Includes bibliographical references / There are still no diagnostic criteria for a spectrum of neurocognitive disorders (ND) secondary to HIV infection for children. The American Academy of Neurology (AAN) proposes guidelines for assessment of HIV associated neurocognitive disorders (HAND) in HIV infected adults. A cross-sectional clinical cohort study was initiated in Cape Town, in which 120 participants, including a HIV negative healthy control group for comparison, completed clinical and neurocognitive assessments. HIV infected children were either stable on antiretroviral treatment (ART) for a minimum of 6 months or ART naïve. Neuroimaging was completed on 105 children in the cohort study. We compared 75 children vertically infected with HIV aged 6 to 16 years, including both children on antiretroviral therapy (ART) and ART-naïve, with 30 matched controls using diffusion tensor imaging (DTI) measures. We then used the detailed neurocognitive battery; an assessment of adaptive functioning and the AAN system for diagnosing ND to establish whether this system could detect a spectrum of ND in HIV infected older children and adolescents. When comparing HIV uninfected children to HIV infected children this DTI study found damaged neuronal microstructure in the HIV infected children. Significant associations were found between failing first line ART regimen, socio-demographic factors, nutritional-hematological status, HIV-relevant clinical variables, cognitive functioning and white matter integrity in children stable on ART. Children with a clinical diagnosis of encephalopathy (HIVE) had greater white matter damage when compared ART treated children without encephalopathy. DTI also found significant myelin loss in ART naïve children when compared with ART treated children. Using the AAN criteria for HAND, we found that 45.35% of the HIV infected children had a ND. ART naïve slow progressors, who receive limited attention from heath care service s, as they are thought to be 'well', were found to have neurocognitive impairment and white matter microstructural damage. HIV infected children were also more likely to have impaired competence in various domains of functioning. The current findings also underline the possible association of first line treatment failure with white matter brain dysfunction in children on ART. Despite the use of ART and improved virological control with immune reconstitution, there were still a significant percentage of children in this study who were found to have ND. Our findings also suggest that children on ART remain at risk for developing CNS disease, and that this risk extends to physically well ARV naïve slow progressors. The AAN HAND criteria designed for adults was able to identify children and adolescents with important functional cognitive impairments who don't fit criteria for HIVE and would therefore not have been identified otherwise.

Although, in the United States HIV infectivity has increased, survival rates have also improved due to highly active antiretroviral therapies (HAART). Adherence to HAART successfully prevents the progression of AIDS and AIDS-related morbidity for many living with HIV. Unfortunately, HAART’s permeability into the central nervous system (CNS) is limited; thus, the prevalence of HIV-associated neurocognitive disorders (HAND) still persists. The health belief model (HBM) is the theory often used to explain and predict behavior in relation to chronic illness. This model incorporates perceptions of susceptibility, vulnerability, and severity towards a particular illness, and beliefs regarding perceived efficacy and benefits of treatment. This study expands the existing model. Many who live with HIV have a long history of negative experiences, such as stigmatization, traumatic events, and discrimination. I examined supplementary psychosocial and physiological predictor variables, such as stigma, trauma, ethnicity, general medical conditions, HIV-opportunistic infections, and falls; all relevant to disease progression in HIV. Previous researchers found links between stigma and immune function, trauma and memory, ethnicity and neuropsychological impairment, and symptom load and CNS-related alterations. Therefore, this study examined how these different psychosocial predictor variables are associated with HIV-related neurocognitive impairment. My model explained 38.6% of the variance in the outcome variable, and I found that trauma (B = -.15, OR = .87; CI 95% = .75, 1.0, p = .05), ethnicity (B = 2.2, OR = 9.0, CI 95% = 1.68, 48.48, p =.01), general medical conditions (B = .30, OR = 1.34; CI 95% = 1.0, 1.81, p = .05), and falls (B = 2.0, OR = 7.2; CI 95% = 1.1, 47.0, p = .04), were all significant predictors of HIV-related neurocognitive impairment. However, contrary to my hypothesis, HIV-related opportunistic infections and HIV-related stigma were not significant predictors of HIV-related neurocognitive impairment. I hope that my results will contribute to revisions of older health models as well as suggest avenues for primary and secondary prevention and intervention to address those living with HIV/AIDS.

