Neurological disorders present a significant challenge in global health. With the increasing availability of imaging datasets and the development of precise machine learning models, early and accurate diagnosis of neurological conditions is a promising and active area of research. However, several characteristic factors in neurology domains, such as heterogeneous imaging, inaccurate labels, or limited data, act as bottlenecks in using deep learning on clinical neuroimaging. Given these circumstances, this dissertation attempts to provide a guideline, proposing several methods and showcasing successful implementations in broad neurological conditions, including epilepsy and neurodegeneration. Methodologically, a particular focus is on comparing a two-dimensional approach as opposed to three-dimensional neural networks. In most clinical domains of neurological disorders, data are scarce and signals are weak, discouraging the use of 3D representation of raw scan data. This dissertation first demonstrates competitive performances with 2D models in tuber segmentation and AD comorbidity detection. Second, the potentials of ensemble learning are explored, further justifying the use of 2D models in the identification of neurodegeneration. Lastly, CleanNeuro is introduced in the context of 2D classification, a novel algorithm for denoising the datasets prior to training. CleanNeuro, on top of 2D classification and ensemble learning, demonstrates the feasibility of accurately classifying patients with comorbid AD and cerebral amyloid angiopathy from AD controls. Methods presented in this dissertation may serve as exemplars in the study of neurological disorders using deep learning and clinical neuroimaging. Clinically, this dissertation contributes to improving automated diagnosis and identification of regional vulnerabilities of several neurological disorders on clinical neuroimaging using deep learning. First, the classification of patients with Alzheimer’s disease from cognitively normal group demonstrates the potentials of using positron emission tomography with tau tracers as a competitive biomarker for precision medicine. Second, the segmentation of tubers in patients with tuberous sclerosis complex proves a successful 2D modeling approach in quantifying neurological burden of a rare yet deadly disease. Third, the detection of comorbid pathologies from patients with Alzheimer’s disease is analyzed and discussed in depth. Based on prior findings that comorbidities of Alzheimer’s disease affect the brain structure in a distinctive pattern, this dissertation proves for the first time the effectiveness of using deep learning on the accurate identification of comorbid pathology in vivo. Leveraging postmortem neuropathology as ground truth labels on top of the proposed methods records competitive performances in comorbidity prediction. Notably, this dissertation discovers that structural magnetic resonance imaging is a reliable biomarker in differentiating the comorbid cereberal amyloid angiopathy from Alzheimer’s disease patients. The dissertation discusses experimental findings on a wide range of neurological disorders, including tuberous sclerosis complex, dementia, and epilepsy. These results contribute to better decision-making on building neural network models for understanding and managing neurological diseases. With the thorough exploration, the dissertation may provide valuable insights that can push forward research in clinical neurology.

Friedreich's ataxia (FRDA) is the most prevalent inherited ataxia, affecting one in every 50,000 individuals in the United States. This hereditary condition is caused by an abnormal GAA trinucleotide repeat expansion within the first intron of the frataxin gene resulting in decreased levels of the frataxin protein (FXN). Insufficient cellular frataxin levels results in iron accumulation, increased reactive oxygen species production and mitochondrial dysfunction. Tissues most heavily impacted are those most dependent on oxidative phosphorylation as an energy source and include the nervous system and muscle tissue. This is evident in the clinical phenotype which includes muscle weakness, ataxia, neurodegeneration and cardiomyopathy. However, there has been a lack of data regarding the cell type specific contributions in FRDA pathogenesis. We generated a cohort of induced pluripotent stem cells (iPSCs) consisting of FRDA patient lines, CRISPR-Cas9 edited controls, carriers and non-related controls. Our preliminary data identified a hyperinflammatory microglial phenotype with extensive defects in mitochondrial function; since microglia are the primary innate immune cell of the brain, we hypothesized microglia may decrease neuronal viability which contributes to FRDA pathology. To investigate this, the iPSC cohort was utilized to generate microglia (iMGs) and neurons to better understand microglia-mediated neurodegeneration and how this contributes to pathology. An in vitro co-culture model composed of neurons, astrocytes and microglia was employed to better understand microglia-neuronal communication in FRDA. Healthy neurons co-cultured with FRDA iMG or with FRDA iMG-conditioned media demonstrated higher incidences of caspase-3 mediated apoptosis. These findings were recapitulated in vivo as xenotransplantation of FRDA microglia progenitors into a murine model resulted in reduced Purkinje cell survival in the cerebellum. Previous research has demonstrated the therapeutic potential of wildtype microglia to rescue the FRDA phenotype in the Y8GR mouse model of FRDA. To further explore the potential mechanisms behind this rescue, the delivery of mitochondria and FXN to FRDA microglia and neurons was investigated. CRISPR-Cas9 edited microglia demonstrated transfer of healthy mitochondria to FRDA microglia and neurons in an in vitro co-culture model. To investigate the transfer of frataxin protein, an FRDA iPSC line was transduced with an FXN-GFP lentivirus. Restoring FXN expression was demonstrated to rescue the FRDA microglial morphological phenotype. FXN-GFP microglia demonstrated transfer of frataxin protein to FRDA microglia suggesting the potential role of microglia as a therapeutic vehicle in FRDA. Together these findings show that FRDA microglia have a deleterious effect on neuronal viability, while healthy microglia may work as a therapeutic vehicle through the delivery of mitochondria and frataxin to FRDA cells.

