Nose to Brain Delivery of Curcumin Loaded Therapeutic Nanostructures for Neurodegenerative Diseases.

Dementia with Lewy bodies (DLB) is a neuropsychiatric disease associated with extrapyramidal features which differ from those of Parkinson's disease, including reduced effectiveness of L-dopa and severe sensitivity reactions to neuroleptic drugs. Distinguishing Alzheimer's disease from DLB is clinically relevant in terms of prognosis and appropriate treatment. Dopaminergic activities have been investigated at coronal levels along the rostrocaudal striatal axis from a post-mortem series of 25 DLB, 14 Parkinson's disease and 17 Alzheimer's disease patients and 20 elderly controls. [(3)H]Mazindol binding to the dopamine uptake site was significantly reduced in the caudal putamen in DLB compared with controls (57%), but not as extensively as in Parkinson's disease (75%), and was unchanged in Alzheimer's disease. Among three dopamine receptors measured (D1, D2 and D3), the most striking changes were apparent in relation to D2. In DLB, [(3)H]raclopride binding to D2 receptors was significantly reduced in the caudal putamen (17%) compared with controls, and was significantly lower than in Parkinson's disease at all levels. D2 binding was significantly elevated at all coronal levels in Parkinson's disease compared with controls, most extensively in the rostral putamen (71%). There was no change from the normal pattern of D2 binding in Alzheimer's disease. The only significant alteration in D1 binding ([(3)H]SCH23390) in the groups examined was an elevation (30%) in the caudal striatum in Parkinson's disease. There were no differences in D3 binding, measured using [(3)H]7-OH-DPAT, in DLB compared with controls. A slight, significant decrease in D3 binding in the caudal striatum of Parkinson's disease (13%) patients and an increase in Alzheimer's disease (20%) in the dorsal striatum at the level of the nucleus accumbens were found. The concentration and distribution of dopamine were disrupted in both DLB and Parkinson's disease, although in the caudate nucleus the loss of dopamine in DLB was uniform whereas in Parkinson's disease the loss was greater caudally. In the caudal putamen, dopamine was reduced by 72% in DLB and by 90% in Parkinson's disease. The homovanillic acid : dopamine ratio, a metabolic index, indicated compensatory increased turnover in Parkinson's disease, which was absent in DLB despite the loss of substantia nigra neurons (49%), dopamine and uptake sites. These differences between DLB, Parkinson's disease and Alzheimer's disease may explain some characteristics of the extrapyramidal features of DLB and its limited response to L-dopa and severe neuroleptic sensitivity. The distinct changes in the rostrocaudal pattern of expression of dopaminergic parameters are relevant to the interpretation of the in vivo imaging and diagnosis of DLB.

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease (AD). Early differentiation of these disorders is crucial for managing core symptoms; however, existing biomarkers remain insufficient. DLB shares motor and cognitive symptoms with Parkinson's disease (PD), and both are classified as synucleinopathies due to abnormal α-synuclein aggregation. Although α-synuclein is predominantly expressed in the central nervous system, it is also abundant in erythrocytes. Recent studies suggest a potential link between erythrocyte-derived α-synuclein and synucleinopathy pathology. Additionally, we previously reported that both erythrocytes and circulating medium and large extracellular vesicles (m/lEVs) in plasma from healthy subjects contain full-length and C-terminally truncated α-synuclein. In this study, we found that erythrocyte α-synuclein levels were significantly lower in DLB compared to AD, PD and healthy controls. Furthermore, α-synuclein levels in circulating m/lEVs were elevated in patients with neurodegenerative diseases. These findings provide new insights into the role of peripheral α-synuclein and suggest its potential utility as a diagnostic marker for DLB. While further validation is needed, erythrocyte-derived α-synuclein may complement nuclear medicine assessments in distinguishing DLB from other neurodegenerative disorders.

Many diverse human diseases are associated with protein aggregation in ordered fibrillar structures called amyloid. Amyloid formation may mediate aberrant protein interactions that culminate in neurodegeneration in Alzheimer, Huntington, and Parkinson diseases and in prion encephalopathies. Studies of protein aggregation in the brain are hampered by limitations in imaging techniques and often require invasive methods that can only be performed postmortem. Here we describe transgenic mice in which aggregation-prone proteins that cause Huntington and Parkinson disease are expressed in the ocular lens. Expression of a mutant huntingtin fragment or alpha-synuclein in the lens leads to protein aggregation and cataract formation, which can be monitored in real time by noninvasive, highly sensitive optical techniques. Expression of a mutant huntingtin fragment in mice lacking the major lens chaperone, alphaB-crystallin, markedly accelerated the onset and severity of aggregation, demonstrating that the endogenous chaperone activity of alphaB-crystallin suppresses aggregation in vivo. These novel mouse models will facilitate the characterization of protein aggregation in vivo and are being used in efficient and economical screens for chemical and genetic modifiers of disease-relevant protein aggregation.

