Mutation analysis of ATP13A2 in early-onset parkinsonism patients

BACKGROUND： A recent study has found that ATP13A2 is the causative gene for PARK9-linked autosomal recessive early-onset parkinsonism, described previously in Jordanian and Chilean families （Kufor-Rakeb syndrome）. OBJECTIVE： To screen eastern Asian patients with early-onset parkinsonism for mutations in ATP13A2 and to describe positron emission tomography （PET） findings of PARK9-linked parkinsonism. DESIGN, TIME AND SETTING： In total, 117 patients were selected from the Department of Neurology, Juntendo University, from February 2003 to October 2006, for this molecular genetics and case-control study. PARTICIPANTS： The patients with parkinsonism consist of two cohorts. Ninety four patients with onset age of less than 30 years were selected for the first cohort. They included 49 males and 44 females, comprising 73 Japanese, 9 Korean, 8 Taiwan Residents, and 4 Mainland Chinese. Eleven patients had parkinsonism complicated with dementia, 15 patients had family histories of parkinsonism （including 2 families）, and 5 patients were from consanguineous parents （including one family）. The second cohort of 23 patients was composed of patients with consanguineous parents （n = 15） or who had affected siblings （n = 6） or both （n = 2）, but the age at onset ranged from 30 to 50 years. METHODS： In 117 patients with parkinsonism, direct sequencing of ATP13A2 exons 13, 16, and 26, in which mutations had been reported previously, were performed. Sequencing was also performed in all 29 exons, including splice sites, in 28 probands who showed homozygosity at the PARK9 locus by haplotype analysis. Mutation analysis was also performed in 150 normal people. Linkage analysis was performed on all 3 parkinsonism families using short tandem repeat markers flanking the PARK9 locus. For patients who had ATP13A2 mutation, we performed brain MRI and ^18F-dopa PET scans. MAIN OUTCOME MEASURES： ATP13A2 DNA sequence, ^18F-dopa PET scan and brain MRI findings. RESULTS： A novel F182L mutation in a consanguineous Japanese family was identified. The patient was homozygous for the F182L mutation and her unaffected parents and two unaffected siblings were heterozygous for the F182L mutation. The patient developed early-onset atypical parkinsonism, which resembled the originally reported Kufor-Rakeb syndrome. MRI examination showed spinal cord atrophy and ^18F-dopa PET scan findings were similar to those of Parkinson＇s disease. CONCLUSION： Detection of the new PARK9 mutation, together with the previously reported cases of PARK9-linked parkinsonism, expand the clinical phenotypic spectrum of levodopa-responsive parkinsonism.

Best early-onset Parkinson dementia predictor using ensemble learning among Parkinson's symptoms,rapid eye movement sleep disorder,and neuropsychological profile

BACKGROUND Despite the frequent progression from Parkinson’s disease(PD)to Parkinson’s disease dementia(PDD),the basis to diagnose early-onset Parkinson dementia(EOPD)in the early stage is still insufficient.AIM To explore the prediction accuracy of sociodemographic factors,Parkinson's motor symptoms,Parkinson’s non-motor symptoms,and rapid eye movement sleep disorder for diagnosing EOPD using PD multicenter registry data.METHODS This study analyzed 342 Parkinson patients(66 EOPD patients and 276 PD patients with normal cognition),younger than 65 years.An EOPD prediction model was developed using a random forest algorithm and the accuracy of the developed model was compared with the naive Bayesian model and discriminant analysis.RESULTS The overall accuracy of the random forest was 89.5%,and was higher than that of discriminant analysis(78.3%)and that of the naive Bayesian model(85.8%).In the random forest model,the Korean Mini Mental State Examination(K-MMSE)score,Korean Montreal Cognitive Assessment(K-MoCA),sum of boxes in Clinical Dementia Rating(CDR),global score of CDR,motor score of Untitled Parkinson’s Disease Rating(UPDRS),and Korean Instrumental Activities of Daily Living(KIADL)score were confirmed as the major variables with high weight for EOPD prediction.Among them,the K-MMSE score was the most important factor in the final model.CONCLUSION It was found that Parkinson-related motor symptoms(e.g.,motor score of UPDRS)and instrumental daily performance(e.g.,K-IADL score)in addition to cognitive screening indicators(e.g.,K-MMSE score and K-MoCA score)were predictors with high accuracy in EOPD prediction.

