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A complex interplay of genetic and environmental risk factors influence global brain structural alterations associated with brain health and disease. Epigenome-wide association studies (EWAS) of global brain imaging phenotypes have the potential to reveal the mechanisms of brain health and disease and can lead to better predictive analytics through the development of risk scores.We perform an EWAS of global brain volumes in Generation Scotland using peripherally measured whole blood DNA methylation (DNAm) from two assessments, (i) at baseline recruitment, ~6 years prior to MRI assessment (N = 672) and (ii) concurrent with MRI assessment (N=565). Four CpGs at baseline were associated with global cerebral white matter, total grey matter, and whole-brain volume (Bonferroni p≤7.41×10-8, βrange = -1.46x10-6 to 9.59 × 10-7). These CpGs were annotated to genes implicated in brain-related traits, including psychiatric disorders, development, and ageing. We did not find significant associations in the meta-analysis of the EWAS of the two sets concurrent with imaging at the corrected level.These findings reveal global brain structural changes associated with DNAm measured ~6 years previously, indicating a potential role of early DNAm modifications in brain structure. Although concurrent DNAm was not associated with global brain structure, the nominally significant findings identified here present a rationale for future investigation of associations between DNA methylation and structural brain phenotypes in larger population-based samples.

Fetal alcohol spectrum disorders (FASD) continue to be the leading preventable cause of intellectual disability in the U.S., Europe, and in endemic areas, such as the Western Cape region of South Africa. Arithmetic is highly sensitive to prenatal alcohol exposure (PAE). The intraparietal sulcus (IPS) is known to play a critical role in number processing. In this study, we investigate whether smaller IPS volumes play a role in the number-processing deficits observed in children with PAE. Participants were 52 9- to 14-year-old children from a historically disadvantaged community in Cape Town, who are participating in our ongoing studies on the effects of PAE on the brain. The IPS was manually parcellated into its medial (MIPS) and lateral (LIPS) walls on magnetic resonance images. The study aimed to examine: (1) the effects of PAE on IPS regional volumes and asymmetry, (2) whether IPS regional volumes are related to number processing performance and, if so, whether these relations are moderated by PAE and (3) potential mediation by regional IPS volumes of the relation between PAE and number processing performance. Total intracranial volume (TIV) was associated with volumes in all regions except the right LIPS. Both left MIPS and left LIPS volumes were significantly smaller in children in the fetal alcohol syndrome (FAS)/partial FAS (PFAS) group compared to controls. The finding in the left LIPS remained significant after controlling for potential confounders and after adjustment for the smaller overall brain size of the children in the FAS/PFAS group. Smaller left LIPS volumes in the FAS/PFAS group may account for the absence of left-right asymmetry in the LIPS in children with FAS/PFAS compared to controls and nonsyndromal heavily exposed (HE) children. Bilaterally, larger MIPS volumes were associated with better WISC IQ Arithmetic scores. These effects, however, were not moderated by the degree of PAE, and regional IPS volumes did not mediate the effect of PAE on WISC Arithmetic scores. Although we found that certain regions of the IPS were smaller in children with FAS and PFAS, these PAE-induced changes in IPS volume did not mediate the alcohol-related deficits in arithmetic.

