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Background: Tubulins are dimeric proteins expressed in all eukaryotic cells, serving as the fundamental building blocks of microtubule filaments. The TUBB4A gene encodes the protein β-tubulin. Mutations of TUBB4A have been associated with two neurodegenerative diseases with very different clinical characteristics: dystonia type 4 (DYT4) and Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC). Several cases of patients with H-ABC or unclassified leukoencephalopathy show spastic ataxia with or without leukodystrophy in association with mutations in exon 5 of TUBB4A gene. Case presentation: We report the case of a 65-year-old woman who has been complaining of progressive difficulty in walking since childhood. The neurological examination revealed, among all, a spastic gait, difficulties in standing on the toes and heels, brisk deep tendon reflexes at upper limbs, clonic patellar reflexes, brisk ankle reflexes, as well as bilateral Babinski and Hoffmann sign, brisk jaw jerk and severe lower limb spasticity. NGS studies for inherited cases of spastic paraplegia revealed a novel variant of unknown significance (VUS) (c.1249A > G, p.D417N), in TUBB4A. To the best of our knowledge, this variant has not been reported in the literature or any databases in association with these diseases. Conclusion: We report the case of a patient carrying a variant of uncertain significance (VUS) of the TUBB4A gene, showing a progressive, spastic paraparesis, supporting the extension of the phenotypic spectrum up to include spastic paraplegia. [ABSTRACT FROM AUTHOR]

Subjective memory decline (SMD) might represent the preclinical phase of Alzheimer's disease (AD), and has been reported in epileptic amnesia associated with accelerated long-term forgetting (ALF). We investigated ALF in SMD subjects by means of RAVLT recall and recognition and ROCF recall after 1-week retention and compared with a control group. Two-way ANOVAs for RAVLT and ROCF were conducted, and stepwise regression analysis was administered considering EMQ and DASS-21 as factors. SMD subjects performed significantly worse than controls at 1-week delay on RAVLT recall and recognition, but not on ROCF, and not associated with depression or memory complaints. SMD patients showed ALF, which is usually associated with temporomesial dysfunctions, representing a cognitive marker to assess objectively memory problems in SMD, and to undisclose initial neurodegenerative disease involving temporal structures usually compromised in AD. Therefore, SMD might no longer be "subjective," but rather a specific and defined clinical entity. [ABSTRACT FROM AUTHOR]

Medicinal plants and phytochemicals are some of the major sources in the treatment of various neurodegenerative disorders including Alzheimer's disease (AD). There is no FDA-approved drug to target AD pathology directly. Full cognitive restoration and management of psychosis-like symptoms are still to be achieved. Being comparatively safer with fewer side effects, medicinal plants have been among the major areas of interest to be researched. Several mechanistic pathways are involved in AD including anticholinesterase activity, glutamate toxicity, free radicals generation, Amyloid β (Aβ) toxicity, inflammation, and mitochondrial dysfunction. Various phytochemicals such as paenol, andrographolide, isoquercitrin, flavonoids, and saponins obtained from different plant sources, various medicinal plants like Spirulina maxima, Salicornia europaea, Curcuma longa, Citrus Junos Tanaka, Cassiae semen, Centella asiatica as well as various traditional medicinal plants of China, Asia, Europe, Turkey, and Iran have been found effective against one or more of these targets. Large numbers of clinical trials are under process to evaluate the role of different phytoconstituents in AD management. Out of 143 agents under clinical trials, 119 have been categorized as disease-modifying agents. The present review extensively covers the recent advancements in the usage of phytochemicals and medicinal plants in various experimental AD models. It involves clinical trials and other research works divided into three sections, including those performed in vitro, in vivo, and in humans mainly from the last five years along with disease markers and mechanistic pathways involved. However, phytochemicals should be explored further in order to achieve neurorestoration in AD. [ABSTRACT FROM AUTHOR]

Background: The Learning Ratio (LR) is a novel learning score that has shown improved utility over other learning metrics in detecting Alzheimer's disease (AD) across multiple memory tasks. However, its utility on the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory Test (CERAD WLMT), a widely used list learning measure sensitive to decline in neurodegenerative disease, is unknown. The goal of the current study was to determine the utility of LR on the CERAD WLMT in differentiating between diagnostic (MiNCD vs MaNCD) and etiologic groups (VaD vs AD) in a veteran sample. Methods: Raw learning slope (RLS) and LR scores were examined in 168 veterans diagnosed with major neurocognitive disorder (MaNCD), mild neurocognitive disorder (MiNCD), or normal aging following neuropsychological evaluation. Patients with MaNCD were further classified by suspected etiology (i.e. microvascular disease vs AD). Results: Whereas RLS scores were not significantly different between MiNCD and MaNCD, LR scores were significantly different between all diagnostic groups (p's <.05). Those with AD had lower LR scores and RLS scores compared to those with VaD (p's <.05). LR classification accuracy was acceptable for MiNCD (AUC =.76), excellent for MaNCD (AUC =.86) and VaD (AUC =.81), and outstanding for AD (AUC =.91). Optimal cutoff scores for WLMT LR were derived from Youden's index. Conclusion: Results support the use of LR scores over RLS when interpreting the CERAD WLMT and highlight the clinical utility of LR in differentiating between diagnostic groups and identifying suspected etiology. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor symptoms (NMS). NMS including sleep disturbances, depression, anxiety, and constipation are diverse, can precede motor symptoms, and significantly impact patients' quality of life. The severity and type of NMS vary based on age, disease severity, and motor symptoms, and while some respond to dopaminergic treatments, others may be induced or exacerbated by such treatments. NMS also play a role in differentiating PD from drug-induced parkinsonism and are related to gait dysfunction in both early and advanced stages. Genetic factors play a significant role in the development of NMS in PD, with mutations in genes such as SNCA, LRRK2, PRKN, and GBA being associated with severe and early NMS. Familial studies and identification of susceptibility factors have provided insights into the genetic underpinnings of NMS in PD. Neurobehavioral changes, including cognitive decline, are common NMS in PD, and their genetic basis involves a spectrum of mutations shared with other neurodegenerative disorders. Further research is needed to elucidate the functional implications of these genetic factors and their contributions to the pathogenesis of NMS in PD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder, affecting millions of people and rapidly increasing over the last decades. Even though there is no intervention yet to stop the neurodegenerative pathology, many efficient treatment methods are available, including for patients with advanced PD. Neuroplasticity is a fundamental property of the human brain to adapt both to external changes and internal insults and pathological processes. In this paper we examine the current knowledge and concepts concerning changes at network level, cellular level and molecular level as parts of the neuroplastic response to protein aggregation pathology, synapse loss and neuronal loss in PD. We analyse the beneficial, compensatory effects, such as augmentation of nigral neurons efficacy, as well as negative, maladaptive effects, such as levodopa-induced dyskinesia. Effects of physical activity and different treatments on neuroplasticity are considered and the opportunity of biomarkers identification and use is discussed. [ABSTRACT FROM AUTHOR]

Objectives: Recent studies suggest that psychological resilience (PR) is associated with more well-preserved cognition in healthy subjects (HS), but an investigation of such phenomenon in patients with motor neuron diseases (MNDs) is still lacking. The aim of our study was therefore to evaluate PR and its relationship with baseline cognitive/behavioral and mood symptoms, as well as longitudinal cognitive functioning, in MNDs. Methods: 94 MND patients and 87 demographically matched HS were enrolled. PR was assessed using the Connor-Davidson Resilience Scale (CD-RISC). Patients were further evaluated both at baseline and every 6 months for cognitive/behavioral disturbances using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), and for mood symptoms using the Hospital Anxiety and Depression Scale (HADS). CD-RISC scores were compared between patients and HS using the Mann–Whitney U test, and regression models were applied to evaluate the role of CD-RISC scores in predicting baseline cognitive/behavioral and mood measures, as well as longitudinal cognitive performances, in MND patients. Results: MND cases showed significantly greater PR compared to HS (p from <0.001 to 0.02). In MNDs, higher PR levels were significant predictors of both greater cognitive performance (p from 0.01 to 0.05) and milder mood symptoms (p from <0.001 to 0.04) at baseline, as well as less severe memory decline (p from 0.001 to 0.04) longitudinally. Conclusions: PR is an important protective factor against the onset and evolution of cognitive/mood disturbances in MNDs, suggesting the usefulness of resilience enhancement psychological interventions to prevent or delay cognitive and mood disorders in these neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

