Background: Carriers of the APOE epsilon 4 allele are at increased risk of developing Alzheimer's disease (AD), and have been shown to have reduced cerebral metabolic rate of glucose (CMRgl) in the same brain areas frequently affected in AD. These individuals also exhibit reduced plasma levels of apolipoprotein E (apoE) attributed to a specific decrease in the apoE4 isoform as determined by quantification of individual apoE isoforms in APOE epsilon 4 heterozygotes. Whether low plasma apoE levels are associated with structural and functional brain measurements and cognitive performance remains to be investigated. Methods: Using quantitative mass spectrometry we quantified the plasma levels of total apoE and the individual apoE3 and apoE4 isoforms in 128 cognitively normal APOE epsilon 3/epsilon 4 individuals included in the Arizona APOE cohort. All included individuals had undergone extensive neuropsychological testing and 25 had in addition undergone FDG-PET and MRI to determine CMRgl and regional gray matter volume (GMV). Results: Our results demonstrated higher apoE4 levels in females versus males and an age-dependent increase in the apoE3 isoform levels in females only. Importantly, a higher relative ratio of apoE4 over apoE3 was associated with GMV loss in the right posterior cingulate and with reduced CMRgl bilaterally in the anterior cingulate and in the right hippocampal area. Additional exploratory analysis revealed several negative associations between total plasma apoE, individual apoE isoform levels, GMV and CMRgl predominantly in the frontal, occipital and temporal areas. Finally, our results indicated only weak associations between apoE plasma levels and cognitive performance which further appear to be affected by sex. Conclusions: Our study proposes a sex-dependent and age-dependent variation in plasma apoE isoform levels and concludes that peripheral apoE levels are associated with GMV, CMRgl and possibly cognitive performance in cognitively healthy individuals with a genetic predisposition to AD.

Made available in DSpace on 2018-08-01T22:57:56Z (GMT). No. of bitstreams: 1 tese_7274_021 - DISSERTAÇÃO JOHNATHAN JUNIOR VAZ CARVALHO.pdf: 702170 bytes, checksum: d050a58ac0d19c54163d1007bd3edd12 (MD5) Previous issue date: 2016-07-19 / A substância cinzenta periaquedutal dorsal (SCPD) é uma estrutura mesencefálica envolvida na mediação de comportamentos defensivos associados aos transtornos de ansiedade generalizada (TAG) e de pânico (TP). Existem evidências que indicam um envolvimento da neurotransmissão noradrenérgica da SCPD na modulação da ansiedade, no entanto, não existe evidência sobre sua participação nos ataques de pânico. Neste sentido, o objetivo do presente estudo foi investigar a participação da neurotransmissão noradrenérgica da SCPD na mediação de comportamentos defensivos relacionados ao TAG e ao TP em animais testados no labirinto em T elevado (LTE), um modelo animal que associa a resposta de esquiva inibitória ao TAG e a resposta de fuga ao TP. Para tal, ratos Wistar receberam a administração intra-SCPD de noradrenalina (10, 30 ou 60 nmoles/0,1μL) ou salina e foram testados no LTE. Adicionalmente, investigamos o efeito do pré-tratamento intra-SCPD com os antagonistas não seletivos de receptores alfa e beta-adrenérgicos, fentolamina e propranolol, respectivamente, no efeito da injeção de noradrenalina na mesma estrutura. Nossos resultados mostram que a administração intra-SCPD de noradrenalina na maior dose prejudicou a aquisição da esquiva inibitória, sugerindo um efeito do tipo ansiolítico, porém não apresentou efeito sobre a resposta de fuga no LTE. Além disso, a injeção de noradrenalina não alterou a atividade locomotora dos animais no teste do campo aberto, sugerindo que o efeito ansiolítico não foi devido a um aumento na atividade exploratória. Os resultados mostram ainda que o pré-tratamento intra-SCPD de fentolamina ou propranolol atenuou o efeito do tipo ansiolítico da noradrenalina. Assim, o presente estudo sugere um envolvimento da neurotransmissão noradrenérgica na SCPD, via receptores alfa e beta-adrenérgicos, em reações defensivas associadas com o TAG, mas não com o TP em animais submetidos ao LTE.

