The understanding of human brain mechanisms has captured the imagination of scientists for ages. From the quantitative perspective, there is evidence that damages to brain structure affect brain function and, as a consequence, cognitive aspects. As there is evidence that brain structure might be affected by altered cognition. However, the complex interplay between the human brain and the mind remains still poorly understood. This fact has important clinical consequences, limiting applications devoted to the prevention and treatment of brain diseases. In the present thesis, we aim to enhance our understanding of human brain mechanisms by means of an integrated and data-driven approach, by adopting a systemic perspective and leveraging on tools from computational and network neuroscience. We successfully enhance the state of the art of computational neuroscience in several manners. Firstly, we inspect human cognition by focusing on the geometric exploration of concepts in the human mind to build new datadriven metrics to complement the neurological assessment and to confirm Alzheimer’s disease diagnosis. We formalize a new stochastic process, the potential-driven random walk, able to model the trade-off between exploitation and exploration of network structure, by accounting for local and global information, providing a flexible tool to span from random walk to shortestpath based navigation. Probing the interplay between brain structure and dynamics by means of its Von Neumann entropy, we develop a new framework for the multiscale analysis of the human connectome, which is effective for discerning between healthy conditions and Alzheimer’s disease. Finally, by integrating data from the human brain structural connectivity, its functional response errors as measured by Direct Electrical Stimulation and semantic selectivity, we propose a new procedure for mapping the human brain triadic nature, thus providing a model-oriented bridge between the human brain and mind. Besides shedding more light on human brain functioning, our findings offer original and promising clues to develop integrated biomarkers for Alzheimer’s disease detection, with the potential of extension for applications to other neurodegenerative diseases and psychiatric disorders.

Yes / We report that performance on neuropsychological tests used in the diagnosis of dementia can be influenced by external factors such as time of day (TOD) and caffeine. This study investigates TOD effects on cognitive performance in the elderly. The optimal TOD at which an individual is at their maximal arousal alters with age and in the elderly typically occurs in the morning. Neuropsychological test scores from healthy elderly participants were analysed to determine whether TOD affected performance. Interactions between caffeine and TOD were also investigated. Across two data sets that were analysed, significant TOD effects were noted for Pattern Comparison Speed (PCS), Letter Comparison Speed (LCS), Trail Making Test Part A, Mini Mental State Examination (MMSE) and the Graded Naming Test (GNT), revealing a decline in test scores as TOD increases. Significant interactions between TOD, age and the PCS, LCS and Trail Making part A were noted in data set one. In data set two, where caffeine intake had been controlled for, significant interactions between caffeine, TOD and scores on the MMSE and GNT were found. The TOD and caffeine effects highlight the need to control for these external factors when scoring the assessments. This conclusion has implications for the clinical procedure of diagnosis and treatment of dementia and Alzheimer’s.

