Early-onset Cases Research Articles

First-trimester metabolic profiling of gestational diabetes mellitus: insights into early-onset and late-onset cases compared with healthy controls

IntroductionGestational diabetes mellitus (GDM) is a global health concern with significant short and long-term complications for both mother and baby. Early prediction of GDM, particularly late-onset, is crucial for implementing timely interventions to mitigate adverse outcomes. In this study, we conducted a comprehensive metabolomic analysis to explore potential biomarkers for early GDM prediction.MethodsPlasma samples were collected during the first trimester from 60 women: 20 with early-onset GDM, 20 with late-onset GDM, and 20 with normal glucose tolerance. Using advanced analytical techniques, including liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS), we profiled over 150 lipid species and central carbon metabolism intermediates.ResultsSignificant metabolic alterations were observed in both early- and late-onset GDM groups compared to healthy controls, with a specific focus on glycerolipids, fatty acids, and glucose metabolism. Key findings revealed a 4.0-fold increase in TG(44:0), TG(46:0), TG(46:1) with p-values <0.001 and TG(46:2) with 4.7-fold increase and p-value <0.0001 as well as changes in several phospholipids as PC(38:3), PC(40:4) with 1.4-fold increase, p < 0.001 and PE(34:1), PE(34:2) and PE(36:2) with 1.5-fold change, p < 0.001 in late-onset GDM.DiscussionObserved lipid changes highlight disruptions in energy metabolism and inflammatory pathways. It is suggested that lipid profiles with distinct fatty acid chain lengths and degrees of unsaturation can serve as early biomarkers of GDM risk. These findings underline the importance of integrating metabolomic insights with clinical data to develop predictive models for GDM. Such models could enable early risk stratification, allowing for timely dietary, lifestyle, or medical interventions aimed at optimizing glucose regulation and preventing complications such as preeclampsia, macrosomia, and neonatal metabolic disorders. By focusing on metabolic disruptions evident in the first trimester, this approach addresses a critical window for improving maternal and fetal outcomes. Our study demonstrates the value of metabolomics in understanding the metabolic perturbations associated with GDM. Future research is needed to validate these biomarkers in larger cohorts and assess their integration into clinical workflows for personalized pregnancy care.

Combined in silico/in vitro approaches for identifying modulators of the activity of the p.Tyr110Cys Carnitine O-Acetyltransferase (CRAT) variant associated to an early onset case of Leigh syndrome.

Carnitine O-acetyltransferase (CRAT) is a crucial enzyme involved in mitochondrial energy metabolism. Alterations in CRAT activity have emerged as significant contributors to the pathogenesis of Leigh syndrome and related mitochondrial disorders. In this study we employed an integrated approach combining in silico docking analysis and virtual screening of chemical libraries with subsequent in vitro validation to identify small molecule modulators of the activity of the wild type (WT) CRAT and the p.Tyr110Cys (Y110C) variant associated to an early onset case of Leigh syndrome. Through 3D molecular modeling, docking simulations, and virtual screening of chemical libraries, potential CRAT modulators were prioritized based on their predicted binding affinities and interactions with the 3D models of the WT-CRAT and of the p.Tyr110Cys-CRAT mutant. The performed in silico analyses were validated through in vitro assays on the purified recombinant CRAT proteins and cell-lysates from control fibroblasts and the fibroblasts of a patient with genetic diagnosis of CRAT-deficiency, carrying the compound heterozygous missense variants in the CRAT gene, namely p.Tyr110Cys and p.Val569Met. Based on the above screening by applying the indicated filtering strategy and mentioned criteria, 3 commercially available approved drugs (also known for their possible interactions with mitochondria) namely glimepiride, artemisinin and dorzolamide, as well as suramin (already known for its ability to interact with mitochondrial proteins) were tested in in vitro assays. We found that suramin (1-1000 μM) dose-dependently inhibited the activity of both WT-CRAT and p.Tyr110Cys_CRAT variant. Artemisinin (0.1-200μM) dose-dependently stimulated the activity ofthe recombinant p.Tyr110Cys CRAT mutant, whereas glimepiride and dorzolamide did not change the activity of these proteins towards acetyl-CoA. This study demonstrates the effectiveness of this combined approach in identifying novel compounds for modulating CRAT enzyme activity, providing valuable insights for potential therapeutic interventions targeting CRAT-related disorders.

