Neurodegenerative Processes Research Articles

Human Endogenous Retroviruses in Neurodegenerative Diseases.

Human endogenous retroviruses (HERVs) are DNA transposable elements that have integrated into the human genome via an ancestral germline infection. The potential importance of HERVs is underscored by the fact that they comprise approximately 8% of the human genome. HERVs have been implicated in the pathogenesis of neurodegenerative diseases, a group of CNS diseases characterized by a progressive loss of structure and function of neurons, resulting in cell death and multiple physiological dysfunctions. Much evidence indicates that HERVs are initiators or drivers of neurodegenerative processes in multiple sclerosis and amyotrophic lateral sclerosis, and clinical trials have been designed to target HERVs. In recent years, the role of HERVs has been explored in other major neurodegenerative diseases, including frontotemporal dementia, Alzheimer's disease and Parkinson's disease, with some interesting discoveries. This review summarizes and evaluates the past and current research on HERVs in neurodegenerative diseases. It discusses the potential role of HERVs in disease manifestation and neurodegeneration. It critically reviews antiretroviral strategies used in the therapeutic intervention of neurodegenerative diseases.

Rodent Models of Alzheimer's Disease: Past Misconceptions and Future Prospects.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective treatments, not least due to the lack of authentic animal models. Typically, rodent models recapitulate the effects but not causes of AD, such as cholinergic neuron loss: lesioning of cholinergic neurons mimics the cognitive decline reminiscent of AD but not its neuropathology. Alternative models rely on the overexpression of genes associated with familial AD, such as amyloid precursor protein, or have genetically amplified expression of mutant tau. Yet transgenic rodent models poorly replicate the neuropathogenesis and protein overexpression patterns of sporadic AD. Seeding rodents with amyloid or tau facilitates the formation of these pathologies but cannot account for their initial accumulation. Intracerebral infusion of proinflammatory agents offer an alternative model, but these fail to replicate the cause of AD. A novel model is therefore needed, perhaps similar to those used for Parkinson's disease, namely adult wildtype rodents with neuron-specific (dopaminergic) lesions within the same vulnerable brainstem nuclei, 'the isodendritic core', which are the first to degenerate in AD. Site-selective targeting of these nuclei in adult rodents may recapitulate the initial neurodegenerative processes in AD to faithfully mimic its pathogenesis and progression, ultimately leading to presymptomatic biomarkers and preventative therapies.

Oxidative stress-mediated neuroinflammation in Alzheimer's disease.

Reactive oxygen species (ROS) are metabolic by-products that constitute an indispensable component of physiological processes, albeit their heightened presence may proffer substantial perils to biological entities. Such a proliferation gives rise to a gradual escalation of oxidative stress within the organism, thereby compromising mitochondrial functionality and inflicting harm upon various bodily systems, with a particular predilection for the central nervous system. In its nascent stages, it is plausible that inflammation has been a facilitator in the progression of the malady. The precise role of inflammation in Alzheimer's disease (AD) remains somewhat enigmatic, although it is conceivable that activated microglia and astrocytes might be implicated in the removal of amyloid-β (Aβ) deposits. Nonetheless, prolonged microglial activation is associated with Tau phosphorylation and Aβ aggregation. Research studies have indicated that AD brains upregulate complementary molecules, inflammatory cytokines, acute phase reacting agents, and other inflammatory mediators that may cause neurodegeneration. In this review, oxidative damage products will be discussed as potential peripheral biomarkers for AD and its early stages. The disordered excretion of pro-inflammatory cytokines, chemokines, oxygen, and nitrogen-reactive species, along with the stimulation of the complement system by glial cells, has the potential to disrupt the functionality of neuronal termini. This perturbation, in turn, culminates in compromised synaptic function, a phenomenon empirically linked to the manifestation of cognitive impairments. The management of neurodegenerative conditions in the context of dementia necessitates therapeutic interventions that specifically target the excessive production of inflammatory and oxidative agents. Furthermore, we shall deliberate upon the function of microglia and oxidative injury in the etiology of AD and the ensuing neurodegenerative processes.