PURPOSE: Extremely low gestation age newborns (ELGANs) are at high risk for developmental brain abnormalities. This study is to determine deep and superficial gray matter volumetric abnormalities of ELGAN children and full term children at 9 to 11 years of age. METHODS: High-resolution magnetic resonance imaging (MRI) scans were obtained from 160 ELGAN children (70 males and 90 females) and 30 full term children (15 males and 15 females) using a dual-echo turbo spin-echo (DE-TSE) pulse sequence at 3.0T (or 1.5T at only one site). The DICOM MR images were processed with quantitative MRI algorithms programmed in Mathcad. The brain deep gray matter (dGM) was manually segmented; dGM and cortical gray matter (cGM) volumes were quantified using semi-automated clustering segmentation algorithms. RESULTS: ELGAN children had smaller deep gray matter volume (41.86 ± 7.42 ml) than full term children (49.24 ± 10.91 ml). Deep gray matter volumes of ELGAN children showed similar distribution range (SD = 7.42 ml) with the full term children (SD = 10.91 ml). About 83% of the ELGAN children had smaller deep gray matter volumes compared to the average volume of full term children at the same ages. Male children had smaller deep gray matter volumes in ELGAN (42.77 ± 7.09 ml) than in full term (51.74 ± 9.76 ml), but female children had similar deep gray matter volumes in ELGAN (41.14 ± 7.62 ml) with full term (44.27 ± 7.56 ml). Additionally, smaller deep gray matter volumes were observed more often in males (90%) than in females (65%). Cortical gray matter volumes of ELGAN children distributed from 345.60 to 1177.50ml. Moreover, female ELGAN children had smaller cortical gray matter volumes (828.14 ± 147.61 ml) than males (883.13 ± 151.34 ml). Correlation analysis revealed a positive correlation between cerebral deep gray matter volumes and total gray matter volumes (total: r = 0.57, p<0.0001; male: r = 0.542, p < 0.0001; female: r = 0.587, p < 0.0001). CONCLUSION: Male ELGAN children had smaller brain deep gray matter volumes than full term children at ages of 9 to 11 years, but not females. Cortical gray matter volumes of female ELGAN were smaller than male ELGAN. Smaller deep gray matter volumes were associated with smaller total gray matter volumes in ELGAN children.

Level of physical fitness may be an important factor influencing the effects of brain aging and age-related cognitive decline. Multiple measures of aerobic fitness were used in a cohort of healthy older adults 50-89 years of age to identify how individual differences in fitness relate to brain aging and age-associated cognitive decline. Healthy adults (n=123; 65 F and 58 M; mean ± sd age = 67.9 ± 10.0; Mini-Mental State Exam = 29.1 ± 1.2) were screened to exclude neurological, psychiatric, and medical illnesses that could affect cognitive function, including hypertension. The Scaled Subprofile Model (SSM) with voxel-based morphometry and Statistical Parametric Mapping version 8 (VBM; SPM8 Dartel) were performed on T1-weighted 3T volumetric magnetic resonance imaging (MRI) scans to identify a gray matter pattern associated with brain aging. Performance on aerobic fitness measures, assessed during a graded exercise treadmill test (GXT), was evaluated in relation to the age-associated MRI gray matter network pattern and indices of neuropsychological function. Multivariate SSM VBM network analysis identified a linear combination of patterns that predicted age (R² = 0.48, p = 8.71e-19). This combined pattern was characterized by reductions in bilateral lateral and medial frontal, parietal, lateral temporal, and cerebellar regions with relative preservations in thalamic, occipital, and medial temporal regions including the hippocampus. Higher expression of the age-related network pattern was associated with poorer performance on multiple fitness indices. The best combination of fitness measures in predicting brain aging included overall treadmill exercise time, ventilatory efficiency, and the difference between basal and maximal respiratory rate (p = 6.67e-7). A higher combined fitness index score related to brain aging was associated with better performance on measures of memory, executive function, and processing speed in this cohort (6.08e-9≤ p≤ 0.05). Those individuals with higher levels of aerobic fitness had lower expression of the gray matter brain aging pattern and better performance on measures of memory, executive function, and processing speed. Identifying those fitness indices that are the best predictors of brain aging and cognitive performance may aid efforts in developing and evaluating exercise based interventions for age-related cognitive decline.