Clinical Characteristics and Risk Factors for Persistent Thrombocytopenia among Pediatric Patients after Bone Marrow Transplant in Saudi Arabia: A 3-Year Retrospective Observational Analysis from Tertiary Hospital

Background Bone marrow transplantation (BMT) is a crucial treatment for pediatric patients with various hematological, oncological, and genetic diseases. However, persistent thrombocytopenia (PT) post-transplantation poses a significant challenge, affecting recovery and prognosis. Purpose This study aimed to identify the clinical characteristics and risk factors associated with PT in pediatric patients post-BMT, specifically in Saudi Arabia. Methods A retrospective cohort study design was employed, involving pediatric patients who underwent BMT between January 2020 and January 2023. Clinical characteristics, laboratory results, treatment data, and outcomes were collected from electronic medical records. Logistic regression analyses were conducted to identify risk factors associated with PT. Results Among the 77 pediatric patients in the study, no significant differences were observed in demographic characteristics, transplant types, or treatment modalities between early-onset and late-onset thrombocytopenia groups. However, the duration of thrombocytopenia post-transplant differed significantly between the groups, with early-onset cases experiencing shorter durations. Infections and graft-versus-host disease were common post-transplant complications. Chemotherapy and antiviral therapy were frequently administered treatments. Pediatric patients undergoing BMT are susceptible to PT, with varying durations based on the onset timing. Conclusion The study emphasizes the importance of risk assessment and tailored management to mitigate thrombocytopenia in pediatric BMT patients. Further research is needed to elucidate the underlying mechanisms and optimize therapeutic interventions for thrombocytopenia in this population.

Four pathogenic variants co-occurring in a MINAS early-onset breast cancer.

Multilocus Inherited Neoplasia Allele Syndrome (MINAS) is a condition defined by the presence of germline pathogenic variants in more than one Cancer Susceptibility Gene (CSG). MINAS is still underreported in the literature and public databases. Since MINAS-related phenotypes are difficult to predict, case descriptions may contribute to risk assessment, treatment, and personalized surveillance for proband and relatives. Here we report a unique case of early onset, bifocal, non-Triple Negative breast cancer in a 31-year-old woman. Fast metastatic dissemination involving the brain caused the death of the patient in a few months. Her multigene panel testing showed the co-occurrence of pathogenic variants in PALB2 (c.1221del; p.Thr408fs*40), ATM (c.8545C>T; p.Arg2849*), PMS2 (c.1919C>A; p.Ser640*), and MUTYH (c.1103G>A; p.Gly368Asp). The patient inherited the ATM and MUTYH variants from the mother, and PALB2 and PMS2 variants from the father. The brother inherited the maternal ATM and paternal PMS2 variants. A baseline imaging-based family screening excluded malignancies in both parents and in the brother. Tailored monitoring is ongoing based on the risk predicted by pathogenic variants identified in family members. Currently, there are no predictive tools available to determine organ-specific cancer risk in MINAS patients. Given the uncertainty in predicting the phenotypic effect of multiple variants in CSGs, ongoing clinical surveillance and sharing data from complex cases are crucial for improving risk stratification in this condition.

Contribution of rare chromosome 22q11.2 copy number variants to non-syndromic bicuspid aortic valve

BackgroundBicuspid aortic valve (BAV) is the most common congenital heart defect in adults, often leading to complications such as thoracic aortic aneurysms and aortic stenosis. While BAV is frequently associated...

MODELING EARLY-ONSET CANCER KINETICS TO STUDY CHANGES IN UNDERLYING RISK, DETECTION, AND IMPACT OF POPULATION SCREENING.