Polymorphism analysis of PARK2 gene mutations in Han Chinese patients with early-onset Parkinson's disease

The PARK2 gene is a common disease gene in Han Chinese patients with Parkinson＇s disease.The detection of mutations in the PARK2 gene remains low.To investigate the role PARK2 gene mutations play in the pathogenesis of Parkinson＇s disease,30 Han Chinese patients with early-onset Parkinson＇s disease and 38 normal controls were studied to determine the sequence changes of 1,4,6 and 7 exon sections.In the 30 patients with Parkinson＇s disease,a heterozygous intron mutation（nt 119,G→G/A）in exon 1 was detected in one case;a homozygous intron mutation（nt 526500,T→C）between intron 3 and exon 4 in fourteen cases was found;a heterozygous intron mutation（nt 526607,G→G/A）between intron 3 and exon 4 was observed in eight cases;an exon 6missense mutation（nt 754317,C→C/T;codon 193,CGG→CGG/TGG;aa 193,Arg→Arg/Trp）in three cases was seen;and an exon 7 missense mutation（nt 941943,C→A/C;codon 272,CTC→CTC/ATC;aa 272,Leu→Leu/lle）was found in one case.These changes were not found in the normal population.The results indicated that the PARK2 exons 6 and 7 mutations are possibly pathogenic mutations,along with the intron 3-exert 4 and exon 1 mutations.PARK2 gene mutations are possible factors leading to the onset of Parkinson＇s disease.

Dopaminergic Dysfunction and Glucose Metabolism Characteristics in Parkin-Induced Early-Onset Parkinson’s Disease Compared to Genetically Undetermined Early-Onset Parkinson’s Disease

While early-onset Parkinson’s disease(EOPD)caused by mutations in the parkin gene(PRKN)tends to have a relatively benign course compared to genetically undetermined(GU)-EOPD,the exact underlying mechanisms remain elusive.We aimed to search for the differences between PRKN-EOPD and GU-EOPD by dopamine transporter(DAT)and glucose metabolism positron-emission-tomography(PET)imaging.Twelve patients with PRKN-EOPD and 16 with GU-EOPD who accepted both ^(11)C-2b-carbomethoxy-3b-(4-trimethylstannylphenyl)tropane(^(11)C-CFT)and ^(18)F-fluorodeoxyglucose PET were enrolled.The ^(11)C-CFT uptake was analyzed on both regional and voxel levels,whereas glucose metabolism was assessed in a voxel-wise fashion.Correlations between DAT and glucose metabolism imaging,DAT imaging and clinical severity,as well as glucose metabolism imaging and clinical severity were explored.Both clinical symptoms and DAT-binding pat-terns in the posterior putamen were highly symmetrical in patients with PRKN-EOPD,and dopaminergic dysfunction in the ipsilateral putamen was severer in patients with PRKN-EOPD than GU-EOPD.Meanwhile,the DAT binding was associ-ated with the severity of motor dysfunction in patients with GU-EOPD only.Patients with PRKN-EOPD showed increased glucose metabolism in the contralateral medial frontal gyrus(supplementary motor area(SMA)),contralateral substantia nigra,contralateral thalamus,and contralateral cerebellum.Notably,glucose metabolic activity in the contralateral medial frontal gyrus was inversely associated with regional DAT binding in the bilateral putamen.Patients with PRKN-EOPD showed enhanced metabolic connectivity within the bilateral putamen,ipsilateral paracentral and precentral lobules,and the ipsilateral SMA.Collectively,compared to GU-EOPD,PRKN-EOPD is characterized by symmetrical,more severe dopaminergic dysfunction and relative increased glucose metabolism.Meanwhile,SMA with elevated glucose metabolism and enhanced connectivity may act as compensatory mechanisms in PRKN-EOPD.