Introduction: Amyotrophic lateral sclerosis (ALS) has heterogeneous manifestations ranging from motor neuron degeneration to cognitive and behavioral impairment. This study aims to clarify the interactions between cognition and behavioral symptoms with relevant disease predictors and with cognitive reserve (CR), quantified through education, physical activity, and occupation proxies. Methods: A prospective sample of 162 ALS patients and 61 controls were evaluated with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (dependent variable), a Cognitive Reserve Index questionnaire (CRIq) and demographic data (age and sex), and, for patients, clinical variables: disease duration, site of onset, the ALS Functional Rating Scale (ALSFRS), forced vital capacity (FVC), and gene mutation chromosome 9 open reading frame 72 (C9orf72) (independent variables). Multiple regression and mediation analyses were performed to predict cognitive and behavioral symptoms. Results: For the ALS group, the statistical model explained 38.8% of variance in ECAS total (p < 0.001), 59.4% of executive functions (p < 0.001), and 55% of behavioral symptoms (p < 0.001). For controls, it accounted for 52.8% of variance in ECAS total (p < 0.001). Interaction effects and mediation analysis showed CR is an ECAS total modulator, with a differential effect within groups (p < 0.001). Verbal fluency was the single best cognitive score to differentiate patients from controls (p = 0.004), and the gene mutation C9orf72 was found to be a behavioral symptom' predictor in patients (p = 0.009). Conclusion: This study supports the proposed concept that CR acts as a cognitive modulator in ALS patients and healthy individuals. Moreover, CR also modulates behavioral manifestations in ALS. [ABSTRACT FROM AUTHOR]

Loss-of-function (LoF) variants in the TANK binding kinase 1 (TBK1) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel TBK1 variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in TBK1. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for TBK1 variants in similar familial cases. [ABSTRACT FROM AUTHOR]

Objective: Huntington's disease (HD) is a neurodegenerative disease caused by a triplet repeat expansion within the gene huntingtin (HTT). Antagonistic pleiotropy is a theory of aging that posits that some genes, facilitating individual fitness early in life through adaptive evolutionary changes, also augment detrimental aging‐related processes. Antagonistic pleiotropy theory may explain a positive evolutionary pressure toward functionally advantageous brain development that is vulnerable to rapid degeneration. The current study investigated antagonistic pleiotropy in HD using a years‐to‐onset paradigm in a unique sample of children and young adults at risk for HD. Methods: Cognitive, behavioral, motor, and brain structural measures from premanifest gene‐expanded (n = 79) and gene nonexpanded (n = 112) participants (6–21 years) in the Kids‐HD study were examined. All measures in the gene‐expanded group were modeled using a mixed‐effects regression approach to assess years‐to‐onset‐based changes while controlling for normal growth. Simultaneously, structure–function associations were also examined. Results: Decades from motor onset, gene‐expanded participants showed significantly better cognitive, behavioral, and motor scores versus gene nonexpanded controls, along with larger cerebral volumes and cortical features. After this initial peak, a prolonged deterioration was observed in both functional and structural measures. Far from onset, brain measures were positively correlated with functional measures, supporting the view that functional advantages were mediated by structural differences. Interpretation: Mutant HTT may drive the development of a larger than normal brain that subserves superior early‐life function. These findings support the antagonistic pleiotropy theory of HTT in HD, where this gene drives early advantage followed by accelerated aging processes. ANN NEUROL 2024;96:1006–1019 [ABSTRACT FROM AUTHOR]

Increasing evidence suggests a potential role for infectious pathogens in the etiology of synucleinopathies, a group of age-related neurodegenerative disorders including Parkinson's disease (PD), multiple system atrophy and dementia with Lewy bodies. In this review, we discuss the link between infections and synucleinopathies from a historical perspective, present emerging evidence that supports this link, and address current research challenges with a focus on neuroinflammation. Infectious pathogens can elicit a neuroinflammatory response and modulate genetic risk in PD and related synucleinopathies. The mechanisms of how infections might be linked with synucleinopathies as well as the overlap between the immune cellular pathways affected by virulent pathogens and disease-related genetic risk factors are discussed. Here, an important role for α-synuclein in the immune response against infections is emerging. Critical methodological and knowledge gaps are addressed, and we provide new future perspectives on how to address these gaps. Understanding how infections and neuroinflammation influence synucleinopathies will be essential for the development of early diagnostic tools and novel therapies. Plain Language Summary: This review explores how infections might contribute to the development of Parkinson's disease and other synucleinopathies. It highlights evidence that microbial pathogens may trigger neurodegeneration by causing neuroinflammation. We emphasize the complex relationship between infections, genetics, and neurodegeneration, and discuss how understanding these connections could lead to earlier diagnosis and new treatments. In this review we also identify key knowledge gaps, and we suggest areas for future research. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral changes, significantly impacting the quality of life of affected individuals and their caregivers. While pharmacological treatments offer limited relief, nonpharmacological interventions, like yoga, have gained attention for their potential therapeutic benefits. This critical review synthesizes findings from various studies on the feasibility, adherence, physical function, cognitive improvements, inflammatory markers, neuroprotection, and mood and behavioral changes associated with yoga interventions for older adults with AD. Despite these promising results, further research with randomized controlled trials, larger sample sizes, control groups, longitudinal follow-ups, standardized protocols, and diverse populations is necessary to confirm these benefits and understand the long-term effects of yoga on AD progression. This critical review highlights yoga's potential as a valuable nonpharmacological intervention in the holistic management of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder responsible for over half of dementia cases, with two-thirds being women. Growing evidence from preclinical and clinical studies underscores the significance of sex-specific biological mechanisms in shaping AD risk. While older age is the greatest risk factor for AD, other distinct biological mechanisms increase the risk and progression of AD in women including sex hormones, brain structural differences, genetic background, immunomodulation and vascular disorders. Research indicates a correlation between declining estrogen levels during menopause and an increased risk of developing AD, highlighting a possible link with AD pathogenesis. The neuroprotective effects of estrogen vary with the age of treatment initiation, menopause stage, and type. This review assesses clinical and observational studies conducted in women, examining the influence of estrogen on cognitive function or addressing the ongoing question regarding the potential use of hormone replacement therapy (HRT) as a preventive or therapeutic option for AD. This review covers recent literature and discusses the working hypothesis, current use, controversies and challenges regarding HRT in preventing and treating age-related cognitive decline and AD. The available evidence indicates that estrogen plays a significant role in influencing dementia risk, with studies demonstrating both beneficial and detrimental effects of HRT. Recommendations regarding HRT usage should carefully consider the age when the hormonal supplementation is initiated, baseline characteristics such as genotype and cardiovascular health, and treatment duration until this approach can be more thoroughly investigated or progress in the development of alternative treatments can be made. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders involve progressive dysfunction and loss of synapses and neurons and brain atrophy, slowly declining memories and cognitive skills, throughout a long process. Alzheimer's disease (AD), the leading neurodegenerative disorder, suffers from a lack of effective therapeutic drugs. Decades of efforts targeting its pathologic hallmarks, amyloid plaques and neurofibrillary tangles, in clinical trials have produced therapeutics with marginal benefits that lack meaningful clinical improvements in cognition. Delivering meaningful clinical therapeutics to treat or prevent neurodegenerative disorders thus remains a great challenge to scientists and clinicians. Emerging evidence, however, suggests that dysfunction of various synaptogenic signaling pathways participates in the neurodegenerative progression, resulting in deterioration of operation/structure of the synaptic networks involved in cognition. These derailed endogenous signaling pathways and disease processes are potential pharmacological targets for the therapies. Therapeutics with meaningful clinical benefit in cognition may depend on the effectiveness of arresting and reversing the neurodegenerative process through these targets. In essence, promoting neuro-regeneration may represent the only option to recover degenerated synapses and neurons. These potential directions in clinical trials for AD therapeutics with meaningful clinical benefit in cognitive function are summarized and discussed. [ABSTRACT FROM AUTHOR]

