Correlations between plasma and PET beta-amyloid levels in individuals with subjective cognitive decline: the Fundació ACE Healthy Brain Initiative (FACEHBI).

BACKGROUND: Peripheral biomarkers that identify individuals at risk of developing Alzheimer's disease (AD) or predicting high amyloid beta (Aß) brain burden would be highly valuable. To facilitate clinical trials of disease-modifying therapies, plasma concentrations of Aß species are good candidates for peripheral AD biomarkers, but studies to date have generated conflicting results. METHODS: The Fundació ACE Healthy Brain Initiative (FACEHBI) study uses a convenience sample of 200 individuals diagnosed with subjective cognitive decline (SCD) at the Fundació ACE (Barcelona, Spain) who underwent amyloid florbetaben(18F) (FBB) positron emission tomography (PET) brain imaging. Baseline plasma samples from FACEHBI subjects (aged 65.9 ± 7.2 years) were analyzed using the ABtest (Araclon Biotech). This test directly determines the free plasma (FP) and total plasma (TP) levels of Aß40 and Aß42 peptides. The association between Aß40 and Aß42 plasma levels and FBB-PET global standardized uptake value ratio (SUVR) was determined using correlations and linear regression-based methods. The effect of the APOE genotype on plasma Aß levels and FBB-PET was also assessed. Finally, various models including different combinations of demographics, genetics, and Aß plasma levels were constructed using logistic regression and area under the receiver operating characteristic curve (AUROC) analyses to evaluate their ability for discriminating which subjects presented brain amyloidosis. RESULTS: FBB-PET global SUVR correlated weakly but significantly with Aß42/40 plasma ratios. For TP42/40, this observation persisted after controlling for age and APOE ε4 allele carrier status (R2 = 0.193, p = 1.01E-09). The ROC curve demonstrated that plasma Aß measurements are not superior to APOE and age in combination in predicting brain amyloidosis. It is noteworthy that using a simple preselection tool (the TP42/40 ratio with an empirical cut-off value of 0.08) optimizes the sensitivity and reduces the number of individuals subjected to Aß FBB-PET scanners to 52.8%. No significant dependency was observed between APOE genotype and plasma Aß measurements (p value for interaction = 0.105). CONCLUSION: Brain and plasma Aß levels are partially correlated in individuals diagnosed with SCD. Aß plasma measurements, particularly the TP42/40 ratio, could generate a new recruitment strategy independent of the APOE genotype that would improve identification of SCD subjects with brain amyloidosis and reduce the rate of screening failures in preclinical AD studies. Independent replication of these findings is warranted.

FACEHBI: A Prospective Study of Risk Factors, Biomarkers and Cognition in a Cohort of Individuals with Subjective Cognitive Decline. Study Rationale and Research Protocols.

BACKGROUND: Long-term longitudinal studies with multimodal biomarkers are needed to delve into the knowledge of preclinical AD. Subjective cognitive decline has been proposed as a risk factor for the development of cognitive impairment. Thus, including individuals with SCD in observational studies may be a cost-effective strategy to increase the prevalence of preclinical AD in the sample. OBJECTIVES: To describe the rationale, research protocols and baseline characteristics of participants in the Fundació ACE Healthy Brain Initiative (FACEHBI). DESIGN: FACEHBI is a clinical trial (EudraCT: 2014-000798-38) embedded within a long-term observational study of individuals with SCD. SETTING: Participants have been recruited at the memory clinic of Fundació ACE (Barcelona) from two different sources: patients referred by a general practitioner and individuals from an Open House Initiative. PARTICIPANTS: 200 individuals diagnosed with SCD with a strictly normal performance in a comprehensive neuropsychological battery. MEASUREMENTS: Individuals will undergo an extensive neuropsychological protocol, risk factor assessment and a set of multimodal biomarkers including florbetaben PET, structural and functional MRI, diffusion tensor imaging, determination of amyloid species in plasma and neurophthalmologic assessment with optical coherence tomography. RESULTS: Two hundred individuals have been recruited in 15 months. Mean age was 65.9 years; mean MMSE was 29.2 with a mean of 14.8 years of education. CONCLUSIONS: FACEHBI is a long-term study of cognition, biomarkers and lifestyle that has been designed upon an innovative symptom-based approach using SCD as target population. It will shed light on the pathophysiology of preclinical AD and the role of SCD as a risk marker for the development of cognitive impairment.