Olfactory dysfunction and its related molecular mechanisms in Parkinson’s disease

Changes in olfactory function are considered to be early biomarkers of Parkinson’s disease.Olfactory dysfunction is one of the earliest non-motor features of Parkinson’s disease,appearing in about 90%of patients with early-stage Parkinson’s disease,and can often predate the diagnosis by years.Therefore,olfactory dysfunction should be considered a reliable marker of the disease.However,the mechanisms responsible for olfactory dysfunction are currently unknown.In this article,we clearly explain the pathology and medical definition of olfactory function as a biomarker for early-stage Parkinson’s disease.On the basis of the findings of clinical olfactory function tests and animal model experiments as well as neurotransmitter expression levels,we further characterize the relationship between olfactory dysfunction and neurodegenerative diseases as well as the molecular mechanisms underlying olfactory dysfunction in the pathology of early-stage Parkinson’s disease.The findings highlighted in this review suggest that olfactory dysfunction is an important biomarker for preclinical-stage Parkinson’s disease.Therefore,therapeutic drugs targeting non-motor symptoms such as olfactory dysfunction in the early stage of Parkinson’s disease may prevent or delay dopaminergic neurodegeneration and reduce motor symptoms,highlighting the potential of identifying effective targets for treating Parkinson’s disease by inhibiting the deterioration of olfactory dysfunction.

Interplay between the glymphatic system and neurotoxic proteins in Parkinson’s disease and related disorders:current knowledge and future directions

Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic protein.Atypical parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related disorders.The glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial fluid.Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage.Therefore,impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration.Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions remain.This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders.The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and gliosis.This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.

Effects of mesenchymal stem cell on dopaminergic neurons,motor and memory functions in animal models of Parkinson's disease:a systematic review and meta-analysis

Parkinson’s disease is chara cterized by the loss of dopaminergic neurons in the substantia nigra pars com pacta,and although restoring striatal dopamine levels may improve symptoms,no treatment can cure or reve rse the disease itself.Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson’s disease.Mesenchymal stem cells are considered a promising option due to fewer ethical concerns,a lower risk of immune rejection,and a lower risk of teratogenicity.We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function,memory,and preservation of dopamine rgic neurons in a Parkinson’s disease animal model.We searched bibliographic databases(PubMed/MEDLINE,Embase,CENTRAL,Scopus,and Web of Science)to identify articles and included only pee r-reviewed in vivo interve ntional animal studies published in any language through J une 28,2023.The study utilized the random-effect model to estimate the 95%confidence intervals(CI)of the standard mean differences(SMD)between the treatment and control groups.We use the systematic review center for laboratory animal expe rimentation’s risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment.A total of 33studies with data from 840 Parkinson’s disease model animals were included in the meta-analysis.Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test.Among the stem cell types,the bone marrow MSCs with neurotrophic factor group showed la rgest effect size(SMD[95%CI]=-6.21[-9.50 to-2.93],P=0.0001,I^(2)=0.0%).The stem cell treatment group had significantly more tyrosine hydroxylase positive dopamine rgic neurons in the striatum([95%CI]=1.04[0.59 to 1.49],P=0.0001,I^(2)=65.1%)and substantia nigra(SMD[95%CI]=1.38[0.89 to 1.87],P=0.0001,I^(2)=75.3%),indicating a protective effect on dopaminergic neurons.Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route(SMD[95%CI]=-2.59[-3.25 to-1.94],P=0.0001,I^(2)=74.4%).The memory test showed significant improvement only in the intravenous route(SMD[95%CI]=4.80[1.84 to 7.76],P=0.027,I^(2)=79.6%).Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson’s disease.Further research is required to determine the optimal stem cell types,modifications,transplanted cell numbe rs,and delivery methods for these protocols.

Cell reprogramming therapy for Parkinson’s disease

Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.

