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1.
BMC Neurol ; 21(1): 459, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34814867

RESUMO

BACKGROUND: Dopamine transporter single-photon emission computed tomography (DaT-SPECT) can quantify the functional integrity of the dopaminergic nerve terminals and has been suggested as an imaging modality to verify the clinical diagnosis of Parkinson's disease (PD). Depending on the stage of progression, approximately 5-15% of participants clinically diagnosed with idiopathic PD have been observed in previous studies to have normal DaT-SPECT patterns. However, the utility of DaT-SPECT in enhancing early PD participant selection in a global, multicenter clinical trial of a potentially disease-modifying therapy is not well understood. METHODS: The SPARK clinical trial was a phase 2 trial of cinpanemab, a monoclonal antibody against alpha-synuclein, in participants with early PD. DaT-SPECT was performed at screening to select participants with DaT-SPECT patterns consistent with degenerative parkinsonism. Acquisition was harmonised across 82 sites. Images were reconstructed and qualitatively read at a central laboratory by blinded neuroradiologists for inclusion prior to automated quantitative analysis. RESULTS: In total, 482 unique participants were screened between January 2018 and May 2019; 3.8% (15/398) of imaged participants were excluded owing to negative DaT-SPECT findings (i.e., scans without evidence of dopaminergic deficit [SWEDD]). CONCLUSION: A smaller proportion of SPARK participants were excluded owing to SWEDD status upon DaT-SPECT screening than has been reported in prior studies. Further research is needed to understand the reasons for the low SWEDD rate in this study and whether these results are generalisable to future studies. If supported, the radiation risks, imaging costs, and operational burden of DaT-SPECT for enrichment may be mitigated by clinical assessment and other study design aspects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03318523 . Date submitted: October 19, 2017. First Posted: October 24, 2017.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Doença de Parkinson , Biomarcadores , Dopamina , Humanos , Doença de Parkinson/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único
2.
J Neurol Neurosurg Psychiatry ; 87(1): 106-12, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25669746

RESUMO

BACKGROUND: Amyloid-related imaging abnormalities due to haemosiderin deposition (ARIA-H) occur in patients with mild to moderate dementia due to Alzheimer's disease (AD) and have been reported with increased incidence in clinical trials of amyloid-lowering therapies under development for AD. OBJECTIVE: Our objective was to explore the relationship between the incidences of ARIA-H during treatment with placebo and different doses of bapineuzumab, a humanised monoclonal antibody directed against amyloid ß. METHODS: Two neuroradiologists independently reviewed 2572 GRE/T2* MRI sequences from 262 participants in two phase two clinical trials of bapineuzumab and an open-label extension study. Readers were blinded to the participant's therapy, APOE ε4 genotype and medical history. RESULTS: Several risk factors for small ARIA-H <10 mm (microhaemorrhages) were identified: APOE ε4, bapineuzumab treatment, pre-existing small ARIA-H and use of antithrombotics. The HR (95%CI) for incident ARIA-H <10 mm associated with the number of APOE ε4 alleles was 11.9 (3.3 to 42.5) for 2 versus no alleles and 3.5 (1.0 to 12.0) for 1 versus no allele. The HR for bapineuzumab therapy was 3.5 (1.0 to 12.0); for the presence of baseline ARIA-H <10 mm, it was 3.5 (1.6 to 7.8), and for the use of antithrombotic agents it was 2.2 (1.0 to 4.8). The incidence rate for ARIA-H <10 mm was elevated only in the initial 6 months of active treatment and declined after this interval to a rate similar to that observed in the group treated with placebo. CONCLUSIONS: ARIA-H represents a spectrum of MRI findings due to haemosiderin deposition that appears to be related to impaired vascular integrity. The increased risk for ARIA-H associated with APOE ε4 allele frequency, pre-existing ARIA-H, treatment with bapineuzumab and use of antithrombotic agents provides additional support for this hypothesis of loss of integrity of cerebral vessels due to amyloid burden. TRIAL REGISTRATION: NCT00112073 and NCT00606476.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Anticorpos Monoclonais Humanizados/uso terapêutico , Hemossiderina/análise , Nootrópicos/uso terapêutico , Placa Amiloide/patologia , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/administração & dosagem , Apolipoproteína E4/sangue , Ensaios Clínicos Fase II como Assunto , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Neuroimagem , Nootrópicos/administração & dosagem , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologia , Substância Branca/patologia
3.
Alzheimer Dis Assoc Disord ; 30(1): 1-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26885819