Recent studies have reported increases in early-onset cancer cases (diagnosed under age 50) and call into question whether the increase is related to earlier diagnosis from other medical tests and reflected by decreasing tumor-size-at-diagnosis (apparent effects) or actual increases in underlying cancer risk (true effects), or both. The classic Multi-Stage Clonal Expansion (MSCE) model assumes cancer detection at the emergence of the first malignant cell, although later modifications have included lag-times or stochasticity in detection to more realistically represent tumor detection requiring a certain size threshold. Here, we introduce an approach to explicitly incorporate tumor-size-at-diagnosis in the MSCE framework and account for improvements in cancer detection over time to distinguish between apparent and true increases in early-onset cancer incidence. We demonstrate that our model is structurally identifiable and provides better parameter estimation than the classic model. Applying this model to colorectal, female breast, and thyroid cancers, we examine changes in cancer risk while accounting for detection improvements over time in three representative birth cohorts (1950-1954, 1965-1969, and 1980-1984). Our analyses suggest accelerated carcinogenic events and shorter mean sojourn times in more recent cohorts. We further use this model to examine the screening impact on the incidence of breast and colorectal cancers, both having established screening protocols. Our results align with well-documented differences in screening effects between these two cancers. These findings underscore the importance of accounting for tumor-size-at-diagnosis in cancer modeling and support true increases in early-onset cancer risk in recent years for breast, colorectal, and thyroid cancer.

Comorbidities in early-onset sporadic versus presenilin-1 mutation-associated Alzheimer disease dementia: Evidence for dependency on Alzheimer disease neuropathological changes.

Studying comorbidities in early onset Alzheimer disease (AD) may provide an advantageous perspective on their pathogenesis because aging factors may be largely inoperative for these subjects. We compared AD comorbidities between early-onset sporadic cases and American and Colombian cases with PSEN1 mutations. AD neuropathological changes (ADNC) were very severe in all groups but more severe in the PSEN1 groups. Lewy body disease and cerebral white matter rarefaction were the most common (up to 60%) of AD comorbidities, followed by arteriolosclerosis (up to 37%), and large-vessel atherosclerosis (up to 20%). Differences between the 3 groups included earlier age of onset in the American PSEN1 cases, shorter disease duration in sporadic cases, and more frequent large-vessel atherosclerosis and cerebral amyloid angiopathy in the Colombian PSEN1 cases. Logistic regression models adjusted for age and sex found the presence of a PSEN1 mutation, an apolipoprotein ε4 allele and TDP-43 pathology to predict an earlier age of onset; Hispanic ethnicity and multiracial subjects were predictive of severe CAA. Comorbidities are common in early onset AD and should be considered when planning clinical trials with such subjects. However, they may be at least partially dependent on ADNC and thus potentially addressable by anti-amyloid or and/anti-tau therapies.

Association Between Placental Pathology and Early-Onset Fetal Growth Restriction: A Systematic Review

Objective: Fetal growth restriction (FGR) is defined as the failure of the fetus to achieve its genetically determined growth potential. Our aim is to compare the placental lesions present in early-onset fetal growth restriction with that of late-onset FGR. Methods: We performed a systematic review according to the PRISMA guideline. Observational studies, only in singleton pregnancies, evaluating the association between fetal growth restriction and placental lesions in early- versus late-onset FGR were included. Results: We included six articles. All studies showed a higher rate of maternal vascular malperfusion (MVM) lesions in the early-onset FGR groups when compared to late-onset ones. Five articles reported that early-onset FGR is often associated with pre-eclampsia. Conclusion: This review shows that early-onset FGR cases are associated with specific placental histopathology, such as maternal vascular malperfusion lesions. Placental histopathological examination is important to better understand the pathophysiology of FGR.

WNT and TGF-Beta Pathway Alterations in Early-Onset Colorectal Cancer Among Hispanic/Latino Populations.

