A wealth of research has reported possible risk and predictive factors for dementia, the variance across populations and the possible reasons for this variance. This thesis attempts to describe demographic and modifiable risk factors for dementia, with the emphasis on the association between (phyto) estrogens and cognitive function.

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Introdução: O Questionário do Informante sobre o Declínio Cognitivo do Idoso (IQCODE) é um instrumento de rastreio que se baseia nas informações fornecidas por familiares ou cuidadores acerca de um possível declínio cognitivo do paciente. Embora tenha boa sensibilidade para a identificação de casos suspeitos de demência, poucos estudos avaliaram as propriedades diagnósticas do IQCODE no rastreio do comprometimento cognitivo leve (CCL). O CCL corresponde a uma condição de risco para o desenvolvimento de demência, sendo caracterizado pela presença de alterações cognitivas que podem ser mensuradas objetivamente, indicando um declínio em relação ao desempenho esperado para indivíduos da mesma faixa etária e nível de instrução. Tais alterações cognitivas (ou déficits) são insuficientes para o diagnóstico de demência, no caso de um funcionamento cognitivo global preservado e da capacidade de desempenhar as atividades da vida diária (Winblad, 2004). Objetivos: Examinar as propriedades diagnósticas do IQCODE no rastreio do CCL, identificando os pontos de corte do teste IQCODE que melhor separam indivíduos idosos cognitivamente normais dos indivíduos com CCL; correlacionar os resultados obtidos com outros testes de rastreio cognitivo amplamente utilizados em nosso meio, como o Mini-Exame do Estado Mental (MEEM), o Teste do Desenho do Relógio (TDR) e o Teste Cognitivo de Cambridge (CAMCOG); identificar entre os 26 itens do IQCODE os agrupamentos (clusters) que contribuem para a identificação dos casos de CCL. Métodos: Estudo de corte transversal em amostra de 167 indivíduos idosos (Controles n=51, CCL n=58 e Demência de Alzheimer (DA) n=58) acompanhados no Ambulatório de Psicogeriatria do LIM-27, Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. O diagnóstico do estado cognitivo (padrão-ouro) estabelecido por meio de consenso multidisciplinar, levando-se em consideração as informações clínicas e o desempenho em testes neuropsicológicos: A idade média dos indivíduos de cada grupo foi, respectivamente, de 67,5 (±5,6), 70,2 (±6,1) e 75,5 (±8,4) anos, e a escolaridade média foi de 12,6 (±5,4), 9,6 (±5,7) e 8,5 (±5,5) anos. Análises de curvas ROC (Receiver Operating Characteristics) foram realizadas para avaliar a acurácia diagnóstica do IQCODE e demais testes comparativos na separação dos pacientes de cada grupo diagnóstico, comparados dois a dois (CCL versus Controles, CCL versus DA, DA versus Controles); por meio de regressão logística, avaliou-se o potencial do uso combinado do IQCODE em conjunto com os demais instrumentos de rastreio para predizer a ocorrência de CCL e DA; finalmente, por meio de análise de clusters, avaliou-se a distribuição dos diferentes itens do IQCODE nos pacientes com CCL e seus subtipos. Resultados: Os pontos de corte do IQCODE para a separação dos grupos diagnósticos foram: (a) DA versus Controles: 3,3 (AUC=0,90; sensibilidade: 84,5%; especificidade: 82,4%); (b) CCL versus Controles: 3,1 (AUC=0,73; sensibilidade: 77,6%; especificidade: 60,8%); (c) CCL versus DA: 3,4 (AUC=0,81; sensibilidade: 79,3%; especificidade: 70,7%). O IQCODE apresentou melhor correlação com o