RESUMO

Amyloid positron emission tomography (PET) imaging is being investigated as a screening tool to identify amyloid-positive patients as an enrichment strategy for Alzheimer disease (AD) clinical trial enrollment. In a multicenter, phase 1b trial, patients meeting clinical criteria for prodromal or mild AD underwent florbetapir PET scanning at screening. PET, magnetic resonance imaging, and coregistered PET/magnetic resonance imaging scans were reviewed by 2 independent readers and binary visual readings tabulated. Semiquantitative values of cortical to whole cerebellar standard uptake value ratios were computed (threshold 1.10). Of 278 patients with an evaluable PET scan, 170 (61%) and 185 (67%) were amyloid-positive by visual reading and quantitative analysis, respectively; 39% were excluded from the study due to an amyloid-negative scan based on visual readings. More ApoE ε4 carriers than noncarriers were amyloid-positive (80% vs. 43%). Comparison of visual readings with quantitative results identified 21 discordant cases (92% agreement). Interreader and intrareader agreements from visual readings were 98% and 100%, respectively. Amyloid PET imaging is an effective and feasible screening tool for enrollment of amyloid-positive patients with early stages of AD into clinical trials.


Assuntos
Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Compostos de Anilina , Anticorpos Monoclonais Humanizados/uso terapêutico , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Encéfalo/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/tratamento farmacológico , Método Duplo-Cego , Etilenoglicóis , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino
4.
Neuroimage ; 71: 224-32, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23353601

RESUMO

BACKGROUND: Quantitative neuroimaging analyses have demonstrated gray and white matter abnormalities in group comparisons of different types of non-lesional partial epilepsy. It is unknown to what degree these type-specific patterns exist in individual patients and if they could be exploited for diagnostic purposes. In this study, a two-level multi-modality imaging Bayesian network approach is proposed that uses information about individual gray matter volume loss and white matter integrity to classify non-lesional temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) mesial-temporal sclerosis and frontal lobe epilepsy (FLE). METHODS: 25 controls, 19 TLE-MTS, 22 TLE-no and 14 FLE were studied on a 4T MRI and T1 weighted structural and DTI images acquired. Spatially normalized gray matter (GM) and fractional anisotropy (FA) abnormality maps (binary maps with voxels 1 SD below control mean) were calculated for each subject. At the first level, each group's abnormality maps were compared with those from all the other groups using Graphical-Model-based Morphometric Analysis (GAMMA). GAMMA uses a Bayesian network and a Markov random field based contextual clustering method to produce maps of voxels that provide the maximal distinction between two groups and calculates a probability distribution and a group assignment based on this information. The information was then combined in a second level Bayesian network and the probability of each subject to belong to one of the three epilepsy types calculated. RESULTS: The specificities of the two level Bayesian network to distinguish between the three patient groups were 0.87 for TLE-MTS and TLE-no and 0.86 for FLE, the corresponding sensitivities were 0.84 for TLE-MTS, 0.72 for TLE-no and 0.64 for FLE. CONCLUSION: The two-level multi-modality Bayesian network approach was able to distinguish between the three epilepsy types with a reasonably high accuracy even though the majority of the images were completely normal on visual inspection.


Assuntos
Mapeamento Encefálico , Epilepsias Parciais/classificação , Interpretação de Imagem Assistida por Computador/métodos , Adulto , Teorema de Bayes , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino
5.
Alzheimers Dement (N Y) ; 9(1): e12377, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36949897

RESUMO

INTRODUCTION: Lecanemab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aß species (protofibrils) with activity at amyloid plaques. Amyloid-related imaging abnormalities (ARIA) profiles appear to differ for various anti-amyloid antibodies. Here, we present ARIA data from a large phase 2 lecanemab trial (Study 201) in early Alzheimer's disease. METHODS: Study 201 trial was double-blind, placebo-controlled (core) with an open-label extension (OLE). Observed ARIA events were summarized and modeled via Kaplan-Meier graphs. An exposure response model was developed. RESULTS: In the phase 2 core and OLE, there was a low incidence of ARIA-E (<10%), with <3% symptomatic cases. ARIA-E was generally asymptomatic, mild-to-moderate in severity, and occurred early (<3 months). ARIA-E was correlated with maximum lecanemab serum concentration and incidence was higher in apolipoprotein E4 (ApoE4) homozygous carriers. ARIA-H and ARIA-E occurred with similar frequency in core and OLE. DISCUSSION: Lecanemab can be administered without titration with modest incidence of ARIA.

