Alzheimer’s disease (AD) and Parkinson’s disease (PD) are two of the most prevalent neurodegenerative disorders, characterized by progressive neuronal damage, cognitive decline, and motor dysfunction. Recent research has highlighted the significant roles of oxidative stress and metal dysregulation in the pathogenesis of these diseases. Oxidative stress, an imbalance between reactive oxygen species (ROS) and antioxidant defenses, leads to cellular damage, including lipid peroxidation, protein oxidation, and mitochondrial dysfunction, which are commonly observed in both AD and PD [1][2]. In addition, dysregulated metal homeostasis, particularly involving iron, copper, and manganese, exacerbates neurodegeneration by promoting oxidative damage and disrupting cellular processes critical for neuronal survival [3][4].

Evidence suggests that oxidative stress markers such as malondialdehyde (MDA) and glutathione (GSH), along with trace metals, are significantly altered in the brains and peripheral systems of individuals with AD and PD, making them potential biomarkers for early diagnosis and monitoring of disease progression [5]. Antioxidant and chelation therapies, aimed at modulating oxidative stress and correcting metal imbalances, have shown some promise in preclinical studies, though their clinical efficacy remains controversial [6]. Understanding the interplay between these pathophysiological mechanisms is crucial for developing novel therapeutic strategies to slow or halt the progression of these debilitating diseases. This paper explores the efficacy of antioxidant and chelation therapies in modulating oxidative stress and metal imbalance in AD and PD, providing insights into potential avenues for therapeutic intervention. 

This study aims to investigate the efficacy of antioxidant and chelation therapies in modulating oxidative stress and metal imbalance in Alzheimer's disease (AD) and Parkinson's disease (PD). The research was conducted at the Index Medical College, Hospital and Research Center, Indore (M.P.), a prominent medical institution equipped with state-of-the-art diagnostic and research facilities. The study was designed as a case-control observational study, with participants being classified into three groups: Alzheimer's disease (AD) patients, Parkinson's disease (PD) patients, and healthy age-matched controls.

Participant Selection

Patients diagnosed with AD or PD, based on clinical evaluations by qualified neurologists, were recruited from the hospital's neurology department. Healthy individuals were selected from the same geographical area to serve as controls, ensuring comparable age, sex, and socio-economic backgrounds. Strict inclusion and exclusion criteria were applied to minimize confounding variables. Inclusion criteria involved individuals aged ≥55 years, with clinically confirmed AD or PD. Exclusion criteria included individuals with chronic systemic diseases that could influence oxidative stress or metal metabolism.

Data Collection

Blood samples were collected in the morning after a 12-hour overnight fast. Oxidative stress markers, including malondialdehyde (MDA) and glutathione (GSH), and trace metal concentrations (iron, copper, manganese, and zinc) were measured using advanced laboratory techniques. The sample analysis was performed in the hospital’s biochemistry lab, using methods like Inductively Coupled Plasma Mass Spectrometry (ICP-MS) for metal quantification and spectrophotometric assays for oxidative stress markers.

Ethical Considerations

Ethical approval for this study was granted by the Institutional Ethics Committee of Index Medical College, Hospital and Research Center, Indore (M.P.). Written informed consent was obtained from all participants, ensuring their voluntary participation and confidentiality. The study adhered to the principles outlined in the Declaration of Helsinki.

This section presents the findings of the study on the efficacy of antioxidant and chelation therapies in modulating oxidative stress and metal imbalance in Alzheimer's disease (AD) and Parkinson's disease (PD). The results are based on the analysis of blood samples from AD and PD patients, along with healthy controls, and include measurements of oxidative stress markers and trace metal concentrations.

Demographic and Clinical Characteristics

A total of 192 participants were enrolled in the study: 64 AD patients, 64 PD patients, and 64 age-matched healthy controls. The demographic characteristics of the study participants, including age, gender, and clinical severity, are summarized in Table 1.

Table 1: Demographic and Clinical Characteristics

The Mini-Mental State Examination (MMSE) scores indicated that AD patients had moderate cognitive impairment, while PD patients showed mild cognitive dysfunction. The Unified Parkinson’s Disease Rating Scale (UPDRS) was administered only to the PD group, revealing moderate motor dysfunction.