One of the fastest-growing minority groups in the U.S. is the Hispanic/Latino population. Recent studies have shown how this population is being disproportionately affected by early-onset colorectal cancer (CRC). Compared to corresponding non-Hispanic White (NHW) patients, Hispanic/Latino patients have both higher incidence of disease and rates of mortality. Two well-established drivers of early-onset CRC in the general population are alterations in the WNT and TGF-Beta signaling pathways; however, the specific roles of these pathways in Hispanics/Latinos are poorly understood. Here, we assessed CRC mutations in the WNT and TGF-Beta pathways by conducting a bioinformatics analysis using cBioPortal. Cases of CRC were stratified both by age and ethnicity: (1) early-onset was defined as <50 years vs. late-onset as ≥50 years; (2) we compared early-onset in Hispanics/Latinos to early-onset in NHWs. No significant differences were evident when we compared early-onset and late-onset CRC cases within the Hispanic/Latino cohort. These results are consistent with findings from large cohorts that do not specify ethnicity. However, we found significant differences when we compared early-onset CRC in Hispanic/Latino patients to early-onset CRC in NHW patients: specifically, alterations in the gene bone morphogenetic protein-7 (BMP7) were more frequent in early-onset CRC for the Hispanic/Latino patients. In addition to these findings, we observed that both NHW patients and Hispanic/Latino patients with early-onset disease had better clinical outcomes when there was evidence of WNT pathway alterations. Conversely, the absence of TGF-Beta pathway alterations was uniquely associated with improved outcomes exclusively in early-onset Hispanic/Latino patients. In toto, these findings underscore how the WNT and TGF-Beta pathways may act differently in different ethnic groups with early-onset CRC. These findings may set a stage for developing new therapies tailored for reducing cancer health disparities.

Age as a Predictor of Overall Survival in Colorectal Cancer.

The diagnosis of colorectal cancer (CRC) at early ages has become a challenging trend for oncology due to high rates of mortality worldwide. The correlation of clinical features with young-age prognosis in CRC remains unclear. Therefore, we aimed to describe the clinicopathological features and their impact on the overall survival of young Mexican adults diagnosed with CRC treated in the National Cancer Institute. This was a retrospective, observational study. The included patients were treated at the National Cancer Institute between 2004 and 2020. The statistical analyses comprised the X2 and t tests, Kaplan-Meier, log rank, and Cox regression. Statistical significances were assessed when p was bilaterally < 0.05. A total of 3652 patients diagnosed with CRC attended the National Cancer Institute. Cases of early onset of CRC increased over the 16 years under study, with significant differences between the median age, from 57 in 2004 to 55 years old in 2020 (F = 5.49; gl: 12 p = 0.019). For this analysis, the population was divided in three groups: young (≤30 years), adults (31-70), and elderly (>70). The young population was mostly composed of men (62%; (n = 63), (p = 0.020), with high rates of metastatic disease (44%) (p = 0.001) and right-side tumors (57%), (p = 0.046), and with 44% with a moderate grade (p = 0.750). According to the overall survival (OS) analysis, the median OS was 29 months for young, versus 170 months for adult and 56 months for elderly patients (p <0.001, HR 1.53, 95% CI 1.11-2.10). A sub-analysis was performed considering only patients with metastatic disease. The median OS was 12 months for young, versus 17 and 9 months for adults and elderly (p = 0.08, HR 1.27, 95% CI 1.02-1.46). CRC diagnosis in the young population is increasing due unhealthy lifestyle habits and lack of screening. This population have clinical features of bad prognosis, such as left side, poor grade differentiation, and metastatic disease, precluding prognosis and OS.

Utility of Tau PET in the diagnostic work up of neurodegenerative dementia among Indian patients

Background and objectivesTau PET is being increasingly appraised as a novel diagnostic modality for dementia work up. Given limited data among South Asians, we assessed the frequency, patterns, phenotypic associations and incremental value of positive Tau PET scans in clinically diagnosed neurodegenerative dementia. MethodsThis cross-sectional study recruited consecutive patients of Alzheimer's disease (AD) and non-AD syndromes (September 2021 to October 2022, India). Participants underwent clinical interview, cognitive assessment, MRI brain and tau PET scan ([F-18]ML-104). Visual read in a priori regions of interest was used to identify patterns of tau deposition in the brain. ResultsWe recruited 54 participants (mean age: 63.2 ± 9.2 years, 64.8 % men, 77.8 % dementia, 70.4 % early onset cases, 37.8 % APOE4+). The analysis identified abnormal tau uptake in 40/54 (74.1 %) participants; with uptake in AD signature areas in 27/40 (67.5 %) cases [cortical subtype (74.1 %), limbic (14.8 %), combined cortical/limbic (11.1 %)], and patterns not conforming to AD in 13/40 (32.5 %) cases. Tau PET substantiated the diagnosis of AD among 17/19 (89.5 %) cases with clinically diagnosed AD dementia, 8/23 (34.8 %) cases with suspected non-AD cause, and 2/12 (16.7 %) cases with mild cognitive impairment. A trend for increasing proportion of early onset cases, and worsening cognition, behavior and functional ability was seen, from ‘limbic’ to ‘combined cortical/limbic’ to ‘cortical’ subgroups. ConclusionTau PET is a useful modality to differentiate AD dementia from other neurodegenerative causes in the Indian setting where amyloid biomarkers are not widely available. Biological subtypes of AD map well onto clinical phenotypes and need study in larger cohorts.

