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Excessive alcohol use damages the brain, especially corticolimbic regions such as the hippocampus and rhinal cortices, leading to learning and memory problems. While neuroimmune reactivity is hypothesized to underly alcohol-induced damage, direct evidence of the causal role of microglia, brain-resident immune cells, in this process is lacking. Here, we depleted microglia using PLX5622 (PLX), a CSF1R inhibitor commonly used in mice, but rarely in rats, and assessed cell death following binge-like alcohol exposure in male rats. Eleven days of PLX treatment depleted microglia > 90%. Further, PLX treatment prevented alcohol-induced neuronal death in the hippocampus and rhinal cortices, as the number of FluoroJade-B-positive cells (dying neurons) was reduced to control diet levels. This study provides direct evidence that alcohol-induced microglial reactivity is neurotoxic in male rats. Improved understanding of alcohol-microglia interactions is essential for developing therapeutics that suppress pro-cytotoxic and/or amplify protective microglia activity to relieve alcohol-related damage. [ABSTRACT FROM AUTHOR]

Chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head injuries, is characterised by perivascular hyperphosphorylated tau (p-tau) accumulations within the depths of cortical sulci. Although the majority of CTE literature focuses on p-tau pathology, other pathological features such as glial reactivity, vascular damage, and axonal damage are relatively unexplored. In this study, we aimed to characterise these other pathological features, specifically in CTE p-tau lesion areas, to better understand the microenvironment surrounding the lesion. We utilised multiplex immunohistochemistry to investigate the distribution of 32 different markers of cytoarchitecture and pathology that are relevant to both traumatic brain injury and neurodegeneration. We qualitatively assessed the multiplex images and measured the percentage area of labelling for each marker in the lesion and non-lesion areas of CTE cases. We identified perivascular glial reactivity as a prominent feature of CTE p-tau lesions, largely driven by increases in astrocyte reactivity compared to non-lesion areas. Furthermore, we identified astrocytes labelled for both NAD(P)H quinone dehydrogenase 1 (NQO1) and L-ferritin, indicating that lesion-associated glial reactivity may be a compensatory response to iron-induced oxidative stress. Our findings demonstrate that perivascular inflammation is a consistent feature of the CTE pathognomonic lesion and may contribute to the pathogenesis of brain injury-related neurodegeneration. [ABSTRACT FROM AUTHOR]

Purpose of Review: Epilepsy has long been considered a late-stage consequence of Alzheimer's Disease (AD), but recent studies highlight its role early in the disease process, even preceding cognitive symptoms. Population studies reveal a two- to fourfold increased epilepsy risk in AD, particularly in early-onset cases, with seizures clustering around diagnosis. Furthermore, individuals with late-onset unexplained epilepsy have an elevated risk of developing mild cognitive impairment and dementia, underscoring a bidirectional relationship between AD and epilepsy. Recent Findings: Experimental models support this connection, demonstrating amyloid and tau pathology-induced hyperexcitability at pre-symptomatic stages, implicating soluble Aβ oligomers and inhibitory interneuron dysfunction in excitatory/inhibitory imbalance. Subclinical or clinical epileptiform activity, detectable in 20–50% of AD patients, is associated with cognitive decline, possibly due to sleep-related memory consolidation disruption. Emerging biomarkers, such as TIRDA and high-frequency oscillations, show promise for early detection and intervention. Anti-seizure medications (ASMs), particularly low-dose levetiracetam, show potential not only for seizure control but also for mitigating amyloid deposition, tau hyperphosphorylation, and cognitive decline. However, treatment complexities remain due to variable ASM efficacy, age-related side effects, and limited clinical trials. Summary: The bidirectional nature of AD and epilepsy emphasizes the need for integrated diagnostics, including EEG and biomarker assessments, to guide early intervention and targeted therapies. Future research should focus on the mechanistic interplay between amyloid, tau, and hyperexcitability, alongside trials of ASM regimens, to refine therapeutic strategies and improve outcomes in this population. [ABSTRACT FROM AUTHOR]

Developmental and epileptic encephalopathy is a rare and severe form of inherited neurodegenerative disorder characterized by various forms of seizures. This condition typically manifests between 4 and 7 months. Recent investigations have established a correlation between mutations in the ARV1 gene and the development of developmental and epileptic encephalopathy-38. Here, we report a 4-year-old girl from a consanguineous Iranian family diagnosed with developmental and epileptic encephalopathy-38. The patient presented with seizures, microcephaly, and abnormal MRI findings. Despite conventional anti-seizure drugs, seizures persisted from infancy. Tragically, her elder sibling with identical symptoms succumbed to the condition at 11 months. In this case report, we performed whole exome sequencing in an individual diagnosed with developmental and epileptic encephalopathy-38 in an Iranian family, revealing a novel homozygous mutation in the ARV1 gene (c.184C > T [p.Gln62Ter] in exon 2, NM_022786.3). Parental carriers displayed no symptoms, underscoring the importance of whole exome sequencing for accurate diagnosis and informed family planning decisions. These findings contribute to the understanding of the genetic spectrum of developmental and epileptic encephalopathy-38. The use of whole exome sequencing revealed a rare and likely pathogenic ARV1 gene mutation, emphasizing the significance of this genetic screening method in unraveling the complexities of developmental and epileptic encephalopathies. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disorder, with limited treatment options. This disease is characterized by differential pathophysiology between grey matter (GM) and white matter (WM). The predominant WM hallmark is the perivascular plaque, associated with blood brain barrier (BBB) loss of function, lymphocytic infiltration, microglial reactivity, demyelination and axonal injury and is adequately addressed with immunomodulatory drugs. By contrast, mechanisms underlying GM damage remain obscure, with consequences for neuroprotective strategies. Cortical GM pathology is already significant in early MS and characterized by reduced BBB disruption and lymphocytic infiltration relative to WM, but a highly inflammatory environment, microglial reactivity, demyelination and neuro/axonal loss. There is no satisfactory explanation for the occurrence of neurodegeneration without large-scale inflammatory cell influx in cortical GM. A candidate mechanism suggests that it results from soluble factors originating from meningeal inflammatory cell aggregates, which diffuse into the underlying cortical tissue and trigger microglial activation. However, the recent literature highlights the central role of platelets in inflammation, together with the relationship between coagulation factors, particularly fibrinogen, and tissue damage in MS. Using the experimental autoimmune encephalomyelitis (EAE) model, we identified platelets as drivers of neuroinflammation and platelet-neuron associations from the pre-symptomatic stage. We propose that fibrinogen leakage across the BBB is a signal for platelet infiltration and that platelets represent a major and early participant in neurodegeneration. This concept is compatible with the new appreciation of platelets as immune cells and of neuronal damage driven by inflammatory cells sequestered in the meninges. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a chronic autoimmune/neurodegenerative disease associated with progressing disability affecting mostly women. We aim to estimate transition probabilities describing MS-related disability progression from no disability to severe disability. Transition probabilities are a vital input for health economics models. In MS, this is particularly relevant for pharmaceutical agency reimbursement decisions for disease-modifying therapies (DMTs). Methods: Data were obtained from Australian participants of the MSBase registry. We used a four-state continuous-time Markov model to describe how people with MS transition between disability milestones defined by the Expanded Disability Status Scale (scale 0–10): no disability (EDSS of 0.0), mild (EDSS of 1.0–3.5), moderate (EDSS of 4.0–6.0), and severe (EDSS of 6.5–9.5). Model covariates included sex, DMT usage, MS-phenotype, and disease duration, and analysis of covariate groups were also conducted. All data were recorded by the treating neurologist. Results: A total of N = 6369 participants (mean age 42.5 years, 75.00% female) with 38,837 person-years of follow-up and 54,570 clinical reviews were identified for the study. Annual transition probabilities included: remaining in the no, mild, moderate, and severe states (54.24%, 82.02%, 69.86%, 77.83% respectively) and transitioning from no to mild (42.31%), mild to moderate (11.38%), and moderate to severe (9.41%). Secondary-progressive MS was associated with a 150.9% increase in the hazard of disability progression versus relapsing–remitting MS. Conclusions: People with MS have an approximately 45% probability of transitioning from the no disability state after one year, with people with progressive MS transitioning from this health state at a much higher rate. These transition probabilities will be applied in a publicly available health economics simulation model for Australia and similar populations, intended to support reimbursement of a plethora of existing and upcoming interventions including medications to reduce progression of MS. [ABSTRACT FROM AUTHOR]