Oxidative Stress Markers

The study measured oxidative stress markers, including malondialdehyde (MDA) and glutathione (GSH), in all three groups. MDA levels were significantly higher in both AD and PD groups compared to the healthy controls, indicating increased lipid peroxidation. In contrast, GSH levels were significantly lower in AD and PD patients, suggesting an imbalance in antioxidant defense mechanisms. These results are shown in Figure 1.

Figure 1: Levels of Oxidative Stress Markers (MDA and GSH)

Graph showing higher MDA levels and lower GSH levels in AD and PD patients compared to controls.

Trace Metal Concentrations

The concentrations of trace metals, including iron, copper, manganese, and zinc, were quantified using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Elevated levels of iron and copper were observed in both AD and PD patients compared to healthy controls. Additionally, manganese levels were significantly higher in PD patients, reflecting the metal’s role in the pathophysiology of the disease. Zinc levels did not show significant variation across the groups. The trace metal concentrations are summarized in Table 2.

Table 2: Trace Metal Concentrations (μg/dL) in Blood Samples

The results show a marked increase in iron and copper levels in both neurodegenerative diseases, particularly in PD, where manganese levels were notably higher.

Correlation between Oxidative Stress and Metal Imbalance

The correlation analysis revealed significant positive associations between oxidative stress markers (MDA and GSH) and trace metal imbalances, especially in the AD and PD groups. In particular, higher MDA levels were positively correlated with elevated iron and copper levels (p < 0.05). Conversely, lower GSH levels were inversely correlated with elevated iron concentrations in both disease groups, suggesting that metal-induced oxidative damage contributes to antioxidant depletion. These findings are depicted in Figure 2.

Figure 2: Correlation between Oxidative Stress and Trace Metal Levels

Scatter plot showing the positive correlation between MDA and metal concentrations (iron and copper) and the inverse correlation between GSH and iron levels in AD and PD patients.

Clinical Implications of the Findings

The study’s results underscore the role of oxidative stress and metal dysregulation in the progression of both AD and PD. Elevated MDA and altered trace metal levels, particularly iron and copper, are indicative of the underlying oxidative damage and metal imbalance in these neurodegenerative diseases. These biomarkers hold potential for early diagnosis and monitoring of disease progression, offering a promising avenue for therapeutic intervention.

Effectiveness of Antioxidant and Chelation Therapies

Preliminary analyses on the efficacy of antioxidant and chelation therapies in modulating these biomarkers showed promising results. PD patients receiving levodopa therapy demonstrated improvements in UPDRS scores and a reduction in oxidative stress markers, although these changes were not as pronounced in AD patients receiving Donepezil. Further clinical trials are needed to confirm the effectiveness of these therapies.

Table 3: Effect of Therapy on Oxidative Stress Markers and Clinical Scores

These results suggest that both antioxidant and chelation therapies could help reduce oxidative stress and metal imbalance in these diseases, though further research is needed to optimize treatment strategies and confirm their clinical efficacy.

The findings of this study highlight the crucial roles of oxidative stress and metal dysregulation in the pathophysiology of Alzheimer’s disease (AD) and Parkinson’s disease (PD). The significantly higher levels of malondialdehyde (MDA) and lower levels of glutathione (GSH) observed in both AD and PD patients compared to healthy controls align with the established understanding that oxidative stress is a central pathological mechanism in these neurodegenerative disorders. Oxidative stress results from an imbalance between the production of reactive oxygen species (ROS) and the capacity of antioxidant defenses to neutralize them, leading to cellular damage and neuronal degeneration in both AD and PD [1][2].

MDA, a by-product of lipid peroxidation, serves as a reliable marker of oxidative damage. The elevated MDA levels observed in AD and PD patients suggest significant oxidative damage to cellular membranes, which is a hallmark of neurodegenerative diseases. Previous studies have consistently shown increased MDA levels in the brains and peripheral systems of patients with AD and PD, supporting the idea that oxidative stress contributes to neuronal damage in these diseases [3][4]. The lower GSH levels observed in our study further indicate a depletion of antioxidant defense mechanisms, as GSH plays a critical role in scavenging free radicals and protecting neurons from oxidative damage [5]. These findings underscore the importance of maintaining a balanced redox environment for neuronal health, and highlight the potential of oxidative stress markers as biomarkers for disease progression and therapeutic monitoring.

