Early-onset Alzheimer's disease explained by polygenic risk of late-onset disease?

Early-onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early-onset AD patients without an identified autosomal dominant cause, we hypothesized that their early-onset disease reflects further enrichment of the common risk-conferring single nucleotide polymorphisms associated with late-onset AD. We applied a previously validated polygenic hazard score for late-onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early-onset AD. For comparison, we included 179 participants with late-onset AD and 70 healthy controls. Polygenic hazard scores were similar in early- versus late-onset AD. The polygenic hazard score was not associated with age-of-onset or disease biomarkers within early-onset AD. Early-onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late-onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted.Highlights: There is a unique genetic architecture of early- versus late-onset Alzheimer's disease (AD).Late-onset AD polygenic risk is not an explanation for early-onset AD.Polygenic risk of late-onset AD does not predict early-onset AD biology.Unique genetic architecture of early- versus late-onset AD parallels AD heterogeneity.

Reconditioned monocytes are immunomodulatory and regulate inflammatory environment in sepsis.

Sepsis is caused by dysregulated immune response to severe infection and hyper inflammation plays a central role in worsening the disease. The immunomodulatory properties of mesenchymal stem cells (MSCs) have been evaluated as a therapeutic candidate for sepsis. Reconditioned monocytes (RM), generated from healthy human peripheral blood mononuclear cells (PBMCs) exhibit both macrophage and MSCs-like properties. RM were administered at different stages of sepsis in a mouse model. It reduced serum levels of IL6, MCP-1, IL-10, improved hypothermia, increased survival, and recovery from 0 to 66% when combined with antibiotics in the mouse model. The reduced human leucocyte antigen DR molecules expression on RM enables their co-culture with PBMCs of sepsis patients which resulted in reduced ROS production, and up-regulated TGF-ß while down-regulating IL6, IL8, and IL-10 in-vitro. RM are potentially immunomodulatory, enhance survival in sepsis mouse model and modulate inflammatory behaviour of sepsis patient's PBMCs.

A novel c.1937T>C (p.Leu646Pro) missense mutation in a patient with Leber congenital amaurosis.

Over 21 genes have been associated with the inherited retinal dystrophy, Leber congenital amaurosis (LCA). A comprehensive genotype-phenotype correlation in such heterogenous cases helps guide further genetic studies and therapies. We report 2 children (10-month-old girl and an 8-month-old boy) who presented with low vision in the first year of life. Both patients manifested nystagmus, sluggish pupillary reactions, hyperopia, and normal fundus. Focussed exome sequencing was performed because LCA was suspected. A novel c.1937T>C (p.Leu646Pro) missense mutation was found in exon 9 of the tyrosine kinase domain of the GUCY2D gene in both patients.

Association of ADHD and Obesity in Hispanic Children on the US-Mexico Border: A Retrospective Analysis.

Pediatric obesity and Attention Deficit Hyperactivity Disorder (ADHD) are rising health concerns in the United States, especially among Hispanic children and adolescents. Research on Hispanic children and adolescents indicates disproportionately higher prevalence rates of obesity in this community but scant data on ADHD prevalence rates. In contrast, a plethora of research studies across the general population examines the relationship between childhood obesity and ADHD. In addition, there is a lack of research that examines the role of ethnicity and sub-ethnic group correlations in ADHD, particularly in the Hispanic population. Existing studies in the general population indicate ADHD may be a risk factor for being overweight compared to normal controls. The objective of the present study is to examine the prevalence of obesity in children with ADHD compared to children in the general population in a predominately Hispanic sample on the US-Mexico border. A total of 7,270 pediatric medical records were evaluated. The retrospective analysis included Body Mass Index (BMI) and related health variables, and ethnicity and showed that children with ADHD are more likely to be underweight. In conclusion, no significant relationship existed between obesity and ADHD among Hispanic children on the US-Mexico Border, and instead we found the opposite correlation.

Role of Therapeutic Plasma Exchange in Resolution of Hyperhemolysis in a Patient Living with HIV/AIDS (PLHA) Diagnosed with Paroxysmal Cold Haemoglobinuria: A Case Report".