In this work, the heterodimeric phospholipase A2, HDP-2, from viper venom was investigated for its hydrolytic activity in model myelin membranes as well as for its effects on intermembrane exchange of phospholipids (studied by phosphorescence quenching) and on phospholipid polymorphism (studied by 1H-NMR spectroscopy) to understand the role of sphingomyelin (SM) in the demyelination of nerve fibers. By using well-validated in vitro approaches, we show that the presence of SM in model myelin membranes leads to a significant inhibition of the hydrolytic activity of HDP-2, decreased intermembrane phospholipid exchange, and reduced phospholipid polymorphism. Using AutoDock software, we show that the NHδ+ group of the sphingosine backbone of SM binds to Tyr22(C=Opbδ–) of HDP-2 via a hydrogen bond which keeps only the polar head of SM inside the HDP-2's active center and positions the sn-2 acyl ester bond away from the active center, thus making it unlikely to hydrolyze the alkyl chains at the sn-2 position. This observation strongly suggests that SM inhibits the catalytic activity of HDP-2 by blocking access to other phospholipids to the active center of the enzyme. Should this observation be verified in further studies, it would offer a tantalizing opportunity for developing effective pharmaceuticals to stop the demyelination of nerve fibers by aberrant PLA2s with overt activity – as observed in brain degenerative diseases – by inhibiting SM hydrolysis and/or facilitating SM synthesis in the myelin sheath membrane. Binding of sphingomyelin (SM) to catalytic subunits of HDP-2 predicted by Autodock. SM is given in sticks representation and HDP-2P is displayed in molecular surface (A) and line stick representation (B). For the stick diagrams, emerald represents carbon, blue–nitrogen, orange–phosphorus, red–oxygen, white–hydrogen. For molecular surface and lines, green represents carbon, blue–nitrogen, red–oxygen, white–hydrogen, yellow–sulfur. Yellow broken lines identify intermolecular bonds. Arrows point to sn-2 bonds. Hydrogen bond between NHδ+ group and Tyr22(C=Opbδ–) and ionic bond between PO4– group and His48 drive the positioning of the sn-2 acyl ester bond away from the active center that suggests that SM binds non-productively in the active center of HDP-2 enzyme. [ABSTRACT FROM AUTHOR]

Background: Huntington disease (HD) is a progressive neurodegenerative disease that causes psychiatric and neurological symptoms, including involuntary and irregular muscle movements (chorea). Chorea can disrupt activities of daily living, pose safety issues, and may lead to social withdrawal. The vesicular monoamine transporter 2 inhibitors tetrabenazine, deutetrabenazine, and valbenazine are approved treatments that can reduce chorea. Objective: This post hoc analysis was conducted to evaluate safety and efficacy among participants who received high-dosage deutetrabenazine treatment (> 48 mg/d) in ARC-HD, an open-label study that assessed long-term safety and efficacy of deutetrabenazine for the treatment of chorea in HD in adults. Methods: ARC-HD was a single-arm, two-cohort, open-label study. Participants either successfully completed the First-HD study or switched overnight from tetrabenazine to deutetrabenazine. Participants were dosed with deutetrabenazine in a response-driven manner (maximum 72 mg/d allowed). For the current analysis, exposure-adjusted incidence rates (EAIRs) for adverse events of interest were analyzed according to daily dosage (≤ 48 mg/d versus > 48 mg/d), and total maximal chorea (TMC) scores were analyzed by cohort during the stable-dose period. Results: In total, 116 of the 119 participants enrolled in ARC-HD entered the stable-dose period, where no apparent differences were seen in EAIRs when receiving deutetrabenazine dosages ≤ 48 mg/d (exposure = 177.7 person-years) compared with > 48 mg/d (exposure = 74.1 person-years). Similar results were found among the subset of participants who received deutetrabenazine dosages > 48 mg/d at least once during the study (n = 49, 42%) when their dosage was ≤ 48 mg/d (exposure = 37.9 person-years) versus > 48 mg/d (74.1 person-years). Efficacy analyses were conducted for participants who had TMC scores available (rollover cohort, n = 77; switch cohort, n = 35). For most participants, the lowest deutetrabenazine dosage needed to achieve a TMC response (≥ 30% improvement from baseline) was between 24 and 48 mg/d in both the rollover (n = 57, 74.0%) and switch (n = 16, 46.0%) cohorts. Whereas the dosage needed for a TMC response was independent of baseline TMC score in the rollover cohort, participants with higher baseline TMC scores in the switch cohort required higher dosages to achieve a TMC response during the trial. Conclusions: In this open-label, long-term study, some participants received deutetrabenazine dosing > 48 mg/d to achieve adequate chorea control. There was no new safety concern or incremental change in the safety profile between dosages of ≤ 48 mg/d and > 48 mg/d. These results include dosages that have not been approved for clinical use, however, they increase our understanding of safety and tolerability of deutetrabenazine doses. Clinical Trials Registration: ARC-HD (ClinicalTrials.gov identifier: NCT01897896); First-HD (ClinicalTrials.gov identifier: NCT01795859). Plain Language Summary: ARC-HD was a medical study in which participants took a medicine called deutetrabenazine. Deutetrabenazine is used to treat unplanned movements known as chorea, which happen in participants who have Huntington disease. At the start of the ARC-HD study, all participants took 6 milligrams per day (mg/d) of the medicine. Each week, the doctor could give them more medicine, but not more than 72 mg/d. The doctor checked if the medicine helped to lower their chorea and if any safety concerns occurred. The highest amount of the medicine that is allowed in the USA is 48 mg/d. Some participants took more than that. We wanted to learn more about the safety (side effects) and the chorea in participants who took more than 48 mg/d. Participants who took more than 48 mg/d had no new side effects of interest. They also reported the same number of side effects as participants who took 48 mg/d or less. For most participants, the lowest amount of medicine they needed to lower their chorea was between 24 and 48 mg/d. [ABSTRACT FROM AUTHOR]

Fluid biomarkers play important roles in many aspects of neurodegenerative diseases, such as Huntington’s disease (HD). However, a main question relates to how well levels of biomarkers measured in CSF are correlated with those measured in peripheral fluids, such as blood or saliva. In this study, we quantified levels of four neurodegenerative disease-related proteins, neurofilament light (NfL), total tau (t-tau), glial fibrillary acidic protein (GFAP) and YKL-40 in matched CSF, plasma and saliva samples from Huntingtin (HTT) gene-positive individuals (n = 21) using electrochemiluminescence assays. In addition, salivary levels of NfL, t-tau, and GFAP were quantified from a larger cohort (n = 95). We found both positive and negative correlations in the levels of these biomarkers among different biofluids. Most notably, in contrast to the significant positive correlations observed between CSF and plasma levels for NfL and GFAP, we detected significant negative correlations between the CSF and saliva levels of NfL and GFAP. With regard to clinical measures, both plasma and CSF levels of NfL were significantly positively correlated with Total Motor Score and chorea, whereas saliva levels of NfL showed significant correlations in the opposite direction. Additional correlations between salivary biomarkers with clinical data, adjusting for age, sex and CAG repeat length, confirmed that salivary NfL was significantly negatively associated with chorea scores in manifest HD, but not premanifest (PM), individuals. In contrast, salivary t-tau was positively associated with measures of cognition in PM participants. These findings suggest that salivary levels of NfL and t-tau proteins may exemplify non-invasive biomarkers for disease symptoms at different stages of illness. Further, these findings highlight the notion that different forms of disease proteins exist in different biological fluids. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) involves a complex interplay between immune-mediated inflammation and neurodegeneration. Recent advances in biomarker research have provided new insights into the molecular underpinnings of MS, including ferritin, neurogranin, Triggering Receptor Expressed on Myeloid cells 2 (TREM2), and neurofilaments light chain. Objectives: This pilot study aims to investigate the levels of these biomarkers in the cerebrospinal fluid (CSF) of MS patients and explore their associations with clinical, cognitive, and optical coherence tomography (OCT) parameters. Methods: This cross-sectional pilot study included 26 patients with relapsing MS (RMS) and 13 symptomatic controls (SCs). Clinical, cognitive, and OCT assessments were performed, and CSF samples were analyzed for ferritin, neurogranin, TREM2, and neurofilaments. Results: Neurogranin levels were significantly higher in RMS patients compared to SCs (p = 0.04), and the receiver-operating characteristic (ROC) analysis indicated that neurogranin could be considered a disease biomarker (AUC = 0.733, p = 0.01). Ferritin and neurogranin showed a strong positive correlation (r = 0.690, p < 0.01), and both were inversely correlated with retinal ganglion cell layer (GCL) thickness. TREM2 was positively associated with baseline Expanded Disability Status Scale score. Conclusion: This pilot study suggests that neurogranin may be a potential biomarker at the time of MS diagnosis, and the interplay between ferritin, neurogranin, and TREM2 highlights the complex relationship between inflammation, oxidative stress, and neuronal damage in MS. The inverse association of ferritin and neurogranin with GCL thickness warrants further investigation into the role of iron metabolism and synaptic damage in the early stages of the disease. [ABSTRACT FROM AUTHOR]