CAMCOG (=0,542; p<0,001). Com base na análise de cluster, estimou-se que o agrupamento que contém itens relacionados à memória episódica foi o mais relevante para identificar os pacientes portadores de CCL amnéstico. Conclusões: O uso do IQCODE obteve melhores resultados para diferenciar idosos cognitivamente normais de CCL quando utilizado em conjunto com o CAMCOG. A análise de cluster do IQCODE melhor prediz CCL e seus subtipos / Introduction: The Informant Questionnaire of Cognitive Decline in the Elderly is a screening diagnostic instrument which is based on given information from family members and caregivers regarding a possible patients cognitive impairment. Despite its good sensitivity for suspected dementia caseness, few studies have been carried out using the diagnosis properties of the IQCODE to screen for Mild Cognitive Impairment (MCI). MCI corresponds to a condition of a risk factor for dementia outcome and is characterized by the presence of cognitive changes measured objectively, indicating an impairment in comparison with the expected performance for individuals at the same age and years of schooling. These deficits are insufficient for dementia diagnosis in case of preserved global cognitive functioning as well as in the capacity to perform daily activities (Winblad, 2004). Objectives: Examine diagnostic properties of the IQCODE in identifying cut-off scores which best distinguish the cognitively normal elderly from those with MCI; to correlate these results with other widely used cognitive tests, such as the Mini Mental State Examination (MMSE), the Clock Drawing Test (CDT) and the Cambridge Cognitive Test (CAMCOG); to identify among the 26 items in the IQCODE those clusters which best contribute to the identification of the cases. Methods: Cross-sectional study in a sample of 167 elderly subjects (Controls: n=51, MCI: n=58 and Alzheimer Disease (AD): n=58) followed at the Psychogeriatric Clinic of the Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo. The cognitive diagnosis was reached by consensus at expert multi-disciplinary meetings (gold standard), taking into account clinical and neuropsychological evaluation. The mean age in each group was respectively: 67.5(±5.6), 70.2 (±6.1) and 75.5 (±8.4) years, and mean of years of schooling were 12.6(±5.4), 9.6(±5.7) and 8.5(±5.5) years. ROC (Receiver Operating Characteristics) Curve analysis were carried out to determine diagnostic accuracy of the IQCODE and the comparative tests in paired sets (MCI versus Controls, MCI versus AD, AD versus Controls); by logistic regression analysis it was evaluated the prediction of MCI and AD with the IQCODE and its combined usage with the comparative tests; finally by cluster analysis it was evaluated the different distribution of the IQCODE items in MCI patients and its subtypes. Results: The IQCODE cut-off scores for diagnostic groups separation were: (a) AD versus Controls: 3.3 (AUC=0.90; sensitivity: 84.5%; specificity: 82.4 %( b) MCI versus Controls: 3.1 (AUC=0.73; sensitivity: 77.6%; specificity%: 60.8); (c) MCI versus AD: 3.4 (AUC=0.81; sensitivity: 79.3%; specificity: 70.7%). The IQCODE had the best correlation with the CAMCOG (=0.542; p<0.001). According to cluster analysis, the episodic memory grouping was the most relevant in identifying amnestic MCI. Conclusions: The IQCODE achieved best results to discriminate cognitively unimpaired elderly from MCI when combined with the CAMCOG. Cluster analysis of the IQCODE better predicts MCI and its subtypes.