Introdução: O consumo de crack tem sido alvo de grande preocupação, em função de sua expansão em várias regiões, além do aumento da prevalência do seu consumo nas últimas décadas, especialmente no Brasil. Os resultados de pesquisa em neuroimagem nesse campo são sobre alterações do uso de cocaína, substância semelhante ao crack, mas este possui diversas particularidades que, clinicamente, o tornam potencialmente mais agressivo e danoso ao organismo. Não se sabe se tais semelhanças também são compartilhadas no que diz respeito a modificações de volumes cerebrais. Os transtornos aditivos, de modo geral, afetam o sistema de recompensa, mas também circuitos cerebrais envolvidos com condicionamento, motivação e função executiva (controle inibitório, atribuição de valores e tomada de decisão). As drogas representam um complexo estressor para o organismo. À medida em que o uso ocasional se torna abusivo e crônico, há recrutamento duradouro dos mecanismos regulatórios do cérebro, modificando eixos fisiológicos de homeostase. Em 2011, Volkow et al propuseram um modelo de alteração do neurocircuito cerebral em um cérebro adicto em comparação com o funcionamento de um cérebro não-adicto. O objetivo desta tese foi investigar as alterações de volume cerebral, corticais e subcorticais, em usuários de crack, bem como avaliar a associação destes achados com o modelo de três estágios proposto por Volkow e Koob. Método: estudo de caso-controle, com amostra de 15 usuários de crack e 15 controles saudáveis, pareados por gênero, idade, escolaridade e lateralidade, recrutados na Unidade de Adição da Unidade Álvaro Alvim do Hospital de Clínicas de Porto Alegre (HCPA). Realizaram exame de Ressonância Magnética Nuclear após pelo menos 15 dias de desintoxicação. Foram excluídas comorbidades neurológicas, inflamatórias, cardiovasculares ou 8 sistêmicas. Os volumes das estruturas corticais e subcorticais foram determinados usando o programa Freesurfer v5.3. Resultados: Artigo 1. Os dois grupos (casos e controles) não diferiram em relação à idade, gênero (todos os indivíduos eram do sexo masculino), educação, estado civil e ocupação principal. Todas as variáveis na amostra tiveram distribuição normal. Os usuários de crack tiveram menores volumes no núcleo accumbens esquerdo (t = 3,604, df = 28, p = 0,001) em relação aos pacientes. Os volumes do núcleo accumbens direito também foram menores nos pacientes e apresentaram diferenças significativas entre os grupos (t = 2,098, df = 28, p = 0,045). Os grupos não diferiram em relação aos volumes intracranianos (p = 0,514). Artigo 2. Os pacientes tiveram volumes de amígdala menores do que os controles, (F (1,28) = 5,885, p = 0,023). O córtex pré-frontal dorsolateral (dLPFC) também foi menor entre os usuários de crack quando comparado aos controles (F (1,28) = 5,447, p = 0,027). Não houve diferença entre os volumes do córtex orbitofrontal (F (1,28) = 2,917, p = 0,100) e ínsula (F (1,28) = 2,815, p = 0,105) entre os grupos. Houve uma tendência à significância entre os grupos no córtex cingulado Anterior (F (1,28) = 3,992, p = 0,056) e hipocampo (F (1,28) = 3,535, p = 0,071). Entre os casos, todos os volumes estudados não se correlacionaram com variáveis clínicas de gravidade (anos de dependência de crack, idade de primeiro uso, número diário de pedras de crack , e duração da abstinência). Os grupos não diferiram em relação à idade, educação, estado civil e ocupação. Todos eram homens e destros. Conclusões: Os resultados deste trabalho mostram que a população de usuários de crack possui volumes cerebrais reduzidos em regiões corticais e subcorticais. Estas regiões estão implicadas nos sistemas de recompensa, de motivação, de funções executivas e memória, e estão de acordo com os estágios propostos por Volkow e Koob e com as teorias de neuroprogressão das adições. Desta forma, tais achados podem auxiliar na compreensão da fisiopatologia do Transtorno por Uso de Crack e corroboram os déficits cognitivos já evidenciados clinicamente nesta população. Entretanto, ressalta-se a importância de estudos longitudinais com o objetivo de avaliar a causalidade e reversibilidade destas alterações, a fim de nortear futuras intervenções terapêuticas em um grupo tão complexo e grave. Introduction: Crack-cocaine consumption has been a major concern due to its geographical expansion, followed by a recent increase in its prevalence especially in Brazil. Neuroimaging research currently available is limited to cocaine use, a precursor of crackcocaine. Clinically, crack-cocaine has several peculiarities that make it potentially more aggressive and damaging to the body when compared to cocaine. It is not known whether such similarities are also shared regarding changes in brain volumes. Addictive disorders, in general, affect the reward system, but also brain circuits involved with conditioning, motivation, and executive function (i.e. inhibitory control and decision making). Drugs represent a complex stressor for the body. As occasional use becomes abusive and chronic, there is a lasting recruitment of the regulatory mechanisms of the brain, modifying physiological axes of homeostasis. In 2011, Volkow et al proposed a model of brain neurocircuit alteration of addicted brains compared to the functioning of a non-addicted brain. In this sense, the aim of this thesis was to investigate changes in cortical and subcortical brain volumes in crack-cocaine users, as well as to evaluate the association of these findings with the three-stage model proposed by Volkow and Koob. Method: This is a case-control study, with a sample of 15 crack-cocaine users and 15 healthy controls, matched