ApoE4 effects on the structural covariance brain networks topology in Mild Cognitive Impairment

The Apolipoprotein E isoform E4 (ApoE4) is consistently associated with an elevated risk of developing late-onset Alzheimer's Disease (AD). However, little is known about his potential genetic modulation on the structural covariance brain networks during prodromal stages like Mild Cognitive Impairment (MCI). The covariance phenomenon is based on the observation that regions correlating in morphometric descriptors are often part of the same brain system. In a first study, I assessed the ApoE4-related changes on the brain network topology in 256 MCI patients, using the regional cortical thickness to define the covariance network. The cross-sectional sample selected from the ADNI database was subdivided into ApoE4-positive (Carriers) and negative (non-Carriers). At the group-level, the results showed a significant decrease in characteristic path length, clustering index, local efficiency, global connectivity, modularity, and increased global efficiency for Carriers compared to non-Carriers. Overall, I found that ApoE4 in MCI shaped the topological organization of cortical thickness covariance networks. In the second project, I investigated the impact of ApoE4 on the single-subject gray matter networks in a sample of 200 MCI from the ADNI database. The patients were classified based on clinical outcome (stable MCI versus converters to AD) and ApoE4 status (Carriers versus non-Carriers). The effects of ApoE4 and disease progression on the network measures at baseline and rate of change were explored. The topological network attributes were correlated with AD biomarkers. The main findings showed that gray matter network topology is affected independently by ApoE4 and the disease progression (to AD) in late-MCI. The network measures alterations showed a more random organization in Carriers compared to non-Carriers. Finally, as additional research, I investigated whether a network-based approach combined with the graph theory is able to detect cerebrovascular reactivity (CVR) changes in MCI. Our findings suggest that this experimental approach is more sensitive to identifying subtle cerebrovascular alterations than the classical experimental designs. This study paves the way for a future investigation on the ApoE4-cerebrovascular interaction effects on the brain networks during AD progression. In summary, my thesis results provide evidence of the value of the structural covariance brain network measures to capture subtle neurodegenerative changes associated with ApoE4 in MCI. Together with other biomarkers, these variables may help predict disease progression, providing additional reliable intermediate phenotypes

Clinical, biochemical and neuroimaging studies in familial Alzheimer's disease.

This thesis investigates several aspects of familial Alzheimer disease (FAD). The specific results of the work undertaken for this thesis were: (1) The proportion of FAD accounted for by mutations in known genes was 68% in 31 FAD families Those without mutations were ten years older and associated with APOE e4 (2) The phenotype of PSEN1 FAD was found to share an early age at onset and features broadly suggestive of AD. However the phenotype was broad and included spastic paraparesis in association with "cotton wool" plaques in PSEN1 E280G (3) Plasma amyloid P peptide was found to be a potentially useful biomarker of FAD with levels being elevated in mutations carriers compared with non-carriers, and levels in at risk subjects falling halfway between the groups (4) Cerebral atrophy in early onset AD was 2-8% (95% CI 2-3-3-3) per year which rose by 0-32% per year (0-15-0-50) (5) Pre-symptomatic medial temporal lobe atrophy in FAD at risk family members who become symptomatic was demonstrated with MRI medial temporal lobe volumes 16.6% lower in patients than controls and a higher rate of atrophy in patients than controls (6) Cerebral atrophy in FAD was shown to begin in the posterior cingulate, temporoparietal and medial temporal cortices in presymptomatic FAD patients, a finding in accordance with previous cross-sectional neuropathological studies (7) By contrast the onset and progression of cerebral atrophy in non-AD familial dementia was shown to markedly different in an presymptomatic FTLD patient with focal left frontal lobe onset reflecting the different clinical presentation (8) Cerebral atrophy in FAD was found not to progress significantly faster than sporadic AD despite a twenty year age difference between the groups

Transcriptomic Profiling in Mild Cognitive Impairment and Alzheimer's Disease Using Neuroimaging Endophenotypes