This work seeks to contribute to the discipline of neuropharmacology by way of structure activity relationship from the standpoint of an organic chemist. More specifically, we sought to develop robust synthetic methodology able to efficiently produce an array of compounds for the purpose of systematic evaluation of their interaction with specific sights within the central nervous system (CNS) in order to better understand the mind and to develop drugs that may have beneficial effects on neurological function. The focus of these studies has been toward the development of novel molecules, using a structure-activity relationship approach, that exhibit binding affinity at specific targets within the CNS. The merit of such studies is twofold: primarily, new compounds are produced that provide valuable scientific insight about their physiological targets, and secondarily, new synthetic methodologies that may arise in order to produce these compounds, thereby contributing to the whole of organic chemistry. As a result of the research described herein, the development of one high affinity and several moderate affinity compounds at the cannabinoid receptor subtype 1 (CB1) has been accomplished. The research demonstrates that a diaryl ether molecular scaffold represents a successful motif in the cannabinoid pharmacophore. The production of the compounds in the SAR studies also introduced a novel general synthetic methodology for the synthesis of diaryl ethers around a phloroglucinol core. A second project was initiated in order to explore the synthetic methods required to develop a general process for the synthesis of rigid aminobenzocyclobutane analogs of known phenethylamines with activity at monoaminergic neurotransmitter sites. Using the synthetic approach devised here, four novel aminobenzocyclobutane isomeric analogs of a known pharmacologically active phenethylamine, (RS)-phenylpropan-amine were synthesized and are currently being evaluated for pharmacological potential.

Introdução - Alterações cardíacas na anemia falciforme (AF) são frequentes e iniciam-se precocemente. Há evidências de que exista também disfunção na regulação do sistema nervoso autônomo o que pode contribuir com eventos de morbidade. Objetivos Avaliar a modulação autonômica cardíaca por meio da variabilidade da frequência cardíaca em crianças e adolescentes com anemia falciforme. Método - Estudo analítico no qual foi realizada uma comparação da variabilidade da frequência cardíaca em 45 crianças e adolescentes, menores de 20 anos, com anemia falciforme, com um grupo controle pareado um a um por idade e sexo. A frequência cardíaca foi obtida pelo frequencímetro de pulso e analisada, batimento a batimento. Estes pacientes são usuários do ambulatório de hematologia pediátrica do Sistema Único de Saúde. Esta pesquisa está em consonância com a resolução 466/2012 do Ministério da Saúde. Resultados - Observamos diferença significativa nos índices do domínio da frequência (VLF, LF, HF e LF/HF). Estas diferenças não foram observadas nos pacientes em uso de hidroxiureia. Conclusão - Existe uma disfunção autonômica na AF que ocorre desde a infância, podendo estar relacionada a uma menor modulação do simpático e uma maior modulação do parassimpático. Esta diferença não foi observada em pacientes em uso de hidroxiureia / Introduction - Cardiac changes in sickle cell disease (AF) are frequent and begin early. There is evidence that there is also dysfunction in the regulation of the autonomic nervous system, which may contribute to morbidity events. Objectives - To evaluate the autonomic cardiac modulation by heart rate variability in children and adolescents with sickle cell anemia. Method - An analytical study comparing the heart rate variability of 45 children and adolescents, younger than 20 years, with sickle cell anemia, with a control group matched one by one by age and sex. The heart rate was obtained by pulse frequency and analyzed, beat by beat. These patients are attending the pediatric hematology outpatient of the National Health System. Results - We observed a significant difference in the frequency domain indexes (VLF, LF, HF and LF / HF). The results of this study are in agreement with resolution 466/2012 of the Ministry of Health of Brazil. These differences were not observed in patients taking hydroxyurea. Conclusion - There is an autonomic dysfunction in AF that occurs from childhood, and may be related to a lower modulation of the sympathetic and greater modulation of the parasympathetic. This difference was not observed in patients taking hydroxyurea