Influencia del polimorfismo del gen de la APOE en la respuesta al tratamiento con interferón beta en esclerosis múltiple / Influence of APOE gene polymorphisms on interferon-beta treatment response in multiple sclerosis

Objetivos: Los ensayos clínicos llevados a cabo con el interferón beta (INFB) en esclerosis múltiple remitente recidivante (EMRR) han mostrado que reducen la tasa de brotes. Sin embargo, no todos los pacientes responden a este tratamiento, si bien aún no hay un absoluto consenso a propósito de la definición de respuesta al tratamiento. Las razones para este fracaso terapéutico no son conocidas, y probablemente hay factores genéticos implicados, como se ha mostrado con los polimorfismos de los genes que codifican la interleuquina 10 o el interferón gamma. El papel del gen de la apolipoproteína E (APOE) en la EM ha sido investigado en los últimos años y no parece aumentar el riesgo de aparición de la enfermedad ni influir en su severidad. Variaciones en este gen influyen en la respuesta al tratamiento con inhibidores de la colinesterasa en la enfermedad de Alzheimer o a las estatinas en la hipercolesterolemia. Esto podría tener implicaciones futuras en la EM. Material y métodos: Hemos revisado retrospectivamente 38 pacientes diagnosticados de EMRR (32 mujeres y 6 varones) tratados con INFB durante al menos dos años. Los criterios para llevar a cabo el tratamiento eran uniformes de acuerdo con las indicaciones del Comité asesor para el tratamiento de la EM. Recogimos datos acerca de la edad y tiempo de evolución de la enfermedad. Al cabo de dos años del inicio del tratamiento los pacientes fueron clasificados como respondedores o no-respondedores de acuerdo con los criterios clínicos disponibles, basados en la presencia de brotes, evolución de la discapacidad, o ambos. El genotipo APOE se determinó de muestras sanguíneas utilizando métodos validados de reacción en cadena de la polimerasa. Se estudió la correlación entre la condición de respondedor o no respondedor y la presencia de los alelos E2 o E4. Resultados: Veinte pacientes (52,6%) recibían INFB1b subcutáneo (Betaferón®), 13 (34,2%) INFB1a intramuscular (Avonex®) y 5 (13,2%) INFB1a subcutáneo (Rebif®) (AU)

Objective: Clinical trials with interferon beta in relapsing remitting multiple sclerosis (RRMS) have demonstrated a reduction in the relapse rate. Nevertheless, not all patients respond tothis treatment, although there is no consensus regarding the definition of response to therapy. The reasons for this failure are not known but genetic factors probably influence this, as hasbeen previously shown with Interleukin 10 or Interferon gamma polymorphisms.The role of apolipoprotein E (APOE) gene in MS has been investigated and does not appear to increase risk for MS or influence disease severity. Interestingly APOE variation influencesresponse to cholinesterase inhibitor treatment in Alzheimer disease or to statins in hypercholesterolemia.This might have future implications for MS. Material and methods: We retrospectively reviewed 38 RRMS patients (32 females and 6 males) treated with interferon beta (INFbeta) over at least two years. Criteria for treatment were uniform accordingly to an ‘‘Advisory Committee for the Treatment of Multiple Sclerosis’’. We collected data variables including age, age of onset, clinical type or diseaseduration. Patients were classified, two years after the start of treatment, as responders and nonrespondersbased upon clinical criteria available in the literature, which rely on the presenceof relapses, increase of disability, or both. APOE genotype was determined from blood samples using validated polymerase chain reaction methods. Correlation between patient respondingstatus with allele E2 or E4 was tested.Results: A total of 20 patients (52.6%) received subcutaneous INFbeta1b (Betaferón®), 13 (34.2%) INFbeta1a intramuscular (Avonex®), and 5 (13.2%) subcutaneous INFbeta1a (Rebif®). We found 2 patients (5.2%) heterozygous for the E2 allele and 9 (23.7%) for the E4 allele. Nopatient was homozygous for E2 or E4 (AU)

Serum uric acid levels in multiple sclerosis patients inversely correlate with disability.

