Identifying healthy individuals with Alzheimer neuroimaging phenotypes in the UK Biobank

Identifying prediagnostic neurodegenerative disease is a critical issue in neurodegenerative disease research, and Alzheimer's disease (AD) in particular, to identify populations suitable for preventive and early disease modifying trials. Evidence from genetic studies suggest the neurodegeneration of Alzheimer's disease measured by brain atrophy starts many years before diagnosis, but it is unclear whether these changes can be detected in sporadic disease. To address this challenge we train a Bayesian machine learning neural network model to generate a neuroimaging phenotype and AD-score representing the probability of AD using structural MRI data in the Alzheimer's Disease Neuroimaging Cohort (cut-off 0.5, AUC 0.92, PPV 0.90, NPV 0.93). We go on to validate the model in an independent real world dataset of the National Alzheimer's Coordinating Centre (AUC 0.74, PPV 0.65, NPV 0.80), and demonstrate correlation of the AD-score with cognitive scores in those with an AD-score above 0.5. We then apply the model to a healthy population in the UK Biobank study to identify a cohort at risk for Alzheimer's disease. This cohort have a cognitive profile in keeping with Alzheimer's disease, with strong evidence for poorer fluid intelligence, and with some evidence of poorer performance on tests of numeric memory, reaction time, working memory and prospective memory. We found some evidence in the AD-score positive cohort for modifiable risk factors of hypertension and smoking. This approach demonstrates the feasibility of using AI methods to identify a potentially prediagnostic population at high risk for developing sporadic Alzheimer's disease.

Band acro-osteolysis in a black female: a case report and review of literature

Acro-osteolysis is a bone resorption reaction that progresses slowly in the distal phalanx of the hand and foot and is associated with various diseases. It can be classified as idiopathic or secondary. Although the mechanism of acro-osteolysis has not been fully elucidated, the chronic ischemic injury appears to have a significant effect, and bone metabolism dysregulation due to the accompanying calcinosis or peripheral neuropathy also appears to contribute. Acro-osteolysis can show various clinical and radiological features, and differential diagnosis of the underlying etiology is essential. It is a rare sporadic disease worldwide, and the authors experienced a patient with acro-osteolysis suspected of idiopathic cause in a black woman, so we report this case with literature reviews.

Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson’s Disease

Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause of cell death is not known but could be due to mitochondrial dysfunction, protein homeostasis failure, and alterations in the secretory/endolysosomal/autophagic pathways. Survival nigral neurons overexpress the small GTPase Rab1. This protein is considered a housekeeping Rab that is necessary to support the secretory pathway, the maintenance of the Golgi complex structure, and the regulation of macroautophagy from yeast to humans. It is also involved in signaling, carcinogenesis, and infection for some pathogens. It has been shown that it is directly linked to the pathogenesis of PD and other neurodegenerative diseases. It has a protective effect against α–σψν toxicity and has recently been shown to be a substrate of LRRK2, which is the most common cause of familial PD and the risk of sporadic disease. In this review, we analyze the key aspects of Rab1 function in dopamine neurons and its implications in PD neurodegeneration/restauration. The results of the current and former research support the notion that this GTPase is a good candidate for therapeutic strategies.

Linking common human diseases to their phenotypes; development of a resource for human phenomics

Background In recent years a large volume of clinical genomics data has become available due to rapid advances in sequencing technologies. Efficient exploitation of this genomics data requires linkage to patient phenotype profiles. Current resources providing disease-phenotype associations are not comprehensive, and they often do not have broad coverage of the disease terminologies, particularly ICD-10, which is still the primary terminology used in clinical settings. Methods We developed two approaches to gather disease-phenotype associations. First, we used a text mining method that utilizes semantic relations in phenotype ontologies, and applies statistical methods to extract associations between diseases in ICD-10 and phenotype ontology classes from the literature. Second, we developed a semi-automatic way to collect ICD-10–phenotype associations from existing resources containing known relationships. Results We generated four datasets. Two of them are independent datasets linking diseases to their phenotypes based on text mining and semi-automatic strategies. The remaining two datasets are generated from these datasets and cover a subset of ICD-10 classes of common diseases contained in UK Biobank. We extensively validated our text mined and semi-automatically curated datasets by: comparing them against an expert-curated validation dataset containing disease–phenotype associations, measuring their similarity to disease–phenotype associations found in public databases, and assessing how well they could be used to recover gene–disease associations using phenotype similarity. Conclusion We find that our text mining method can produce phenotype annotations of diseases that are correct but often too general to have significant information content, or too specific to accurately reflect the typical manifestations of the sporadic disease. On the other hand, the datasets generated from integrating multiple knowledgebases are more complete (i.e., cover more of the required phenotype annotations for a given disease). We make all data freely available at 10.5281/zenodo.4726713.

