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MedRxiv : the Preprint Server For... May 2024Numerous research groups worldwide have focused on postmortem imaging to bridge the resolution gap between clinical neuroimaging and neuropathology data. We developed a...
Numerous research groups worldwide have focused on postmortem imaging to bridge the resolution gap between clinical neuroimaging and neuropathology data. We developed a standardized protocol for brain embedding, imaging, and processing, facilitating alignment between antemortem MRI, postmortem MRI, and pathology to observe brain atrophy and structural damage progression over time. Using 7T postmortem ex vivo MRI, we explore the potential correlation of amygdala and hippocampal atrophy with neuropathological burden in both Down syndrome (DS) and Alzheimer's disease (AD) cohorts. Using 7T postmortem ex vivo MRI scans from 66 cases (12 DS and 54 AD) alongside a subset of antemortem scans (n=17), we correlated manually segmented hippocampal and amygdala volumes, adjusted for age, sex, and ApoE4 status, with pathological indicators such as Thal phase, Braak stage, limbic-predominant age-related TDP-43 encephalopathy (LATE) stage, hippocampal sclerosis (HS), and Lewy body (LB) stage. A significant correlation was observed between postmortem and antemortem volumes for the hippocampus, but a similar trend observed for the amygdala did not reach statistical significance. DS individuals exhibited notably smaller hippocampal and amygdala volumes compared to AD subjects. In DS, lower hippocampal and amygdala volumes correlated with more severe Braak stage, without significant associations with Thal phase. LATE and HS pathologies were uncommon in DS cases but trended toward smaller hippocampal volumes. In AD, lower hippocampal volume associated with dementia duration, advanced Thal phase, Braak stage, LATE stage, and HS presence, whereas reduced amygdala volume correlated mainly with severe LATE stage and HS, but not with Thal or Braak stages. No significant LB correlation was detected in either DS or AD cohorts. Hippocampal volume in AD appears influenced by both AD and LATE pathologies, while amygdala volume seems primarily influenced by LATE. In DS, smaller hippocampal volume, relative to AD, appears primarily influenced by tau pathology.
PubMed: 38798514
DOI: 10.1101/2024.05.15.24307354 -
Mathematical Biosciences May 2024This paper develops a theory for anaphase in cells. After a brief description of microtubules, the mitotic spindle and the centrosome, a mathematical model for anaphase...
This paper develops a theory for anaphase in cells. After a brief description of microtubules, the mitotic spindle and the centrosome, a mathematical model for anaphase is introduced and developed in the context of the cell cytoplasm and liquid crystalline structures. Prophase, prometaphase and metaphase are then briefly described in order to focus on anaphase, which is the main study of this paper. The entities involved are modelled in terms of liquid crystal defects and microtubules are represented as defect flux lines. The mathematical techniques employed make extensive use of energy considerations based on the work that was developed by Dafermos (1970) from the classical Frank-Oseen nematic liquid crystal energy (Frank, 1958; Oseen, 1933). With regard to liquid crystal theory we introduce the concept of regions of influence for defects which it is believed have important implications beyond the subject of this paper. The results of this paper align with observed biochemical phenomena and are explored in application to HeLa cells and Caenorhabditis elegans. This unified approach offers the possibility of gaining insight into various consequences of mitotic abnormalities which may result in Down syndrome, Hodgkin lymphoma, breast, prostate and various other types of cancer.
PubMed: 38795952
DOI: 10.1016/j.mbs.2024.109219 -
Medicina (Kaunas, Lithuania) Apr 2024The risks of uveitis development among pediatric patients with Down syndrome (DS) remain unclear. Therefore, we aimed to determine the risk of uveitis following a...