Foi caracterizada uma amostra de 81 doentes com dor relevante crônica pélvica de origem indefinida e na ausência de afecções viscerais, segundo a expressão sintomática, aspectos clínicos e síndromes álgicas. A média das idades foi de 48,6 anos. Foram identificadas anormalidades miofasciais pélvica em 55 doentes (67,9%), neuropáticas em 10 (12,3%) e miofasciais e neuropáticas em 16 (19,8%). A descrição verbal da dor e as regiões acometidas pela dor, impactos funcionais, a evidenciação de pontos dolorosos e em gatilhos e os aspectos psicossociais dos doentes foram estabelecidos para melhorar a compreensão da condição clínica dos doentes. Traumatismos decorrentes de traumatismos cirúrgicos estavam relacionados à ocorrência da dor em 36 (44,4%) doentes, sendo dor miofascial em 15 doentes (18,5%), 6 (7,4%) como neuropática e 15 (18,5%) como dor miofascial e neuropática / Eighty-one chronic pelvic pain patients (mean of ages 48.6 years old) without visceral abnormalities and uncertain etiology were characterized according to the symptomatic expression, clinical findings and pain syndromes. It was observed that in 55 patients there was pelvic miofascial pain (67.9%), in 10 patients neuropathic (12.3%) conditions and 16 (19.8%) had miofascial and neuropathic abnormalities. The verbal description of pain, pain aspects as localization, aggravating and improvement factors, functional impact, the occurrence of trigger or tender points and the psychosocial aspects were determined to improve the comprehension of the clinical presentation of the patients. Surgical traumas were related to pain in 26 (32.0%) patients, miofascial pain in 11 (13.6%), neuropathic pain in 5 (6.2%) and miofascial and neuropathic pain in 10 (12.3%)

INTRODUÇÃO: A neuropatia periférica induzida por quimioterapia (NPIQ) está entre os efeitos colaterais mais comuns decorrentes da quimioterapia antineoplásica e uma das principais causas da redução da dose ou interrupção do tratamento. Os sintomas mais prevalentes são a dor e a parestesia, acarretando desconfortos crônicos e perda de habilidades funcionais, interferindo negativamente na qualidade de vida dos pacientes. Estudos recentes têm avaliado o uso da Estimulação Elétrica Nervosa Transcutânea (TENS) nesta patologia, apresentando evidências positivas na redução da dor, porém seu efeito nos sintomas de parestesia e nas atividades de vida diária destes pacientes ainda não foram avaliados. OBJETIVO: Investigar os efeitos da Estimulação Elétrica Nervosa Transcutânea (TENS) nos sintomas de dor, parestesia e nas atividades de vida diária da NPIQ em indivíduos com diagnóstico de câncer de mama e colorretal, submetidos ao tratamento de quimioterapia. MÉTODOS: Trata-se de um ensaio clínico duplo-cego, controlado, randomizado e multicêntrico, com abordagem quantitativa, em pacientes submetidos ao tratamento de quimioterapia, contendo em seu protocolo os seguintes quimioterápicos: paclitaxel e oxaliplatina. Os sujeitos da pesquisa utilizaram o dispositivo terapêutico TENS com modulação de frequência entre 7 e 75 Hz na região distal dos membros, no local de maior desconforto, com intervenções diárias de 60 minutos, durante três ciclos de quimioterapia (45 dias). Os participantes foram divididos em dois grupos: grupo TENS ativa (GTA) e grupo TENS placebo (GTP). A avaliação dos efeitos da TENS foi medida através dos seguintes instrumentos: a Escala Visual Analógica (EVA) para avaliar os sintomas de dor e parestesia e Questionário de Neurotoxicidade Induzida por Anti-neoplásicos (QNIA) para avaliação dos sintomas da NPIQ. RESULTADOS: Finalizaram a pesquisa 24 pacientes. Não se observou uma diferença significativa entre os 2 grupos no que se refere ao desfecho primário de redução dos sintomas de dor (p = 0.666), parestesia (p = 0,673) e impacto da TENS na frequência dos sintomas (p = 0,5906) e atividades de vida diária (p = 0,8565). CONCLUSÃO: Estes resultados sugerem que a TENS aplicada no modo de modulação de