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There is growing recognition of early-onset gastrointestinal (GI) malignancies in young adults < 50 years of age. While much of the literature has emphasized colorectal cancer, these also include esophageal, gastric, liver, pancreatic, and biliary tract malignancies. Various factors, including lifestyle, hereditary, and environmental elements, have been proposed to explain the rising incidence of GI malignancies in the younger population. This review aims to provide an overview of the recent literature, including global trends and information regarding genetic and environmental risk factors.

INTRODUCTION This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. METHODS AD polygenic risk scores (PRS) were tested for association with DS‐related traits. RESULTS The AD risk PRS was associated with disease status in several cohorts of sporadic late‐ and early‐onset and familial late‐onset AD, but not in familial early‐onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRSAPOE, p = 2.84 × 10−4; PRS excluding APOE, PRSnonAPOE, p = 1.60 × 10−2). PRSAPOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS. DISCUSSION These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits. Highlights Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults.

Treatment of young adults with colorectal cancer (CRC) represents an unmet clinical need, especially as diagnosis in this population might lead to the greatest loss of years of life. Since 1994, CRC incidence in individuals younger than 50 years has been increasing by 2% per year. The surge in CRC incidence in young adults is particularly alarming as the overall CRC frequency has been decreasing. Early‐onset CRC are characterized by a more advanced stage at diagnosis, poorer cell differentiation, higher prevalence of signet ring cell histology, and left colon‐sided location of the primary tumor. Among EO‐CRC, approximately 30% of patients are affected by tumors harboring mutations causing hereditary cancer predisposing syndromes, and 20% have familial CRC. Most notably, the remaining 50% of EO‐CRC patients have neither hereditary syndromes nor familial CRC, thus representing a formidable challenge for research. In this review article we summarize epidemiology, clinical and molecular features, heredity and outcome of treatments of EO‐CRC, and provide considerations for future perspectives. The prevalence of hereditary syndromes, familial syndromes and neither hereditary or familial (‘terra incognita’) syndromes among early‐onset colorectal cancer in young individuals. Figures are derived from studies in the text.

Objective To compare the clinical symptomatology in patients with Early‐Onset Schizophrenia (EOS, N = 176), especially the subgroup Very Early Onset Schizophrenia (VEOS) and Adult Onset Schizophrenia (AOS, N = 551). Method In a large French multicentric sample, 727 stable schizophrenia patients, classified by age at onset of the disorder, were assessed using standardized and extensive clinical and neuropsychological batteries: AOS with onset ≥ 18 years and EOS with onset < 18 years (including 22 VEOS < 13 years). Results The importance of better diagnosing EOS group, and in particularly VEOS, appeared in a longer DUP Duration of Untreated Psychosis (respectively, 2.6 years ± 4.1 and 8.1 years ± 5.7 vs. 1.0 years ± 2.5), more severe symptomatology (PANSS Positive And Negative Syndrome Scale scores), and lower educational level than the AOS group. In addition, the VEOS subgroup had a more frequent childhood history of learning disabilities and lower prevalence of right‐handedness quotient than the AOS. Conclusion The study demonstrates the existence of an increased gradient of clinical severity from AOS to VEOS. In order to improve the prognosis of the early forms of schizophrenia and to reduce the DUP, clinicians need to pay attention to the prodromal manifestations of the disease. To describe schizophrenia from childhood to adulthood is complex and patients with early‐onset schizophrenia (EOS) remain undiagnosed or misclassified, especially the subgroup with very early‐onset schizophrenia (VEOS). In patients with VEOS, the DUP which exceeds 8 years, almost eight times higher than in patients with AOS, objective the problem of early diagnosis and the need to develop diagnostic programs and management cares.

INTRODUCTION Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller‐scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD. METHODS Z‐score cognitive‐domain composites for 311 amyloid‐positive sporadic EOAD and 314 amyloid‐positive LOAD participants were calculated from baseline data from age‐appropriate control cohorts. Z‐score composites were compared between AD groups for each domain. RESULTS After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory. DISCUSSION Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non‐amnestic impairments in younger patients to ensure proper identification and intervention using disease‐modifying treatments. Highlights Both early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) participants displayed widespread cognitive impairments relative to their same‐aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv‐PPA), and frontal‐variant AD.

Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders characterized by chronic relapsing intestinal inflammation. Although etiology remains largely unknown, recent research has suggested that genetic factors, environment, microbiota, and immune response are involved in the pathogenesis. Epidemiological evidence for a genetic contribution is defined: 15% of patients with Crohn's Disease (CD) have an affected family member with IBD, and twin studies for CD have shown 50% concordance in monozygotic twins compared to <10% in dizygotics. The most recent and largest genetic association studies, which employed genome-wide association data for over 75,000 patients and controls, identified 163 susceptibility loci for IBD. More recently, a trans-ethnic analysis, including over 20,000 individuals, identified an additional 38 new IBD loci. Although most cases are correlated with polygenic contribution toward genetic susceptibility, there is a spectrum of rare genetic disorders that can contribute to early-onset IBD (before 5 years) or very early onset IBD (before 2 years). Genetic variants that cause these disorders have a wide effect on gene function. These variants are so rare in allele frequency that the genetic signals are not detected in genome-wide association studies of patients with IBD. With recent advances in sequencing techniques, ~50 genetic disorders have been identified and associated with IBD-like immunopathology. Monogenic defects have been found to alter intestinal immune homeostasis through many mechanisms. Candidate gene resequencing should be carried out in early-onset patients in clinical practice. The evidence that genetic factors contribute in small part to disease pathogenesis confirms the important role of microbial and environmental factors. Epigenetic factors can mediate interactions between environment and genome. Epigenetic mechanisms could affect development and progression of IBD. Epigenomics is an emerging field, and future studies could provide new insight into the pathogenesis of IBD.

INTRODUCTION Neuroinflammation, a key player in Alzheimer's disease (AD) pathogenesis, may be differentially involved in young‐onset (YOAD) compared to late‐onset (LOAD) AD. METHODS Using proximity extension assay technology, we examined 737 inflammatory markers in the CSF of 26 healthy controls (63.9 ± 8.7; 12♀), 57 patients with YOAD (60.8 ± 4.9 y/o; 40♀), and 33 with LOAD (76.6 ± 4.5 y/o; 18♀). We also assessed biomarkers of AD pathology (Aβ42, p‐tau181, t‐tau) and neurodegeneration (neurofilament light‐chain [NfL]). RESULTS Compared to controls, SCRN1 and MMP10 were increased in LOAD and YOAD, but 16 markers showed YOAD‐specific increases. Forty‐six markers were significantly associated with NfL. P‐tau181 and t‐tau mediated the association between inflammatory markers and NfL in YOAD. In LOAD we could not identify a direct or indirect relationship between neuroinflammation and neurodegeneration. DISCUSSION Using a proteomics approach, we observed an exacerbation of neuroinflammatory changes and a differential contribution of neuroinflammation to AD pathology and neurodegeneration in YOAD compared to LOAD. Highlights Olink's Proximity Extension Assay was used to compare the inflammatory profile of 26 healthy controls and 90 Alzheimer's disease (AD) patients. AD patients were further stratified into young‐onset (YOAD, n = 57) and late‐onset (LOAD, n = 33) AD. Cerebrospinal fluid (CSF) levels of MMP10 and SCRN1 were increased in both YOAD and LOAD, but 16 proteins were only increased in YOAD. Tau mediated the association between inflammatory markers and neurodegeneration in YOAD. Neuroinflammation may be differentially involved in the pathogenesis of YOAD compared to LOAD.

