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PURPOSE: Neuropathological studies have demonstrated distinct profiles of microglia activation and myelin injury among different multiple sclerosis (MS) phenotypes and disability stages. PET imaging using specific tracers may uncover the in vivo molecular pathology and broaden the understanding of the disease heterogeneity. METHODS: We used the 18-kDa translocator protein (TSPO) tracer (R)-[11C]PK11195 and [11C]PIB PET images acquired in a hybrid PET/MR 3 T system to characterize, respectively, the profile of innate immune cells and myelin content in 47 patients with MS compared to 18 healthy controls (HC). For the volume of interest (VOI)-based analysis of the dynamic data, (R)-[11C]PK11195 distribution volume (VT) was determined for each subject using a metabolite-corrected arterial plasma input function while [11C]PIB distribution volume ratio (DVR) was estimated using a reference region extracted by a supervised clustering algorithm. A voxel-based analysis was also performed using Statistical Parametric Mapping. Functional disability was evaluated by the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Symbol Digit Modality Test (SDMT). RESULTS: In the VOI-based analysis, [11C]PIB DVR differed between patients and HC in the corpus callosum (P = 0.019) while no differences in (R)-[11C]PK11195 VT were observed in patients relative to HC. Furthermore, no correlations or associations were observed between both tracers within the VOI analyzed. In the voxel-based analysis, high (R)-[11C]PK11195 uptake was observed diffusively in the white matter (WM) when comparing the progressive phenotype and HC, and lower [11C]PIB uptake was observed in certain WM regions when comparing the relapsing-remitting phenotype and HC. None of the tracers were able to differentiate phenotypes at voxel or VOI level in our cohort. Linear regression models adjusted for age, sex, and phenotype demonstrated that higher EDSS was associated with an increased (R)-[11C]PK11195 VT and lower [11C]PIB DVR in corpus callosum (P = 0.001; P = 0.023), caudate (P = 0.015; P = 0.008), and total T2 lesion (P = 0.007; P = 0.012), while better cognitive scores in SDMT were associated with higher [11C]PIB DVR in the corpus callosum (P = 0.001), and lower (R)-[11C]PK11195 VT (P = 0.013). CONCLUSIONS: Widespread innate immune cells profile and marked loss of myelin in T2 lesions and regions close to the ventricles may occur independently and are associated with disability, in both WM and GM structures.
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Esclerose Múltipla , Humanos , Esclerose Múltipla/metabolismo , Bainha de Mielina/patologia , Tomografia Computadorizada por Raios X , Tomografia por Emissão de Pósitrons/métodos , Imunidade Inata , Imageamento por Ressonância Magnética/métodos , Encéfalo/metabolismo , Receptores de GABA/metabolismoRESUMO
INTRODUCTION: Neuroimaging studies have shown callosal abnormalities among maltreated subjects, but little is known about the functional and neurobiological correlates of these supposed developmental alterations. The aim of this study was to investigate childhood maltreatment (CM), neurocognitive functioning, cortisol levels, and corpus callosum (CC) integrity among adolescents. METHODS: One hundred and seven subjects underwent magnetic resonance imaging (MRI) with voxel-based diffusion-tensor imaging (DTI) and the Crossed Finger Localization Test (CFLT). Psychopathology was investigated with the Schedule for Affective Disorders and Schizophrenia (K-SADS-PL); CM was detailed by the Childhood Trauma Questionnaire (CTQ), and salivary cortisol levels were measured by immunoassay. RESULTS: Higher levels of CM were associated with current lower CFLT scores, mainly in the CROSSED condition, involving interhemispheric communication of sensorimotor information (p < .05) and with reduced fractional anisotropy (FA) in the splenium of the CC (p < .01). Deficits in the CFLT were also associated with higher cortisol levels (p < .05). CONCLUSION: The association among CM, neuropsychological abnormalities, callosal microstructure alterations, and cortisol levels suggests an altered pattern of brain interhemispheric connectivity among maltreated adolescents. Further studies are needed to investigate the extent to which these sensorimotor deficits and abnormal cortisol levels may be possible mediators of negative neurodevelopmental trajectories and adult psychopathology.