Controversy surrounds the idea that bilingualism leads to enhanced executive function (EF) and brain volume changes, potentially leading to delays in cognitive decline and dementia onset. The purpose of this research was to explore these claims in a sample of elderly monolinguals and bilinguals. This study explored gray matter volume (GMV) in 214 monolinguals and bilinguals (Mage = 71.21, SD = 7.53) who were cognitively normal (CN) or diagnosed with Mild Cognitive Impairment (MCI) or dementia. Neuropsychological performance was also examined between CN and MCI monolinguals and bilinguals (N = 153) across two visits. Scores from the Digit Span Backwards, Stroop interference, Trail Making Test A minus Trail Making Test B, and category fluency average scores were used. Magnetic Resonance Imaging (MRI) brain regions associated with memory, language, and EF were selected. Additionally, the study examined how a Bilingualism Index (BI) and the age of acquisition of English could predict GMV and EF in Spanish/English bilinguals whose native language was Spanish. Lastly, the initial age of cognitive decline across language groups was compared. Results suggested higher GMV in language and EF regions in bilinguals, but differences were not found in memory regions. Furthermore, neuropsychological performance over time did not vary across language groups; however, bilinguals exhibited reduced Stroop interference as well as lower scores on Digit Span Backwards and category fluency. The age of acquisition of English did not predict GMV or EF scores, while the BI predicted category fluency, with lower scores associated with a higher degree of balanced bilingualism. Overall, the influence of bilingualism appears to be reflected in increased GMV in specific language and EF regions relative to neuropsychological performance. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20257号 / 医博第4216号 / 新制||医||1020(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 宮本 享, 教授 村井 俊哉, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20567号 / 医博第4252号 / 新制||医||1022(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 古川 壽亮, 教授 髙橋 良輔, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23776号 / 医博第4822号 / 新制||医||1057(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 花川 隆, 教授 古川 壽亮, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

As reações incondicionadas de defesa observadas em mamíferos são organizadas pelo Sistema Encefálico de Aversão (SEA), composto, entre outras estruturas, pela substância cinzenta periaquedutal dorsal (SCPd) e o colículo inferior (CI). Tem sido proposto que o CI seja parte do circuito sensoriomotor para os estímulos auditivos de natureza aversiva e a SCPd como a principal via de saída (output) do SEA para a elaboração de comportamentos defensivos. Ambas as estruturas são reguladas tonicamente pelo neurotransmissor inibitório ácido gama-aminobutírico (GABA). Este trabalho aborda a mediação química GABA/Benzodiazepínica (BZD) do processamento da informação aversiva no CI e das respostas de medo elaboradas pela SCPd. Grupos independentes de animais submetidos ao implante de quimitrodos (eletrodos acoplados a cânulas-guia para injeção de drogas) foram usados para avaliar no CI e SCPd os efeitos de injeções locais de muscimol (agonista de receptores GABA-A), semicarbazida (inibidor da síntese da enzima precursora do GABA descarboxilase do ácido glutâmico) ou midazolam (agonista BZD). Foram registrados potenciais evocados auditivos (PEA) no CI como medida eletrofisiológica da ativação neuronial, além da determinação dos limiares de congelamento e fuga, com o procedimento de estimulação elétrica (EE), tanto do CI quanto da SCPd. A mesma abordagem farmacológica com injeções de drogas intra-CI foi empregada em animais submetidos ao teste do Labirinto em Cruz Elevado (LCE), um modelo animal tradicional de ansiedade. Adicionalmente, investigou-se a participação de ambas as estruturas na expressão do comportamento de desligar uma luz de intensidade aversiva em um novo teste de medo incondicionado (Light Switch Off Test; LSOT) recentemente proposto pelo nosso grupo. Encontramos uma clara segregação funcional entre a porção dorsal e ventral do CI, sendo a última envolvida nos comportamentos defensivos. Mecanismos GABAérgicos em ambas as estruturas influenciam a amplitude do PEA e o congelamento pós-fuga da EE, sugerindo uma relação funcional entre as duas estruturas. Já no LSOT, os resultados indicam o envolvimento de mecanismos GABAérgicos do vCI, mas não da SCPd, na modulação da resposta incondicionada à luz em ratos. Os resultados obtidos permitem ampliar o conhecimento atual sobre a neurobiologia dos estados de medo e ansiedade, em uma abordagem integrada dos mecanismos de processamento das informações sensoriais e da expressão de reações de defesa. / Unconditioned defense reactions observed in mammals are organized by the Brain Aversive System, comprising, among other structures, the dorsal periaqueductal gray matter (dPAG) and the inferior colliculus (IC). It has been proposed that the IC is part of the sensorimotor circuitry that processes aversive auditory information and the dPAG is considered the main neural substrate for the expression of defensive behaviors. Both structures are tonically regulated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This work addresses the chemical mediation of GABA/Benzodiazepine (BZD) on aversive information processing in the IC and the elaboration of fear responses by dPAG. Independent groups of animals implanted with chemitrodes (electrodes attached to a guide cannula for drug injection) have been used to evaluate the IC and dPAG regarding the effects of local injections of GABAergic agents (muscimol, semicarbazide, and midazolam). Auditory evoked potentials (AEP) have been recorded in the IC as a measure of electrophysiological neuronal activation, in addition to determining the thresholds of defensive freezing and flight behaviors, using the electrical stimulation (EE) procedure in both IC and dPAG. The same pharmacological regimen of drug injections intra-dPAG and intra-CI have been applied to animals subjected to the elevated plus maze (EPM), a well-known animal model of anxiety, and also to a novel animal test for innate fear (Light Switch Off Test, LSOT) that has been developed and proposed by our group. We found a clear functional segregation between the dorsal and ventral portions of the IC, the latter being the specific collicular substrate of defensive behaviors. GABAergic mechanisms in both structures influence the amplitude of the AEP and post-stimulation freezing of EE, suggesting a functional link between the two structures. In the LSOT, our data indicate the involvement of GABAergic mechanisms of the ICv, but not the dPAG, in the modulation of the unconditioned response to light in rats. These original findings presented here contribute to broaden the current knowledge on the neurobiology of fear and anxiety, in an integrative approach of the mechanisms underlying sensory processing and the expression of defensive behaviors.

