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    Authors: Bertoldo, Alessandra; Cobelli, Claudio; Squarcina, Letizia;
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  • Authors: Zhuang, Lin;

    Early diagnosis of Alzheimer’s disease (AD) is indispensable for the future success of disease-modifying interventions. Given the recent advances in neuroimaging technology, considerable efforts are underway to identify early diagnostic imaging markers of AD by studying in-vivo cerebral grey matter (GM) damage in AD. By contrast, the evaluation of in-vivo cerebral white matter (WM) degradation in patients with early AD is still in its infancy, although animal and post-mortem studies have demonstrated WM pathological changes are widespread and even precede GM alterations in the AD brain. Diffusion tensor imaging (DTI) can provide useful information regarding microstructural WM changes in-vivo, thus may permit earlier diagnosis of AD from the perspective of WM abnormalities. The overall objective of this thesis is to investigate in-vivo microstructural WM changes as measured by DTI in individuals with amnestic mild cognitive impairment (aMCI) at a high risk of developing AD. Microstructural WM integrity was first examined in the whole sample of aMCI subjects, then in different stages of aMCI, finally in cognitively normal individuals who are destined to develop aMCI. In the whole aMCI group, widespread microstructural WM changes were observed in distributed brain regions, particularly in the medial temporal lobe known to be preferentially vulnerable in AD. Further analysis using fibre tracking technique revealed that disrupted microstructural integrity of the fornix linking the hippocampus contributed more to episodic memory dysfunction than did hippocampal atrophy in aMCI. Additional analysis showed that microstructural WM damage began in the fornix in the early stage of aMCI before spreading to the uncinate fasciculus and the parahippocampal cingulum in the later stage of aMCI. Fornical damage in the early stage of aMCI was found to be independent of hippocampal atrophy. Moreover, in cognitively normal individuals who subsequently developed aMCI during 2-year follow-up, substantial WM alterations consistent with AD were reported in the absence of GM atrophy. The results from this thesis improve our understanding of in-vivo WM changes in the earlier preclinical stages of AD. DTI may enable us to make an earlier and more accurate diagnosis of AD in the near future.

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    Doctoral thesis . 2012
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      Doctoral thesis . 2012
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    This thesis set out to investigate the relation between sleep and psychopathology. We examined two groups; bipolar patients and adolescents from the general population that are both characterized by mood fluctuations and are vulnerable for disturbances in sleep-wake pattern. Using wearables (watches) to obtain actigraphy measurements, we found that bipolar patients had normal sleep patterns outside their episodes, suggesting that bipolar sleep disturbances are mainly state-dependent, rather than a trait of the disorder. A remarkable finding of our studies was that effective sleep was related to lower integrity of white matter tracts in bipolar disorder patients, whereas in the general population this relationship was the reverse (better tracts in those that slept well). A likely explanation for this difference is the use of antipsychotic medication in the patient group. In a large epidemiological sample of over 15,000 youth we found that poor sleep was related to psychosocial problems, suicidality and health risk behavior. The association between sleep and health risk behavior was only partially mediated by emotional problems, suggesting that not only the relation between emotional deregulation and sleep disturbances plays a role in the occurrence of behavioural problems, but that sleep deprivation in itself may lead to risky behaviour.

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    Doctoral thesis . 2017
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      Doctoral thesis . 2017
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    Authors: Verkooijen, Susanne;

    This thesis set out to investigate the relation between sleep and psychopathology. We examined two groups; bipolar patients and adolescents from the general population that are both characterized by mood fluctuations and are vulnerable for disturbances in sleep-wake pattern. Using wearables (watches) to obtain actigraphy measurements, we found that bipolar patients had normal sleep patterns outside their episodes, suggesting that bipolar sleep disturbances are mainly state-dependent, rather than a trait of the disorder. A remarkable finding of our studies was that effective sleep was related to lower integrity of white matter tracts in bipolar disorder patients, whereas in the general population this relationship was the reverse (better tracts in those that slept well). A likely explanation for this difference is the use of antipsychotic medication in the patient group. In a large epidemiological sample of over 15,000 youth we found that poor sleep was related to psychosocial problems, suicidality and health risk behavior. The association between sleep and health risk behavior was only partially mediated by emotional problems, suggesting that not only the relation between emotional deregulation and sleep disturbances plays a role in the occurrence of behavioural problems, but that sleep deprivation in itself may lead to risky behaviour.

