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Neurodegenerative diseases (NDs) and Long COVID represent critical and growing global health challenges, characterized by complex pathophysiological mechanisms including neuronal deterioration, protein misfolding, and persistent neuroinflammation. The emergence of innovative therapeutic approaches, such as whole-body hyperthermia (WBH), offers promising potential to modulate underlying pathophysiological mechanisms in NDs and related conditions like Long COVID. WBH, particularly in fever-range, enhances mitochondrial function, induces heat shock proteins (HSPs), and modulates neuroinflammation—benefits that pharmacological treatments often struggle to replicate. HSPs such as HSP70 and HSP90 play pivotal roles in protein folding, aggregation prevention, and cellular protection, directly targeting pathological processes seen in NDs like Alzheimer's, Parkinson's, and Huntington's disease. Preliminary findings also suggest WBH's potential to alleviate neurological symptoms in Long COVID, where persistent neuroinflammation and serotonin dysregulation are prominent. Despite the absence of robust clinical trials, the therapeutic implications of WBH extend to immune modulation and the restoration of disrupted physiological pathways. However, the dual nature of hyperthermia's effects—balancing pro-inflammatory and anti-inflammatory responses—emphasizes the need for dose-controlled applications and stringent patient monitoring to minimize risks in vulnerable populations. While WBH shows potential interest, significant challenges remain. These include individual variability in response, limited accessibility to advanced hyperthermia technologies, and the need for standardized clinical protocols. Future research must focus on targeted clinical trials, biomarker identification, and personalized treatment strategies to optimize WBH's efficacy in NDs and Long COVID. The integration of WBH into therapeutic paradigms could mark a transformative step in addressing these complex conditions. [ABSTRACT FROM AUTHOR]

Protein misfolding, aggregation, and aberrant aggregate accumulation play a central role in neurodegenerative disease progression. The proteotoxic factors also govern the aging process to a large extent. Molecular chaperones modulate proteostasis and thereby impact aberrant-protein-induced proteotoxicity. These chaperones have a diverse functional spectrum, including nascent protein folding, misfolded protein sequestration, refolding, or degradation. Small heat shock proteins (sHsps) possess an ATP-independent chaperone-like activity that prevents protein aggregation by keeping target proteins in a folding-competent state to be refolded by ATP-dependent chaperones. Due to their near-universal upregulation and presence in sites of proteotoxic stress like diseased brains, sHsps were considered pathological. However, gene knockdown and overexpression studies have established their protective functions. This review provides an updated overview of the sHsp role in protein aggregation amelioration and highlights evidence for sHsp modulation of neurodegenerative disease-related protein aggregation and aging. [ABSTRACT FROM AUTHOR]

Background: This study focuses on the investigation of the antioxidant and anti-inflammatory activities of alcohol extracts from Ribes nigrum leaves on murine BV-2 microglial Wt and Acyl-CoA oxidase 1 deficient (Acox1−/−) cell line models, useful for the investigation of some neurodegenerative disorders. Methods: The extract chemical composition was analyzed via LC-Q-Orbitrap HRMS. Various assays, including DPPH, MTT, and H2DCFDA, were used to assess the extract's antioxidant capacity, cell viability, and reactive oxygen species (ROS) production. Immunoblotting and RT-qPCR techniques were employed to measure protein expression and gene transcription in treated cells. Statistical analysis was conducted using GraphPad Prism, with significance determined at p < 0.05. Results: Investigations showed the presence of phenolic compounds in this extract, among which flavan-3-ols, flavonols, furanocoumarins, hydroxycinnamates were major components, which are known for their biological activity in various test systems. The MTT test revealed a concentration of 0.125 mg/mL of R. nigrum extract as the highest non-toxic. The investigated extract showed high antioxidant activity in chemical-based tests. The antioxidant potential of the R. nigrum leaf extract was furtherly explored using the BV-2 microglial cell line models. Moreover, the extract was found to alter the activity of the main antioxidant enzyme, catalase and fatty acid oxidation enzyme, Acyl-CoA oxidase 1 (ACOX1) as well as the expression of appropriate genes in Wt and Acox1−/− BV-2 microglial cells such as Cat, iNos, Il-1β, Tnf-α, and Abcd1. In Wt cells, after the 24-hour treatment with R. nigrum leaf extract, ACOX1 activity was downregulated, meanwhile the catalase activity remains unchanged. Further treatment led to the downregulation of catalase and the upregulation of ACOX1 activity. However, in Acox1−/− cells, which represent a model of oxidative stress, an increase in catalase activity was observed only after 48 h of treatment. It was also observed the reduced ROS and NO formation in cells, showing the pronounced antioxidant capacity of R. nigrum extract in the investigated cell-models. Conclusion: Our study demonstrated the protective effects of R. nigrum leaf extracts on BV-2 microglial cells by reducing oxidative and nitrosative stress, decreasing pro-inflammatory gene expression, and normalizing peroxisomal function, highlighting the potential of these extracts as therapeutic agents for managing oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