Neuroprotective effects of resveratrol on retinal ganglion cells in glaucoma in rodents: A narrative review.

Glaucoma, an irreversible optic neuropathy, primarily affects retinal ganglion cells (RGC) and causes vision loss and blindness. The damage to RGCs in glaucoma occurs by various mechanisms, including elevated intraocular pressure, oxidative stress, inflammation, and other neurodegenerative processes. As the disease progresses, the loss of RGCs leads to vision loss. Therefore, protecting RGCs from damage and promoting their survival are important goals in managing glaucoma. In this regard, resveratrol (RES), a polyphenolic phytoalexin, exerts antioxidant effects and slows down the evolution and progression of glaucoma. The present review shows that RES plays a protective role in RGCs in cases of ischemic injury and hypoxia as well as in ErbB2 protein expression in the retina. Additionally, RES plays protective roles in RGCs by promoting cell growth, reducing apoptosis, and decreasing oxidative stress in H2O2-exposed RGCs. RES was also found to inhibit oxidative stress damage in RGCs and suppress the activation of mitogen-activated protein kinase signaling pathways. RES could alleviate retinal function impairment by suppressing the hypoxia-inducible factor-1 alpha/vascular endothelial growth factor and p38/p53 axes while stimulating the PI3K/Akt pathway. Therefore, RES might exert potential therapeutic effects for managing glaucoma by protecting RGCs from damage and promoting their survival.

Heightened Prevalence of Common Hospital-Treated Infections Preceding Dementia Diagnosis with Accelerated Dementia Onset after Influenza

BackgroundSince the beginning of Alzheimer’s disease research, the hypothesis that infections are to some extent associated with neurodegenerative processes has been tested repeatedly. Epidemiological studies on the associations between infections and dementia have reported conflicting results.ObjectivesThis study analyses common hospital-treated infections (herpes, influenza, intestinal infections, pneumonia, sepsis, urinary tract infections) and their association with subsequent dementia and time until dementia onset.Design, Setting, and ParticipantsFor this nationwide population-based case-control study, the dataset of the Austrian National Health Insurance Association was used, including dementia patients (dementia cohort) and age- and gender-matched non-demented individuals (control cohort). Only subjects with data availability of at least 10 years prior to the index date (date of dementia diagnosis or date of censoring) were included.MeasurementsThe incidence of six common infections in older adults (herpes, influenza, intestinal infections, pneumonia, sepsis, and urinary tract infections) was analyzed over a period of 10 years before the censoring date.ResultsThe study population consists of 58208 subjects (29104 per study cohort), mean age: 81 years, 54% females. Patients of the dementia cohort had suffered from infections significantly more often than patients of the control cohort (6002, 20.6% vs. 4826, 16.6%; p < 0.001). Influenza, urinary tract infections, intestinal infections, and sepsis showed independent positive associations with subsequent dementia diagnosis, irrespective of other comorbidities (odds ratios: 1.26 (95% CI: 1.06–1.49), 1.23 (95% CI: 1.16–1.30), 1.16 (95% CI: 1.07–1.27), 1.17 (95% CI: 1.01–1.37), respectively). Time from infection to dementia diagnosis was shorter after influenza compared to all other infections (median: 3.4 years (95% CI: 3.1–3.7) vs. 6.6 years (95% CI: 6.4–6.8); p < 0.001).ConclusionThis is the first study to assess the association between infections and dementia over such a long minimum reporting period. These results, supported by consistent data from other epidemiological studies, emphasize the critical importance of infection prevention measures, especially for older adults. Further research is crucial to better understand the nature of the relationship between infections and dementia.

The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.

Although large-scale genetic association studies have proven opportunistic for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.