Neurodegenerative diseases represent a formidable global health challenge, affecting millions and imposing substantial burdens on healthcare systems worldwide. Conditions, like Alzheimer's, Parkinson's, and Huntington's diseases, among others, share common characteristics, such as neuronal loss, misfolded protein aggregation, and nervous system dysfunction. One of the major obstacles in treating these diseases is the presence of the blood-brain barrier, limiting the delivery of therapeutic agents to the central nervous system. Nanotechnology offers promising solutions to overcome these challenges. In Alzheimer's disease, NPs loaded with various compounds have shown remarkable promise in preventing amyloid-beta (Aβ) aggregation and reducing neurotoxicity. Parkinson's disease benefits from improved dopamine delivery and neuroprotection. Huntington's disease poses its own set of challenges, but nanotechnology continues to offer innovative solutions. The promising developments in nanoparticle-based interventions for neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), have offered new avenues for effective treatment. Nanotechnology represents a promising frontier in biomedical research, offering tailored solutions to the complex challenges posed by neurodegenerative diseases. While much progress has been made, ongoing research is essential to optimize nanomaterial designs, improve targeting, and ensure biocompatibility and safety. Nanomaterials possess unique properties that make them excellent candidates for targeted drug delivery and neuroprotection. They can effectively bypass the blood-brain barrier, opening doors to precise drug delivery strategies. This review explores the extensive research on nanoparticles (NPs) and nanocomposites in diagnosing and treating neurodegenerative disorders. These nanomaterials exhibit exceptional abilities to target neurodegenerative processes and halt disease progression.

The Role of NAC in Amyloidogenesis in Alzheimer's Disease

Metal welding produces gaseous fumes that contain manganese, resulting in potential occupational exposure to welders. It has been hypothesized that occupational exposure among welders could increase risk of Parkinson's disease and other neurodegenerative diseases. The present study examines welding occupation and mortality from neurodegenerative diseases among men in the United States using the National Cause of Death databases 1985 to 1999. Information was abstracted from death certificates for states that collected data on occupation. Of 4,252,490 men who died during the study period, 107,773 had welding-related occupations. Multivariable logistic regression models were used to calculate mortality odds ratios (MOR) and 95% confidence intervals (CI) for odds of dying from Parkinson's disease or other neurodegenerative diseases among men who were welders as compared with men of other occupations, adjusting for attained age, race, region of residence, and year of death. During the study period, 49,174 deaths were attributed to Parkinson's disease, 54,892 to Alzheimer's disease, and 19,018 to presenile dementia. There was no evidence of an increased odds of Parkinson's disease mortality among welders as compared with men with other occupations (MOR = 0.83, 95% CI 0.78–0.88). Furthermore, welding occupation was unrelated to the odds of mortality from Alzheimer's disease (MOR = 0.94, 95% CI 0.89–1.00) or presenile dementia (MOR = 0.96, 95% CI 0.87–1.06). Earlier research suggested that welding exposures could predispose individuals to earlier onset Parkinson's disease. However, there was no evidence in this data of an increased mortality odds ratio associated with welding occupations among men younger than 65 (MOR = 1.03, 95% CI 0.74–1.44); while there was a suggestion of a lower odds Parkinson's disease death among men age 65 years and older (MOR = 0.82, 95% CI 0.77–0.88). Data from this large study do not support an association between welding occupations and death from Parkinson's disease or other neurodegenerative diseases, nor that welders are at increased odds of dying from Parkinson's disease at a younger age.