Indiana University-Purdue University Indianapolis (IUPUI)Alzheimer’s disease (AD) is a devastating neurodegenerative disease affecting more than 6 million Americans and 50 million people worldwide currently. It is an irreversible neurodegenerative disease which causes decline in memory, cognition, personality, and other functions which eventually lead to death due to complete brain failure. Recently there has been a lot of research that has focused on enabling early intervention and disease prevention in AD which could have a significant impact on this disease, be crucial for life management, assessment of risk for future generations, and assistance in end-of-life preparation. For a late-life complex multifactorial disease, such as AD, where both genetic and environmental factors are involved, integrating multiple layers of genetic, imaging, and other biomarker data is a critical step for therapeutic discovery and building predictive risk assessment tools. The multifactorial nature of AD suggests that multiple therapeutic targets need to be identified and tested together. Hence, we need a systems-level approach to build biomarker profiles which can be used for drug discovery and screening/risk assessment. The research presented in this dissertation focuses on utilizing a systems level approach to identify promising imaging genetics biomarkers that provide insight into dysregulated biological pathways in AD pathogenesis and identify critical mRNA measures that can be investigated further within the scope of novel therapeutics, as well as input variables in predictive models for AD risk, screening, and diagnosis. The overall research goal was the development of systems level, imaging genetics biomarker signatures to serve as tools for risk analysis and therapeutic discovery in AD. The specific outcomes of the analyses were characterization of patterns in gene expression at systems level using neuroimaging endophenotypes, and identification of specific driver genes and genotypic variants, which can inform predictive modeling for diagnosis, risk, and pathogenic profiling in AD

Understanding Cognitive Variability in Alzheimer’s Disease

Alzheimer’s Disease (AD) is highly heterogenous, both clinically and biologically. This variability is exacerbated by the ways within which, the clinical presentation is assessed with cognitive measures. This inhibits clinical trial success and earlier diagnosis of individuals. Marrying the clinical presentation to the pathology of the disease has so far proved troublesome. This thesis will look at how cognitive measures can best capture the clinical presentation of AD and how these measures can link to the underlying pathology using machine learning methods. This thesis studied this problem across four analyses and two cohorts. Each study looked at a different aspect of cognitive testing within AD. This was done with the overarching aim to interrogate the cognitive variability across the spectrum of AD. Study 1 showed a novel discrepancy score is different to memory measures at screening for AD. It also showed it tracks with AD severity, in the same way memory recall does. Studies 2 & 3 uncovered broad psychometric variance within amnestic measurement of impairment due to AD. This was done in two different populations across two different constructs of amnestic measurement, story recall and verbal list learning. These tests are frequently used interchangeably. These two studies show they should not be. Finally, Study 4 built models from cognitive measures to predict AD pathology. The performance of these models was moderate showing that even with novel cognitive measures, further work is needed to link the clinical and amyloid related biological presentations of AD. Bridging the gap between clinical presentation and pathology of AD using clinical and cognitive markers alone is not possible. Even when using a novel measure of discrepancy score. The discrepancy measure shows promise but was limited due to the inability of the MMSE to measure verbal ability. Conceptually a discrepancy score remains a promising avenue of research for screening, but broader language measures, as well as other AD biomarkers are needed to further test the construct validity of this measure

Pattern recognition and machine learning for magnetic resonance images with kernel methods

The aim of this thesis is to apply a particular category of machine learning and pattern recognition algorithms, namely the kernel methods, to both functional and anatomical magnetic resonance images (MRI). This work specifically focused on supervised learning methods. Both methodological and practical aspects are described in this thesis. Kernel methods have the computational advantage for high dimensional data, therefore they are idea for imaging data. The procedures can be broadly divided into two components: the construction of the kernels and the actual kernel algorithms themselves. Pre-processed functional or anatomical images can be computed into a linear kernel or a non-linear kernel. We introduce both kernel regression and kernel classification algorithms in two main categories: probabilistic methods and non-probabilistic methods. For practical applications, kernel classification methods were applied to decode the cognitive or sensory states of the subject from the fMRI signal and were also applied to discriminate patients with neurological diseases from normal people using anatomical MRI. Kernel regression methods were used to predict the regressors in the design of fMRI experiments, and clinical ratings from the anatomical scans