Plasma phosphorylated-tau217 (p-tau217) has been shown to be one of the most accurate diagnostic markers for Alzheimer's disease. No studies have compared the clinical performance of p-tau217 as assessed by the fully automated Lumipulse and single molecule array (SIMOA) AlZpath p-tau217. The study included 392 participants, 162 with Alzheimer's disease, 70 with other neurodegenerative diseases with CSF biomarkers and 160 healthy controls. Plasma p-tau217 levels were measured using the Lumipulse and ALZpath SIMOA assays. The ability of p-tau217 assessed by both techniques to discriminate Alzheimer's disease from other neurodegenerative diseases and controls was investigated using receiver operating characteristic analyses. The p-tau217 levels measured by the two techniques demonstrated a strong correlation, showing a consistent relationship with CSF p-tau181 levels. In head-to-head comparison, Lumipulse and SIMOA showed similar diagnostic accuracy for differentiating Alzheimer's disease from other neurodegenerative diseases [area under the curve (AUC) 0.952, 95% confidence interval (CI) 0.927–0.978 versus 0.955, 95% CI 0.928–0.982, respectively] and healthy controls (AUC 0.938, 95% CI 0.910–0.966 and 0.937, 95% CI 0.907–0.967 for both assays). This study demonstrated the high precision and diagnostic accuracy of p-tau217 for the clinical diagnosis of Alzheimer's disease using fully automated or semi-automated techniques. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) and osteoporosis (OP) pose distinct but interconnected health challenges, both significantly impacting the aging population. AD, a neurodegenerative disorder characterized by memory impairment and cognitive decline, is primarily associated with the accumulation of abnormally folded amyloid beta (Aβ) peptides and neurofibrillary tangles in the brain. OP, a skeletal disorder marked by low bone mineral density, involves dysregulation of bone remodeling and is associated with an increased risk of fractures. Recent studies have revealed an intriguing link between AD and OP, highlighting shared pathological features indicative of common regulatory pathophysiological pathways. In this article, we elucidate the signaling mechanisms that regulate the pathology of AD and OP and offer insights into the intricate network of factors contributing to these conditions. We also examine the role of bone-derived factors in the progression of AD, underscoring the plausibility of bidirectional communication between the brain and the skeletal system. The presence of amyloid plaques in the brain of individuals with AD is akin to the accumulation of brain Aβ in vascular dementia, pointing towards the need for further investigation of shared molecular mechanisms. Moreover, we discuss the role of bone-derived microRNAs that may regulate the pathological progression of AD, providing a novel perspective on the role of skeletal factors in neurodegenerative diseases. The insights presented here should help researchers engaged in exploring innovative therapeutic approaches targeting both neurodegenerative and skeletal disorders in aging populations. [ABSTRACT FROM AUTHOR]

Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well-characterized. The cannabinoid receptor type 1 (CB1) is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2) in the brain and spinal cord of healthy individuals are relatively low. However, recent studies demonstrated a CB2 upregulation on activated microglia upon neuroinflammation, an indicator of neurodegeneration. Our research group aims to develop a suitable positron emission tomography (PET) tracer to visualize the CB2 receptor in patients suffering from neurodegenerative diseases. Herein we report two novel thiophene-based 11C-labeled PET ligands designated [11C]AAT-015 and [11C]AAT-778. The reference compounds were synthesized using Gewald reaction conditions to obtain the aminothiophene intermediates, followed by amide formation. Saponification of the esters provided their corresponding precursors. Binding affinity studies revealed Ki-values of 3.3 ± 0.5 nM (CB2) and 1.0 ± 0.2 μM (CB1) for AAT-015. AAT-778 showed similar Ki-values of 4.3 ± 0.7 nM (CB2) and 1.1 ± 0.1 μM (CB1). Radiosynthesis was carried out under basic conditions using [11C]iodomethane as methylating agent. After semi-preparative HPLC purification both radiolabeled compounds were obtained in 99% radiochemical purity and the radiochemical yields ranged from 12 to 37%. Specific activity was between 96 and 449 GBq/μmol for both tracers. In order to demonstrate CB2 specificity of [11C]AAT-015 and [11C]AAT-778, we carried out autoradiography studies using CB2-positive mouse/rat spleen tissues. The obtained results revealed unspecific binding in spleen tissue that was not blocked by an excess of CB2-specific ligand GW402833. For in vivo analysis, [11C]AAT-015 was administered to healthy rats via tail-vein injection. Evaluation of the CB2-positive spleen, however, showed no accumulation of the radiotracer. Despite the promising in vitro binding affinities, specific binding of [11C]AAT-015, and [11C]AAT-778 could not be demonstrated. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) crucial for regulating gene expression at the post-transcriptional level. Recent evidence has shown that miRNAs are also found in mitochondria, organelles that produce energy in the cell. These mitochondrial miRNAs, also known as mitomiRs, are essential for regulating mitochondrial function and metabolism. MitomiRs can originate from the nucleus, following traditional miRNA biogenesis pathways, or potentially from mitochondrial DNA, allowing them to directly affect gene expression and cellular energy dynamics within the mitochondrion. While miRNAs have been extensively investigated, the function and involvement of mitomiRs in the development of neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis remain to be elucidated. This review aims to discuss findings on the role of mitomiRs in such diseases and their potential as therapeutic targets, as well as to highlight future research directions. [ABSTRACT FROM AUTHOR]

Background/Objectives: Parkinson's disease (PD) is a neurodegenerative disorder that significantly impairs motor function, leading to mobility challenges and an increased risk of falls. Current assessment tools often inadequately measure the complexities of motor impairments associated with PD, highlighting the need for a reliable tool. This study introduces the Motor Assessment Timed Test (MATT), designed to assess functional mobility in PD patients. Methods: A cross-sectional study was conducted involving 57 participants (38 men and 19 women) aged 44 to 84, diagnosed with idiopathic PD. Participants were recruited from three PD associations and underwent a series of assessments, including MATT, to evaluate gait, balance, and dual-task performance under conditions that reflect real-life challenges faced by individuals with PD. Results: MATT demonstrated excellent reliability with intra-rater reliability (ICC = 0.99), inter-rater reliability (ICC = 0.96–0.99), and test–retest reliability (ICC = 0.93–0.99). The coefficient of variation for total time and each segment ranged from 4.73% to 13.71%, indicating consistent performance across trials. The concurrent validity showed very high correlations with established tools such as the Timed Up and Go (TUG) test (ρ = 0.86, p < 0.001) and the Berg Balance Scale (BBS) (ρ = −0.83, p < 0.001), among others. Only 7.3% of participants reported difficulties in understanding the MATT, predominantly those in advanced stages of the disease. In addition, 23.6% of participants experienced significant challenges in performing the test, particularly individuals with lower Mini-Mental State Examination (MMSE) scores (≤ 26) and more advanced disease progression. Conclusions: MATT is a promising tool for assessing motor complications in PD, offering a comprehensive evaluation of functional mobility. Its implementation in clinical practice could enhance the management of PD, facilitating tailored interventions and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Observational studies suggested a potential correlation between dietary intake and amyotrophic lateral sclerosis (ALS), but conflicting findings exist and causality remains unclear. Here, we performed a Mendelian randomization (MR) analysis to evaluate the causal impact of relative intake of (i) carbohydrate, (ii) fat, and (iii) protein on ALS risk. Methods: The genome-wide association summary statistics of three dietary macronutrient intake traits and ALS were obtained. Initially, forward and reverse univariable MR (UVMR) analysis were conducted using the inverse variance weighted (IVW) method as the primary approach, supplemented by MR-Egger, weighted median, and maximum likelihood. Subsequently, multivariable MR (MVMR) analysis was performed to assess the independent causal effects of each dietary. Additionally, diverse sensitivity tests were conducted to evaluate the reliability of the MR analyses. Results: The forward UVMR analysis conducted by IVW indicated that relative carbohydrate intake significantly increased ALS risk. Furthermore, results from three other MR methods paralleled those from IVW. However, the other two dietary intake traits did not have a causative impact on ALS risk. The reverse UVMR analysis indicated that ALS did not causatively influence the three dietary intake traits. The MVMR analysis showed that after adjusting for the effects of the other two dietary intake traits, relative carbohydrate intake independently and significantly increased ALS risk. Sensitivity tests indicated no significant heterogeneity or horizontal pleiotropy. Discussion: MR analysis supported relative carbohydrate independently increasing ALS risk. Nevertheless, further validation of this finding in future large cohorts is required. [ABSTRACT FROM AUTHOR]