Ataxia-Telangiectasia (A-T) is a very rare multisystem disease of DNA repair, associated with progressive disabling neurological symptoms, respiratory failure, immunodeficiency and cancer predisposition, leading to premature death. There are no curative treatments available for A-T but clinical trials have begun. A major limiting factor in effectively evaluating therapies for A-T is the lack of suitable outcome measures and biomarkers. We have performed a systematic review to collect the information currently available on biomarkers for A-T both in patients and preclinical studies. We have identified 56 reports discussing potential A-T biomarkers in both pre-clinical models and patients. These studies report on diagnostic biomarkers but prognostic biomarkers and responsive markers of clinical status are currently lacking. Some biomarkers of neurodegeneration in A-T show promise, including non-invasive neuroimaging biomarkers. Some biomarkers of oxidative stress and responsive markers to radiotherapy and steroid treatment have potential value in clinical trials. The formation of the A-T biomarker working group with international experts is an important step forward to facilitate the sharing of materials, data and expertise with the common goal of finding effective biomarkers for A-T. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of isolated REM sleep behavior disorder (IRBD) requires video polysomnography (V-PSG) showing increased muscle activity and abnormal behaviors in REM sleep. Objective: To describe in IRBD the behavioral manifestations occurring during REM sleep in the diagnostic V-PSG. Methods: This is a systematic audiovisual V-PSG analysis of consecutive IRBD patients. According to the International RBD Study Group recommendations, REM sleep movements and vocalizations were classified into categories and severity. Results: We analyzed the V-PSG of 62 IRBD patients with a mean age of 67.6 ± 8.1 years. Of 6,330 30-s epochs of REM sleep, 55.1% epochs exhibited motor events, 5.5% contained vocalizations and 39.4% were silent. Among the epochs with motor manifestations, 66.1% contained simple minor movements, 25.0% simple major and 8.9% complex movements. Motor severity of the epochs was mild in 82.2%, moderate in 13.2% and severe in 4.6%. Most movements were bilateral (62.4%) and located in the upper limbs (42.5%). Of the epochs with vocalizations, 61.5% were simple minor, 20.7% complex and 17.8% simple major of mild (72.7%), moderate (23.0%) and severe (4.3%) severity. Complex movements occurred in 87.1% of the patients and complex vocalizations in 38.7%. Conclusions: In IRBD, the most common manifestations in REM sleep are simple minor movements and vocalizations of mild intensity. Complex movements are observed during REM sleep in most patients but are much less frequent than simple minor and major motor events. These findings should be considered for the routine diagnosis of IRBD when reviewing the V-PSG studies. [ABSTRACT FROM AUTHOR]

Neurodegeneration involves a wide range of neuropathological alterations affecting the integrity, physiology, and architecture of neural cells. Many studies have demonstrated neurodegeneration in different animals. In the case of Alzheimer's disease (AD), spontaneous animal models should display two neurohistopathological hallmarks: the deposition of β-amyloid and the arrangement of neurofibrillary tangles. However, no natural animal models that fulfill these conditions have been reported and most research into AD has been performed using transgenic rodents. Recent studies have also demonstrated that toothed whales - homeothermic, long-lived, top predatory marine mammals - show neuropathological signs of AD-like pathology. The neuropathological hallmarks in these cetaceans could help to better understand their endangered health as well as neurodegenerative diseases in humans. This systematic review analyzes all the literature published to date on this trending topic and the proposed causes for neurodegeneration in these iconic marine mammals are approached in the context of One Health/Planetary Health and translational medicine. [ABSTRACT FROM AUTHOR]

Human microbiota is known to influence immune and cerebral responses by direct and/or indirect mechanisms, including hypothalamic–pituitary–adrenal axis signaling, activation of neural afferent circuits to the brain, and by altering the peripheral immune responses (cellular and humoral immune function, circulatory inflammatory cells, and the production of several inflammatory mediators, such as cytokines, chemokines, and reactive oxygen species). The inflammatory responses in the nasal mucosa (rhinitis) or paranasal sinuses (chronic rhinosinusitis) are dual conditions related with a greater risk for developing depression. In the nasal cavity, anatomic components of the olfactive function are in direct contact with the CNS through the olfactory receptors, neurons, and axons that end in the olfactory bulb and the entorhinal cortex. Local microbiome alterations (dysbiosis) are linked to transepithelial translocation of microorganisms and their metabolites, which disrupts the epithelial barrier and favors vascular permeability, increasing the levels of several inflammatory molecules (both cytokines and non-cytokine mediators: extracellular vesicles (exosomes) and neuropeptides), triggering local inflammation (rhinitis) and the spread of these components into the central nervous system (neuroinflammation). In this review, we discuss the role of microbiota-related immunity in conditions affecting the nasal mucosa (chronic rhinosinusitis and allergic rhinitis) and their relevance in major depressive disorders, focusing on the few mechanisms known to be involved and providing some hypothetical proposals on the pathophysiology of depression. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an unknown pathogenesis. It has been reported that mutations in the gene for Cu/Zn superoxide dismutase (SOD1) cause familial ALS. Mutant SOD1 undergoes aggregation and forms amyloid more easily, and SOD1-immunopositive inclusions have been observed in the spinal cords of ALS patients. Because of this, SOD1 aggregation is thought to be related to the pathogenesis of ALS. Some core regions of amyloid have been identified, but the issue of whether these regions form aggregates in living cells remains unclear, and the mechanism responsible for intracellular SOD1 aggregation also remains unclear. The findings reported in this study indicate that the aggregation of the ALS-linked mutant SOD1-EGFP was significantly enhanced when the BioID2 gene was fused to the N-terminus of the mutant SOD1-EGFP plasmid for cellular expression. Expression of a series of BioID2-(C-terminal deletion peptides of SOD1)-EGFP permitted us to identify 1–35 as a minimal N-terminal sequence and Ile35 as an essential amino acid residue that contributes to the intracellular aggregation of SOD1. The findings also showed that an additional substitution of Ile35 with Ser into the ALS mutant SOD1 resulted in the significant suppression of aggregate formation. The fact that no Ile35 mutations have been reported to date in ALS patients indicates that all ALS mutant SOD1s contain Ile35. Taken together, we propose that Ile35 plays a pivotal role in the aggregation of the ALS-linked SOD1 and that this study will contribute to our understanding of the mechanism responsible for SOD1 aggregation. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) plays a pivotal role in neuronal development, synaptic plasticity, and overall neuronal health by binding to its receptor, tyrosine receptor kinase B (TrkB). This review delves into the intricate mechanisms through which BDNF-TrkB signaling influences mitochondrial function and potentially influences pathology in neurodegenerative diseases. This review highlights the BDNF-TrkB signaling pathway which regulates mitochondrial bioenergetics, biogenesis, and dynamics, mitochondrial processes vital for synaptic transmission and plasticity. Furthermore, we explore how the BDNF-TrkB-PKA signaling in the cytosol and in mitochondria affects mitochondrial transport and distribution and mitochondrial content, which is crucial for supporting the energy demands of synapses. The dysregulation of this signaling pathway is linked to various neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by mitochondrial dysfunction and reduced BDNF expression. By examining seminal studies that have characterized this signaling pathway in health and disease, the present review underscores the potential of enhancing BDNF-TrkB signaling to mitigate mitochondrial dysfunction in neurodegenerative diseases, offering insights into therapeutic strategies to enhance neuronal resilience and function. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) poses a significant health challenge worldwide, affecting millions of individuals, and projected to increase further as the global population ages. Current pharmacological interventions primarily target acetylcholine deficiency and amyloid plaque formation, but offer limited efficacy and are often associated with adverse effects. Given the multifactorial nature of AD, there is a critical need for novel therapeutic approaches that simultaneously target multiple pathological pathways. Targeting key enzymes involved in AD pathophysiology, such as acetylcholinesterase, butyrylcholinesterase, beta-site APP cleaving enzyme 1 (BACE1), and gamma-secretase, is a potential strategy to mitigate disease progression. To this end, our research group has conducted comprehensive in silico screening to identify some lead compounds, including IQ6 (SSZ), capable of simultaneously inhibiting the enzymes mentioned above. Building upon this foundation, we synthesized SSZ, a novel multitargeted ligand/inhibitor to address various pathological mechanisms underlying AD. Chemically, SSZ exhibits pharmacological properties conducive to AD treatment, featuring pyrrolopyridine and N-cyclohexyl groups. Preclinical experimental evaluation of SSZ in AD rat model showed promising results, with notable improvements in behavioral and cognitive parameters. Specifically, SSZ treatment enhanced locomotor activity, ameliorated gait abnormalities, and improved cognitive function compared to untreated AD rats. Furthermore, brain morphological analysis demonstrated the neuroprotective effects of SSZ, attenuating Aβ-induced neuronal damage and preserving brain morphology. Combined treatment of SSZ and conventional drugs (DON and MEM) showed synergistic effects, suggesting a potential therapeutic strategy for AD management. Overall, our study highlights the efficacy of multitargeted ligands like SSZ in combating AD by addressing the complex etiology of the disease. Further research is needed to elucidate the full therapeutic potential of SSZ and the exploration of similar compounds in clinical settings, offering hope for an effective AD treatment in the future. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles are the key players responsible for the pathogenesis of the disease. The accumulation of Aβ plaques and tau affect the balance in chemical neurotransmitters in the brain. Thus, the current review examined the role of neurotransmitters in the pathogenesis of Alzheimer's disease and discusses the alterations in the neurochemical activity and cross talk with their receptors and transporters. In the presence of Aβ plaques and neurofibrillary tangles, changes may occur in the expression of neuronal receptors which in turn triggers excessive release of glutamate into the synaptic cleft contributing to cell death and neuronal damage. The GABAergic system may also be affected by AD pathology in a similar way. In addition, decreased receptors in the cholinergic system and dysfunction in the dopamine neurotransmission of AD pathology may also contribute to the damage to cognitive function. Moreover, the presence of deficiencies in noradrenergic neurons within the locus coeruleus in AD suggests that noradrenergic stimulation could be useful in addressing its pathophysiology. The regulation of melatonin, known for its effectiveness in enhancing cognitive function and preventing Aβ accumulation, along with the involvement of the serotonergic system and histaminergic system in cognition and memory, becomes remarkable for promoting neurotransmission in AD. Additionally, nitric oxide and adenosine-based therapeutic approaches play a protective role in AD by preventing neuroinflammation. Overall, neurotransmitter-based therapeutic strategies emerge as pivotal for addressing neurotransmitter homeostasis and neurotransmission in the context of AD. This review discussed the potential for neurotransmitter-based drugs to be effective in slowing and correcting the neurodegenerative processes in AD by targeting the neurochemical imbalance in the brain. Therefore, neurotransmitter-based drugs could serve as a future therapeutic strategy to tackle AD. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is characterised primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. We have shown previously that resting-state EEG captures dysfunction in motor and cognitive networks in ALS. However, the longitudinal development of these dysfunctional patterns, especially in networks linked with cognitive-behavioural functions, remains unclear. Longitudinal studies on non-motor changes in ALS are essential to further develop our understanding of disease progression, improve care and enhance the evaluation of new treatments. To address this gap, we examined 124 ALS individuals with 128-channel resting-state EEG recordings, categorised by cognitive impairment (ALSci, n = 25), behavioural impairment (ALSbi, n = 58), or non-impaired (ALSncbi, n = 53), with 12 participants meeting the criteria for both ALSci and ALSbi. Using linear mixed-effects models, we characterised the general and phenotype-specific longitudinal changes in brain network, and their association with cognitive performance, behaviour changes, fine motor symptoms, and survival. Our findings revealed a significant decline in -band spectral power over time in the temporal region along with increased -band power in the fronto-temporal region in the ALS group. ALSncbi participants showed widespread β-band synchrony decrease, while ALSci participants exhibited increased co-modulation correlated with verbal fluency decline. Longitudinal network-level changes were specific of ALS subgroups and correlated with motor, cognitive, and behavioural decline, as well as with survival. Spectral EEG measures can longitudinally track abnormal network patterns, serving as a candidate stratification tool for clinical trials and personalised treatments in ALS. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) constitutes a significant global health issue. In the next 40 years, it is expected to affect 106 million people. Although more and more people are getting AD, there are still no effective drugs to treat it. Insightful information about how important it is to find and treat AD quickly. Recently, Deep Learning (DL) techniques have been used more and more to diagnose AD. They claim better accuracy in drug reuse, medication recognition, and labeling. This essay meticulously examines the works that have talked about using DL with Alzheimer's disease. Some of the methods are Natural Language Processing (NLP), drug reuse, classification, and identification. Concerning these methods, we examine their pros and cons, paying special attention to how easily they can be explained, how safe they are, and how they can be used in medical situations. One important finding is that Convolutional Neural Networks (CNNs) are most often used for AD research and Python is most often used for DL issues. Some security problems, like data protection and model stability, are not looked at enough in the present research, according to us. This study thoroughly examines present methods and also points out areas that need more work, like better data integration and AI systems that can be explained. The findings should help guide more research and speed up the creation of DL-based AD identification tools in the future. [ABSTRACT FROM AUTHOR]

