Benito Pereira Damasceno

Asymmetrical hippocampal connectivity in mesial temporal lobe epilepsy: evidence from resting state fMRI

BackgroundMesial temporal lobe epilepsy (MTLE), the most common type of focal epilepsy in adults, is often caused by hippocampal sclerosis (HS). Patients with HS usually present memory dysfunction, which is material-specific according to the hemisphere involved and has been correlated to the degree of HS as measured by postoperative histopathology as well as by the degree of hippocampal atrophy on magnetic resonance imaging (MRI). Verbal memory is mostly affected by left-sided HS, whereas visuo-spatial memory is more affected by right HS. Some of these impairments may be related to abnormalities of the network in which individual hippocampus takes part. Functional connectivity can play an important role to understand how the hippocampi interact with other brain areas. It can be estimated via functional Magnetic Resonance Imaging (fMRI) resting state experiments by evaluating patterns of functional networks. In this study, we investigated the functional connectivity patterns of 9 control subjects, 9 patients with right MTLE and 9 patients with left MTLE.ResultsWe detected differences in functional connectivity within and between hippocampi in patients with unilateral MTLE associated with ipsilateral HS by resting state fMRI. Functional connectivity resulted to be more impaired ipsilateral to the seizure focus in both patient groups when compared to control subjects. This effect was even more pronounced for the left MTLE group.ConclusionsThe findings presented here suggest that left HS causes more reduction of functional connectivity than right HS in subjects with left hemisphere dominance for language.

Diagnóstico de doença de Alzheimer no Brasil: avaliação cognitiva e funcional. Recomendações do Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia

The educational and cultural heterogeneity of the Brazilian population leads to peculiar characteristics regarding the diagnosis of Alzheimers disease (AD). This consensus had the objective of recommending evidence-based guidelines for the clinical diagnosis of AD in Brazil. Studies on the diagnosis of AD published in Brazil were systematically evaluated in a thorough research of PUBMED and LILACS databases. For global cognitive evaluation, the Mini-Mental State Examination was recommended; for memory evaluation: delayed recall subtest of CERAD or of objects presented as drawings; attention: trail-making or digit-span; language: Boston naming, naming test from ADAS-Cog or NEUROPSI; executive functions: verbal fluency or clock-drawing; conceptualization and abstraction: similarities from CAMDEX or NEUROPSI; construction: drawings from CERAD. For functional evaluation, IQCODE, or Pfeffer Questionnaire or Bayer Scale for Activities of Daily Living was recommended. The panel concluded that the combined use of cognitive and functional evaluation based on interview with informant is recommended.The educational and cultural heterogeneity of the Brazilian population leads to peculiar characteristics regarding the diagnosis of Alzheimers disease (AD). This consensus had the objective of recommending evidence-based guidelines for the clinical diagnosis of AD in Brazil. Studies on the diagnosis of AD published in Brazil were systematically evaluated in a thorough research of PUBMED and LILACS databases. For global cognitive evaluation, the Mini-Mental State Examination was recommended; for memory evaluation: delayed recall subtest of CERAD or of objects presented as drawings; attention: trail-making or digit-span; language: Boston naming, naming test from ADAS-Cog or NEUROPSI; executive functions: verbal fluency or clock-drawing; conceptualization and abstraction: similarities from CAMDEX or NEUROPSI; construction: drawings from CERAD. For functional evaluation, IQCODE, or Pfeffer Questionnaire or Bayer Scale for Activities of Daily Living was recommended. The panel concluded that the combined use of cognitive and functional evaluation based on interview with informant is recommended.

Promoter Polymorphisms in the Plasma Glutathione Peroxidase (GPx-3) Gene: A Novel Risk Factor for Arterial Ischemic Stroke among Young Adults and Children

Background and Purpose— Plasma glutathione peroxidase (GPx-3)–deficiency increases extracellular oxidant stress, decreases bioavailable nitric oxide, and promotes platelet activation. The aim of this study is to identify polymorphisms in the GPx-3 gene, examine their relationship to arterial ischemic stroke (AIS) in a large series of children and young adults, and determine their functional molecular consequences. Methods— We studied the GPx-3 gene promoter from 123 young adults with idiopathic AIS and 123 age- and gender- matched controls by single-stranded conformational polymorphism and sequencing analysis. A second, independent population with childhood stroke was used for a replication study. We identified 8 novel, strongly linked polymorphisms in the GPx-3 gene promoter that formed 2 main haplotypes (H1 and H2). The transcriptional activity of the 2 most prevalent haplotypes was studied with luciferase reporter gene constructs. Results— The H2 haplotype was over-represented in both patient populations and associated with an independent increase in the risk of AIS in young adults (odds ratio=2.07, 95% CI=1.03 to 4.47; P=0.034) and children (odds ratio=2.13, 95% CI=1.23 to 4.90; P=0.027). In adults simultaneously exposed to vascular risk factors, the risk of AIS approximately doubled (odds ratio=5.18, 95% CI=1.82 to 15.03; P<0.001). Transcriptional activity of the H2 haplotype was lower than that of the H1 haplotype, especially after upregulation by hypoxia (normalized relative luminescence: 3.54±0.32 versus 2.47±0.26; P=0.0083). Conclusion— These findings indicate that a novel GPx-3 promoter haplotype is an independent risk factor for AIS in children and young adults. This haplotype reduces the genes transcriptional activity, thereby compromising gene expression and plasma antioxidant and antithrombotic activities.