Uric acid (UA) is an endogenous antioxidant. Some studies have described that multiple sclerosis (MS) patients have lower serum UA levels than controls, although it has not been established whether UA is primarily deficient, or secondarily reduced due to its scavenging activity. UA has also been proposed as an indicator of disease activity. We, retrospectively, reviewed 478 serum UA levels obtained in 94 MS patients. Ninety samples were collected during a relapse. Correlation between UA levels obtained during a relapse or in a relapse-free period, and comparison between UA and expanded disability status scale (EDSS) score was tested using a two-tailed Student's t test and Spearman correlation coefficients test. UA levels were significantly lower when measured during a relapse (n 90) than in a remission period (n 368) (r -0.16, p 0.003) UA levels measured outside a relapse inversely correlated with EDSS score (r -0.15, p 0.001). Lower uric acid levels in MS patients are associated with clinical relapse. This is the first description of an inverse correlation of serum UA levels with disability as assessed by EDSS score.

Influence of APOE gene polymorphisms on interferon-beta treatment response in multiple sclerosis.

OBJECTIVE: Clinical trials with interferon beta in relapsing remitting multiple sclerosis (RRMS) have demonstrated a reduction in the relapse rate. Nevertheless, not all patients respond to this treatment, although there is no consensus regarding the definition of response to therapy. The reasons for this failure are not known but genetic factors probably influence this, as has been previously shown with Interleukin 10 or Interferon gamma polymorphisms. The role of apolipoprotein E (APOE) gene in MS has been investigated and does not appear to increase risk for MS or influence disease severity. Interestingly APOE variation influences response to cholinesterase inhibitor treatment in Alzheimer disease or to statins in hypercholesterolemia. This might have future implications for MS. MATERIAL AND METHODS: We retrospectively reviewed 38 RRMS patients (32 females and 6 males) treated with interferon beta (INFbeta) over at least two years. Criteria for treatment were uniform accordingly to an "Advisory Committee for the Treatment of Multiple Sclerosis". We collected data variables including age, age of onset, clinical type or disease duration. Patients were classified, two years after the start of treatment, as responders and non-responders based upon clinical criteria available in the literature, which rely on the presence of relapses, increase of disability, or both. APOE genotype was determined from blood samples using validated polymerase chain reaction methods. Correlation between patient responding status with allele E2 or E4 was tested. RESULTS: A total of 20 patients (52.6%) received subcutaneous INFbeta1b (Betaferón(®)), 13 (34.2%) INFbeta1a intramuscular (Avonex(®)), and 5 (13.2%) subcutaneous INFbeta1a (Rebif(®)). We found 2 patients (5.2%) heterozygous for the E2 allele and 9 (23.7%) for the E4 allele. No patient was homozygous for E2 or E4. Comparison of patients with and without E2 or E4 allele showed no significant differences in any of the ten therapy response variables assessed. CONCLUSION: Findings of a recent meta-analysis have not supported a role for APOE in MS susceptibility or severity. We have not found, in our data, any influence of this gene in the RRMS response to INFbeta. However, larger series would be required to validate these results.

Patrones estacionales de nacimiento en esclerosis múltiple / Seasonal birth patterns in multiple sclerosis

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Hematomas cerebrales espontáneos múltiples. Descripción de una serie y revisión de la bibliografía / Multiple spontaneous cerebral haemorrahges. Descriptión of a series and review of the literature

