In der Differentialdiagnose von Parkinson-Syndromen wurden in frühen und in fortgeschrittenen Stadien insgesamt 138 Patienten mit der Verdachtsdiagnose eines Morbus Parkinson und mit der Verdachtsdiagnose einer progressiven supranukleären Blickparese untersucht. Es wurden klinische Verlaufsbeobachtungen sowie die dopaminerge Stimulation mit Apomorphin, die Kernspintomographie und die single photon emission computed tomography (SPECT) mit dem Liganden Jodobenzamid für die Untersuchungen eingesetzt. Die Ergebnisse der zu untersuchenden Hypothesen können wie folgt zusammengefaßt werden: Bei bis dato unbehandelten Patienten mit akinetisch-rigiden Syndromen kann mittels einer Testinjektion von 3 -5 mg Apomorphin mit einer Sensitivität und Spezifität von etwa 90 % das Ansprechen auf eine L-Dopa-Langzeittherapie korrekt vorhergesagt werden. Das IBZM-SPECT ist in der Lage, mit einem positiven Vorhersagewert von 72 % und einem negativen Vorhersagewert von 89 % das Ansprechen auf eine spätere orale L-Dopa-Therapie korrekt vorherzusagen. In der Langzeitbeobachtung entwickeln sich aus den 10 Patienten im Frühstadium, die nach den klinischen Kriterien nicht eindeutig zuzuordnen waren, die eine verminderte Ligandenaufnahme haben, und die nicht auf Apomorphin reagieren, 7 ein "atypisches" Parkinson-Syndrom im Sinne einer MSA (n = 5), einer PSP (n = 1) oder einer CBGD (n = 1) Von diesen 7 Patienten hatten 5 bereits in der Erstdiagnostik eine verminderte IBZM-Bindung im SPECT. Vaskuläre Syndrome entwickeln nicht nur das klinische Bild des "lower body parkinsonism", sondern auch Zeichen einer vertikalen Blickparese mit Demenz bei akinetisch-rigidem Syndrom. Bei gut 30 % der untersuchten Patienten mit der klinischen Diagnose der PSP wurden vaskulär gedeutete Läsionen im MRT in der weißen Substanz und in den Basalganglien gefunden; diese hatten signifikant häufiger eine normale Bindung im IBZM-SPECT und unterschieden sich von degenerativen PSP-Patienten mit erniedrigter IBZM-Bindung. Wir deuten diese Patienten als eine andere nosologische Entität. Außerdem konnte erstmals gezeigt werden, daß bei Patienten, die klinisch wahrscheinlich oder möglicherweise eine PSP hatten, der antero-posteriore Durchmesser des Mittelhirns nach kernspintomographischer Messung mit der Ligandenaufnahme im IBZM-SPECT korreliert. Dies gilt für die Gesamtgruppe der untersuchten Patienten, aber auch für die Untergruppe, die keine hyperintensen T2-Läsionen haben. Diese Ergebnisse bedeuten für den klinische Alltag, daß nach einer sorgfältigen klinischen Untersuchung von Patienten mit Parkinson-Syndromen, die die gültigen Kriterien für die klinische Diagnose des Morbus Parkinson, der progressiven supranukleären Blickparese und auch der Multi-System-Atrophie beachtet, das Kernspintomogramm und das IBZM-SPECT notwendige Untersuchungen in der korrekten ätiologischen Zuordnung von Parkinson-Syndromen, insbesondere auch der progressiven supranukleären Blickparese sind. Dies ist für die weitere Planung insbesondere von neuroprotektiven Strategien bei diesen Krankheitsbildern von essentieller Bedeutung. / One hundred thirty eight patients, in whom the diagnoses of Parkinson's disease or progressive supranuclear palsy (PSP) was suspected, were examined in order to improve the differential diagnosis of these syndromes. We observed the clinical course, tested for the dopaminergic response to the dopamine receptor agonist apomorphine, and used the technical measures of MRI and single photon emission computed tomography (SPECT) with the ligand 123[I] Iodobenzamide (IBZM) in all patients. Apomorphine correctly predicts the response to long term levodopa therapy with a sensitivity and specificity of approximately 90 % in previously untreated parkinsonian patients. The positive predictive value and negative predictive value of IBZM SPECT are 72 % and 89 % respectively. Ten early stage patients, who could not explicitly be assigned according to the clinical criteria, who had reduced IBZM SPECT binding and who did not respond to apomorphine, developed atypical parkinsonian syndromes in the sense of multiple system atrophy (MSA, n = 5), PSP (n = 1) or corticobasal degeneration (n = 1). Five of these 7 patients had a reduced IBZM binding in SPECT already during the early stage. Vascular syndromes depict not only the clinical picture of lower body parkinsonism, but also of supranuclear palsy, dementia and akinetic-rigid syndrome. We found MRI lesions within the white matter and the basal ganglia in about 30 % of our patients with the clinical diagnosis of PSP; we interpreted these lesions as vascular. In contrast to patients without these MRI lesions, who