The search for reliable early indicators of age-related cognitive decline represents an important avenue in aging research. Most research on late-life development charts cognitive change as a function of chronological age (CA), however, although CA is a commonly used developmental index, it offers little insight into the mechanisms underlying cognitive decline. In contrast, biological age (BioAge), reflecting the vitality of essential biological processes, represents a promising operationalization of developmental time. My overall programmatic doctoral research interests involve the identification of biological risk factors that predict age-related cognitive decline, impairment and dementia. In this dissertation document, I present: an overview of my empirical contributions to the BioAge and cognitive aging literature throughout my doctoral training; the dissertation project which uses preliminary data from the PREVENT study and provides evidence that elevated plasma pro-inflammatory proteins are associated with cognitive status (healthy controls (HC) vs Alzheimer’s disease dementia (AD)), cognitive performance and are related to poorer cognitive performance in amnestic mild cognitive impairment (a-MCI); and a discussion on the broad implications of the project results and future directions in BioAge research. / Graduate

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.

Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion, with approximately 3.6 million sports related concussions occurring yearly in the United States alone (Bailes, 2015, Azad et al., 2015). An MTBI is an acute brain injury resulting from mechanical energy to the head from external forces (Bailes 2015). Symptoms of an MTBI include visual disturbances, dizziness, nausea and vomiting, light sensitivity, loss of balance, and a general feeling of fatigue (Bailes 2015). MTBI’s are first diagnosed through changes in ImPACT baseline scores as well as Vestibular Ocular Motor Screening (Mucha et al., 2014). Repetitive MTBI and/or repetitive sub-concussive head trauma have been tentatively linked to increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE) (Gardner et al., 2015). The major limitation of the link between MTBI and CTE is that CTE can only be diagnosed post-mortem (Azad et al., 2015). Due to that limitation, the prevalence of CTE is unknown and the amount of MTBI or sub-concussive trauma exposure necessary to produce CTE is unclear (Gardner et al., 2015). Newer methods of research including SNTF immunostaining and L-COSY are being further developed and studied to better diagnose MTBI and its link to CTE by exploring changes in brain protein formation and brain neurochemistry (Johnson et al., 2015, Lin et al., 2015). Through research development and case studies on professional American football players and boxers, a link between MTBI, particularly repetitive MTBI and CTE has been formed (Maroon et al., 2014).

Traumatic brain injury (TBI) is a serious public health concern. Although moderate and severe forms of TBI receive considerable attention, mild TBI accounts for the majority of all injuries. The first two aims of this work used a rodent model of mild blast to simulate primary injury (damage from the blast wave only). The first aim evaluated potential changes in interneurons containing the calcium-binding proteins calretinin or parvalbumin. In addition, morphological changes in astrocytes and microglia were assessed. Brains were analyzed 48 hours and one month following exposure to single or repeated blasts, with a focus on the hippocampus due to its integral role in learning and memory. Results showed significant region-specific alterations in microglia morphology 48 hours following blast. The absence of structural alterations in microglia one month following blast indicated that the regional hippocampal vulnerability may be transient. The second aim compared glial morphologies in the retina and brain (the lateral geniculate nucleus, superior colliculus, and visual cortex) 48 hours or one month following multiple blasts. Fiber degeneration has received considerable attention, however, less is known about the status of glia throughout the visual pathway following mild blasts. Although no structural alterations were detected, it is possible that alterations in glia occurred at a more acute time scale as changes in glia can be rapid and reversible. The final aim of this work focused on the immunocytochemical characterization of tau pathology in the visual cortices of human postmortem brains with advanced chronic traumatic encephalopathy (CTE). CTE is a devastating tauopathy associated with mild, repetitive TBIs. Although visual deficits are reported in CTE, the primary visual cortex is often spared. The main hypothesis under investigation was whether visual association areas would have tau pathology, despite sparing of primary visual cortex. In addition, a sub-class of interneurons containing parvalbumin was used to evaluate a potential cell-specific vulnerability. Results showed increased tau pathology in visual association areas in advanced CTE, that was largely absent from the primary visual cortex. There was no effect on parvalbumin positive interneurons. The results of this work provides valuable insight regarding potential cell-specific resistance to CTE pathology. / 2018-11-03T00:00:00Z