Resumen. Introducción. La aparición simultánea de hemorragias cerebrales en diferentes territorios arteriales ocurre en el 2-3% de los accidentes cerebrovasculares. Diversos factores de riesgo se han asociado con la presentación de múltiples hemorragias cerebrales, pero ninguno ha sido confirmado. Presentamos los síntomas clínicos, las manifestaciones radiológicas y la evolución clínica de siete casos admitidos en nuestro centro durante los últimos nueve años, así como los distintos factores etiológicos. Pacientes y métodos. Se revisaron retrospectivamente los pacientes con un episodio de accidente cerebrovascular agudo ingresados en nuestro servicio durante el período comprendido entre enero de 1998 y febrero de 2007. Se excluyó a los pacientes con historia de traumatismo cerebral o infartos hemorrágicos. Se analizaron la edad, los factores de riesgo, la presentación clínica, el número y localización de los hematomas y su evolución. Resultados. Presentamos 7 casos (5 hombres y 2 mujeres). La edad media fue de 78 años. Las manifestaciones clínicas más frecuentes fueron la disminución del nivel de conciencia y la pérdida de fuerza. El total de hematomas fue de 20, de los cuales 19 (95%) eran supratentoriales, y 15 (75%), lobares. En un paciente la hemorragia se extendió al sistema ventricular. Tres pacientes (43%) tuvieron historia de hipertensión, un caso se asoció con la toma de anticoagulación oral (14%) y otro con discrasias sanguíneas (14%). Tres pacientes fallecieron (43%). Conclusión. Nuestra serie de pacientes con múltiples hemorragias cerebrales, respecto a los síntomas, los hallazgos radiológicos y la evolución es similar a otras previamente descritas, pero nuestros pacientes son mayores. La avanzada edad y la localización de los hematomas sugieren que la angiopatía amiloidea puede ser un importante factor de riesgo para presentar hemorragias cerebrales múltiples (AU)

Summary. Introduction. The simultaneous occurrence of intracerebral haemorraghes in different arterial territories is an clinical event that develops in 2% to 3% of hemorrhagic strokes. Multiple risk factors have been associated with multiple intracerebral haemorraghes, but none of them are clearly defined. We reported clinical features, radiological findings, and outcome of 7 patients admitted to our department during last nine years and the diverse etiologic factors are discussed. Patients and methods.We retrospectively reviewed all patients with acute stroke admitted to our department during the period January 1998-February 2007. Patients with a history of traumatic brain injury or suspected hemorrhagic infarctions were excluded. We collected data concerning age, risk factors, clinical features, number and location of haematomas and outcome. Results. We studied 7 patients (5 males and 2 females) Mean age was 78. The most common clinical manifestations were decreased alertness and weakness. Total number of haematomas was 20, 19 (95%) supratentorial and 15 (75%) in lobar area. One patient haemorrhage extended into the ventricular system. Three patients (43%) had hipertensive history, and in only one case was associated with oral anticoagulant (14%) and one blood dyscrasia (14%). Three patients died (43%). Conclusion. In our series of patients with multiple intracerebral haemorraghes, clinical and radiological findings and outcome were comparable to others previously described, but our patients were older. The advanced age and lobar localization suggest amyloid angiopathy is an important risk factor to multiple intracerebral haemorraghes (AU)

[Multiple spontaneous cerebral haemorrhages. Description of a series and review of the literature]. / Hematomas cerebrales espontáneos múltiples. Descripción de una serie y revisión de la bibliografía.

INTRODUCTION: The simultaneous occurrence of intracerebral haemorraghes in different arterial territories is an clinical event that develops in 2% to 3% of hemorrhagic strokes. Multiple risk factors have been associated with multiple intracerebral haemorraghes, but none of them are clearly defined. We reported clinical features, radiological findings, and outcome of 7 patients admitted to our department during last nine years and the diverse etiologic factors are discussed. PATIENTS AND METHODS: We retrospectively reviewed all patients with acute stroke admitted to our department during the period January 1998-February 2007. Patients with a history of traumatic brain injury or suspected hemorrhagic infarctions were excluded. We collected data concerning age, risk factors, clinical features, number and location of haematomas and outcome. RESULTS: We studied 7 patients (5 males and 2 females) Mean age was 78. The most common clinical manifestations were decreased alertness and weakness. Total number of haematomas was 20, 19 (95%) supratentorial and 15 (75%) in lobar area. One patient haemorrhage extended into the ventricular system. Three patients (43%) had hipertensive history, and in only one case was associated with oral anticoagulant (14%) and one blood dyscrasia (14%). Three patients died (43%). CONCLUSION: In our series of patients with multiple intracerebral haemorraghes, clinical and radiological findings and outcome were comparable to others previously described, but our patients were older. The advanced age and lobar localization suggest amyloid angiopathy is an important risk factor to multiple intracerebral haemorraghes.

Afectación trigeminal en el SUNCT / Trigeminal involvement in SUNCT syndrome

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Variation of serum uric acid levels in multiple sclerosis during relapses and immunomodulatory treatment.