Toxic milk (txJ) is an autosomal recessive mutation in the Atp7b gene in the C3H/HeJ strain, observed at The Jackson Laboratory in Maine, USA. TxJ mice exhibit symptoms similar to those of human Wilson's disease (WD). The study aimed to verify organ involvement in a mouse model of WD. TxJ mice and control animals were sacrificed at 2, 4, 8, and 14 months of age. Total X-ray Fluorescence Spectroscopy (TXRF) was used to determine the elemental concentration in organs. Tissue chemical composition was measured by Fourier Transform Infrared Spectroscopy (FTIR). Additionally, hybrid mapping of FTIR and microXRF was performed. Elevated concentrations of Cu were observed in the liver, striatum, eye, heart, and duodenum of txJ mice across age groups. In the striatum of the oldest txJ mice, there was lower lipid content and a higher fraction of saturated fats. The secondary structure of striatum proteins was disturbed in txJ mice. In the livers of txJ mice, higher concentrations of saturated fats and disturbances in the secondary structure of proteins were observed. The concentration of neurofilaments was significantly higher in txJ serum. The distribution of Cu deposits in brains was uniform with no prevalence in any anatomic structure in either group, but significant protein structure changes were observed exclusively in the striatum of txJ. In this txJ animal model of WD, pathologic copper accumulation occurs in the duodenum, heart, and eye tissues. Increased copper concentration in the liver and brain results in increased saturated fat content and disturbances in secondary protein structure, leading to hepatic injury and neurodegeneration. [ABSTRACT FROM AUTHOR]

Aging is a worldwide socioeconomic burden. Cerebellar aging is an enigma contributing to many behavioral aging disorders, hence is its hindering by prophylactic measurements is a crucial geriatric research target. Red dragon fruit (RDF) is a tropical fruit with antioxidant, anti-inflammatory and anti-apoptotic properties. This study aimed to determine the protective effect of RDF extract against cerebellar aging. Thirty-two male albino rats were randomly allocated into 4 groups: Control, RDF, aged and RDF-aged groups. Aged group revealed structural distortion affecting cerebellar layers including a significant (P < 0.05) decrease in Purkinje cells number and decrease in granular cell layer thickness by comparison to the control and RDF groups. Additionally, distorted capillary endothelium, and defective myelination were noticed. Interestingly, cerebellar active caspase-3, iNOS, MDA and 3-NT and serum TNF-α levels significantly increased with aging by comparison to the control and RDF groups (all P < 0.05). Biochemical analysis revealed a significant (P < 0.05) decrease in cerebellar SOD and serum GSH levels in aged rats. RDF extract remarkably ameliorated most of the neuronal degenerative changes with a significant (P < 0.05) increase in Purkinje cells numbers, and granular cell layer thickness by comparison to the aged group. Furthermore, it resulted in a significant (P < 0.05) decrease in cerebellum expression of active caspase-3, iNOS, MDA, 3-NT, and serum TNF-α levels associated with a significant (P < 0.05) increase in cerebellar SOD and serum GSH levels by comparison to the aged group. To the best of our knowledge this is the first study showing a neuroprotective effect for RDF against cerebellar aging. RDF might be effective in attenuation of age-induced cerebellar degenerative changes through its anti-apoptotic, antioxidant and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

This narrative review explores the relationship between air pollution and neurodegenerative diseases (NDs). Historically, air pollution has been linked primarily to respiratory and cardiovascular issues, but recent evidence suggests that it may also impact neurological health. With the global increase in neurodegenerative diseases, understanding environmental risk factors has become crucial. The review synthesizes findings from recent studies, highlighting the potential role of air pollutants—particularly fine particulate matter (PM2.5), ozone, nitrogen dioxide (NO2), and heavy metals—in the onset and progression of NDs. Key mechanisms under investigation include brain inflammation and microglial activation, which are believed to contribute to neurodegenerative processes. Animal and human studies have shown correlations between air pollution exposure and increased risk of cognitive decline and neurodegenerative disorders. Research indicates that air pollution may exacerbate neuroinflammation and cause white matter abnormalities, which disrupt neural communication and cognitive function. Additionally, emerging evidence suggests that environmental factors like residential greenness and climate action could mitigate some of these adverse effects. Despite advancements, significant knowledge gaps remain, particularly regarding the long-term impact of chronic exposure and the specific molecular pathways involved. This review shows the need for further research to clarify these mechanisms and develop targeted interventions. Addressing air pollution's impact on neurodegenerative diseases requires comprehensive public health strategies, including stricter environmental regulations and increased awareness, alongside continued research into preventive and therapeutic measures. [ABSTRACT FROM AUTHOR]