Assessing diagnostic accuracy: 18F-FDG PET-CT scans in low-grade infection detection among post-traumatic long bone non-unions; a literature review and clinical data

IntroductionThe diagnosis of low-grade infection in post-traumatic long bone non-unions poses challenges due to the absence of clinical signs. This study aimed to review the available literature on the diagnostic accuracy of imaging techniques for low-grade infections and assess the diagnostic accuracy of 18F-FDG PET-CT scans for low-grade infection in post-traumatic long bone non-unions. MethodsA mini-review was conducted using Pubmed in March 2024. A retrospective study was conducted including adult patients with a long bone non-union, suspected of infection. All patients underwent 18F-FDG PET-CT scans as the index test before surgical intervention, with peri‑operative cultures obtained during surgery serving as the reference standard. Quantitative analyses were performed on the standardized uptake value (SUV) measurements obtained from the 18F-FDG PET-CT scans. Diagnostic accuracy measures including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Receiver operating characteristic (ROC) curve analysis was employed to evaluate the discriminatory ability of SUV measurements. ResultsLiterature suggests that 18F-FDG PET-CT is the most accurate imaging technique to detect low-grade infections. The study included a total of 51 18F-FDG PET-CT scans and cultures from 50 patients with long bone non-unions. The diagnostic accuracy was found to be 0.67 (95 % CI 0.44–0.87). The PPV and NPV were calculated as 0.79 (95 % CI 0.53–1.00) and 0.52 (95 % CI 0.30–0.73), respectively. Quantitative analyses of SUV measurements demonstrated a low level of accuracy, with all area under the curve (AUC) values < 0.75 and ROC curves showing a trajectory fairly parallel to the diagonal line. Conclusion and discussionThe findings of this study indicate that in post-traumatic long bone non-unions, where a low-grade fracture-related infection (FRI) is suspected, the 18F-FDG PET-CT has a performance that is advantageous over other imaging techniques. A careful interpretation of the scan results is warranted, possibly including the quantitative analysis on tracer uptake as an adjunct. Nevertheless, the diagnostic accuracy in this condition is not as good as in early-onset FRI cases, and this should be taken into account when treating these challenging cases.

Novel FLNC variants in pediatric cardiomyopathy: an insight into disease mechanisms

BackgroundFLNC gene variants have predominantly been reported in adult populations with cardiomyopathies, and early-onset cases are less common. The genotype–phenotype relationship indicates that dilated cardiomyopathy (DCM) is often associated with FLNC truncating variants.MethodsWe conducted a comprehensive genetic analysis using next generation sequencing (NGS) to identify FLNC variants in patients with cardiovascular conditions. Detailed phenotypic and variant analyses were performed to characterize the clinical features and genetic alterations. Minigene assays and structural modeling were used to investigate the pathogenicity caused by the identified variants.ResultsIn a cohort of 58 patients, novel heterozygous FLNC variants, c.3962A > T (p.Glu1321Val) and c.7543C > T (p.Leu2515Phe), were identified in patients presenting with dilated and mixed restrictive/hypertrophic cardiomyopathies, respectively. The c.3962A > T variant disrupted normal splicing, as demonstrated through the splicing prediction tool and minigene studies, further emphasizing its pathogenic potential.ConclusionFor missense variants of FLNC in patients with DCM, the splicing effect of the variant should be carefully checked. Early detection and intervention are crucial given the high risk of sudden cardiac death and severe cardiac complications.