Roles of neuronal lysosomes in the etiology of Parkinson’s disease

Therapeutic progress in neurodegenerative conditions such as Parkinson’s disease has been hampered by a lack of detailed knowledge of its molecular etiology.The advancements in genetics and genomics have provided fundamental insights into specific protein players and the cellular processes involved in the onset of disease.In this respect,the autophagy-lysosome system has emerged in recent years as a strong point of convergence for genetics,genomics,and pathologic indications,spanning both familial and idiopathic Parkinson’s disease.Most,if not all,genes linked to familial disease are involved,in a regulatory capacity,in lysosome function(e.g.,LRRK2,alpha-synuclein,VPS35,Parkin,and PINK1).Moreover,the majority of genomic loci associated with increased risk of idiopathic Parkinson’s cluster in lysosome biology and regulation(GBA as the prime example).Lastly,neuropathologic evidence showed alterations in lysosome markers in autoptic material that,coupled to the alpha-synuclein proteinopathy that defines the disease,strongly indicate an alteration in functionality.In this Brief Review article,I present a personal perspective on the molecular and cellular involvement of lysosome biology in Parkinson’s pathogenesis,aiming at a larger vision on the events underlying the onset of the disease.The attempts at targeting autophagy for therapeutic purposes in Parkinson’s have been mostly aimed at“indiscriminately”enhancing its activity to promote the degradation and elimination of aggregate protein accumulations,such as alpha-synuclein Lewy bodies.However,this approach is based on the assumption that protein pathology is the root cause of disease,while pre-pathology and pre-degeneration dysfunctions have been largely observed in clinical and pre-clinical settings.In addition,it has been reported that unspecific boosting of autophagy can be detrimental.Thus,it is important to understand the mechanisms of specific autophagy forms and,even more,the adjustment of specific lysosome functionalities.Indeed,lysosomes exert fine signaling capacities in addition to their catabolic roles and might participate in the regulation of neuronal and glial cell functions.Here,I discuss hypotheses on these possible mechanisms,their links with etiologic and risk factors for Parkinson’s disease,and how they could be targeted for disease-modifying purposes.

A review of the neurotransmitter system associated with cognitive function of the cerebellum in Parkinson's disease

The dichotomized brain system is a concept that was generalized from the‘dual syndrome hypothesis’to explain the heterogeneity of cognitive impairment,in which anterior and posterior brain systems are independent but partially overlap.The dopaminergic system acts on the anterior brain and is responsible for executive function,working memory,and planning.In contrast,the cholinergic system acts on the posterior brain and is responsible for semantic fluency and visuospatial function.Evidence from dopaminergic/cholinergic imaging or functional neuroimaging has shed significant insight relating to the involvement of the cerebellum in the cognitive process of patients with Parkinson’s disease.Previous research has reported evidence that the cerebellum receives both dopaminergic and cholinergic projections.However,whether these two neurotransmitter systems are associated with cognitive function has yet to be fully elucidated.Furthermore,the precise role of the cerebellum in patients with Parkinson’s disease and cognitive impairment remains unclear.Therefore,in this review,we summarize the cerebellar dopaminergic and cholinergic projections and their relationships with cognition,as reported by previous studies,and investigated the role of the cerebellum in patients with Parkinson’s disease and cognitive impairment,as determined by functional neuroimaging.Our findings will help us to understand the role of the cerebellum in the mechanisms underlying cognitive impairment in Parkinson’s disease.

Gut microbiota dysbiosis contributes toα-synuclein-related pathology associated with C/EBPβ/AEP signaling activation in a mouse model of Parkinson’s disease

Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease,whether it plays a causal role in motor dysfunction,and the mechanism underlying this potential effect,remain unknown.CCAAT/enhancer binding proteinβ/asparagine endopeptidase(C/EBPβ/AEP)signaling,activated by bacterial endotoxin,can promoteα-synuclein transcription,thereby contributing to Parkinson’s disease pathology.In this study,we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling,α-synuclein-related pathology,and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation.We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier,as well as activation of the C/EBP/AEP pathway,α-synuclein aggregation,and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits.However,treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics.Importantly,we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits,intestinal inflammation,and endotoxemia.Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits,intestinal inflammation,endotoxemia,and intestinal barrier impairment.These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits,C/EBPβ/AEP signaling activation,andα-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s disease.Additionally,our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson’s disease.