Objectives: Our systematic review and meta-analysis aimed to uncover the relationship between UPFs intake and neurodegenerative disorders, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), cognitive impairment, and dementia. Setting: A systematic search was conducted using the Scopus, PubMed/MEDLINE, and ISI Web of Science databases without any limitation until June 24, 2023. Relative risk (RR) and 95% confidence interval (CI) were pooled by using a random-effects model, while validated methods examined quality and publication bias via Newcastle-Ottawa Scale, Egger's regression asymmetry, and Begg's rank correlation tests, respectively. Results: Analysis from 28 studies indicated that a higher UPFs intake was significantly related to an enhanced risk of MS (RR = 1.15; 95% CI: 1.00, 1.33; I2 = 37.5%; p = 0.050; n = 14), PD (RR = 1.56; 95% CI: 1.21, 2.02; I2 = 64.1%; p = 0.001; n = 15), and cognitive impairment (RR = 1.17; 95% CI: 1.06, 1.30; I2 = 74.1%; p = 0.003; n = 17), although not AD or dementia. We observed that a 25 g increment in UPFs intake was related to a 4% higher risk of MS (RR = 1.04; 95% CI: 1.01, 1.06; I2 = 0.0%; p = 0.013; n = 7), but not PD. The non-linear dose–response relationship indicated a positive non-linear association between UPF intake and the risk of MS (Pnonlinearity = 0.031, Pdose-response = 0.002). This association was not observed for the risk of PD (Pnonlinearity = 0.431, Pdose-response = 0.231). Conclusion: These findings indicate that persistent overconsumption of UPFs may have an adverse impact on neurodegenerative conditions, potentially leading to a decline in quality of life and reduced independence as individuals age. [ABSTRACT FROM AUTHOR]

Background Due to the ability of metal ions to cross the blood–brain barrier, there has been interest in analyzing cerebrospinal fluid (CSF) for trace element concentrations to investigate possible correlations with neurodegenerative diseases. In this study, Sarstedt polypropylene CSF collection tubes were analyzed to determine the contamination levels of aluminum, titanium, chromium, manganese, cobalt, nickel, molybdenum, gadolinium, vanadium, arsenic, cadmium, mercury, lead, thallium, selenium, copper, zinc, and iron. Methods Sarstedt polypropylene CSF collection tubes from 2 separate lots (n = 10 per lot) were filled with a 2 mL aliquot of a CSF pool with known element concentrations. After 24 hours of leaching at room temperature, all 18 elements were analyzed via inductively coupled plasma mass spectrometry (ICP-MS). Results were subtracted from the initial pool concentration to determine contamination levels. Results No detectable contamination above the assay limit of detection was found in 11 analytes. Molybdenum and selenium contamination was measured in all tubes, and aluminum, titanium, manganese, thallium, and zinc had minimal levels of sporadic detectable contamination in 25% or fewer of the tubes tested. Conclusions Sarstedt polypropylene CSF tubes are an acceptable collection tube for the analysis of most assessed metals in CSF. [ABSTRACT FROM AUTHOR]