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    Authors: Hooijmans, M.T.;

    The overall aim of this thesis was to combine various quantitative MR measurements and compare these combined measurements between Duchenne Muscular Dystrophy (DMD) patients and healthy age-matched controls both on a cross-sectional and longitudinal level, in order to generate a better understanding of the underlying pathophysiology of the disease and ideally to determine the potential of these MRI outcome parameters for monitoring muscle tissue changes in a clinical setting. In order to achieve this aim, we assessed the effect of spatial localization, data quality and confounding effects on the quantification process for various MR outcome parameters. We found that, sufficient SNR is a prerequisite for reliable MR measurements. In addition, we found that út and water T2 changes need to be monitored in DTI in skeletal muscle. Second, we used a combination of quantitative MRI and spatially resolved 31P MRS to contribute to the understanding of the pathophysiology in DMD. We found that PDE-levels and water T2 changes occurred prior to the replacement of muscle tissue by fat. Subsequently, we found that PDE-levels had the potential to function as a marker to monitor muscle tissue changes in DMD

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    Doctoral thesis . 2017
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      Doctoral thesis . 2017
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    Authors: Rafipooraskestani, Hossein; Tax, Chantal;

    Enclosed within a protective bony shell, the human brain poses a significant challenge for direct physical examination. Therefore, non-invasive methods, such as Magnetic Resonance Imaging (MRI), have become very important tools for exploring the brain’s structure and functionality. Nevertheless, these indirect techniques are not without their limitations, notably a lack of specificity. Although they are sensitive to microstructural variations, their capacity to link changes in signals to meaningful biophysical processes is limited. Microstructural modelling has risen to address this problem, offering a means to correlate these otherwise abstract measurements with meaningful biophysical parameters. However, as the complexity of these models, either in terms of geometry or physical properties, improves, so does the number of free parameters required, posing a substantial challenge for reliable parameter estimation. This thesis seeks to address two substantial issues within the field of microstructural modelling of diffusion MRI data. Firstly, it proposes a novel approach to identify the microstructural parameter alterations that can explain observed differences in diffusion MRI between diseased and control group. This approach enables the application of highly specific models without the associated concerns about parameter estimation. Secondly, it advocates for the development of a tool that extracts fibre-specific features from diffusion MRI data in a manner that promotes comparability across different subjects, facilitated by the use of hierarchical Bayesian models. By offering these approaches to analyze diffusion MRI data, this research aims to circumventing the constraints imposed by existing microstructural modeling techniques, thus improve the precision of brain structure diagnosis and comprehension.

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    DataBank, Bodleian Libraries, University of Oxford
    Doctoral thesis . 2023
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      DataBank, Bodleian Libraries, University of Oxford
      Doctoral thesis . 2023
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    Authors: Takahashi, Masato; Kitamura, Soichiro; Matsuoka, Kiwamu; Yoshikawa, Hiroaki; +6 Authors

    Background: Recognising facial emotions involves visual and emotional information processing. Patients with dementia, including dementia of Alzheimer's type (DAT), are known to poorly recognise facial emotions, especially negative facial emotions. In this study, we aimed to assess if DAT patients exhibit poor facial emotional recognition, and to identify a neural basis for how poor facial emotional recognition might occur. Methods: Magnetic resonance imaging and diffusion tensor imaging (DTI) analysis were conducted in 20 DAT patients and 15 cognitive normal (CN) subjects. The uncinate fasciculus (UF), inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus were delineated by deterministic tractography. DTI parameters were calculated for each fibre. Facial emotion recognition was evaluated with the Facial Emotion Selection Test (FEST). The relationships between FEST scores and DTI parameters in each fibre were measured by partial correlation analyses with age, gender, and the Mini-Mental State Examination as covariates. Group-wise comparisons between DAT and CN subjects were performed for each DTI parameter in each fibre. Results: DAT patients showed lower FEST negative emotion scores than CN subjects (P < 0.05). The score of negative emotion subscale was negatively correlated (r = -0.770, P < 0.001) to mean diffusivity of the left UF in DAT patients. There were no relationships between negative emotion subscale and the other fibre tracts. DAT patients showed no differences in the DTI parameters for each fibre compared to CN subjects. Conclusions: DAT-related prefrontal-limbic network dysfunction is associated with poor recognition of unpleasant emotions; consequently, worse facial recognition of negative emotion is observed in DAT patients. This is the peer reviewed version of the following article: https://onlinelibrary.wiley.com/doi/full/10.1111/psyg.12498, which has been published in final form at https://doi.org/10.1111/psyg.12498 . This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. © 2020 Japanese Psychogeriatric Society 博士(医学)・甲第763号・令和2年12月24日

