Emerging role of galectin 3 in neuroinflammation and neurodegeneration

Neuroinflammation and neurodegeneration are key processes that mediate the development and progression of neurological diseases.However,the mechanisms modulating these processes in different diseases remain incompletely understood.Advances in single cell based multi-omic analyses have helped to identify distinct molecular signatures such as Lgals3 that is associated with neuroinflammation and neurodegeneration in the central nervous system(CNS).Lgals3 encodes galectin-3(Gal3),aβ-galactoside and glycan binding glycoprotein that is frequently upregulated by reactive microglia/macrophages in the CNS during various neurological diseases.While Gal3 has previously been associated with non-CNS inflammatory and fibrotic diseases,recent studies highlight Gal3 as a prominent regulator of inflammation and neuroaxonal damage in the CNS during diseases such as multiple sclerosis,Alzheimer’s disease,and Parkinson’s disease.In this review,we summarize the pleiotropic functions of Gal3 and discuss evidence that demonstrates its detrimental role in neuroinflammation and neurodegeneration during different neurological diseases.We also consider the challenges of translating preclinical observations into targeting Gal3 in the human CNS.

Increased retinal venule diameter as a prognostic indicator for recurrent cerebrovascular events:a prospective observational study

Microvasculature of the retina is considered an alternative marker of cerebral vascular risk in healthy populations.However,the ability of retinal vasculature changes,specifically focusing on retinal vessel diameter,to predict the recurrence of cerebrovascular events in patients with ischemic stroke has not been determined comprehensively.While previous studies have shown a link between retinal vessel diameter and recurrent cerebrovascular events,they have not incorporated this information into a predictive model.Therefore,this study aimed to investigate the relationship between retinal vessel diameter and subsequent cerebrovascular events in patients with acute ischemic stroke.Additionally,we sought to establish a predictive model by combining retinal veessel diameter with traditional risk factors.We performed a prospective observational study of 141 patients with acute ischemic stroke who were admitted to the First Affiliated Hospital of Jinan University.All of these patients underwent digital retinal imaging within 72 hours of admission and were followed up for 3 years.We found that,after adjusting for related risk factors,patients with acute ischemic stroke with mean arteriolar diameter within 0.5-1.0 disc diameters of the disc margin(MAD_(0.5-1.0DD))of≥74.14μm and mean venular diameter within 0.5-1.0 disc diameters of the disc margin(MVD_(0.5-1.0DD))of≥83.91μm tended to experience recurrent cerebrovascular events.We established three multivariate Cox proportional hazard regression models:model 1 included traditional risk factors,model 2 added MAD_(0.5-1.0DD)to model 1,and model 3 added MVD0.5-1.0DD to model 1.Model 3 had the greatest potential to predict subsequent cerebrovascular events,followed by model 2,and finally model 1.These findings indicate that combining retinal venular or arteriolar diameter with traditional risk factors could improve the prediction of recurrent cerebrovascular events in patients with acute ischemic stroke,and that retinal imaging could be a useful and non-invasive method for identifying high-risk patients who require closer monitoring and more aggressive management.

Pyrroloquinoline quinone:a potential neuroprotective compound for neurodegenerative diseases targeting metabolism

Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/tissues.Pyrroloquinoline quinone is present in the diet being available in foodstuffs,conferring the potential of this compound to be supplemented by dietary administration.Pyrroloquinoline quinone’s nutritional role in mammalian health is supported by the extensive deficits in reproduction,growth,and immunity resulting from the dietary absence of pyrroloquinoline quinone,and as such,pyrroloquinoline quinone has been considered as a“new vitamin.”Although the classification of pyrroloquinoline quinone as a vitamin needs to be properly established,the wide range of benefits for health provided has been reported in many studies.In this respect,pyrroloquinoline quinone seems to be particularly involved in regulating cell signaling pathways that promote metabolic and mitochondrial processes in many experimental contexts,thus dictating the rationale to consider pyrroloquinoline quinone as a vital compound for mammalian life.Through the regulation of different metabolic mechanisms,pyrroloquinoline quinone may improve clinical deficits where dysfunctional metabolism and mitochondrial activity contribute to induce cell damage and death.Pyrroloquinoline quinone has been demonstrated to have neuroprotective properties in different experimental models of neurodegeneration,although the link between pyrroloquinoline quinone-promoted metabolism and improved neuronal viability in some of such contexts is still to be fully elucidated.Here,we review the general properties of pyrroloquinoline quinone and its capacity to modulate metabolic and mitochondrial mechanisms in physiological contexts.In addition,we analyze the neuroprotective properties of pyrroloquinoline quinone in different neurodegenerative conditions and consider future perspectives for pyrroloquinoline quinone’s potential in health and disease.