The risks of uveitis development among pediatric patients with Down syndrome (DS) remain unclear. Therefore, we aimed to determine the risk of uveitis following a diagnosis of DS. This multi-institutional retrospective cohort study utilized the TriNetX database to identify individuals aged 18 years and younger with and without a diagnosis of DS between 1 January 2000 and 31 December 2023. The non-DS cohort consisted of randomly selected control patients matched by selected variables. This included gender, age, ethnicity, and certain comorbidities. The main outcome is the incidence of new-onset uveitis. Statistical analysis of the uveitis risk was reported using hazard ratios (HRs) and 95% confidence intervals (CIs). Separate analyses of the uveitis risk among DS patients based on age groups and gender were also performed. A total of 53,993 individuals with DS (46.83% female, 58.26% white, mean age at index 5.21 ± 5.76 years) and 53,993 non-DS individuals (45.56% female, 58.28% white, mean age at index 5.21 ± 5.76 years) were recruited from the TriNetX database. Our analysis also showed no overall increased risk of uveitis among DS patients (HR: 1.33 [CI: 0.89-1.99]) compared to the non-DS cohort across the 23-year study period. Subgroup analyses based on different age groups showed that those aged 0-1 year (HR: 1.36 [CI: 0.68-2.72]), 0-5 years (HR: 1.34 [CI: 0.75-2.39]), and 6-18 years (HR: 1.15 [CI: 0.67-1.96]) were found to have no association with uveitis risk compared to their respective non-DS comparators. There was also no increased risk of uveitis among females (HR: 1.49 [CI: 0.87-2.56]) or males (HR: 0.82 [CI: 0.48-1.41]) with DS compared to their respective non-DS comparators. Our study found no overall increased risk of uveitis following a diagnosis of DS compared to a matched control population.
Topics: Humans; Down Syndrome; Male; Female; Uveitis; Child; Retrospective Studies; Child, Preschool; Adolescent; Infant; Databases, Factual; Incidence; Cohort Studies; Risk Factors; Risk Assessment
PubMed: 38792893
DOI: 10.3390/medicina60050710 -
International Journal of Environmental... May 2024Down syndrome (DS) is characterised by a duplication of chromosome-21 and is linked to co-occurring physical and mental health conditions, including low self-efficacy...
Down syndrome (DS) is characterised by a duplication of chromosome-21 and is linked to co-occurring physical and mental health conditions, including low self-efficacy and disturbed mood states. The purpose of this study was to investigate the effects of an eight-week prescribed physical and/or cognitive training intervention on measures of mood disturbance, life satisfaction and self-efficacy in a population of adults with DS. Eighty-three participants (age 27.1 ± 8.0 years) from across five continents volunteered. Participants were assigned using matched groups based upon performance in a modified six-minute walk test to either an exercise (EXE) 3 × 30 min of walking/jogging per week, cognitive training (COG) 6 × 20 min per week, a combined group (COM) or the control (CON) who did not complete any intervention. Profile of Mood States (POMS) were assessed using a five-point scale across 65 categories pre- and post-study as well as upon completion of each week of the intervention. In addition, Satisfaction with Life Scale (SWLS) and self-efficacy using the Generalised Self-Efficacy scale (GSE) were recorded before and after the intervention. GSE increased for all participants by 1.9 ± 5.2 ( = 0.002) from pre- to post-intervention, while POMS showed significant changes for the whole group from pre- to post-intervention for tension ( < 0.001), depression ( < 0.001) and for anger ( < 0.001). In addition, significant correlations were observed between SWLS and ΔTMD, Δtension, Δanger, and Δfatigue ( < 0.05) for EXE. Both COG and EXE provide a framework for empowering enhancements in life satisfaction, self-efficacy and mood states fostering improvements in quality of life.
Topics: Humans; Self Efficacy; Adult; Male; Female; Affect; Personal Satisfaction; Young Adult; Down Syndrome; Exercise; Cognition; Quality of Life; Adolescent
PubMed: 38791824
DOI: 10.3390/ijerph21050610 -
International Journal of Molecular... May 2024Dementia exists as a 'progressive clinical syndrome of deteriorating mental function significant enough to interfere with activities of daily living', with the most... (Review)
Review
Dementia exists as a 'progressive clinical syndrome of deteriorating mental function significant enough to interfere with activities of daily living', with the most prevalent type of dementia being Alzheimer's disease (AD), accounting for about 80% of diagnosed cases. AD is associated with an increased risk of comorbidity with other clinical conditions such as hypertension, diabetes, and neuropsychiatric symptoms (NPS) including, agitation, anxiety, and depression as well as increased mortality in late life. For example, up to 70% of patients diagnosed with AD are affected by anxiety. As aging is the major risk factor for AD, this represents a huge global burden in ageing populations. Over the last 10 years, significant efforts have been made to recognize the complexity of AD and understand the aetiology and pathophysiology of the disease as well as biomarkers for early detection. Yet, earlier treatment options, including acetylcholinesterase inhibitors and glutamate receptor regulators, have been limited as they work by targeting the symptoms, with only the more recent FDA-approved drugs being designed to target amyloid-β protein with the aim of slowing down the progression of the disease. However, these drugs may only help temporarily, cannot stop or reverse the disease, and do not act by reducing NPS associated with AD. The first-line treatment options for the management of NPS are selective serotonin reuptake inhibitors/selective noradrenaline reuptake inhibitors (SSRIs/SNRIs) targeting the monoaminergic system; however, they are not rational drug choices for the management of anxiety disorders since the GABAergic system has a prominent role in their development. Considering the overall treatment failures and side effects of currently available medication, there is an unmet clinical need for rationally designed therapies for anxiety disorders associated with AD. In this review, we summarize the current status of the therapy of AD and aim to highlight novel angles for future drug therapy in our ongoing efforts to alleviate the cognitive deficits and NPS associated with this devastating disease.