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    Authors: Santillo, Alexander;

    The present thesis explores alterations in brain morphology in the neurodegenerative disorder of frontotemporal dementia (FTD). With the aim to improve the clinical diagnostics of FTD, we explored the diagnostic potential of measuring morphological alterations in the white matter by diffusion tensor imaging (DTI)- MRI, compared with the more commonly used assessment of grey matter thickness and volume. DTI-MRI was better at separating FTD cases from controls than grey matter parameters, and may thus be a promising supplementary imaging tool for the diagnostic work in FTD. We used DTI in combination with grey matter imaging to explore the morphological underpinnings of one of the central behavioural symptoms in FTD, disinhibition. Our results show that this symptom appears related to the integrity of an orbitofrontal-temporal network, as opposed to the prevailing view of a degeneration of the orbitofrontal cortex. An important question in FTD is what constitutes the morphological link between the molecular pathologies and the characteristic frontotemporal pattern of cortical degeneration. The von Economo neurons (VENs), are a particular type of neurons that are proposed to constitute this link. We confirm results from others, showing that these neurons are selectively degenerated in FTD. In addition we show that these neurons are more afflicted than pyramidal neurons in the superficial cortical layers, previously thought to be the most selectively degenerated in the cortex of FTD. The findings presented in this thesis will hopefully contribute both to improved diagnostics, understanding of clinico-pathological relationships, and of the pathophysiology of this condition. Frontotemporal demens är ett sjukdomstillstånd där nervceller i hjärnans pann- (“fronto”) och tinninglober (“temporal”) förtvinar, vilket leder till en tilltagande cellförlust och uttunning av hjärnbarken i dessa områden. Till skillnad från Alzheimers sjukdom, den vanligaste demenssjukdomen, leder frontotemporal demens i första hand inte till försämrat minne och orienteringsförmåga, utan till förändringar av personlighet och beteende hos den drabbade. Orsakerna till sjukdomen är till största delen okända, det finns idag ingen bot och begränsade möjligheter till lindrande behandling. Det övergripande syftet med denna avhandling är att studera strukturella hjärnförändringar på såväl mikroskopisk nivå som med nyare bildgivande metoder, för att bättre kunna diagnosticera sjukdomen, för att belysa hur förändringarna leder till några av de typiska symtomen och hur dessa kan hjälpa oss att förstå de underliggande mekanismerna vid frontotemporal demens. Avhandlingens första del rör hjärnavbildande tekniker. Diagnosen frontotemporal demens kan vara svår att ställa och läkaren tar idag alltid hjälp av en hjärnavbildande undersökning (“röntgen”), såsom skiktröntgen (datortomografi) eller magnetkameraundersökning (MR) av hjärnan, för att påvisa en uttunning av hjärnbarken i pann- och tinninglober. MR anses vara den känsligare av de två undersökningarna. Den typ av MR som används idag är dock inte alltid tillräckligt känslig för att i tidigt skede av sjukdomen kunna svara på om patienten har tecken till frontotemporal demens eller inte. Det finns alltså ett behov av att utveckla andra typer av MR undersökningar som lättare kan påvisa tidiga sjukdomsförändringar. Vid frontotemporal demens drabbas hjärnbarken (den grå substansen), men också de nervtrådar som går till och från barken, och som tillsammans utgör den så kallade vita substansen. Den vita substansen kan idag undersökas på ett detaljerat sätt med hjälp av en ny MR metod, så kallad ”diffusion tensor imaging” (DTI). Huruvida MR-DTI har fördelar jämfört med att mäta uttunning av hjärnbarken för att diagnosticera frontotemporal demens vet man inte. Syftet med den första delstudien i avhandlingen var att undersöka om MR-DTI var bättre på att särskilja en grupp patienter med frontotemporal demens från en grupp friska individer jämfört med mätning av barkens tjocklek och volym, vilket visade sig vara fallet. DTI används idag inte för diagnostik inom rutinsjukvård men studien är ett incitament till att anpassa och vidareutveckla metoden för vardagligt kliniskt bruk. I avhandlingens andra dels var syftet att undersöka bakgrunden till ett av de viktigaste symtomen vid frontotemporal demens, nämligen bristande hämning. Bristande hämning innebär att en person följer impulser som den tidigare kunde kontrollera och tar risker, gör oövervägda handlingar och tar mindre social hänsyn. Tidigare har bristande hämning framförallt kopplats till skada och uttunning i pannlobens nedre delar. Bristande hämning har undersökts med tester och frågeformulär hos patienter med frontotemporal demens, och kopplingarna till sjukliga förändringar av den vita och grå substansen har undersökts. Vi fann att bristande hämning inte endast är kopplat till förändring av pannlobens nedre delar, utan till ett större nätverk bestående av pann- och tinningloben i höger hjärnhalva, och de nervtrådar som kopplar samman dessa områden. Resultaten har betydelse för att förstå flera tillstånd i hjärnan där bristande hämning förekommer, till exempel olika psykiatriska sjukdomstillstånd. Varför drabbas just pann- och tinningloberna vid frontotemporal demens, i alla fall i sjukdomens tidiga skeden? Om vi kunde påvisa att det är någon särskild nervcell eller egenskap hos nervceller som förklarar detta, skulle detta kunna bidra till att hitta angreppspunkter för att utveckla sjukdomsmodifierande behandling. I avhandlingens tredje och fjärde del studeras en typ av nervceller, som nästan enbart finns i de områden som drabbas tidigast vid frontotemporal demens. Dessa nervceller kallas von Economo neuron efter den person som först beskrev dem. I tidigare, mindre studier har von Economo neuron visat sig vara särskilt drabbade vid frontotemporal demens, men inte vid exempelvis Alzheimers sjukdom. I avhandlingens tredje delstudie bekräftas de tidigare fynden från andra forskare, men i ett betydligt större material än tidigare. I den fjärde delstudien visas att von Economo neuron är mer drabbade än de nervceller som tidigare ansågs vara den absolut mest känsliga vid frontotemporal demens. Forskningsresultaten stärker hypotesen om att von Economo neuron kan vara en av förklaringarna till att frontotemporal demens drabbar just pann- och tinningloberna, och pekar på vikten av fortsatt forskning för att fördjupa vår förståelse av dessa nervcellers funktion i både den sjuka och friska hjärnan.