frequência não foi eficaz para melhorar os sintomas de neuropatia periférica induzida por quimioterapia, durante os ciclos de quimioterapia. Não houve, porém, agravamento dos sintomas em ciclos subsequentes ao início dos sintomas da doença / BACKGROUND: Peripheral neuropathy induced by chemotherapy (PNIC) is amongst the most common side effects derived from antineoplastic chemotherapy and one of the principal causes of dose reduction or treatment interruption. The most prevalent symptoms are pain and numbness, resulting from chronic discomfort to loss of functional abilities, negatively affecting quality of life and autonomy of patients. Recent studies have evaluated the use of Transcutaneous Electrical Nerve Stimulation (TENS) in this disease, pointing to evidence of pain reduction, but its effect on symptoms of paresthesia and in daily life activities have not yet been evaluated. OBJECTIVE: To investigate the effects of Transcutaneous Electrical Nerve Stimulation (TENS) for reducing the symptoms of pain, paresthesia and the daily activities of PNIC in patients diagnosed with breast cancer and colorectal cancer undergoing chemotherapy treatment. METHODS: It is a double-blind, controlled, randomized, multicenter clinical trial with a quantitative approach in a sample of 24 patients undergoing chemotherapy treatment, containing in its protocol the following chemotherapeutic agents: paclitaxel and oxaliplatin. The research subjects used the TENS therapeutic device with frequency modulation between 7 and 75 Hz in the distal limb, on the location of greatest discomfort with daily interventions lasting 60 minutes for three chemotherapy cycles (45 days). Participants were divided into two groups: active TENS group (ATG) and placebo TENS group (PTG). The assessment of the effects of TENS was measured by the following instruments: The Visual Analogue Scale (VAS) to assess the symptoms of pain and numbness and Questionnaire for Neurotoxicity Induced by Anti-neoplastic (QNIA) to assess the symptoms of PNIC. RESULTS: A 24-patient study was completed. There was no significant difference between the two groups regarding the primary endpoint of reduced pain symptoms (p = 0.666) and paresthesia (p = 0.673), neither any measurable impact of TENS in the frequency of symptoms (p = 0.5906) or activities of daily living (p = 0.8565). CONCLUSION: These results suggest that TENS applied in frequency modulation mode is not effective for ameliorating the symptoms of peripheral neuropathy induced by chemotherapy during chemotherapy cycles. There was, however, no worsening of symptoms in subsequent cycles after the onset of symptoms

O aumento do consumo de frutose nas últimas décadas está intimamente associado à maior incidência de obesidade e síndrome metabólica e co-morbidades associadas , como , a dislipidemia, a disautonomia e o diabetes. No entanto, a literatura não apresenta caracterização temporal dos eventos que ocorrem até o estabelecimento das doenças. Com base nisso, este trabalho tem como objetivo avaliar as alterações temporais autônomicas e metabólicas em modelo de síndrome metabólica induzida por sobrecarga de frutose, com ênfase no papel do barorreflexo, aqui testado pelo uso da desnervação sinoaórtica. Adicionalmente, pretende-se identificar neste modelo, se as alterações autonômicas precedem ou se seguem às alterações metabólicas. Foram utilizados quatro grupos experimentais (ratos), seguidos por 90 dias: controle (C), tratados com frutose (F), controle desnervado (D) e desnervados tratados com frutose (DF). A sobrecarga de frutose foi feita através de solução em água de beber (10%). A avaliação dos parâmetros cardiovasculares ocorreu pelo registro da pressão arterial via radiotelemetria durante 13 semanas. A frutose foi capaz de promover desenvolvimento de síndrome metabólica, causando aumento da pressão arterial, glicemia de jejum, gordura abdominal e do perfil lipídico em média a partir da sétima semana de tratamento. As alterações autonômicas, principalmente aumento da modulação cardíaca e periférica simpática, ocorreram já na segunda semana de protocolo. Este grupo apresentou ainda alterações de função renal e inflamação. O barorreflexo parece participar das alterações induzidas pela frutose durante o desenvolvimento da