Vagus Nerve Stimulation (VNS) has been approved by the FDA as a treatment for epilepsy, depression, post-ischemic stroke rehabilitation, and migraine in patients. It is emerging as a potential treatment for neurodegenerative diseases. Herein, we summarize the research on VNS and its application in common neurodegenerative diseases. A literature search was completed in PubMed, ScienceDirect, and Google Scholar using the terms: "neurodegeneration," "neuromodulation," "Vagus Nerve Stimulation," "Parkinson's Disease (PD)," "Alzheimer's Disease (AD)," "dementia," "neuroinflammation," and "cognitive dysfunction." Animal and clinical studies using VNS as a primary intervention in neurodegenerative diseases were included. The studies of VNS application in Parkinson's and Alzheimer's models were reviewed. In animal studies, VNS was associated with increased locomotion and balance, as well as reduced cognitive impairments. The underlying neuroprotective mechanisms included: increased dopaminergic neurons, reduced α-synuclein concentration in the brain, preservation of the nigrostriatal dopaminergic pathway, increased α7nAChR expression, reduced apoptotic markers, reduced neuroinflammation, and significant reductions in microglial and astrocytic densities. In clinical studies with small patient populations of PD or AD/mild cognitive impairment, VNS was associated with improved gait parameters and enhanced performance in memory-based tasks. Vagus Nerve Stimulation (VNS) shows neuroprotective and anti-inflammatory effects in animal models of Alzheimer's and Parkinson's disease, but clinical results remain inconsistent due to variability in treatment duration, outcome measures, and reliance on subjective assessments. Emerging physiologic biomarkers such as VSEP, EEG, and magnetoencephalography may provide more objective measures of therapeutic response. The systematic review highlights the potential of VNS as a therapeutic approach for managing neurodegenerative diseases. The efficacy of VNS in animal models of Parkinson's and Alzheimer's diseases involves both neuroprotection and anti-neuroinflammation, while additional protective mechanisms require further exploration.

POLICY PAPER - COST Exploratory Workshop on Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU

Editorial???Behavioural Aspects of Neurodegeneration and Neuroprotection

940. Neuroprotective Effects of XIAP Gene Therapy in Models of Neurodegenerative Diseases

Identification of MOAG-4/SERF as a Regulator of Age-Related Proteotoxicity

Anomalies occurring in lipid profiles and protein distribution in frontal cortex lipid rafts in dementia with Lewy bodies disclose neurochemical traits partially shared by Alzheimer's and Parkinson's diseases

MicroRNAs (miRNA) are small noncoding RNAs that play a significant role in the regulation of gene expression. The literature has explored the key involvement of miRNAs in the diagnosis, prognosis, and treatment of various neurodegenerative diseases (NDD), such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). The miRNA regulates various signalling pathways; its dysregulation is involved in the pathogenesis of NDD. The present review is focused on the involvement of miRNAs in the pathogenesis of NDD and their role in the treatment or management of NDD. The literature provides comprehensive and cutting-edge knowledge for students studying neurology, researchers, clinical psychologists, practitioners, pathologists, and drug development agencies to comprehend the role of miRNAs in the NDD's pathogenesis, regulation of various genes/signalling pathways, such as α-synuclein, P53, amyloid-β, high mobility group protein (HMGB1), and IL-1β, NMDA receptor signalling, cholinergic signalling, etc. Methods: The issues associated with using anti-miRNA therapy are also summarized in this review. The data for this literature were extracted and summarized using various search engines, such as Google Scholar, Pubmed, Scopus, and NCBI using different terms, such as NDD, PD, AD, HD, nanoformulations of mRNA, and role of miRNA in diagnosis and treatment. The miRNAs control various biological actions, such as neuronal differentiation, synaptic plasticity, cytoprotection, neuroinflammation, oxidative stress, apoptosis and chaperone-mediated autophagy, and neurite growth in the central nervous system and diagnosis. Various miRNAs are involved in the regulation of protein aggregation in PD and modulating β-secretase activity in AD. In HD, mutation in the huntingtin (Htt) protein interferes with Ago1 and Ago2, thus affecting the miRNA biogenesis. Currently, many anti-sense technologies are in the research phase for either inhibiting or promoting the activity of miRNA. This review provides new therapeutic approaches and novel biomarkers for the diagnosis and prognosis of NDDs by using miRNA.

Use of Risperidone in Psychosis Associated With Huntington's Disease

Parkinson's and Alzheimer's diseases are widespread neurodegenerative pathologies. Parkinson's disease affects about 1% of the population over the age of 65years, while Alzheimer is considered the most common cause of dementia, with an annual incidence of 1% in persons aged 65years. It has been demonstrated that both these neurodegenerative diseases are associated with smell dysfunction. The aim of the present review is to describe briefly modern olfactory evaluation tools as well as the importance of olfactory sensitivity screening in the elderly, especially where cognitive disorders, such as Alzheimer's or Parkinson's diseases, are suspected. A brief literature review focusing on the basic principle of smell tests is illustrated together with their application in elderly patients affected by cognitive disorders, in particular Parkinson's and Alzheimer's diseases. Alzheimer's and Parkinson's diseases are both neurodegenerative disorders typically found in the elderly. As both diseases are characterized by the early presence of dysosmia, simple validated smell tests could very well help clinicians in the early diagnosis of these neuropathological conditions. Elderly patients complaining of smell loss and found to be dysosmic, by means of validated olfactory tests, should be neurologically evaluated as early as possible to detect slight motor abnormalities in an at-risk population.