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    Authors: Heikkila, Heini;

    The asymptomatic phase of familial Alzheimer’s disease caused by E280A mutation in presenilin-1 gene is characterized by intact performance in traditional neuropsychological tasks including memory, language, and executive functions. However, asymptomatic mutation carriers are already impaired in tasks that require visual short-term memory binding. Meanwhile, neuropathological changes in white matter integrity take place during the course of familial Alzheimer’s disease. We investigated whether the behavioural short-term memory binding deficits are accompanied by changes in white matter integrity in asymptomatic and clinical phases of familial Alzheimer’s disease. Three groups - asymptomatic carriers of presenilin-1 gene mutation, familial Alzheimer’s disease patients, and healthy controls - underwent an assessment consisting of a neuropsychological test battery, two visual short-term memory binding tasks, and diffusion tensor imaging. Group comparisons indicated changes in white matter integrity in familial Alzheimer’s disease patients and to smaller extent already in asymptomatic carriers. Higher performance in visual shape-colour binding task was related to higher white matter integrity in frontal areas, and higher performance in visual colour-colour binding task was related to higher white matter integrity in frontal and parietal areas. Thus, we demonstrate the early changes in white matter integrity already in asymptomatic phase of familial Alzheimer’s disease. These changes become more widespread in the course of the disease. In addition, impaired performance in visual short-term memory binding tasks is accompanied by changes in white matter integrity which might implicate loss of connectivity. The results help to shed light on the neural underpinnings of familial Alzheimer’s disease and might lead to development of new methods for the early diagnosis of Alzheimer’s disease.

