Search Results (1,038)

Parkinson’s disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons. Its symptoms affect both motor functions—such as bradykinesia, rigidity, resting tremor, and postural instability—and non-motor functions, including neuropsychiatric issues, sleep disorders, and constipation. Drawing on the literature, the following topics were developed and presented: Pathophysiology; Treatment; Neuropsychiatric and Cognitive Function; Sleep Challenges; Exercise and Movement; Striving for Wellness; and Obstacles/Paths Forward. These seven categories form the foundation of this review, which centers on four main areas related to PD: dopamine biology and pathophysiology; management of key motor and non-motor symptoms; strategies for achieving wellness; and unresolved issues in PD. The complexity of PD’s clinical features is highlighted by describing patient–healthcare provider interactions, elucidating disease mechanisms, managing motor and non-motor symptoms, highlighting the benefits of exercise, emphasizing the importance of sleep, addressing mental health challenges and cognitive changes, fostering a hopeful and resilient mindset, potentially slowing disease progression, treating comorbidities, and promoting overall wellness. Although there have been tremendous advances in the basic science and clinical management of PD in recent years, PD remains incurable. Thus, we describe several roadblocks that have hindered progress in understanding PD. Only by integrating historical insights with the latest PD advances can we acquire the knowledge needed to change the disease’s trajectory. Finally, this review aims to provide a meaningful summary for healthcare professionals (and students) caring for patients with PD. Full article

Neurodegenerative conditions are incurable, progressive disorders characterized by the slow and irreversible loss of neurons. This neuronal loss can lead to several neuropsychiatric disorders and long-term complications. Despite significant advances in understanding the mechanisms of neurodegenerative disease, currently, there is no cure for neurodegenerative diseases, highlighting the urgent need for novel neuroprotective strategies. Alkaloids are an important class of bioactive substances that exhibit neuroprotection against several neurodegenerative diseases. Tryptanthrin, an indoloquinazoline alkaloid, shows strong anti-inflammatory, antioxidant, and neuroprotective properties. In this review, we described the pathophysiology of neurodegenerative diseases and summarized several alkaloids’ neuroprotective properties. Furthermore, we showed protective benefits of tryptanthrin and its derivatives against neurodegenerative illnesses, focusing on their modulation of oxidative stress, neuroinflammation, neuronal death, and related signaling pathways in cellular and animal models of neurodegenerative diseases. However, various challenges, such as clinical evidence, pharmacokinetic studies, and long-term treatment effects, are not well documented. Future research on tryptanthrin and its derivatives should focus on the optimization of drug delivery methodologies and clinical studies to establish its potential as a therapeutic candidate for neurodegenerative diseases. Full article

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe manifestation of lupus marked by cognitive and mood disorders, yet the molecular mechanisms underlying hippocampal dysfunction remain poorly understood. To address this, we performed bulk RNA sequencing on hippocampal tissue from 17-week-old female MRL/Lpr mice and MRL^+/+ controls, followed by an integrative multi-layered analytical workflow. Differential gene expression analysis identified 223 significant differentially expressed genes, with a predominant downregulation of myelin-related transcripts. Gene set enrichment analysis confirmed coordinated suppression of oligodendrocyte differentiation, neuron ensheathment, and Wnt signaling programs. Weighted gene co-expression network analysis identified a disease-associated module enriched in myelination and glial developmental pathways, with hub genes spanning structural, transcriptional, and adhesion-related functions. Cell-type deconvolution revealed a selective reduction in mature oligodendrocytes, while oligodendrocyte precursor cells remained largely unaffected, consistent with impaired lineage maturation rather than global loss. RT-qPCR and Western blot validated the repression of key myelin-related genes and MBP protein in MRL/Lpr hippocampi. Collectively, these findings challenge an inflammation-centric interpretation of NPSLE hippocampal pathology, highlighting instead an additional contribution of impaired oligodendrocyte maturation. This transcriptomic resource establishes a molecular foundation for future mechanistic and histological investigations. Full article