had decreased IBZM binding in SPECT, these patients with vascular disorders had significantly more frequently a normal binding. We interpret our results in that way that these patients represent another nosological entity. In addition, we showed for the first time that the anteroposterior diameter (measured in midbrain MRI scans) correlates to ligand binding measured by IBZM SPECT. This applies as well to all PSP patients as well to the sub-group without hyperintense MRI lesions. The in vivo diagnosis of bradykinetic syndromes relies on clinical examination; after careful observation of valid criteria for Parkinson's disease, PSP and MSA, MRI and IBZM SPECT are mandatory for the correct differential diagnosis, especially for PSP. This applies in particular, if neuroprotective therapies are to be investigated.

There has been considerable progress in the clinical, pathological and genetic fractionation of frontotemporal lobar degeneration syndromes in recent years, driving the development of novel diagnostic criteria. However, phenotypic boundaries are not always distinct and syndromes converge with disease progression, limiting the insights available from traditional diagnostic classification. Alternative transdiagnostic approaches may provide novel insights into the neurobiological underpinnings of symptom commonalities across the frontotemporal lobar degeneration spectrum. In this thesis, I illustrate the use of transdiagnostic methods to investigate apathy and impulsivity. These two multifaceted constructs are observed across all frontotemporal lobar degeneration syndromes, including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. They cause substantial patient morbidity and carer distress, often coexist and are undertreated. Using data from the Pick’s disease and Progressive supranuclear palsy Prevalence and INcidence (PiPPIN) Study, I examine the frequency, characteristics and components of apathy and impulsivity across the frontotemporal lobar degeneration spectrum. A principal component analysis of the neuropsychological data identified eight distinct components of apathy and impulsivity, separating patient ratings, carer ratings and behavioural tasks. Apathy and impulsivity measures were positively correlated, frequently loading onto the same components and providing evidence of their overlap. The data confirmed that apathy and impulsivity are common across the spectrum of frontotemporal lobar degeneration syndromes. Voxel based morphometry revealed distinct neural correlates for the components of apathy and impulsivity. Patient ratings correlated with white matter changes in the corticospinal tracts, which may reflect retained insight into their physical impairments. Carer ratings correlated with grey and white matter changes in frontostriatal, frontotemporal and brainstem systems, which have previously been implicated in motivation, arousal and goal directed behaviour. Response inhibition deficits on behavioural tasks correlated with focal frontal cortical atrophy in areas implicated in goal-directed behaviour and cognitive control. Diffusion tensor imaging was highly sensitive to the white matter changes underlying apathy and impulsivity in frontotemporal lobar degeneration syndromes. Diffusion tensor imaging findings were largely consistent with voxel-based morphometry, with carer ratings reflecting widespread changes while objective measures showed changes in focal, task-specific brain regions. White matter abnormalities often extended beyond observed grey matter changes, providing supportive evidence that white matter dysfunction represents a core pathophysiology in frontotemporal lobar degeneration. Apathy was a significant predictor of death within two and a half years from assessment, consistent with studies linking apathy to poor outcomes. The prognostic importance of apathy warrants more accurate measurement tools to facilitate clinical trials. Although causality remains unclear, the influence of apathy on survival suggests effective symptomatic treatments may also prove disease-modifying. These findings have several implications. First, clinical studies for apathy/impulsivity in frontotemporal lobar degeneration syndromes should target patients who present with these symptoms, irrespective of their diagnostic category. Second, data-driven approaches can inform the choice of assessment tools for clinical trials, and their link to neural drivers of apathy and impulsivity. Third, the components and their neural correlates provide a principled means to measure (and interpret) the effects of novel treatments in the context of frontotemporal lobar degeneration.