Association of third-trimester N-terminal pro-brain natriuretic peptide levels and pre-eclampsia development

Abstract Background Pre-eclampsia shares numerous risk factors with cardiovascular diseases and is associated with postpartum cardiovascular complications. Natriuretic peptides, outside pregnancy valid biomarkers for detecting subclinical cardiac dysfunction, are typically elevated at the time of pre-eclampsia diagnosis. However, their role before disease manifestation is still puzzling. Aims To assess whether third-trimester natriuretic peptide levels are associated with a diagnosis of pre-eclampsia in pregnant individuals. Methods This study measured NT-proBNP levels in third-trimester samples of 1454 pregnant individuals prior to disease manifestation. Pre-eclampsia was diagnosed using the American College of Obstetrics and Gynecology (ACOG) criteria. Linear regression analyses were performed, and multivariable adjustments were done for age, body mass index (BMI), preexisting hypertension, diabetes, and chronic kidney disease. Odds ratios were calculated per doubling of NT-proBNP levels. Results Of the 1454 individuals, 118 (7.6 %) developed pre-eclampsia. The median week of gestation for blood sampling was 29.0 (IQR 28.4 – 29.4) in both groups (p = 0.68). Individuals with pre-eclampsia manifestation had higher BMI, were more often nulliparous, and had lower placental growth factor levels (all p &amp;lt; 0.01). Higher NT-proBNP levels were associated with a lower risk of pre-eclampsia, which persisted after controlling for confounders (adjusted odds ratio (OR), 0.84; 95 % CI, 0.70 - 1.00). This inverse relationship was particularly pronounced in cases of late-onset pre-eclampsia, defined as onset after 34 + 0 weeks of gestation. Specifically, for preterm pre-eclampsia between weeks 34 + 0 and 36 + 9, the adjusted OR was 0.78 (95 % CI, 0.56-1.09), and for term pre-eclampsia at or after week 37 + 0, the adjusted OR was 0.77 (95 % CI, 0.61 - 0.95). Conversely, a positive association was observed between NT-proBNP levels and the occurrence of early-onset pre-eclampsia &amp;lt; 34 + 0 weeks, with an adjusted OR of 1.69 (95 % CI, 1.00 - 2.91). Causal mediation analyses indicated that the association between higher BMI and pre-eclampsia mediated only a minor fraction (11.5 % [95 % CI, 4.3 % - 36.0 %, p &amp;lt; 0.01]) of the observed association. Conclusion These findings reveal the complex interplay between third-trimester NT-proBNP levels and the risk of pre-eclampsia. They unravel an inverse association for late-onset disease but a contrasting positive correlation for early-onset cases in temporal proximity to NT-proBNP assessment. The latter may reflect acute physiological responses to pre-eclampsia nearing diagnosis. However, the inverse relationship observed for later manifestations underscores the importance of further research to dissect the underlying pathophysiological mechanisms, which suggest cardiovascular maladaption to pregnancy prior to pre-eclampsia manifestation.

Parkinson’s families project: a UK-wide study of early onset and familial Parkinson’s disease

The Parkinson’s Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson’s disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset ≤45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruited affected and unaffected relatives. We analysed DNA samples with a combination of single nucleotide polymorphism (SNP) array genotyping, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing (WGS). We investigated the association between identified pathogenic mutations and demographic and clinical factors such as age at motor symptom onset, family history, motor symptoms (MDS-UPDRS) and cognitive performance (MoCA). We performed baseline genetic analysis in 718 families, of which 205 had sporadic early-onset PD (sEOPD), 113 had familial early-onset PD (fEOPD), and 400 had late-onset familial PD (fLOPD). 69 (9.6%) of these families carried pathogenic variants in known monogenic PD-related genes. The rate of a molecular diagnosis increased to 28.1% in PD with motor onset ≤35 years. We identified pathogenic variants in LRRK2 in 4.2% of families, and biallelic pathogenic variants in PRKN in 3.6% of families. We also identified two families with SNCA duplications and three families with a pathogenic repeat expansion in ATXN2, as well as single families with pathogenic variants in VCP, PINK1, PNPLA6, PLA2G6, SPG7, GCH1, and RAB32. An additional 73 (10.2%) families were carriers of at least one pathogenic or risk GBA1 variant. Most early-onset and familial PD cases do not have a known genetic cause, indicating that there are likely to be further monogenic causes for PD.