Backtranslation of EEG biomarkers of Alzheimer's disease from patients to mouse model

The present Ph.D. thesis has been mainly developed on the data of the project with the short name PharmaCog (2010-2015), granted by the European Framework Programme 7 with about 28 millions of Euro (i.e. Innovative Medicine Initiative, IMI, grant agreement n°115009; www.pharmacog.org). This project involved 15 academic institutions, 12 global pharmaceutical companies, and 5 small and medium sized enterprises (SMEs). The PharmaCog project aimed at improving the pathway of drug discovery in Alzheimer’s disease (AD), based on a major interest of pharma companies, namely the validation of electrophysiological, neuroimaging, and blood biomarkers possibly sensitive to the effect of disease-modifying drugs reducing Ab42 in the brain in AD patients at the prodromal stage of amnesic mild cognitive impairment (aMCI). The core concept of the PharmaCog project was that the pathway of drug discovery in AD may be enhanced by (1) the validation of biomarkers derived from blood, EEG, magnetic resonance imaging (MRI), and positron emission tomography (PET) in patients with aMCI due to AD diagnosed by in-vivo measurement of Ab42 and phospho-tau in the brain and (2) the evaluation of the translational value of those human biomarkers in wild type (WT) mice and animal models of AD including transgenic mice with the mutation of PS1 and/or APP (i.e. PDAPP and TASTPM strains). Those genetic factors induce an abnormal accumulation of Ab42 in the brain and related cognitive deficits. The expected results may be (1) the identification of a matrix of biomarkers sensitive to the prodromal AD (aMCI cognitive status) and its progression in patients and (2) the selection of similar biomarkers related to AD neuropathology and cognitive deficits in PDAPP and TASTPM strains. These biomarkers were expected to be very useful in clinical trials testing the efficacy and neurobiological impact of new disease-modifying drugs against prodromal AD. For the development of this Ph.D. thesis, the access to the experiments and the data of the PharmaCog project was allowed by Prof. Claudio Babiloni, leader of an Italian Unit (University of Foggia in 2010-2012 and Sapienza University of Rome in 2013-2015) of the PharmaCog Consortium and coordinator of study activities relative to biomarkers derived from electroencephalographic (EEG) signals recorded from human subjects and animals in that project. Specifically, Prof. Claudio Babiloni was in charge for the centralized qualification and analysis of EEG data recorded from aMCI patients (Work Package 5, WP5) and transgenic mouse models of AD such as PDAPP and TASTPM strains (WP6). The data of the present Ph.D. thesis mostly derived from the WP5 and WP6. This document illustrating the Ph.D. thesis is structured in three main Sections: ▪ An Introductive part illustrating concisely the AD neuropathology, the mouse models of AD used in this thesis, and basic concepts of EEG techniques useful to understand the present study results; ▪ An Experimental part describing the result of the four research studies led in the framework of this Ph.D. project. Two of these studies were published in international journals registered in ISI/PubMed with impact factor, while the other two are being currently under minor revisions in those journals; ▪ A Conclusion section

Abnormal reactivity of resting-state EEG alpha rhythms during eyes open in patients with Alzheimer's and Lewy body diseases