Yes / Social restriction measures imposed to curb the spread of COVID-19 in the United Kingdom impacted on carers of people with dementia, limiting access to support services and increasing perceived burden of caring. Few studies have compared data collected both during and before the pandemic to examine the effect of these changes. To explore whether the COVID-19 pandemic affected the well-being of carers of people with dementia living in the community, and their ability to cope with their caring responsibilities. Methods: Analysis was conducted on two groups of carers who were enrolled in the IDEAL programme; the ‘pre-pandemic group’ (n = 312), assessed at two time points prior to the pandemic, and the ‘pandemic group’, assessed prior to and several months into the pandemic (n = 156). For the pre-pandemic group, carers were matched 2:1 to carers in the pandemic group on certain characteristics. Differences in change over time between the two groups on self-reported well-being, quality of life, coping, perceived competence, and role captivity, were investigated using mixed effect modelling. Results: Compared to the pre-pandemic group, those in the pandemic group appeared to cope better and had more stable self-rated competency and role captivity. They did not differ in terms of well-being or quality of life. Conclusion: Despite reports of negative impacts on carers early in the pandemic, the findings suggest the pandemic had little negative longer-term impact on carers of people with dementia, and in fact they appeared to have a more positive attitude towards coping several months into the pandemic. / We acknowledge the support of NIHR Dementias and Neurodegeneration Specialty (DeNDRoN) and Health and Care Research Wales with IDEAL cohort recruitment and data collection. We gratefully acknowledge the local principal investigators and researchers involved in participant recruitment and assessment within these networks. We are grateful to the IDEAL study participants for their participation in the IDEAL and INCLUDE studies, to the wider group of IDEAL programme researchers, and to members of the ALWAYs group and the Project Advisory Group for their support. ‘Identifying and mitigating the individual and dyadic impact of COVID19 and life under physical distancing on people with dementia and carers (INCLUDE)’ was funded by the Economic and Social Research Council (ESRC) through grant ES/V004964/1. Investigators: L. Clare, C. Victor, F.E. Matthews, C. Quinn, A. Hillman, A. Burns, L. Allan, R. Litherland, A. Martyr, R. Collins, & C. Pentecost. ESRC is part of UK Research and Innovation (UKRI). ‘Improving the experience of Dementia and Enhancing Active Life: living well with dementia. The IDEAL study’ was funded jointly by the Economic and Social Research Council (ESRC) and the National Institute for Health Research (NIHR) through grant ES/L001853/2. Investigators: L. Clare, I.R. Jones, C. Victor, J.V. Hindle, R.W. Jones, M. Knapp, M. Kopelman, R. Litherland, A. Martyr, F.E. Matthews, R.G. Morris, S.M. Nelis, J.A. Pickett, C. Quinn, J. Rusted, J. Thom. ‘Improving the experience of Dementia and Enhancing Active Life: a longitudinal perspective on living well with dementia. The IDEAL-2 study’ is funded by Alzheimer’s Society, grant number 348, AS-PR2-16-001. Investigators: L. Clare, I.R. Jones, C. Victor, C. Ballard, A. Hillman, J.V. Hindle, J. Hughes, R.W. Jones, M. Knapp, R. Litherland, A. Martyr, F.E. Matthews, R.G. Morris, S.M. Nelis, C. Quinn, J. Rusted. L. Clare and L. Allan acknowledge support from the NIHR Applied Research Collaboration SouthWest Peninsula. This report is independent research supported by the National Institute for Health and Care Research Applied Research Collaboration South West Peninsula. The views expressed in this publication are those of the author(s) and not necessarily those of the ESRC, UKRI, NIHR, the Department of Health and Social Care, the National Health Service, or Alzheimer’s Society. The support of ESRC, NIHR and Alzheimer’s Society is gratefully acknowledged. Authors’ disclosures available online (https:// www.j-alz.com/manuscript-disclosures/22-0221r1).

Yes / Background:With current treatments for Alzheimer’s disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. Objective:The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. Methods:Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). Results:Acute ICV administration of Aβo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. Conclusion:Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.