Deep brain implantable microelectrode arrays for detection and functional localization of the subthalamic nucleus in rats with Parkinson’s disease

The subthalamic nucleus(STN)is considered the best target for deep brain stimulation treatments of Parkinson’s disease(PD).It is difficult to localize the STN due to its small size and deep location.Multichannel microelectrode arrays(MEAs)can rapidly and precisely locate the STN,which is important for precise stimulation.In this paper,16-channel MEAs modified with multiwalled carbon nanotube/poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate)(MWCNT/PEDOT:PSS)nanocomposites were designed and fabricated,and the accurate and rapid identification of the STN in PD rats was performed using detection sites distributed at different brain depths.These results showed that nuclei in 6-hydroxydopamine hydrobromide(6-OHDA)-lesioned brains discharged more intensely than those in unlesioned brains.In addition,the MEA simultaneously acquired neural signals from both the STN and the upper or lower boundary nuclei of the STN.Moreover,higher values of spike firing rate,spike amplitude,local field potential(LFP)power,and beta oscillations were detected in the STN of the 6-OHDA-lesioned brain,and may therefore be biomarkers of STN localization.Compared with the STNs of unlesioned brains,the power spectral density of spikes and LFPs synchronously decreased in the delta band and increased in the beta band of 6-OHDA-lesioned brains.This may be a cause of sleep and motor disorders associated with PD.Overall,this work describes a new cellular-level localization and detection method and provides a tool for future studies of deep brain nuclei.

A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease

Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.

Survival outcomes in early-onset oesophageal adenocarcinoma patients:A systematic review and meta-analyses

BACKGROUND The incidence of oesophageal adenocarcinoma(OAC)has been reported to be increasing in many countries.Alongside this trend,an increase in incidence of early-onset OAC,defined as OAC in adults aged under 50 years,has been observed.It is unclear whether survival outcomes for early-onset OAC patients differ from older age groups.AIM To investigate survival outcomes in early-onset OAC patients.METHODS Ovid Medline and Embase were searched from inception to January 2022 for relevant studies relating to early-onset OAC and survival outcomes.Results regarding the overall five-year survival and risk of death of younger and older patients with OAC were extracted and pooled using meta-analyses to produce pooled estimates and 95%CIs where possible.RESULTS Eleven studies which compared survival of early-onset OAC,defined as age at diagnosis of<50 years,with older patients were included.A narrative review of median and mean survival demonstrated conflicting results,with studies showing early-onset OAC patients having both better and worse outcomes compared to older age groups.A meta-analysis of five-year survival demonstrated similar outcomes across age groups,with 22%-25%of patients in the young,middle and older age groups alive after five years.A meta-analysis of four studies demon-strated that early-onset OAC patients did not have a significantly increased risk of death compared to middle-aged patients(hazard ratio 1.12,95%CI:0.85-1.47).INTRODUCTION There is concern that the incidence of oesophageal adenocarcinoma(OAC)in patients under 50,described as early-onset OAC,is increasing.However,data regarding survival of younger patients with OAC is sparse.Globally,while increasing age remains a major non-modifiable risk factor for cancer,the incidence of early-onset cancers,largely accepted to be in adults aged under 50 years,is increasing[1].This includes an observed increase in the incidence of gastrointestinal malignancies such as colorectal,oesophageal,gastric and hepatobiliary cancers[2-4].Despite oesophageal squamous cell carcinoma(OSCC)being more common globally(88%of cases)[5],a striking increase in oesophageal OAC incidence has been reported in developed countries,such as the United States and Europe[6,7].Worryingly,the United Kingdom has the highest incidence of OAC cases in the world[8].In addition to the increase in OAC,an increase in incidence of early-onset OAC,defined as OAC in adults aged under 50 years,has been observed[9,10].A population-based cohort in the Netherlands,consisting of 59584 patients,demonstrated the incidence of early-onset OAC to have tripled from 1989 to 2018,while OSCC cases declined in this age group[7].OAC usually develops in the lower third of the oesophagus and the gastro-oesophageal junction,with risk factors including obesity and gastro-oesophageal reflux disease[11].A poor prognosis is observed,with the overall five-year survival rate for oesophageal cancer between 15%-20%,even with treatment[12,13].These low survival rates are likely due to a combination of late diagnosis,intrinsic resistance to systemic therapy and the limited efficacy of surgical resection.Younger patients tend to present at a more advanced stage at diagnosis compared to those diagnosed later in life.A single centre,retrospective study found that 33.3%of patients in the younger age category(<50 years old)presented with stage IV OAC,compared to the 20.6%of the oldest age category(>70 years old)[14].Another population-based study in the Netherlands observed that OAC patients under 50 years old also presented with distant metastasis more often in comparison to older patients(50.5%vs 44.7%),and that tumour differentiation also varied between age groups[15].Reports of survival estimates in patients with early-onset OAC compared with older patients have resulted in contrasting findings to date.Some studies report that due to the advanced stage and aggressiveness of the tumours seen that the prognosis of these patients is almost always worse than their older counterparts[16].In contrast,another study found that the overall survival,as well as stage-specific survival was higher in those who were younger[17].A Dutch study which included only resectable cases found no difference in 5-year disease specific survival[18].Given the conflicting evidence to date,the aim of this systematic review was to investigate survival in OAC patients according to age at diagnosis.A protocol was composed,and the reporting of this systematic review designed,using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines[19].The protocol included:The review question,search strategy,inclusion criteria,type of quality assessment,the strategy for data analysis,and the‘population,intervention,comparator,and outcome’criteria.These are expanded below.

