A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.

BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

De Novo PS1 Mutation (Pro436Gln) in a Very Early-Onset Posterior Variant of Alzheimer's Disease Associated with Spasticity: A Case Report.

We report a patient with sporadic Alzheimer's disease with onset in his twenties found to carry the de novo Pro436Gln mutation in the presenilin 1 gene (PS1). Clinical phenotype featured a posterior cortical syndrome with severe visual agnosia and mild limb spasticity with brisk reflexes. Brain MRI and FDG-PET scans revealed severe parieto-occipital atrophy/hypometabolism. Cerebrospinal fluid biomarkers showed a decrease in Aß42 level and Aß42/40 ratio, increased phospho-tau, and normal total tau. Amyloid PET identified a very high burden of amyloid-ß neuritic plaques in the posterior cortex. Similarities between this and two previously reported cases with this variant support that this mutation has a very strong impact on the clinical phenotype and is consistently associated with spasticity.

Leuko-platelet index predicts thrombotic events in patients with acute coronary syndrome.

PURPOSE: To evaluate the predictive value of a bedside index in hospitalized patients with acute coronary syndromes (ACS). METHODS: We studied the association of leuko-platelet index (LPI: platelet count * leukocyte count/108) with risk of mortality, shock, or heart failure (combined end point-CEP), and with the response to antiplatelet therapy, measured by light transmission aggregometry. RESULTS: In the derivation cohort we included 1100 patients with non STEM-ACS, GRACE score of 133 ± 52, Crusade score 24,3 ± 14, 66% male, 65 + 11 years. LPI was 17 (12-24). LPI was higher (19 (13-25)) in patients with MI than in patients with unstable angina (16 (12-22) in (p < 0.001)). A total of 115 patients (10.5%) had the CEP. CEP was associated to LPI (OR 1.04 (1.002-1.08), p = 0.03), age (OR 1.01 (0.97-1.05), p = 0.62) and GRACE>140 (OR 8.1 (2.2-29), p = 0.02). LPI (OR 1.04 (1.004-1.07) p = 0.03) and GRACE score (OR 1.02 (1.01-1.03) p < 0.01) were associated to cardiovascular mortality. We confirmed these results in the validation cohort #1 (686 patients, 61 + 11 years old, 47% nonST-ACS, 53% ST-ACS, 21% had CEP) and in validation cohort #2 (218 patients, 56.8% males, 73 + 7 years old, 79% nonST-ACS, GRACE score 136 + 30) and 8.3% with CEP. We used the cutoff points of LPI obtained in the derivation cohort (>24). CONCLUSIONS: LPI > 24 was associated to CEP (OR (1.7-5.2), p 0.01), independently of age (OR 1 (0.98-1.02), p = 0.8), and GRACE score (OR 1.01 (0.99-1.01), p 0.69), and It was associated to antiplatelet resistance (OR 1.03 (95% CI 1.00-1.06) p = 0.05).

α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer's disease.

BACKGROUND: The disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the non-amyloidogenic processing of APP. Some ADAM10 gene variants have been associated with higher susceptibility to develop late-onset AD, though clear clinical-genetic correlates remain elusive. METHODS: Clinical-genetic and biomarker study of a first family with early- and late-onset AD associated with a nonsense ADAM10 mutation (p.Tyr167*). CSF analysis included AD core biomarkers, as well as Western blot of ADAM10 species and sAPPα and sAPPß peptides. We evaluate variant's pathogenicity, pattern of segregation, and further screened for the p.Tyr167* mutation in 197 familial AD cases from the same cohort, 200 controls from the same background, and 274 AD cases from an independent Spanish cohort. RESULTS: The mutation was absent from public databases and segregated with the disease. CSF Aß42, total tau, and phosphorylated tau of affected siblings were consistent with AD. The predicted haploinsufficiency effect of the nonsense mutation was supported by (a) ADAM10 isoforms in CSF decreased around 50% and (b) 70% reduction of CSF sAPPα peptide, both compared to controls, while sAPPß levels remained unchanged. Interestingly, sporadic AD cases had a similar decrease in CSF ADAM10 levels to that of mutants, though their sAPPα and sAPPß levels resembled those of controls. Therefore, a decreased sAPPα/sAPPß ratio was an exclusive feature of mutant ADAM10 siblings. The p.Tyr167* mutation was not found in any of the other AD cases or controls screened. CONCLUSIONS: This family illustrates the role of ADAM10 in the amyloidogenic process and the clinical development of the disease. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model for sporadic late-onset AD due to age-related downregulation of α-secretase. This report encourages future research on ADAM10 enhancers.