Alzheimer's disease (AD) is the most common form of dementia and results in progressive cognitive decline, particularly in regards to memory (National Institute on Aging, 2012). Prior research has shown sex differences in brain-atrophy rates of AD patients, with women experiencing a higher rate of progression in volume reduction (Skup et al., 2011). This suggests that there may also be differences in cognitive functioning between sexes, particularly in the rate of cognitive decline with a more rapid disease progression for dementing females compared to dementing males. The current study monitored memory function longitudinally in approximately 200 total participants, 100 with Mild Cognitive Impairment (MCI) or probable AD and 100 healthy controls enrolled in an aging study through the Arizona Alzheimer's Disease Research Consortium. Memory performance was evaluated with two memory tests, the Rey Auditory Verbal Learning Test (RAVLT; Rey, 1941) and the Brief Visuospatial Memory Test-Revised (BVMT-R; Benedict, 1997). Memory function was evaluated in participants with at least three data points over a five-year span. A multivariate regression model was used that includes controls for disease severity, age, age at disease onset, education, ethnicity, and medical comorbidities. Results indicated that females in the MCI and AD groups initially performed better than the males, but that over time, female scores had dropped significantly lower than male scores, suggesting a more rapid decline in females. Significant sex differences in cognitive decline may yield a deeper understanding of the development and progression of AD and aid in more effective and sex-specific treatment.

Although there are ample studies confirming that memory self-efficacy (MSE) declines with age, less is known about what factors account for the variation in MSE among older adults. The purpose of this study was to examine the relationship between MSE, diagnostic and clinical characteristics, and subsequent episodic memory performance in older adults. A nonprobability sample of 200 cognitively normal and older adults with mild cognitive impairment (MCI) participating in a longitudinal population-based study investigating the incidence, prevalence and risk factors for MCI completed a questionnaire about self-referent beliefs of MSE. Bandura's (1989) selfefficacy theory and the Integration Model (Whittemore, 2005) informed the descriptive study. Pearson product-moment correlations, a general linear model and a multiple linear regression analysis were conducted. The difference in MSE ratings between the cognitively normal group and the MCI group tested as a whole was significant when adjusting for age, gender and educational attainment (p < .001; ES= 0.585). The overall regression model explained 17 % of the variance of MSE (p < .001) and included age, gender, educational attainment, APOE 4 genotype, family history of dementia, cognitive diagnosis and depressive symptoms. After controlling for age and the other variables of interest, cognitive classification and depression were significant predictors of MSE. Higher MSE ratings were correlated with better episodic memory performance for both groups (r = .273, p < .001). Memory training that capitalizes on the benefits accruing from higher MSE is needed for cognitively normal older adults and older adults with MCI.

The purpose of this study was to measure the academic performance of children with mild hearing loss (20-45 dB) by comparing them with a normal control group. Twenty-four pairs of children in the first through fourth grades were compared. The achievement scores of the second and fourth grade student pairs were compared for the current academic year and for the previous academic year. A two-way analysis of Variance was used to compare the achievement scores from the Iowa Test of Basic Skills of the two groups. The results indicated statistical significance on some subtests of the first and fourth grade student's scores. The standard mean scores of the hearing impaired group was almost always poorer than the normal control group in every grade. The interaction between the two groups in the second and fourth grade showed no significance statistically. The improvement in scores between the two years for the two groups was relatively parallel, however, the hearing impaired group's improvement was usually poorer in most of the subtests. The discussion includes the implications of these results indicating a negative effect of mild hearing loss particularly as the hearing impaired child gets older. It also includes interesting points related to hearing aid management and special services.

This dissertation is a critical examination of the relationship between sleep problems and/or disorders, particularly Obstructive Sleep Apnea (OSA) and Alzheimer Disease (AD). First, I conducted an exhaustive systematic review of existing literature, and identified gaps in research that led to specific research aims. For the first aim, I conducted the first ever-published meta-analysis examining sleep, cognitive decline and AD, providing an aggregate effect of sleep on AD. Second, focusing on OSA, I conducted a study examining OSA’s effect on longitudinal changes on AD biomarkers in cognitive normal, MCI and AD subjects, using data from the Alzheimer Disease Neuroimaging Initiative (ADNI). Lastly, I conducted a review, integrating over 3 decades of research examining OSA and cognition; OSA and subsequent cognitive decline; and OSA and AD; with particular focus in appreciating the heterogeneity of OSA and its outcomes in distinct age groups. Results and implications from my research indicate that ample evidence exists linking sleep impairments and circadian regulating mechanisms directly to clinical symptoms in AD. Sleep problems and/or disorders increases your risk of cognitive decline and AD. OSA is associated with increased AD biomarker burden over time, and effects longitudinal changes in these biomarkers, such that OSA subjects progress faster than non-OSA subjects do. OSA may be age-dependent in older adults (60 – 70 years old) and the elderly (70 years and above) and is associated with neurodegenerative diseases particularly, cognitive decline and AD. Intermittent hypoxia and sleep fragmentation are two main processes by which OSA induces neurodegenerative changes. Therefore, clinical interventions aimed at OSA, such as treatment with CPAP or dental appliances, in cognitive normal and MCI patients, could possibly slow the progression of cognitive impairment to AD.