6.
Alzheimers Dement (Amst) ; 15(4): e12503, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38026755

RESUMO

INTRODUCTION: Anti-amyloid-ß (Aß) monoclonal antibodies (mAbs) offer the promise of disease modification and are emerging treatment options in Alzheimer's disease. Anti-Aß mAbs require brain magnetic resonance imaging (MRI) examinations to detect anti-amyloid-induced amyloid-related imaging abnormalities (ARIA), important adverse drug reactions associated with some anti-Aß mAbs currently available in the United States and in clinical development. We present a simple rating system for ARIA-edema (ARIA-E) that can assess severity on a 3- or 5-point scale based upon a single linear measurement of the largest area of lesion, and dissemination in space, termed the 3-point Severity Scale of ARIA-E (SSAE-3) and the 5-point Severity Scale of ARIA-E (SSAE-5), respectively. METHODS: MRI results were collected from 75 participants from the SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) studies of gantenerumab. Three neuroradiologists experienced with the detection of ARIA-E were selected to read all cases independently. One rater was then chosen for a second read to assess intra-reader reproducibility. RESULTS: The three raters had high agreement in identifying and grading ARIA-E. The Cohen/Fleiss kappa (κ) scores (95% confidence interval [CI]) for the inter- and intra-reader comparisons for SSAE-3 and SSAE-5 were 0.79 (0.70-1.00), 0.94 (0.94-1.00), 0.73 (0.66-1.00), and 0.90 (0.90-1.00), respectively. DISCUSSION: Our study suggests that SSAE-3 and SSAE-5 are valid ARIA-E rating scales for use in routine clinical practice by experienced radiologists in specialized settings. The application of these scales in everyday use in clinical practice will support the expansion of anti-Aß mAbs as a treatment option for people living with Alzheimer's disease. Highlights: A simple rating scale is needed to rate severity of amyloid-related imaging abnormalities-edema (ARIA-E) in both research and clinical settings.The 3- and 5-point Severity Scales of ARIA-E (SSAE-3/-5) have good inter- and intra-reader agreement.The SSAE-3/-5 have been used in most major Alzheimer's disease (AD) trials to date and are suitable for large-scale use in routine clinical practice, which may help support the expansion of anti-amyloid antibodies as treatment options for AD.

7.
Alzheimers Dement (N Y) ; 9(1): e12372, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36873926

RESUMO

Background: The positron emission tomography (PET) radiotracer [18F]MK-6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within-brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK-6240 use to identify and stage AD subjects versus non-AD and controls. Methods: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter-reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30-scan set, providing initial validation. Inter-rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. Results: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter-rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131-scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. Discussion: This four-class [18F]MK-6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. Highlights: A visual read method has been developed for [18F]MK-6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter-rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK-6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature.

8.
Alzheimers Dement (Amst) ; 14(1): e12376, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36474747

RESUMO

Introduction: Amyloid-related imaging abnormalities-edema (ARIA-E) is associated with anti-amyloid beta monoclonal antibody treatment. ARIA-E severity may be assessed using the Barkhof Grand Total Scale (BGTS) or the 3- or 5-point Severity Scales of ARIA-E (SSAE-3/SSAE-5). We assessed inter- and intra-reader correlations between SSAE-3/5 and BGTS. Methods: Magnetic resonance imaging scans were collected from 75 participants in the SCarlet RoAD and Marguerite RoAD studies. Three neuroradiologists reviewed scans at baseline and at follow-up. Concordance in dichotomized ARIA-E ratings was assessed for a range of BGTS thresholds. Results: SSAE-3/5 scores correlated with BGTS scores, with high inter-reader intraclass correlation coefficients across all scales. There was high agreement in dichotomized ratings for SSAE-3 > 1 versus BGTS > 3 for all readers (accuracy 0.85-0.93) and between pairs of readers. Discussion: SSAE-3/5 showed high degrees of correlation with BGTS, potentially allowing seamless transition from the BGTS to SSAE-3/5 for ARIA-E management.