síndrome metabólica, uma vez que sua ausência determina mudanças em vários dos parâmetros metabólicos além dos hemodinâmicos já esperados. Adicionalmente, no grupo frutose, o prejuízo funcional do controle reflexo da circulação se estabelece mais tardiamente. Com base em nossos resultados podemos concluir que as alterações no controle autonômico são anteriores e provavelmente contribuem para as alterações metabólicas causadas pelo consumo excessivo de frutose / The increased consumption of fructose in recent decades is closely associated with the higher incidence of obesity, metabolic syndrome and associated comorbidities, such as Dyslipidemia, Dysautonomia, and diabetes. However, the literature does not present temporal characterization of the events that occur until the establishment of the diseases. On this basis, this work aims to evaluate the temporal autonomic and metabolic changes in metabolic syndrome model induced by fructose overload, with emphasis on the role of the baroreflex, here tested using sinoaortic denervation. Additionally, we intend to identify in this model, if autonomic changes precede or follow the metabolic changes. Four experimental groups were used (rats), followed by 90 days: control (C), treated with fructose (F), sinoaortic denervated (D) and denervated treated with fructose (DF). Fructose overload was performed using drinking water solution (10%). Blood pressure recording was performed via radio telemetry for 13 weeks. Fructose was able to promote development of metabolic syndrome, causing blood pressure, fasting blood glucose and abdominal fat increase and changing lipid profile (from the seventh week to thirteenth week of treatment). Autonomic changes, characterized by increased cardiac and peripheral sympathetic modulation, occurred in the second week of Protocol. Fructose group presented changes of renal function and inflammation. The baroreflex seems to participate in the changes induced by fructose during the development of the metabolic syndrome, since his absence determines changes in various metabolic parameters in addition to the expected hemodynamic. Additionally, fructose treatment induced late functional impairment of blood pressure reflex control. Based on our results we can conclude that the changes in autonomic control precede and probably contribute to the metabolic changes induced by the excessive consumption of fructose

Introdução - Alterações cardíacas na anemia falciforme (AF) são frequentes e iniciam-se precocemente. Há evidências de que exista também disfunção na regulação do sistema nervoso autônomo o que pode contribuir com eventos de morbidade. Objetivos Avaliar a modulação autonômica cardíaca por meio da variabilidade da frequência cardíaca em crianças e adolescentes com anemia falciforme. Método - Estudo analítico no qual foi realizada uma comparação da variabilidade da frequência cardíaca em 45 crianças e adolescentes, menores de 20 anos, com anemia falciforme, com um grupo controle pareado um a um por idade e sexo. A frequência cardíaca foi obtida pelo frequencímetro de pulso e analisada, batimento a batimento. Estes pacientes são usuários do ambulatório de hematologia pediátrica do Sistema Único de Saúde. Esta pesquisa está em consonância com a resolução 466/2012 do Ministério da Saúde. Resultados - Observamos diferença significativa nos índices do domínio da frequência (VLF, LF, HF e LF/HF). Estas diferenças não foram observadas nos pacientes em uso de hidroxiureia. Conclusão - Existe uma disfunção autonômica na AF que ocorre desde a infância, podendo estar relacionada a uma menor modulação do simpático e uma maior modulação do parassimpático. Esta diferença não foi observada em pacientes em uso de hidroxiureia / Introduction - Cardiac changes in sickle cell disease (AF) are frequent and begin early. There is evidence that there is also dysfunction in the regulation of the autonomic nervous system, which may contribute to morbidity events. Objectives - To evaluate the autonomic cardiac modulation by heart rate variability in children and adolescents with sickle cell anemia. Method - An analytical study comparing the heart rate variability of 45 children and adolescents, younger than 20 years, with sickle cell anemia, with a control group matched one by one