Chronic Traumatic Encephalopathy (CTE) has been linked to contact sports, most notably boxing and American football, due to their propensity for repetitive head impacts. Concerns in the community for the safety of athletes in all contact sports has driven a significant amount of research into concussions, their long term effects, and strategies for treatment and prevention. Knowledge of long term brain health in response to neurotrauma is limited, a gap especially noticeable in the literature on non-catastrophic brain injuries sustained as a child. Concussion is a common injury that is often self-resolving with no lasting neurologic or cognitive deficits. Although repetitive brain trauma is hypothesized to be necessary and sufficient to lead to CTE, no human or animal models have definitively demonstrated the pathophysiologic connection or confirmed the mechanism of symptoms. The research to date has been case based, lacking prospective cohorts, with data complicated by convenience sampling. These factors limit the generalizability of conclusions. CTE is neuropathologically defined with variable symptoms; however, it is only diagnosable at postmortem autopsy making the etiology and prevalence difficult to understand. As more research is published to understand if there is an association between a neurocognitive degenerative disease and contact sports, the concentration is on professional athletes. Yet professional athletes do not represent the overwhelming majority of all contact sport participants. The proposed study will compare adults who participated in youth football, but not beyond the high school level, to a control group of adults who did not play contact sports. Evaluating their cognitive function with an online assessment, the Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A), data will be analyzed for signs of clinical cognitive impairment. The objective is to measure adults who represent the high percentage of youth football players who do not continue to the advanced levels. Data obtained from this study will help communities make informed decisions, and create the foundation for future studies on long term benefits and risks of contact sports for children.

The prevalence of milder forms of HIV-associated neurocognitive disorders (HAND) is rising despite combination antiretroviral therapy (cART). Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, but causes neurological symptoms that may interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HAND in patients on cART. Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human “Swedish” mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Aβ) production (Chapter 3). Treatment with EFV or the EFV containing regimen generated significantly increased soluble Aβ, and promoted increased β-secretase-1 (BACE-1) expression while 3TC, AZT, or, vehicle control did not significantly alter these endpoints. Further, EFV or the EFV containing regimen promoted significantly more mitochondrial stress in SweAPP N2a cells as compared to 3TC, AZT, or vehicle control. We next tested the EFV containing regimen in Aβ - producing Tg2576 mice combined or singly using clinically relevant doses. EFV or the EFV containing regimen promoted significantly more BACE-1 expression and soluble Aβ generation while 3TC, AZT, or vehicle control did not. Finally, microglial Aβ phagocytosis was significantly reduced by EFV or the EFV containing regimen but not by AZT, 3TC, or vehicle control alone. These data suggest the majority of Aβ promoting effects of this cART regimen are dependent upon EFV as it promotes both increased production, and decreased clearance of Aβ peptide. Further (Chapter 4), there is evidence that neural stem cells (NSCs) can migrate to sites of brain injury such as those caused by inflammation and oxidative stress, which are pathological features of HAND. Thus, reductions in NSCs may contribute to HAND pathogenesis. Since the HIV non-nucleoside reverse transcriptase inhibitor EFV has previously been associated with cognitive deficits and promotion of oxidative stress pathways, we examined its effect on NSCs in vitro as well as in C57BL/6J mice. Here we report that EFV induced a decrease in NSC proliferation in vitro as indicated by MTT assay, as well as BrdU and nestin immunocytochemistry. In addition, EFV decreased intracellular NSC adenosine triphosphate (ATP) stores and NSC mitochondrial membrane potential (MMP). Further, we found that EFV promoted increased lactate dehydrogenase (LDH) release, activation of p38 mitogen-activated protein kinase (MAPK), and increased Bax expression in cultured NSCs. Moreover, EFV reduced the quantity of proliferating NSCs in the subventricular zone (SVZ) of C57BL/6 mice as suggested by BrdU, and increased apoptosis as measured by active caspase-3 immunohistochemistry. If these in vitro and in vivo models translate to the clinical syndrome, then a pharmacological or cell-based therapy aimed at opposing EFV-mediated reductions in NSC proliferation may be beneficial to prevent or treat HAND in patients receiving EFV. 1 Portions of this abstract have been previously published (Brown LAM, et al., 2014; Jin, J, et al, 2016) and are utilized with permission of the publisher.1