L'objectif de cette thèse est d'explorer la stigmatisation perçue liée à la maladie d'Alzheimer (MA) parmi une population d'aidants familiaux (enfants adultes ou conjoints) accompagnant leurs proches (conjoints ou parents) vivant avec une probable MA. Parmi les patients, non seulement, il est examiné les sources de stigmatisation envers les personnes vivant avec une probable MA associées aux réactions émotionnelles et comportementales d'affiliation ou de distance sociale de l'entourage. Mais encore il est observé les facteurs de stigmatisation qui prédisent une variation de leur qualité de vie. Parmi, leurs aidants familiaux, il est étudié les facteurs de stigmatisation qui prédisent une variation de la symptomatologie dépressive et du fardeau de soins. Dans cette relation, il est étudié le rôle modérateur du soutien social. Nos résultats indiquent parmi les patients, que la fréquence des symptômes comportementaux liés à la dépression prédisent les émotions négatives et les comportements de distance sociale de l'entourage. Aussi, nous observons que la qualité de vie du patient varie selon son lieu de résidence. Au domicile, il est observé davantage de comportements de distance sociale venant de l'entourage. Parmi les proches aidants, il est constaté que soutien social modère les effets entre les émotions négatives, les comportements de distance sociale de l'entourage envers le patient, et la symptomatologie, le fardeau de soins des aidants. Mais que le soutien social exacerbe les effets entre les émotions positives de l'entourage et le fardeau de soins. Cette thèse permet d'objectiver la stigmatisation liée à la maladie d'Alzheimer parmi les patients et leurs proches aidants. Les résultats obtenus justifieraient l'élaboration d'actions de communication centrées sur la nécessité du soutien social auprès de l'ensemble des personnes affectées par la maladie d'Alzheimer. / This thesis aims at exploring the perceived stigmatization towards persons possibly leaving with Alzheimer’s disease among the population of the family caregivers – grown-up children and spouses. Not only do we have observed sources of stigmatizations aimed at patients possibly leaving with Alzheimer’s disease, in relation with emotional reactions and either affiliation behavior, or social distancing from the family and social circle, but we have also observed factors of stigmatization leading to variations in patients’ quality of life. Amongst family caregivers, we have studied factors of stigmatization leading to changes in the associated depressive symptoms and the increased caregiver burden. With respect to the relationship induced, we have given attention to the moderating role of social support. Our results show that, among patients, the negative emotions and the social distancing behavior from social circle can be linked to the frequency of behavioral symptoms related to the depression. With respect to this observation, we show an variation in the patients’ quality of life according to the places they live in. At home, we have noted increased social distancing behavior from the social circle. Amongst the relatives caregivers, we have also noticed that social support has a moderating influence on the effects of negative emotions, the social distancing behavior from the social circle towards the patient, the symptoms and the burden of care felt by the caregivers. However, the social support exacerbates the relation between positive emotions among the relatives and the burden of care. This thesis gives us the opportunity to objectify the stigmatization process with respect to Alzheimer’s disease amongst patients and their relatives caregivers. Our results could open the way to specific communications promoting the necessity for social support in favor of the entire population concerned by Alzheimer’s disease.

Alzheimer’s disease (AD) is a neurodegenerative disorder, with extensive evidence implicating the misfolding, aggregation and deposition of the amyloid-β (Aβ) peptide as central to the pathogenesis. Heparan sulfate (HS) is an interactive glycosaminoglycan, attached to core proteins as HS proteoglycans (HSPGs). HSPGs are present on cell surfaces and in the extracellular matrix where they facilitate multiple signaling functions, but HS is also consistently present in all amyloid deposits, including those of AD. In amyloidosis HS has been studied as an aggregation template, promoting fibril formation and serving a scaffold function in the resulting deposits. The objective of this thesis was to assess how cell surface HS is potentially implicated in Aβ amyloidosis and the associated neuroinflammation of AD.   In AD brain we determined that HS predominantly accumulated in Aβ deposits with dense cores and found glial-expressed HSPGs within these deposits. Aβ elevated HSPG levels in primary glial cultures, implicating activated glia as one source of the Aβ-associated HS. Next, we determined that microglial HSPGs are critical for the upregulation of interleukin-1β and tumor necrosis factor-α following exposure to lipopolysaccharide, an established inflammatory insult. Together these results raise the possibility that Aβ-induced expression of microglial HSPGs may promote neuroinflammation.   Multiple mechanisms of Aβ toxicity have been proposed and different Aβ assemblies exert their toxicity through alternative routes. We found that three different preparations of Aβ aggregates all exhibited HS-dependent cytotoxicity, which in part correlated with Aβ internalization. Furthermore, heparin treatment attenuated Aβ cytotoxicity and uptake. In Aβ-positive AD microvasculature, HS deposited with Apolipoprotein E (ApoE) and its receptor, the low density lipoprotein receptor-related protein 1 (LRP1). In cell culture, HS and LRP1 co-operated in Aβ interactions and the addition of ApoE increased the levels of cell-associated Aβ in a HS- and LRP1-dependent manner. This ApoE-mediated increase in cell-associated Aβ may promote toxicity and vascular degeneration, but equally HS-mediated internalization of Aβ could represent a clearance route across the blood-brain-barrier. The findings presented here illustrate multiple roles for cell-surface HSPGs in interactions relevant to the pathogenesis of AD.