Functional impairments in the brain's insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver of the Alzheimer's disease (AD) neurodegeneration cascade. AD-associated insulin-deficient and insulin-resistant states mimic those of diabetes mellitus and affect all cell types in the brain. Besides accounting for abundant amyloid-β and hyperphosphorylated tau lesions in AD, insulin/IGF pathway dysfunctions cause cortical atrophy, loss of synaptic plasticity, white matter myelin/oligodendrocyte degeneration, astrocyte and microglial neuroinflammation and oxidative stress, deficits in energy metabolism, mitochondrial dysfunction, and microvascular disease. These same neuropathological processes have been linked to cognitive impairment in type 2 diabetes mellitus, Parkinson's disease, and vascular dementia. Strategies to address metabolic mediators of cognitive impairment have been borrowed from diabetes and other insulin-resistant diseases and leveraged on preclinical AD model data. The repurposing of diabetes drugs led to clinical trials with intranasal insulin, followed by insulin sensitizers including metformin and peroxisome-proliferator-activated receptor agonists, and then incretin mimetics primarily targeting GLP-1 receptors. In addition, other glucose-lowering agents have been tested for their efficacy in preventing cognitive declines. The strengths and limitations of these approaches are discussed. The main conclusion of this review is that we have now arrived at a stage in which it is time to address long-term deficits in trophic factor availability and receptor responsiveness, signaling abnormalities that extend beyond insulin and include IGFs and interconnected pathways, and the need for multi-pronged rather than single-pronged therapeutic targeting to remediate AD and other forms of neurodegeneration. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairments. Despite extensive research efforts, effective treatment options for AD remain limited. Recently, gene therapy has emerged as a promising avenue for targeted intervention in the pathogenesis of AD. This review will provide an overview of clinical and preclinical studies where gene therapy techniques have been utilized in the context of AD, highlighting their potential as novel therapeutic strategies. While challenges remain, ongoing research and technological advancement continue to enhance the potential of gene therapy as a targeted and personalized therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

This review is an attempt to compile existing hypotheses on the mechanisms underlying the initiation and progression of Alzheimer's disease (AD), starting from sensory impairments observed in AD and concluding with molecular events that are typically associated with the disease. These events include spreading of amyloid plaques and tangles of hyperphosphorylated tau and formation of Hirano and Biondi bodies as well as the development of oxidative stress. We have detailed the degenerative changes that occur in several neuronal populations, including the cholinergic neurons in the nucleus basalis of Meynert, the histaminergic neurons in the tuberomammillary nucleus, the serotonergic neurons in the raphe nuclei, and the noradrenergic neurons in the locus coeruleus. Furthermore, we discuss the potential role of iron accumulation in the brains of subjects with AD in the disease progression which served as a basis for the idea that iron chelation in the brain may mitigate oxidative stress and decelerate disease development. We also draw attention to possible role of sympathetic system and, more specifically, noradrenergic neurons of the superior cervical ganglion in triggering of the disease. We also explore the alternative possibility of compensatory protective changes that may occur in these neurons to support cholinergic function in the forebrain of subjects with AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common neurodegenerative disorder which primarily involves memory and cognitive functions. It is increasingly recognized that motor involvement is also a common and significant aspect of AD, contributing to functional decline and profoundly impacting quality of life. Motor impairment, either at early or later stages of cognitive disorders, can be considered as a proxy measure of cognitive impairment, and technological devices can provide objective measures for both diagnosis and prognosis purposes. However, compared to other neurodegenerative disorders, the use of technological tools in neurocognitive disorders, including AD, is still in its infancy. Objective: This report aims to evaluate the role of technological devices in assessing motor involvement across the AD spectrum and in other dementing conditions, providing an overview of the existing devices that show promise in this area and exploring their clinical applications. Methods: The evaluation involves a review of the existing literature in the PubMed, Web of Science, Scopus, and Cochrane databases on the effectiveness of these technologies. 21 studies were identified and categorized as: wearable inertial sensors/IMU, console/kinect, gait analysis, tapping device, tablet/mobile, and computer. Results: We found several parameters, such as speed and stride length, that appear promising for detecting abnormal motor function in MCI or dementia. In addition, some studies have found correlations between these motor aspects and cognitive state. Conclusions: Clinical application of technological tools to assess motor function in people with cognitive impairments of a neurodegenerative nature, such as AD, may improve early detection and stratification of patients. [ABSTRACT FROM AUTHOR]

Histone deacetylase 6 (HDAC6) was a potential target for Alzheimer's disease (AD). In this study, a series of novel oxyevodiamine-based HDAC6 inhibitors with a variety of linker moieties were designed, synthesized and evaluated. Compound 12 with a benzyl linker was identified as a high potent and selective HDAC6 inhibitor. It inhibited HDAC6 with an IC50 value of 6.2 nM and was more than 200 fold selectivity over HDAC1. It also had lower cytotoxicity and higher anti-H2O2 activity in vitro comparing with other derivatives. Compound 12 might be a good lead as novel HDAC6 inhibitor for the treatment of AD. [ABSTRACT FROM AUTHOR]

For caregivers of people living with major neurocognitive disorders (MNCD), adapting and applying methods optimizing learning (MOL) to a specific situation, based on preserved cognitive skills, can be challenging. This study aimed to 1) co-develop workshops, a web application and accompanying materials to support the operationalization of MOL; 2) better understand the factors influencing caregivers' use of MOL, and 3) evaluate the perceived effects of the workshops. A participatory action research study was conducted in collaboration with family caregivers of people living with MNCD and healthcare and community organization workers (HCOW). Qualitative questionnaires and interviews were conducted and transcribed in verbatim. Thematic content analysis was conducted. Workshops and accompanying materials were co-developed and continuously improved based on conceptual framework and feedback from the participants. The final version of the workshops consisted of seven two-hour sessions structured around the type of cognitive deficits affecting the realization of activities. Facilitators (e.g. help to identify the person's capabilities) and barriers (e.g. fluctuation of MNCD symptoms) for caregivers' use of the MOL were reported. The identification of the cause of reactive behavioral expressions could be challenging for some family caregivers, reducing the use of MOL. Caregivers mentioned their increased preparedness to support and relationship with the person living with MNCD and feeling of competence for analyzing the reactive behavioral expressions and to use MOL. This participatory action research has shown that caregivers can acquire abilities to adapt and apply MOL in specific situations with people living with MNCD. [ABSTRACT FROM AUTHOR]