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Imagem de Tensor de Difusão , Hidrocortisona , Adolescente , Adulto , Anisotropia , Corpo Caloso/diagnóstico por imagem , Humanos , Imageamento por Ressonância MagnéticaRESUMO
OBJECTIVES: Although a large number of studies have shown brain volumetric differences between men and women, only a few investigations have analyzed brain tissue volumes in representative samples of the general elderly population. We investigated differences in gray matter (GM) volumes, white matter (WM) volumes, and intracranial volumes (ICVs) between the sexes in individuals older than 66 years using structural magnetic resonance imaging (MRI). METHODS: Using FreeSurfer version 5.3, we obtained the ICVs and GM and WM volumes from the MRI datasets of 84 men and 92 women. To correct for interindividual variations in ICV, GM and WM volumes were adjusted with a method using the residuals of a least-square-derived linear regression between raw volumes and ICVs. We then performed an analysis of covariance comparing men and women, including age and years of schooling as confounding factors. RESULTS: Women had a lower socioeconomic status overall and fewer years of schooling than men. The comparison of unadjusted brain volumes showed larger GM and WM volumes in men. After the ICV correction, the adjusted volumes of GM and WM were larger in women. CONCLUSION: After the ICV correction and taking into account differences in socioeconomic status and years of schooling, our results confirm previous findings of proportionally larger GM in women, as well as larger WM volumes. These results in an elderly population indicate that brain volumetric differences between sexes persist throughout the aging process. Additional studies combining MRI and other biomarkers to identify the hormonal and molecular bases influencing such differences are warranted.
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Encéfalo , Substância Branca , Idoso , Encéfalo/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Modelos Lineares , Imageamento por Ressonância Magnética , MasculinoRESUMO
OBJECTIVES: Although a large number of studies have shown brain volumetric differences between men and women, only a few investigations have analyzed brain tissue volumes in representative samples of the general elderly population. We investigated differences in gray matter (GM) volumes, white matter (WM) volumes, and intracranial volumes (ICVs) between the sexes in individuals older than 66 years using structural magnetic resonance imaging (MRI). METHODS: Using FreeSurfer version 5.3, we obtained the ICVs and GM and WM volumes from the MRI datasets of 84 men and 92 women. To correct for interindividual variations in ICV, GM and WM volumes were adjusted with a method using the residuals of a least-square-derived linear regression between raw volumes and ICVs. We then performed an analysis of covariance comparing men and women, including age and years of schooling as confounding factors. RESULTS: Women had a lower socioeconomic status overall and fewer years of schooling than men. The comparison of unadjusted brain volumes showed larger GM and WM volumes in men. After the ICV correction, the adjusted volumes of GM and WM were larger in women. CONCLUSION: After the ICV correction and taking into account differences in socioeconomic status and years of schooling, our results confirm previous findings of proportionally larger GM in women, as well as larger WM volumes. These results in an elderly population indicate that brain volumetric differences between sexes persist throughout the aging process. Additional studies combining MRI and other biomarkers to identify the hormonal and molecular bases influencing such differences are warranted.
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Humanos , Masculino , Feminino , Idoso , Encéfalo/diagnóstico por imagem , Substância Branca , Imageamento por Ressonância Magnética , Modelos Lineares , Substância Cinzenta/diagnóstico por imagemRESUMO
BACKGROUND: Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system. Its diagnosis is clinical, often confirmed by magnetic resonance imaging. This image modality, however, is not ideal for discrimination of demyelination in grey and white matter regions from inflammatory lesions. Positron Emission Tomography (PET), using specific radiopharmaceuticals, can be a tool to differentiate between these processes. The radiopharmaceutical [11C]PIB is widely used for detection of ß-amyloid plaques, but has also been suggested for the analysis of myelin content due to its consistent uptake in white matter. The aim of this study was to evaluate [11C]PIB PET imaging as a tool for detecting demyelinated regions in white and grey matter of non-human primate model of progressive MS. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in marmosets by injection of recombinant human myelin oligodendrocyte glycoprotein (rhMOG) emulsified in either Incomplete Freund's Adjuvant (IFA) or Complete Freund's Adjuvant (CFA). [11C]PIB PET images were acquired prior to immunization (baseline) and after symptoms were present (end of experiment). Brain tissue was isolated for histochemical analysis. RESULTS: All rhMOG/IFA-treated and rhMOG/CFA-treated animals showed clinical signs of EAE. The rhMOG/CFA group presented a significant [11C]PIB uptake reduction only in the left motor cortex (9%, Pâ¯=â¯0.011). For the rhMOG/IFA group, significant decrease in [11C]PIB uptake was observed in the whole brain (15%, Pâ¯=â¯0.015), in the right hemisphere of body of corpus callosum (34%, Pâ¯=â¯0.02), splenium of corpus callosum (38%, Pâ¯=â¯0.004), hippocampus (19%, Pâ¯=â¯0.036), optic tract (13%, Pâ¯=â¯0.025), thalamus (14%, Pâ¯=â¯0.041), Globus pallidus (23%, Pâ¯=â¯0.017), head of caudate nucleus (25%, Pâ¯=â¯0.045), tail of caudate nucleus (29%, Pâ¯=â¯0.003), putamen (28%, Pâ¯=â¯0.047) and left hemisphere of body of corpus callosum (14%, Pâ¯=â¯0.037) and head of caudate nucleus (23%, Pâ¯=â¯0.023). [11C]PIB uptake significantly correlated with luxol fast blue histology (myelin marker), both in the rhMOG/IFA (r2= 0.32, P < 0.0001) and the rhMOG/CFA group (r2= 0.46, P < 0.0001). CONCLUSION: [11C]PIB PET imaging is an efficient tool for detecting demyelination in grey and white matter, in a non-human primate model of progressive MS.