Previous studies suggest that resting-state electroencephalographic (rsEEG) rhythms recorded in old patients with dementia due to different neurodegenerative diseases have a significant heuristic and clinical potential in identifying peculiar abnormalities of the ascending activating systems and reciprocal thalamocortical circuits in which oscillatory (de)synchronizing signals dynamically underpin cortical arousal in the regulation of quiet vigilance. In the present PhD program, a new methodological approach based on rsEEG cortical source estimation and individually-based frequency bands was used to test the hypothesis of significant abnormalities in the neurophysiological oscillatory mechanisms underlying the regulation of the quiet vigilance during the transition from an eyes-closed to an eyes-open condition in patients with the most prevalent neurodegenerative dementing disorders such as Alzheimer’s disease and Lewy Body and Parkinson’s diseases and initial abnormalities in the prodromal stage of ADD, characterized by mild cognitive impairment. Three rsEEG studies were performed for that purpose. In the first study, we tested if the reactivity of posterior rsEEG alpha rhythms from the eye- closed to the eyes-open condition may differ in patients with dementia due to Lewy Bodies (DLB) and Alzheimer’s disease (ADD) as a functional probe of the dominant neural synchronization mechanisms regulating the vigilance in posterior visual systems. We used clinical, demographical, and rsEEG datasets in 28 healthy elderly (Healthy) seniors, 42 DLB, and 48 ADD participants. The eLORETA freeware estimated rsEEG cortical sources at individual delta, theta, and alpha frequencies. Results showed a substantial (> -10%) reduction in the posterior alpha activities during the eyes-open condition in 24 Healthy, 26 ADD, and 22 DLB subjects. There were lower reductions in the posterior alpha activities in the ADD and DLB groups than in the Healthy group. The reduction in the occipital region was lower in the DLB than in the ADD group. These results suggest that DLB patients may suffer a greater alteration in the neural synchronization mechanisms regulating vigilance in occipital cortical systems compared to ADD patients. In the second study, we hypothesized that the vigilance dysregulation seen in PDD patients might be reflected by altered reactivity of posterior rsEEG alpha rhythms during the vigilance transition from an eyes-closed to an eyes-open condition. We used clinical, demographical, and rsEEG datasets in 28 healthy elderly (Healthy), 73 PDD, and 35 ADD participants. We have applied the same methodology used for the first study. Results showed substantial (> -10%) reduction (reactivity) in the posterior alpha source activities from the eyes-closed to the eyes-open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients. In these alpha-reactive participants, there was lower reactivity in the parietal alpha source activities in the PDD group than in the Healthy and the ADD groups. These results suggest that PDD is characterized by poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. This finding could be an interesting biomarker of impaired vigilance regulation in quiet wakefulness in PDD patients. Indeed, such biomarkers may provide endpoints for pharmacological intervention and brain electromagnetic stimulations to improve the PDD patients’ general ability to regulate vigilance and primary visual consciousness in the activities of daily living. In the third study, we tested the exploratory hypothesis that rsEEG alpha rhythms may predict and be sensitive to mild cognitive impairment due to AD (ADMCI) progression at a 6-month follow- up (a relevant feature for intervention clinical trials). Clinical, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 Healthy seniors were used. We applied the same methodology used for the first and the second studies. Results showed a substantial (> -10%) reduction in the posterior alpha source activities during the eyes-open condition in about 90% and 70% of the Healthy and ADMCI participants, respectively. In the younger ADMCI patients (mean age of 64.3±1.1) with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes closed condition predicted the global cognitive status at the 6-month follow-up. In all ADMCI participants with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes-closed condition reduced in magnitude at that follow-up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD. These results suggest that in ADMCI patients, the true (“reactive”) posterior rsEEG alpha rhythms, when present, predict (in relation to younger age) and are quite sensitive to the effects of the disease progression on neurophysiological mechanisms underpinning vigilance regulation. The results of the three studies unveiled the significant extent to which the well-known impairments in the cholinergic and dopaminergic neuromodulatory ascending systems could affect the brain neurophysiological oscillatory mechanisms underpinning the reactivity of rsEEG alpha rhythms during eyes open and, then, the regulation of quiet vigilance in ADD, PDD, and DLB patients, thus enriching the neurophysiological model underlying their known difficulties to remain awake in quiet environmental conditions during daytime