[Display omitted] • Selective autophagy is characterized by its ability to specifically degrade a certain substrate, rather than causing widespread cell autophagy. • The mechanisms underlying selective autophagy can be broadly dispersed in three steps: designation, targeting and sequestration, and degradation. • Numerous human diseases and their progression are closely linked to aberrant selective autophagy. • Deciphering the molecular mechanisms underlying selective autophagy provides a theoretical framework for treating relevant clinical disorders. • Regulation of selective autophagy by discovering and developing small-molecule agents has great clinical application prospects for the treatment of related diseases. Autophagy is an evolutionarily conserved turnover process for intracellular substances in eukaryotes, relying on lysosomal (in animals) or vacuolar (in yeast and plants) mechanisms. In the past two decades, emerging evidence suggests that, under specific conditions, autophagy can target particular macromolecules or organelles for degradation, a process termed selective autophagy. Recently, accumulating studies have demonstrated that the abnormality of selective autophagy is closely associated with the occurrence and progression of many human diseases, including neurodegenerative diseases, cancers, metabolic diseases, and cardiovascular diseases. This review aims at systematically and comprehensively introducing selective autophagy and its role in various diseases, while unravelling the molecular mechanisms of selective autophagy. By providing a theoretical basis for the development of related small-molecule drugs as well as treating related human diseases, this review seeks to contribute to the understanding of selective autophagy and its therapeutic potential. In this review, we systematically introduce and dissect the major categories of selective autophagy that have been discovered. We also focus on recent advances in understanding the molecular mechanisms underlying both classical and non-classical selective autophagy. Moreover, the current situation of small-molecule drugs targeting different types of selective autophagy is further summarized, providing valuable insights into the discovery of more candidate small-molecule drugs targeting selective autophagy in the future. On the other hand, we also reveal clinically relevant implementations that are potentially related to selective autophagy, such as predictive approaches and treatments tailored to individual patients. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that non‐neuronal oligodendrocyte plays an important role in Amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. In patient's brain, the impaired myelin structure is a pathological feature with the observation of TDP‐43 in cytoplasm of oligodendrocyte. However, the mechanism underlying the gain of function by TDP‐43 in oligodendrocytes, which are vital for the axonal integrity, remains unclear. Recently, we found that the primate‐specific cleavage of truncated TDP‐43 fragments occurred in cytoplasm of monkey neural cells. This finding opened up the avenue to investigate the myelin integrity affected by pathogenic TDP‐43 in oligodendrocytes. In current study, we demonstrated that the truncated TDP‐35 in oligodendrocytes specifically, could lead to the dysfunctional demyelination in corpus callosum of monkey. As a consequence of the interaction of myelin regulatory factor with the accumulated TDP‐35 in cytoplasm, the downstream myelin‐associated genes expression was downregulated at the transcriptional level. Our study aims to investigate the potential effect on myelin structure injury, affected by the truncated TDP‐43 in oligodendrocyte, which provided the additional clues on the gain of function during the progressive pathogenesis and symptoms in TDP‐43 related diseases. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP‐43 aggregates. Recent evidence has been indicated that phosphorylated TDP‐43 (pTDP‐43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP‐43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP‐43 detectable in routine biopsied muscles? (ii) Can detection of pTDP‐43 aggregation discriminate between ALS and non‐ALS patients? (iii) Can pTDP‐43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non‐ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP‐43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP‐43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non‐ALS controls (16/54; p < 0.001). The pTDP‐43 aggregates were mainly close to the sarcolemma. Using a semi‐quantified pTDP‐43 aggregates score, we applied a cut‐off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP‐43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof‐of‐concept for the detection of pTDP‐43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS. [ABSTRACT FROM AUTHOR]

Cellular protein kinases are involved in diverse normal cellular functions. Many types of dysregulation of protein kinases are the molecular basis for development of common cancers and neurodegenerative diseases. More than 80 small-molecule protein kinase inhibitors are available now and approved by the US Food and Drug Administration for successful treatment of cancers and neurodegenerative diseases. Newly designed protein kinase inhibitors and related forms of therapy based on a greater understanding of molecular mechanisms have diminished the appearance of disease resistance to protein kinase inhibitors and other side effects. These advances will further promote the success of protein kinase inhibitors in treatment of common cancers, Alzheimer's disease, and other neurodegenerative conditions. [ABSTRACT FROM AUTHOR]

With the progress of modern science and technology, magnetic therapy technology develops rapidly, and many types of magnetic therapy methods continue to emerge, making magnetic therapy one of the main techniques of physiotherapy. With the continuous development of magnetic field research and clinical applications, magnetic therapy, as a non-invasive brain stimulation therapy technology, has attracted much attention due to its potential in the treatment of motor dysfunction, cognitive impairment and speech disorders in patients with neurodegenerative diseases. However, the role of magnetic fields in the prognosis and treatment of neurodegenerative diseases and their mechanisms remain largely unexplored. In this paper, the therapeutic effect and neuroprotective mechanism of the magnetic field on neurodegenerative diseases are reviewed, and the new magnetic therapy techniques are also summarized. Although the neuroprotective mechanism of magnetic field cannot be fully elaborated, it is helpful to promote the application of magnetic field in neurodegenerative diseases and provide a new theoretical basis for the related magnetic field research in the later period. • Summarize the therapeutic effect of magnetic field on neurodegenerative diseases and new magnetic therapy technology. • A variety of potential mechanisms play a neuroprotective role of magnetic field. • Magnetic therapy technology have great potential in the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Molecular modelling suggests that citral, one of the main components of lemongrass, interacts with Kelch‐like ECH‐associated protein 1, which is involved in the transcription of the antioxidant enzyme haeme oxygenase (HO)‐1. A citral treatment of the pheochromocytoma (PC)12D cell line, an in vitro model of neurons, up‐regulated the expression of HO‐1 (mRNA: 28.7 ± 22.6, protein: 3.3 ± 0.8). The inhalation of lemongrass or citral aroma by mice decreased HO‐1 mRNA levels in the ventral striatum (VSt) (0.68 ± 0.14, 0.72 ± 0.18, respectively), but not in the lateral hypothalamus or ventral tegmental area, which play important roles in appetite. Dopamine levels, which positively correlated with HO‐1 mRNA expression levels in PC12D, were decreased in the murine brain by the inhalation of citral (0.79 ± 0.23). This reduction was cancelled by an injection of 6‐hydroxydopamine, a selective inducer of dopaminergic neuron degeneration, into the nucleus accumbens, which is involved in pleasure, in VSt. Mice displayed aversion behaviour to the odour of citral, but no changes in their body weight. However, the oral administration of citral increased HO‐1 protein levels in the murine VSt (1.25 ± 0.16). Subjects completed a questionnaire on the aroma of lemongrass essential oil, which revealed that most found it to be pleasant and it did not affect their appetite. Collectively, the present results demonstrated that humans perceive the aroma of lemongrass differently from mice, indicating its utility as a vermin repellent and antioxidant food. [ABSTRACT FROM AUTHOR]

Background: With rapidly rising life expectancy and ageing populations, interest has grown in the survival patterns and ages at death at the highest ages. In Scandinavia, the accumulation of very old population segments coupled with long-established, high-quality population registers permit meaningful analysis. Methods: This study is based on individual level data from extinct Norwegian birth cohorts using data obtained from the Norwegian Civil Register System. We assess trends in the ages at death of centenarians in Norway for cohorts born between 1870 and 1904 for evidence of any secular increase using quantile regression. Results: We observed that there is no upward trend in centenarian lifespans, in line with recent observations in Sweden, but contrary to the upward trend at the very highest percentiles as observed in Denmark. Conclusions: The available evidence suggests that the stagnation in centenarian lifespans may be partly due to the failure to find ways of dealing with neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Millions of people worldwide are affected by neurodegenerative diseases and cognitive impairment, which includes dementia, while there are only symptomatic treatments available for this syndrome at present. However, several important prospective drug targets have been identified in recent years that can potentially arrest or even reverse the progression of neurodegenerative diseases. Their natural or synthetic ligands are currently in the experimental stage of drug development. In vitro and preclinical (e.g. using animal models) studies confirm their therapeutic potential, but clinical trials often fail or produce conflicting results. Here, we first review the complexity and typology of dementia, followed by the discussion of currently available treatments, and, finally, some novel molecular and cellular approaches to this problem. [ABSTRACT FROM AUTHOR]