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Compostos de Anilina , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Tiazóis , Substância Branca/diagnóstico por imagem , Animais , Callithrix , Modelos Animais de Doenças , Feminino , Masculino , Tomografia por Emissão de PósitronsRESUMO
Background: Mnemonic strategy training (MST) has been shown to improve cognitive performance in amnestic mild cognitive impairment (a-MCI), however, several questions remain unresolved. The goal of the present study was to replicate earlier pilot study findings using a randomized controlled design and to evaluate transfer effects and changes in brain activation. Methods: Thirty patients with a-MCI were randomized into MST or education program. At baseline, participants completed clinical and neuropsychological assessments as well as structural and functional magnetic resonance imaging (fMRI). Interventions were administered individually and comprised four sessions, over 2 weeks. MST taught patients to use a three-step process to learn and recall face-name associations. Post-treatment assessment included fMRI, a separate face-name association task, neuropsychological tests, and measures of metamemory. Behavioral (i.e., non-fMRI) measures were repeated after one and 3-months. Results: Participants in the MST condition showed greater improvement on measures of face-name memory, and increased associative strategy use; effects that were accompanied by increased fMRI activation in the left anterior temporal lobe. While all participants reported greater contentment with their everyday memory following intervention, only the MST group reported significant improvements in their memory abilities. There was no clear indication of far-transfer effects to other neuropsychological tests. Conclusion: Results demonstrate that patients with a-MCI not only show stimulus specific benefits of MST, but that they appear capable of transferring training to at least some other cognitive tasks. MST also facilitated the use of brain regions that are involved in face processing, episodic and semantic memory, and social cognition, which are consonant with the cognitive processes engaged by training.
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Background: White matter (WM) structural changes, particularly affecting the corpus callosum (CC), seem to be critically implicated in psychosis. Whether such abnormalities are progressive or static is still a matter of debate in schizophrenia research. Aberrant maturation processes might also influence the longitudinal trajectory of age-related CC changes in schizophrenia patients. We investigated whether patients with first-episode schizophrenia-related psychoses (FESZ) would present longitudinal CC and whole WM volume changes over the 5â¯years after disease onset. Method: Thirty-two FESZ patients and 34 controls recruited using a population-based design completed a 5-year assessment protocol, including structural MRI scanning at baseline and follow-up. The linear effects of disease duration, clinical outcome and antipsychotic (AP) use over time on WM and CC volumes were studied using both voxelwise and volume-based morphometry analyses. We also examined maturation/aging abnormalities through cross-sectional analyses of age-related trajectories of total WM and CC volume changes. Results: No interaction between diagnosis and time was observed, and clinical outcome did not influence CC volumes in patients. On the other hand, FESZ patients continuously exposed to AP medication showed volume increase over time in posterior CC. Curve-estimation analyses revealed a different aging pattern in FESZ patients versus controls: while patients displayed a linear decline of total WM and anterior CC volumes with age, a non-linear trajectory of total WM and relative preservation of CC volumes were observed in controls. Conclusions: Continuous AP exposure can influence CC morphology during the first years after schizophrenia onset. Schizophrenia is associated with an abnormal pattern of total WM and anterior CC aging during non-elderly adulthood, and this adds complexity to the discussion on the static or progressive nature of structural abnormalities in psychosis.
