Patients with Alzheimer’s disease (AD) experience sleep disturbances, including disruption in slow-wave sleep (SWS). Slow oscillations (≤1 Hz), a brain rhythm prevalent during SWS, play a role in memory consolidation. Interestingly, patients with AD exhibit slow oscillations of low amplitude, which might contribute to their memory impairments. The mechanisms underlying slow-wave disruptions in AD remain unknown. Slow oscillations originate in the neocortex. Cortical neurons from all layers oscillate between UP and DOWN states during slow oscillations. Astrocytes are known to support neuronal circuit functions, and disruptions in astrocyte activity might contribute to slow-wave aberrations. Here, we investigated astrocytic contributions to slow-wave disruptions in an animal model of beta-amyloidosis (APP mice). First, we monitored astrocytic calcium transients to determine whether astrocytic calcium dynamics were disrupted in APP mice. Fourier transform analysis revealed that the power, but not the frequency of astrocytic calcium transients, was disrupted in young APP mice. This suggested calcium dynamic of astrocytic network was altered and might contribute to the disruption of slow waves in APP mice. Second, we used optogenetics to synchronize cortical astrocyte activity at 0.6 Hz to drive slow oscillations in APP mice. Our results showed that optogenetic activation of ChR2-expressing astrocytes at the endogenous frequency of slow waves restored slow-wave power. Furthermore, chronic optogenetic stimulation of astrocytes at 0.6Hz for 14 or 28 days reduced amyloid plaque deposition, prevented calcium overload in neurites, and improved memory performance in APP mice. These results revealed a malfunction of the astrocytic network driving slow-wave disruptions, and suggested a novel target to restore slow-wave power in APP mice, with translational potential to treat AD.

Neuropsychological testing is one method used in the diagnosis of Alzheimer’s disease and other cognitive disorders. However, the testing process may be affected by subtle external factors which if not controlled for may have the ability to affect the scores obtained. The primary aim of this thesis was to investigate the effects of some of these external factors, namely caffeine, non-oily fish consumption and time of day. A secondary aim was to evaluate the use of a novel virtual assessment as a possible tool for the early detection of AD. Healthy elderly participants over the age of sixty with no existing cognitive impairment or neurological condition were recruited to take part. For each external factor investigated participants were required to undertake a cognitive assessment. The results demonstrated that subtle external factors present during a typical testing session have the ability to significantly affect the scores obtained. Scores on one part of the virtual test correlated with existing tests used for the early detection of cognitive impairment and were significantly lower in participants classified as mildly impaired. With further modification this test has the potential to be used as an early detection tool. The results have implications for the interpretation of neuropsychological test scores which may be considered when classifying participants, determining treatment interventions, selecting participants for research and making a diagnosis. These findings have important considerations for psychological and cognitive research that investigates human brain function.

Indiana University-Purdue University Indianapolis (IUPUI) / Alzheimer’s disease (AD) is typified by a robust microglial-mediated immune response. Genetic studies have demonstrated that many genes that alter AD risk are involved in the innate immune response and are primarily expressed in microglia. Among these genes is phospholipase C gamma 2 (PLCG2), a critical element for various immune receptors and a key regulatory hub for immune signaling. PLCG2 genetic variants are associated with altered AD risk. The primary objective of this thesis was to determine the role of PLCG2 in AD pathogenesis. We observed significant upregulation of PLCG2 expression in three brain regions of late-onset AD (LOAD) patients and a significant positive correlation of PLCG2 expression with amyloid plaque density. Furthermore, the differential gene expression analysis highlighted inflammatory response-related pathways. These results suggest that PLCG2 plays an important role in AD. We systematically investigated the impact of PLCG2 haploinsufficiency on the microglial response and amyloid pathology in the amyloidogenic 5xFAD mouse model. The results demonstrated that Plcg2 haploinsufficiency altered the phenotype of plaqueassociated microglia, suppressed cytokine levels, increased compact X34-positive plaque deposition, and downregulated the expression of microglial genes associated with immune cell activation and phagocytosis. Our study highlights the role of PLCG2 in immune responses; loss of function of PLCG2 exacerbates the amyloid pathology of AD. Genetic studies demonstrated that the hypermorphic P522R variant is protective and that the loss of function M28L variant confers an elevated risk for AD. Our results demonstrated that PLCG2 variants modulate disease pathologies through specific transcriptional programs. In the presence of amyloid pathology, the M28L risk variant impaired microglial response to plaques, suppressed cytokine release, downregulated disease-associated microglial genes, and increased plaque deposition. However, microglia harboring the P522R variant exhibit a transcriptional response endowing them with a protective immune response signature linked to their association with plaques and Aβ clearance, attenuating disease pathogenesis in an amyloidogenic mouse model of AD. Collectively, our study provides evidence that the M28L variant is associated with accelerated and exacerbated disease-related pathology, and conversely, the P522R variant appeared to attenuate disease severity and progression. / 2024-10-03

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.

Severely life-impairing and often lethal dementia illnesses such as Alzheimer’s disease are of the greatest medical interest. And while a cure might yet be years in the future, there are immense benefits to gain from detecting disease debut as early as possible, from both an individual and a societal perspective. In this study we explore new approaches to Alzheimer’s screening, utilizing the recent technology leaps within natural language processing and automated speech recognition. We propose a digital, mobile application based platform for psychometric data collection that can be used by patients and research participants in a non-clinical environment. In particular, we implement automated versions of two well-recognized psychometric tests for Alzheimer’s screening: the Verbal Learning Test and the Story Recall Task. We perform a qualitative evaluation of results from 46 sessions of these tests, as well as a semi-structured interview with a clinician, and find automated psychometric tools promising for future endeavors within Alzheimer’s screening, but that the method has inherent difficulties that needs to be counteracted. We also discuss the potential economic upsides with automating parts of the screening and diagnosis processes for dementia related diseases, and conclude that there are massive savings to make – up to 600 million SEK yearly in Sweden alone. / Kraftigt livshämmande och ofta dödliga demenssjukdomar som Alzheimers är av stort medicinskt intresse. Och medan ett botemedel ännu kan vara långt borta finns det stora fördelar att dra från tidigare upptäckande av sjukdomens debut, ur både ett individuellt och ett samhälleligt perspektiv. I den här studien utforskar vi nya tillvägagångssätt för screening av Alzheimers och drar nytta av nya framsteg inom natural language processing och automated speech recognition. Vi föreslår en digital, mobilapplikations-baserad plattform för psykometrisk datainsamling, som kan användas av patienter och forskningsdeltagare i en icke-klinisk miljö. Rent konkret implementerar vi automatiserade versioner av två vedertagna psykometriska tester för Alzheimers-screening: Verbal Learning Test och Story Recall Task. Vi utför en kvalitativ evaluering av resultaten från 46 sessioner av dessa tester samt en semistrukturerad intervju med en kliniker, och finner att automatiserade psykometriska verktyg är lovande för framtida ansträngningar inom Alzheimers-screening, men att metoden har inneboende svårigheter som måste motarbetas. Vi diskuterar även de potentiella ekonomiska fördelarna med att automatisera delar av screening- och diagnosticeringsprocesserna för demensrelaterade sjukdomar, och kommer fram till att det finns massiva besparingar att göra – uppåt 600 miljoner kronor årligen bara i Sverige.

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.