Myelin loss induces neural dysfunction and contributes to the pathophysiology of neurodegenerative diseases, injury conditions, and aging. Because remyelination is often incomplete, better understanding endogenous remyelination and developing remyelination therapies that restore neural function are clinical imperatives. Here, we use in vivo two-photon microscopy and electrophysiology to study the dynamics of endogenous and therapeutic-induced cortical remyelination and functional recovery after cuprizone-mediated demyelination in mice. We focus on the visual pathway, which is uniquely positioned to provide insights into structure-function relationships during de/remyelination. We show endogenous remyelination is driven by recent oligodendrocyte loss and is highly efficacious following mild demyelination, but fails to restore the oligodendrocyte population when high rates of oligodendrocyte loss occur quickly. Testing a thyromimetic (LL-341070) compared to clemastine, we find it better enhances oligodendrocyte gain and hastens recovery of neuronal function. The therapeutic benefit of the thyromimetic is temporally restricted, and it acts exclusively following moderate to severe demyelination, eliminating the endogenous remyelination deficit. However, we find regeneration of oligodendrocytes and myelin to healthy levels is not necessary for recovery of visual neuronal function. These findings advance our understanding of remyelination and its impact on functional recovery to inform future therapeutic strategies. Remyelination can restore neural function. Here, the authors characterize the drivers and limits of endogenous remyelination and explore a therapy that rescued remyelination deficits and accelerated neuronal functional recovery, although complete remyelination was not required. [ABSTRACT FROM AUTHOR]

Cerebral microbleeds (CMBs) are small, hypointense hemosiderin deposits in the brain measuring 2–10 mm in diameter. As one of the important biomarkers of small vessel disease, they have been associated with various neurodegenerative and cerebrovascular diseases. Hence, automated detection, and subsequent extraction of clinically useful metrics (e.g., size and spatial distribution) from CMBs are essential for investigating their clinical impact, especially in large-scale studies. While some work has been done for CMB segmentation, extraction of clinically relevant information is not yet explored. Herein, we propose the first automated method to characterise CMBs using their size and spatial distribution, i.e., CMB count in three regions (and their substructures) used in Microbleed Anatomical Rating Scale (MARS): infratentorial, deep, and lobar. Our method uses structural atlases of the brain for determining individual regions. On an intracerebral haemorrhage study dataset, we achieved a mean absolute error of 2.5 mm for size estimation and an overall accuracy > 90% for automated rating. The code and the atlas of MARS regions in Montreal Neurological Institute—MNI space are publicly available. Relevance statement: Our method to automatically characterise cerebral microbleeds (size and location) showed a mean absolute error of 2.5 mm for size estimation and an over 90% accuracy for rating of infratentorial, deep and lobar regions. This is a promising approach to automatically provide clinically relevant cerebral microbleeds metrics. Key Points: We present a method to automatically characterise cerebral microbleeds according to size and location. The method achieved a mean absolute error of 2.5 mm for size estimation. Automated rating for infratentorial, deep, and lobar regions achieved an over 90% overall accuracy. We made the code and atlas of Microbleed Anatomical Rating Scale regions publicly available. [ABSTRACT FROM AUTHOR]

Nicotinamide Adenine Dinucleotide (NAD+) is implicated in bioenergetics, DNA repair, and senescence. Depletion of NAD+ is associated with aging and neurodegenerative disease, prompting a growing interest in NAD+ supplementation. With rising over-the-counter use of NAD, understanding their impact on anesthetic recovery becomes essential. This study investigates the effect of NADH, a common NAD+ precursor, on anesthesia in rodents. Baseline and post-anesthesia (1.5% isoflurane) open field and Y-maze activity were recorded in adult male and female C57BL/6 mice (n = 8–10/group). NADH (150 mg/kg, intraperitoneal) or vehicle (0.9% normal saline) were given at baseline or during anesthesia. The NADH-treated group exhibited a significant decrease in open-field activity relative to vehicle-treated. This diminished activity was reflected in reduced distance travelled and average velocity after emergence from anesthesia in the NADH-treated group. NADH treatment did not improve Y-maze performance after anesthesia, partly related to reduced locomotor activity in the NADH-treated group. This study demonstrates that NADH does not appear to hasten recovery from anesthesia. Instead, there was a depression in open-field activity and no change in Y-maze performance with NADH supplementation, indicators of locomotive and cognitive recovery in rodents. The broad implications of NAD+ in aging are likely to shape supplementation trends, highlighting the importance of understanding the potential influence of administering NAD+ on anesthetic sensitivity and recovery. [ABSTRACT FROM AUTHOR]

An aberrant pro-inflammatory microglia response has been associated with most neurodegenerative disorders. Identifying microglia druggable checkpoints to restore their physiological functions is an emerging challenge. Recent data have shown that microglia produce de novo neurosteroids, endogenous molecules exerting potent anti-inflammatory activity. Here, the role of neurosteroidogenesis in the modulation of microgliosis was explored in human microglia cells. In particular, CYP11A1 inhibition or TSPO pharmacological stimulation, crucial proteins involved in the rate limiting step of the neurosteroidogenic cascade, were employed. CYP11A1 inhibition led microglia to acquire a dysfunctional and hyperreactive phenotype, while selective TSPO ligands promoted the establishment of an anti-inflammatory one. Analysis of specific neurosteroid levels (neurosteroidome) identified allopregnanolone/pregnanolone as crucial metabolites allowing controlled activation of microglia. Importantly, the neurosteroid shift towards a greater androgenic/estrogenic profile supported the transition from pro-inflammatory to neuroprotective microglia, suggesting the therapeutic potential of de novo microglial neurosteroidogenesis stimulation for neuroinflammatory-related disorders. [ABSTRACT FROM AUTHOR]

Fatigue is prevalent in immune-mediated inflammatory and neurodegenerative diseases, yet its assessment relies largely on patient-reported outcomes, which capture perception but not fluctuations over time. Wearable sensors, like inertial measurement units (IMUs), offer a way to monitor daily activities and evaluate functional capacity. This study investigates the relationship between sit-to-stand and stand-to-sit transitions and self-reported physical and mental fatigue in participants with Parkinson's, Huntington's, rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren's syndrome and inflammatory bowel disease. Over 4 weeks, participants wore an IMU and reported fatigue levels four times daily. Using mixed-effects models, associations were identified between fatigue and specific kinematic features, such as 5th and 95th percentiles of sit-to-stand performance, suggesting that fatigue alters the control and effort of movement. These kinematic features show promise as indicators for fatigue in these patient populations. [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder characterized by physical, cognitive, and behavioral impairments. The PSP Rating Scale (PSPRS) is a widely used and validated, clinical scale to monitor disease progression. Here we show the modification of PSPRS to improve clinical meaningfulness and sensitivity. A conceptual framework was used to select meaningful items. Datasets were analyzed to improve the psychometric properties, understand factor structure, and develop a scoring algorithm. Fifteen items of the PSPRS were selected based on whether the items reflect concepts specific to the disease and those responsive to change over 12 months. Some items were rescored to reflect meaningful changes and to improve discrimination and reliability. The rescored 15-item PSPRS was more interpretable and sensitive to disease progression over 12 months. The approach to develop the 15-item PSPRS provides an example of how to modify an existing clinical outcome assessment for use as a primary endpoint in a clinical trial of a progressive neurological disorder. The Progressive Supranuclear Palsy Rating Scale (PSPRS) was modified to improve clinical meaningfulness and sensitivity. Fifteen items were selected, and rescored PSPRS was more practical and sensitive to disease progression over 12 months. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC)-6 has overwhelming implications in multiple cancers and neurodegenerative disorders. Unusual HDAC6 expression modulates various signalling mechanisms which in turn forms the aetiology of the above-mentioned disorders. Thus, restoring the typical activity of HDAC6 through small molecules may prove as a promising approach to beat these disorders. Herein, we employed an integrated approach for exploring the high binding affinity manifesting molecules against HDAC6. We screened the entire PubChem database using Tubastatin A as the reference (query) molecule following which we carried out 110 molecular docking (XP-mode) and 110 MM-GBSA experiments. Thirty-three molecules demonstrated raised binding affinity than query in the HDAC6 active site. Further, the top 3 binders selected on logical grounds were subjected to interaction study, two hit molecules and tubastatin-A were subjected to convoluted molecular dynamics and three-dimensional e-Pharmacophores mapping was done to delineate the rationale behind the high binding tendency of hit molecules over control molecule. This work provides a solid foundation for additional research towards the development of lead molecules from the said hits for therapeutic intervention against HDAC6 overexpression-driven disorders. [ABSTRACT FROM AUTHOR]