Dementia with Lewy bodies (DLB) is increasingly conceptualised not merely as a disorder of neuronal death but as a primary synaptopathy in which the functional collapse of synaptic transmission and plasticity precedes, and predicts, neurodegeneration and clinical decline. Two genetic determinants dominate the heritable risk architecture of DLB: the α-synuclein gene SNCA, in which both copy-number variation and missense mutations exert dose- and conformation-dependent effects, and GBA1, encoding the lysosomal hydrolase glucocerebrosidase (GCase), the single most influential genetic risk factor for the disease. Here we synthesise evidence that these loci converge on a shared pathogenic endpoint—the impairment of activity-dependent synaptic plasticity. We argue that GBA1 loss-of-function and the resulting accumulation of glucosylceramide stabilise specific neurotoxic α-synuclein proteoforms, including soluble oligomers and self-templating conformational strains bearing defined post-translational modifications. These proteoforms are trafficked to, and enriched within, presynaptic terminals, where they disrupt SNARE-complex assembly and synaptic-vesicle dynamics, while postsynaptically they perturb NMDA and AMPA receptor trafficking, dysregulate dendritic calcium, and compromise synaptic mitochondrial bioenergetics. The net consequence is a metaplastic shift away from long-term potentiation (LTP) and toward aberrant long-term depression (LTD), a signature of synaptic failure detectable before frank pathology. We map these molecular events onto disease-relevant circuits—particularly the cholinergic basal forebrain and hippocampal–cortical and thalamocortical networks—and relate them to the defining neuropsychiatric features of DLB, including cognitive fluctuations and recurrent visual hallucinations. Finally, we evaluate emerging therapeutic strategies that target the GBA1–α-synuclein axis and that aim to restore synaptic plasticity directly. Positioning DLB within the framework of genetically determined plasticity deficits clarifies its kinship with other neuropsychiatric disorders and identifies the synapse as the most tractable node for early, disease-modifying intervention. We further examine how GBA1 allele severity and zygosity grade the phenotype, which genetic and environmental factors modify penetrance in carriers, and what distinguishes this synaptopathy from those driven by PSEN1/PSEN2, MAPT, or HTT, and we summarise the therapeutic pipeline—including enzyme augmentation and adeno-associated viral GBA1 gene therapy—that targets it. Full article

Objectives: To examine the association between premorbid personality in people with Alzheimer’s disease and caregiver well-being, while accounting for caregiver personality, sociodemographic characteristics, and behavioural and psychological symptoms of dementia. Methods: This cross-sectional observational study included 56 dyads consisting of people with mild-to-moderate Alzheimer’s disease and their informal caregiver. Caregiver well-being was operationalised using a continuous index derived from a principal component analysis integrating depressive and anxiety symptoms, burden, loneliness, perceived social support, quality of life and happiness. Caregiver personality and the premorbid personality of people with Alzheimer’s disease (assessed retrospectively by an informant) were assessed according to the Big Five model. Behavioural and psychological symptoms of dementia were assessed using the Neuropsychiatric Inventory. Associations were examined using correlation analyses and hierarchical multiple linear regression models. Results: Caregivers had a mean age of 55.2 years (SD = 11.0), and 82.1% were women. Higher premorbid extraversion of people with Alzheimer’s disease was significantly associated with better caregiver well-being (β = 0.123; p < 0.05), and this association remained significant after adjustment for caregiver personality and other covariates. The final model explained 57.3% of the variance in caregiver well-being (R² = 0.573; p < 0.001). Conclusions: Premorbid extraversion of people with Alzheimer’s disease was independently associated with caregiver well-being. These findings suggest that personality characteristics of both may be relevant for understanding caregiver well-being within a relational perspective of caregiving. Full article

Background: Translocator Protein (TSPO) is a transmembrane protein located in the mitochondrial outer membrane and highly expressed in the brain, which makes it a potential biomarker for microglial activation and neuroinflammation in neurodegenerative diseases. However, its role in neuropsychiatric disorders and its contribution to methamphetamine (METH) addiction (MA) remain unclear. Here, we aimed to investigate the association of the TSPO rs6971 with susceptibility to MA and METH-associated psychosis (MAP) and to evaluate its effect on TSPO expression. Methods: We investigated the association of TSPO/rs6971 (Ala147Thr) with susceptibility to MA and METH-associated psychosis (MAP). Genotyping was performed on 300 individuals, including 200 diagnosed with METH use disorder, with 100 of these exhibiting MAP, along with 100 healthy controls (HCs). We explored how different genotypes influence TSPO expression at both the transcript and protein levels using RT-qPCR and ELISA. Results: Age- and sex-adjusted logistic regression analysis revealed nominal associations between the rs6971 AA genotype and MAP under the recessive and co-dominant genetic models, with stronger associations observed after excluding individuals with a family history of psychiatric disorders. Within the MAP group, carriers of the A allele exhibited increased circulating TSPO levels compared to those with the GG genotype. Additionally, higher protein concentrations (p = 0.036) were observed in heterozygous individuals with MAP, compared to METH users without psychosis. Conclusions: Our findings suggest that the expression of TSPO may be influenced by genotype, with A allele carriers showing elevated TSPO expression. Overall, these exploratory findings suggest potential for TSPO-based translational strategies for patients with MA, and highlight the need for more comprehensive evaluations in future research. Full article