MRI-Based Multi-Class Relevance Vector Machine Classification of Neurodegenerative Diseases.

Machine learning algorithms are a promising automated candidate that can help mitigate the growing need for dementia experts. Despite the substantial development in MRI-based machine learning analyses, case misclassification is a universal finding, yet the reasons behind misclassification are poorly understood. We implemented a multi-class classification approach that uses relevance vector machine and logistic classification to classify research participants based on their whole-brain T1-weighted MRI scans. A total of 468 participants from seven diagnostic classes were included: 144 healthy controls, 84 Alzheimer's disease, 108 behavioral variant frontotemporal dementia (bvFTD), 30 semantic variant primary progressive aphasia (svPPA), 30 non-fluent variant primary progressive aphasia (nfvPPA), 30 corticobasal syndrome (CBS), and 42 progressive supranuclear palsy syndrome (PSPS). We compared the algorithm's diagnostic accuracy against the clinical, pathological, genetic, and quantitative imaging data. The exact neurodegenerative syndrome was predicted in 71% of the cases, the neurodegenerative disease spectrum was predicted in 80% of the cases, and the algorithm distinguished controls from any dementia in 85% of the cases. The algorithm showed high performance in diagnosing healthy controls, moderate performance in diagnosing AD, bvFTD, and svPPA, and low performance in diagnosing CBS, nfvPPA, and PSPS. Based on the quantitative imaging data, most of the misclassified neurodegenerative cases had minimal atrophy and brain volumes comparable to healthy controls. In AD, early-onset AD cases with minimal brain atrophy represented most of the misclassified cases. In bvFTD, FTD genetic mutation carriers (predominantly C9orf72 repeat expansion), FTD phenocopy, patients meeting only possible bvFTD criteria represented most misclassified cases. Case misclassification in machine learning studies in neurodegenerative diseases results from neurodegenerative disease heterogeneity and the limitations of structural MRI's ability to capture the whole gamut of biological changes. Larger and more inclusive datasets that are representative of population biologic heterogeneity are needed to train better machine learning techniques, and a margin of error is expected and should be acceptable, like the uncertainty of a clinical diagnosis by a dementia expert.

S5093 A Case of Early Onset Y-90 Radiation-Induced Gastritis

S5093 A Case of Early Onset Y-90 Radiation-Induced Gastritis

COVID-19 and Its Influence on Prevalence of Dementia and Agitation in Australian Residential Aged Care: A Comparative Study

Agitation is one of the most common and persistent behavioral and psychological symptoms among persons with dementia (PWD) in residential aged care facilities (RACFs). While most studies have explored the general impact of COVID-19 on the mental health and well-being of aged care residents, there has been limited research on the pandemic’s impact on agitation in dementia within RACFs. This knowledge is crucial to ensuring that RACFs are better equipped to handle future public health emergencies. Therefore, this retrospective cohort study investigates the impact of the pandemic on agitation incidents within 40 Australian RACFs. Using Python, we extracted agitation symptoms from nursing notes and compared the frequency and percentage of symptom occurrence pre-pandemic versus during-pandemic. Chi-square tests examined any significant change in the prevalence of dementia and agitation in dementia between the comparative groups and periods. Dementia prevalence dropped significantly during the second year of the pandemic, with a concurrent increase in early-onset dementia cases. Overall, agitation symptoms decreased by 20.1%, but six symptoms significantly increased: resisting (28.98%), wandering (11.78%), restlessness (3.19%), complaining (10.1%), arguing (2.36%), and outbursts (1.74%). Conversely, pacing decreased by 15.88% and speaking loudly decreased by 10.9%. Over half of the care recipients with dementia experienced agitation symptoms 2–5 times each year, increasing from 50.56% in 2019 to 58.28% in 2021. Despite the co-occurrence of symptoms such as falls, confusion, and weakness, there was no evidence to suggest that these comorbidities were specific to COVID-19; rather, they appeared to be prevalent even before the pandemic. Persons with agitation in dementia had a significantly higher death rate during the COVID-19 pandemic than otherwise.