Topics: Humans; Alzheimer Disease; Cognitive Dysfunction; Animals; Cholinesterase Inhibitors
PubMed: 38791206
DOI: 10.3390/ijms25105169 -
Biomedicines May 2024Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for the treatment of cancer. Given the many cellular commonalities between... (Review)
Review
Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for the treatment of cancer. Given the many cellular commonalities between cancer and neurodegeneration (i.e., different faces of the same coin), it seems rational to consider targeting Pol I or, more generally, rRNA synthesis for the treatment of disorders associated with the death of terminally differentiated neurons. Principally, ribosomes synthesize proteins, and, accordingly, Pol I can be considered the starting point for protein synthesis. Given that cellular accumulation of abnormal proteins such as α-synuclein and tau is an essential feature of neurodegenerative disorders such as Parkinson disease and fronto-temporal dementia, reduction of protein production is now considered a viable target for treatment of these and closely related neurodegenerative disorders. Abnormalities in polymerase I activity and rRNA production may also be associated with nuclear and nucleolar stress, DNA damage, and childhood-onset neuronal death, as is the case for the UBTF E210K neuroregression syndrome. Moreover, restraining the activity of Pol I may be a viable strategy to slow aging. Before starting down the road of Pol I inhibition for treating non-cancerous disorders of the nervous system, many questions must be answered. First, how much Pol I inhibition can neurons tolerate, and for how long? Should inhibition of Pol I be continuous or pulsed? Will cells compensate for Pol I inhibition by upregulating the number of active rDNAs? At present, we have no effective and safe disease modulatory treatments for Alzheimer disease, α-synucleinopathies, or tauopathies, and novel therapeutic targets and approaches must be explored.
PubMed: 38791054
DOI: 10.3390/biomedicines12051092 -
Antioxidants (Basel, Switzerland) Apr 2024To date, there have been no review articles specifically relating to the general efficacy and safety of coenzyme Q10 (CoQ10) supplementation in younger subjects. In this... (Review)
Review
To date, there have been no review articles specifically relating to the general efficacy and safety of coenzyme Q10 (CoQ10) supplementation in younger subjects. In this article, we therefore reviewed the efficacy and safety of CoQ10 supplementation in neonates (less than 1 month of age), infants (up to 1 year of age) and children (up to 12 years of age). As there is no rationale for the supplementation of CoQ10 in normal younger subjects (as there is in otherwise healthy older subjects), all of the articles in the medical literature reviewed in the present article therefore refer to the supplementation of CoQ10 in younger subjects with a variety of clinical disorders; these include primary CoQ10 deficiency, acyl CoA dehydrogenase deficiency, Duchenne muscular dystrophy, migraine, Down syndrome, ADHD, idiopathic cardiomyopathy and Friedreich's ataxia.