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    Authors: Yamamoto, Utako;
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    Authors: Bertoldo, Alessandra; Cobelli, Claudio; Squarcina, Letizia;
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  • Authors: Zhuang, Lin;

    Early diagnosis of Alzheimer’s disease (AD) is indispensable for the future success of disease-modifying interventions. Given the recent advances in neuroimaging technology, considerable efforts are underway to identify early diagnostic imaging markers of AD by studying in-vivo cerebral grey matter (GM) damage in AD. By contrast, the evaluation of in-vivo cerebral white matter (WM) degradation in patients with early AD is still in its infancy, although animal and post-mortem studies have demonstrated WM pathological changes are widespread and even precede GM alterations in the AD brain. Diffusion tensor imaging (DTI) can provide useful information regarding microstructural WM changes in-vivo, thus may permit earlier diagnosis of AD from the perspective of WM abnormalities. The overall objective of this thesis is to investigate in-vivo microstructural WM changes as measured by DTI in individuals with amnestic mild cognitive impairment (aMCI) at a high risk of developing AD. Microstructural WM integrity was first examined in the whole sample of aMCI subjects, then in different stages of aMCI, finally in cognitively normal individuals who are destined to develop aMCI. In the whole aMCI group, widespread microstructural WM changes were observed in distributed brain regions, particularly in the medial temporal lobe known to be preferentially vulnerable in AD. Further analysis using fibre tracking technique revealed that disrupted microstructural integrity of the fornix linking the hippocampus contributed more to episodic memory dysfunction than did hippocampal atrophy in aMCI. Additional analysis showed that microstructural WM damage began in the fornix in the early stage of aMCI before spreading to the uncinate fasciculus and the parahippocampal cingulum in the later stage of aMCI. Fornical damage in the early stage of aMCI was found to be independent of hippocampal atrophy. Moreover, in cognitively normal individuals who subsequently developed aMCI during 2-year follow-up, substantial WM alterations consistent with AD were reported in the absence of GM atrophy. The results from this thesis improve our understanding of in-vivo WM changes in the earlier preclinical stages of AD. DTI may enable us to make an earlier and more accurate diagnosis of AD in the near future.

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    Doctoral thesis . 2012
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      Doctoral thesis . 2012
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    This thesis set out to investigate the relation between sleep and psychopathology. We examined two groups; bipolar patients and adolescents from the general population that are both characterized by mood fluctuations and are vulnerable for disturbances in sleep-wake pattern. Using wearables (watches) to obtain actigraphy measurements, we found that bipolar patients had normal sleep patterns outside their episodes, suggesting that bipolar sleep disturbances are mainly state-dependent, rather than a trait of the disorder. A remarkable finding of our studies was that effective sleep was related to lower integrity of white matter tracts in bipolar disorder patients, whereas in the general population this relationship was the reverse (better tracts in those that slept well). A likely explanation for this difference is the use of antipsychotic medication in the patient group. In a large epidemiological sample of over 15,000 youth we found that poor sleep was related to psychosocial problems, suicidality and health risk behavior. The association between sleep and health risk behavior was only partially mediated by emotional problems, suggesting that not only the relation between emotional deregulation and sleep disturbances plays a role in the occurrence of behavioural problems, but that sleep deprivation in itself may lead to risky behaviour.

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    Doctoral thesis . 2017
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    Authors: Verkooijen, Susanne;

    This thesis set out to investigate the relation between sleep and psychopathology. We examined two groups; bipolar patients and adolescents from the general population that are both characterized by mood fluctuations and are vulnerable for disturbances in sleep-wake pattern. Using wearables (watches) to obtain actigraphy measurements, we found that bipolar patients had normal sleep patterns outside their episodes, suggesting that bipolar sleep disturbances are mainly state-dependent, rather than a trait of the disorder. A remarkable finding of our studies was that effective sleep was related to lower integrity of white matter tracts in bipolar disorder patients, whereas in the general population this relationship was the reverse (better tracts in those that slept well). A likely explanation for this difference is the use of antipsychotic medication in the patient group. In a large epidemiological sample of over 15,000 youth we found that poor sleep was related to psychosocial problems, suicidality and health risk behavior. The association between sleep and health risk behavior was only partially mediated by emotional problems, suggesting that not only the relation between emotional deregulation and sleep disturbances plays a role in the occurrence of behavioural problems, but that sleep deprivation in itself may lead to risky behaviour.