[Display omitted] • Early life exposure to cisplatin induces TRPV1 and nociceptor sensitisation. • Cisplatin alters the developmental trajectory of nociceptors to be TrkA dependent. • Cisplatin induced survivorship pain is dependent upon TrkA signalling. Cisplatin-based chemotherapy is a common treatment for paediatric cancer. Unfortunately, cisplatin treatment causes neuropathic pain, a highly prevalent adverse health related complication in adult childhood cancer survivors. Due to minimal understanding of this condition, there are currently no condition tailored analgesics available. Here we investigated an alteration in nociceptor maturation that results in neuronal sensitisation and manifestation of cisplatin induced survivorship pain in a TrkA dependent manner. Cisplatin was administered (i.p. 0.1 mg/kg Postnatal day 14 and 16) to neonatal male and female Wistar rats and nociceptive behavioural assays were performed. In vitro studies utilised isolated neonatal dorsal root ganglia sensory neurons treated with cisplatin (5 μg/ml) to elucidate impact upon nociceptor activation and neurite growth, in combination with TrkA inhibition (GW441756 10 nM and 100 nM). Cisplatin treated male and female neonatal Wistar rats developed a delayed but lasting mechanical and heat hypersensitivity. Cisplatin administration led to increased TrkA expression in dorsal root ganglia sensory neurons. Nerve growth factor (NGF) induced TrkA activation led to sensory neuritogenesis and nociceptor sensitisation, which could be prevented through pharmacological TrkA inhibition (GW441756 either s.c. 100 nM or i.p. 2 mg/kg). Administration of TrkA antagonist suppressed cisplatin induced TRPV1 mediated nociceptor sensitisation and prevented cisplatin induced neuropathic pain. These studies provide greater understanding of the underlying mechanisms that cause cisplatin induced childhood cancer survivorship pain and allowing identification of potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Alzheimer's disease, is one of the irreversible neurodegenerative disorders among older people, causes behavior, memory, and thinking problems. This study aim is to synthesize of 4‐({8‐[3‐(dimethylamino)phenoxy]octyl}oxy)phthalonitrile, zinc(II) phthalocyanine and its water soluble derivative containing ({8‐[3‐(dimethylamino)phenoxy]octyl}oxy) substituents at the peripheral positions first time. To determine the potential of water soluble silicon(IV) and zinc(II) phthalocyanines for use in AD, spectrophotometric assays were performed to determine their acetylcholinesterase/butyrylcholinesterase inhibitory effects. In addition, their DNA nuclease properties were evaluated by agarose gel electrophoresis. The results showed that the compounds inhibited acetylcholinesterase/butyrylcholinesterase. They did not damage pBR322 plasmid DNA depending on time and concentration. As a result of the experiments, it is revealed that the compounds may be the potential for use as cholinesterase inhibitors, which is a promising approach for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Delirium is a state of altered level of consciousness often leading to confusion, inattention, and changes to levels of cognition. Delirium increases average length of stay in the hospital and costs the US health care system approximately $148 billion each year in associated medical costs. Sleep hygiene is an important factor in delirium prevention for all hospitalized patients. Objectives: This quality improvement project was designed to increase implementation of an evidence-based sleep hygiene bundle in the neurocritical care population in order to decrease rates of hospital-acquired delirium. Methods: This project followed the Plan, Do, Study, Act (PDSA) framework to facilitate a continuous quality improvement intervention at amid-Atlantic academicmedical center in the neurocritical care population. The continuous quality improvement included the incorporation of "sleep" as a topic into the daily rounding checklist, thus optimizing the ability to improve adherence to a multicomponent sleep hygiene bundle. The intervention includes the preintervention-postintervention occurrences of delirium and use of the daily rounding checklist. Results: Nursing adherence to documentation of delirium assessments was high at approximately 99%. Following the intervention, there was a 41% decrease in the number of patients who screened positive for hospital-acquired delirium. Discussion: The improvement in cases of hospital-acquired delirium may be attributed to the project intervention. Recommendations for future interventions include analysis of training on sleep plans, focus on nursing education regarding delirium assessment tools, or a measure of staff and/or patient satisfaction related to the intervention. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Swim training and regulation of copper metabolism result in clinical benefits in amyotrophic lateral sclerosis (ALS) mice. Therefore, the study aimed to determine whether swim training improves copper metabolism by modifying copper metabolism in the skeletal muscles of ALS mice. Methods: SOD1G93A mice (n = 6 per group) were used as the ALS model, and wild‐type B6SJL (WT) mice as controls (n = 6). Mice with ALS were analyzed before the onset of ALS (ALS BEFORE), at baseline ALS (first disease symptoms, trained and untrained, ALS ONSET), and at the end of ALS (last stage disease, trained and untrained, ALS TERMINAL). Copper concentrations and the level of copper metabolism proteins in the skeletal muscles of the lower leg were determined. Results: ALS disease caused a reduction in the copper concentration in ALS TERMINAL untrained mice compared with the ALS BEFORE (10.43 ± 1.81 and 38.67 ± 11.50 μg/mg, respectively, p =.0213). The copper chaperon for SOD1 protein, which supplies copper to SOD1, and ATPase7a protein (copper exporter), increased at the terminal stage of disease by 57% (p =.0021) and 34% (p =.0372), while the CTR1 protein (copper importer) decreased by 45% (p =.002). Swim training moderately affected the copper concentration and the concentrations of proteins responsible for copper metabolism in skeletal muscles. Discussion: The results show disturbances in skeletal muscle copper metabolism associated with ALS progression, which is moderately affected by swim training. From a clinical point of view, exercise in water for ALS patients should be an essential element of rehabilitation for maintaining quality of life. [ABSTRACT FROM AUTHOR]

Traumatic spinal cord injuries (SCI) result in devastating impairment to an individual's functional ability. The pathophysiology of SCI is related to primary injury but further propagated by secondary reactions to injury, such as inflammation and oxidation. The inflammatory and oxidative cascades ultimately cause demyelination and Wallerian degeneration. Currently, no treatments are available to treat primary or secondary injury in SCI, but some studies have shown promising results by lessening secondary mechanisms of injury. Interleukins (ILs) have been described as key players in the inflammation cascade after neuronal injury; however, their role and possible inhibition in the context of acute traumatic SCIs have not been widely studied. Here, we review the relationship between SCI and IL-6 concentrations in the CSF and serum of individuals after traumatic SCIs. Furthermore, we explore the dual IL-6 signaling pathways and their relevance for future IL-6 targeted therapies in SCI. [ABSTRACT FROM AUTHOR]

Aim of the project was to evaluate the technical and clinical validity of plasma Lumipulse p-tau, Aβ42 and Aβ40 species and their correlation with CSF core Alzheimer's Disease (AD) markers; a method comparison with SIMOA was also performed. One-hundred-thirthy-three participants, namely 55 A+T+N+ AD, 28 Neurodegenerative disorders (NDD) and 50 controls were enrolled for the study. Lumipulse technical validity showed high stability for p-tau181, Aβ42, and Aβ40, with higher stability of p-tau to repeated freezing thaw cycles. p-tau181 levels detected by both techniques were higher in AD compared to both NDD/controls and exhibited a similar correlation with CSF p-tau levels, whereas Aβ42 levels were slightly lower in AD with both methods. In the comparison between SIMOA and Lumipulse plasma markers, both techniques exhibited similar diagnostic accuracy for AD for p-tau181 (0.87; 95 %CI 0.81–0.94, vs 0.85; 95 %CI 0.78–0.93), whereas the best performance was reached by p-tau181/ Aβ42 Lumipulse ratio (ROC AUC 0.915, 95 %CI 0.86–0.97). The study thus confirmed the construct validity of both Lumipulse and SIMOA techniques for the identification of CSF AD pattern in clinical settings. • Lumipulse technical validity showed high stability for p-tau181, Aβ42, and Aβ40 species. • Lumipulse and SIMOA AD-related markers showed a fair correlation in plasma. • Plasma and CSF p-tau181 and amyloid markers are correlated. • Both techniques showed consistently increased plasma p-tau181 levels in AD. [ABSTRACT FROM AUTHOR]