Transtornos mentais graves são doenças crônicas altamente incapacitantes que geram um alto custo para a sociedade. Indivíduos acometidos por essas doenças apresentam maior morbidade e mortalidade. Dentre elas, a esquizofrenia parece possuir os piores desfechos. Portanto, estudar a esquizofrenia pode trazer contribuições importantes para o entendimento e manejo de transtornos mentais graves como a depressão maior e o transtorno bipolar. Esse trabalho buscou compreender mecanismos fisiopatológicos da esquizofrenia ao longo de quatro artigos que exploram aspectos de funcionamento cognitivo, funcionamento intelectual, de biomarcadores e de estrutura cerebral. O primeiro artigo investigou as alterações de performance de memória em indivíduos com esquizofrenia em estágios iniciais e tardios da doença comparadas ao transtorno bipolar e a sujeitos saudáveis. Os resultados mostraram que indivíduos com esquizofrenia apresentaram precoces prejuízos cognitivos de memória, diferentemente de indivíduos com transtorno bipolar quando comparados a controles. O segundo artigo investigou as influências das performances cognitiva e intelectual em estruturas cerebrais de indivíduos com esquizofrenia comparados a controles saudáveis. Os resultados indicaram que o funcionamento intelectual pré-morbido estava relacionado ao volume de estruturas globais, enquanto o funcionamento cognitivo estava relacionado ao volume e espessura de massa cinzenta cortical, sugerindo influências diferentes e complementares relacionadas a neurodesenvolvimento e neurodegeneração. O terceiro artigo investigou um biomarcador de envelhecimento precoce, um possível mecanismo para a neuroprogressão na esquizofrenia. Os resultados monstraram que indivíduos com esquizofrenia apresentaram encurtamento de telômero quando comparados a controles, mas não houveram diferenças entre o tamanho de telômero de pacientes e seus irmãos não afetados pela doença. Por fim, o quarto artigo buscou investigar a teoria do envelhecimentoa patológico acelerado na esquizofrenia, integrando os achados dos artigos anteriores. Os resultados demonstraram correlações entre comprimento de telômero, níveis de CCL11, performance de memória, volume de massa cinzenta e tempo de doença em indivíduos com esquizofrenia. Esses achados sugerem que a esquizofrenia seria uma doença do neurodesenvolvimento associada a uma carga adicional ao longo do curso da doença que levaria a um envelhecimento patológico precoce. A partir dos achados em esquizofrenia, pode-se ampliar a compreensão de alterações percebidas nas trajetórias de outras psicopatologias. Com adequado entendimento desses mecanismos, será possível o desenvolvimento de novos tratamentos e intervenções mais efetivas e eficazes. / Severe mental disorders are debilitating chronic diseases that have a high cost to society. Individuals affected by these diseases have increased morbidity and mortality. Among them, schizophrenia seems to have the worst outcomes. Therefore, studying schizophrenia may provide important contributions to the understanding and management of severe mental disorders such as major depression and bipolar disorder. The present study aimed to understand the pathophysiological mechanisms of schizophrenia over four articles that explore aspects of cognitive functioning, intellectual functioning, biomarkers and brain structure. The first article investigated changes in memory performance in individuals with schizophrenia in early and late stages of disease compared to bipolar disorder and healthy subjects. The results showed that subjects with schizophrenia had early cognitive deficits of memory, unlike individuals with bipolar disorder compared to controls. The second article investigated influences of cognitive and intellectual performances on brain structures of individuals with schizophrenia compared to healthy controls. The results indicated that premorbid intellectual functioning was related to volume of global structures, while cognitive functioning was related to volume and thickness of cortical gray matter, suggesting different and complementary influences related to neurodevelopment and neurodegeneration. The third article investigated an early aging biomarker, a possible mechanism of neuroprogression in schizophrenia. The results showed that individuals with schizophrenia had shortened telomeres when compared to controls, but there were no differences between the telometer length of patients and their siblings not affected by the disease. Finally, the fourth article sought to investigate the theory of pathological accelerated aging in schizophrenia, integrating the findings of the previous articles. The results demonstrated correlations between telometer length, CCL11 levels, memory performance, gray matter volume and illness duration in individuals with schizophrenia. These findings suggest that schizophrenia is a neurodevelopmental disorder associated with an additional burden over the course of the disease that leads to a pathological accelerated agig.