Insulin resistance (IR) represents one of the most pressing problems in contemporary public health. Its estimated global prevalence ranges from approximately 15.5% to over 61%, depending on the population studied, the diagnostic criteria applied, and the method used for its assessment. Despite the scale of the problem, IR remains underrecognized and lacks formal definition as a distinct disease entity, even as a growing number of clinicians and researchers worldwide describe it as such. Its asymptomatic or mildly symptomatic course allows it to remain undetected for years, during which it makes a significant contribution to the development of type 2 diabetes, cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), and has been increasingly linked to cellular senescence, certain cancers, neuropsychiatric disorders, and other metabolic conditions. The aim of this review was to summarize current knowledge on the pathophysiology, diagnosis, and clinical implications of insulin resistance, to discuss current challenges in its diagnosis, and to evaluate whether available scientific evidence supports its recognition as a distinct disease entity. This narrative review is based on clinical, epidemiological, and mechanistic data retrieved from PubMed and Google Scholar. Meta-analyses, systematic reviews, clinical and observational studies, clinical guidelines, and expert position statements were analyzed. Animal studies were excluded to maintain a focus on human public health implications. The diagnostic gold standard—the hyperinsulinemic-euglycemic clamp—was discussed, along with surrogate methods used in clinical practice (HOMA-IR, OGTT with insulin measurements, the TyG index, and the TG/HDL-C ratio). Factors potentially contributing to the pathogenesis of IR were examined, including hyperinsulinemia (HI), high-carbohydrate diets, inflammation, stress, and sleep disturbances, as well as conditions in which IR occurs physiologically. The findings indicate that current evidence supports the need for a clearer clinical and diagnostic framework for insulin resistance and suggest that its recognition as a distinct disease entity could facilitate earlier diagnosis, improve the standardization of clinical management, and enable earlier metabolic intervention. Given the steadily rising prevalence of metabolic disease, systemic efforts directed at the early identification and treatment of IR may be a key component of strategies aimed at reducing the population-level burden of metabolic disease and its negative consequences. Full article

Chronic stress is increasingly recognized as a major contributor to systemic disease. Prolonged or repeated activation of the hypothalamic–pituitary–adrenal (HPA) axis and sympathoadrenal systems may contribute to glucocorticoid receptor resistance and chronic low-grade inflammation, although stress-related responses vary depending on stressor characteristics, population, age, sex, health status, and study design. Elevated levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), oxidative stress, and NF-κB activation contribute to immune dysfunction, neuroinflammation, metabolic disturbances, reproductive and endocrine imbalance, as well as structural and functional alterations in stress-sensitive brain regions. Prolonged exposure to stress may contribute to the development of neuropsychiatric, cardiovascular, metabolic, neurodegenerative, and malignant diseases, highlighting the need for effective strategies to mitigate the detrimental consequences of chronic stress. Given the limitations and adverse effects associated with conventional pharmacological approaches, increasing attention has been directed toward natural bioactive compounds. Terpenes represent a diverse class of phytochemicals with reported anti-inflammatory, antioxidant, and neuromodulatory properties. Terpenes such as limonene and β-caryophyllene, as well as terpenoids such as linalool, may modulate NF-κB, MAPK, and Nrf2 signaling pathways and interact with the endocannabinoid system, thereby attenuating neuroinflammation, oxidative stress, and stress-induced immune dysregulation. This review summarizes current evidence regarding the mechanisms linking chronic stress, HPA axis dysfunction, and systemic disease, with particular emphasis on endocrine, immune, and nervous system alterations. In addition, it critically evaluates the mechanistic and translational potential of terpenes as possible indirect neuroimmune and redox modulators of stress-related pathophysiology. Full article