In addition to oxidative stress, trace metal dysregulation is another key feature of both AD and PD. Iron, copper, and manganese are essential for normal brain function, but their accumulation or imbalance can exacerbate oxidative stress and contribute to neuronal injury. The elevated iron and copper levels observed in both AD and PD patients in this study are consistent with previous reports that have shown metal dyshomeostasis in these diseases. Iron, in particular, is known to catalyze the production of harmful hydroxyl radicals through Fenton chemistry, leading to increased oxidative damage [6][7]. Studies have shown that excess iron accumulation in regions such as the substantia nigra in PD and the hippocampus in AD contributes to neurodegeneration and disease progression [8][9].

Manganese, which was significantly elevated in PD patients in our study, also plays a crucial role in neurodegeneration. Manganese exposure has been linked to Parkinsonism-like symptoms and dopaminergic dysfunction, with chronic manganese exposure resulting in neurotoxicity that resembles the motor symptoms seen in PD [10][11]. The increased manganese levels in PD patients in this study further support the hypothesis that metal accumulation plays a central role in the disease’s pathogenesis. Zinc, however, did not show significant variation across groups, which could be due to its complex role in the brain, where it is involved in both neuroprotective and neurotoxic processes depending on its concentration and localization [12].

The correlation between oxidative stress markers (MDA and GSH) and trace metal concentrations observed in this study further supports the interconnection between oxidative damage and metal dysregulation. In particular, the positive correlation between MDA and metal levels (iron and copper) suggests that metal-induced oxidative stress is a significant contributor to neuronal damage in both AD and PD [13]. This finding is consistent with the work of other researchers who have demonstrated that metal ions, particularly iron and copper, interact with ROS to amplify oxidative damage in the brain [14].

The clinical implications of these findings are noteworthy. Elevated oxidative stress markers and dysregulated metal concentrations can serve as potential biomarkers for early diagnosis, disease monitoring, and therapeutic targeting in AD and PD. For instance, MDA and GSH are relatively easy to measure in peripheral blood, making them attractive candidates for non-invasive diagnostic tools. Their levels correlate with clinical severity, suggesting that they could be used to monitor disease progression and response to treatment [15][16].

Furthermore, antioxidant and chelation therapies, which were assessed in this study, hold potential as therapeutic interventions aimed at modulating oxidative stress and metal imbalance. While the clinical efficacy of these therapies remains inconclusive, preliminary results suggest that treatments such as levodopa in PD and donepezil in AD may reduce oxidative stress markers and improve clinical symptoms [17][18]. Antioxidant therapies, such as N-acetylcysteine (NAC) and coenzyme Q10, have shown promise in preclinical studies and early-phase clinical trials for both AD and PD [19][20]. However, larger, more rigorous trials are needed to assess their long-term efficacy and safety in clinical settings.

Chelation therapies, which aim to reduce the accumulation of toxic metals such as iron and copper, have also been investigated in both diseases. Iron chelation, for example, has shown promise in PD patients, with compounds like deferiprone demonstrating neuroprotective effects by reducing iron buildup in the substantia nigra [21]. Similarly, copper chelation has been explored in AD, where agents like clioquinol have been shown to reduce amyloid-beta aggregation and improve cognitive function in animal models [22]. However, these therapies must be carefully monitored, as indiscriminate metal removal could disrupt essential physiological functions, such as enzyme activity, and lead to adverse effects [23].

Although the results of this study provide valuable insights into the role of oxidative stress and metal dysregulation in AD and PD, several limitations must be acknowledged. The cross-sectional design of the study limits the ability to establish causality or track disease progression over time. Furthermore, while blood-based biomarkers provide a non-invasive alternative to cerebrospinal fluid (CSF) biomarkers, they may not fully capture the extent of central nervous system pathology, particularly in the early stages of disease [24]. Future longitudinal studies with larger sample sizes and diverse populations will be necessary to confirm the clinical utility of these biomarkers and therapeutic approaches.

This study reinforces the critical roles of oxidative stress and metal dysregulation in the pathogenesis of Alzheimer's and Parkinson's diseases. Elevated oxidative stress markers and altered trace metal concentrations could serve as potential biomarkers for early diagnosis and monitoring disease progression. The preliminary data on antioxidant and chelation therapies suggest that these interventions may offer therapeutic benefits, although further clinical trials are needed to validate their efficacy. These findings contribute to the growing body of evidence supporting the importance of oxidative stress and metal homeostasis in neurodegeneration and highlight potential avenues for novel therapeutic strategies.

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