by age and sex. The heart rate was obtained by pulse frequency and analyzed, beat by beat. These patients are attending the pediatric hematology outpatient of the National Health System. Results - We observed a significant difference in the frequency domain indexes (VLF, LF, HF and LF / HF). The results of this study are in agreement with resolution 466/2012 of the Ministry of Health of Brazil. These differences were not observed in patients taking hydroxyurea. Conclusion - There is an autonomic dysfunction in AF that occurs from childhood, and may be related to a lower modulation of the sympathetic and greater modulation of the parasympathetic. This difference was not observed in patients taking hydroxyurea

Thesis (doctoral)--University of Limburg, Maastricht, 1992. / Summary in Dutch. Includes bibliographical references (p. 109-119)

Profound lymphopenia has been observed during many acute viral infections, and our laboratory has previously documented a type 1 IFN-dependent loss of most memory (CD44hi) and some naïve (CD44lo) CD8 T cells immediately preceding the development of the antiviral T cell response at days 2-4 following lymphocytic choriomeningitis virus (LCMV) infection. In this thesis, I will examine additional mechanisms involved in the early attrition of CD8 T cells and evaluate whether antigen-specific and non-specific CD8 T cells are equally susceptible. Lastly, I will examine whether the early attrition of CD8 T cells contributes to the generation of an effective immune response. Poly(I:C), a potent inducer of type 1 IFN, was previously shown to cause the attrition and apoptosis of CD8α+CD44hi cells in normal mice, but not in type 1 IFN receptor–deficient mice (IFN1-R KO). I questioned whether additional molecule(s) might contribute to the type 1 IFN-induced apoptosis of CD8α+CD44hi cells. I used a PCR array to determine the expression of 84 apoptosis-related genes at 6 hours post-poly(I:C) treatment, relative to an untreated control. There was an 11-fold increase in CD40 RNA expression in CD8α+CD44hi cells isolated from poly(I:C)-treated mice. CD40 protein expression was also increased on CD8α+CD44hi cells, peaking between 9 and 12 hours following poly(I:C) treatment, before declining thereafter. This increase in CD40 protein expression directly correlated with an increase in Annexin V reactivity, an indicator of early apoptosis. Nevertheless, CD40 was not required for the loss of CD8α+CD44hi cells, as both wildtype and CD40-deficient mice were equally susceptible to the poly(I:C)-induced attrition. Upon further characterization, I found this population of CD40+CD8α+CD44hi cells to be CD11c+B220-Thy1.2- MHCIIhi, which is consistent with a “lymphoid” CD8α+ DC phenotype. Kinetic analysis revealed a type 1 IFN-dependent increase in this CD8α+ DC population at 12 hours post-poly(I:C) treatment. This increase was only observed in the spleen, as no increase in percentage was observed in the peritoneal cavity (PEC), lungs, inguinal lymph nodes (iLN), or peripheral blood. Collectively, these results suggest that the type 1 IFN-dependent increase in splenic CD8α+DCs accounts for the observed increase in Annexin V reactive cells following poly(I:C) treatment. These findings required a re-evaluation of the type 1 IFN-induced attrition of CD8+CD44hi T cells with an anti-CD8β antibody, which is a more exclusive marker for T cells than the anti-CD8α antibody. Kinetic analysis revealed a significant decrease in splenic CD8β+CD44hi T cells at 12 hours post-poly(I:C) treatment. This reduction in splenic CD8β+CD44hi T cells was not due to trafficking to other organs, as the PECs, lungs, iLN, lungs, and peripheral blood all exhibited significant, although varying, decreases in the percentage of CD8β+CD44hi T cells at 12 hour following poly(I:C) treatment. These data support the notion that the type 1 IFN-induced attrition of CD8β+CD44hiT cells was a “global” phenomenon and could not be completely due to migration out of the spleen. The attrition of CD8β+CD44hi T cells was also dependent upon type 1 IFN at 3 days post-LCMV infection, as there was no significant reduction of this population in IFN1-R KO mice. The loss of wildtype CD8β+CD44hi T cells correlated with an increased activation of caspases 3 and 8, which are