Management and outcome of metastatic pheochromocytomas/paragangliomas: a monocentric experience

Background Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors releasing catecholamines. Metastatic pheochromocytomas/paragangliomas (PPGLs) occur in about 5–26% of cases. To date, the management of patients affected by metastatic disease is a challenge in the absence of guidelines. Aim The aim of this study was to evaluate the overall survival (OS) and the progression-free survival (PFS) in metastatic PPGLs. Methods Clinical data of 20 patients referred to the Careggi University Hospital (Florence, Italy) were retrospectively collected. Follow-up ranged from 1989 to 2019. Site and size of primary tumor, biochemical activity, genetic analysis and employed therapies were considered. Data were analyzed with SPSS version 27. Results Nine PHEOs (45%) and 11 PGLs (55%) were enrolled. Median age at diagnosis was 43.5 years [30–55]. Mean follow-up was 104.6 ± 89.3 months. Catecholamines were released in 70% of cases. An inherited disease was reported in 50% of patients. OS from the initial diagnosis (OSpt) and from the metastatic appearance (OSmtx) were lower in older patients (OSpt p = 0.028; OSmtx p < 0.001), abdominal PGLs (OSpt p = 0.007; OSmtx p = 0.041), larger tumors (OSpt p = 0.008; OSmtx p = 0.025) and sporadic disease (OSpt p = 0.013; OSmtx p = 0.008). Conclusion Our data showed that older age at the initial diagnosis, sympathetic extra-adrenal localization, larger tumors and wild-type neoplasms are related to worse prognosis. Notably, the employed therapies do not seem to influence the survival of our patients. At present, effective treatments for metastatic PPGLs are missing and a multidisciplinary approach is indispensably required.

Chondrosarcoma of the Thyroid Cartilage Successfully Treated With Partial Resection of the Thyroid Cartilage

Chondrosarcoma of the thyroid cartilage is a sporadic disease with nonspecific clinical presentation. Smooth swelling of the supraglottic area should arouse suspicion of possible pathology. In addition to laryngoceles, which usually do not have a significant impact, otolaryngologists should consider chondrosarcoma of the thyroid cartilage and indicate computed tomography (CT). Late diagnosis leads to worse prognosis, particularly worse voice after more extensive surgery, need for tracheostomy, and worse survival from higher degree chondrosarcomas.

POS1326 FAMILIAL PERIODIC FEVER, APHTHOUS STOMATITIS, PHARYNGITIS AND ADENITIS (PFAPA)SYNDROME; IS IT A SEPARATE DISEASE?