Parkinson’s disease is a neurodegenerative disease caused by a loss of dopamine-producing neurons in the basal ganglia. Primary motor deficits include resting tremor, bradykinesia, muscular rigidity, and postural instability. Most importantly, patients have difficulty both initiating movements and performing well-timed movements. This study explored the effect of rhythm on the timing of upper extremity movements in patients with Parkinson’s disease. Comparisons were made between an external rhythmic cue, an external rhythmic cue in combination with auditory feedback, and no cue. Fifteen participants performed a simple reaching task in each of the four cueing conditions with the use of an interactive touch table. Condition 1 consisted of no cue. Condition 2 included a metronome set to the participant’s baseline tempo. Condition 3 included a metronome set to the participant’s baseline tempo, and a synthesized tone that occurred as a result of contact with the table. Finally, Condition 4 included no cue, similar to Condition 1. Participants were placed into either a mild/moderate level of impairment group, or a severe level of impairment group. Data were collected for total movement time, initiation time, and delta time for each participant in all four conditions. Results of the study did not reveal a main effect of condition on total movement time, initiation time or delta time. However, post-hoc pair-wise comparisons revealed significant decreases between Condition 1 and Condition 4, which were both uncued conditions, for both total movement time and delta time. In addition, for total movement time, a significant decrease was found between Condition 2 (external rhythmic cue) and Condition 4 (no cue). An immediate effect of cueing was found for initiation time and delta time, but did not reach a level of significance. An immediate effect of cueing on total movement time was not evident. Overall, from Condition 1 to Condition 2 as well as Condition 1 to Condition 3, initiation time and delta time decreased, but total movement time did not. Further analysis of level of impairment could not be conducted because of the small number of participants in the severe level of impairment group. The results suggest that one auditory cue was not more beneficial than the other for improving total movement time, initiation time, or delta time. In addition, the improvement from Condition 1 to Condition 4 for total movement time and delta time suggests that a practice effect was evident for the participants. The results of the study suggest that long-term training of either auditory cue can be an effective rehabilitation technique for patients with Parkinson’s disease to improve the timing of upper extremity movements.

Bakgrund: Under de senaste decennierna har det skett en förändring med minskad svårighetsgrad av symtom och en minskad dödlighet vid stroke. Termen ”minor stroke” används för patienter med milda neurologiska handikapp. Inom hälso- och sjukvården görs bedömningen att dessa patienter inte har funktionsnedsättningar och förväntningarna är att de ska återhämta sig snabbt. Detta är den vanligaste stroke diagnosen men ändå den som får minst uppmärksamhet både kliniskt och vetenskapligt. Syfte: Syftet med undersökningen var att beskriva patienters erfarenhet efter minor stroke. Metod: Kvalitativ ansats med intervju som insamlingsmetod. Urvalet bestod av 10 in remitterade patienter till strokemottagningen Länssjukhuset Kalmar. Data analyserades med innehållsanalys. Resultat: I studiens resultat framkommer tre teman: det var inte som vanligt i kroppen, det fungerade inte som förr och det var inte lätt att återta kontrollen . Informanterna beskrev en bristande delaktighet från sjukvården, generell information och en oklar utskrivning. Först då de kom hem till sin vardag började de förstå vilka svårigheter som stroke hade fört med sig. Deras största svårigheter var dolda funktionshinder såsom kognitiva symtom framför allt hjärntrötthet. De hade svårt att acceptera situationen och till en början negligerade de allvaret. Allt eftersom började de att återta kontrollen i sin vardag, de skapade copingstrategier och hitta en ny livsstil på egen hand. Konklusion: Patienter med minor stroke beskriver svårigheter efter insjuknandet som de behöver fortsatt stöd i att hantera. Tidig uppföljning och fortsatt stöd från sjukvården är viktig. / Background: In recent decades there has been a change with reduced severity of symptoms and reduced mortality of stroke. The term “minor stroke” is used for patients with mild neurological disabilities. In the health care field, it is considered that these patients do not have disabilities, and are expected to recover quickly. This is the most common stroke diagnosis, yet the one who gets the least attention, both clinically and scientifically. Aim: The aim of the study was to describe patients experience after minor stroke. Method: Qualitative approach with interview data collection method. The sample consisted of 10 patients with minor stroke at stroke clinic Länssjukhuset Kalmar. Data were analyzed by content analysis. Results: The result of the study reveals three themes: it was not as before in the body, it did not work as before and it was not easy to regain control. The informants describe a lack of participation from the health care field, no specific information’s and a lack of participation. When the patients came home to their everyday lives, they began to understand the difficulties that stroke had brought them. Their greatest difficulty was hidden disabilities such as cognitive symptoms, especially brain fatigue. They found it difficult to accept the situation and initially ignored the gravity. As they began to regain control in their everyday lives, they created coping strategies and find a new life on their own. Conclusion: Patients suffering from minor stroke that has had onset of difficulties need continued support to manage. Early follow-up and continued support of health care field is important.