Increased anterior insula connectivity associated with cognitive maintenance in amnestic mild cognitive impairment: a longitudinal study

The insula, a crucial hub of the human brain network, can be divided into anterior and posterior regions. Previous studies have reported that different insula subregions play various roles in amnestic mild cognitive impairment (aMCI). However, the longitudinal changes in the functional connectivity (FC) of each insula subregion in aMCI patients over time remain unclear. Twenty aMCI patients and 20 healthy controls (HCs) were recruited and underwent resting-state functional magnetic resonance imaging (fMRI) scans and neuropsychological assessments at baseline and at the 15-month follow-up. FMRI data were preprocessed using SPM 12 and the CONN toolbox. Two-way analysis of covariance was used to compare longitudinal changes in the FC of each insula subregion with covariates including sex, age, education, follow-up interval, volume of gray matter, and global correlation (GCOR). Pearson’s correlation was used to evaluate the relationship between insula subregional FC and neuropsychological performance in aMCI patients. In aMCI patients, the right anterior insula exhibited significantly increased FC with the left anterior cingulate cortex, whereas the left posterior insula exhibited decreased FC with the right precuneus compared with HCs. Furthermore, FC between the right anterior insula and left anterior cingulate cortex was significantly correlated with global cognition at follow-up. The current findings revealed different functional alterations in the insula subregions and provided new insights into the neurodegenerative process in aMCI patients.

GR.3 Distinct longitudinal brain atrophy trajectories in parkinson’s disease clinical subtypes: insight towards precision medicine

Background: Parkinson’s disease (PD) varies widely across individuals in terms of clinical manifestations and course of progression. We aimed to compare patterns of brain atrophy between PD clinical subtypes using longitudinally acquired brain MRIs. Methods: We used T1-weighted MRIs from Parkinson’s Progression Markers Initiative (PPMI) on 134 PD individuals and 60 healthy controls with at least two MRIs. Patients were classified into three clinical subtypes at de novo stage using validated subtyping criteria based on major motor and non-motor classifiers (early cognitive impairment, RBD, dysautonomia): mild-motor predominant (n=74), intermediate (n=44), and diffuse-malignant (n=16). Deformation-based morphometry (DBM) maps were calculated and mixed effect models were used to examine the interaction between PD subtypes and rate of atrophy across brain regions over time, controlling for sex and age at baseline. Results: Individuals with ‘diffuse malignant’ PD showed a significantly higher rate of atrophy across multiple brain regions, including lateral nucleus of the forebrain, precuneus, paracentral lobule, inferior temporal gyrus, fusiform gyrus, and lateral hemisphere of the cerebellum (FDR corrected p&lt;0.05). Conclusions: We demonstrated an accelerated atrophy pattern within several brain regions in ‘diffuse malignant’ PD subtype. These findings suggest the presence of a more diffuse multidomain neurodegenerative process in a subgroup of people with PD, favoring the existence of diverse underlying pathophysiologies.

A novel in vitro model for investigating oligodendroglial maturation and myelin deposition under demyelinating and remyelinating conditions: Impact of microglial depletion and repopulation

Experimental models of multiple sclerosis (MS) have significantly contributed to our understanding of pathophysiology and the development of therapeutic interventions. Various in vivo animal models have successfully replicated key features of MS and associated pathophysiological processes, shedding light on the sequence of events leading to disease initiation, progression, and resolution. Nevertheless, these models often entail substantial costs and prolonged treatment periods. In contrast, in vitro models offer distinct advantages, including cost-effectiveness and precise control over experimental conditions, thereby facilitating more reproducible results. We have developed a novel in vitro model tailored to the study of oligodendroglial maturation and myelin deposition under demyelinating and remyelinating conditions, which encompasses all the cell types present in the central nervous system (CNS). Of note, our model enables the evaluation of microglial cell commitment through a protocol involving their depletion and subsequent repopulation. Given that the development and survival of microglia are critically reliant on colony-stimulating factor-1 receptor (CSF-1R) signaling, we have employed CSF-1R inhibition to effectively deplete microglia. This versatile model holds promise for the assessment of potential therapies aimed at promoting oligodendroglial differentiation to safeguard and repair myelin, hence mitigate neurodegenerative processes.