enzymes that play essential roles in apoptosis and inflammation. A significant loss of CD4+CD44hi T cells, which also correlated with an increased activation of caspases 3 and 8, was observed at 3 days post-LCMV infection. Collectively, these results suggest that attrition of both CD4+CD44hi and CD8β+CD44hiT cell populations is type 1 IFN-dependent and associated with the activation of caspases following LCMV infection. At 3 days post-LCMV infection, both wildtype CD8β+CD44hi and CD4+CD44hi T cell populations had a higher frequency of cells with fragmented DNA, a hallmark characteristic of the late stages of apoptosis, as revealed by terminal transferase dUTP nick end labeling (TUNEL), relative to uninfected controls. This suggests that the loss of both populations was due to apoptosis. Therefore, I questioned whether the LCMV-induced apoptosis of both CD4+CD44hi and CD8β+CD44hi T cell populations occurred through a mitochondrial-induced pathway involving the pro-apoptotic molecule Bim. The attrition of both CD4+CD44hi and CD8β+CD44hi T cells was significantly higher in wildtype mice compared to Bim KO mice at 3 days post-LCMV infection. Moreover, both wildtype CD8β+CD44hi and CD4+CD44hi T cell populations had higher frequency of TUNEL+ cells, relative to Bim KO populations. These results suggest that the apoptosis of CD8β+CD44hi and CD4+CD44hiT cells, following LCMV infection, might occur through a mitochondrial-induced pathway involving Bim. Studies have shown “lymphoid” CD8α+ DCs to be involved in the phagocytosis of apoptotic lymphocytes. Therefore, I evaluated whether host CD8α+ DCs are capable of phagocytosing apoptotic lymphocytes by adoptively transferring CFSE-labeled wildtype donor splenocytes (Ly5.1) into congenic wildtype hosts (Ly5.2), followed by inoculation with poly(I:C). There was an increased frequency of donor cells (Ly5.1, CFSE+) within the host CD8α+CD11c+ gate at 9 and 12 hours post-poly(I:C) treatment. The results suggest that type 1 IFN-activated CD8α+DCs might aid in the rapid clearance of apoptotic cells during the type 1 IFN-induced attrition associated with viral infections. I next questioned whether TCR engagement by antigen would render CD8 T cells resistant to attrition. I tested whether a high concentration of antigen (GP33 peptide) would protect LCMV-specific naïve TCR transgenic P14 cells specific for the GP33 epitope of LCMV and GP33-specific LCMV-immune cells from depletion. Both naïve P14 and memory GP33-specific donor CD8 T cells decreased substantially 16 hours after inoculation poly(I:C), regardless of whether a high concentration of GP33 peptide was administered to host mice beforehand. The increased activation status of naïve antigen-specific cells via peptide inoculation did not confer resistance to type 1 IFN-induced depletion. Donor naïve P14 and LCMV-specific memory cells were also depleted from day 2 LCMV-infected (Clone 13) hosts by 16 hours post-transfer. These results indicate that antigen engagement does not protect CD8 T cells from the type 1 IFN-induced attrition associated with viral infections. Computer models indicated that early depletion of memory T cells may allow for the generation for a more diverse T cell response to infection by reducing the immunodomination caused by cross-reactive T cells. To test this in a biological system, I questioned whether the reduced apoptosis of the crossreactive memory CD8 population (NP205), in aged LCMV-immune mice (18-22 months), following heterologous virus challenge (PV), would allow it to dominate the immune response. At day 8 post-PV infection, the cross-reactive memory CD8 T cell response (NP205) was more immunodominating in aged LCMV-immune mice relative to younger LCMV-immune mice. This was indicated by the increased ratio of the cross-reactive NP205 response to the newly arising noncross-reactive, PV-specific NP38 response in older LCMV-mice relative to younger LCMV immune-mice, at day 8 post-PV infection. These data suggest that the early attrition of T cells allows for the generation of a more diverse T cell response to infection by reducing the immunodomination caused by crossreactive T cells. Collectively, these findings offer further insight into the early attrition of T cells associated with viral infections.