PubMed: 38790635
DOI: 10.3390/antiox13050530 -
Children (Basel, Switzerland) May 2024This narrative review study investigates the correlations between obesity, allergies, and sleep-disordered breathing in pediatric populations. Searches for pertinent... (Review)
Review
This narrative review study investigates the correlations between obesity, allergies, and sleep-disordered breathing in pediatric populations. Searches for pertinent articles were conducted on the Medline PubMed Advanced Search Builder, Scopus, and Web of Science databases from unlimited to April 2024. Sleep-disordered breathing causes repeated upper airway obstructions, leading to apneas and restless sleep. Childhood obesity, which affects around 20% of children, is often associated with sleep-disordered breathing and allergies such as asthma and allergic rhinitis. It is distinguished between diet-induced obesity (resulting from excess of diet and physical inactivity) and genetic obesity (such as is seen in Down syndrome and Prader-Willi syndrome). In children with diet-induced obesity, chronic inflammation linked to weight can worsen allergies and increase the risk and severity of asthma and rhinitis. Furthermore, the nasal congestion typical of rhinitis can contribute to upper respiratory tract obstruction and obstructive sleep apnea. A vicious circle is created between asthma and sleep-disordered breathing: uncontrolled asthma and sleep-disordered breathing can worsen each other. In children with genetic obesity, despite alterations in the immune system, fewer allergies are observed compared to the broader population. The causes of this reduced allergenicity are unclear but probably involve genetic, immunological, and environmental factors. Additional research is necessary to elucidate the underlying mechanisms. The present narrative review study emphasizes the importance of jointly evaluating and managing allergies, obesity, and obstructive sleep apnea in children considering their close interconnection.
PubMed: 38790590
DOI: 10.3390/children11050595 -
Children (Basel, Switzerland) Apr 2024This population-based study aimed to assess the prevalence of congenital hypothyroidism (CH) and overt hypothyroidism (OH) and their association with congenital heart...
This population-based study aimed to assess the prevalence of congenital hypothyroidism (CH) and overt hypothyroidism (OH) and their association with congenital heart defects (CHDs) in patients with Down syndrome (DS). The population included all live births residing in Tuscany (Italy) diagnosed with DS recorded in the Registry of Congenital Defects and in the Registry of Rare Diseases of Tuscany in the years 2003-2017. The prevalence of CH and OH in DS patients was calculated by sex and by period. The association of CH and OH with CHDs in DS patients was assessed using multivariate logistic regression. The cohort included 228 subjects. The prevalence of CH and OH was 11.4% (95%CI: 7.4-16.7%) and 12.7% (95%CI: 8.5-12.3%), respectively, with no significant difference by sex. A significant increase in the prevalence of CH ( < 0.0001) was found in the years 2010-2017 compared to the previous period, and among preterm infants ( = 0.009). The presence of CH was associated with a higher prevalence of CHDs (adjusted OR = 2.24, = 0.082). A significant association between ventricular septal defects (VSDs) and the occurrence of OH (adjusted OR = 3.07, = 0.025) was also observed. This study confirmed the higher prevalence of both CH and OH in DS compared to the general population. Furthermore, the risk of association between DS and CHDs was higher in the presence of CH, while VSDs are associated with OH, providing relevant insights into the epidemiology of hypothyroidism in DS and associated anomalies.
PubMed: 38790508
DOI: 10.3390/children11050513 -
Genes May 2024Sjögren's disease (SjD) is a common systemic autoimmune disease that affects mainly women. Key pathologic features include the infiltration of exocrine glands by...
BACKGROUND
Sjögren's disease (SjD) is a common systemic autoimmune disease that affects mainly women. Key pathologic features include the infiltration of exocrine glands by lymphocytes and the activation of B lymphocytes with the production of autoantibodies. We aimed to analyze the transcriptome of circulating B cells from patients with SJD and healthy controls to decipher the B-cell-specific contribution to SJD.
METHODS
RNA from peripheral blood B cells of five untreated female patients with SjD and positive ANA, positive anti-SSA (both Ro-52 and Ro-60), positive anti-SSB and positive rheumatoid-factor, and five healthy controls was subjected to whole-transcriptome sequencing. A false discovery rate of < 0.1 was applied to define differentially expressed genes (DEG).
RESULTS
RNA-sequencing identified 56 up and 23 down DEG. Hierarchal clustering showed a clear separation between the two groups. Ingenuity pathway analysis revealed that these genes may play a role in interferon signaling, chronic mycobacterial infection, and transformation to myeloproliferative disorders.
CONCLUSIONS
We found upregulated expression of type-I and type-II interferon (IFN)-induced genes, as well as genes that may contribute to other concomitant conditions, including infections and a higher risk of myeloproliferative disorders. This adds insight into the autoimmune process and suggests potential targets for future functional and prognostic studies.
Topics: Humans; Sjogren's Syndrome; Female; B-Lymphocytes; Middle Aged; Transcriptome; Gene Expression Profiling; Interferons; Adult; Autoantibodies; Aged
PubMed: 38790257
DOI: 10.3390/genes15050628