Uric acid (UA), a product of purine metabolism, may be an antioxidant, perhaps acting as a scavenger of peroxynitrite. Patients with gout have a reduced incidence of multiple sclerosis (MS). A number of studies found that patients with MS have low serum levels of UA, although it has not been established whether this represents a primary deficit or a secondary effect. UA has also been proposed as a marker of disease activity and response to immunosuppressive or immunomodulatory treatment. We retrospectively reviewed 83 relapsing-remitting or secondary progressive MS patients (64 females and 19 males) followed in our Neurology Unit. We collected data concerning demographic variables as age and sex, and clinical variables as age of onset, clinical type, disease duration, EDSS score and total number of relapses. We considered UA levels in three different situations: during a relapse, during remission period and during remission period under immunomodulatory treatment [Interferon Beta 1a i.m. (Avonex; Biogen Idec Inc., Cambridge, MA, USA), Interferon Beta 1a s.c. (Rebif; Serono Europe Limited, London, UK), Interferon Beta 1b (Betaferon; Bayer Schering Pharma AG, Berlin, Germany) or Glatiramer Acetate (Copaxone; TEVA Neuroscience LLC, Kansas City, MO, USA)]. A Wilcoxon matched pairs test was carried out to determine differences between groups. A P-value less than 0.05 was considered statistically significant. In 33 patients, we were able to compare at least one UA value obtained during a relapse with at least one when remission without treatment. Mean serum UA levels were significantly lower when measured during a relapse (r: 0.39, P: 0.024). In 27 cases, we compared at least one remission value without treatment with at least one obtained during remission and immunomodulatory treatment. Mean serum UA levels significantly increased when determined during Interferon Beta or Glatiramer Acetate therapy (r: 0.84, P < 0.001). Although we do not know exactly whether and how UA is involved in MS pathogenesis, our data suggest that UA might reflect disease activity or treatment response in MS.

Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most frequent sustained arrhythmia. After restoration of normal sinus rhythm, the recurrence rate of AF is high. Antiarrhythmic drugs have been widely used to prevent recurrence, but the effect of these drugs on mortality and other clinical outcomes is unclear. OBJECTIVES: To determine, in patients who recovered sinus rhythm after AF, the effect of long-term treatment with antiarrhythmic drugs on death, stroke and embolism, adverse effects, pro-arrhythmia and recurrence of AF. If several antiarrhythmics were effective our secondary aim was to compare them. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Libary (Issue 2, 2005), MEDLINE (1950 to May 2005) and EMBASE (1966 to May 2005) were searched. The reference lists of retrieved articles, recent reviews and meta-analyses were checked. No language restrictions were applied. SELECTION CRITERIA: Two independent reviewers selected randomised controlled trials comparing any antiarrhythmic with a control (no treatment, placebo or drugs for rate control) or with another antiarrhythmic, in adults who had AF and in whom sinus rhythm was restored. Post-operative AF was excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed quality and extracted data, on an intention-to-treat basis. Disagreements were resolved by discussion. Studies were pooled, if appropriate, using Peto odds ratio (OR). MAIN RESULTS: 45 studies met inclusion criteria, comprising 12,559 patients. All results were calculated at 1 year of follow-up. Class IA drugs (disopyramide, quinidine) were associated with increased mortality compared with controls (OR 2.39, 95% confidence interval (CI) 1.03 to 5.59, P = 0.04, number needed to harm (NNH) 109, 95% CI 34 to 4985). Other antiarrhythmics did not modify mortality. Several class IA (disopyramide, quinidine), IC (flecainide, propafenone) and III (amiodarone, dofetilide, dronedarone, sotalol) drugs significantly reduced recurrence of AF (OR 0.19 to 0.60, number needed to treat 2 to 9), but all increased withdrawals due to adverse affects (NNH 17 to 36) and all but amiodarone and propafenone increased pro-arrhythmia (NNH 17 to 119). AUTHORS' CONCLUSIONS: Several class IA, IC and III drugs are effective in maintaining sinus rhythm but increase adverse events, including pro-arrhythmia, and disopyramide and quinidine are associated with increased mortality. Any benefit on clinically relevant outcomes (embolisms, heart failure, mortality) remains to be established.

Incidence of neutropenia during treatment of bone-related infections with piperacillin-tazobactam.