Alterations of cholinergic and serotonergic neurochemistry in alzheimer's disease: Correlations with cognitive and behavioral symptoms

Ph.DDOCTOR OF PHILOSOPH

Integrating cerebrospinal fluid and [18F]-fluorodeoxyglucose positron emission tomography to diagnose Alzheimer's disease and research its pathophysiological substrates

Revealing the complex interactions and assessing potential integration between biomarkers is essential, especially in the early stages of AD, when biomarker alterations may serve to stage patients throughout the disease spectrum, improve phenotyping, and indicate the likelihood of progression to dementia. In this research, the integration of [18F]-FDG-PET and CSF biomarkers, two of the most used biomarkers in centers focused on neurocognitive disorders, enabled us to collect evidence on their analytical and diagnostic performance when used in a step-wise fashion. As part of the ongoing endeavor to create a common diagnostic chart for the precise and cost-effective use of biomarkers in neurocognitive diseases with neurodegenerative origin, these data gain further significance. Additionally, by combining semiquantitative [18F]-FDG-PET and CSF data, we were able to identify precise topographic correlations between metabolic values and CSF proteins that indicated distinct underlying disease processes. These findings add to the knowledge regarding the distribution of hypometabolism linked to neuronal loss, which is distinct from metabolic changes reflecting synaptic or axonal injury, and provide an indirect insight of the pathological processes taking place at various times in different parts of the brain. These results will be expanded into bigger cohorts in future research, which will also integrate additional newly discovered synaptopathy-expressing proteins for diagnostic and prognostic purposes

Brain plasticity after cognitive intervention in patients with mild cognitive impairment (MCI) evaluated by multimodal MR imaging in a randomized, controlled trial.