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13372号 / 論医博第2209号 / 新制||医||1047(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 髙橋 良輔, 教授 小柳 義夫 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Heterogeneity in the profile of HIV-associated neuropsychological disorder (HAND) may obscure understanding of its etiology and prognosis. Despite longstanding acknowledgement of this heterogeneity, HAND diagnostic approaches such as the Frascati criteria characterize neuropsychological function based on the level of impairment, without regard to the pattern of strengths and weaknesses. Attention to these patterns may enhance etiologic and prognostic specificity. We used latent class analysis (LCA) to identify relatively homogeneous subtypes of neurocognitive function in adults with well-treated HIV infection. We compared the diagnostic agreement of latent classes and Frascati categories, as well as their associations with demographics, HIV markers and antiretroviral factors, comorbid medical and psychiatric conditions, and everyday functioning. LCA identified four classes, whose cognitive profiles are depicted in Figure 1: cognitively intact, mild-to-moderate motor/speed impairment, mild-to-moderate memory/visuoconstruction impairment, and moderate mixed impairment. Latent classes and Frascati categories demonstrated good agreement in the overall classification of impaired cognition but more disagreement regarding subtypes of impairment. Both latent classes and Frascati categories demonstrated unique associations with etiologic factors and significant associations with functional outcomes. However, only latent classes, not Frascati categories, were associated with HIV variables. Additionally, functional difficulties were significantly elevated in the motor impairment class but not the memory impairment class despite similar levels of cognitive impairment in the two groups. Findings support the utility of a diagnostic approach that accounts for both the level and pattern of neurocognitive impairment. Future research should examine the neuropathological mechanisms, longitudinal trajectories, and treatments of empirically identified HAND subtypes. / Psychology

Submitted by Claudia Cristina de Góes null (claudia_crgoes@hotmail.com) on 2016-10-25T00:07:10Z No. of bitstreams: 1 Dissertação versão final_claudia_c_goes.pdf: 2050683 bytes, checksum: 70e8dfcecbdd00db785d6e0d61886ba7 (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2016-10-31T13:53:47Z (GMT) No. of bitstreams: 1 goes_cc_me_bauru.pdf: 2050683 bytes, checksum: 70e8dfcecbdd00db785d6e0d61886ba7 (MD5) / Made available in DSpace on 2016-10-31T13:53:47Z (GMT). No. of bitstreams: 1 goes_cc_me_bauru.pdf: 2050683 bytes, checksum: 70e8dfcecbdd00db785d6e0d61886ba7 (MD5) Previous issue date: 2016-06-03 / A estimativa de pessoas vivendo com HIV/AIDS é de 734mil, a maior concentração de casos é na população com idade entre 25 e 39 anos desde 1980 até junho de 2014. Devido à supressão do sistema imune e queda do número de células de defesa CD4, o paciente pode ser acometido por alterações no funcionamento fisiológico e por doenças oportunistas, incluindo as manifestações neurológicas, como os transtornos neurocognitivos associados ao HIV (HAND; HIV-associated neurocognitive disorders). Pessoas com HAND geralmente apresentam comprometimento da aprendizagem e das habilidades motoras, alterações de humor e déficits nos domínios cognitivos, os quais são classificados conforme a gravidade como leve, moderada ou grave e podem comprometer a adesão ao tratamento com antirretrovirais e à qualidade de vida. Contudo, a relação entre estas variáveis, cruciais para a sobrevivência do paciente, não se encontra estabelecida, sendo o envelhecimento uma das variáveis a esclarecer. Objetivou-se traduzir e adaptar o instrumento Simplified Medication Adherence Questionnaire (SMAQ); avaliar e comparar diferenças do desempenho cognitivo entre dois grupos em função da idade e identificar relações entre Qualidade de Vida e adesão à Terapia Antirretroviral combinada. Foram avaliados 50 voluntários com idades entre 21 e 58 anos e divididos em dois grupos (jovens e maduros) que participaram do protocolo completo, composto por testes cognitivos (domínios cognitivos: atenção, memória, linguagem e inteligência) e escalas de rastreio de depressão, ansiedade, uso de drogas psicoativas, adesão ao tratamento e qualidade de vida e situação socioeconômica. Como resultados, foram encontradas diferenças significativas entre os grupos nos seguintes domínios cognitivos: memória episódica, memória operacional, linguagem, processamento visuoespacial e função sensório-motora, tornando possível observar a influência da idade sobre o comprometimento cognitivo em pessoas vivendo com HIV. / In Brazil, 734,000 people are currently estimated to live with HIV / AIDS, and most cases concentrate in the 25 to 39 year-old population born from 1980 to June 2014. Due to suppression of immune system and fall in the number of CD4 T immune cells, a patient may be affected by changes in physiologic functioning and opportunistic diseases, including neurological manifestations such as HIV-associated neurocognitive disorders (HAND). People with HAND usually present learning and motor skills impairments, mood changes, and deficits in cognitive domains, which are classified according to gravity as mild, moderate or severe and may compromise adherence to antiretroviral therapy and quality of life. However, the relation between those variables, which are critical to a patient’s survival, has not been established yet, and aging is a variable to be clarified. The objective of this study was to translate and to adapt the Simplified Medication Adherence Questionnaire (SMAQ) to Brazilian Portuguese; to evaluate and to compare differences in cognitive performance between two groups according to age; and to identify and to compare relations between quality of life and adherence to cART (Combination Antiretroviral Therapy) In this study, 50 volunteers, aged from 21 to 58 years old, were assessed and divided into two groups (young adults and mature). Both groups took part of the full protocol, composed by cognitive tests (cognitive domains: attention, memory, language, and intelligence) and screening scales for depression, anxiety, use of psychoactive drugs, treatment adherence and quality of life, and socioeconomic status. As a result, significant differences between the groups were found in the following cognitive domains: episodic memory, working memory, language, visuospatial processing and sensory-motor function, which made it possible to observe age influence on the cognitive impairment of people living with HIV.