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    Authors: Hooijmans, M.T.;

    The overall aim of this thesis was to combine various quantitative MR measurements and compare these combined measurements between Duchenne Muscular Dystrophy (DMD) patients and healthy age-matched controls both on a cross-sectional and longitudinal level, in order to generate a better understanding of the underlying pathophysiology of the disease and ideally to determine the potential of these MRI outcome parameters for monitoring muscle tissue changes in a clinical setting. In order to achieve this aim, we assessed the effect of spatial localization, data quality and confounding effects on the quantification process for various MR outcome parameters. We found that, sufficient SNR is a prerequisite for reliable MR measurements. In addition, we found that út and water T2 changes need to be monitored in DTI in skeletal muscle. Second, we used a combination of quantitative MRI and spatially resolved 31P MRS to contribute to the understanding of the pathophysiology in DMD. We found that PDE-levels and water T2 changes occurred prior to the replacement of muscle tissue by fat. Subsequently, we found that PDE-levels had the potential to function as a marker to monitor muscle tissue changes in DMD

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      Doctoral thesis . 2017
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    Authors: Rafipooraskestani, Hossein; Tax, Chantal;

    Enclosed within a protective bony shell, the human brain poses a significant challenge for direct physical examination. Therefore, non-invasive methods, such as Magnetic Resonance Imaging (MRI), have become very important tools for exploring the brain’s structure and functionality. Nevertheless, these indirect techniques are not without their limitations, notably a lack of specificity. Although they are sensitive to microstructural variations, their capacity to link changes in signals to meaningful biophysical processes is limited. Microstructural modelling has risen to address this problem, offering a means to correlate these otherwise abstract measurements with meaningful biophysical parameters. However, as the complexity of these models, either in terms of geometry or physical properties, improves, so does the number of free parameters required, posing a substantial challenge for reliable parameter estimation. This thesis seeks to address two substantial issues within the field of microstructural modelling of diffusion MRI data. Firstly, it proposes a novel approach to identify the microstructural parameter alterations that can explain observed differences in diffusion MRI between diseased and control group. This approach enables the application of highly specific models without the associated concerns about parameter estimation. Secondly, it advocates for the development of a tool that extracts fibre-specific features from diffusion MRI data in a manner that promotes comparability across different subjects, facilitated by the use of hierarchical Bayesian models. By offering these approaches to analyze diffusion MRI data, this research aims to circumventing the constraints imposed by existing microstructural modeling techniques, thus improve the precision of brain structure diagnosis and comprehension.

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    Doctoral thesis . 2023
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      DataBank, Bodleian Libraries, University of Oxford
      Doctoral thesis . 2023
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    Authors: Takahashi, Masato; Kitamura, Soichiro; Matsuoka, Kiwamu; Yoshikawa, Hiroaki; +6 Authors

    Background: Recognising facial emotions involves visual and emotional information processing. Patients with dementia, including dementia of Alzheimer's type (DAT), are known to poorly recognise facial emotions, especially negative facial emotions. In this study, we aimed to assess if DAT patients exhibit poor facial emotional recognition, and to identify a neural basis for how poor facial emotional recognition might occur. Methods: Magnetic resonance imaging and diffusion tensor imaging (DTI) analysis were conducted in 20 DAT patients and 15 cognitive normal (CN) subjects. The uncinate fasciculus (UF), inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus were delineated by deterministic tractography. DTI parameters were calculated for each fibre. Facial emotion recognition was evaluated with the Facial Emotion Selection Test (FEST). The relationships between FEST scores and DTI parameters in each fibre were measured by partial correlation analyses with age, gender, and the Mini-Mental State Examination as covariates. Group-wise comparisons between DAT and CN subjects were performed for each DTI parameter in each fibre. Results: DAT patients showed lower FEST negative emotion scores than CN subjects (P < 0.05). The score of negative emotion subscale was negatively correlated (r = -0.770, P < 0.001) to mean diffusivity of the left UF in DAT patients. There were no relationships between negative emotion subscale and the other fibre tracts. DAT patients showed no differences in the DTI parameters for each fibre compared to CN subjects. Conclusions: DAT-related prefrontal-limbic network dysfunction is associated with poor recognition of unpleasant emotions; consequently, worse facial recognition of negative emotion is observed in DAT patients. This is the peer reviewed version of the following article: https://onlinelibrary.wiley.com/doi/full/10.1111/psyg.12498, which has been published in final form at https://doi.org/10.1111/psyg.12498 . This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. © 2020 Japanese Psychogeriatric Society 博士(医学)・甲第763号・令和2年12月24日