Autolysosomal acidification impairment as a mediator for TNFR1 induced neuronal necroptosis in Alzheimer’s disease

Neuronal necroptosis-an emerging form of regulated cell death associated with neuroinflammatory signaling:Alzheimer’s disease(AD)is characterized by the presence of extracellular amyloid-β(Aβ)plaques and intracellular tau neurofibrillary tangles as well as progressive neuronal loss.Recent evidence has suggested that prolonged neuroinflammation with increased levels of cytokines,arising from neuronal injury,innate immune responses from glial cells,and peripheral inflammation,leads to neuronal death and AD progression.

Small molecular decoys in Alzheimer's disease

Recent progress in the treatment of Alzheimer’s disease(AD)using antibodies against amyloid sustains amyloid generation as a key process in AD.Amyloid formation starts with two amyloidbeta(Aβ)molecules interacting(dimer formation)followed by an accelerating build-up of socalled protofibrils,which turn into fibrils,which accumulate in the characteristic plaques.

Glycolysis and glucose metabolism as a target for bioenergetic and neuronal protection in glaucoma

Vision is arguably our most valued sense,yet approximately 340 million people globally suffer blindness or moderate visual impairment,highlighting the need to further develop and advance treatments for ophthalmic diseases.Glaucoma refers to a group of ocular disorders united by a clinically characteristic optic neuropathy with associated retinal ganglion cell loss.

Movement analysis in the diagnosis and management of Parkinson’s disease

Challenges in the diagnosis and treatment of Parkinson’s disease:Parkinson’s disease(PD)is an increasingly prevalent neurodegenerative disease,at first sight primarily characterized by motor symptoms,although non-motor symptoms also constitute a major part of the overall phenotype.Clinically,this disease cannot be diagnosed reliably until a large part of the vulnerable dopaminergic neurons has been irretrievably lost,and the disease progresses inexorably.New biological criteria for PD have been proposed recently and might eventually improve early diagnosis,but they require further validation,and their use will initially be restricted to a research environment(Darweesh et al.,2024).

Insight into endoplasmic reticulum-mitochondria contacts in human amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS) is a fastprogressing fatal neurodegenerative disease and the most common form of motor neuron disease.There is currently no cure and approximately 90% of cases are sporadic.ALS shares genetic causes,clinical and neuropathological features with frontotemporal dementia,the second most common form of presenile dementia.ALS and frontotemporal dementia are therefore considered a disease spectrum(Abramzon et al.,2020).

Psychiatric comorbidities in epilepsy:population co-occurrence,genetic correlations and causal effects

Background Psychiatric comorbidities are common in patients with epilepsy.Reasons for the co-occurrence of psychiatric conditions and epilepsy remain poorly understood.Aim We aimed to triangulate the relationship between epilepsy and psychiatric conditions to determine the extent and possible origins of these conditions.Methods Using nationwide Swedish health registries,we quantified the lifetime prevalence of psychiatric disorders in patients with epilepsy.We then used summarydata from genome-wide association studies to investigate whether the identified observational associations could be attributed to a shared underlying genetic aetiology using cross-trait linkage disequilibrium score regression.Finally,we assessed the potential bidirectional relationships using two-sample Mendelian randomisation.Results In a cohort of 7628495 individuals,we found that almost half of the 94435 individuals diagnosed with epilepsy were also diagnosed with a psychiatric condition in their lifetime(adjusted lifetime prevalence,44.09%;95%confidence interval(Cl)43.78%to 44.39%).We found evidence for a genetic correlation between epilepsy and some neurodevelopmental and psychiatric conditions.For example,we observed a genetic correlation between epilepsy and attention-deficit/hyperactivity disorder(r,=0.18,95%Cl 0.09 to 0.27,p<0.001)—a correlation that was more pronounced in focal epilepsy(r=0.23,95%CI 0.09 to 0.36,p<0.001).Findings from Mendelian randomisation using common genetic variants did not support bidirectional effects between epilepsy and neurodevelopmental or psychiatric conditions.Conclusions Psychiatric comorbidities are common in patients with epilepsy.Genetic correlations may partially explain some comorbidities;however,there is little evidence of a bidirectional relationship between the genetic liability of epilepsy and psychiatric conditions.These findings highlight the need to understand the role of environmental factors or rare genetic variations in the origins of psychiatric comorbidities in epilepsy.