Vascular risk factors inducing a state of chronic cerebral hypoperfusion and metabolic stress are thought to influence the onset and progression of Alzheimer’s disease (AD). To investigate the complex molecular changes underpinning cellular adaptation to metabolic stress, the first aim of this thesis was to define the proteomic response of the SH-SY5Y human neuroblastoma cell line after exposure to the metabolic challenge of oxygen glucose deprivation (OGD). 958 proteins across multiple subcellular compartments were detected and quantified by label-free liquid chromatography mass spectrometry (LC-MS). The levels of 130 proteins were significantly increased (P<0.01) after OGD and the levels of 63 proteins were significantly decreased (P<0.01) while expression of the majority of proteins (765) was not altered. Ingenuity Pathway Analysis identified novel protein-protein interactomes involved with mitochondrial energy production, protein folding, and protein degradation, indicative of coherent and integrated proteomic responses to the metabolic challenge. Approximately one third (61) of the differentially expressed proteins were associated with the endoplasmic reticulum and mitochondria. Electron microscopic analysis of these subcellular structures showed morphologic changes consistent with the identified proteomic alterations. Pertinent to AD research, amyloid binding alcohol dehydrogenase (ABAD) was found to be significantly increased in response to OGD. ABAD is emerging as a key player in mitochondrial dysfunction in AD, yet full understanding of the biochemical pathways in which this protein is involved remain elusive. Using immunoprecipitation coupled to LC-MS (IP-MS), the second aim of the thesis was to characterise the ABAD protein interactome in SH-SY5Y cells and its response to metabolic stress. 67 proteins were identified as potential ABAD interactors under control conditions, and 69 proteins were identified as potential ABAD interactors under OGD conditions. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to determine the subcellular locations and biological functions of the ABAD interacting proteins in control and OGD conditions. DAVID identified the nuclei and mitochondria to contain the greatest number of changes in ABAD interacting proteins following OGD. “Glucose Metabolic Process” (GO:0006006) was the top functional cluster for ABAD interacting proteins in both control and OGD conditions. Independent immunoprecipitations, western blotting, immunohistochemistry and electron microscopy were used to validate specific protein interactions. OGD was found to initiate a novel interaction between ABAD and glucose-regulated protein 75 (GRP75), a finding confirmed in human AD tissue. GRP75 is a mitochondrial protein and marker of the mitochondrial associated membrane (MAM), a specialised region between the mitochondria and the ER. The MAM is known to be enriched with presenilin proteins, involved in the proteolytic cleavage of amyloid precursor protein (APP). These data were used to generate an “ABAD-GRP75-MAM hypothesis of mitochondrial dysfunction in AD”, which might provide a novel link between chronic metabolic stress, ABAD, mitochondrial dysfunction and the onset / progression of AD. The third aim of the thesis was to test this novel hypothesis. Western blotting revealed APP to be significantly decreased following OGD, concurrent with an increase in ABAD protein levels. Over-expression of ABAD protein in SH-SY5Y cells was used to test whether the increased levels of ABAD following OGD were the driving force behind APP down-regulation. ABAD over-expression in SH-SY5Y cells was found to have no detectable effect on APP. Conversely, electron microscopy revealed a dynamic response of the MAM to metabolic stress. This result, along with the interaction of ABAD with GRP75, and the enrichment of presenilins at the MAM, suggests that this specialised membrane region may have an important role to play in AD.