Introduction: Hepatitis C virus (HCV) infection often coexists with comorbidities, increasing vulnerability, complications, and adverse events. Direct-acting antivirals (DAAs) have dramatically improved HCV management, but they differ in drug–drug interaction (DDI) profiles. Sofosbuvir/velpatasvir (SOF/VEL) is associated with minimal clinically relevant interactions. Areas covered: A narrative review of the literature was conducted by searching PubMed and major international guidelines, focusing on studies published in the DAA era addressing HCV patients with major comorbidities, focusing on diabetes, metabolic syndrome, and cardiovascular disease; neuropsychiatric disorders; cancer; transplants; and use of substances or treatment with opioid agonists; and patients requiring hormone therapy including transgender patients. Expert opinion: Based on the literature and real-world data, managing polypharmacy in HCV patients with comorbidities is effective and well-tolerated, provided thorough drug review, potential DDI analysis, proactive monitoring, and coordinated multidisciplinary care are ensured. DAAs have dramatically improved the management of HCV patients; however, they have different DDI profiles that should be carefully checked. SOF/VEL has been shown to be associated with minimal clinically relevant interactions and offers a simple dosing regimen. DAA treatment is strongly advised in HCV comorbid patients not only to cure HCV but also to improve the course of comorbidities, provided that DDIs are no longer considered mere minor details. Full article

The SARS-CoV-2 virus has infected approximately 778 million people worldwide since the pandemic. Patients who have survived coronavirus disease (COVID-19) may experience long-term symptoms related to cognitive deficits, mood changes, and depressive disorders. The mechanisms underlying the long-term effects of COVID-19 on the brain are being actively investigated. SARS-CoV-2 infection triggers various mechanisms, such as hyperstimulation of the immune response, which may lead to changes in the central nervous system. In this article, we review the evidence linking COVID-19 to neurodegenerative disorders and cognitive impairment. Current research indicates that patients with pre-existing cognitive and neuropsychiatric deficits have a poorer prognosis after SARS-CoV-2 infection, and patients who have survived COVID-19 may be at increased risk of developing dementia and mood disorders. We analyse the available evidence regarding SARS-CoV-2 brain infection, induction of inflammation, coagulopathy, and blood–brain barrier (BBB) dysfunction as possible mechanisms underlying the disorders in the acute phase of COVID-19 disease and contributing to the development of neurodegenerative disorders in long COVID. Viral infection can trigger inflammation of the central nervous system (CNS), leading to damage and contributing to the development of cognitive dysfunction. Full article

Gamma-band oscillations centered around 40 Hz play an important role in cortical communication, and their disruption has been documented as a neurophysiological feature of several neurodegenerative and neuropsychiatric disorders. This narrative review synthesizes preclinical and early-phase clinical evidence for 40 Hz non-invasive brain stimulation across five delivery modalities: (1) auditory stimulation, which leverages the 40 Hz auditory steady-state response (ASSR) to probe parvalbumin-positive (PV⁺) interneuron circuits and serves as a validated neurophysiological biomarker in schizophrenia; (2) visual stimulation, using luminance or invisible spectral flicker to induce steady-state visually evoked potentials (SSVEPs) and, in animal models, to activate microglial phagocytosis; (3) transcranial alternating current stimulation (tACS), which delivers sinusoidal sub-threshold membrane polarization at gamma frequency, with preliminary case-series evidence suggesting tau burden reduction and EEG-based biomarker changes in Alzheimer’s disease; (4) repetitive transcranial magnetic stimulation (rTMS), offering focal cortical entrainment that, when combined with tACS in phase-synchronized protocols, produces sustained gamma enhancement in the dorsolateral prefrontal cortex; and (5) multisensory combined stimulation, which engages multiple convergent pathways and currently represents the approach with the most promising early translational signal, including cognitive stabilization and hippocampal volume preservation in small AD trials. While single-session entrainment does not reliably yield cognitive gains, multi-week applications have shown neurophysiological and preliminary biomarker-level changes in selected populations. It should be emphasized, however, that the human evidence base remains early-phase and largely derived from small, often uncontrolled studies; 40 Hz stimulation should accordingly be regarded as a biologically plausible and well-tolerated investigational approach rather than an established therapeutic intervention. Adequately powered, randomized, sham-controlled trials are required before clinical conclusions can be drawn. Full article