Postponed access: the file will be accessible after 2023-12-16Hjerneplasitisitet undersøkt hos individer med mild kognitiv svikt etter PC-administrert arbeidsminnetrening, evaluert med multimodal MRI teknikk, en randomisert kontroll studie. Formål: Hovedmålet med studien var å undersøke effekten av pc-administrert arbeidsminne trening, hos personer med mild kognitive svikt(MCI), samt få kjennskap til grad av nevrokognitive funksjonstap og nevrodegenerative forandringer synlig ved MR avbildning av hjernen. Man ønsket videre å korrelere om det var en sammenheng mellom utfall i kognitive områder og visuelle scoring systemer på MR. Vi forsøkte å avklare om individer med MCI har bevart plastisitet med undersøkelser av hjernebarkens tykkelse (strukturell MR teknikk) og endringer i hvit substans (tensor basert MR teknikk). Videre ønsket vi å avklare om bærerskap av spesifikke APOE og LMX1a gener påvirket treningseffekt. Bakgrunn: MCI er en tilstand med redusert hukommelse som ikke påvirker dagliglivets funksjoner. Tilstanden ses på som et forstadie til demens, og om lag 10-15 % av denne gruppen glir over i en demenstilstand hvert år. En teori ved MCI-tilstander er at hjernens kompensatoriske mekanismer er ikke tilstrekkelige til å håndtere bakenforliggende hjernesykdom. MCI gruppen kan deles inn i to grupper; amnestisk MCI med redusert hukommelse og ikke-amnestisk MCI hvor funksjonstapet er i ikke-hukommelses relaterte kognitive domener. Felles for begge gruppene er ofte redusert arbeidsminne. Det finnes i dag ingen behandling for denne tilstanden. Av den grunn ønsket vi å undersøke om pc-administrert arbeidsminne trening kunne bedre pasientens arbeidsminne. Arbeidsminnetrening er basert på teorier om nevroplastisitet og kognitiv motstandsdyktighet. Nevroplastisitet er hjernens evne til å tilpasse seg ytre påvirkninger ved å øke tettheten av nerveender og volumet på hjerneceller. Repetert stimulering over tid er vist å kunne igangsette nevroplastisitet og dermed kunne bidra til økte kognitive reserver. Disse mikrostrukturelle forandringene kan påvises ved endringer i hjernebarkens tykkelse eller hvit substans på MR bilder. I studier hos friske personer med normal hukommelse har arbeidsminnetrening en påvisbar effekt ved nevrokognitive tester som også gjenfinnes på MR bilder, men effekten hos eldre med kognitiv svikt er ikke undersøkt i samme grad. Det foreligger noen preliminære rapporter om positiv treningseffekt på arbeidsminne hos personer med MCI, men studiene har hatt lav statistisk styrke, og varierende resultater. Det er mange bakenforliggende sykdommer som kan føre til en MCI tilstand. Dette gir utslag i varierende grad av påvisbare endringer i hjernen. Design: Individer med MCI ble rekruttert fra fire hukommelsesklinikker i Helse-Sør Øst. Deltagerne gjennomgikk nevrokognitive tester og MR undersøkelser ved baseline, 4 uker og 4 mnd etter trening. Ved inklusjon ble deltagerne randomisert inn i to grupper, adaptiv og aktiv kontroll. Vi brukte et PC-administrert arbeidsminnetreningsprogram med en adaptiv og en placebo arm. Gruppen med adaptiv trening fikk vanskelighetsgraden på oppgavene automatisk regulert slik at de trente dynamisk på egen maksimal vanskelighetsgrad. Den aktive kontrollgruppen brukte samme treningsprogram, men med fast lav vanskelighetsgrad uten individuell tilpasning. Videre undersøkte vi en sammenlignbar gruppe individer uten kognitiv svikt med MR undersøkelser og kognitive tester tilsvarende treningsgruppene ved baseline. Denne gruppen ble rekruttert vi media og Sørlandet sykehus sin hjemmeside. For å måle lokalisert atrofi eller hvitsubstans forandringer i hjernen, ofte er assosiert med spesifikke nevrodegenerative sykdommer eller skade på hvit substans mikrostruktur, brukte vi 4 aldersjusterte kliniske visuelle skalaer. Resultater: Det ble rekruttert 84 deltagere i studien, hvor 62 individer hadde minst to MR undersøkelser. Genetisk profil tilgjengelig for 54 personer. Den amnestiske MCI gruppen hadde økt andel av MRI identifiserte hjerneforandringer sammenlignet med ikke-amnestisk gruppe og de kognitivt friske. Scheltens skala for å måle medial temporal lapps atrofi, viste seg å være den beste til å skille mellom MCI og kontrollgruppen. Amnestisk-MCI gruppen hadde høyere grad av hjernesvinn i tinninglappen enn både ikke-amnestisk MCI og kontroll gruppen. Hjernebarkens tykkelse endret seg ikke signifikant hos gruppen MCI pasientene etter arbeidsminnetrening. LMX1a-AA viste seg å ha en mulig modulerende treningseffekt uttrykt ved økning av tykkelse i hjernebarken hos pasienter med MCI. APOE genet hadde ingen signifikant modulerende effekt på hjernebarken etter arbeidsminne trening. Endringer i hvit substans etter trening ble undersøkt ved «mean diffusivity». Denne undersøkelse gir et bilde på synaptisk tetthet, dvs antall nerveender i et område. I denne studien fant vi en økning i «mean diffusivity» i venstre sagital stratum hos den adaptive gruppen, men ikke hos non-adaptiv gruppe ved kontrollen fire måneder etter trening. Dette området rommer flere store hjernebaner og endringen er et tegn på treningseffekt bare hos den gruppen