Paraoxonase 192 Gln→Arg Polymorphism An Independent Risk Factor for Nonfatal Arterial Ischemic Stroke Among Young Adults

Background and Purpose— The etiology of arterial ischemic stroke (AIS) in the young remains unknown in one third of patients. Serum paraoxonase (PON1) is an HDL-associated esterase that hydrolyzes products of lipid peroxidation and prevents the oxidation of LDL. Two common polymorphisms in the PON1 gene, the 192 Gln (Q) → Arg (R) and 55 Leu (L) → Met (M) substitutions, determine interindividual variation in PON1 activity. The association of these polymorphisms with the risk of AIS remains controversial. Methods— We analyzed 118 patients (64 women) with a first nonfatal AIS occurring <45 years of age and 118 1:1 age (±2 years)- and sex-matched controls. The PON1 polymorphisms were determined by polymerase chain reaction amplification and restriction digestion. Results— The prevalence of the PON1 192RR genotype (P =0.006) and the frequency of the R allele (P =0.010) were significantly increased among young AIS patients compared with controls. After adjustment for conventional vascular and prothrombotic risk factors, the 192RR genotype remained independently associated with a 4-fold increase in the risk of AIS (odds ratio=4.1; 95% CI, 1.14 to 14.73). Subanalyses stratified by the presence of vascular risk factors and ethnicity did not significantly modify the effect of the PON1 192 polymorphism on AIS risk. No significant differences were found between patients and controls regarding the PON1 55 polymorphism. Conclusions— These findings suggest that the PON 192RR genotype is independently associated with an increased risk of nonfatal AIS among young adults. Further studies are necessary to understand better the mechanistic implications of these observations in the development of AIS in the young.

Differences in memory performance and other clinical characteristics in patients with mesial temporal lobe epilepsy with and without hippocampal atrophy

Mesial temporal lobe epilepsy (MTLE) is usually accompanied by memory deficits due to damage to the hippocampal system. In most studies, however, the influence of hippocampal atrophy (HA) is confounded with other variables, such as: type of initial precipitating injury and pathological substrate, effect of lesion (HA) lateralization, history of febrile seizures, status epilepticus, age of seizure onset, duration of epilepsy, seizure frequency, and antiepileptic drugs (AEDs). To investigate the relationship between memory deficits and these variables, we studied 20 patients with MTLE and signs of HA on MRI and 15 MTLE patients with normal high-resolution MRI. The findings indicated that (1) HA, earlier onset of seizures, longer duration of epilepsy, higher seizure frequency, and AEDs (polytherapy) are associated with memory deficits; and (2) there is a close relationship between deficits of verbal memory and left HA, but not between visual memory and right HA.

Memory and language impairments and their relationships to hippocampal and perirhinal cortex damage in patients with medial temporal lobe epilepsy

Chronic medial temporal lobe epilepsy (MTLE) is associated with memory loss due to damage in the hippocampal system. To investigate the relationship between volume of medial temporal lobe structures and performance on neuropsychological tests, we studied 39 consecutive patients with MTLE and unilateral hippocampal atrophy (HA) determined by volumetric magnetic resonance imaging (MRI). Structures of interest comprised hippocampus, amygdala, and entorhinal, perirhinal, parahippocampal, and temporopolar cortices. The findings indicated that (1) performance was significantly worse in the group with left HA as compared with the group with right HA on general memory, verbal memory, delayed recall, and verbal fluency tests and the Boston Naming Test (BNT), and (2) the volume of the left hippocampus and also the degree of asymmetry of perirhinal cortex volume were significant and independent predictors of performance on general memory, verbal memory, and verbal fluency tests and the BNT in patients with MTLE.

Diagnóstico de doença de Alzheimer no Brasil: critérios diagnósticos e exames complementares. Recomendações do Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia

This panel had the objective of recommending evidence-based guidelines for the clinical diagnosis of Alzheimers disease (AD) in Brazil. Guidelines from other countries and papers on the diagnosis of AD in Brazil were systematically evaluated in a thorough research of PUBMED and LILACS databases. The panel concluded that dementia diagnosis should be based on the DSM criteria and AD diagnosis, on the McKhann et al. criteria (NINCDS-ADRDA). The recommended auxiliary tests are: blood cell count, blood urea nitrogen, serum levels of creatinine, free-tyroxine, thyroid-stimulant hormone, albumin, hepatic enzymes, vitamin B12 and calcium, serological tests for syphilis and, for those aged less than 60 years, serological tests for HIV. Cerebrospinal fluid examination is recommended in special situations. Computed tomography (or preferentially magnetic resonance imaging, when available) is mandatory and has the main objective of excluding other diseases. SPECT and EEG are optional diagnostic methods.