Mitochondrial dysfunction is increasingly recognized as a major contributor to central nervous system (CNS) disorders, including neurodegenerative and neuropsychiatric diseases. Animal models are essential for elucidating disease mechanisms and supporting the development of new therapeutic strategies. Among these models, non-mammalian organisms offer distinct advantages, including low cost, rapid life cycles, genetic tractability, and suitability for large-scale, high-throughput studies. Organisms such as Saccharomyces cerevisiae, Dictyostelium discoideum, Caenorhabditis elegans, Drosophila melanogaster, and Danio rerio have substantially advanced the understanding of mitochondrial processes relevant to CNS pathology. Studies using these models have revealed conserved mechanisms involving mitophagy, mitochondrial quality control, respiratory function, bioenergetic signaling, and neurodegenerative pathways. Their strengths, including scalability, live imaging capacity, and efficient genetic manipulation, have accelerated disease modeling and therapeutic discovery. However, simplified physiology, evolutionary distance from humans, and the incomplete representation of complex CNS organization limit their translational relevance and often require validation in higher-order organisms. Nevertheless, integrating these models into CNS research, particularly alongside emerging technologies, provides a powerful strategy for linking fundamental mitochondrial biology with translational neuroscience. This review summarizes the use of non-mammalian models in neuroscience research, with an emphasis on mitochondrial dysfunction in CNS disorders and their potential to support future therapeutic advances. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder of motor function, while at advanced stages it includes memory deficits and neuropsychiatric conditions. It is characterized primarily by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and reduced dopamine levels in the striatum. Accumulating evidence highlights the role of polyphenols against oxidative stress and neuroinflammatory processes, underlying key factors of PD pathogenesis. The present study used a rotenone rat model to determine the involvement of inflammatory cytokines in the basal ganglia, hippocampus, basolateral amygdala, and prefrontal cortex and to evaluate the potential of black Corinthian currant, a fruit abundant in antioxidant polyphenols, to attenuate brain inflammatory responses. Rotenone is known to trigger oxidative stress by inhibiting mitochondrial complex I and thus induce dopaminergic neurodegeneration, further amplified by inflammation. Our findings clearly demonstrated that rotenone treatment resulted in significant increases in pro-inflammatory cytokines as well as MAO-B expression within the rat brain motor and limbic regions. Importantly, dietary supplementation with black Corinthian currant mitigated rotenone-induced overexpression of IL-1β, TNFα, and MAO-B. Moreover, double immunofluorescence suggested the microglial localization of these inflammatory markers in SNpc. Overall, our data highlight the neuroprotective potential of dietary Corinthian currant polyphenols, modulating glial-mediated neuroinflammation in a rotenone PD model. Full article

The gut microbiota actively metabolizes steroid hormones, but the mechanisms of these transformations—particularly the sequence of enzymatic reactions and the source of hydrogen atoms—remain poorly understood. Conventional analytical approaches are hampered by the complex fecal matrix, isomeric metabolites, and the lack of authentic reference standards. Here we present a strategy based on parallel incubation of steroids with pooled human gut microbiota in H₂O and D₂O, followed by HPLC-HRMS, with the aim of determining the sequence of reductive steps and tracking the incorporation of atoms into steroid metabolites. Using a pooled fecal inoculum from multiple donors (n = 18) and three steroid substrates, we demonstrate that the characteristic mass shift (1.0063 Da per deuterium atom) enables detection of metabolites and distinguishes multi-step enzymatic reactions in the microbial community without recombinant enzymes and authentic standards. Progesterone and 19-hydroxy-4-androstene-3,17-dione underwent sequential two-step reduction incorporating up to three deuterium atoms, while 17α-hydroxypregnenolone followed a three-step pathway incorporating up to four deuterium atoms, consistent with localization to the A-ring. This workflow provides a practical tool for investigating gut microbial steroid metabolism in the context of human physiology and disease, with potential applications in monitoring microbial activity in endocrine disorders, inflammatory bowel disease, and neuropsychiatric conditions. Full article

The cerebellum is traditionally considered a structure responsible for motor control, but it is also involved in auditory perception, vocalization, speech, memory, emotional control, and social cognition. Due to its high intrinsic synaptic plasticity and complex connectivity with other brain regions, it is of potential interest for monitoring adaptive responses under various physiological and pathological conditions to capture global brain dynamics. Nevertheless, the use of electrocerebellography (ECeG) to detect changes in cerebellar electrical activity is limited, and a systematic evaluation of ECeG data to inform future research directions is lacking. This review summarizes recent ECeG research to explore the contribution of this time-honored method to deciphering the cerebellum’s spatial and temporal dynamics in health and disease. ECeG studies from the past three decades examining the slow and fast adaptive responses of the cerebellum in different cerebellar layers during sleep, anesthesia, brain injury, epilepsy, neurodegenerative diseases, and neuropsychiatric disorders are compiled from the PubMed, Scopus, and Google Scholar databases and discussed accordingly. It can be concluded that, despite certain limitations, ECeG is a practical, valuable, and reliable technique for detecting and predicting the complex spatial and temporal features of cerebellar electrical activity. Full article