A 5-year review of preeclampsia screening in a tertiary private hospital in the Philippines: A retrospective cohort study

Preeclampsia remains a significant cause of maternal and perinatal morbidity and mortality worldwide, contributing to about 76,000 maternal deaths and 150,000 perinatal deaths annually. Despite numerous studies on predictive factors and screening tests for preeclampsia, local consensus on the optimal strategy remains elusive. This study aimed to assess the predictive accuracy and detection rate of preeclampsia screening in a tertiary private hospital. A retrospective descriptive cohort study was conducted on pregnant patients who underwent preeclampsia screening from 2018 to 2022. Data analysis involved quantitative methods, assessing predictive accuracy and detection rates for preeclampsia onset at &lt; 34, &lt; 37, and &lt; 40 weeks of gestation. Of the 156 subjects, 8.3% developed preeclampsia, with most cases exhibiting severe features (3.8%). Based on the onset, 3.8% were late-onset, 3.2% early-onset, and 1.2% postpartum. Chronic hypertension emerged as a significant risk factor. Predictive accuracy was highest for early-onset preeclampsia (&lt;34 weeks), reaching 94.23%, while overall predictive accuracy across all gestational ages was 83.12%. Detection rate was also highest for early-onset preeclampsia (100%) but was noted to decrease in later onset specifically 75% and 25% for &lt;37 weeks and &lt;40 weeks, respectively. Aspirin prophylaxis was administered to screen-positive patients, resulting in a 75% reduction in preeclampsia development. This local study underscores the importance of preeclampsia screening, showcasing its strengths in detecting early-onset cases but also its limitations, particularly in identifying term preeclampsia. Compared to traditional tests relying on maternal factors, it demonstrated superior accuracy and higher detection rates, maximizing the benefits of aspirin prophylaxis.

Findings from the individualized management of a patient with Acyl-CoA Oxidase-1 (ACOX1) deficiency: A bedside-to-bench-to-bedside strategy

Acyl-CoA Oxidase-1 (ACOX1) deficiency (MIM 264470) is an autosomal recessive disease characterized by impairments in the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs, which is the first step in the catalysis of the β-oxidative breakdown of very long chain fatty acids (VLCFA) occuring in peroxisomes. The deleterious accumulation of VLCFA in several organs, including the brain, is a key biochemical feature of this disease which has devastating neurological consequences. ACOX1 deficiency is ultra-rare; as such, few studies have been conducted to determine the leading causes of symptoms or uncover new therapeutics. When confronted with one such case, we decided to bring drug discovery tools to the patient's bedside in an attempt to identify a cure. A skin biopsy was performed on a young patient with ACOX1 deficiency, following which screening technologies and mass spectrometry analysis techniques were applied to design a cellular assay that enabled the direct measurement of the effect of small molecules on the patient's primary fibroblasts. This approach is particularly well adapted to inherited metabolic disorders such as ACOX1 deficiency. Through the evaluation of a proprietary library of repurposable drugs, we found that the anthelmintic drug niclosamide led to a significant reduction in VLCFA in vitro. This drug was subsequently administered to the patient for more than six years. This study outlines the screening and drug selection processes. Additionally, we present our comprehensive clinical and biochemical findings that aided in understanding the patient's natural history and analysis of the progression of the patient's symptoms throughout the treatment period. Although the patient's overall lifespan was extended compared to the average age at death in severe early onset cases of ACOX1 deficiency, we did not observe any definitive evidence of clinical or biochemical improvement during niclosamide treatment. Nonetheless, our study shows a good safety profile of long-term niclosamide administration in a child with a rare neurodegenerative disease, and illustrates the potential of individualized therapeutic strategies in the management of inherited metabolic disorders, which could benefit both patients and the broader scientific and medical communities.