A review of treatment of relapsing-remitting type of multiple sclerosis (RRMS)

Introduction Multiple sclerosis (SM) is the most common chronic inflammatory-demyelinating disease of the Central Nervous System. In its course, a multifocal damage is done to a nervous tissue - myelin sheaths surrounding axons become disintegrated. This process leads to a dysfunction of the electrical impulses passage along nerve fibers which occurs as various symptoms that hinder the functioning of the patients. Aim of the study This review aims to summarize treatment methods of relapsing-remitting type of multiple sclerosis (RRMS). Following information will be presented: groups of medications, mechanism of its action, its most important side effects and its effectiveness. Material and method This review presents the current state of knowledge about relapsing-remitting type of multiple sclerosis (RRMS) treatment - it is based on Pubmed database and was carried out using keywords concerning the issues of multiple sclerosis. Cited articles were selected in order to base on up-to-date investigation results. Summary A wide range of therapeutic options let neurologists treat their patients accurately, but the basic knowledge about each substance should be assimilated to choose the best individual therapy. Patients suffering from multiple sclerosis differ from each other and a personal approach is needed to implement appropriate treatment as soon as possible. Early start allows patients to not to lose their everyday functioning areas, as the neurodegenerative process is stopped at the initial stage. If some changes in brain tissue structure are permanently done, neurologists should know the options of symptomatic treatment to alleviate a patient's suffering.

MRI-derived brain iron, grey matter volume, and risk of dementia and Parkinson's disease: Observational and genetic analysis in the UK Biobank cohort

BackgroundIron overload is observed in neurodegenerative diseases, especially Alzheimer's disease (AD) and Parkinson's disease (PD). Homozygotes for the iron-overload (haemochromatosis) causing HFE p.C282Y variant have increased risk of dementia and PD. Whether brain iron deposition is causal or secondary to the neurodegenerative processes in the general population is unclear. MethodsWe analysed 39,533 UK Biobank participants of European genetic ancestry with brain MRI data. We studied brain iron estimated by R2* and quantitative susceptibility mapping (QSM) in 8 subcortical regions: accumbens, amygdala, caudate, hippocampus, pallidum, putamen, substantia nigra, and thalamus. We performed genome-wide associations studies (GWAS) and used Mendelian Randomization (MR) methods to estimate the causal effect of brain iron on grey matter volume, and risk of AD, non-AD and PD. We also used MR to test whether genetic liability to AD or PD causally increased brain iron (R2* and QSM). FindingsIn GWAS of R2* and QSM we replicated 83% of previously reported genetic loci and identified 174 further loci across all eight brain regions. Higher genetically predicted brain iron, using both R2* and QSM, was associated with lower grey matter volumes in the caudate, putamen and thalamus (e.g., Beta-putamenQSM: −0.37, p = 2*10–46). Higher genetically predicted thalamus R2* was associated with increased risk of non-AD dementia (OR 1.36(1.16;1.60), p = 2*10–4) but not AD (p > 0.05). In males, genetically predicted putamen R2* increased non-AD dementia risk, but not in females. Higher genetically predicted iron in the caudate, putamen, and substantia nigra was associated with an increased risk of PD (Odds Ratio QSM ∼ substantia-nigra 1.21(1.07;1.37), p = 0.003). Genetic liability to AD or PD was not associated with R2* or QSM in the dementia or PD-associated regions. InterpretationOur genetic analysis supports a causal effect of higher iron deposition in specific subcortical brain regions for Parkinson's disease, grey matter volume, and non-Alzheimer's dementia.

In Vivo Assessment of Astrocyte Reactivity in Patients with Progressive Supranuclear Palsy.