by gender, age, education and handedness, recruited at the Álvaro Alvim Addiction Unit of the Hospital de Clinicas de Porto Alegre (HCPA). They underwent structural MRI after at least 15 days of detoxification. Neurological, inflammatory, 11 cardiovascular or systemic comorbidities were excluded. The volumes of the cortical and subcortical structures were determined using the Freesurfer v5.3 program. Results: Article 1. The two groups (patients and controls) did not differ regarding age, gender (all individuals were male), education, marital status and occupation. Controls had higher volumes in the left nucleus accumbens (t = 3.604, df = 28, p = 0.001) compared to patients. Right nucleus accumbens volumes were also higher in controls and showed significant differences between groups (t = 2.098, df = 28, p = 0.045). Groups did not differ in relation to intracranial volumes (p = 0.514). Article 2. Patients had lower amygdala volumes than controls (F (1,28) = 5.885, p = 0.023). The dorsolateral prefrontal cortex (DLPFC) volumes were reduced among crack-cocaine users when compared to controls (F (1,28) = 5.447, p = 0.027). No difference was found between groups in Orbitofrontal cortex (F (1,28) = 2.917, p = 0.100) and insula (F (1,28) = 2.815, p = 0.105) . There was a trend toward significance between groups in the anterior cingulate cortex (F (1,28) = 3.992, p = 0.056) and hippocampus (F (1,28) = 3.535, p = 0.071). Among patients, volumes of all structures assessed were not correlated with clinical variables of severity (years of crack dependence, age of first use, daily number of crack-cocaine rocks, and duration of abstinence). Groups did not differ regarding age, education, marital status and occupation. They were all men and right-handed. Conclusions: Our findings show that the population of crack users had smaller cerebral volumes in cortical and also subcortical regions compared to matched controls. These regions are implicated in reward systems, motivation, executive functions, and memory; and are in line with the theories of neoruprogression in substance use disorders. Thus, our findings may help in 12 understanding the pathophysiology of Crack-cocaine Use Disorder and it is in agreement with the cognitive deficits already clinically evidenced in this population. However, the importance of longitudinal studies evaluating the causality and reversibility of these alterations, in order to guide future therapeutic interventions in such a complex and severe group, is emphasized.

There is increasing evidence showing that brain atrophy varies between patients with Alzheimer's disease (AD), suggesting that different anatomical patterns might exist within the same disorder. We investigated AD heterogeneity based on cortical and subcortical atrophy patterns in 299 AD subjects from 2 multicenter cohorts. Clusters of patients and important discriminative features were determined using random forest pairwise similarity, multidimensional scaling, and distance-based hierarchical clustering. We discovered 2 typical (72.2%) and 3 atypical (28.8%) subtypes with significantly different demographic, clinical, and cognitive characteristics, and different rates of cognitive decline. In contrast to previous studies, our unsupervised random forest approach based on cortical and subcortical volume measures and their linear and nonlinear interactions revealed more typical AD subtypes with important anatomically discriminative features, while the prevalence of atypical cases was lower. The hippocampal-sparing and typical AD subtypes exhibited worse clinical progression in visuospatial, memory, and executive cognitive functions. Our findings suggest there is substantial heterogeneity in AD that has an impact on how patients function and progress over time.

ObjectiveGender differences, including younger age of onset and greater premorbid deficits in men, have been reported in adult-onset schizophrenia. This study comprehensively evaluated gender differences in childhood-onset schizophrenia (COS), a rare variant of the disorder.MethodDemographic, premorbid, clinical, familial, and cognitive characteristics, presence of chromosomal abnormalities, and brain magnetic resonance imaging cortical volumes were evaluated in 133 patients with COS. Cortical analyses included age- and gender-matched healthy volunteers (n = 124).ResultsMales with COS (n = 72) had a slightly but significantly younger age of onset than females with COS (mean age 9.51 ± 2.28 versus 10.29 ± 1.63 years, t131 = 2.21, p = .03), higher verbal IQ scores (83.00 ± 15.97 versus 75.58 ± 15.10, t89 = 2.24, p = .03), and higher rates of comorbid pervasive developmental disorder (28.17% versus 6.90%, χ21 = 9.54, p < .01) and attention-deficit/hyperactivity disorder (43.86% versus 21.43%, χ21 = 5.40, p = .02). There were no significant gender differences across other demographic, IQ, or clinical measurements, frequency of chromosomal abnormalities, family clinical measurements, premorbid functioning, or in gender-by-disorder interactions for magnetic resonance imaging brain measurements.ConclusionThe present comprehensive examination found few remarkable gender differences in COS. Although less striking than that seen in adult-onset schizophrenia, males with COS had a younger age of onset. Attention-deficit/hyperactivity disorder and pervasive developmental disorder rates were high in COS overall, suggesting greater neurodevelopmental vulnerability in COS. However, the gender ratios of these comorbidities in COS mirror those of the general populations, indicating that these gender differences might be unrelated to COS.