As alterações neurocognitivas associadas ao HIV-1 (HAND) são frequentes em adultos infectados pelo HIV-1 via transmissão sexual. Existe pouca informação sobre HAND em adultos infectados pelo HIV-1 via transmissão vertical. Este estudo teve como objetivos identificar a prevalência das HAND em adultos infectados por transmissão vertical assim como identificar a prevalência de depressão nessa população. Pacientes e métodos: trata-se de um estudo de delineamento transversal, realizado entre janeiro 2016 e maio de 2017, no Serviço de Extensão ao Atendimento de Pacientes HIV/aids (SEAP) da Divisão de Moléstias Infecciosas e Parasitárias do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo. O SEAP é um serviço exclusivamente ambulatorial, localizado na cidade de São Paulo. Os critérios de inclusão foram: (i) pacientes com diagnóstico de infecção pelo HIV-1 por transmissão vertical; (ii) idade igual ou superior a 18 anos; (iii) escolaridade mínima de 4 anos; e (iv) consentimento para participar do estudo. Os critérios de exclusão foram: (i) diagnóstico concomitante de doenças neurológicas oportunistas ou condições neurológicas, previamente documentadas; (ii) uso de substâncias psicoativas; (iii) incapacidade física para aplicação dos testes, (iv) recusa da assinatura do Termo de Consentimento Livre e Esclarecido. Foram utilizados como instrumentos de pesquisa: questionário sociodemográfico, escala de ansiedade e depressão hospitalar, escala de atividades de vida diária de Lawton e bateria neuropsicológica formal. Para análise estatística foram calculadas frequência, média e desvio padrão, assim como testes qui-quadrado, anova e análise posthoc. Valores de p < 0.05 foram considerados estatisticamente significativos. Foi utilizado o programa SPSS 21.0. Resultados: foram avaliados 28 participantes: 15 (53.6%) foram do sexo feminino e a idade média e o desvio padrão (DP) foi de 22 (6.7) anos. Foi identificado HAND em 23 (82,1%) pacientes: 12 (42.9%) tiveram alteração neurocognitiva assintomática (ANI), 6 (21,4%) tiveram comprometimento neurocognitivo leve (MND) e 5 (17.9%) tiveram demência associada ao HIV-1 (HAD). A atenção, velocidade de processamento e velocidade motora foram as funções cognitivas mais comprometidas. 3 (10.7%) pacientes apresentaram depressão; 3 (60%) dos 5 pacientes com HAD apresentaram depressão. Conclusões: neste estudo encontramos elevada prevalência de HAND em adultos infectados pelo HIV-1 via transmissão vertical, chamando atenção também a elevada proporção de pacientes com HAD. Por outro lado, identificamos baixa prevalência de depressão na população total do estudo, mas a prevalência de depressão foi elevada dentre os pacientes com HAD / Neurocognitive disorders associated with HIV-1 (HAND) are common in adults sexually infected with HIV-1. There is little information about HAND in adults vertically infected with HIV-1. This study aimed to identify the prevalence of HAND in adults vertically infected with HIV-1 as well as to identify the prevalence of depression in this population. Patients and methods: This is a cross-sectional study, conducted between January 2016 and May 2017, at the Extension Service for HIV/aids Patients (SEAP) of the Division of Infectious and Parasitic Diseases of the Hospital das Clínicas of University of São Paulo Medical School. SEAP is an exclusively outpatient service, located in the city of São Paulo. Inclusion criteria were: (i) patients diagnosed with HIV-1 infected by vertical transmission; (ii) age equal to or more than 18 years; (iii) minimum schooling of 4 years; and (iv) consent to participate in the study. Exclusion criteria were: (i) concomitant diagnosis of opportunistic neurological diseases or neurological conditions, previously documented; (ii) use of psychoactive substances; (iii) physical incapacity to apply the tests, (iv) refusal to sign the Free and Informed Consent Form. The following research assessment tools were used: sociodemographic questionnaire, hospital anxiety and depression scale, Lawton daily life activity scale and formal neuropsychological battery. For statistical analysis, we calculated frequency, mean and standard deviation, as well as chi-square, anova and post-hoc analysis. Values of p < 0.05 were considered statistically significant. The SPSS 21.0 program was used. Results: 28 participants were evaluated: 15 (53.6%) were female and the mean age and standard deviation (SD) were 22 (6.7) years. HAND was identified in 23 (82.1%) patients: 12 (42.9%) had asymptomatic neurocognitive impairment (ANI), 6 (21.4%) had mild neurocognitive impairment and 5 (17.9%) had dementia associated with HIV-1 (HAD). Attention, processing speed and motor speed were the most compromised cognitive functions. 