9.
JAMA Neurol ; 79(1): 13-21, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34807243

RESUMO

Importance: The EMERGE and ENGAGE phase 3 randomized clinical trials of aducanumab provide a robust data set to characterize amyloid-related imaging abnormalities (ARIA) that occur with treatment with aducanumab, an amyloid-ß (Aß)-targeting monoclonal antibody, in patients with mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia. Objective: To describe the radiographic and clinical characteristics of ARIA that occurred in EMERGE and ENGAGE. Design, Setting, and Participants: Secondary analysis of data from the EMERGE and ENGAGE trials, which were 2 double-blind, placebo-controlled, parallel-group, phase 3 randomized clinical trials that compared low-dose and high-dose aducanumab treatment with placebo among participants at 348 sites across 20 countries. Enrollment occurred from August 2015 to July 2018, and the trials were terminated early (March 21, 2019) based on a futility analysis. The combined studies consisted of a total of 3285 participants with Alzheimer disease who received 1 or more doses of placebo (n = 1087) or aducanumab (n = 2198; 2752 total person-years of exposure) during the placebo-controlled period. Primary data analyses were performed from November 2019 to July 2020, with additional analyses performed through July 2021. Interventions: Participants were randomly assigned 1:1:1 to high-dose or low-dose intravenous aducanumab or placebo once every 4 weeks. Dose titration was used as a risk-minimization strategy. Main Outcomes and Measures: Brain magnetic resonance imaging was used to monitor patients for ARIA; associated symptoms were reported as adverse events. Results: Of 3285 included participants, the mean (SD) age was 70.4 (7.45) years; 1706 participants (52%) were female, 2661 (81%) had mild cognitive impairment due to Alzheimer disease, and 1777 (54%) used symptomatic medications for Alzheimer disease. A total of 764 participants from EMERGE and 709 participants from ENGAGE were categorized as withdrawn before study completion, most often owing to early termination of the study by the sponsor. Unless otherwise specified, all results represent analyses from the 10-mg/kg group. During the placebo-controlled period, 425 of 1029 patients (41.3%) experienced ARIA, with serious cases occurring in 14 patients (1.4%). ARIA-edema (ARIA-E) was the most common adverse event (362 of 1029 [35.2%]), and 263 initial events (72.7%) occurred within the first 8 doses of aducanumab; 94 participants (26.0%) with an event exhibited symptoms. Common associated symptoms among 103 patients with symptomatic ARIA-E or ARIA-H were headache (48 [46.6%]), confusion (15 [14.6%]), dizziness (11 [10.7%]), and nausea (8 [7.8%]). Incidence of ARIA-E was highest in aducanumab-treated participants who were apolipoprotein E ε4 allele carriers. Most events (479 of 488 [98.2%]) among those with ARIA-E resolved radiographically; 404 of 488 (82.8%) resolved within 16 weeks. In the placebo group, 29 of 1076 participants (2.7%) had ARIA-E (apolipoprotein E ε4 carriers: 16 of 742 [2.2%]; noncarriers, 13 of 334 [3.9%]). ARIA-microhemorrhage and ARIA-superficial siderosis occurred in 197 participants (19.1%) and 151 participants (14.7%), respectively. Conclusions and Relevance: In this integrated safety data set from EMERGE and ENGAGE, the most common adverse event in the 10-mg/kg group was ARIA-E, which occurred in 362 of the 1029 patients (35.2%) in the 10-mg/kg group with at least 1 postbaseline MRI scan, with 94 patients (26.0%) experiencing associated symptoms. The most common associated symptom was headache. Trial Registrations: ClinicalTrials.gov Identifiers: NCT02484547, NCT02477800.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Idoso , Doença de Alzheimer/patologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Resultado do Tratamento
11.
Alzheimers Dement ; 7(4): 396-401, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21784350