Consultas vía WhatsApp en un servicio de electrofisiología de un hospital público de la Ciudad de Buenos Aires en tiempos de COVID-19 / WhatsApp Consultations in the Department of Electrophysiology of a Public Hospital of the City of Buenos Aires in Times of COVID-19

RESUMEN Introducción: La pandemia por coronavirus (COVID-19) es altamente contagiosa. La telemedicina emerge como una opción para mantener a nuestros pacientes dentro del sistema sanitario. Objetivo: Implementar consultas por WhatsApp durante 30 días en un hospital de la Ciudad Autónoma de Buenos Aires (CABA) durante la cuarentena impuesta por COVID-19. Material y métodos: Se analizaron consultas por WhatsApp durante 30 días consecutivos. Se envió un formulario antes de la consulta telefónica con el especialista. Se realizó un análisis descriptivo de las consultas y los planes propuestos para el seguimiento. Resultados: Se realizaron 263 consultas en 205 pacientes. La cantidad promedio de consultas telefónicas fue de 7,8 mensajes. Las consultas más frecuentes fueron: palpitaciones (12%) y vacunación antigripal (11,7%). El seguimiento quedó dividido en grupos: 1) Resueltos vía WhatsApp: 154 pacientes; 2) Derivados a un hospital zonal: 25; 3) Derivados a nuestro hospital: 26 pacientes. Conclusión: La telemedicina vía WhatsApp es factible de ser desarrollada en un hospital público de la CABA, con una sustancial reducción de consultas presenciales.

ABSTRACT Background: Coronavirus (COVID-19) pandemic is highly infectious. Telemedicine emerges as an option to keep patients within the healthcare system. Objective: The aim of this study was to implement WhatsApp consultations during 30 days in a hospital of the City of Buenos Aires (CABA) during the lockdown imposed due to COVID-19. Methods: Consultations via WhatsApp were analyzed for 30 consecutive days. A form was sent prior to telephone consultation with the specialist. A descriptive analysis of consultations and proposed follow-up plans was carried out. Results: A total of 263 consultations were performed in 205 patients. The average number of telephone consultations was 7.8 messages. The most common topics for consultation were palpitations (12%) and influenza vaccine (11.7%). Follow-up was divided into groups: 1) Solved via WhatsApp: 154 patients; 2) Referred to a local hospital: 25; 3) Referred to our hospital: 26 patients. Conclusion: Telemedicine via WhatsApp can be developed in public hospitals of CABA, with a substantial reduction of in-person consultations.

Muerte súbita en el ámbito prehospitalario en época de COVID-19 / Sudden death in the prehospital setting in times of COVID-19

RESUMEN Una de cada cinco muertes de adultos en países desarrollados se debe a causas cardiovasculares; la mitad de esas muertes se produce de forma súbita y un gran porcentaje en el ámbito extrahospitalario. Múltiples estudios demostraron que el acceso de la población general al aprendizaje de maniobras de reanimación cardiopulmonar sencillas y pragmáticas y la presencia de desfibrilador externo automático se traducen en un gran aumento de sobrevida sin secuelas en casos de muerte súbita cardíaca extrahospitalaria. Hoy en día existe una situación especial representada por la pandemia por COVID -19, que deja bajo un interrogante todo lo aprendido hasta la fecha y nos enfrenta a dos situaciones sumamente complejas. Por un lado, la afectación cardiovascular y el aumento consecuente de arritmias ventriculares malignas que genera esta infección, tanto en pacientes sanos como en sujetos con patologías preexistentes, han puesto de manifiesto un aumento en la incidencia de episodios de muerte súbita extrahospitalaria. Por otro lado, se vuelve necesario reevaluar todo el accionar puesto en marcha cuando un paciente presenta un episodio de muerte súbita cardíaca extrahospitalaria, ya que ahora se agrega la posibilidad de transmisión de esta enfermedad de alta contagiosidad durante las maniobras de reanimación. Volver a encontrar un equilibrio riesgo-beneficio que permita aumentar la sobrevida del paciente con el mínimo riesgo posible para la persona que realiza la reanimación es el verdadero desafío hoy en día.

ABSTRACT One in five adult deaths in developed countries is due to cardiovascular causes; half of these deaths occur suddenly and a large percentage in the out-of-hospital setting. Multiple studies demonstrated that the access of the general population to learning simple and pragmatic cardiopulmonary resuscitation maneuvers and the presence of automatic external defibrillator translates into a large increase in survival without sequelae in victims of sudden out-of-hospital sudden cardiac death. Today there is a situation represented by the pandemic by COVID -19, which questions what we have learned to date and makes us face two extremely complex situations. On the one hand, the cardiovascular involvement and the consequent increase in malignant ventricular arrhythmias generated by this infection, both in patients with previous pathologies or not, has shown an increase in the incidence of episodes of sudden out-of-hospital death. On the other hand, it forces us to rethink all the actions put into place at the moment that a patient presents with an episode of sudden out-of-hospital sudden cardiac death since now the possibility of transmission of this highly contagious disease is added during resuscitation maneuvers. Refinding a risk-benefit balance that allows increasing the patient's survival with the least possible risk for the person who is resuscitating is the real challenge we are facing today.

SORL1 Variants in Familial Alzheimer's Disease.

The SORL1 gene encodes a protein involved in the amyloidogenic process, and its variants have been associated with Alzheimer's disease (AD) physiopathology. We screened for SORL1 variants in 124 familial (44 early- and 80 late-onset) dementia of Alzheimer type (DAT) cases. Nine potentially pathogenic changes (three not previously reported and six rare variants) were found in nine probands (7%). After screening the control population and siblings (presence in at least 1/200 controls and/or absence of segregation pattern), a causal relationship with the disease was considered unlikely in six variants and uncertain in one. The change Trp848Ter and a splice-site variant remained likely correlated with the disease. SORL1 mutations are present in 7% of our familial DAT cohort, though in most cases cannot be considered the direct cause of the disease.