Background: Rheum tanguticum root, cataloged as "Daehwang" in the Korean Pharmacopeia, is rich in various anthraquinones known for their anti-inflammatory and antioxidant properties. Formulations containing Daehwang are traditionally employed for treating neurological conditions. This study aimed to substantiate the antiepileptic and neuroprotective efficacy of R. tanguticum root extract (RTE) against trimethyltin (TMT)-induced epileptic seizures and hippocampal neurodegeneration. Methods: The constituents of RTE were identified by ultra-performance liquid chromatography (UPLC). Experimental animals were grouped into the following five categories: control, TMT, and three TMT+RTE groups with dosages of 10, 30, and 100 mg/kg. Seizure severity was assessed daily for comparison between the groups. Brain tissue samples were examined to determine the extent of neurodegeneration and neuroinflammation using histological and molecular biology techniques. Network pharmacology analysis involved extracting herbal targets for Daehwang and disease targets for epilepsy from multiple databases. A protein-protein interaction network was built using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and pivotal targets were determined by topological analysis. Enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool to elucidate the underlying mechanisms. Results: The RTE formulation was found to contain sennoside A, sennoside B, chrysophanol, emodin, physcion, (+)-catechin, and quercetin-3-O-glucuronoid. RTE effectively inhibited TMT-induced seizures at 10, 30, and 100 mg/kg dosages and attenuated hippocampal neuronal decay and neuroinflammation at 30 and 100 mg/kg dosages. Furthermore, RTE significantly reduced mRNA levels of tumor necrosis factor (TNF-α), glial fibrillary acidic protein (GFAP), and c-fos in hippocampal tissues. Network analysis revealed TNF, Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Protein c-fos (FOS), RAC-alpha serine/threonine-protein kinase (AKT1), and Mammalian target of rapamycin (mTOR) as the core targets. Enrichment analysis demonstrated significant involvement of R. tanguticum components in neurodegeneration (p = 4.35 x 10-5) and TNF signaling pathway (p = 9.94 x 10-5). Conclusions: The in vivo and in silico analyses performed in this study suggests that RTE can potentially modulate TMT-induced epileptic seizures and neurodegeneration. Therefore, R. tanguticum root is a promising herbal treatment option for antiepileptic and neuroprotective applications. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We aimed to evaluate the feasibility of the 2024 Alzheimer's Association Workgroup's integrated clinical‐biological staging scheme in outpatient settings within a tertiary memory clinic. METHODS: The 2018 syndromal cognitive staging system, coupled with a binary biomarker classification, was implemented for 236 outpatients with cognitive concerns. The 2024 numeric clinical staging framework, incorporating biomarker staging, was specifically applied to 154 individuals within the Alzheimer's disease (AD) continuum. RESULTS: The 2024 staging scheme accurately classified 95.5% AD. Among these, 56.5% exhibited concordant clinical and biological stages (canonical), 34.7% demonstrated more advanced clinical stages than biologically expected (susceptible), and 8.8% displayed the inverse pattern (resilient). The susceptible group was characterized by a higher burden of neurodegeneration and inflammation than anticipated from tau, whereas the resilient group showed the opposite. DISCUSSION: The 2024 staging scheme is generally feasible. A discrepancy between clinical and biological stages is relatively frequent among symptomatic patients with AD. Highlights: The 2024 AA staging scheme is generally feasible in a tertiary memory clinic.A discrepancy between clinical and biological stages is relatively frequent in AD.The mismatch may be influenced by a non‐specific pathological process involved in AD.Individual profiles like aging and lifestyles may contribute to such a mismatch.Matched and mismatched cases converge toward similar clinical outcomes. [ABSTRACT FROM AUTHOR]

INTRODUCTION: MicroRNAs (miRNAs) play important roles in gene expression regulation and Alzheimer's disease (AD) pathogenesis. METHODS: We investigated the association between baseline plasma miRNAs and central AD biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 803): amyloid, tau, and neurodegeneration (A/T/N). Differentially expressed miRNAs and their targets were identified, followed by pathway enrichment analysis. Machine learning approaches were applied to investigate the role of miRNAs as blood biomarkers. RESULTS: We identified nine, two, and eight miRNAs significantly associated with A/T/N positivity, respectively. We identified 271 genes targeted by amyloid‐related miRNAs with estrogen signaling receptor–mediated signaling among the enriched pathways. Additionally, 220 genes targeted by neurodegeneration‐related miRNAs showed enrichment in pathways including the insulin growth factor 1 pathway. The classification performance of demographic information for A/T/N positivity was increased up to 9% with the inclusion of miRNAs. DISCUSSION: Plasma miRNAs were associated with central A/T/N biomarkers, highlighting their potential as blood biomarkers. Highlights: We performed association analysis of microRNAs (miRNAs) with amyloid/tau/neurodegeneration (A/T/N) biomarker positivity.We identified dysregulated miRNAs for A/T/N biomarker positivity.We identified Alzheimer's disease biomarker‐specific/common pathways related to miRNAs.miRNAs improved the classification for A/T/N positivity by up to 9%.Our study highlights the potential of miRNAs as blood biomarkers. [ABSTRACT FROM AUTHOR]

This comprehensive review discusses the crucial role of copper in human health and disease as an essential trace mineral. It emphasizes the significance of copper while addressing potential risks from imbalances in copper levels, be it excessive or inadequate. The review outlines various challenges in copper research, including toxicity concerns, data limitations, metabolic complexities, genetic influences, nutrient interactions, and resource constraints. Despite these challenges, the review identifies specific research areas needing exploration, such as copper homeostasis regulation, transport mechanisms, gut microbiome interactions, immune function, neurodegenerative diseases, cardiovascular health, cancer, fertility, and reproductive health. The purpose of this review is to explore the important role of copper in human health and disease, which highlights the delicate balance required to avoid deficiency or toxicity. For the researchers and scientists, it provides the gaps in the research, so it aims to provide insights that could advance diagnostic and therapeutic strategies across various medical disciplines. [ABSTRACT FROM AUTHOR]

Phosphodiesterase type 5 (PDE5) is an enzyme primarily found in the smooth muscle of the corpus cavernosum and also highly expressed in the substantia nigra, cerebellum, caudate, hippocampal regions and cerebellar purkinje cells, responsible for selectively breaking down cyclic guanosine monophosphate (cGMP) into 5′‐GMP and regulate intracellular cGMP levels. As a second messenger, cyclic GMP enhances signals at postsynaptic receptors and triggers downstream effector molecules, leading to changes in gene expression and neuronal responses. Additionally, cGMP signaling transduction cascade, present in the brain, is also essential for learning and memory processes. Mechanistically, PDE5 inhibitors share structural similarities with cGMP, competitively binding to PDE5 and inhibiting cGMP hydrolysis. This action enhances the effects of nitric oxide, resulting in anti‐inflammatory and neuroprotective effects. Neurodegenerative disorders entail the progressive loss of neuron structure, culminating in neuronal cell death, with currently available drugs providing only limited symptomatic relief, rendering neurodegeneration considered incurable. PDE5 inhibitors have recently emerged as a potential therapeutic approach for neurodegeneration, neuroinflammation, and diseases involving cognitive impairment. This review elucidates the principal roles of 3′,5′‐cyclic adenosine monophosphate (cAMP) and cGMP signaling pathways in neuronal functions, believed to play pivotal roles in the pathogenesis of various neurodegenerative disorders. It provides an updated assessment of PDE5 inhibitors as disease‐modifying agents for conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischemia, Huntington's disease, and neuroinflammation. The paper aims to review the current understanding of PDE5 inhibitors, which concurrently regulate both cAMP and cGMP signaling pathways, positing that they may exert complementary and synergistic effects in modifying neurodegeneration, thus presenting a novel direction in therapeutic discovery. Moreover, the review provides critical about biological functions, therapeutic potentials, limitations, challenges, and emerging applications of selective PDE5 inhibitors. This comprehensive overview aims to guide future academic and industrial endeavors in this field. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) causes deficits in neurological function, induces pathological changes, and increases oxidative stress. The current investigation aimed to determine Daidzein's neuroprotective potential in experimental TBI. Initially, the HT‐22 cell line exposed to H2O2 underwent in vitro examination, and the results showed that Daidzein had a neuroprotective effect evident from enhanced cell viability and decreased NO generation. Using three different Daidzein doses—1 mg/kg, 5 mg/kg, and 10 mg/kg—in the in vivo experiment, the potential of Daidzein was evaluated against TBI. The neurological severity score (NSS), kondziela's screen test, and elevated plus maze showed improvements after treatment with Daidzein manifested by decreased score, enhanced motor coordination, and anti‐anxiety effects. Additionally, Daidzein improved mechanical allodynia and restored the breakdown of the blood‐brain barrier. The FTIR spectral analysis showed restoration of the biochemical compositional changes. Furthermore, H & E and Toluidine blue staining revealed an improvement in the histopathological alterations. The RT‐qPCR revealed an increase in mRNA expression level of Nrf2, HO‐1, and Bcl‐2 and the downregulation of Keap‐1, Bax and Cleaved caspase‐3 expressions. Thus, exhibiting its antioxidant and antiapoptotic potential. The RT‐qPCR also manifested a decrease in mRNA expression of GFAP and Iba‐1. Further immunohistochemistry results indicated Daidzein's antioxidant and antiapoptotic properties by upregulating Nrf2 and downregulating cleaved caspase‐3. Daidzein also lowered the apoptosis index and improved neuronal survival evidenced by flow cytometric analysis. In addition to this, Daidzein notably increased the antioxidant enzyme levels and decreased the oxidative stress markers. The current study's findings point to the neuroprotective potential of the phytoestrogen Daidzein as it lessened neurological abnormalities, decreased oxidative stress, and lowered proapoptotic protein expression. [ABSTRACT FROM AUTHOR]