RESUMO

BACKGROUND: Cerebral vasogenic edema (VE) has been reported to occur during antiamyloid immunotherapy. VE may be associated with central nervous system pathology with blood-brain barrier disruptions; however, less is known about the prevalence of naturally occurring VE in patients with Alzheimer's disease (AD). METHODS: Fluid-attenuated inversion recovery imaging sequences were obtained from four ongoing multicenter, randomized, double-blind, placebo-controlled, phase 3 trials in patients with mild-to-moderate AD. The first set of baseline scans was from patients in volumetric magnetic resonance imaging addenda in the Interrupting Alzheimer's Dementia by EvaluatiNg Treatment of Amyloid PaThologY (IDENTITY) studies examining semagacestat, a γ-secretase inhibitor (cohort 1, n = 621). The second set of baseline scans was from the EXPanding alzhEimer's Disease InvestigaTIONs (EXPEDITION) studies examining solanezumab, an anti-Aß monoclonal antibody (cohort 2, n = 2141). Readers were blinded to patient-identifying information and future treatment. A third set of baseline scans was from the first 700 patients who underwent protocol-specified magnetic resonance imaging before randomization in the EXPEDITION studies (cohort 3). The analysis used three neuroradiologists: two performed independent primary interpretations and the third was the adjudicator. Readers were blinded to patient information, treatment, protocol, and time point. RESULTS: Four cases of asymptomatic VE were detected at baseline/screening. Two VE cases were due to underlying extra-axial mass lesions. The third VE case was associated with numerous microhemorrhages in keeping with cerebral amyloid angiopathy-related inflammation or Aß-related angiitis. The final VE case demonstrated localized sulcal fluid-attenuated inversion recovery imaging hyperintensity. No VE was detected in cohort 3 by readers blinded to patient baseline status. CONCLUSIONS: VE seems to be rare at baseline in patients with AD in clinical trials, 2 of 2,762 associated with AD. Additional cohorts should be evaluated to support these findings.


Assuntos
Alanina/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Azepinas/uso terapêutico , Edema Encefálico/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Alanina/uso terapêutico , Doença de Alzheimer/complicações , Doença de Alzheimer/epidemiologia , Edema Encefálico/epidemiologia , Edema Encefálico/etiologia , Estudos de Coortes , Método Duplo-Cego , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Escalas de Graduação Psiquiátrica
12.
Epilepsia ; 51(8): 1436-45, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20002143

RESUMO

PURPOSE: The thalamus plays an important role in seizure propagation in temporal lobe epilepsy (TLE). This study investigated how structural abnormalities in the focus, ipsilateral thalamus and extrafocal cortical structures relate to each other in TLE with mesiotemporal sclerosis (TLE-MTS) and without hippocampal sclerosis (TLE-no). METHODS: T1 and high-resolution T2 images were acquired on a 4T magnet in 29 controls, 15 TLE-MTS cases, and 14 TLE-no. Thalamus volumes were obtained by warping a labeled atlas onto each subject's brain. Deformation-based morphometry was used to identify regions of thalamic volume loss and FreeSurfer for cortical thickness measurements. CA1 volumes were obtained from high-resolution T2 images. Multiple regression analysis and correlation analyses for voxel- and vertex-based analyses were performed in SPM2 and FreeSurfer. RESULTS: TLE-MTS had bilateral volume loss in the anterior thalamus, which was correlated with CA1 volume and cortical thinning in the mesiotemporal lobe. TLE-no had less severe volume loss in the dorsal lateral nucleus, which was correlated with thinning in the mesiotemporal region but not with extratemporal thinning. DISCUSSION: The findings suggest that seizure propagation from the presumed epileptogenic focus or regions close to it into the thalamus occurs in TLE-MTS and TLE-no and results in circumscribed neuronal loss in the thalamus. However, seizure spread beyond the thalamus seems not to be responsible for the extensive extratemporal cortical abnormalities in TLE.


Assuntos
Córtex Cerebral/patologia , Epilepsia do Lobo Temporal/patologia , Tálamo/patologia , Adulto , Mapeamento Encefálico , Epilepsia do Lobo Temporal/complicações , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Vias Neurais/patologia , Esclerose/complicações , Esclerose/patologia , Adulto Jovem
13.
Alcohol Clin Exp Res ; 34(1): 175-82, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19860794

RESUMO

BACKGROUND: We previously demonstrated, in a small sample, steeper age-related gray matter shrinkage in treatment naïve alcohol-dependent (TxN) men compared to nonalcoholic controls, but could not separate out the contributions of age and lifetime duration of alcohol use (which were highly correlated) to this effect. In the current study, we have quadrupled the sample size and expanded it to include both men and women to try to replicate and extend the previous findings and to separate the contributions of age and alcohol use to the phenomenon. METHODS: In the current study, we examine cortical gray matter volumes in 18- to 50-year-old TxN (n = 84) versus age and gender comparable controls (n = 67). We used a new Region of Interest Analysis method which accounts for differences in sulcal and gyral enfolding between individuals (Fein et al., 2009a). RESULTS: We found greater age-related gray matter shrinkage in TxN than in controls. Partial correlation analysis showed that the effect was a function of age and not lifetime alcohol burden. CONCLUSIONS: Implications of the findings are discussed in terms of their contribution toward our knowledge of differences between different subpopulations of alcoholics and in terms of their implications for the morbidity of alcohol dependence in an aging national population.