Paroxysmal cold haemoglobinuria (PCH) is an acquired cause of haemolytic anaemia. It is caused by the biphasic IgG antibodies that sensitize and attach the red cells at lower temperature; detach and rebind on rewarming. Donath-Landsteiner antibody test is the diagnostic test for PCH. Management of PCH mainly includes supportive care but sometimes disease becomes severe and life-threatening. We describe a similar severe and life-threatening case of PCH who was managed by plasma exchange followed by packed red cell transfusion.

Role of Emergency Automated Red Cell Exchange in Sickle Cell Crisis: A Case Report.

For many years main stay of treatment for sickle cell anaemia was transfusion therapy. But repeated transfusions put the patient at risk of iron overload. Automated red cell exchange is an evolving and newer technique which rapidly removes the sickle cells and has benefit in decreasing sickle cell load and related complications. Red cell exchange is a therapeutic procedure in which the patient's whole blood is processed centrifugally in cell separator. Patient's red cells are separated from other blood components and removed and replaced with donor red cells and colloids. We report our first experience of automated red cell exchange in 24-year-old female diagnosed case of sickle cell anaemia presented to us with acute chest syndrome with septic shock. Red cell exchange was planned to tide over the acute sickle cell crisis and provide symptomatic improvement. We also highlight that compound heterozygous thalassaemia could be associated with sickle cell disease which could make the diagnosis difficult. New generation automated Apheresis equipment's provides better monitoring of the procedure that can be useful in severely ill patients also.

Activity Wise Unit Cost of Blood Components in a Tertiary Care Hospital Blood Bank for the Year 2018.

The present study on cost of a unit of blood was conducted in blood bank of a tertiary care public hospital with an annual collection of 20,748. A retrospective chart review was done to calculate the activity wise annual unit cost of blood, based on WHO guidelines (Blood Safety Unit. safe blood and blood products: costing blood transfusion services, World Health Organization, Geneva, 1998). Cost of blood collection, processing and storage were included. Annualized economic cost of equipments, maintenance, personnel salaries, and consumables were enlisted. It was assumed that all component units prepared carried equal cost. The cost of building, maintenance and office stationary were excluded. Data extracted from records was compiled and analysed using MS Excel. The annual unit cost of blood with component preparation and NAT testing was Rs 1829. Unit cost of blood without NAT testing was Rs 1255. Unit cost of blood if total collection was in-house, that is, excluding expenditure on camps was Rs 1738. The cost of whole blood (that is, if no components were prepared) with ELISA testing, done to ascertain cost at basic functioning was Rs 2521. With NAT testing the unit cost increased by Rs 575, the additional expenditure being equally divided among all components. Expenditure on NAT was high which was 1/3rd of the total expenditure on consumables. The additional cost incurred on each unit due to expenditure on camps was small i.e. only Rs 91 with 30% collection from camps. Voluntary camps ensures safe blood at minimal cost increment and component separation reduces cost and permits judicious use. Hence these activities should be promoted.

Rare case of Auto immune haemolytic anaemia in an infant with auto "f & kidd antibodies".

BACKGROUND: "f" antigen is a compound antigen in Rh blood group system. Anti f has haemolytic potential as described in literature. Its occurrence in an infant as autoantibody with another blood group system ie Jka is very rare. Case report We report a case of 10-month-old infant diagnosed with AIHA with autoantibodies directed towards "f" and Jka antigen. Antibody identification was done and antigen negative blood units were crossmatched & transfused with demonstrable haemoglobin rise and subsequent decrease in DAT grading. RESULT: Auto anti f + Jka was identified in a 10 months old infant. Autoantibodies were identified by identification 3 & 11 cell panel and select cell panel. Results were later confirmed by allogenic adsorption & elution. Patient was transfused antigen negative blood unit which lead to haemoglobin rise & gradual decrease in direct coombs test grading CONCLUSION: To our knowledge, this is the first case report of auto anti f + Jka having haemolytic potential in an infant which shows the importance of extensive immmunohaematology workup in providing compatible blood unit in patients with autoantibody.

Prospective longitudinal atrophy in Alzheimer's disease correlates with the intensity and topography of baseline tau-PET.

ß-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer's disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients' diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether ß-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not ß-amyloid-PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient's progression and design future clinical trials.

Tau PET and multimodal brain imaging in patients at risk for chronic traumatic encephalopathy.

