José Eriton Gomes da Cunha

Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice

Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor β (PDGF-Rβ) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-Rβ. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.

Quantification of CSF biomarkers using an electrochemiluminescence-based detection system in the differential diagnosis of AD and sCJD

The identification of reliable diagnostic tools for the differential diagnosis between sporadic Creutzfeldt–Jakob Disease (sCJD) and Alzheimer’s disease (AD) remains impeded by the existing clinical, neuropathological and molecular overlap between both diseases. The development of new tools for the quantitative measurement of biomarkers is gaining experimental momentum due to recent advances in high-throughput screening analysis and with the optimization of assays for their quantification in biological fluids, including cerebrospinal fluid (CSF). Electrochemiluminescence (ECL)-based immunoassays have demonstrated to achieve clinical quality performance in a variety of sample types due to its high sensitivity and dynamic range. Here, we quantified the CSF levels of Tau-protein, β-amyloid 1-42 (Aβ42) and α-synuclein, as important biomarkers in CSF used in the differential diagnosis of neurodegenerative disorders in 12 AD, 12 sCJD and 12 control cases by singleplex ECL-based technology. Its performance has been compared to classical enzyme-linked immunosorbent assays (ELISA) to confront their clinical accuracy. ECL-based technology validates previous data obtained with ELISA and presents a higher performance in the discrimination of three analysed groups as determined by increased area under the curve (AUC) values for the three biomarkers. Importantly, α-synuclein levels detected by ECL allow an excellent discrimination between sCJD cases and AD and control cases, unveiling a new clinical approach for the differential diagnosis of sCJD.

Exaggerated blood pressure response during the exercise treadmill test as a risk factor for hypertension

Exaggerated blood pressure response (EBPR) during the exercise treadmill test (ETT) has been considered to be a risk factor for hypertension. The relationship of polymorphisms of the renin-angiotensin system gene with hypertension has not been established. Our objective was to evaluate whether EBPR during exercise is a clinical marker for hypertension. The study concerned a historical cohort of normotensive individuals. The exposed individuals were those who presented EBPR. At the end of the observation period (41.7 months = 3.5 years), the development of hypertension was analyzed within the two groups. Genetic polymorphisms and blood pressure behavior were assessed as independent variables, together with the classical risk factors for hypertension. The I/D gene polymorphism of the angiotensin-converting enzyme and M235T of angiotensinogen were ruled out as risk factors for hypertension. EBPR during ETT is not an independent influence on the chances of developing hypertension. No differences were observed between the hypertensive and normotensive individuals regarding gender (P = 0.655), skin color (P = 0.636), family history of hypertension (P = 0.225), diabetes mellitus (P = 0.285), or hypertriglyceridemia (P = 0.734). The risk of developing hypertension increased with increasing body mass index (BMI) and advancing age. The risk factors, which independently influenced the development of hypertension, were age and BMI. EBPR did not constitute an independent risk factor for hypertension and is probably a preclinical phase in the spectrum of normotension and hypertension.

Exaggerated blood pressure response during exercise treadmill testing: functional and hemodynamic features, and risk factors

The factors which contribute to an exaggerated blood pressure response (EBPR) during the exercise treadmill test (ETT) are not wholly understood. The association between the insertion/deletion polymorphisms of the angiotensin-converting enzyme (ACE) and M235T of the angiotensinogen with EBPR during ETT still remains unstudied. To identify and compare the risk factors for hypertension between normotensive subjects with EBPR and those who exhibit a normal curve of blood pressure (BP) during ETT. In a series of EBPR cases from a historical cohort of normotensive individuals, a univariate analysis was performed to estimate the association of the studied factors with BP behavior during ETT. Additionally, logistic multivariate regression was conducted to analyze the joint effects of the variables. P-values above 0.05 were considered statistically significant. From a total of 10 027 analyzed examinations, only 219 met the criteria employed to define EBPR, which resulted in a prevalence of 12.6%. For the systolic component of the BP, hyperreactive subjects displayed a mean age and body mass index (BMI) significantly higher than the others (P=0.002 and <0.001, respectively). No association was observed between the polymorphisms cited above and EBPR. An analysis of the joint effect of variables has indicated that only age (P< 0.001) and BMI (P=0.001) were specifically associated with systolic BP during exercise. Age and BMI were the only factors that independently influenced EBPR during ETT.