Assuntos
Envelhecimento/patologia , Consumo de Bebidas Alcoólicas/patologia , Alcoolismo/patologia , Córtex Cerebral/patologia , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Alcoolismo/epidemiologia , Atrofia/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Dis Aquat Organ ; 91(3): 243-56, 2010 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-21133324

RESUMO

Our goal in this study was to compare magnetic resonance images and volumes of brain structures obtained alive versus postmortem of California sea lions Zalophus californianus exhibiting clinical signs of domoic acid (DA) toxicosis and those exhibiting normal behavior. Proton density-(PD) and T2-weighted images of postmortem-intact brains, up to 48 h after death, provided similar quality to images acquired from live sea lions. Volumes of gray matter (GM) and white matter (WM) of the cerebral hemispheres were similar to volumes calculated from images acquired when the sea lions were alive. However, cerebrospinal fluid (CSF) volumes decreased due to leakage. Hippocampal volumes from postmortem-intact images were useful for diagnosing unilateral and bilateral atrophy, consequences of DA toxicosis. These volumes were similar to the volumes in the live sea lion studies, up to 48 h postmortem. Imaging formalin-fixed brains provided some information on brain structure; however, images of the hippocampus and surrounding structures were of poorer quality compared to the images acquired alive and postmortem-intact. Despite these issues, volumes of cerebral GM and WM, as well as the hippocampus, were similar to volumes calculated from images of live sea lions and sufficient to diagnose hippocampal atrophy. Thus, postmortem MRI scanning (either intact or formalin-fixed) with volumetric analysis can be used to investigate the acute, chronic and possible developmental effects of DA on the brain of California sea lions.


Assuntos
Encefalopatias/veterinária , Encéfalo/anatomia & histologia , Ácido Caínico/análogos & derivados , Toxinas Marinhas/toxicidade , Leões-Marinhos , Animais , Encéfalo/patologia , Encefalopatias/induzido quimicamente , Encefalopatias/patologia , Ácido Caínico/toxicidade , Imageamento por Ressonância Magnética
17.
Epilepsia ; 50(6): 1474-83, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19400880

RESUMO

PURPOSE: High-resolution magnetic resonance imaging (MRI) at 4 Tesla depicts details of the internal structure of the hippocampus not visible at 1.5 Tesla, and so allows for in vivo parcellation of different hippocampal subfields. The aim of this study was to test if distinct subfield atrophy patterns can be detected in temporal lobe epilepsy (TLE) with mesial temporal sclerosis (TLE-MTS) and without (TLE-no) hippocampal sclerosis. METHODS: High-resolution T(2)-weighted hippocampal images were acquired in 34 controls: 15 TLE-MTS and 18 TLE-no. Entorhinal cortex (ERC), subiculum (SUB), CA1, CA2, and CA3, and dentate (CA3&DG) volumes were determined using a manual parcellation scheme. RESULTS: TLE-MTS had significantly smaller ipsilateral CA1, CA2, CA3&DG, and total hippocampal volume than controls or TLE-no. Mean ipsilateral CA1 and CA3&DG z-scores were significantly lower than ipsilateral CA2, ERC, and SUB z-scores. There were no significant differences between the various subfield or hippocampal z-scores on either the ipsi- or the contralateral side in TLE-no. Using a z-score

Assuntos
Epilepsia do Lobo Temporal/patologia , Hipocampo/patologia , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Adulto , Atrofia/patologia , Epilepsia do Lobo Temporal/classificação , Epilepsia do Lobo Temporal/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Esclerose/patologia , Adulto Jovem
18.
Alcohol Clin Exp Res ; 33(10): 1806-14, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19645730