Background: Mild Cognitive Impairment (MCI) is a clinical construct reputed to represent an intermediate stage on a continuum between normal aging and cognitive decline. Conceptual and prognostic ambiguity can lead to significant diagnostic challenges and there is a need for accurate screening tests which can assist clinicians with decision-making. A diagnosis of MCI is also associated with considerable uncertainty for patients who may be adjusting to cognitive difficulties along with an increased risk of developing dementia. Beliefs about MCI may influence psychosocial adjustment, and individual differences in ‘psychological flexibility (PF)’, as conceptualised by the Acceptance and Commitment Therapy (ACT) model, may also be involved in this process. Objectives: In order to evaluate the accuracy and clinical utility of a recently developed screening tool for MCI, the Montreal Cognitive Assessment (MoCA), a systematic review of validation and diagnostic test accuracy (DTA) studies for this measure was conducted. Psychosocial adjustment to a diagnosis of MCI was also a key focus. An empirical study was therefore carried out with the aim of evaluating the possible relationships between cognitive impairment, illness representations about MCI, psychological wellbeing and quality of life (QoL), and to assess the potential involvement of PF. Method: Following a systematic search of relevant electronic databases and reference lists, validation and DTA studies of the MoCA were identified and evaluated for methodological quality. For the empirical study, patients recently diagnosed with MCI were recruited from local NHS memory clinic services and completed the MoCA and a questionnaire pack assessing illness representations, PF, mood, anxiety and QoL. Results: The systematic review identified 18 validation and DTA studies. Few of the studies achieved high ratings for methodological quality and problems with representativeness and generalisability were identified. Nevertheless, sensitivity levels appeared robust across studies, though specificity was variable. For the present empirical study, participants reported a spectrum of positive and negative beliefs about MCI. Distress attributed to MCI was associated with anxiety, along with perceptions of more serious illness consequences, while higher PF was associated with higher perceived QoL and mood. Lived experience of MCI appeared to have more relevance to psychosocial adjustment than objective cognitive impairment. Conclusions: The results of the systematic review indicate that while the MoCA is a robust tool overall in the identification of cognitive impairment, estimates of accuracy may be exaggerated by inter-study variation and bias. More rigorous validation studies are therefore needed. Implications for clinical decision-making regarding MCI are discussed and recommendations for future accuracy studies are outlined. The empirical study supported the findings of previous studies of the relevance of illness representations to psychosocial adjustment in MCI and added to the evidence base by providing preliminary support for the possible involvement of PF. The results suggest that both cognitive content and PF may represent possible vehicles for therapeutic change in patients with adjustment difficulties, and indicate that further investigation of these factors is warranted. Conclusions are limited, however, by small sample size and low statistical power. Replication of these findings with a larger and more representative sample is therefore recommended.

One in nine North American women will be diagnosed with breast cancer in their lifetime and most will receive chemotherapy as part of their treatment. Although advances in treatment have increased survivorship, some research suggests chemotherapy results in cognitive deficits in a subset of recipients, a condition known as chemo-fog, thereby compromising quality of life. However, inconsistencies in methodology and neuropsychological assessment have complicated comparison of findings. The first objective of this thesis was to review the methodological issues with an emphasis on the quantitative techniques typically employed. A comparison of group and individual based analyses found negligible effects for both univariate and multivariate approaches while individual based analyses identified severe declines in function in a subset of participants. A standardized-regression based (SRB) approach was recommended as the method of choice. Furthermore, it was recommended that the number of tests be limited since comprehensive batteries can complicate identification due to increased risk of misclassification. Therefore, the second goal of the thesis was to evaluate the sensitivity of a reduced battery to the declines associated with chemo-fog. A comprehensive neuropsychological battery comprising 23 tests was compared to a subset of nine tests. SRB analyses demonstrated that a more selective battery was equally useful and may be appropriate for identification of chemo-fog. Given the variability in the composition of neuropsychological test batteries, the final aim of this thesis was to compare the structure of the theoretical cognitive domains with ones identified through exploratory factor analyses (principle axis factoring) to evaluate the convergence between the two. The results demonstrated there is statistical support for the conceptual framework that underlies the composition of the domains. The contributions of this thesis include providing methodological guidelines for those conducting future research in this area to ensure that results are comparable across studies and are meaningful, and evaluating the utility of a screening battery to facilitate identification of chemo-fog. In addition, it was demonstrated that despite the lack of professional guidelines informing the selection and construction of neuropsychological test batteries, there is statistical evidence to support the practice of grouping tests into domains based on theoretical grounds.