The “Brain Stress Timing” phenomenon and other misinterpretations of randomized clinical trial on aneurysmal subarachnoid hemorrhage

Clipping and coiling are currently the two alternatives in treatment of ruptured cerebral aneurysms. In spite of some meritorious analysis, further discussion is helpful to understand the actual state of art. Retreatment and rebleeding rates clearly favors clipping, although short-term functional outcome seems to be beneficial for clipping, while this different is not such if we perform the comparison at a longer follow up. Longterm follow ups and cost analysis are mandatory to have a clear view of the current picture in treatment of subarachnoid hemorrhage. Treatment strategy should be made by a multi-disciplinary team in accredited centers with proficient experience in both techniques.

Opiate exposure increases arterial stiffness, advances vascular age and is an independent cardiovascular risk factor in females: A cross-sectional clinical study

Background: Whilst several studies have demonstrated poor cardiovascular health in opiate dependence, its role as a cardiovascular risk factor has not been considered. Methods: Pulse wave analysis was undertaken by radial arterial tonometry (SphygmoCor) in female control and opiate-dependent patients and compared to lifetime opiate use. Results: 222 opiate dependent women were compared to 175 controls. Opiate dependent patients were receiving treatment with buprenorphine (83.3%), methadone (13.5%), or naltrexone (3.2%). Non log transformed chronologic age (CA) for the two groups was 33.58 ± 0.57 (opiate) vs. 32.62 ± 0.96 (controls) years (mean ± S.E.M.;P = 0.39). Vascular Reference Age (RA) 39.30 ± 1.28, vs. 35.03 ± 1.41 the RA-CA difference (5.73 ± 1.02 vs. 2.41 ± 0.91) and the RA/CA ratio (1.16 ± 0.03 vs. 1.07 ± 0.02;all P < 0.02), and all measurements of central arterial stiffness (P < 0.02) were significantly worse for opiates compared to controls. When adjusted for CA, RA and central augmentation pressure and index were all worse by themselves and in interaction with CA (all P < 0.005). At 60 years the modelled RA’s were 83.79 and 67.52 years respectively. The opiate dose-duration interaction showed a dose-response effect with RA (P = 0.0033). After full adjustment for established cardiovascular risk factors, the dose-duration interaction remained significant (P = 10-6), was included in 10 other terms, and dose or duration was included in 15 other interactions. Conclusion: These data show that lifetime opiate use is significantly associated with increased arterial stiffness and vascular age and suggest a dose-response relationship. This relationship is robust and persists after full multivariate adjustment. These findings carry far-reaching implications for opiate-induced generalized acceleration of organismal ageing.

Clinical Experience with Generic Rasagiline (Ralago^&reg;) in Patients with Parkinson’s Disease: An Open-Label, Multicenter, Observational Study

Background: Antiparkinsonian pharmacotherapy represents one of the most important expenses related to Parkinson’s disease. The application of generic drugs may help to reduce the economic burden of the disease;however, efficacy and safety of these products have been less studied. Objective: To investigate the efficacy and safety of generic rasagiline (Ralago?) from a clinical perspective. Methods: The Clinical Global Impression of Severity scale was used to rate the most important motor and non-motor symptoms at baseline and 12 weeks after the initiation of Ralago?. Patients also identified symptoms which were the main sources of their disability and distress in everyday life. Results: A total of 499 patients were enrolled (231 females, mean age: 73.2 ± 9.1 years, mean duration of disease: 3.6 ± 3.7 years). Of them, 486 patients completed the study protocol. Both motor and non-motor symptoms showed improvement during 12-week Ralago? treatment. Adverse events were rare, and the majority of them were not considered as serious. Conclusions: The generic rasagiline (Ralago?) is an effective and safe generic product.