Although astrocytic pathology is a pathological hallmark of progressive supranuclear palsy (PSP), its pathophysiological role remains unclear. This study aimed to assess astrocyte reactivity in vivo in patients with PSP. Furthermore, we investigated alterations in brain lactate levels and their relationship with astrocyte reactivity. We included 30 patients with PSP-Richardson syndrome and 30 healthy controls; in patients, tau deposition was confirmed through 18F-florzolotau positron emission tomography. Myo-inositol, an astroglial marker, and lactate were quantified in the anterior cingulate cortex through magnetic resonance spectroscopy. We measured plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker. The anterior cingulate cortex was histologically assessed in postmortem samples of another 3 patients with PSP with comparable disease durations. The levels of myo-inositol and plasma glial fibrillary acidic protein were significantly higher in patients than those in healthy controls (p < 0.05); these increases were significantly associated with PSP rating scale and cognitive function scores (p < 0.05). The lactate level was high in patients, and correlated significantly with high myo-inositol levels. Histological analysis of the anterior cingulate cortex in patients revealed reactive astrocytes, despite mild tau deposition, and no marked synaptic loss. We discovered high levels of astrocyte biomarkers in patients with PSP, suggesting astrocyte reactivity. The association between myo-inositol and lactate levels suggests a link between reactive astrocytes and brain energy metabolism changes. Our results indicate that astrocyte reactivity in the anterior cingulate cortex precedes pronounced tau pathology and neurodegenerative processes in that region, and affects brain function in PSP. ANN NEUROL 2024;96:247-261.

Рroblems of diagnostics of dysfunctions of the olfactory analyzer of laboratory animals on the basis of behavioral and electrophysiological methods of research

Olfactory impairment (decreased acuity, impaired adequate identification of odorants) reduces the quality of life of patients and can be a symptom of a wide range of pathologies of the organism, in particular neurodegenerative processes in the brain. Quantitative measurement of olfactory acuity is necessary for diagnostics of olfactory dysfunctions, monitoring the dynamics of olfaction after pharmacological or surgical treatment. The searching for optimal methods of analyzing olfactory thresholds on animal models of human diseases accompanied by anosmia and comparing them with those in humans seems to be especially urgent problem at the moment. This is necessary for the selection of a valid animal model for the evaluation of new drugs and development the therapy for a wide range of pathologies. The review analyzes publications devoted to the study of diseases accompanied by anosmia or hyposmia, their zootropic models, and methods of olfactory function assessment. Models for COVID19, Alzheimer’s disease, Parkinson’s disease, diabetes types (1 and 2 type), Kalman syndrome, and Bardet-Biedl syndrome, for which olfactory dysfunction and/or defects of olfactory system are present, were analyzed. The review notes the paucity of data on the measurement of olfactory thresholds in model animals.

Inflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect clinical and radiographic disease activity in multiple sclerosis

The multifaceted nature of multiple sclerosis requires quantitative biomarkers that can provide insights related to diverse physiological pathways. To this end, proteomic analysis of deeply-phenotyped serum samples, biological pathway modeling, and network analysis were performed to elucidate inflammatory and neurodegenerative processes, identifying sensitive biomarkers of multiple sclerosis disease activity. Here, we evaluated the concentrations of > 1400 serum proteins in 630 samples from three multiple sclerosis cohorts for association with clinical and radiographic new disease activity. Twenty proteins were associated with increased clinical and radiographic multiple sclerosis disease activity for inclusion in a custom assay panel. Serum neurofilament light chain showed the strongest univariate correlation with gadolinium lesion activity, clinical relapse status, and annualized relapse rate. Multivariate modeling outperformed univariate for all endpoints. A comprehensive biomarker panel including the twenty proteins identified in this study could serve to characterize disease activity for a patient with multiple sclerosis.