Clinical variants of dementia are limiting their diagnosis and can leads to underdiagnosing or substitution of two different diseases with the same symptomatology. The aim of this study is a better understanding of a factors involved in the clinical variability of rare dementias. Progressive supranuclear palsy and Gerstmann-Sträussler-Scheinker syndrome caused by mismatch mutation P102L in Prion protein are used as model diseases. In this thesis, we firstly demonstrate the influence of the distribution of neuropathology and its spread on the clinical phenotype of the disease. Although a single neurodegenerative disease increases the risk of neurodegenerative comorbidity, this other neuropathology does not affect the phenotypic presentation of the primary disease. Monogenetically inherited proteinopathies can have a different clinical subtype, which is not only conditioned by causal protein polymorphisms, but can be influenced by the wild type allele of causal protein. A more accurate understanding of the symptomatic variability in dementias will allow a better focus of a drug studies and, in the future a treatment, but it will also lead to a better understanding of the pathogenesis of neurodegenerative diseases. Keywords: dementia, Progressive supranuclear palsy, Gerstmann-Sträussler-Scheinker...

Tesis por compendio / [ES] El aumento del envejecimiento de la población a nivel mundial y la limitada eficacia de los tratamientos disponibles para la demencia plantean la necesidad de desarrollar intervenciones dirigidas al envejecimiento y a las enfermedades neurodegenerativas. También se hace necesario promover cambios relacionados con la percepción negativa sobre la vejez en la sociedad. Ante estos planteamientos se está informando de los posibles beneficios terapéuticos de las intervenciones basadas en las artes, como la arteterapia, en la promoción de la salud, prevención de la demencia y manejo de la sintomatología asociada. Debido al interés de este tema nos propusimos evaluar los principales efectos de la arteterapia en el envejecimiento y enfermedades neurodegenerativas, analizar los posibles beneficios de esta terapia dirigida a personas mayores durante la pandemia y conocer los efectos del arte respuesta como activismo artístico para promover el cambio social en los estereotipos asociados al envejecimiento. Con el fin de alcanzar estos objetivos se plantearon 5 estudios que han dado lugar a los 5 artículos publicados en revistas de impacto que componen la tesis doctoral. El primer estudio incluye una revisión sistemática que analiza los beneficios de la arteterapia en personas con Enfermedad de Alzheimer (EA): los resultados informan de mejoras en bienestar, calidad de vida, estado anímico y depresión. El segundo artículo muestra un estudio de un caso de Parálisis Supranuclear Progresiva (un parkinsonismo atípico) evaluando posibles beneficios de la arteterapia en la sintomatología asociada a la enfermedad. Los resultados informan de mejoras significativas en expresión emocional, aspectos conductuales y relaciones sociales. El tercer trabajo analiza la relación entre EA y el duelo crónico basándose en un estudio de caso de EA, evaluando los efectos de la arteterapia en los síntomas cognitivos, somáticos y psicológicos. Se observó un impacto positivo en la expresión emocional, aspectos cognitivos (concentración, control, memoria), relaciones sociales y cambios en el sentido de identidad. El cuarto estudio describe una intervención de arteterapia en un grupo de mujeres de edad avanzada realizada durante las restricciones impuestas por la pandemia analizando las dificultades asociadas a este periodo y proponiendo su abordaje a través de la arteterapia. Los resultados sugieren mejoras en aspectos cognitivos (concentración, memoria y atención), expresión e identificación emocional, socialización y disminución de la ansiedad. El quinto estudio consta de dos proyectos relacionados (exposición virtual y talleres intergeneracionales) que tienen como denominador común el arte respuesta como activismo artístico, promoviendo la concienciación y el cambio social, y utilizando el arte respuesta para dar sentido y significado a las reflexiones relacionadas con el envejecimiento. Las experiencias incluidas en las 5 publicaciones contribuyen a generar avance del conocimiento acerca de las posibles aplicaciones de la arteterapia en el envejecimiento, enfermedades neurodegenerativas y prevención de la demencia. También se muestra su utilidad para contrarrestar la privación sensorial y social que conllevan las situaciones de crisis como las vividas durante la pandemia. Además, se han diseñado intervenciones basadas en el activismo artístico que pueden contribuir a desafiar estereotipos y superar actitudes