Common and Trace Metals in Alzheimer's and Parkinson's Diseases.

Trace elements and metals play critical roles in the normal functioning of the central nervous system (CNS), and their dysregulation has been implicated in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). In a healthy CNS, zinc, copper, iron, and manganese play vital roles as enzyme cofactors, supporting neurotransmission, cellular metabolism, and antioxidant defense. Imbalances in these trace elements can lead to oxidative stress, protein aggregation, and mitochondrial dysfunction, thereby contributing to neurodegeneration. In AD, copper and zinc imbalances are associated with amyloid-beta and tau pathology, impacting cognitive function. PD involves the disruption of iron and manganese levels, leading to oxidative damage and neuronal loss. Toxic metals, like lead and cadmium, impair synaptic transmission and exacerbate neuroinflammation, impacting CNS health. The role of aluminum in AD neurofibrillary tangle formation has also been noted. Understanding the roles of these elements in CNS health and disease might offer potential therapeutic targets for neurodegenerative disorders. The Codex Alimentarius standards concerning the mentioned metals in foods may be one of the key legal contributions to safeguarding public health. Further research is needed to fully comprehend these complex mechanisms and develop effective interventions.

The Relationships between Cerebrospinal Fluid Glial (CXCL12, CX3CL, YKL-40) and Synaptic Biomarkers (Ng, NPTXR) in Early Alzheimer's Disease.

In addition to amyloid and tau pathology in the central nervous system (CNS), inflammatory processes and synaptic dysfunction are highly important mechanisms involved in the development and progression of dementia diseases. In the present study, we conducted a comparative analysis of selected pro-inflammatory proteins in the CNS with proteins reflecting synaptic damage and core biomarkers in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). To our knowledge, no studies have yet compared CXCL12 and CX3CL1 with markers of synaptic disturbance in cerebrospinal fluid (CSF) in the early stages of dementia. The quantitative assessment of selected proteins in the CSF of patients with MCI, AD, and non-demented controls (CTRL) was performed using immunoassays (single- and multiplex techniques). In this study, increased CSF concentration of CX3CL1 in MCI and AD patients correlated positively with neurogranin (r = 0.74; p < 0.001, and r = 0.40; p = 0.020, respectively), ptau181 (r = 0.49; p = 0.040), and YKL-40 (r = 0.47; p = 0.050) in MCI subjects. In addition, elevated CSF levels of CXCL12 in the AD group were significantly associated with mini-mental state examination score (r = -0.32; p = 0.040). We found significant evidence to support an association between CX3CL1 and neurogranin, already in the early stages of cognitive decline. Furthermore, our findings indicate that CXCL12 might be a useful marker for tract severity of cognitive impairment.

Potential Utility of Cerebrospinal Fluid Glycoprotein Nonmetastatic Melanoma Protein B as a Neuroinflammatory Diagnostic Biomarker in Mild Cognitive Impairment and Alzheimer's Disease.

Alzheimer's disease (AD) is a very common neurodegenerative disorder characterized by the gradual loss of neurons and extracellular amyloid-peptide buildup. There is compelling evidence that the disease process depends on neuroinflammatory alterations, such as the activation of astrocytes and microglia cells. A transmembrane glycoprotein known as glycoprotein nonmetastatic melanoma protein B (GPNMB) plays a neuroprotective role during the development of neurodegeneration. To the best of our knowledge, this is the first investigation discussing the potential clinical usefulness of this protein in the AD continuum, especially in the MCI (mild cognitive impairment) stage. A total of 71 patients with AD or MCI as well as controls were enrolled in this study. The concentrations of GPNMB, YKL-40, Aß1-42 (amyloid beta 1-42), Tau, and pTau and the Aß1-42/1-40 ratio in the CSF (cerebrospinal fluid) were tested using immunological methods. The concentrations of both GPNMB and YKL-40 in the cerebrospinal fluid were significantly higher in patients with AD and MCI compared to the controls. Moreover, both proteins were biochemically associated with classical biomarkers of AD and were especially associated with the Aß1-42/1-40 ratio and Tau and pTau levels in the whole study group. Elevated concentrations of GPNMB were observed in the Aß(+) group of AD patients compared to the Aß(-) subjects. Additionally, the diagnostic performance (AUC value) of GPNMB was higher than that of amyloid ß1-42 in MCI patients compared with controls. Our study indicates that GPNMB might be a promising neuroinflammatory biomarker for the early diagnosis and prognosis of the AD continuum, with potential utility as a therapeutic target.

Molecular Aspects of a Diet as a New Pathway in the Prevention and Treatment of Alzheimer's Disease.

Alzheimer's disease is the most common cause of dementia in the world. Lack of an established pathology makes it difficult to develop suitable approaches and treatment for the disease. Besides known hallmarks, including amyloid ß peptides cumulating in plaques and hyperphosphorylated tau forming NFTs, inflammation also plays an important role, with known connections to the diet. In AD, adhering to reasonable nutrition according to age-related principles is recommended. The diet should be high in neuroprotective foods, such as polyunsaturated fatty acids, antioxidants, and B vitamins. In addition, foods capable of rising BDNF should be considered because of the known profitable results of this molecule in AD. Adhering to beneficial diets might result in improvements in memory, cognition, and biomarkers and might even reduce the risk of developing AD. In this review, we discuss the effects of various diets, foods, and nutrients on brain health and possible connections to Alzheimer's disease.

New Possibilities in the Therapeutic Approach to Alzheimer's Disease.