Citrus fruits are extensively cultivated and eaten both raw and in refined forms. Citrus fruit peels are highly concentrated in polyphenolic substances. This makes them useful resources. Polymethoxyflavones (PMFs), found in citrus peels, belong to a specific subclass of flavonoids where most or all hydroxyl groups are methylated. PMFs have been documented to possess chemopreventive actions, anticancer, anti‐inflammatory, and anti‐atherosclerosis properties, as well as neuroprotective effects. Sudachitin, a PMF, is primarily found in Citrus sudachi. Japan's Tokushima prefecture is home to this famous fruit. In recent years, there has been a growing interest among researchers in exploring the potential health benefits of sudachitin, spurred by its presence in traditional diets and its association with various positive health outcomes. Studies conducted over the past decade have revealed promising effects of sudachitin in multiple health conditions, including cancer, skin disorders, inflammatory conditions, diabetes, obesity, and neurodegenerative disorders. Although these promising results exist, there is still a need for thorough preclinical and clinical research to confirm sudachitin's effectiveness in treating chronic conditions. This review seeks to summarize animal and cell studies exploring sudachitin's pharmacological properties and the potential molecular pathways underlying its therapeutic effects. Through this, we aim to clarify the clinical potential of sudachitin across various disorders, paving the way for future research and the development of sudachitin‐based therapies. [ABSTRACT FROM AUTHOR]

Nanoparticles (NPs) that target multiple transport mechanisms facilitate targeted delivery of active therapeutic agents to the central nervous system (CNS) and improve therapeutic transport and efficacy across the blood‐brain barrier (BBB). CNS nanotherapeutics mostly target neurons and endothelial cells, however, microglial immune cells are the first line of defense against neuronal damage and brain infections. Through triggering release of inflammatory cytokines, chemokines and proteases, microglia can however precipitate neurological damage—a significant factor in neurodegenerative diseases. Thus, microglial inhibitory agents are attracting much attention among those researching and developing novel treatments for neurodegenerative disorders. The most established inhibitors of microglia investigated to date are resveratrol, curcumin, quercetin, and minocycline. Thus, there is great interest in developing novel agents that can bypass or easily cross the BBB. One such approach is the use of modified‐nanocarriers as, or for, delivery of, therapeutic agents to the brain and wider CNS. For microglial inhibition, polymeric NPs are the preferred vehicles for choice. Here, we summarize the immunologic and neuroinflammatory role of microglia, established microglia inhibitor agents, challenges of CNS drug delivery, and the nanotherapeutics explored for microglia inhibition to date. We also discuss applications of the currently considered "most useful" polymeric NPs for microglial‐inhibitor drug delivery in CNS‐related diseases. [ABSTRACT FROM AUTHOR]

Transient receptor potential canonical 3 (TRPC3) protein belongs to the TRP family of nonselective cation channels. Its activation occurs by signaling through a G protein‐coupled receptor (GPCR) and a phospholipase C‐dependent (PLC) pathway. Perturbations in the expression of TRPC3 are associated with a plethora of pathophysiological conditions responsible for disorders of the cardiovascular, immune, and central nervous systems. The recently solved cryo‐EM structure of TRPC3 provides detailed inputs about the underlying mechanistic aspects of the channel, which in turn enables more efficient ways of designing small‐molecule modulators. Pharmacologically targeting TRPC3 in animal models has demonstrated great efficacy in treating diseases including cancers, neurological disorders, and cardiovascular diseases. Despite extensive scientific evidence supporting some strong correlations between the expression and activity of TRPC3 and various pathophysiological conditions, therapeutic strategies based on its pharmacological modulations have not led to clinical trials. The development of small‐molecule TRPC3 modulators with high safety, sufficient brain penetration, and acceptable drug‐like profiles remains in progress. Determining the pathological mechanisms for TRPC3 involvement in human diseases and understanding the requirements for a drug‐like TRPC3 modulator will be valuable in advancing small‐molecule therapeutics to future clinical trials. In this review, we provide an overview of the origin and activation mechanism of TRPC3 channels, diseases associated with irregularities in their expression, and new development in small‐molecule modulators as potential therapeutic interventions for treating TRPC3 channelopathies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is a major health threat globally. Its prevalence is forecasted to exponentially increase during the next 30 years due to the global aging population. Currently, approved drugs are merely symptomatic, being ineffective in delaying or blocking the relentless disease advance. Intensive AD research describes this disease as a highly complex multifactorial disease. Disclosure of novel pathological pathways and their interconnections has had a major impact on medicinal chemistry drug development for AD over the last two decades. The complex network of pathological events involved in the onset of the disease has prompted the development of multitarget drugs. These chemical entities combine pharmacological activities toward two or more drug targets of interest. These multitarget‐directed ligands are proposed to modify different nodes in the pathological network aiming to delay or even stop disease progression. Here, we review the multitarget drug development strategy for AD during the last decade. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is the most common form of dementia and is a challenge for the modern world due to the due to aging populations. Researchers are trying their best to understand the mechanisms of onset and find effective ways to treat and prevent this disease. The purpose of the following paper is to present the impact of physical activity in the development of Alzheimer's disease. Numerous studies confirm that regular workouts have a positive reflection in the form of slowing the aging of the brain and alleviation of neuropsychiatric symptoms in affected individuals. During muscle work irisin is produced, which plays an important role in the formation of neurons and exhibits an anti-inflammatory effects. This review also looks at the aspect of maintaining proper composition of the gut microbiota, whose imbalance can promote the process of neuronal inflammation and cognitive dysfunction. Attention is also given to issues of training intensity and the effect of of exercise on blood flow in the brain. All of these elements play an important role in preventing and slowing down neurodegeneration. Purpose : The purpose of this scientific paper is to review the current knowledge of the effects of physical activity on the development of Alzheimer's disease. Review methods : We conducted our study as a literature review based on information gathered from PubMed, Embase, Google Scholar using combinations of the following keywords : Alzheimer's disease ; dementia ; physical activity ; cerebral blood flow ; gut-brain axis ; irisin. The state of knowledge : Alzheimer's disease is the most common type of dementia and one of the main neurodegenerative disorders affecting elderly people. Numerous studies confirm that regular exercise has a positive effect on slowing down brain aging and alleviating neuropsychiatric symptoms in patients. According to current knowledge, nerve cell degeneration can be exacerbated by peripheral inflammation that occurs in obesity. An imbalance of bacterial flora in the gastrointestinal tract causes systemic inflammation in the body. This in turn leads to excessive production of pro-inflammatory cytokines and activation of microglia so that the blood-brain barrier becomes leaky. Maintaining the appropriate composition of the gut microbiota plays an important role, as its imbalance can promote neuronal inflammation and cognitive impairment. During physical activity, irisin protein is produced in muscle tissue, which plays an important role in neuronal formation and exhibits anti-inflammatory effects. Currently, there is evidence that irisin can provide a number of beneficial effects, mainly through mechanisms that positively affect the gut microbiome. Attention is also given to issues of training intensity and the effect of exercise on cerebral blood flow. All these factors play an important role in preventing and slowing down neurodegeneration. Conclusion : Based on a review of the available literature, a significant effect of physical activity on the development of Alzheimer's disease can be demonstrated. The accumulated data suggest that physical activity is one of the main protective factors against the development and progression of Alzheimer's disease. Physical activity is associated with a reduction in cardiovascular risk factors and an increase in neuroprotective changes. The neuroprotective effect of physical exercise is dependent on its intensity. In addition, the role of the gut microbiota has been shown to be important for maintaining normal cognitive function. The protein irisin may also have significant neuroprotective potential in relation to the development and progression of cognitive disorders. Physical activity may be one of the strategies to prevent an increase in the incidence of Alzheimer's disease with positive health, economic and social implications in the future. [ABSTRACT FROM AUTHOR]