Since it first appeared, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has had a significant and lasting negative impact on the health and economies of millions of individuals all over the globe. At the level of individual health too, many patients are not recovering fully and experiencing a long-term condition now commonly termed 'long-COVID'. Long-COVID is a collection of symptoms which must last more than 12 weeks following initial COVID infection, and which cannot be adequately explained by alternate diagnoses. The neurological and psychosocial impact of long-COVID is itself now a global health crisis and therefore preventing, diagnosing, and managing these patients is of paramount importance. This review focuses primarily on: neurological functioning deficits; mental health impacts; long-term mood problems; and associated psychosocial issues, among patients suffering from long-COVID with an eye towards the neurological basis of these symptoms. A concise account of the clinical relevance of the neurological and psychosocial impacts of long-COVID, the effects on long-term morbidity, and varied approaches in managing patients with significant chronic neurological symptoms and conditions was extracted from the literature, analysed and reported. A comprehensive account of plausible pathophysiological mechanisms involved in the development of long-COVID, its management, and future research needs have been discussed. [ABSTRACT FROM AUTHOR]

Objective: To explore retinal changes in patients with Dementia with Lewy Bodies (DLB) using Spectral Domain-Optical Coherence Tomography (SD-OCT) and Optical Coherence Tomography Angiography (OCTA), aiming to identify potential biomarkers for diagnosis and monitoring. Methods: A cross-sectional study analyzed 15 DLB patients and 18 matched controls. Participants underwent physical, neurological, neuropsychological, and ophthalmological evaluations, including SD-OCT and OCTA. Logistic regression, adjusted for age, sex, and inter-eye correlation, was employed to identify retinal alterations in patients affected by DLB. Results: OCTA revealed that DLB is associated with reduced superficial and deep vessel densities (SVD and DVD) in the macula (p < 0.01), as well as decreased peripapillary vessel density (ppVD, p < 0.01). SD-OCT parameters showed correlations with DLB, including reduced central macular thickness (CMT, p < 0.001) and thinning of the ganglion cell layer-inner plexiform layer (GCL-IPL, p < 0.01). Logistic regression (R²=0.26) identified reduced ppVD as a significant predictor of DLB (p = 0.030). Conclusions: Impairments in retinal capillaries, especially lower ppVD, might mirror cerebral hypoperfusion in DLB, potentially due to reduced Vascular Endothelial Growth Factor (VEGF) levels and increased α-synuclein. Further investigations are warranted to confirm the causal relationship between these observations, disease severity, and progression, as well as their potential role as biomarkers for DLB. [ABSTRACT FROM AUTHOR]

Despite offering significant conveniences, plastic materials contribute substantially in developing environmental hazards and pollutants. Plastic trash that has not been adequately managed may eventually break down into fragments caused by human or ecological factors. Arguably, the crucial element for determining the biological toxicities of plastics are micro/nano-forms of plastics (MPs/NPs), which infiltrate the mammalian tissue through different media and routes. Infiltration of MPs/NPs across the intestinal barrier leads to microbial architectural dysfunction, which further modulates the population of gastrointestinal microbes. Thereby, it triggers inflammatory mediators (e.g., IL-1α/β, TNF-α, and IFN-γ) by activating specific receptors located in the gut barrier. Mounting evidence indicates that MPs/NPs disrupt host pathophysiological function through modification of junctional proteins and effector cells. Moreover, the alteration of microbial diversity by MPs/NPs causes the breakdown of the blood–brain barrier and translocation of metabolites (e.g., SCFAs, LPS) through the vagus nerve. Potent penetration affects the neuronal networks, neuronal protein accumulation, acceleration of oxidative stress, and alteration of neurofibrillary tangles, and hinders distinctive communicating pathways. Conclusively, alterations of these neurotoxic factors are possibly responsible for the associated neurodegenerative disorders due to the exposure of MPs/NPs. In this review, the hypothesis on MPs/NPs associated with gut microbial dysbiosis has been interlinked to the distinct neurological impairment through the gut–brain axis. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs, worsened in the evening, occurring at rest, and relieved temporarily by movement. Although its pathophysiology remains incompletely understood, oxidative stress has been suggested. Uric acid (UA) is a marker associated with oxidative stress, and its reduced levels pose a risk for certain neurodegenerative diseases. In this study, we aimed to assess serum UA concentrations in RLS patients to gain insights into its role in the etiopathogenesis of the condition.: This study involved 200 individuals. Serum UA levels were compared with clinical parameters. Disease severity was assessed, categorizing patients into "mild," "moderate," "severe," and "very severe" subgroups. Comparative analysis of UA levels was conducted between these subgroups and the control group. Patients exhibited a statistically significant reduction in UA levels compared to controls (p = 0.001; p < 0.01). No significant disparities in UA levels were observed among patients based on RLS scores (p > 0.05). The generalized linear model in which UA serves as the dependent variable revealed statistically significant associations with the "moderate" and "severe" stages of RLS, as well as age (p < 0.05). Additionally, a ROC curve analysis was executed to evaluate the potential of UA as a biomarker. The ROC analysis, focusing on the patient-control classification, revealed a statistically significant area under the curve (AUC = 0.848, p < 0.001). Our study supports the hypothesis implicating serum UA levels in RLS pathogenesis. Further understanding of UA and its physiological effects will clarify on its role in RLS pathophysiology. [ABSTRACT FROM AUTHOR]

Traumatic brain injuries (TBI) commonly occur following head trauma. TBI may result in short- and long-term complications which may lead to neurodegenerative consequences, including cognitive impairment post-TBI. When investigating the neurodegeneration following TBI, studies have highlighted the role reactive astrocytes have in the neuroinflammation and degeneration process. This review showcases a variety of markers that show reactive astrocyte presence under pathological conditions, including glial fibrillary acidic protein (GFAP), Crystallin Alpha-B (CRYA-B), Complement Component 3 (C3) and S100A10. Astrocyte activation may lead to white-matter inflammation, expressed as white-matter hyperintensities. Other white-matter changes in the brain following TBI include increased cortical thickness in the white matter. This review addresses the gaps in the literature regarding post-mortem human studies focussing on reactive astrocytes, alongside the potential uses of these proteins as markers in the future studies that investigate the proportions of astrocytes in the post-TBI brain has been discussed. This research may benefit future studies that focus on the role reactive astrocytes play in the post-TBI brain and may assist clinicians in managing patients who have suffered TBI. [ABSTRACT FROM AUTHOR]

People living with HIV (PLHIV) are known to be at a higher risk of developing an array of aging-related diseases despite well-adhered combined antiretroviral therapy (cART). The present study aimed to investigate the impact of chronic HIV infection on neurocognitive function in virally suppressed PLHIV. We enrolled HIV-positive individuals randomly from an ART Center in Chennai, South India. A similar number of HIV-uninfected individuals matched for age and gender with the HIV-infected individuals served as controls. All individuals provided a detailed clinical history and underwent neuropsychological assessment using the International HIV Dementia Scale (IHDS). Plasma proteome analysis was performed using the Proximity extension assay (PEA) with the Olink® neuroexploratory panel, and untargeted metabolomics was performed using Ultra-High-Performance Liquid Chromatography/Mass Spectrometry/Mass Spectrometry. Despite a median duration of 9 years on first-line cART and suppressed viremia, a significant proportion of PLHIV registered significant levels of asymptomatic neurocognitive impairment, with 71% of these individuals scoring ≤ 10 in the IHDS test. We also observed significant alterations in a number of proteins and metabolites that are known to be associated with neuroinflammation, neurodegeneration, cognitive impairment, and gastrointestinal cancers, in the PLHIV group. Thus the study provides clinical as well as laboratory evidence to substantiate the presence of asymptomatic neurocognitive impairment in a large proportion of PLHIV, despite adequate cART and undetectable viremia, thereby supporting the view that HIV infection potentiates the risk for accelerated and accentuated neurological aging. This observation highlights the need to devise and implement appropriate intervention strategies for better long term management of HIV-infected persons. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy (PN) is one of the most common disorders characterized by the dysfunction or degeneration of peripheral nerves and has many different causes. PN often causes weakness, numbness, and pain, usually in the hands and feet, which can cause physical disability and a reduced quality of life. The purpose of this study was to conduct a review of the potential neuroprotective properties of progesterone against PN. A comprehensive systematic search was performed in many electronic databases (Scopus, PubMed, and Web of Science) until January 2024, following the PRISMA principles. A total of 72 studies underwent screening based on predetermined criteria for inclusion and exclusion. Ultimately, the present systematic review comprised 18 publications that satisfied the inclusion criteria. The data indicate that progesterone medication decreases PN by inhibiting the biochemical and morphological abnormalities caused by aging, diabetes, chemotherapy, and physical injury to peripheral nerves. However, as compared to the PN groups alone, progesterone treatment demonstrated tendencies towards being anti-oxidant, anti-inflammatory, anti-nociceptive, and neurodegenerative. Other studies have shown that PN also induces substantial biochemical changes in neuronal cells and tissues. Furthermore, we observed histological changes in the peripheral nerve tissue after PN. Overall, progesterone administration reversed these biochemical and histological alterations induced by PN in the vast majority of instances. Notably, the PN is ameliorated through progesterone administration. Progesterone achieves these neuroprotective effects through the inhibition of multiple mechanisms that are implicated in PN. [ABSTRACT FROM AUTHOR]