3 (10.7%) patients presented depression; 3 (60%) of the 5 patients with HAD had depression. Conclusions: in this study we found a high prevalence of HAND in adults vertically infected, also calling attention to the high proportion of patients with HAD. On the other hand, we identified a low prevalence of depression in the total study population, but the prevalence of depression was high among patients with HAD

HIV associado a desordens neurocognitivas (HAND) continua a ser um grave problema atualmente devido à alta prevalência de suas formas mais brandas. Indivíduos HIV+ possuem o comprimento dos telômeros significativamente mais curtos nas células mononucleares do sangue periférico e células T CD8+, quando comparados aos indivíduos HIV negativos. Diante do exposto, o objetivo deste estudo foi avaliar a associação do comprimento dos telômeros de leucócitos em indivíduos infectados pelo HIV com deficiências cognitivas, pois ainda é um assunto bastante controverso. Métodos: Um total de 73 pacientes infectados pelo HIV-1 de ambos os sexos, com idades entre 20 a 60 anos, participaram deste estudo. Entre 19 indivíduos HIV(+) sem comprometimento cognitivo e 54 indivíduos HIV(+) com distúrbios neurocognitivos: 29 alteração neurocognitiva assintomático (ANI), 15 comprometimento neurocognitivo leve a moderado (MND) e, 10 demência associada ao HIV (HAD); 118 indivíduos HIV negativos formaram o grupo controle. Todos os participantes foram submetidos a uma série de testes neuropsicológicos previamente validados. Determinou-se a carga viral de HIV-1 nas células do líquido cefalorraquidiano (LCR) e em PBMC. Utilizou-se DNA a partir de leucócitos periféricos para calcular o comprimento de telômeros por PCR em tempo real. Resultados: O comprimento dos telômeros não foi associado com gêneros e diminuiu com a idade, independentemente do status de HIV. Indivíduos infectados pelo HIV-1com formas mais leves de deficiência neurocognitiva apresentaram um comprimento dos telômeros reduzida em comparação com pacientes HIV+ sem comprometimento neurocognitivo. Não houve correlação entre a carga viral plasmática e o tamanho dos telômeros. Conclusões: Nossos resultados sugerem que o comprimento dos telômeros pode ser considerado um marcador de senescência celular em indivíduos com alterações neurocognitivas / HIV associated neurocognitive disorders (HAND) remains a serious problem today because of the high prevalence of its milder forms. HIV + individuals have the length substantially shorter telomeres in peripheral blood mononuclear cells and CD8 + T cells compared to HIV negative individuals. Given the above, the objective of this study was to evaluate the association of telomere length of leukocyte (LTL) in HIV-infected individuals with cognitive disabilities because it is still a very controversial subject. Methods: A total of 73 patients infected with HIV-1 of both sexes, aged 20 to 60 years participated in this study. Among 19 HIV patients (+) without cognitive impairment and 54 HIV patients (+) with neurocognitive disorders: 29 asymptomatic neurocognitive disorder (ANI), 15 mild neurocognitive disorder to moderate (MND) and 10 HIVassociated dementia (HAD); 118 HIV-negative individuals formed the control group. All participants underwent a series of previously validated neuropsychological tests. Determined if the viral load of HIV-1 in cerebrospinal fluid cells (CSF) and in PBMC. We used DNA from peripheral leukocytes to calculate the length of telomeres by real time PCR. Results: The telomere length was not associated with genres and decreased with age, irrespective of HIV status. HIV-1-infected individuals with milder forms of neurocognitive impairment had a significantly length of telomeres reduced compared to HIV + patients without neurocognitive impairment. There was no correlation between plasma viral load and the size of telomeres. Conclusions: Our results suggest that telomere length can be considered a marker of cellular senescence in individuals with neurocognitive abnormalities