Alzheimer's disease, the most common form of dementia, is characterized by the deposition of amyloid plaques and neurofibrillary tangles in the brain, leading to the loss of neurons and a decline in a person's memory and cognitive function. As a multifactorial disease, Alzheimer's involves multiple pathogenic mechanisms, making its treatment particularly challenging. Current drugs approved for the treatment of Alzheimer's disease only alleviate symptoms but cannot stop the progression. Moreover, these drugs typically target a single pathogenic mechanism, leaving other contributing factors unaddressed. Recent advancements in drug design have led to the development of multi-target-directed ligands (MTDLs), which have gained popularity for their ability to simultaneously target multiple pathogenic mechanisms. This paper focuses on analyzing the activity, mechanism of action, and binding properties of the anti-Alzheimer's MTDLs developed between 2020 and 2024. [ABSTRACT FROM AUTHOR]

Background: Sexual dysfunction (SD) in Parkinson's Disease (PD) patients is a common and distressing concern, although it remains an underdiagnosed and undertreated condition. Indeed, the prevalence of SD in PD ranges from 42.6% to 79% in men and from 36% to 87.5% in women. PD-related SD etiology is multifactorial and includes biological, psychological, and socio-relational factors. In a previous multicenter study on 203 PD patients, we found that there was no gender difference in dysfunction severity, although men were significantly more affected by SD than women. Methods: This paper is a secondary analysis of this previous multicenter study, and aims to investigate the potential risk factors that contribute to SD. The relationship between dysfunction and the experimental factors was assessed using Generalized Linear Mixed-Effects (GLME) model. Results: The final analysis was conducted on a sample of 177 patients (76 women), after excluding individuals with incomplete data, non-compliance with inclusion criteria, or delays in assessment tool administration. The analysis, performed using the GLME model (R2 = 0.68), revealed that gender (p = 0.01), age (p = 0.02), and depression status (HAMD) (p = 0.01) were significant predictors of SD. In contrast, other factors considered in the model, such as diabetes, and autonomic symptoms, did not significantly influence SD. Conclusions: This study demonstrates that age, gender, and depression are important predictors of SD in patients with PD. Although SD is a common NMS in PD patients, it is often neglected in clinical practice and the research on this hot topic is still poor. Then, a multidisciplinary approach, including nursing and coaching, is mandatory in order to improve sexual health in this patient population. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases are a major public health challenge, mainly affecting the elderly population and compromising their cognitive, sensory, and motor functions. Currently, available therapies focus on alleviating symptoms and slowing the progression of these conditions, but they do not yet offer a definitive cure. In this scenario, terpenes emerge as promising natural alternatives due to their neuroprotective properties. These compounds can reduce the formation of protein aggregates, neutralize free radicals, and inhibit pro-inflammatory enzymes, which are crucial factors in the development of neurodegenerative diseases. In addition, terpenes also play an important role in the regulation and remodeling of the extracellular matrix, a key target for improving neuronal functions. Substances such as linalool, pinene, and eugenol, among others, have potential therapeutic effects by modulating inflammatory and oxidative stress processes, the main factors that contribute to the progression of these diseases. Studies suggest that these compounds act on signaling pathways that regulate the extracellular matrix, improving neuronal integrity and, consequently, cognitive and motor function. This work aims to review the potential of terpenes in the treatment of neurodegenerative disorders, with emphasis on their ability to regulate oxidative stress and inflammation, as well as to remodel the extracellular matrix. The interaction between these mechanisms points to the promising use of terpenes as an innovative and natural therapeutic approach to combat these diseases. [ABSTRACT FROM AUTHOR]