Objective electrophysiological contrast sensitivity with monofocal and multifocal intraocular lenses:a prospective clinical study

Background:To compare objective electrophysiological contrast sensitivity function(CSF)in patients implanted with either multifocal intraocular lenses(MIOLs)or monofocal intraocular lenses(IOLs)by pattern reversal visual evoked potentials(prVEP)measurements.Methods:Fourty-five cataract patients were randomly allocated to receive bilaterally:apodized diffractive-refractive Alcon Acrysof MIOL(A),full diffractive AMO Tecnis MIOL(B)or monofocal Alcon Acrysof IOL(C).Primary outcomes:1-year differences in objective binocular CSF measured by prVEP with sinusoid grating stimuli of 6 decreasing contrast levels at 6 spatial frequencies.Secondary outcomes:psychophysical CSF measured with VCTS-6500,photopic uncorrected distance(UDVA),and mesopic and photopic uncorrected near and intermediate visual acuities(UNVA and UIVA respectively).Results:Electrophysiological CSF curve had an inverted U-shaped morphology in all groups,with a biphasic pattern in Group B.Group A showed a lower CSF than group B at 4 and 8 cpd,and a lower value than group C at 8 cpd.Psychophysical CSF in group A exhibited a lower value at 12 cpd than group B.Mean photopic and mesopic UNVA and UIVA were worse in monofocal group compared to the multifocal groups.Mesopic UNVA and UIVA were better in group B.Conclusions:Electrophysiological CSF behaves differently depending on the types of multifocal or monofocal IOLs.This may be related to the visual acuity under certain conditions or to IOL characteristics.This objective method might be a potential new tool to investigate on MIOL differences and on subjective device-related quality of vision.

Optical coherence tomography in neuro-ophthalmology: bridging the gap between scientific discovery and clinical practice

Over the past two decades,optical coherence tomography(OCT)has transitioned from being an ocular imaging technology used predominantly in the management of patients with glaucoma and retinal diseases,to an invaluable tool in neuro-ophthalmic practice.As a surrogate marker of neuroaxonal integrity,OCT and recent advancements in OCT-angiography(OCT-A),are now used to diagnose many optic neuropathies,and prognosticate visual recovery over time.OCT provides highly reliable and reproducible measures of retinal integrity that enable structure-function correlations,which can in turn be used to explore mechanisms of injury and repair affecting the afferent visual pathway;a region of the central nervous system(CNS)that is both functionally eloquent and topographically elegant(1).Moreover,OCT measures of peripapillary retinal nerve fiber layer(RNFL)and macular ganglion cell layer structure inform our understanding regarding the pathogenesis and disease progression for many CNS disorders that impact visual function.

The Clinical Strategies Implementation Scale Revised(CSI-R).Fidelity Assessment of Resource Group Assertive Community Treatment

The Clinical Strategies Implementation scale (CSI) was originally designed to be used by external reviewers in order to measure the extent to which evidence-based strategies had been implemented in the treatment of persons with schizophrenia spectrum disorders according to Resource-group Assertive Community Treatment (RACT). The present investigation had two aims: 1) to conduct a revision of CSI and to examine the revised instrument (CSI-R) in terms of interrater reliability (Study I);2) to compare assessments of CSI-R made by experienced assessors with assessments made by students in case management (Study II) in order to determine whether the instrument has validity even when more inexperienced persons are using it. In Study I six raters, who took part in 12 to 15 cases from three outpatient community mental health teams, participated. Results indicated that internal consistency of the CSI-R was strong (alpha = 0.89) as well as correlations between individual raters’ (r between 0.80-0.98). In Study II 91 newly trained RACT praxis trainees participated. Each of them followed one case for eighteen months, i.e., the client which they had been assigned during training (n = 91). The five external auditors in the education program then independently assessed the 91 cases with the CSI-R. Results showed significant correlations between experts and trainees (rho = 0.68,

