in eAD patients, particularly in the cingulate cortex and hippocampal regions.35

Defects in mitochondrial function and redox imbalance are hypothesized to be responsible for Huntington's disease (HD), a genetic neurodegenerative disorder that primarily affects the striatum. Lopes et al. utilized 64Cu-ATSM PET to analyze alterations in mitochondrial function and reactive oxygen species (ROS) production in humans and mice during the early stages of disease progression, as well as in ex vivo studies in human skin fibroblasts from presymptomatic and prodromal (Pre-M) and symptomatic HD carriers. The study's results revealed a significant increase in 64Cu-ATSM uptake in various brain regions of presymptomatic and prodromal (Pre-M) Huntington's disease human carriers and presymptomatic animal models. Ex vivo experiments also suggest that onset is associated with a significant compensatory increase in mitochondrial respiratory chain activity and changes in organellar morphology.36

In the context of ischemic brain disease, the delayed/early ratio (D/E) of 62Cu-ATSM SUV has been shown to exhibit a strong correlation with local changes in cerebral blood flow (CBF) and oxygen extraction fraction (OEF). 62Cu-ATSM uptake is observed to be reduced in the early phase, indicative of diminished local cerebral blood flow and perfusion. Conversely, during the delayed phase, there was no significant change in 62Cu-ATSM uptake in the affected brain area when compared to normal brain tissue, suggesting that normal 62Cu-ATSM retention during the delayed phase reflects the viability of brain tissue (Fig. 5). Therefore, 62Cu-ATSM PET imaging is an effective and noninvasive method of assessing hemodynamics when compared to the invasive 15O2-PET technique.37 The investigators successfully employed dual-tracer 62Cu-ATSM/18F-FDG PET imaging to evaluate regional oxidative stress (hyper-reductive state), glucose metabolism, and cerebral blood flow (CBF) in patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) across various disease stages, revealing the pathophysiological interplay between redox imbalance and metabolic dysregulation. Acute-stage lesions demonstrated mild CBF elevation, accompanied by compensatory glucose hypermetabolism and emerging oxidative stress. Subacute lesions exhibited marked intensification of redox stress concurrent with declining cerebral blood flow (CBF) and metabolic suppression. Chronic lesions showed significant CBF reduction and elimination of oxidative stress, suggesting terminal neuronal death.38 Some researchers have made comparisons between the diagnostic efficacy of classic hypoxic imaging agents (e.g., 18F-fluoromisonidazole (18F-FMISO), 18F-fluoroazomycin arabinoside (18F-FAZA)) and two 64Cu-bis(thiosemicarbazone) complexes (i.e., 64Cu-ATSM and 64Cu-ATSE) in rodent models of ischemic encephalopathy. Despite the superior pharmacokinetic profiles of ⁶⁴Cu-ATSM and ⁶⁴Cu-ATSE, including rapid in vivo uptake, favorable brain penetration, swift washout kinetics, and high selectivity for hypoxic tissues, these complexes failed to demonstrate significant radioactive accumulation in lesion areas, exhibiting inferior imaging performance compared to 18F-FMISO. This finding suggests that ⁶²Cu-ATSM has not yet surpassed 18F-FMISO in the diagnostic evaluation of ischemic encephalopathy.27

Additional 62/64Cu-ATSM derivatives and structural analogs have demonstrated diagnostic potential for neurodegenerative pathologies in preclinical investigations. 64Cu-GTSM, a structural analog of 64Cu-ATSM (Fig. 1), exhibits elevated cerebral uptake in Alzheimer’s disease mouse models, yet immunohistochemical staining and autoradiographic analysis reveal no spatial colocalization with amyloid-β plaques.39,40 This distinctive targeting profile differentiates the radioligand from conventional Alzheimer's disease (AD) biomarkers focused on amyloid-β or tau pathology. Instead, this ligand provides insights into additional pathological factors, including alterations in cerebral copper homeostasis and mitochondrial dysfunction-induced hyper-reductive states. These factors have been proven crucial for evaluating disease progression and prognostic assessment. Hickey et al. successfully synthesized a hybrid thiosemicarbazone-pyridine hydrazone ligand that retains its inherent capacity for detecting over-reductive conditions while incorporating supplementary functional moieties capable of targeting Aβ plaques.41 In a recent study, Yoo et al. developed a fluorescent conjugate based on a bis(thiosemicarbazone) scaffold that utilizes the radioligand ⁶⁴Cu-ATSM-FITC (Fig. 1). This compound has been reported to be the first of its kind to enable in vivo imaging of endogenous H2S in live mouse brains, with the potential to diagnose neuroinflammation in murine models. In addition, both in vitro cellular studies and in vivo PET imaging investigations confirmed that the uptake of 64Cu-ATSM-FITC exhibits a positive correlation with H2S levels.42 The employment of alternative types of PET ligands, such as 18F-FASu (targeting the cystine/glutamate transporter),4318F-ROStrace (targeting superoxide)44 and 18F-FDHM (targeting reactive oxygen species),45 is also possible for evaluating redox status. Nevertheless, the radioligands above have thus far been confined to preclinical studies utilizing rodent models. Consequently, there is a need for systematic translational research to validate the diagnostic efficacy and therapeutic relevance of these approaches in human neurological disorders. Emerging MR imaging techniques, such as hyperpolarised ¹³C-MR spectroscopy46 and novel MR contrast agents47, 48, 49 (including paramagnetic nitroxide radicals and paramagnetic chemical exchange saturation transfer (CEST) agents), represent additional imaging modalities capable of assessing redox status and hypoxia. Compared with MR, PET demonstrates superior detection sensitivity at the nanomolar level. Consequently, multimodal imaging integrating PET and MR may represent a more promising direction for future research in this field.50