This dissertation describes separate but related studies that explore the prospective memory abilities of older adults and individuals with Mild Cognitive Impairment/Early Alzheimer’s disease. Prospective memory (PM) refers to the type of memory utilized to execute planned actions in accordance with a specific event. PM is critical to maintaining functional independence in older adults, as it can refer to such basic acts as remembering to turn off a stove or taking one’s medication. Research suggests PM abilities decline within normal aging and to a greater extent in Mild Cognitive Impairment (MCI) and early Alzheimer’s Disease (AD). Together, the studies assessed and compared the PM abilities across healthy younger and older adults, individuals with MCI, and individuals with early AD while exploring two major theories that seek to explain PM retrieval. The preparatory attentional and memory process theory of PM (PAM) assumes that PM retrieval requires resource-demanding preparatory attentional processes, whereas the Dynamic Multiprocess theory (DMPT) assumes that retrieval can also occur spontaneously (Scullin, McDaniel, & Shelton, 2013; Smith & Bayen, 2006). Study 1 used a novel laboratory PM task in which the focality and the frequency of PM cues were manipulated to compare the PM abilities of cognitively healthy younger and older adults. The results revealed significant differences in the patterns of performance between the younger and older adults based on the focality and frequency of cues which indicated different attentional allocation strategies. Study 2 examined the impact of cognitive impairment on PM abilities by using the same paradigm to compare the performance of cognitively healthy older adults to individuals with MCI and early AD. The results again revealed significant differences in the patterns of performance which indicated that these groups may have used different strategies of attentional allocation depending on the focality and cue frequency. Taken together, the findings in Studies 1 and 2 were mixed with respect to the predictions of the DMPT and PAM. The MCI group, in particular, demonstrated a unique performance profile that suggests the neuropathophysiological changes associated with this diagnosis may lead to the reliance on different PM retrieval processes compared to healthy older adults. Finally, Study 3 explored the use of a more naturalistic and ecologically valid PM task to compare the PM performance of individuals with MCI and early AD to healthy older adults without cognitive impairment. The results showed that, after taking the learning and retrospective memory scores into account, the significant differences between groups in PM accuracy on this task can mostly be accounted for by these factors. Nevertheless, the AD group was found to display significantly lower PM accuracy with event-based cues with a weak association between cue and action compared to the older adult and MCI groups after controlling for these factors. These findings provide valuable theoretical, methodological, and clinical contributions which will be discussed.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22732号 / 医博第4650号 / 新制||医||1046(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 髙橋 良輔, 教授 中山 健夫, 教授 川上 浩司 / 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(人間健康科学) / 甲第23129号 / 人健博第91号 / 新制||人健||6(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 澤本 伸克, 教授 十一 元三, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

BACKGROUND: It has long been accepted that the environment we experience can impact our well-being; throughout recorded history, the greatest prevalence and severity of disease has been experienced by marginalized and underserved populations. However, the translation of such nontangible influences into biological changes in our health has been elusive until the recent advent of epigenetic studies. Modifications outside of the genome play a critical role in regulating transcription as well as subsequent gene expression without altering DNA sequencing by controlling the accessibility of the DNA for interaction with key initiation proteins and enzymes. These modifications, which include DNA methylation, histone acetylation, and small noncoding microRNA regulation, have increasingly been found to have a fluid, adaptive response to experiences throughout life. Based on the literature supporting societal stressors negatively impacting neurologic outcome, as well as elucidating an association between epigenetic changes and adverse neurologic outcome, we hypothesize that alterations in CpG methylation sites associated with socioeconomic adversity will also be correlated with the incidence of Neurodevelopmental Disorders. METHODS: 889 of the 1,506 neonates initially recruited from 14 medical centers throughout the United States at their time of birth qualified to participate in this study. Placental samples were taken immediately following delivery