The increasing prevalence of Alzheimer’s disease poses a considerable socioeconomic challenge in the years ahead. There are few clinical treatments available and none capable of halting or slowing the progressive nature of the condition. Despite decades of experimental research and testing over 300 interventions in transgenic mouse models of the condition, clinical success has remained elusive. Deepening our understanding of how such studies have been conducted is likely to provide insights which could inform future preclinical and clinical research. Therefore I performed a systematic review and meta-analysis on interventions tested in transgenic mouse models of Alzheimer’s disease. My systematic search was performed by electronically searching for publications reporting the efficacy of interventions tested in transgenic models of Alzheimer's disease. Across these publications I extracted data regarding study characteristics and reported study quality alongside outcome data for pathology (i.e. plaque burden, amyloid beta species, tau, cellular infiltrates and neurodegeneration) and neurobehaviour. From these data I calculated estimates of efficacy using random effects meta-analysis and subsequently investigated the potential impact of study quality and study characteristics on observed effect size. My search identified 427 publications, 357 interventions and 55 transgenic models representing 11, 688 animals and 1774 experiments. There were a number of principal concerns regarding the dataset: (i) the reported study quality of such studies was relatively low; less than 1 in 5 publications reported blinded assessment of outcome or random allocation to group and no studies reported a sample size calculation, (ii) the depth of data on any individual intervention was relatively poor-only 16 interventions had outcomes described in 5 or more publications and (iii) publication bias analyses suggested 1 in 5 pathological and 1 in 7 neurobehavioural experiments remain unpublished. Where I inspected relationships between outcomes, meta-regression identified a number of notable associations. Changes in amyloid beta 40 were reflective of changes in amyloid beta 42 (R2 = 0.84, p<0.01) and within the Morris water maze changes in the ‘training’ acquisition phase could explain 44% of the changes in the probe ‘test’ phase (p<0.05). Additionally, I identified measures of neurodegeneration as the best pathological predictors of changes in neurobehaviour (R2 = 0.72, p<0.01). Collectively this work identifies a number of potential weaknesses within in vivo modelling of Alzheimer’s disease and demonstrates how the use of empirical data can inform both preclinical and clinical studies.

Cerebral hypoperfusion can occur in normal ageing and is proposed to underlie white matter disturbances observed in the ageing brain. Moreover, cerebral hypoperfusion and white matter attenuation are early events in the progression of Alzheimer’s disease (AD). White matter mostly consists of myelinated axons which have distinct protein architecture, segregated into defined regions; the axon initial segment (AIS), the node of Ranvier, paranode, juxtaparanode, and internode. These sites are essential for action potential initiation and/or propagation and subsequently effective brain function. At the outset of the studies in the thesis there was evidence that the different regions within the myelinated axons are vulnerable to injury and disease. Thus it is hypothesised that in response to normal ageing and/or cerebral hypoperfusion these structures are altered and associated with cognitive impairment and that these effects are exacerbated in a transgenic mouse model (APPSw,Ind, J9 line) which develops age-dependent amyloid-β (Αβ) pathology. The first study aims to investigate the effect of normal ageing and Aβ deposition on myelinated axons and on learning and memory. To address this, the effects of normal ageing on the integrity of the AIS, nodes of Ranvier, myelin, axons, synapses and spatial working memory are examined in young and aged wild-type and TgAPPSw,Ind mice. A significant reduction in the length of nodes of Ranvier is demonstrated in aged wild-type and TgAPPSw,Ind mice. In addition, the length of AIS, is significantly reduced in the aged wild-type animals while the young TgAPPSw,Ind have significantly shorter AIS than the young wild-type mice. These effects are not influenced by the presence of Aβ. Myelin integrity is affected by age but this is more prominent in the wild-type animals whilst axonal integrity is intact. Moreover, there is