Background:Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome (PFAPA) is the most common periodic fever syndrome in the pediatric population. Unlike other periodic fever syndromes, the pathogenesis and genetics of PFAPA is unknown. Until recently, PFAPA was believed to be a sporadic disease, yet family clustering has been widely observed and current research indicates that heredity is likely.Objectives:To identify demographic and clinical differences between patients with PFAPA who have a positive family history (FH+) compared to those with PFAPA with no family history (FH-) that can reveal if heritable and sporadic subtypes of this disorder exist.Methods:In a database comprising demographic and clinical data of 273 pediatric PFAPA patients treated at two tertiary centers in Israel, 31(14.3%) of patients were PFAPA FH+. Data from patients with FH+ for PFAPA was compared to data from those with FH- of the disorder. Furthermore, family members (FMs) of those with FH+ were contacted via telephone for more demography and clinical details.Results:FH+ group had more headaches (32% vs.2%; p= 0.016), myalgia (56% vs. 19%; p= 0.001), higher carrier frequency of M694V mutation (54% vs. 25%; p=0.053), greater family history of FMF (30% vs. 15%; p=0.096) and better outcomes with colchicine (82% vs. 52%; p=0.096) compared to those with FH-. FMs displayed almost identical characteristics to the FH+ group except for greater arthralgia during flares (64% vs. 23%; p=0.008) and compared to the FH- group, more oral aphthae (68% vs. 43%; p=0.002), myalgia/arthralgia (64% vs. 19%/16%; p<0.0001), and higher rates of FH of FMF (45% vs.15%; p=0.003).Conclusion:Our findings suggest that FH+ had probably different subset of disease with higher frequency of family history of FMF arthralgia, myalgia and better response to colchicine. Colchicine prophylaxis for PFAPA should be considered in FH+.Disclosure of Interests:None declared

Main Results of the Research on the Far Eastern Scarlet-Like Fever as a Specific Clinical and Epidemic Manifestation of Pseudotuberculosis: A Review of Comprehensive Studies

Introduction: Until 1950s, pseudotuberculosis in humans was known in the world as a sporadic disease with appendicular syndrome. In 1959, the first outbreak of a previously unknown disease called Far Eastern scarlet-like fever (FESLF) was registered in Vladivostok. The purpose of this article is to review priority achievements of the Research Institute of Epidemiology and Microbiology named after G.P. Somov in the field of studying FESLF as a specific clinical and epidemic manifestation of pseudotuberculosis in Russia. Materials and methods: The priority data were obtained based on microbiological, epidemiological, molecular genetic, as well as pathomorphological and electron microscopic studies of biological samples from human FESLF cases and experimental animals infected with Yersinia pseudotuberculosis strains with different plasmid characteristics. Results: It has been proven that the FESLF pathogen is a specific clone of Yersinia pseudotuberculosis having a certain plasmid profile pVM82, pYV 48 MDa, sequence type (2ST) and the first allele of the yadA gene. The causative agent of FESLF is characterized by the phenomenon of psychrophilicity, which consists in its ability to multiply in the environment with its biologically low and changing temperature (4–12 °C), at which the pathogen multiplies and accumulates while preserving or increasing its virulence, thus inducing the epidemic process. The article describes the main genetic and biochemical mechanisms of Y. pseudotuberculosis adaptation to changing environmental conditions, reveals morphological manifestations of the adaptive variability of these bacteria under different conditions of their habitat, and presents the main features of the pathogenesis and morphogenesis of FESLF, including those associated with plasmid characteristics and toxigenicity of Y. pseudotuberculosis. Conclusion: Currently, the epidemic process of pseudotuberculosis/FESLF is characterized by a decrease in the proportion of outbreaks and predominance of sporadic cases. The relevance of further research is associated with the study of the dormant forms of Y. pseudotuberculosis and the formation of ideas about pseudotuberculosis as a persistent infectious disease.

Bone disorders in type 1 multiple endocrine neoplasia syndrome: A review of clinical data

Primary hyperparathyroidism (PHPT) is a result of the parathyroid tumors, usually manifesting by elevated serum parathyroid hormone and hypercalcemia. One of the most common complications of PHPT are bone disorders. It mainly occurs as sporadic disease, while the remaining 5–10% is the component of hereditary syndromes, more often – type 1 multiple endocrine neoplasia syndrome (MEN1). MEN1 is caused by the germinal mutation of the oncosuppressor menin gene, founded in all cells of the human body, including the osteogenic cells. Data on the bone state in MEN1 is limited and contradictory. At the same time, some studies indicate that MEN1-related PHPT differs from sporadic form in bone manifestation, which can be presumably associated with the inadequate functioning of mutant menin. The results of experimental works suggest that menin plays an important role in the metabolism and differentiation of bone cells. This article is a literature review on this problem and contains information on the current clinical data on the bone state in patients with MEN1.