Despite the fact that Alzheimer's disease (AD) is the most common cause of dementia, after many years of research regarding this disease, there is no casual treatment. Regardless of the serious public health threat it poses, only five medical treatments for Alzheimer's disease have been authorized, and they only control symptoms rather than changing the course of the disease. Numerous clinical trials of single-agent therapy did not slow the development of disease or improve symptoms when compared to placebo. Evidence indicates that the pathological alterations linked to AD start many years earlier than a manifestation of the disease. In this pre-clinical period before the neurodegenerative process is established, pharmaceutical therapy might prove invaluable. Although recent findings from the testing of drugs such as aducanumab are encouraging, they should nevertheless be interpreted cautiously. Such medications may be able to delay the onset of dementia, significantly lowering the prevalence of the disease, but are still a long way from having a clinically effective disease-modifying therapy.

Comparative Analysis of Neurodegeneration and Axonal Dysfunction Biomarkers in the Cerebrospinal Fluid of Patients with Multiple Sclerosis.

BACKGROUND: Given the significant role of neurodegeneration in the progression of multiple sclerosis (MS) and insufficient therapies, there is an urgent need to better understand this pathology and to find new biomarkers that could provide important insight into the biological mechanisms of the disease. Thus, the present study aimed to compare different neurodegeneration and axonal dysfunction biomarkers in MS and verify their potential clinical usefulness. METHODS: A total of 59 patients, who underwent CSF analysis during their diagnostics, were enrolled in the study. Quantitative analysis of neurodegeneration biomarkers was performed through immunological tests. Oligoclonal bands were detected by isoelectric focusing on agarose gel, whereas the concentrations of immunoglobulins and albumin were measured using nephelometry. RESULTS: Our studies showed that NfL, RTN4, and tau protein enabled the differentiation of MS patients from the control group. Additionally, the baseline CSF NfL levels positively correlated with the tau and MRI results, whereas the RTN4 concentrations were associated with the immunoglobulin quotients. The AUC for NfL was the highest among the tested proteins, although the DeLong test of the ROC curves showed no significant difference between the AUCs for NfL and RTN4. CONCLUSION: The CSF NfL, RTN-4, and tau levels at the time of diagnosis could be potential diagnostic markers of multiple sclerosis, although NfL seems to have the best clinical value.

Molecular Biomarkers and Their Implications for the Early Diagnosis of Selected Neurodegenerative Diseases.

The degeneration and dysfunction of neurons are key features of neurodegenerative diseases (NDs). Currently, one of the main challenges facing researchers and clinicians is the ability to obtain reliable diagnostic tools that will allow for the diagnosis of NDs as early as possible and the detection of neuronal dysfunction, preferably in the presymptomatic stage. Additionally, better tools for assessing disease progression in this group of disorders are also being sought. The ideal biomarker must have high sensitivity and specificity, be easy to measure, give reproducible results, and reflect the disease progression. Molecular biomarkers include miRNAs and extracellular microvesicles known as exosomes. They may be measured in two extracellular fluids of the highest importance in NDs, i.e., cerebrospinal fluid (CSF) and blood. The aim of the current review is to summarize the pathophysiology of the four most frequent NDs-i.e., Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)-as well as current progress in the research into miRNAs as biomarkers in these major neurodegenerative diseases. In addition, we discuss the possibility of using miRNA-based therapies in the treatment of neurodegenerative diseases, and present the limitations of this type of therapy.

Inflammation in the CNS: Understanding Various Aspects of the Pathogenesis of Alzheimer's Disease.

Alzheimer's disease is a progressive and deadly neurodegenerative disorder and one of the most common causes of dementia globally. Current, insufficiently sensitive and specific methods of early diagnosing and monitoring this disease prompt a search for new tools. Numerous literature data have indicated that the pathogenesis of Alzheimer's disease (AD) is not limited to the neuronal compartment but involves various immunological mechanisms. Neuroinflammation has been recognized as a very important process in AD pathology. It seems to play pleiotropic roles, both neuroprotective and neurodegenerative, in the development of cognitive impairment depending on the stage of the disease. Mounting evidence demonstrates that inflammatory proteins could be considered biomarkers of disease progression. Therefore, the present review summarizes the role of some inflammatory molecules and their potential utility in detecting and monitoring dementia severity. This paper also provides a valuable insight into new mechanisms leading to the development of dementia, which might be useful in discovering possible anti-inflammatory treatment.

The Role of Gut Microbiota and Gut-Brain Interplay in Selected Diseases of the Central Nervous System.

The gut microbiome has attracted increasing attention from researchers in recent years. The microbiota can have a specific and complex cross-talk with the host, particularly with the central nervous system (CNS), creating the so-called "gut-brain axis". Communication between the gut, intestinal microbiota, and the brain involves the secretion of various metabolites such as short-chain fatty acids (SCFAs), structural components of bacteria, and signaling molecules. Moreover, an imbalance in the gut microbiota composition modulates the immune system and function of tissue barriers such as the blood-brain barrier (BBB). Therefore, the aim of this literature review is to describe how the gut-brain interplay may contribute to the development of various neurological disorders, combining the fields of gastroenterology and neuroscience. We present recent findings concerning the effect of the altered microbiota on neurodegeneration and neuroinflammation, including Alzheimer's and Parkinson's diseases, as well as multiple sclerosis. Moreover, the impact of the pathological shift in the microbiome on selected neuropsychological disorders, i.e., major depressive disorders (MDD) and autism spectrum disorder (ASD), is also discussed. Future research on the effect of balanced gut microbiota composition on the gut-brain axis would help to identify new potential opportunities for therapeutic interventions in the presented diseases.