som trener på høy vanskelighetsgrad. VI fant ingen tegn til at lett trening ga økt antall nerveender. Gruppen med ikke amnestisk MCI hadde fremdeles etter fire måneder høyere andel nerveender i to områder assosiert med hukommelse og arbeidsminne sammenlignet med de som hadde amnestisk MCI. Bærerskap av undergrupper av APOE-genet og LMX1aa hadde ingen innvirkning på treningseffekten målt i hvit substans. Konklusjon: Individer med MCI som fikk adaptiv trening hadde treningseffekt målt med MR. Dette tyder på at adaptiv arbeidsminnetrening kan bidra til å forbedre forbindelse mellom nerveceller også ved begynnende hukommelsessvikt. Videre fant vi at det var en sammenheng mellom nedsatt funksjon i forskjellige nevropsykologiske domener og funn på MR bilder. Bærere av LMX1a-AA fikk en positiv utvikling av hjernebarktykkelsen etter trening, som vedvarte etter fire måneder sammenlignet med bærere av LMX1a-GG/GA. Vi finner ingen påvirkning av bærerskap av forskjellige APOE gener på treningseffekt.Aim: The main aim of this study was to investigate the effects of computer-based working memory training, measured by MRI in individuals with Mild cognitive impairment (MCI), and to investigate a possible correlation between the structural loss detectable with the radiological visual scoring systems and domain-specific function loss. Furthermore, we wanted to investigate if the neuroplasticity in MCI patients was workload-dependent or if the effect of the training was modulated by the genotypes LMX1a or APOE. Background: Individuals with MCI have a cognitive decline above expected for normal aging, but the decline does not affect activities of daily living. A high annual transition rate from MCI to dementia of 10-15% targets this population as suitable for any delaying interventions. Currently, no treatments are available for MCI. . Depending on whether the impairment primarily affects memory, MCI is subdivided into amnestic and non-amnestic(aMCI/naMCI) groups. A common feature in both MCI groups is often the decline in working memory function. The concept behind the effect of working memory training(WMT) is based on neuroplasticity; repeated stimuli trigger a neuroplastic response in the brain resulting in increased glial volume or increased synaptic density, leading to increased connectivity. Investigating the neuroplastic process in response to WMT can be done objectively with structural or diffusion-weighted MRI imaging techniques. This is previously reported in cognitively healthy adults, but few studies with divergent results have investigated if WMT can induce brain changes detectable on MRI in MCI patients. A knowledge gap exists regarding the ability of the MCI brain to utilize neuroplasticity after stimuli. Design: A total of 84 individuals diagnosed with MCI from four hospitals in the South-East Health Care region were included in the study. Of these, 63 had at least two MRI images harvested, and genetic results were available for 54 individuals. The participants were randomized to either adaptive working memory training or active control at inclusion. The participants participated in a computer-based WMT program for 25 sessions over five weeks and underwent cognitive testing and MRI imaging at baseline, four weeks, and four months after training . To investigate the computerized working memory training (CMWT)effect, we utilized longitudinal multimodal MRI techniques. A group of 51 healthy controls was recruited through media and Sorlandet hospital’s web page. This group underwent testing and MRI similar to baseline. Results: The MCI group had a greater degree of brain pathology than the non-amnestic and healthy control groups, as previously reported. Age-adjusted Schelten’s medial temporal atrophy (MTA) was superior to the other three visual scoring systems for measuring localized atrophy or white matter structural damage. The decline was diverse, ranging from single domain MCI to multiple domains MCI. This is in accordance with previous studies both radiologically and neurocognitively. No significant cortical thickness changes longitudinally after CWMT were found, nor any significant differences after adaptive or non-adaptive CMWT training measured by cortical thickness. Carriers of the LMX1a-AA had a significantly greater cortical thickness trajectory than the LMX1a-GG/GA group in the right superior frontal gyrus, indicating a possible modulating effect. These findings are considered promising for further studies. Diffusion-weighted MRI found significantly decreased mean diffusivity in the left sagittal stratum in the adaptive training group at four months compared to the non-adaptive. The sagittal stratum is a junction region for several large tracts associated with working memory. The finding indicates that some white matter changes are workload-dependent. Four months after training, significant changes were observed favoring the naMCI group compared to the aMCI group in the left posterior thalamic radiation and left hippocampal cingulum. We did not detect any modulating training effect on the white matter from APOE and LMX1a.Doktorgradsavhandlin