Propionic and methylmalonic acidemias (PAcidemia and MMAcidemia, respectively) are genetic disorders characterized by acute metabolic decompensation and neurological complications. L-carnitine (LC) is effective in reducing toxic metabolites that are related to the pathophysiology of these diseases. Therefore we investigated biomarkers of inflammation (cytokines and C-reactive protein (CRP)), neurodegeneration (BDNF, NCAM-1 and cathepsin-D) and biomolecules oxidation (sulfhydryl content and thiobarbituric acid-reactive species (TBARS)), as well as carnitine concentrations in untreated patients with PAcidemia and MMAcidemia, in patients under treatment with LC and a protein-restricted diet for until 2 years and in patients under the same treatment for more than 2 years. It was verified an increase of CRP, IL-6, IL-8, TNF-α, IL-10, NCAM-1 and cathepsin-D in untreated patients compared to controls. On the other hand, reduced levels of TNF-α, CRP, IL-10, NCAM-1 and cathepsin-D were found in plasma from treated patients, as well as increased concentrations of LC. Furthermore, oxidative biomarkers were increased in untreated patients and were normalized with the prolonged treatment with LC. In conclusion, this work shows, for the first time, that inflammatory and neurodegenerative peripheral biomarkers are increased in patients with PAcidemia and MMAcidemia and that treatment with LC is effective to protect against these alterations. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) involves a complex interplay of communications between the neurons and various glial cells, which is crucial for brain functions. The major interactomes are exosomes that transmit sundry molecules (DNA, miRNAs, and proteins) between the cells and thus alter cell physiology. Exosomes can act as neuroprotective or neurodegenerative agents depending on the microenvironment of cells secreting them. Therefore, revealing exosome proteome becomes important to understand donor cells' physiology and its effect on the recipient cell. In this study, oxidative stress was induced by Aβ25-35 in the human neuroblastoma SH-SY5Y cells and the protective effects of phytochemical ferulic acid (FA) were evaluated alone and in combination with Aβ25-35 (pre-treated for 3 h before Aβ25-35 exposure) and proteome of their secreted exosomes was analyzed, which was carried out via a high-resolution LC–MS Triple-ToF and further network-based analysis has been carried out using various bioinformatics tools. The proteomic profiling enlightened the multiple roles of exosomes as proteins associated with the various pathways advocate that exosomes can mediate a wide range of effects, from normal physiological processes like synaptic plasticity, neuronal metabolic support, nerve regeneration, DNA repair, axon guidance, and long-term potentiation (LTP) to abnormal pathological processes like inflammatory responses, oxidative stress, apoptosis, and formation of neutrophil extracellular traps (NETs). On comparison, treatment with Aβ25-35 resulted in a significant modulation of the exosomal proteome, promoting pathways associated with neurodegeneration. Conversely, the phytochemical FA displayed a protective effect by effectively countering Aβ25-35-induced oxidative stress responses linked with neurodegeneration, as seen in Alzheimer’s disease (AD). Taken together, this study highlights the dual role of exosomes in physiological and pathophysiological neurodegenerative AD, which intricately depend on the particular cellular milieu. [ABSTRACT FROM AUTHOR]

Episodic memory (EM) alterations are a hallmark of Alzheimer’s disease (AD). We assessed EM longitudinally in cognitively normal elders at-risk for AD (with subjective memory complaints), as a function of amyloid-β (Aβ) burden, neurodegeneration (N), and progression to prodromal AD. We stratified 264 INSIGHT-preAD study subjects in controls (Aβ-/N−), stable/N− or N + (Aβ +), and progressors/N− or N + (Aβ +) groups (progressors were included only until AD-diagnosis). We used linear mixed-effect models with Aβ and N status, or progression to AD as factors, to analyze behavioral performance in an old/new word-recognition task based on the free and cued selective reminding test (FCSRT). The controls and stable/N− groups showed near-ceiling accuracy and RT improvement across follow-up. The stable/N + group showed accuracy reduction and no RT improvement, i.e., Aβ + /N + cumulative effect. The progressors showed a marked performance decline. EM alterations may constitute early preclinical markers of progression to prodromal AD, while individuals are cognitively normal according to neuropsychological standards. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is a prevalent, chronic neurodegenerative disorder characterised by the progressive loss of dopaminergic neurons in the substantia nigra and other brain regions. The aggregation of alpha-synuclein (α-syn) into Lewy bodies and neurites is a key pathological feature associated with PD and its progression. Many therapeutic studies aim to target these aggregated forms of α-syn to potentially slow down or stop disease progression in PD. This review provides a comprehensive analysis of recent clinical trials involving vaccines and monoclonal antibodies targeting α-syn. Specifically, UB-312, AFFITOPE PD01A, PD03A and ACI-7104.056 are designed to provoke an immune response against α-syn (active immunisation), while Prasinezumab and Cinpanemab, MEDI1341 and Lu AF82422 focus on directly targeting α-syn aggregates (passive immunisation). Despite some promising results, challenges such as variable efficacy and trial discontinuations persist. Future research must address these challenges to advance disease-modifying therapies for PD around this therapeutic target. [ABSTRACT FROM AUTHOR]

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer’s disease (AD), yet it remains under-recognized and frequently misdiagnosed due to heterogenous clinical presentations, the presence of co-pathology, and the lack of specific diagnostic tools. Pathologically, DLB is characterized by the accumulation of misfolded alpha-synuclein (aSyn) aggregates, known as Lewy bodies. Recent advancements have improved in vivo detection of aSyn pathology through techniques such as seed amplification assays, monoclonal antibodies, and positron emission tomography using novel small-molecule ligands. The ability to detect aSyn in vivo has sparked dialogue about using biomarkers to identify individuals with aSyn, similar to the approach influencing the field of AD. Proponents argue that biological staging could facilitate the detection of preclinical disease stages, allowing for earlier intervention and targets for disease modification, and could improve diagnostic sensitivity and accuracy in selecting patients for clinical trials. However, critics caution that this method may oversimplify the complexity of DLB and overlook its clinical heterogeneity, also highlighting practical challenges related to implementation, cost, and global access to advanced diagnostic technologies. Importantly, although significant progress has been made in detecting aSyn for diagnostic purposes, disease-modifying therapies targeting aSyn have yet to demonstrate clear efficacy in slowing disease progression. Elucidating the physiological and pathophysiological roles of aSyn remains an urgent priority in neurodegenerative research. Other experimental research priorities for DLB include developing improved cellular and animal models that reflect epigenetic and environmental factors, mapping post-translational modifications, and systematically characterizing neurons that are vulnerable and resistant to lewy pathology using a multi-omic approach. Clinically, there is an urgent need for international, prospective, longitudinal studies and for validated, disease-specific outcome measures. Addressing these priorities is essential for advancing our understanding of DLB and developing effective therapies. [ABSTRACT FROM AUTHOR]