Early-onset gastrointestinal cancer:An epidemiological reality with great significance and implications

During the last few years,epidemiological data from many countries suggest that the incidence and prevalence of many cancers of the digestive system are shifting from the older to the younger ages,the so-called“early-onset cancer”.This is particularly evident in colorectal cancer and secondarily in other malignant digestive neoplasms,mainly stomach and in a lesser degree pancreas,and biliary tract.It should be emphasized that data concerning digestive neoplasms,except for those referring to the colon and stomach,could be characterized as rather insufficient.The exact magnitude of the shift in younger ages is expected to become clearer shortly,as long as relevant epidemiological data from many parts of the world would be available.The most important question concerns the etiology of this phenomenon,since its magnitude cannot be explained solely by the better diagnostic methodology and the preventive programs applied in many countries.The existing data support the assumption that a number of environ-mental factors may play a primary role in influencing carcinogenesis,sometimes from childhood.Changes that have appeared in the last decades related mainly to eating habits,consistency of gut microbiome and an increase of obese people interacting with genetic factors,ultimately favor the process of carcinogenesis.Even these factors however,are not entirely sufficient to explain the age-related changes in the frequency of digestive neoplasms.Studies of the individual effect of each of the already known factors or factors likely to be involved in the etiology of this phenomenon and studies using state-of-the-art technologies to accurately determine the degree of the population exposure to these factors are required.In this article,we attempt to describe the epidemiological data supporting the age-shifting of digestive malignancies and their possible pathogenesis.Finally,we propose some measures regarding the attitude of the scientific community to this alarming phenomenon.

Treatment patterns and survival outcomes in patients with nonmetastatic early-onset pancreatic cancer