GDF11 improves hippocampal neurogenesis and cognitive abilities in diabetic mice by reducing neural inflammation

BackgroundThe cognitive decline associated with type 2 diabetes (T2D) is often attributed to compromised hippocampal neurogenesis and exacerbated neural inflammation. This study investigates the therapeutic potential of growth differentiation factor 11 (GDF11) in reversing these neurodegenerative processes in diabetic mice. ResultWe utilized a murine model of T2D and examined the effects of GDF11 on learning, memory, neurogenesis, and neuroinflammatory markers. Our results indicate that diabetic mice exhibit significant deficits in cognitive function, mirrored by reduced hippocampal neurogenesis and increased neuroinflammation. Chronic administration of GDF11 was observed to significantly enhance cognitive abilities, as evidenced by improved performance in learning and memory tasks. Concurrently, GDF11 treatment restored neural activity and promoted the regeneration of new neurons within the hippocampus. Inflammatory profiling revealed a reduction in neuroinflammatory markers, which was further supported by reduced microglia numbers. To delineate the role of neuroinflammation, we pharmacologically depleted microglia, leading to a restoration of neurogenesis and cognitive functions in diabetic mice. ConclusionThese findings endorse the hypothesis that GDF11 exerts its beneficial effects by modulating neuroinflammatory pathways. Consequently, GDF11 represents a promising intervention to ameliorate diabetes-induced cognitive impairments and neural degeneration through its anti-inflammatory properties.

Neuronopathic Gaucher disease: Rare in the West, common in the East.

Gaucher disease (GD) stands as one of the most prevalent lysosomal disorders, yet neuronopathic GD (nGD) is an uncommon subset characterized by a wide array of clinical manifestations that complicate diagnosis, particularly when neurological symptoms are understated. nGD may manifest as the acute neuronopathic type, or GD type 2 (GD2), either prenatally or within the first weeks to months of life, whereas GD type 3 (GD3) symptoms may emerge at any point during childhood or occasionally in adolescence. The clinical presentation encompasses severe systemic involvement to mild visceral disease, often coupled with a spectrum of progressive neurological signs and symptoms such as cognitive impairment, ataxia, seizures, myoclonus, varying degrees of brainstem dysfunction presenting with stridor, apneic episodes, and/or impaired swallowing. This manuscript aims to provide a comprehensive review of the incidence, distinctive presentations, and diverse clinical phenotypes of nGD across various countries and regions. It will explore the natural history of the neurodegenerative process in GD, shedding light on its various manifestations during infancy and childhood, and offer insights into the diagnostic journey, the challenges faced in the clinical management, and current and investigative therapeutic approaches for GD's neurological variants.

Therapeutic role of voltage-gated potassium channels in age-related neurodegenerative diseases.

Voltage-gated ion channels are essential for membrane potential maintenance, homeostasis, electrical signal production and controlling the Ca2+ flow through the membrane. Among all ion channels, the key regulators of neuronal excitability are the voltage-gated potassium channels (KV), the largest family of K+ channels. Due to the ROS high levels in the aging brain, K+ channels might be affected by oxidative agents and be key in aging and neurodegeneration processes. This review provides new insight about channelopathies in the most studied neurodegenerative disorders, such as Alzheimer Disease, Parkinson's Disease, Huntington Disease or Spinocerebellar Ataxia. The main affected KV channels in these neurodegenerative diseases are the KV1, KV2.1, KV3, KV4 and KV7. Moreover, in order to prevent or repair the development of these neurodegenerative diseases, previous KV channel modulators have been proposed as therapeutic targets.

Potential use of antioxidants for the treatment of chronic inflammatory diseases.