Challenging the concept of diffuse neurofibrillary tangles with calcification (Kosaka-Shibayama disease).

S INCE 1994, THE term ‘diffuse neurofibrillary tangles with calcification’ (DNTC) has defined a novel and independent neurological condition, also known as Kosaka–Shibayama disease. This condition is characterized by dementia, psychosis, localized brain atrophy, and bilateral brain calcification with neurofibrillary tangles (NFT). According to Ukai and Kosaka, those characteristics set DNTC distinctly apart from primary familial brain calcification (PFBC), a neuropsychiatric condition, also known as ‘Fahr’s disease’ (now considered a misnomer), which is also characterized by bilateral and symmetrical brain calcifications. Another characteristic of DNTC identified by those authors is the absence of familial cases. Intriguingly, the majority of DNTC cases are from necropsies carried out in Japan. First of all, the clinical symptoms of DNTC might also be found in PFBC cases, as well as brain atrophy. Ukai and Kosaka performed a historic review of DNTC cases and suggested clinical criteria to classify suspect cases as possible or probable DNTC. However, we postulate that DNTC could be a different phenotype of PFBC. Considering the obvious clinical and neuroimaging resemblances between DNTC and PFBC, we suggest that NFT findings could be due to cohort bias, considering that, according to the same authors, 57.6% of cases were over 60 years old. Moreover, genetic studies provide the most powerful evidence of our hypothesis. Since 2012, four genes have been linked to PFBC, SLC20A2, PDGFRB, PDGFB, and XPR1, explaining approximately 60% of the familial cases and a few sporadic subjects with de novo mutations, in many different countries and from various ethnic backgrounds, including Japan. Recently, Yamada et al. reported a family linked to a SLC20A2 mutation, with a proband previously diagnosed as having DNTC. Additionally, Kimura et al. reported another PFBC case linked to a different SLC20A2 mutation, also presenting NFT. This confirms that Tau deposition might be an incidental finding linked to an older population of patients. Nunomura wrote a recent editorial in this journal regarding some of the issues we highlighted here. Hence, we strongly suggest that all patients diagnosed with or suspected of having DNTC need to be screened for mutations linked to PFBC. Only with genetic studies we can ensure that DNTC is really a new entity and not a phenotype of PFBC.

Are Brazilian cervids at risk of prion diseases

ABSTRACT Prion diseases are neurodegenerative fatal disorders that affect human and non-human mammals. Chronic Wasting Disease (CWD) is a prion disease of cervids regarded as a public health problem in North America, and polymorphisms at specific codons in the PRNP gene are associated with this disease. To assess the potential CWD susceptibility of South American free-ranging deer, the presence of these polymorphisms was examined in Mazama gouazoubira, Ozotoceros bezoarticus and Blastocerus dichotomus. Despite the lack of CWD reports in Brazil, the examined codons (95, 96, 116, 132, 225, and 226) of the PRNP gene showed potential CWD susceptibility in Brazilian deer. Low abundancy of deer in Brazil possibly difficult both CWD proliferation and detection, however, CWD surveillance may not be neglected.

Epidemiological genetics and meta-analysis of a polymorphism at codon 129 of the PRNP gene in Alzheimer's disease in Brazil

Abstract The polymorphism at codon 129 of the prion protein gene (PRNP) is a major risk factor for Creutzfeldt–Jakob disease (CJD). Several authors reported neuropathological and clinical overlapping between CJD and Alzheimer’s disease (AD), with a few association studies generating conflicting results. To investigate the distribution of this polymorphism in AD, we selected 58 patients with probable AD and 73 controls from a Brazilian population. There was no association between the PRNP polymorphism at codon 129 and AD. Our meta-analysis (performed using Alzgene; http://www.alzgene.org) along with previous studies conducted in Brazil demonstrated a negative association.