negativas de la sociedad hacia la vejez. En futuros estudios sería de interés realizar intervenciones en muestras más amplias y con seguimiento longitudinal, así como el uso complementario de biomarcadores o técnicas de neuroimagen para evaluar los resultados de la intervención en la población de edad avanzada. Estas intervenciones arteterapéuticas pueden contribuir a crear experiencias participativas intergeneracionales basadas en las artes sobre la experiencia del envejecimiento / [CA] L'augment de l'envelliment de la població a nivell mundial i la limitada eficàcia dels tractaments disponibles per a la demència plantegen la necessitat de desenvolupar intervencions dirigides a l'envelliment i a les malalties neurodegeneratives. També es fa necessari promoure canvis relacionats amb la percepció negativa sobre la vellesa en la societat. Davant estos plantejaments s'està informant dels possibles beneficis terapèutics de les intervencions basades en les arts, com l'artteràpia, en la promoció de la salut, prevenció de la demència i maneig de la simptomatologia associada. A causa de l'interés d'este tema ens vam proposar avaluar els principals efectes de l'artteràpia en l'envelliment i malalties neurodegeneratives, analitzar els possibles beneficis d'esta teràpia dirigida a persones majors durant la pandèmia i conéixer els efectes de l'art resposta com a activisme artístic per a promoure el canvi social en els estereotips associats a l'envelliment. Amb la finalitat d'aconseguir estos objectius es van plantejar 5 estudis que han donat lloc als 5 articles publicats en revistes d'impacte que componen la tesi doctoral. El primer estudi inclou una revisió sistemàtica que analitza els beneficis de l'artteràpia en persones amb Malaltia d'Alzheimer: els resultats informen de millores en benestar, qualitat de vida, estat anímic i depressió. El segon article mostra un estudi de cas de Paràlisis Supranuclear Progressiva (un parkinsonisme atípic) avaluant possibles beneficis de l'artteràpia en la simptomatologia associada a la malaltia. Els resultats informen de millores significatives en expressió emocional, aspectes conductuals i relacions socials. El tercer treball analitza la relació entre Malaltia d'Alzheimer i el dol crònic basant-se en un estudi de un cas de Malaltia d'Alzheimer, avaluant els efectes de l'artteràpia en els símptomes cognitius, somàtics i psicològics. Es va observar un impacte positiu en l'expressió emocional, aspectes cognitius (concentració, control, memòria), relacions socials i canvis en el sentit d'identitat. El quart estudi descriu una intervenció d'artteràpia en un grup de dones d'edat avançada realitzada durant les restriccions imposades per la pandèmia analitzant les dificultats associades a este període i proposant el seu abordatge a través de l'artteràpia. Els resultats suggerixen millores en aspectes cognitius (concentració, memòria i atenció), expressió i identificació emocional, socialització i disminució de l'ansietat. El quint estudi consta de dos projectes relacionats (exposició virtual i tallers intergeneracionals) que tenen com a denominador comú l'art resposta com a activisme artístic, promovent la conscienciació i canvi social, i utilitzant l'art resposta per a donar sentit i significat a les reflexions relacionades amb l'envelliment. Les experiències incloses en les 5 publicacions contribuïxen a generar avanç del coneixement sobre les possibles aplicacions de l'artteràpia en l'envelliment, malalties neurodegeneratives i prevenció de la demència. També es mostra la seua utilitat per a contrarestar la privació sensorial i social que comporten les situacions de crisis com les viscudes durant la pandèmia. A més, s'han dissenyat intervencions basades en l'activisme artístic que poden contribuir a desafiar estereotips i superar actituds negatives de la societat cap a la vellesa. En futurs estudis seria d'interés realitzar intervencions en mostres més àmplies i amb seguiment longitudinal, així com l'ús complementari de biomarcadors o tècniques de neuroimatgeria per a avaluar els resultats de la intervenció en la població d'edat avançada. Estes intervencions artterapèutiques poden contribuir a crear experiències participatives intergeneracionals basades en les arts sobre l'experiència de l'envelliment / [EN] The increasing aging of the world's population and the limited effectiveness of available treatments for dementia increase the need to develop interventions that target aging and neurodegenerative diseases. There is also a need to promote changes in negative societal perceptions of old age. In light of these approaches, the potential therapeutic benefits of arts-based interventions, such as art therapy, in health promotion, dementia prevention and management of associated