OBJECTIVE: To characterize individual and group-level neuroimaging findings in patients at risk for Chronic Traumatic Encephalopathy (CTE). METHODS: Eleven male patients meeting criteria for Traumatic Encephalopathy Syndrome (TES, median age: 64) underwent neurologic evaluation, 3-Tesla MRI, and PET with [18F]-Flortaucipir (FTP, tau-PET) and [11C]-Pittsburgh compound B (PIB, amyloid-PET). Six patients underwent [18F]-Fluorodeoxyglucose-PET (FDG, glucose metabolism). We assessed imaging findings at the individual patient level, and in group-level comparisons with modality-specific groups of cognitively normal older adults (CN). Tau-PET findings in patients with TES were also compared to a matched group of patients with mild cognitive impairment or dementia due to Alzheimer's disease (AD). RESULTS: All patients with TES sustained repetitive head injury participating in impact sports, ten in American football. Three patients met criteria for dementia and eight had mild cognitive impairment. Two patients were amyloid-PET positive and harbored the most severe MRI atrophy, FDG hypometabolism, and FTP-tau PET binding. Among the nine amyloid-negative patients, tau-PET showed either mildly elevated frontotemporal binding, a "dot-like" pattern, or no elevated binding. Medial temporal FTP was mildly elevated in a subset of amyloid-negative patients, but values were considerably lower than in AD. Voxelwise analyses revealed a convergence of imaging abnormalities (higher FTP binding, lower FDG, lower gray matter volumes) in frontotemporal areas in TES compared to controls. CONCLUSIONS: Mildly elevated tau-PET binding was observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with CTE pathology stages III-IV. FTP-PET may be useful as a biomarker of tau pathology in CTE but is unlikely to be sensitive to early disease stages.

Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia.

Importance: Amyloid positron emission tomography (PET) detects amyloid plaques in the brain, a core neuropathological feature of Alzheimer disease. Objective: To determine if amyloid PET is associated with subsequent changes in the management of patients with mild cognitive impairment (MCI) or dementia of uncertain etiology. Design, Setting, and Participants: The Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study was a single-group, multisite longitudinal study that assessed the association between amyloid PET and subsequent changes in clinical management for Medicare beneficiaries with MCI or dementia. Participants were required to meet published appropriate use criteria stating that etiology of cognitive impairment was unknown, Alzheimer disease was a diagnostic consideration, and knowledge of PET results was expected to change diagnosis and management. A total of 946 dementia specialists at 595 US sites enrolled 16 008 patients between February 2016 and September 2017. Patients were followed up through January 2018. Dementia specialists documented their diagnosis and management plan before PET and again 90 (±30) days after PET. Exposures: Participants underwent amyloid PET at 343 imaging centers. Main Outcomes and Measures: The primary end point was change in management between the pre- and post-PET visits, as assessed by a composite outcome that included Alzheimer disease drug therapy, other drug therapy, and counseling about safety and future planning. The study was powered to detect a 30% or greater change in the MCI and dementia groups. One of 2 secondary end points is reported: the proportion of changes in diagnosis (from Alzheimer disease to non-Alzheimer disease and vice versa) between pre- and post-PET visits. Results: Among 16 008 registered participants, 11 409 (71.3%) completed study procedures and were included in the analysis (median age, 75 years [interquartile range, 71-80]; 50.9% women; 60.5% with MCI). Amyloid PET results were positive in 3817 patients with MCI (55.3%) and 3154 patients with dementia (70.1%). The composite end point changed in 4159 of 6905 patients with MCI (60.2% [95% CI, 59.1%-61.4%]) and 2859 of 4504 patients with dementia (63.5% [95% CI, 62.1%-64.9%]), significantly exceeding the 30% threshold in each group (P < .001, 1-sided). The etiologic diagnosis changed from Alzheimer disease to non-Alzheimer disease in 2860 of 11 409 patients (25.1% [95% CI, 24.3%-25.9%]) and from non-Alzheimer disease to Alzheimer disease in 1201 of 11 409 (10.5% [95% CI, 10.0%-11.1%]). Conclusions and Relevance: Among Medicare beneficiaries with MCI or dementia of uncertain etiology evaluated by dementia specialists, the use of amyloid PET was associated with changes in clinical management within 90 days. Further research is needed to determine whether amyloid PET is associated with improved clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02420756.