Neurocognitive profile and cognitive intervention in Alzheimer's disease

Tese de Doutoramento em Psicologia (Especialidade de Psicologia Clínica)

The role of IFNγ in higher brain function: in health and under chronic stress

Tese de Doutoramento em Ciências da Saúde

From the periphery to the brain: Lipocalin-2, a friend or foe?

Lipocalin-2 (LCN2) is an acute-phase protein that, by binding to iron-loaded siderophores, acts as a potent bacteriostatic agent in the iron-depletion strategy of the immune system to control pathogens. The recent identification of a mammalian siderophore also suggests a physiological role for LCN2 in iron homeostasis, specifically in iron delivery to cells via a transferrin-independent mechanism. LCN2 participates, as well, in a variety of cellular processes, including cell proliferation, cell differentiation and apoptosis, and has been mostly found up-regulated in various tissues and under inflammatory states, being its expression regulated by several inducers. In the central nervous system less is known about the processes involving LCN2, namely by which cells it is produced/secreted, and its impact on cell proliferation and death, or in neuronal plasticity and behaviour. Importantly, LCN2 recently emerged as a potential clinical biomarker in multiple sclerosis and in ageing-related cognitive decline. Still, there are conflicting views on the role of LCN2 in pathophysiological processes, with some studies pointing to its neurodeleterious effects, while others indicate neuroprotection. Herein, these various perspectives are reviewed and a comprehensive and cohesive view of the general function of LCN2, particularly in the brain, is provided.

Age effects on EEG correlates of the Wisconsin card sorting test

Body and brain undergo several changes with aging. One of the domains in which these changes are more remarkable relates with cognitive performance. In the present work, electroencephalogram (EEG) markers (power spectral density and spectral coherence) of age-related cognitive decline were sought whilst the subjects performed the Wisconsin Card Sorting Test (WCST). Considering the expected age-related cognitive deficits, WCST was applied to young, mid-age and elderly participants, and the theta and alpha frequency bands were analyzed. From the results herein presented, higher theta and alpha power were found to be associated with a good performance in the WCST of younger subjects. Additionally, higher theta and alpha coherence were also associated with good performance and were shown to decline with age and a decrease in alpha peak frequency seems to be associated with aging. Additionally, inter-hemispheric long-range coherences and parietal theta power were identified as age-independent EEG correlates of cognitive performance. In summary, these data reveals age-dependent as well as age-independent EEG correlates of cognitive performance that contribute to the understanding of brain aging and related cognitive deficits.

The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a marked decline in cognition and memory function. Increasing evidence highlights the essential role of neuroinflammatory and immune-related molecules, including those produced at the brain barriers, on brain immune surveillance, cellular dysfunction and amyloid beta (Aß) pathology in AD. Therefore, understanding the response at the brain barriers may unravel novel pathways of relevance for the pathophysiology of AD. Herein, we focused on the study of the choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, in aging and in AD. Specifically, we used the PDGFB-APPSwInd (J20) transgenic mouse model of AD, which presents early memory decline and progressive Aß accumulation, and littermate age-matched wild-type (WT) mice, to characterize the CP transcriptome at 3, 5-6 and 11-12months of age. The most striking observation was that the CP of J20 mice displayed an overall overexpression of type I interferon (IFN) response genes at all ages. Moreover, J20 mice presented a high expression of type II IFN genes in the CP at 3months, which became lower than WT at 5-6 and 11-12months. Importantly, along with a marked memory impairment and increased glial activation, J20 mice also presented a similar overexpression of type I IFN genes in the dorsal hippocampus at 3months. Altogether, these findings provide new insights on a possible interplay between type I and II IFN responses in AD and point to IFNs as targets for modulation in cognitive decline.

An efficient chronic unpredictable stress protocol to induce stress-related responses in C57BL/6 mice

Exposure to chronic stress can have broad effects on health ranging from increased predisposition for neuropsychiatric disorders to deregulation of immune responses. The chronic unpredictable stress (CUS) protocol has been widely used to study the impact of stress exposure in several animal models and consists in the random, intermittent, and unpredictable exposure to a variety of stressors during several weeks. CUS has consistently been shown to induce behavioral and immunological alterations typical of the chronic stress-response. Unfortunately C57BL/6 mice, one of the most widely used mouse strains, due to the great variety of genetically modified lines, seem to be resistant to the commonly used 4-week-long CUS protocol. The definition of an alternative CUS protocol allowing the use of C57BL/6 mice in chronic stress experiments is a need. Here, we show that by extending the CUS protocol to 8?weeks is possible to induce a chronic stress-response in C57BL/6 mice, as revealed by abrogated body weight gain, increased adrenals weight, and an overactive hypothalamic-pituitary-adrenal axis with increased levels of serum corticosterone. Moreover, we also observed stress-associated behavioral alterations, including the potentiation of anxious-like and depressive-like behaviors and a reduction of exploratory behavior, as well as subtle stress-related changes in the cell population of the thymus and of the spleen. The present protocol for C57BL/6 mice consistently triggers the spectrum of CUS-induced changes observed in rats and, thus, will be highly useful to researchers that need to use this particular mouse strain as an animal model of neuropsychiatric disorders and/or immune deregulation related to CUS.

Cognitive functioning and efficacy of cognitive intervention in Multiple Sclerosis

Tese de Doutoramento em Psicologia Clínica / Psicologia

Stress, cognitive appraisal, and psychological health: testing instruments for health professionals

The job of health professionals, including nurses, is considered inherently stressful (Lee & Wang, 2002; Rutledge et al., 2009), and thus it is important to improve and develop specific measures that are sensitive to the demands that health professionals face. This study analysed the psychometric properties of three instruments that focus on the professional experiences of nurses in aspects related to occupational stress, cognitive appraisal, and mental health issues. The evaluation protocol included the Stress Questionnaire for Health Professionals (SQHP; Gomes, 2014), the Cognitive Appraisal Scale (CAS; Gomes, Faria, & Gonçalves, 2013), and the General Health Questionnaire-12 (GHQ-12; Goldberg, 1972). Validity and reliability issues were considered with statistical analysis (i.e. confirmatory factor analysis, convergent validity, and composite reliability) that revealed adequate values for all of the instruments, namely, a six-factor structure for the SQHP, a five-factor structure for the CAS, and a two-factor structure for the GHQ-12. In conclusion, this study proposes three consistent instruments that may be useful for analysing nurses’ adaptation to work contexts.