symptoms are being reported. Due to the interest of this topic, we proposed to evaluate the main effects of art therapy in ageing and neurodegenerative diseases, to analyze the possible benefits of this therapy for older people during the pandemic, and to know the effects of response art as artistic activism to promote social change in the stereotypes associated with ageing. In order to achieve these objectives, 5 studies were proposed, which gave rise to the 5 articles published in high impact journals that make up the thesis. The first study is a systematic review analyzing the benefits of art therapy in people with Alzheimer's disease: the results report improvements in well-being, quality of life, mood and depression. The second article presents a case study of a person living with Progressive Supranuclear Palsy (atypical parkinsonism), evaluating the potential benefits of art therapy on the symptomatology associated with the disease. The results report significant improvements in emotional expression, behavioral aspects and social relationships. The third paper analyses the relationship between Alzheimer's disease and chronic grief based on a case study of a woman diagnosed with Alzheimer's disease, evaluating the effects of art therapy on cognitive, somatic and psychological symptoms. Positive effects were observed on emotional expression, cognitive aspects (concentration, control, memory), social relationships and changes in sense of identity. The fourth study describes an art therapy intervention with a group of old women, carried out during the restrictions imposed by the pandemic, analyzing the difficulties associated with this period and proposing an approach through art therapy. The results suggest improvements in cognitive aspects (concentration, memory and attention), emotional expression and identification, socialization and reduction of anxiety. The fifth study consists of two related projects (virtual exhibition and intergenerational workshops) that share the common denominator of Response Art as artistic activism, promoting awareness and social change, and using Response Art to give sense and meaning to reflections related to aging. The experiences included in the 5 publications contribute to the advancement of knowledge about the possible applications of art therapy in ageing, neurodegenerative diseases and dementia prevention. They also demonstrate its usefulness in counteracting the sensory and social deprivation associated with crisis situations such as those experienced during the pandemic. In addition, interventions based on artistic activism have been developed that can help to challenge stereotypes and overcome negative societal attitudes towards old age. In future studies, it would be interesting to carry out interventions in larger samples and with longitudinal follow-up, as well as the complementary use of biomarkers or neuroimaging techniques to assess the results of the intervention with older people. These art-therapeutic interventions can contribute to the creation of art-based intergenerational participatory experiences of aging / Marco Martínez, P. (2024). Arteterapia en el envejecimiento y enfermedades neurodegenerativas. Experiencias basadas en la prevención, intervención y el activismo artístico [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/206125 / Compendio

Hyperfosforylering av biomarkörproteinet Tau förekommer i flera neurodegenerativa sjukdomar som kallas Taupathies. Proteinets huvudfunktion i människokroppen är att modulera flexibilitet och stabilitet för axonal-mikrotubulin. I Taupathies utlöser hyperfosforyleringen av Tau instabilitet och neurodegenerationen. I dagens läge kan hyperfosforylering av treonin 217 (P217) endast mätas i hjärnan. I den här studien undersöks hyperfosforyleringen av treonin 217 (P217). I syfte att se om nivåerna av P217 är mätbara i cerebrospinalvätska (CSV) och i blodet. Samt för att evaluera hur nivåer av P217 förändras i olika Taupathies, genom att testa hjärnprover från friska kontroller och olika Taupathies. Studien görs för att öka kunskapen om effekten av hyperfosforylering av treonin 217 i Taupathies och för att bidra med en ny provtagningsmetod för P217. Simoa HD-1 Analyzer var instrumentet som användes för analyserna av P217. Det är ett instrument som kan upptäcka onormala nivåer av biomarkörer genom kvantifiering, med hjälp av antikroppar och ett enzym. Enzymet kallas Streptavidin β-galaktosidas och omvandlar en befintlig P217-molekyl i proven till en fluorescerande produkt. Genom Simoa HD-1 Analyzer utvecklades en ultrasensitiv analys med antikropparna P217 och Tau 12, som kunde upptäcka mycket låga nivåer av P217 i hjärnan, CSF och i blod. Förändring av P217-nivåer hittades även i olika Taupathies. De