RESUMO

BACKGROUND: We previously demonstrated relatively intact cognitive function (with the exception of suggestive evidence for persistent deficits in spatial information processing) in middle-aged long-term abstinent alcoholics (LTAA, abstinent for 6 months or more) compared to age and gender comparable nonalcoholic controls (NAC) (Fein et al., 2006). METHODS: In the current study, we examine cortical gray matter volumes in the same samples to determine whether gray matter volumes in LTAA are consistent with the cognitive results--i.e., exhibiting gray matter volumes comparable to NAC in most brain regions, except for possible indications of persistent shrinkage in the parietal lobe subserving spatial information processing. RESULTS: We found gray matter shrinkage in LTAA in the parietal lobe consistent with the spatial processing deficits in this same sample. More compelling, in LTAA, the magnitude of parietal gray matter shrinkage was negatively associated with spatial processing domain performance and positively associated with alcohol dose. Gray matter volume deficits were present in the occipital and other cortical tissue, but poorer visuospatial test performance correlated significantly with smaller volumes in the parietal cortex only. CONCLUSIONS: Taken together, the cognitive and structural imaging data provide compelling evidence that chronic alcohol abuse results in shrinkage of the parietal cortex with associated deficits in spatial information processing.


Assuntos
Alcoolismo/patologia , Alcoolismo/psicologia , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Lobo Parietal/patologia , Percepção Espacial/efeitos dos fármacos , Adulto , Cognição/efeitos dos fármacos , Feminino , Lobo Frontal/patologia , Cabeça/anatomia & histologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Desempenho Psicomotor/efeitos dos fármacos , Temperança
19.
Alcohol Clin Exp Res ; 33(1): 70-8, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18976350

RESUMO

BACKGROUND: The harmful effects of alcohol dependence on brain structure and function have been well documented, with many resolving with sufficient abstinence. White matter signal hyperintensities (WMSH) are thought to most likely be consequences secondary to the vascular (i.e., hypertension and atherosclerosis) effects of AD. We hypothesized that such effects would persist into long-term abstinence, and evaluated them in middle-aged long-term abstinent alcoholics (LTAA) compared with age and gender comparable nonalcoholic controls (NAC). METHODS: Ninety-seven participants (51 LTAA and 46 NAC) underwent cognitive, psychiatric, and structural brain magnetic resonance image evaluations. WMSH were identified and labeled as deep or periventricular by an automated algorithm developed in-house. WMSH volumes were compared between groups, and the associations of WMSH measures with demographic, alcohol use, psychiatric, and cognitive measures were examined within group. RESULTS: Long-term abstinent alcoholics had more WMSH than NAC. There was a significant group by age interaction, with WMSH increasing with age in LTAA, but not in NAC. Within LTAA, WMSH load was independently positively associated with alcohol burden and with age. No associations were evident between WMSH volumes and abstinence duration, family drinking history, years of education, or psychiatric or cognitive variables. CONCLUSION: The magnitude of alcohol abuse was related to increased WMSH volume. The presence of an age effect in the LTAA but not the controls indicates a synergistic effect wherein alcohol advances the onset of aging-related WMSH formation. The increased WMSH load did not appear to have any significant clinical correlates, indicating that the white matter lesions in our sample may not have been severe enough to manifest as cognitive deficits. A limitation of the study is that we did not have data on the presence or severity of lifetime or current indices of vascular risk factors such as hypertension, smoking, or diabetes.


Assuntos
Alcoolismo/patologia , Alcoolismo/psicologia , Imageamento por Ressonância Magnética , Fibras Nervosas Mielinizadas/patologia , Temperança/psicologia , Adulto , Alcoolismo/diagnóstico , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
20.
Alzheimers Dement (Amst) ; 2: 75-85, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27239538

RESUMO

INTRODUCTION: Solanezumab, a humanized monoclonal antibody that binds soluble amyloid beta peptide, is being developed for treatment of Alzheimer's disease (AD). METHODS: Patients (n = 2042) with mild and moderate AD were randomized 1:1 to 400-mg solanezumab or placebo infusion every 4 weeks for 80 weeks and 1457 patients entered an open-label extension. Magnetic resonance imaging scans monitored for amyloid-related imaging abnormalities-edema/effusion (ARIA-E) and amyloid-related imaging abnormalities-hemorrhage/hemosiderin deposition. RESULTS: Sixteen patients (solanezumab, n = 11; placebo, n = 5) developed ARIA-E during the double-blind phase, and 7 patients developed ARIA-E during the open-label extension as of July 31, 2014. Unique cases are discussed including solanezumab patients who were given solanezumab, while ARIA-E was present and a patient who developed ARIA-E during placebo treatment and again during solanezumab treatment. DISCUSSION: Asymptomatic ARIA-E was detected in solanezumab-treated and placebo-treated AD patients. ARIA-E occurs infrequently during solanezumab and placebo treatments but may occur repeatedly in some patients.

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