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    Authors: Santillo, Alexander;

    The present thesis explores alterations in brain morphology in the neurodegenerative disorder of frontotemporal dementia (FTD). With the aim to improve the clinical diagnostics of FTD, we explored the diagnostic potential of measuring morphological alterations in the white matter by diffusion tensor imaging (DTI)- MRI, compared with the more commonly used assessment of grey matter thickness and volume. DTI-MRI was better at separating FTD cases from controls than grey matter parameters, and may thus be a promising supplementary imaging tool for the diagnostic work in FTD. We used DTI in combination with grey matter imaging to explore the morphological underpinnings of one of the central behavioural symptoms in FTD, disinhibition. Our results show that this symptom appears related to the integrity of an orbitofrontal-temporal network, as opposed to the prevailing view of a degeneration of the orbitofrontal cortex. An important question in FTD is what constitutes the morphological link between the molecular pathologies and the characteristic frontotemporal pattern of cortical degeneration. The von Economo neurons (VENs), are a particular type of neurons that are proposed to constitute this link. We confirm results from others, showing that these neurons are selectively degenerated in FTD. In addition we show that these neurons are more afflicted than pyramidal neurons in the superficial cortical layers, previously thought to be the most selectively degenerated in the cortex of FTD. The findings presented in this thesis will hopefully contribute both to improved diagnostics, understanding of clinico-pathological relationships, and of the pathophysiology of this condition. Frontotemporal demens är ett sjukdomstillstånd där nervceller i hjärnans pann- (“fronto”) och tinninglober (“temporal”) förtvinar, vilket leder till en tilltagande cellförlust och uttunning av hjärnbarken i dessa områden. Till skillnad från Alzheimers sjukdom, den vanligaste demenssjukdomen, leder frontotemporal demens i första hand inte till försämrat minne och orienteringsförmåga, utan till förändringar av personlighet och beteende hos den drabbade. Orsakerna till sjukdomen är till största delen okända, det finns idag ingen bot och begränsade möjligheter till lindrande behandling. Det övergripande syftet med denna avhandling är att studera strukturella hjärnförändringar på såväl mikroskopisk nivå som med nyare bildgivande metoder, för att bättre kunna diagnosticera sjukdomen, för att belysa hur förändringarna leder till några av de typiska symtomen och hur dessa kan hjälpa oss att förstå de underliggande mekanismerna vid frontotemporal demens. Avhandlingens första del rör hjärnavbildande tekniker. Diagnosen frontotemporal demens kan vara svår att ställa och läkaren tar idag alltid hjälp av en hjärnavbildande undersökning (“röntgen”), såsom skiktröntgen (datortomografi) eller magnetkameraundersökning (MR) av hjärnan, för att påvisa en uttunning av hjärnbarken i pann- och tinninglober. MR anses vara den känsligare av de två undersökningarna. Den typ av MR som används idag är dock inte alltid tillräckligt känslig för att i tidigt skede av sjukdomen kunna svara på om patienten har tecken till frontotemporal demens eller inte. Det finns alltså ett behov av att utveckla andra typer av MR undersökningar som lättare kan påvisa tidiga sjukdomsförändringar. Vid frontotemporal demens drabbas hjärnbarken (den grå substansen), men också de nervtrådar som går till och från barken, och som tillsammans utgör den så kallade vita substansen. Den vita substansen kan idag undersökas på ett detaljerat sätt med hjälp av en ny MR metod, så kallad ”diffusion tensor imaging” (DTI). Huruvida MR-DTI har fördelar jämfört med att mäta uttunning av hjärnbarken för att diagnosticera frontotemporal demens vet man inte. Syftet med den första delstudien i avhandlingen var att undersöka om MR-DTI var bättre på att särskilja en grupp patienter med frontotemporal demens från en grupp friska individer jämfört med mätning av barkens tjocklek och volym, vilket visade sig vara fallet. DTI används idag inte för diagnostik inom rutinsjukvård men studien är ett incitament till att anpassa och vidareutveckla metoden för vardagligt kliniskt bruk. I avhandlingens andra dels var syftet att undersöka bakgrunden till ett av de viktigaste symtomen vid frontotemporal demens, nämligen bristande hämning. Bristande hämning innebär att en person följer impulser som den tidigare kunde kontrollera och tar risker, gör oövervägda handlingar och tar mindre social hänsyn. Tidigare har bristande hämning framförallt kopplats till skada och uttunning i pannlobens nedre delar. Bristande hämning har undersökts med tester och frågeformulär hos patienter med frontotemporal demens, och kopplingarna till sjukliga förändringar av den vita och grå substansen har undersökts. Vi fann att bristande hämning inte endast är kopplat till förändring av pannlobens nedre delar, utan till ett större nätverk bestående av pann- och tinningloben i höger hjärnhalva, och de nervtrådar som kopplar samman dessa områden. Resultaten har betydelse för att förstå flera tillstånd i hjärnan där bristande hämning förekommer, till exempel olika psykiatriska sjukdomstillstånd. Varför drabbas just pann- och tinningloberna vid frontotemporal demens, i alla fall i sjukdomens tidiga skeden? Om vi kunde påvisa att det är någon särskild nervcell eller egenskap hos nervceller som förklarar detta, skulle detta kunna bidra till att hitta angreppspunkter för att utveckla sjukdomsmodifierande behandling. I avhandlingens tredje och fjärde del studeras en typ av nervceller, som nästan enbart finns i de områden som drabbas tidigast vid frontotemporal demens. Dessa nervceller kallas von Economo neuron efter den person som först beskrev dem. I tidigare, mindre studier har von Economo neuron visat sig vara särskilt drabbade vid frontotemporal demens, men inte vid exempelvis Alzheimers sjukdom. I avhandlingens tredje delstudie bekräftas de tidigare fynden från andra forskare, men i ett betydligt större material än tidigare. I den fjärde delstudien visas att von Economo neuron är mer drabbade än de nervceller som tidigare ansågs vara den absolut mest känsliga vid frontotemporal demens. Forskningsresultaten stärker hypotesen om att von Economo neuron kan vara en av förklaringarna till att frontotemporal demens drabbar just pann- och tinningloberna, och pekar på vikten av fortsatt forskning för att fördjupa vår förståelse av dessa nervcellers funktion i både den sjuka och friska hjärnan.