The excessive production of various reactive oxidant species over endogenous antioxidant defense mechanisms leads to the development of a state of oxidative stress, with serious biological consequences. The consequences of oxidative stress depend on the balance between the generation of reactive oxidant species and the antioxidant defense and include oxidative damage of biomolecules, disruption of signal transduction, mutation, and cell apoptosis. Accumulating evidence suggests that oxidative stress is involved in the physiopathology of various debilitating illnesses associated with chronic inflammation, including cardiovascular diseases, diabetes, cancer, or neurodegenerative processes, that need continuous pharmacological treatment. Oxidative stress and chronic inflammation are tightly linked pathophysiological processes, one of which can be simply promoted by another. Although, many antioxidant trials have been unsuccessful (some of the trials showed either no effect or even harmful effects) in human patients as a preventive or curative measure, targeting oxidative stress remains an interesting therapeutic approach for the development of new agents to design novel anti-inflammatory drugs with a reliable safety profile. In this regard, several natural antioxidant compounds were explored as potential therapeutic options for the treatment of chronic inflammatory diseases. Several metalloenzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, are among the essential enzymes that maintain the low nanomolar physiological concentrations of superoxide (O2•-) and hydrogen peroxide (H2O2), the major redox signaling molecules, and thus play important roles in the alteration of the redox homeostasis. These enzymes have become a striking source of motivation to design catalytic drugs to enhance the action of these enzymes under pathological conditions related to chronic inflammation. This review is focused on several major representatives of natural and synthetic antioxidants as potential drug candidates for the treatment of chronic inflammatory diseases.

(+)-Borneol Protects Dopaminergic Neuronal Loss in Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson's Disease Mice: A Study of Dopamine Level using In Vivo Brain Microdialysis.

Considerable research efforts have been directed toward the symptom relief of Parkinson's disease (PD) by attenuating dopamine (DA) depletion. One common feature of these existing therapies is their unavailability of preventing the neurodegenerative process of dopaminergic neurons. (+)-Borneol, a natural highly lipid-soluble bicyclic monoterpene, has been reported to regulate the levels of monoamine neurotransmitters in the central nervous system and exhibit neuroprotective effects. However, the effect of (+)-borneol on the dopaminergic neuronal loss of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice is not defined. Herein, we first report that 30 mg/kg (+)-borneol significantly attenuated the motor deficits of PD mice, which benefits from markedly increasing the level of DA and decreasing the metabolic rate of DA in the striatum of conscious and freely moving mouse detected by ultraperformance liquid chromatography tandem mass spectrometry online combined with in vivo brain microdialysis sampling. It is worth noting that the enhanced level of DA by (+)-borneol was enabled by the reduction in loss of tyrosine hydroxylase-immunoreactive dopaminergic neurons in the substantia nigra and striatum and promotion of reserpine- or nomifensine-induced DA release in PD mice. Interestingly, (+)-borneol evidently inhibited the decreased expression levels of DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) on the MPTP mouse model of PD. Moreover, (+)-borneol suppressed the neuroinflammation by inhibiting the production of IL-1β, IL-6, and TNF-α and attenuated oxidative stress by decreasing the level of MDA and increasing the activities of SOD and GSH-px in PD mice. These findings demonstrate that (+)-borneol protects DA neurons by inhibiting neuroinflammation and oxidative stress. Further research work for the neuroprotection mechanism of (+)-borneol will focus on reactive oxygen species-mediated apoptosis. Therefore, (+)-borneol is a potential therapeutic candidate for retarding the neurodegenerative process of PD.

Multiscale brain age prediction reveals region-specific accelerated brain aging in Parkinson's disease

Brain biological age, which measures the aging process in the brain using neuroimaging data, has been used to assess advanced brain aging in neurodegenerative diseases, including Parkinson disease (PD). However, assuming that whole brain degeneration is uniform may not be sufficient for assessing the complex neurodegenerative processes in PD. In this study we constructed a multiscale brain age prediction models based on structural MRI of 1240 healthy participants. To assess the brain aging patterns using the brain age prediction model, 93 PD patients and 91 healthy controls matching for sex and age were included. We found increased global and regional brain age in PD patients. The advanced aging regions were predominantly noted in the frontal and temporal cortices, limbic system, basal ganglia, thalamus, and cerebellum. Furthermore, region-level rather than global brain age in PD patients was associated with disease severity. Our multiscale brain age prediction model could aid in the development of objective image-based biomarkers to detect advanced brain aging in neurodegenerative diseases.