Visual perception alterations in COVID-19:a preliminary study

AIM:To compare the visual perception(color and chromatic-achromatic contrast vision)of a small cohort of COVID-19 patients at the time of infection and after 6mo with that of a healthy population matched for sex and age.METHODS:A total of 25 patients(9 females,16 males,mean age:54±10y)with COVID-19 hospitalized in the COVID-19 Unit of the University Clinical Hospital of Valladolid were recruited for this preliminary study.Visual perception,as determined by monocular measurement of contrast sensitivity function(CSF)and color vision was assessed in each patient using the Optopad test.The results obtained were then compared with those of a sample of 16 age-and sex-matched healthy controls(5 females,11 males,mean age:50±6y)in which the same measurement procedure was repeated.Statistically significant differences between groups were assessed using the Mann-Whitney U test.Measurements were repeated after a minimum follow-up period of 6mo and statistically significant differences between the two time points in each group were assessed using the Wilcoxon signed rank test.RESULTS:Discrimination thresholds(color and chromatic-achromatic contrast vision)and their corresponding sensitivity,calculated as the inverse of the discrimination threshold,were evaluated.Analysis of the data revealed higher contrast threshold results(i.e.,worse contrast sensitivity)in the COVID-19 group than in the control group for all spatial frequencies studied in the Optopad-CSF achromatic test and most of the spatial frequencies studied in the Optopad-CSF chromatic test for the red-green and blue-yellow mechanisms.In addition,color threshold results in the COVID-19 group were also significantly higher(i.e.,worse color sensitivity)for almost all color mechanisms studied in the Optopad-Color test.At 6mo,most of the differences found between the groups were maintained despite COVID-19 recovery.CONCLUSION:The present results provide preliminary evidence that visual perception may be impaired in COVID-19,even when the infection has passed.Although further research is needed to determine the precise causes of this finding,analysis of CSF and color vision could provide valuable information on the visual impact of COVID-19.

Trick or treat?Does cancer fool Schwann cells by mimicking axons to promote metastasis into nerves?

The Schwann cell reaction to nerve injury,termed the repair program,is crucial to successful nerve regeneration.Over the last decade,substantial advances have been made in elucidating the underlying molecular mechanisms in Schwann cells that lead to functional nerve repair.Moreover,the field has identified situations,such as aging and chronic denervation where these mechanisms go awry,paving the way for the development of therapeutic interventions(Arthur-Farraj and Coleman,2021;Cattin and Lloyd,2016;Jessen and Mirsky,2019).A recent article by Deborde et al.(2022)has demonstrated that unfortunately there is a downside to Schwann cells having such an efficient regeneration-promoting program;the promotion of tumor invasion of peripheral nerves.

Alexander disease:the road ahead

Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and adult onsets of the disease are known and,in both cases,astrocytes present characteristic aggregates,named Rosenthal fibers.Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner.Although the presence of aggregates suggests a proteostasis problem of the mutant forms,this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased.Additionally,several isoforms of glial fibrillary acidic protein have been described to date,while the impact of the mutations on their expression and proportion has not been exhaustively studied.Moreover,the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered,leading to functional changes that may modify the morphology,positioning,and/or the function of several organelles,in turn,impairing astrocyte normal function and subsequently affecting neurons.In particular,mitochondrial function,redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes.To study the disease and to develop putative therapeutic strategies,several experimental models have been developed,a collection that is in constant growth.The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations,together with the availability of new and more relevant experimental models,holds promise for the design and assay of novel therapeutic strategies.

CD34^(+ )progenitor cells as diagnostic and therapeutic targets in Alzheimer's disease

Alzheimer’s disease(AD)is the main neurodegenerative disease leading to dementia and cognitive impairment in the elderly.Considering AD to be an epidemic,an increase from the current 50 million to more than 150 million patients is expected by the year 2050.

Synaptopathy in CHMP2B frontotemporal dementia highlights the synaptic vesicle cycle as a therapeutic target

Amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD)are both devastating neurodegenerative conditions.Despite affecting different regions of the nervous system(FTD affecting primarily the frontal and temporal lobes,whilst ALS presents with motor neuron loss),there is significant overlap between these conditions in terms of genetics,pathology,and disease mechanisms,and they are therefore often grouped as a spectrum of symptoms under the heading FTD/ALS(Abramzon et al.,2020).Significantly,there is currently no cure for ALS or FTD.However,recent mechanistic insight points to a novel pathway to target for potential therapeutic intervention.