Neuropsychiatric symptoms in Alzheimer's disease are related to functional connectivity alterations in the salience network

Neuropsychiatric syndromes are highly prevalent in Alzheimers disease (AD), but their neurobiology is not completely understood. New methods in functional magnetic resonance imaging, such as intrinsic functional connectivity or “resting‐state” analysis, may help to clarify this issue. Using such approaches, alterations in the default‐mode and salience networks (SNs) have been described in Alzheimers, although their relationship with specific symptoms remains unclear. We therefore carried out resting‐state functional connectivity analysis with 20 patients with mild to moderate AD, and correlated their scores on neuropsychiatric inventory syndromes (apathy, hyperactivity, affective syndrome, and psychosis) with maps of connectivity in the default mode network and SN. In addition, we compared network connectivity in these patients with that in 17 healthy elderly control subjects. All analyses were controlled for gray matter density and other potential confounds. Alzheimers patients showed increased functional connectivity within the SN compared with controls (right anterior cingulate cortex and left medial frontal gyrus), along with reduced functional connectivity in the default‐mode network (bilateral precuneus). A correlation between increased connectivity in anterior cingulate cortex and right insula areas of the SN and hyperactivity syndrome (agitation, irritability, aberrant motor behavior, euphoria, and disinhibition) was found. These findings demonstrate an association between specific network changes in AD and particular neuropsychiatric symptom types. This underlines the potential clinical significance of resting state alterations in future diagnosis and therapy. Hum Brain Mapp 35:1237–1246, 2014.

Cerebral venous thrombosis: influence of risk factors and imaging findings on prognosis.

PURPOSE To investigate imaging findings, risk factors and outcome in patients with cerebral venous thrombosis (CVT). METHODS Records of all patients with diagnosis of CVT between 1992 and 2002 were reviewed. Patients with CNS infection and with CVT secondary to invasive procedures were excluded. Inherited and acquired thrombophilia were searched in all patients. RESULTS Twenty-four patients (18 women, 6 men) with mean age of 29.5 years (range 3-48 years) were identified. Mean follow-up was 44 months (range 11-145 months). The most common symptoms were headache (75%), vomiting (33%) and impairment of consciousness (21%). Probable causes of CVT could be determined in 21 (88%) patients: pregnancy or puerperium in six (25%), oral contraceptive use in four (17%), head trauma in two (8%), mastoiditis in one (4%), nephrotic syndrome in one (4%), systemic disease in three (13%), and inherited thrombotic risk factors in four (17%) patients. CVT associated with pregnancy, puerperium and use of oral contraceptives had a significant better outcome than CVT caused by inherited thrombophilia or systemic disease (OR=14.4; p=0.02). CT scans were abnormal in 15 (62.5%) patients and MRI with gadolinium was abnormal in all. Those with parenchymal involvement had neurological sequelae during follow-up. All were treated with heparin followed by oral anticoagulants, and none had new or worsening of pre-existing intracerebral hemorrhage. CONCLUSION MRI is superior to conventional CT for diagnosing CVT. Patients with parenchymal lesions, thrombophilia and antiphospholipid syndrome had greater risk to be left with neurological sequelae. Anticoagulant therapy did not predispose to further intracerebral hemorrhage.

Extrahippocampal gray matter atrophy and memory impairment in patients with medial temporal lobe epilepsy

Memory impairment observed in patients with medial temporal lobe epilepsy (MTLE) is classically attributed to hippocampal atrophy. The contribution of extrahippocampal structures in shaping memory impairment in patients with MTLE is not yet completely understood, even though atrophy in MTLE extends beyond the hippocampus. We aimed to evaluate the neuropsychological profile of patients with MTLE focusing on memory, and to investigate whether gray matter concentration (GMC) distribution within and outside the medial portion of the temporal lobes would be associated with their neuropsychological performance. We performed a voxel based morphometry study of 36 consecutive patients with MTLE and unilateral hippocampal atrophy. We observed a significant simple regression between general and verbal memory performance based on Wechsler Memory Scale—Revised and the GMC of medial temporal and extratemporal structures in patients with left MTLE. We also performed a “regions of interest analysis” of the medial temporal lobe, and we observed that the GMC of the hippocampus, entorhinal, and perirhinal cortices were consistently associated with general and verbal memory performance in patients with MTLE. We also observed that the GMC of the cingulate and orbito‐frontal cortex are independently associated with verbal and general memory performances. Our results suggest that general and verbal memory impairments in patients with left MTLE are associated with atrophy of the hippocampus, the entorhinal, and the perirhinal cortex. We also suggest that atrophy and dysfunction of limbic and frontal structures such as the cingulate and the orbito‐frontal cortex contribute to memory impairment in MTLE. Hum Brain Mapp 2007.