an age-related decrease of presynaptic boutons only in the TgAPPSw,Ind mice. Contrary to the original hypothesis, working memory performance is not altered with age or influenced by increasing Aβ levels. The second study aims to examine the effects of cerebral hypoperfusion in combination with Αβ pathology and/or ageing on cognitive performance and the structure of myelinated axons. To address this, the effects of surgically induced cerebral hypoperfusion on the integrity of the nodes of Ranvier, paranodes, myelin, axons and spatial working memory performance are investigated in young and aged wild-type and TgAPPSw,Ind mice. A decrease in nodal length is observed in response to hypoperfusion in young and aged animals. This effect is shown to be exacerbated in the young TgAPPSw,Ind animals. Moreover, the disruption of the nodal domain is shown to occur without any gross alterations in myelin and axonal integrity. It is also demonstrated that in response to hypoperfusion, spatial working memory performance is defected in young and aged animals of both genotypes. This deficit is exacerbated in the young TgAPPSw,Ind. The observed changes in the nodal structure are associated with poor working memory performance indicating functional implication for the nodal changes. These data highlight that structures within myelinated axons are vulnerable to ageing and cerebral hypoperfusion. Therefore, the development of strategies that minimize injury or drive repair to these regions is necessary together with therapeutic approaches against the vascular insults that induce hypoperfusion and lead to white matter attenuation and cognitive decline. In the future, it would be interesting to investigate how alterations at the AIS/nodes of Ranvier affect neuronal excitability.

Background: Dementia impairs cognitive functions, such as memory and speech, changing a person’s life forever. Providing person-centred care to these persons intend to retain their identities, dignity and autonomy. Such care demands time, devotion and good knowledge of the caring nurse. Dementia is expected to increase in the future and therefore nurses will have to face new challenges. Aim: To describe nurses’ experience of providing person-centred care for people with dementia. Method: A literature review of 15 articles, published between 2009-2016, that have been read and analysed through content-analysis. Results: Nurses experience a positive change in their attitudes, when providing person-centred care to people with dementia, as they gained better understanding of their patients’ dignity and integrity. Education, training and support from management were seen as key factors for providing up-to-date care. Time was viewed as a hindrance for person-centred care, and often led to nurses prioritizing other routines. Two common outcomes of person-centred care were increased satisfaction as well as emotional burnout. Conclusion: Since dementia is increasing and nurses find person-centred care time-consuming, there is a risk of such care becoming poor. To prevent this nurses need good leadership and education. / Bakgrund: Demenssjukdomar försämrar den kognitiva funktionen, så som minne och tal, vilket förändrar en persons liv för alltid. Att ge personcentrerad vård till dessa personer ämnar behålla deras identitet, värdighet och autonomi. En sådan typ av vård kräver tid, hängivenhet och god kunskap av den behandlande sjuksköterskan. I framtiden förväntas alltfler att insjukna i demenssjukdom och sjuksköterskan kommer därför att behöva möta nya utmaningar. Syfte: Att beskriva sjuksköterskans upplevelse av att ge personcentrerad vård till personer med demenssjukdom. Metod: En litteraturstudie där 15 artiklar, publicerade mellan 2009-2016, har blivit lästa och analyserade genom innehållsanalys. Resultat: Sjuksköterskor upplevde en positiv förändring i sin inställning när de gav personcentrerad vård till personer med demenssjukdom. Framförallt då de fick ökad förståelse för deras patienters värdighet och integritet. Utbildning, övning och stöd från ledningen sågs som nyckelfaktorer för att kunna ge aktuell vård. Tiden sågs som ett hinder för personcentrerad vård och ledde ofta till att sjuksköterskorna prioriterade andra rutiner. Två vanliga följder av vårdandet rapporterades vara såväl ökad tillfredsställelse som emotionell utmattning. Konklusion: Eftersom demenssjukdomar ökar och sjuksköterskor finner personcentrerad vård som tidskrävande, finns det en risk att sådan vård fallerar. För att förhindra detta behöver sjuksköterskor gott ledarskap och utbildning.