BACKGROUND The incidence of patients with early-onset pancreatic cancer(EOPC;age≤50 years at diagnosis)is on the rise,placing a heavy burden on individuals,families,and society.The role of combination therapy including surgery,radiotherapy,and chemotherapy in non-metastatic EOPC is not well-defined.AIM To investigate the treatment patterns and survival outcomes in patients with non-metastatic EOPC.METHODS A total of 277 patients with non-metastatic EOPC who were treated at our institution between 2017 and 2021 were investigated retrospectively.Overall survival(OS),disease-free survival,and progression-free survival were estimated using the Kaplan-Meier method.Univariate and multivariate analyses with the Cox proportional hazards model were used to identify prognostic factors.RESULTS With a median follow-up time of 34.6 months,the 1-year,2-year,and 3-year OS rates for the entire cohort were 84.3%,51.5%,and 27.6%,respectively.The median OS of patients with localized disease who received surgery alone and adjuvant therapy(AT)were 21.2 months and 28.8 months,respectively(P=0.007).The median OS of patients with locally advanced disease who received radiotherapy-based combination therapy(RCT),surgery after neoadjuvant therapy(NAT),and chemotherapy were 28.5 months,25.6 months,and 14.0 months,respectively(P=0.002).The median OS after regional recurrence were 16.0 months,13.4 months,and 8.9 months in the RCT,chemotherapy,and supportive therapy groups,respectively(P=0.035).Multivariate analysis demonstrated that carbohydrate antigen 19-9 level,pathological grade,T-stage,N-stage,and resection were independent prognostic factors for non-metastatic EOPC.CONCLUSION AT improves postoperative survival in localized patients.Surgery after NAT and RCT are the preferred therapeutic options for patients with locally advanced EOPC.

The Application of Analytical Techniques to Alpha-Synuclein in Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms such as tremors, rigidity, and bradykinesia, as well as non-motor symptoms including cognitive impairment and mood disorders. A hallmark of PD is the accumulation of alpha-synuclein, a presynaptic neuronal protein that aggregates to form Lewy bodies, leading to neuronal dysfunction and cell death. The study of alpha-synuclein and its pathological forms is crucial for understanding the etiology of PD and developing effective diagnostic and therapeutic strategies. Analytical techniques play a pivotal role in elucidating the structure, function, and aggregation mechanisms of alpha-synuclein. Biochemical methods such as Western blotting and enzyme-linked immunosorbent assay (ELISA) are employed to detect and quantify alpha-synuclein in biological samples, offering insights into its expression levels and post-translational modifications. Imaging techniques like immunohistochemistry and positron emission tomography (PET) allow for the visualization of alpha-synuclein aggregates in tissue samples and in vivo, respectively, facilitating the study of its spatial distribution and progression in PD Spectroscopic methods, including nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry, provide detailed structural information on alpha-synuclein and its isoforms, aiding in the identification of conformational changes associated with aggregation. Emerging techniques such as cryo-electron microscopy (Cryo-EM) and single-molecule fluorescence enable high-resolution structural analysis and real-time monitoring of alpha-synuclein aggregation dynamics, respectively. The application of these analytical techniques has significantly advanced our understanding of the pathophysiological role of alpha-synuclein in PD. They have contributed to the identification of potential biomarkers for early diagnosis and the evaluation of therapeutic interventions targeting alpha-synuclein aggregation. Despite technical limitations and challenges in clinical translation, ongoing advancements in analytical methodologies hold promise for improving the diagnosis, monitoring, and treatment of Parkinson’s disease through a deeper understanding of alpha-synuclein pathology.

Serum ferritin and the risk of early-onset colorectal cancer

BACKGROUND The incidence of early-onset colorectal cancer(EO-CRC)is rising in the United States,and is often diagnosed at advanced stages.Low serum ferritin is often incidentally discovered in young adults,however,the indication for endoscopy in EO-CRC is unclear.AIM To compare serum ferritin between patients with EO-CRC and healthy controls(HCs),and examine the association of serum ferritin in EO-CRC with patient-and disease-specific characteristics.METHODS A retrospective study of patients<50 years with newly-diagnosed EO-CRC was conducted from 1/2013-12/2023.Patients were included if serum ferritin was measured within 2 years prior to 1 year following CRC histologic diagnosis.To supplement the analysis,a cohort of HCs meeting similar inclusion and exclusion criteria were identified for comparison.A sensitivity analysis including only patients with serum ferritin obtained at or before diagnosis was separately performed to minimize risk of confounding.RESULTS Among 85 patients identified with EO-CRC(48 females),the median serum ferritin level was 26 ng/mL(range<1-2759 ng/mL).Compared to HCs(n=80211),there were a higher proportion of individuals with EO-CRC with serum ferritin<20 ng/mL(female 65%,male 40%)versus HCs(female 32.1%,male 7.2%)age 29-39 years(P=0.002 and P<0.00001,respectively).Stage IV disease was associated with significantly higher serum ferritin compared to less advanced stages(P<0.001).Serum ferritin obtained before or at the time of diagnosis was lower than levels obtained after diagnosis.Similar findings were confirmed in the sensitivity analysis.CONCLUSION Severe iron deficiency may indicate an increased risk of EO-CRC,particularly at earlier stages.Further studies defining the optimal serum ferritin threshold and routine incorporation of serum ferritin in screening algorithms is essential to develop more effective screening strategies for EO-CRC.