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    Authors: Heikkila, Heini;

    The asymptomatic phase of familial Alzheimer’s disease caused by E280A mutation in presenilin-1 gene is characterized by intact performance in traditional neuropsychological tasks including memory, language, and executive functions. However, asymptomatic mutation carriers are already impaired in tasks that require visual short-term memory binding. Meanwhile, neuropathological changes in white matter integrity take place during the course of familial Alzheimer’s disease. We investigated whether the behavioural short-term memory binding deficits are accompanied by changes in white matter integrity in asymptomatic and clinical phases of familial Alzheimer’s disease. Three groups - asymptomatic carriers of presenilin-1 gene mutation, familial Alzheimer’s disease patients, and healthy controls - underwent an assessment consisting of a neuropsychological test battery, two visual short-term memory binding tasks, and diffusion tensor imaging. Group comparisons indicated changes in white matter integrity in familial Alzheimer’s disease patients and to smaller extent already in asymptomatic carriers. Higher performance in visual shape-colour binding task was related to higher white matter integrity in frontal areas, and higher performance in visual colour-colour binding task was related to higher white matter integrity in frontal and parietal areas. Thus, we demonstrate the early changes in white matter integrity already in asymptomatic phase of familial Alzheimer’s disease. These changes become more widespread in the course of the disease. In addition, impaired performance in visual short-term memory binding tasks is accompanied by changes in white matter integrity which might implicate loss of connectivity. The results help to shed light on the neural underpinnings of familial Alzheimer’s disease and might lead to development of new methods for the early diagnosis of Alzheimer’s disease.

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    Authors: Yamamoto, Utako;
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