Abstract Background Whether primary sclerosing cholangitis related to inflammatory bowel disease (PSC-IBD) diagnosed before 6 years (ie, VEO-IBD) has a distinct phenotype and disease course is uninvestigated. We aimed to analyze the characteristics and natural history of VEO-PSC-IBD, compared with early and adolescent-onset PSC-IBD. Methods This is a multicenter, retrospective, case-control study from 15 centers affiliated with the Porto and Interest IBD group of ESPGHAN. Demographic, clinical, laboratory, endoscopic, and imaging data were collected at baseline and every 6 months. Inflammatory bowel disease–related (clinical remission, need for systemic steroids and biologics, and surgery) and PSC-related (biliary and portal hypertensive complications, need for treatment escalation and liver transplantation, cholangiocarcinoma, or death) outcomes were compared between the 2 groups. Results Sixty-nine children were included, with a median follow-up of 3.63 years (interquartile range, 1-11): 28 with VEO-PSC-IBD (23 UC [82%], 2 IBD-U [7%] and 3 [11%] CD), and 41 with PSC-IBD (37 UC [90%], 3 IBDU [7.5%] and 1 [2.5%] CD). Most patients with UC presented with pancolitis (92% in VEO-PSC-UC vs 85% in PSC-UC, P = .2). A higher number of patients with VEO-PSC-IBD were diagnosed with PSC/autoimmune hepatitis overlap syndrome than older children (24 [92%] vs 27 [67.5%] PSC-IBD, P = .03), whereas no other differences were found for PSC-related variables. Time to biliary strictures and infective cholangitis was lower in the VEO-PSC-IBD group (P = .01 and P = .04, respectively), while no difference was found for other outcomes. No cases of cholangiocarcinoma were reported. Conclusions Primary sclerosing cholangitis related to inflammatory bowel disease has similar baseline characteristics whether diagnosed as VEO-IBD or thereafter. A milder disease course in terms of biliary complications characterizes VEO-PSC-IBD. Lay Summary Very early onset primary sclerosing cholangitis associated with IBD (VEO-PSC-IBD) often presents with autoimmune features and shows a milder PSC disease course than later-onset disease. These findings highlight the significance of studying the distinctive genetic and pathophysiological factors specific to VEO disease.

INTRODUCTION Early‐onset Alzheimer's disease dementia (EOAD) is characterized by more pronounced cognitive decline than late‐onset AD dementia (LOAD). Characteristic performance in spoken language remains undefined. METHOD A cross‐sectional analysis of 1189 people with EOAD and 4646 with LOAD from the National Alzheimer's Coordinating Center (NACC) was conducted. RESULT Based on data from their first NACC visit with AD, there was considerable heterogeneity in language performance across people with EOAD and LOAD. The distribution of naming ability was similar across these groups. On average, people with LOAD performed better than those with EOAD in category fluency, letter fluency, and spoken lexical retrieval, and had lower Clinical Dementia Rating (CDR) Language scores, although there was considerable overlap in the distributions for participants with EOAD and those with LOAD. DISCUSSION At diagnosis, the language profiles of EOAD and LOAD are distinct. There is substantial variability in both groups in multiple aspects of language. Highlights Early‐onset Alzheimer's disease (EOAD) is associated with significantly poorer category and phonemic fluency and global spoken lexical retrieval compared to late‐onset Alzheimer's disease (LOAD) at time of diagnosis. Participants with EOAD dementia show greater severity and variability in clinician‐rated language functioning, as measured by Clinical Dementia Rating (CDR) Language scores. No significant group differences were observed in confrontation naming performance between EOAD and LOAD dementia. Findings support that there are distinct profiles of language performance in EOAD and LOAD at time of dementia diagnosis.

The incidence of early‐onset cancers, commonly defined as cancers diagnosed before age 50 years, has been increasing globally over recent decades. In particular, the incidence of several early‐onset digestive system cancers, including cancers of the esophagus, stomach, colorectum, liver, extrahepatic bile duct, gallbladder, and pancreas, has been reported to be increasing in multiple regions. To elucidate carcinogenic mechanisms and develop effective prevention, earlier detection, and treatment strategies, further evidence is needed on risk factors and clinical, pathological, and molecular characteristics. In this review, we summarize the current evidence on these characteristics, highlight shared and distinct features across organ sites, and discuss research opportunities to address the rising burden of early‐onset digestive system cancers. Shared risk factors, clinical features, and tumor characteristics across multiple early‐onset cancer types are shown in this Graphical . Integrative approaches combining molecular pathology, oncology, and population sciences offer opportunities to clarify underlying mechanisms and help us develop preventive strategies for early‐onset cancers.