Face au déclin cognitif, à la perte progressive de l'autonomie et aux troubles du comportement accompagnant l'évolution de la maladie d'Alzheimer et des maladies apparentées (MA2), l'implication de l'aidant naturel auprès de son proche atteint s'intensifie et s'accompagne d'un fardeau. Les données de la littérature montrent que les interventions psychosociales évaluées ont un impact modeste et à court terme sur le fardeau de l'aidant. Par ailleurs, les patients âgés atteints de MA2 et leurs aidants sont exposés à un risque important d'iatrogénie médicamenteuse. L'objectif de ce travail de thèse était de concevoir une prise en soin pharmaceutique intégrée à une intervention psychosociale efficiente permettant de réduire le fardeau des aidants de patients âgés atteints de MA2. Afin de garantir l'efficience de l'intervention à concevoir, des études préalables ont été réalisées afin : (1) d'identifier les facteurs prédictifs de fardeau de l'aidant via une étude transversale, une étude longitudinale et à partir des données de la littérature ; (2) d'identifier les besoins prioritaires des aidants via une enquête Delphi incluant le domaine pharmaceutique après réalisation d'une revue systématique de la littérature ; (3) d'identifier les critères d'efficacité des interventions psychosociales et l'étendue du rôle du pharmacien auprès de la dyade patient/aidant à partir des données de la littérature. Ces différents éléments ont permis de concevoir de façon multidisciplinaire et multicentrique, le protocole de l'étude interventionnelle PHARMAID. Il s'agit d'un essai clinique randomisé, contrôlé, à trois bras parallèles, multicentrique dont l'objectif principal est d'évaluer l'impact d'un suivi pharmaceutique personnalisé intégré à une intervention psychociale sur le fardeau des aidants de patients âgés atteints de MA2 à 18 mois. A ce jour, 72 dyades patient/aidant ont été inclues, soit 30% de l'effectif attendu. Si l'intervention psychosociale combinée ou non aux soins pharmaceutiques de l'étude PHARMAID s'avère efficace, sa pérénnité dans les centres participants et son extension au sein des autres centres mémoires, des services de neurologie ou de gériatrie pourront être envisagées. L'étude médico-économique associée permettra d'estimer les coûts engagés par la mise en place d'une telle intervention, tout en prenant en compte les coûts directs de consommation de soins / Alzheimer’s disease and Related Disorders (ADRD) are associated with a caregiver burden that increases with the progression of the disease. Previous psychosocial interventions reported a moderate improvement on caregiver burden. Patients with ADRD and their caregivers are also exposed to higher risk of developing drug-related problems.Our objective was to design an integrated pharmaceutical care at a multidisciplinary psychosocial intervention that reduces the caregiver burden of aged patient with ADRD.To guarantee the effectiveness of the intervention, preliminary studies were conducted to: (1) identify predicting factors that increase the caregiver burden through a cross-sectional study, a longitudinal study and from a literature review ; (2) to identify the prioritized caregivers’ needs through a Delphi survey, including the pharmaceutical field, after conducting a systematic review of the literature; (3) to identify the effectiveness criteria of psychosocial interventions and the extent of the pharmacist's role with the patient / caregiver dyad from a literature review. Our work leaded to design, in a multidisciplinary and multicentric way, the protocol of the PHARMAID study. The PHARMAID study is a 18-month randomized, controlled, with three parallel groups, and multi-center trial. The primary objective is to measure the impact of personalized pharmaceutical collaborative care integrated to a multidisciplinary psychosocial intervention on the caregiver burden of aged patient with ADRD. To date, 72 dyads have been included, representing 30% of the expected sample. If the effectiveness of this collaborative approach is demonstrated, its durability in the participating centers and its extension in the other memory centers, neurology or geriatric wards could be considered. The costs and the cost-effectiveness of different interventions will also be evaluated through detailed analyses of formal and informal resource consumption during the study