Accumulating preclinical evidence demonstrates the therapeutic potential of Cu(II)-ATSM in neurological disease models, which is attributed to its SOD1-mimetic antioxidant properties. Cu(II)-ATSM exhibits neuroprotective effects in ischemia-reperfusion injury models by mitigating lipid peroxidation and alleviating free radical-mediated tissue damage.51 Cu(II)-ATSM demonstrates therapeutic efficacy in SOD1 G93A transgenic mouse models by mitigating oxidative and nitrosative damage, attenuating TDP-43 proteinopathy, and reducing motor neuron degeneration, thereby ameliorating ALS symptom progression and prolonging survival duration.52,53 Spinal copper deficiency-induced accumulation of zinc-binding superoxide dismutase (SOD) is implicated in the progression of amyotrophic lateral sclerosis (ALS). Cu-ATSM serves as a copper chaperone capable of safely restoring CNS copper homeostasis, which significantly enhanced survival rates in SOD1G93A mice, demonstrating copper repletion as a critical therapeutic mechanism for mitigating motor neuron pathology in this model.54 Recent studies by Hilton et al. have highlighted that in sporadic ALS patients, the dysregulated expression of copper-handling genes impairs copper utilization, leading to a diminished activity of copper-dependent ferroxidases. This dysfunction suppresses the iron efflux capacity mediated by ceruloplasmin and its homologs. Cu-ATSM has been demonstrated to facilitate the safe transportation of copper to the central nervous system, thereby restoring the activity of Cu-dependent cytochrome c oxidase and providing an effective treatment for the motor neuron disease exhibited by SODG93A mice.55,56 Cu-ATSM exhibits potent scavenging activity against peroxynitrite (ONOO⁻), effectively inhibiting the nitration and oligomerization of α-synuclein. In various Parkinson’s disease animal models, this compound demonstrates therapeutic efficacy through the amelioration of motor and cognitive deficits, rescue of nigrostriatal neuronal loss, and normalization of dopaminergic metabolism.57 Subsequent whole-transcriptome sequencing analyses by Cheng et al. on substantia nigra samples from MPTP-lesioned mice demonstrated that Cu-ATSM administration restored the expression of 40 genes functionally associated with dopamine biosynthesis, calcium signaling cascades, and synaptic plasticity modulation.58 Southon et al. demonstrated that Cu-ATSM exerts anti-lipid peroxidation and anti-ferroptotic effects in both primary neuronal cultures and immortalized neuronal cell lines, suggesting that these actions may underlie its therapeutic efficacy in neurodegenerative disorders.59

The copper-bis(thiosemicarbazone) complex, Cu-ATSM, has also been reported to alleviate neuroinflammation. Specifically, Cu-ATSM demonstrates the capability to suppress activation states in both astrocytes and microglia,60 suggesting that glial cells may also be targeted for neuroprotection by Cu-ATSM. Choo et al.61 demonstrated that Cu-ATSM alleviates acute neuroinflammation induced by bacterial lipopolysaccharide (LPS) in mice. Further in vitro experiments revealed that its anti-inflammatory effects correlate with elevated copper levels and increased expression of the neuroprotective protein metallothionein-1 (MT1) in microglia and astrocytes.9 In cerebral ischemic tissues, Cu-ATSM reduces the proportion of infiltrating monocytes in lesioned areas, suppresses the secretion of associated inflammatory mediators, and protects endogenous microglia from neuroinflammatory damage.62 Joanna et al. constructed a chemical library of Cu-ATSM structural derivatives and demonstrated that treatment with these compounds downregulates the expression of pro-inflammatory cytokine genes. Furthermore, they reversed the detrimental effects of TNF-α and IFN-γ on the integrity and functionality of induced brain endothelial-like cell (iBEC) monolayers.63 Choo et al. subsequently reported a novel thiosemicarbazone-pyridylhydrazone copper(II) complex that reduces secretion of the pro-inflammatory cytokine monocyte chemoattractant protein-1 (MCP-1), suppresses tumor necrosis factor-α (TNF-α) expression, increases metallothionein-1 (MT1) levels, and modulates expression of Alzheimer’s disease-associated risk genes TREM2 and CD33.64 In a separate study, Pyun et al. demonstrated that Cu-ATSM and Cu-GTSM may regulate P-glycoprotein (P-gp) expression and function at the blood-brain barrier (BBB), potentially enhancing cerebral drug delivery and amyloid-β (Aβ) clearance.65

Two clinical trials (NCT03204929, NCT02870634) have analyzed the effects of Cu(II) ATSM in patients with Parkinson’s disease or amyotrophic lateral sclerosis/motor neuron disease.66 A recent histological analysis by Yang et al. of autopsy tissues from participants in the NCT02870634 trial concluded that no definitive evidence of attenuated neuropathological changes, including neuronal density and TDP-43 pathology, was observed in the limited cohort (6 Cu(II)-ATSM-treated vs. 6 untreated cases). However, significant reductions in neurons with TDP-43 pathology in the motor cortex and p62-expressing cells in the spinal cord were identified in this study.67,68 However, the findings of these studies are limited by the relatively small sample sizes employed, and the effects of Cu(II)-ATSM still require further substantiation. To validate the therapeutic efficacy of Cu(II)-ATSM in neurodegenerative diseases, further clinical and translational research is needed.