Background: Neurodegenerative diseases show various phenotypes of molecular and cellular malfunction including mitochondrial dysfunction and neuroinflammation. These molecular dynamics are based on the epigenetic regulation of the gene expression in the cells, which are vulnerable to progressive neurodegeneration. Histone deacetylases (HDAC) are the enzymes that remove acetyl group from histones or non-histone proteins for the transcriptional control. Thus, HDAC inhibitors (HDACi) have been proposed as prominent drugs for neurodegenerative diseases. Objectives: In this study, we explain the molecular targets of the HDACi in the processes of neurodegeneration and neuroprotection. Results: Treatment with HDACi altered the expression of specific genes that are associated with mitochondrial bioenergetics and neuroinflammation. Conclusions: Mitochondrial bioenergetics- and neuroinflammation-related molecular targets of HDACi may be the key to the use of HDACi therapy for neurodegenerative diseases. Purpose of review: We aimed to discover molecular targets of HDACi in progressive neurodegeneration and to use these targets in potential therapeutics to induce neuroprotection. Recent findings: HDACi reverse cellular pathology in a mechanism involving mitochondrial bioenergetics and neuroinflammation, and the result is alleviation of pathologic phenotypes of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Purpose of Review: Multiple Sclerosis (MS) is a chronic inflammatory neurological disorder affecting over 2.8 million people worldwide. It is characterized by distinct phenotypes, such as relapsing-remitting MS (RRMS) and progressive forms (SPMS, PPMS). While disease-modifying therapies (DMTs) effectively target inflammation and reduce relapse rates in RRMS, they are less effective in progressive MS, where neurodegeneration becomes more prominent. This review explores the emerging role of the microtubule-associated protein tau, typically associated with neurodegenerative diseases like Alzheimer’s disease, in MS pathology and its potential as a therapeutic target. Recent Findings: Tau is primarily involved in stabilizing neuronal microtubules. Under pathological conditions, tau alters and aggregates into neurofibrillary tangles, contributing to neuronal dysfunction and degeneration. Recent studies have identified tau seeds and pathological tau in MS, particularly in and adjacent to lesions in human brain tissue and rodent models of MS. Evidence suggests a bidirectional relationship between tau pathology and inflammation, where tau drives inflammatory responses, and inflammation exacerbates tau aggregation. However, understanding the role of tau in MS remains limited, particularly in progressive forms where neurodegeneration is most severe. Summary: The involvement of tau in MS represents a promising avenue for research and therapeutic intervention, particularly in progressive forms of the disease. Addressing gaps in knowledge, such as developing better MS models, investigating tau aggregation in MS, and identifying reliable biomarkers, could pave the way for novel tau-targeted therapies. Such approaches hold the potential to mitigate neurodegeneration and improve outcomes for patients with progressive MS. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases have a complex origin and are composed of genetic and environmental factors. Both DNA damage and chromatin rearrangement are important processes that occur under pathological conditions and in neurons functioning properly. While numerous studies have demonstrated the inseparable relationship between DNA damage and chromatin organization, understanding of this relationship, especially in neurodegenerative diseases, requires further study. Interestingly, recent studies revealed that known hallmark proteins involved in neurodegenerative diseases function in both DNA damage and chromatin reorganization, and this review discusses the current knowledge of this relationship. This review focused on hallmark proteins involved in various neurodegenerative diseases, such as the microtubule-associated protein tau, TAR DNA/RNA binding protein 43 (TDP-43), superoxide dismutase 1 (SOD1), fused in sarcoma (FUS), huntingtin (HTT), α-synuclein, and β-amyloid precursor protein (APP). Hence, DNA damage and chromatin rearrangement are associated with disease mechanisms in distinct neurodegenerative diseases. Targeting common modulators of DNA repair and chromatin reorganization may lead to promising therapies for treating neurodegeneration. [ABSTRACT FROM AUTHOR]

Elastin is a stable protein present in many tissues, including brain tissues, and is one of the most long-life proteins with a half-life of approximately 70 years. The peptide with a Val-Gly-Val-Ala-Pro-Gly (VGVAPG) amino acid sequence is released during elastin decay, which correlates with aging-related neurodegeneration. A recent study has shown enhanced protein expression of Sirtuin 2 (SIRT2 – one of the redox homeostatic factors) in aged rodent brains, while the correlation between VGVAPG and SIRT2 has never been evaluated so far. Therefore, the study aimed to determine the impact of the VGVAPG hexapeptide on SIRT2 and neuronal functions in differentiated SH-SY5Y cells at the gene and protein expression levels. The present results showed that VGVAPG caused a 52.69% decrease in the level of reactive oxygen species (ROS), as in the case of neurons treated with AGK2 (Sirtuin 2 inhibitor) after 24h and 48h. Furthermore, a decrease in superoxide dismutase (SOD) activity was observed. The SIRT2 gene expression was found to fluctuate after 6h and 24h as a result of the exposure to the VGVAPG peptide. In turn, a decrease in the PPARγ, P53, SOD2, and CAT mRNA expression was shown in VGVAPG-treated cells. Additionally, an increase in the Sirtuin 2 protein expression was recorded after 24h and 48h in the VGVAPG peptide-treated neurons. Last but not least, the decrease in the level of acetylation of α-tubulin after the hexapeptide treatment was correlated with shortening of neurites, which may indicate the destabilization of the microtubule and ROS-independent induction of neurodegeneration. [ABSTRACT FROM AUTHOR]

MicroRNA (miRNA) are usually 18–25 nucleotides long non-coding RNA targeting post-transcriptional regulation of genes involved in various biological processes. The function of miRNA is essential for maintaining a homeostatic cellular condition, regulating autophagy, cellular motility, and inflammation. Dysregulation of miRNA is responsible for multiple disorders, including neurodegeneration, which has emerged as a severe problem in recent times and has verified itself as a life-threatening condition that can be understood by the continuous destruction of neurons affecting various cognitive and motor functions. Parkinson's disease (PD) is the second most common, permanently debilitating neurodegenerative disorder after Alzheimer's, mainly characterized by uncontrolled tremor, stiffness, bradykinesia or akinesia (slowness in movement), and post-traumatic stress disorder. PD is mainly caused by the demolition of the primary dopamine neurotransmitter secretory cells and dopaminergic or dopamine secretory neurons in the substantia nigra pars compacta of the midbrain, which are majorly responsible for motor functions. In this study, a systematic evaluation of research articles from year 2017 to 2022 was performed on multiple search engines, and lists of miRNA being dysregulated in PD in different body components were generated. This study highlighted miR-7, miR-124, miR-29 family, and miR-425, showing altered expression levels during PD's progression, further regulating the expression of multiple genes responsible for PD. [ABSTRACT FROM AUTHOR]

Neurodegeneration, which manifests as several chronic and incurable diseases, is an age-related condition that affects the central nervous system (CNS) and poses a significant threat to the public's health for the elderly. Recent decades have experienced an alarming increase in the incidence of neurodegenerative disorders (NDDs), a severe public health issue due to the ongoing development of people living in modern civilizations. Alzheimer's disease (AD) is a leading trigger of age-related dementia. Currently, there are no efficient therapeutics to delay, stop, or reverse the disease's course development. Several studies found that dietary bioactive phytochemicals, primarily flavonoids, influence the pathophysiological processes underlying AD. Flavonoids work well as a supplement to manufactured therapies for NDDs. Flavonoids are effective in complementing synthetic approaches to treat NDDs. They are biologically active phytochemicals with promising pharmacological activities, for instance, antiviral, anti-allergic, antiplatelet, anti-inflammatory, antitumor, anti-apoptotic, and antioxidant effects. The production of nitric oxide (NO), tumor necrosis factor (TNF-α), and oxidative stress (OS) are downregulated by flavonoids, which slow the course of AD. Hence, this research turned from preclinical evidence to feasible clinical applications to develop newer therapeutics, focusing on the therapeutic potential of flavonoids against AD. [ABSTRACT FROM AUTHOR]

Neurological conditions encompassing a wide range of disorders pose significant challenges globally. The complex interactions among signaling pathways and molecular elements play pivotal roles in the initiation and progression of neurodegenerative diseases. Isoflavones have emerged as a promising candidate to fight against neurodegenerative diseases. Daidzein, a 7-hydroxy-3-(4-hydroxyphenyl)-chromen-4-one, belongs to the isoflavone class and exhibits a diverse pharmacological profile. It is found primarily in soybeans and soy products, as well as in some other legumes and herbs. Investigations into daidzein have revealed that it confers neuroprotection by inhibiting oxidative stress, inflammation, and apoptosis, which are key contributors to neuronal damage and degeneration. Activating pathways like PI3K/Akt/mTOR and promoting neurotrophic factors like BDNF by daidzein underscore its potential in supporting neuronal function and combating neurodegeneration. Daidzein's effects on dopamine provide further avenues for intervention in conditions like Parkinson's disease. Additionally, the modulation of inflammatory and NRF-2-antioxidant signaling by daidzein reinforces its neuroprotective role. Moreover, daidzein's interaction with receptors and cellular processes like ER-β, GPR30, MAO, VEGF, and GnRH highlights its multifaceted effects across multiple pathways involved in neuroprotection and neuronal function. This review article delves into the mechanistic interplay of various mediators in mediating the neuroprotective effects of daidzein. The review article consolidates and analyzes research published over nearly two decades (2005–2024) from various databases, including PubMed, Scopus, ScienceDirect, and Web of Science, to provide a comprehensive understanding of daidzein's effects and mechanisms in neuroprotection. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, pose significant health challenges and economic burdens worldwide. Recent studies have emphasized the potential therapeutic value of activating silent information regulator-1 (SIRT1) in treating these conditions. Resveratrol, a compound known for its ability to potently activate SIRT1, has demonstrated promising neuroprotective effects by targeting the underlying mechanisms of neurodegeneration. In this review, we delve into the crucial role of resveratrol-mediated SIRT1 upregulation in improving neurodegenerative diseases. The role of the activation of SIRT1 by resveratrol was reviewed. Moreover, network pharmacology was used to elucidate the possible mechanisms of resveratrol in these diseases. Activation of SIRT1 by resveratrol had positive effects on neuronal function and survival and alleviated the hallmark features of these diseases, such as protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction. In terms of network pharmacology, the signaling pathways by which resveratrol protects against different neurodegenerative diseases were slightly different. Although the precise mechanisms underlying the neuroprotective effects of resveratrol and SIRT1 activation remain under investigation, these findings offer valuable insights into potential therapeutic strategies for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]