Cath-KP,a novel peptide derived from frog skin,prevents oxidative stress damage in a Parkinson’s disease model

Parkinson’s disease(PD)is a neurodegenerative condition that results in dyskinesia,with oxidative stress playing a pivotal role in its progression.Antioxidant peptides may thus present therapeutic potential for PD.In this study,a novel cathelicidin peptide(Cath-KP;GCSGRFCNLF NNRRPGRLTLIHRPGGDKRTSTGLIYV)was identified from the skin of the Asiatic painted frog(Kaloula pulchra).Structural analysis using circular dichroism and homology modeling revealed a uniqueαββconformation for Cath-KP.In vitro experiments,including free radical scavenging and ferric-reducing antioxidant analyses,confirmed its antioxidant properties.Using the 1-methyl-4-phenylpyridinium ion(MPP^(+))-induced dopamine cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced PD mice,Cath-KP was found to penetrate cells and reach deep brain tissues,resulting in improved MPP^(+)-induced cell viability and reduced oxidative stress-induced damage by promoting antioxidant enzyme expression and alleviating mitochondrial and intracellular reactive oxygen species accumulation through Sirtuin-1(Sirt1)/Nuclear factor erythroid 2-related factor 2(Nrf2)pathway activation.Both focal adhesion kinase(FAK)and p38 were also identified as regulatory elements.In the MPTP-induced PD mice,Cath-KP administration increased the number of tyrosine hydroxylase(TH)-positive neurons,restored TH content,and ameliorated dyskinesia.To the best of our knowledge,this study is the first to report on a cathelicidin peptide demonstrating potent antioxidant and neuroprotective properties in a PD model by targeting oxidative stress.These findings expand the known functions of cathelicidins,and hold promise for the development of therapeutic agents for PD.

Association of serum interleukin-6 with negative symptoms in stable early-onset schizophrenia

BACKGROUND Accumulating evidence suggests that the inflammatory cytokine interleukin-6(IL-6)contributes to the pathophysiology of psychiatric disorders.However,there was no study concerning the relationship between IL-6 concentrations and clinical features in the chronic phase of early-onset schizophrenia(EOS).AIM To investigate the relationship between serum IL-6 concentration and the clinical features of EOS.METHODS We measured serum IL-6 Levels from 74 patients with chronic schizophrenia,including 33 with age at onset<21 years(EOS group)and 41 with onset≥21 years in[adult-onset schizophrenia(AOS)group],and from 41 healthy controls.Symptom severities were evaluated using the Positive and Negative Syndrome Scale(PANSS).RESULTS Serum IL-6 concentrations were higher in both EOS and AOS groups than healthy controls(F=22.32,P<0.01),but did not differ significantly between EOS and AOS groups(P>0.05)after controlling for age,body mass index,and other covariates.Negative symptom scores were higher in the EOS group than the AOS group(F=6.199,P=0.015).Serum IL-6 concentrations in the EOS group were negatively correlated with both total PANSS-negative symptom score(r=-0.389,P=0.032)and avolition/asociality subscore(r=-0.387,P=0.026).CONCLUSION Patients with EOS may have more severe negative symptoms than those with adult-onset schizophrenia during the chronic phase of the illness.IL-6 signaling may regulate negative symptoms and its avolition/asociality subsymptoms among the early-onset chronic schizophrenic patients.