Introduction: Recent research has recognized executive dysfunction as another component affected in Primary Progressive Aphasia (PPA). This systematic review aimed to examine what information distinctive neurophysiological markers can provide in the evaluation of executive function (EF) deficits in PPA, and to what effect executive function deficits can be assessed through the characteristics of functional markers. Methods: We conducted a systematic literature search following the PRISMA guidelines across studies that employed neuropsychological assessments and neurophysiological imaging techniques (EEG, MEG; PET, SPECT, fMRI, fNIRS) to investigate executive dysfunction correlates in PPA. Results: Findings from nine articles including a total number of 111 individuals with PPA met our inclusion criteria and were synthesized. Although research on the neural correlates of EF deficits is scarce, MEG studies revealed widespread oscillatory slowing, with increased delta and decreased alpha power, where alterations in alpha, theta, and beta activities were significant predictors of executive function deficits. PET findings demonstrated significant correlations between executive dysfunction and hypometabolism in frontal brain regions. fMRI results indicated elevated homotopic connectivity in PPA patients, with a broader and more anterior distribution of abnormal hippocampal connections of which were associated with reduced executive performance. Conclusion: Our study provides indirect support for the assumption regarding the significance of the frontal regions and inferior frontal junction in executive control and demonstrates that neurophysiological tools can be a useful aid to further investigate clinical-neurophysiological correlations in PPA. [ABSTRACT FROM AUTHOR]

Neurogenesis occurs throughout life in the hippocampus of the brain, and many environmental toxicants inhibit neural stem cell (NSC) function and neuronal generation. Bisphenol-A (BPA), an endocrine disrupter used for surface coating of plastic products causes injury in the developing and adult brain; thus, many countries have banned its usage in plastic consumer products. BPA analogs/alternatives such as bisphenol-F (BPF) and bisphenol-S (BPS) may also cause neurotoxicity; however, their effects on neurogenesis are still not known. We studied the effects of BPF and BPS exposure from gestational day 6 to postnatal day 21 on neurogenesis. We found that exposure to non-cytotoxic concentrations of BPF and BPS significantly decreased the number/size of neurospheres, BrdU+ (proliferating NSC marker) and MAP-2+ (neuronal marker) cells and GFAP+ astrocytes in the hippocampus NSC culture, suggesting reduced NSC stemness and self-renewal and neuronal differentiation and increased gliogenesis. These analogs also reduced the number of BrdU/Sox-2+, BrdU/Dcx+, and BrdU/NeuN+ co-labeled cells in the hippocampus of the rat brain, suggesting decreased NSC proliferation and impaired maturation of newborn neurons. BPF and BPS treatment increases BrdU/cleaved caspase-3+ cells and Bax-2 and cleaved caspase protein levels, leading to increased apoptosis in hippocampal NSCs. Transmission electron microscopy studies suggest that BPF and BPS also caused degeneration of neuronal myelin sheath, altered mitochondrial morphology, and reduced number of synapses in the hippocampus leading to altered cognitive functions. These results suggest that BPF and BPS exposure decreased the NSC pool, inhibited neurogenesis, induced apoptosis of NSCs, caused myelin degeneration/synapse degeneration, and impaired learning and memory in rats. [ABSTRACT FROM AUTHOR]

The biological substrate of persistent post-COVID-19 hyposmia is still unclear. However, as many neurodegenerative diseases present with smell impairment at onset, it may theoretically reflect degeneration within the central olfactory circuits. However, no data still exist regarding the post-COVID-19 patients. As the olfactory neurons (ONs) mirror pathological changes in the brain, allowing for tracking the underlying molecular events, here, we performed a broad analysis of ONs from patients with persistent post-COVID-19 OD to identify traces of potential neurodegeneration. ONs were collected through the non-invasive brushing of the olfactory mucosa from ten patients with persistent post-COVID-19 hyposmia (lasting > 6 months after infection) and ten age/sex-matched controls. Immunofluorescence staining for protein quantification and RT-PCR for gene expression levels were combined to measure ONs markers of α-synuclein, amyloid-β, and tau pathology, axonal injury, and mitochondrial network. Patients and controls had similar ONs levels of oligomeric α-synuclein, amyloid-β peptide, tau protein, neurofilament light chain (NfL), cytochrome C oxidase subunit 3 (COX3), and the heat shock protein 60 (HSP60). Our findings thus did not provide evidence for synucleinopathy and amyloid-β mismetabolism or gross traces of neuronal injury and mitochondrial dysfunction within the olfactory system in the early phase of persistent post-COVID-19 hyposmia. [ABSTRACT FROM AUTHOR]

Parkinson's disease is one of the most common neurodegenerative disorders characterized by a multitude of motor and non-motor clinical symptoms resulting from the progressive and long-lasting abnormal loss of nigrostriatal dopaminergic neurons. Currently, the available treatments for patients with Parkinson's disease are limited and exert only symptomatic effects, without adequate signs of delaying or stopping the progression of the disease. Atsttrin constitutes the bioengineered protein which ultrastructure is based on the polypeptide chain frame of the progranulin (PGRN), which exerts anti-inflammatory effects through the inhibition of TNFα. The conducted preclinical studies suggest that the therapeutic implementation of Atsttrin may be potentially effective in the treatment of neurodegenerative diseases that are associated with the occurrence of neuroinflammatory processes. The aim of the proposed study was to investigate the effect of direct bilateral intracerebral administration of Atsttrin using stereotactic methods in the preclinical C57BL/6 mouse model of Parkinson's disease inducted by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. The analysis of the dose dependency effects of the increasing doses of Atsttrin has covered a number of parameters and markers regarding neurodegenerative processes and inflammatory responses including IL-1α, TNFα, IL-6, TH, and TG2 mRNA expressions. Accordingly, the evaluation of the changes in the neurochemical profile included DA, DOPAC, 3-MT, HVA, NA, MHPG, 5-HT, and 5-HIAA concentration levels. The intracerebral administration of Atsttrin into the striatum effectively attenuated the neuroinflammatory reaction in evaluated neuroanatomical structures. Furthermore, the partial restoration of monoamine content and its metabolic turnover were observed. In this case, taking into account the previously described pharmacokinetic profile and extrapolated bioavailability as well as the stability characteristics of Atsttrin, an attempt was made to describe as precisely as possible the quantitative and qualitative effects of increasing doses of the compound within the brain tissue microenvironment in the presented preclinical model of the disease. Collectively, this findings demonstrated that the intracerebral administration of Atsttrin may represent a potential novel therapeutic method for the treatment of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive neurogenerative movement disorder characterized by dopaminergic cell death within the substantia nigra pars compacta (SNpc) due to the aggregation-prone protein α-synuclein. Accumulation of α-synuclein is implicated in mitochondrial dysfunction and disruption of the autophagic turnover of mitochondria, or mitophagy, which is an essential quality control mechanism proposed to preserve mitochondrial fidelity in response to aging and stress. Yet, the precise relationship between α-synuclein accumulation, mitochondrial autophagy, and dopaminergic cell loss remains unresolved. Here, we determine the kinetics of α-synuclein overexpression and mitophagy using the pH-sensitive fluorescent mito-QC reporter. We find that overexpression of mutant A53T α-synuclein in either human SH-SY5Y cells or rat primary cortical neurons induces mitophagy. Moreover, the accumulation of mutant A53T α-synuclein in the SNpc of rats results in mitophagy dysregulation that precedes the onset of dopaminergic neurodegeneration. This study reveals a role for mutant A53T α-synuclein in inducing mitochondrial dysfunction, which may be an early event contributing to neurodegeneration. [ABSTRACT FROM AUTHOR]