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Antipsicóticos/uso terapêutico , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/patologia , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Masculino , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/patologia , Esquizofrenia/diagnósticoRESUMO
OBJECTIVE:: Using magnetic resonance imaging, we aimed to assess the presence of silent brain vascular lesions in a sample of apparently healthy elderly individuals who were recruited from an economically disadvantaged urban region (São Paulo, Brazil). We also wished to investigate whether the findings were associated with worse cognitive performance. METHODS:: A sample of 250 elderly subjects (66-75 years) without dementia or neuropsychiatric disorders were recruited from predefined census sectors of an economically disadvantaged area of Sao Paulo and received structural magnetic resonance imaging scans and cognitive testing. A high proportion of individuals had very low levels of education (4 years or less, n=185; 21 with no formal education). RESULTS:: The prevalence of at least one silent vascular-related cortical or subcortical lesion was 22.8% (95% confidence interval, 17.7-28.5), and the basal ganglia was the most frequently affected site (63.14% of cases). The subgroup with brain infarcts presented significantly lower levels of education than the subgroup with no brain lesions as well as significantly worse current performance in cognitive test domains, including memory and attention (p<0.002). CONCLUSIONS:: Silent brain infarcts were present at a substantially high frequency in our elderly sample from an economically disadvantaged urban region and were significantly more prevalent in subjects with lower levels of education. Covert cerebrovascular disease significantly contributes to cognitive deficits, and in the absence of magnetic resonance imaging data, this cognitive impairment may be considered simply related to ageing. Emphatic attention should be paid to potentially deleterious effects of vascular brain lesions in poorly educated elderly individuals from economically disadvantaged environments.
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Doenças Assintomáticas/epidemiologia , Infarto Encefálico/complicações , Infarto Encefálico/epidemiologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Fatores Etários , Idoso , Análise de Variância , Infarto Encefálico/fisiopatologia , Brasil/epidemiologia , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Testes de Inteligência , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Prevalência , Escalas de Graduação Psiquiátrica , Valores de Referência , Medição de Risco , Fatores de Risco , Fatores SocioeconômicosRESUMO
BACKGROUND: Structural brain abnormalities in schizophrenia have been repeatedly demonstrated in magnetic resonance imaging (MRI) studies, but it remains unclear whether these are static or progressive in nature. While longitudinal MRI studies have been traditionally used to assess the issue of progression of brain abnormalities in schizophrenia, information from cross-sectional neuroimaging studies directly comparing first-episode and chronic schizophrenia patients to healthy controls may also be useful to further clarify this issue. With the recent interest in multisite mega-analyses combining structural MRI data from multiple centers aiming at increased statistical power, the present multisite voxel-based morphometry (VBM) study was carried out to examine patterns of brain structural changes according to the different stages of illness and to ascertain which (if any) of such structural abnormalities would be specifically correlated to potential clinical moderators, including cumulative exposure to antipsychotics, age of onset, illness duration and overall illness severity. METHODS: We gathered a large sample of schizophrenia patients (161, being 99 chronic and 62 first-episode) and controls (151) from four previous morphometric MRI studies (1.5 T) carried out in the same geographical region of Brazil. Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8) software with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. Group effects on regional gray matter (GM) volumes were investigated through whole-brain voxel-wise comparisons using General Linear Model Analysis of Co-variance (ANCOVA), always including total GM volume, scan protocol, age and gender as nuisance variables. Finally, correlation analyses were performed between the aforementioned clinical moderators and regional and global brain volumes. RESULTS: First-episode schizophrenia subjects displayed subtle volumetric deficits relative to controls in a circumscribed brain regional network identified only in small volume-corrected (SVC) analyses (p < 0.05, FWE-corrected), including the insula, temporolimbic structures and striatum. Chronic schizophrenia patients, on the other hand, demonstrated an extensive pattern of regional GM volume decreases relative to controls, involving bilateral superior, inferior and orbital frontal cortices, right middle frontal cortex, bilateral anterior cingulate cortices, bilateral insulae and right superior and middle temporal cortices (p < 0.05, FWE-corrected over the whole brain). GM volumes in several of those brain regions were directly correlated with age of disease onset on SVC analyses for conjoined (first-episode and chronic) schizophrenia groups. There were also widespread foci of significant negative correlation between duration of illness and relative GM volumes, but such findings remained significant only for the right dorsolateral prefrontal cortex after accounting for the influence of age of disease onset. Finally, significant negative correlations were detected between life-time cumulative exposure to antipsychotics and total GM and white matter volumes in schizophrenia patients, but no significant relationship was found between indices of antipsychotic usage and relative GM volume in any specific brain region. CONCLUSION: The above data indicate that brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients. Our findings also suggest that relative GM volume deficits may be greater in (presumably more severe) cases with earlier age of onset, as well as varying as a function of illness duration in specific frontal brain regions. Finally, our results highlight the potentially complex effects of the continued use of antipsychotic drugs on structural brain abnormalities in schizophrenia, as we found that cumulative doses of antipsychotics affected brain volumes globally rather than selectively on frontal-temporal regions.