Of 41 patients with bone-related infections who were treated for > or =10 days with piperacillin-tazobactam, 14 (34%) developed neutropenia. Cumulative doses of piperacillin administered to neutropenic patients were higher than those administered to nonneutropenic ones (330 vs. 237 g; P=.008), and an inverse correlation was detected between the absolute neutrophil count at the end of treatment and the cumulative dose of piperacillin (r=-0.47, P=.002). Moreover, the incidence of piperacillin-tazobactam-induced neutropenia increased with an increase in the cumulative dose of piperacillin: 0% of patients in the first quartile of cumulative piperacillin doses, 33.3% in the second quartile, 40% in the third quartile, and 66.7% in the fourth quartile.

Odontogenic cysts. Analysis of 856 cases.

Odontogenic cysts (OC) are one of the main causes of jaw destruction. Information about these lesions in the Mexican population is scant. And for this reason the purpose of this work is to describe the frequency of the different varieties of OC recorded in two oral pathology services in Mexico City. As well as to compare the findings with those previously reported in other studies and to analyze the association of these lesions with the gender of the affected patients and the type of oral pathology service. There were a total of 856 OC; of these, 449 (52.5%) occurred in men, 403 in women (47%), and in 4 cases (0.5%) gender was not stated. There were 8 out of the 10 different types of OC recognized by the WHO. The most frequently diagnosed OC were radicular cyst (342 cases), dentigerous cyst (283 cases) and odontogenic keratocyst (184 cases). Together, these three entities represented 94.5% of all OC. Both the gender and the type of oral pathology service showed a significant association with radicular and dentigerous cysts (p<0.01). The knowledge of the origin, clinico-pathological features and the biological behavior of these lesions are basic aspects to achieve an early diagnosis and a proper treatment.

Coma fulminante como forma de presentación de intoxicación por organofosforados / Fulminant coma as the first manifestation of organophosphate poisoning

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[Prevalence of hypertensive response to exercise in a group of healthy young male athletes. Relationship with left ventricular mass and prospective clinical implications]. / Prevalencia de reacciones hipertensivas durante el esfuerzo en un grupo de deportistas varones jóvenes sanos. Relación con la masa ventricular izquierda e implicaciones clínicas prospectivas.

AIM: We examined the prevalence of hypertensive response to exercise in a group of healthy young male athletes and evaluate the relationship between this exaggerated blood pressure response to exercise and left ventricular mass. METHODS: We studied 37 healthy male athletes (18 soccer players, 12 mountain climbers and 7 canoeists) at a similar level of physical conditioning at the time of the study. The age ranged from 16 to 37 (mean +/- SD: 25.9 +/- 6 yrs.). They underwent basal measurements of heart rate and blood pressure, maximum cycle ergometry in the erect position (increasing 50 W each 3 minutes until exhaustion) and basal echocardiography-Doppler. The statistical analysis was performed using a non-paired Student-t-test. RESULTS: A hypertensive response to exercise was observed in 8 of the 37 athletes (21.6%). In these 8 athletes the mean left ventricular mass index was 204.88 +/- 63.22 g/m2 estimated by echocardiography, whereas the mean in athletes without exaggerated blood pressure response to exercise was 143.29 +/- 27.51 g/m2 (p < 0.0001). All the athletes with hypertensive response to exercise showed left ventricular hypertrophy, being severe in 75% of them. Of the athletes without hypertensive response to exercise, 44.9% did not exhibit left ventricular hypertrophy. A left ventricular mass index of > or = 190 g/m2 was observed in 50% of athletes with exaggerated blood pressure response to exercise, versus only 6.8% of athletes without it. CONCLUSIONS: A fairly high prevalence of hypertensive response to exercise was observed in our series of healthy young male athletes. The athletes with exaggerated blood pressure response to exercise exhibited a significantly greater left ventricular mass than athletes without it. According to current general knowledge, this group of healthy athletes with hypertensive response to exercise could be prone to develop future chronic high blood pressure at rest and non-physiologic left ventricular hypertrophy. Thus, ergometry may be a useful test to prospectively identify a group of individuals at increased risk for developing essential arterial hypertension, potentially allowing early intervention before hypertension may contribute to cardiovascular risk.