Taupathies med de högsta nivåerna av P217 var Progressiv supranukleär pares, Corticobasal degeneration och Globular glial Taupathies. / Hyperphosphorylation of the biomarker protein Tau occurs in many neurodegenerative diseases called Taupathies. The proteins main function in the human body is to modulate flexibility and stability for axonal microtubules. In Taupathies the hyperphosphorylation of the Tau triggers instability and neurodegeneration. Nowdays hyperphoshorylation on threonine 217 (P217) can only be measured in the brain. In this study the hyperphoshorylation on the phosphorylation site of threonine 217 (P217) is examined. In aim to see if levels of P217 is measurable in cerebrospinal fluid (CSF) and in blood. As well to evaluate how P217 variate in different Taupathies, through the use of brain samples from healthy controls and different Taupathies. The study is made for the purpose of enhancing the pure knowledge about the effect of hyperphosphorylation on threonine 217 in Taupathies and to contribute with a new sampling method for P217. Simoa HD-1 Analyzer was the key instrument of the analyses of P217. It’s an instrument which can detect abnormal levels of biomarkers through quantification, with help of antibodies and an enzyme. The enzyme is called Streptavidin β-galactosidase and converts an existing P217 molecule in the samples to a fluoresce product. Through the use of Simoa HD-1 Analyzer an ultrasensitive assay with antibodies P217 and Tau 12 was developed which could detect very low levels of P217 in brain, CSF and in blood. Variation of P217 levels was also found in different Taupathies. The Taupathies with the highest levels of P217 was Progressive supranuclear palsy, Corticobasal Degeneration and Globular glial Taupathies.

Le rôle que pourrait jouer l’interaction des systèmes cholinergiques (ACh) et dopaminergiques (DA) semble crucial dans la physiopathologie de certaines maladies neurodégénératives, en particulier dans la démence à corps de Lewy (DCL). Ce travail de thèse se propose de valider un protocole d’imagerie moléculaire en tomographie d’émission monophotonique, consistant en un marquage de l’ACh et de la DA chez un même individu, afin de pouvoir étudier in vivo les interactions ACh/DA.Après avoir mis au point chez des sujets âgés et des patients atteints de maladie d’Alzheimer une méthode d’imagerie cérébrale quantitative des neurones ACh utilisant un radioligand sélectif du transporteur vésiculaire de l’ACh, le [123I]-IBVM, et basée sur une modélisation pharmacocinétique, nous avons montré le potentiel de cette méthode à mettre en évidence une atteinte différentielle des circuits ACh dans la Paralysie Supranucléaire Progressive et l’Atrophie Multisystématisée. Dans la dernière partie de ce travail de thèse, nous avons pour la première fois réalisé un double marquage des systèmes ACh et DA dans la DCL, en utilisant, en plus du [123I]-IBVM, un radioligand sélectif du transporteur de la dopamine et validé en routine clinique, le [123I]-FP-CIT. En parallèle, une étude comportementale évaluant la présence d’hallucinations, de fluctuations cognitives, d’altérations des rythmes circadiens ainsi qu’un bilan des performances neuropsychologiques, ont été menés. Cette étude est actuellement en cours de réalisation. Les tous premiers résultats montrent l’existence de liens cohérents entre les données d’imagerie moléculaire et les données cliniques. / The question of how acetylcholine (ACh) and dopamine (DA) could be involved together in the pathophysiology of some neurodegenerative disorders is essential, particularly in dementia with Lewy bodies (DLB). The present study aims at assessing an in vivo molecular imaging method of both ACh and DA brain systems using single photon emission computed tomography. In the first part of the present study, a method based on pharmacokinetic analysis making it possible to quantify ACh neurons in vivo, using [123I]-IBVM, a specific radioligand of vesicular acetylcholine transporter, was developed and validated in healthy subjects and Alzheimer’s disease patients. Then, we showed the ability of our method to demonstrate a differential alteration of ACh pathways in Progressive Supranuclear Palsy and Multiple System Atrophy patients. In the last part of this study, we imaged for the first time both ACh and DA systems in DLB patients, using not only [123I]-IBVM, but also [123I]-FP-CIT, a specific radioligand of dopamine transporter. Concomitantly, a behavioral exploration of hallucinations, fluctuating cognition and disturbances of circadian rhythms was achieved in these patients, as well as a neuropsychological examination. This study is currently in progress. The first results show consistent links between imaging and clinical data.