and neonatal blood samples were taken within the first month of life. Children that survived were followed at 2 years old and 10 years old to evaluate for the presence of four possible Neurodevelopmental Disorders: cognitive impairment, Cerebral Palsy, Autism Spectrum Disorder, and epilepsy. Taking this data as well as demographic information into consideration, the entire cohort included in this study was first evaluated for aberrant methylation levels at 33 CpG sites previously associated with socioeconomic adversity to analyze the degree of significant correlation between altered methylation status and Neurodevelopmental Disorder prevalence. A secondary Epigenome-Wide Association Study was conducted for each of our 889 participants to pinpoint significant changes in CpG methylation in order to evaluate the relationship between altered methylation of particular genes and incidence of Neurodevelopmental Disorders. Taking the previous finding that cognitive impairment imposes a greater burden on both the individual and society than non-cognitive impairment into consideration, both analyses were categorized based on this measure of impairment severity: No Impairment, Non-Cognitive Impairment (diagnosed with Cerebral Palsy, Autism Spectrum Disorder, and/or epilepsy without cognitive deficit), and Cognitive Impairment (cognitive deficit with or without other neurodevelopmental disorders present). RESULTS: Primary analysis of the 33 CpG sites previously associated with socioeconomic adversity did not reveal any significant associations with Non-Cognitive or Cognitive Impairment. However, cg15519318 and cg10613063 (located in the PCCB gene) were marginally associated with Non-Cognitive Impairment while cg02765535 (located in the NTN4 gene) was marginally associated with Cognitive Impairment. Secondary analysis of the entire epigenome found 4 CpG sites significantly associated with Non-Cognitive Impairment (cg07322235, cg13592565, cg13723879, and cg24387818) as well as 4 CpG sites significantly associated with Cognitive Impairment (cg23081580, cg14134658, cg00762003, and cg08546514). DISCUSSION: We were not able to define a significant relationship between the CpG methylation sites related to socioeconomic adversity and adverse neurodevelopmental outcomes. This could stem from several causes, including insufficient power as well as limiting our evaluation of the extensive list of environmental influences to the four measures of societal stress focused on in this study (low educational attainment, single relationship status, public health insurance, and receiving supplemental nutrition assistance). Investigating the epigenome for differential methylation that was significantly associated with the incidence of Neurodevelopmental Disorders identified CpGs associated with several important genes, including genes coding for Neuregulin-3 (NRG3) and Premature Ovarian Failure Actin Binding Protein 1B (POF1B) region with Non-Cognitive Impairment as well as genes coding for Six-Transmembrane Epithelial Antigen of Prostate 2 Metalloreductase (STEAP2), Ly1 Antibody Reactive (LYAR), 1-Acylglycerol-3-Phosphate O-Acyltransferase 3 (AGPAT3), and Ninein-like protein (NINL) with Cognitive Impairment.

Individuals with mild neurocognitive disorder complete many activities of daily living independently; however, they may require the use of compensatory strategies while performing everyday tasks. Compensatory strategies, such as external memory aids, incorporate a strengths-based approach to enhance the functional needs of individuals. Although external memory aids have a strong evidence-base, limited assessment tools and interventions are available to facilitate the development of individualized treatment plans that promote sustained strategy use. To better support the everyday needs of individuals with mild neurocognitive disorder and to inform clinicians who are developing interventions, the current dissertation includes four paper that examine a functional framework for external memory aid assessment and intervention. The first paper examined a group intervention teaching three types of external memory aids on functional strategy use, perceived strategy use, and cognitive skills. The second paper identified individual preferences for experiences with external memory aids during and following intervention. The third paper examined individual changes in functional and perceived strategy use following a group-based intervention teaching external memory aids. Lastly, the fourth paper examined the content validity and internal structure of the Functional External Memory Aid Tool: a measure that explores external memory aid use with simulated everyday tasks. By understanding the weaknesses in currently used assessment and intervention practices and the unique preferences of clients, this multi-manuscript dissertation aims to enhance the immediate and long-term needs of individuals with mild neurocognitive disorder.