Parkinson’s disease (PD) is next to Alzheimer’s disease (AD) the second most common neurodegenerative disease. PD has traditionally been characterised as a motor disorder, but more recent research has revealed that cognitive impairments are frequent. Cognitive impairments in executive functions, attention, and working memory with reliance on dopaminergic transmission, are often described as dominating the cognitive profile in early-phase PD. However, although knowledge about the neuropathology that underlies the cognitive impairments in PD has increased, its features are complex and knowledge remains insufficient. Therefore, the aim of the current thesis was to improve the understanding of how task-evoked brain responses relate to cognitive status in patients with PD, with and without mild cognitive impairment (MCI), and to evaluate the predictive value of PD-MCI in respect of prodromal Parkinson’s disease dementia (PDD). This was conducted within the “new Parkinsonism in Umeå” (NYPUM) project, which is a prospective cohort study. Patients with idiopathic PD were included in this thesis, and the patients were examined with a comprehensive neuropsychological battery and with a functional MRI (fMRI) working memory protocol. During scanning, patients conducted a verbal two-back task in which they needed to maintain and actively update relevant information, and the primary outcome measure was blood-oxygen-level-dependent (BOLD) signal. This thesis shows that patients with PD-MCI had significantly lower BOLD signal responses than patients without MCI in frontal (anterior cingulate cortex) and striatal (right caudate) regions (Study I). The altered BOLD response in the right caudate was associated with altered presynaptic dopamine binding. The fronto-striatal alterations persisted across time but without any additional change. However, decreased posterior cortical (right fusiform gyrus) BOLD signal responses were observed in patients with PD-MCI relative to patients without MCI across time (Study II). Finally, PD-MCI at baseline examination is highly predictive for prodromal PDD with a six-fold increased risk. Cognitive tests with a posterior cortical basis, to a greater extent, are predictive for prodromal PDD than tests with a fronto-striatal basis. The observed working memory related alterations in patients with PD-MCI suggest that early cognitive impairments in PD are linked to fronto-striatal dopaminergic dysfunction. The longitudinal development of cognitive impairment in PD reflects additional posterior cortical dysfunction. This might reflect a dual syndrome, with dopamine-depleted fronto-striatal alterations that characterise PD-MCI in general, whereas additional posterior cortical cognitive alterations with a non-dopaminergic basis to a greater extent characterise prodromal PDD. If, and how, the two potential syndromes interact, is still unclear. Thus, this thesis provides information on cognitive neuropathological changes in PD that might contribute to more relevant choices of pharmacotherapy and diagnostic accuracy in respect of PDD. However, additional large-scale longitudinal imaging studies are needed to further clarify the neuropatholgogical features of PD-MCI in respect of prodromal PDD.

Parkinson’s disease (PD) is frequently compounded by neruropsychiatric complications, increasing disability. The combined effect of motor and mental status on care-dependency in PD outpatients is not well characterized. We conducted a cross-sectional study of 1449 PD outpatients. The assessment comprised the Montgomery–Asberg Depression Rating Scale (MADRS) and the diagnostic criteria for dementia. PD severity and treatment complications were rated using Hoehn and Yahr staging and the Unified Parkinson’s Disease Rating Scale (UPDRS) IV. The acknowledged level of care-dependency was documented. Care-dependency was present in 18.3% of all patients. A total of 13.9% had dementia, 18.8% had depression, and 14.3% had both. Regression analyses revealed increasing effects of age, PD duration, and PD severity on care-dependency in all three mental-disorder subgroups with the strongest effects in patients with depression only. Depressed patients with antidepressive treatment still had significantly higher PD severity, higher MADRS and UPDRS-IV scores but were not more likely to be care-dependent than non-depressed patients. Older age, longer duration and increased severity of PD contribute to care-dependency in patients with untreated depression. Treatment of depression is associated with lower rates of care-dependency.

Background: Parkinson’s disease (PD) is often accompanied by non-motor complications, such as dementia, depression, and psychotic symptoms, which worsen the prognosis and increase the personal and socioeconomic burden of disease. Prevalence estimates of these complications are quite variable and are lacking for the outpatient care sector. Methods: As part of a larger, nationwide, cross-sectional epidemiological study in n=315 neurological outpatient settings in Germany, this paper estimates the frequency of dementia and cognitive impairment in n=873 outpatients meeting the UK Brain Bank criteria for idiopathic PD. Assessments were based on a clinical interview and neuropsychological assessments, including the Hoehn & Yahr rating and Unified Parkinson’s Disease Rating Scale (UPDRS). Cognitive impairment was assessed by the Mini-Mental State Exam (MMSE), Clock Drawing Test (CDT) and the Parkinson Neuropsychometric Dementia Assessment (PANDA) and the clinician’s diagnosis of dementia was based on the diagnostic criteria of DSMIV. Results Using standardized cutoff scores, the prevalence of cognitive impairment in the study sample as measured by various methods was 17.5% by MMSE (≤ 24), 41.8% by CDT (≥ 3), 43.6% by PANDA (≤ 14), and 28.6% met the DSM-IV criteria for dementia. All estimates increased with age and PD severity. Gender was an inconsistent contributor while illness duration had no significant impact on cognition. Multiple regression analyses revealed PD severity to be the strongest predictor of dementia risk (OR=4.3; 95 % CI: 2.1–9.1), while neuropsychiatric syndromes had independent, although modest additional contributions (OR=2.5, 95% CI: 1.6–3.8). Conclusion: Estimates of cognitive impairment and dementia in PD patients are largely dependent on the diagnostic measure used. Using established clinical diagnostic standards for dementia the overall rate on routine outpatient neurological care is 28.6%, but using more sensitive neuropsychological measures, rates for cognitive impairment might be up to 2-fold higher. The MMSE revealed strikingly low sensitivity. Neuropsychiatric syndromes, in addition to PD severity and age, have an independent – although modest – additional contribution to patients’ risk for cognitive impairment and dementia.

Hintergrund: Die Parkinson-Krankheit (PK) ist häufig durch Demenz und Depression gekennzeichnet, die den Krankheitsverlauf erschweren und das Risiko einer Pflegebedürftigkeit zusätzlich erhöhen können. Über die genauen Zusammenhänge zwischen PK und diesen Komplikationen liegen für Ambulanzpatienten jedoch bislang keine Zahlen vor. Patienten und Methode: Bundesweit wurden 1449 Patienten mit PK von 315 niedergelassenen Fachärzten untersucht. Neben dem neurologischen Zustand und der Pflegebedürftigkeit wurden auch demenzielle Syndrome nach DSM-IV-Kritierien sowie Depressionen mit der Montgomery-Asberg Depression Rating Scale (MADRS) dokumentiert. Ergebnisse: Insgesamt 18,3% der Patienten waren pflegebedürftig, hiervon hatten 51,9% und 43,2% die Pflegestufen I und II. Auch nach Kontrolle des PK-Schweregrads hatten Patienten mit Depression (OR=2,8, 95%-KI:1,8–4,3), Demenz (OR=2,7; 95%-KI:1,8–4,1) bzw. mit beiden Störungen (OR=3,9, 95%-KI:2,5–6,0) ein höheres Risiko für Pflegebedürftigkeit als Patienten ohne diese Störungen. Patienten ≥76 Jahre hatten ein 4fach höheres Risiko für eine Pflegestufe als Patienten ≤65 Jahre (OR=3,5, 95%-KI:2,3–5,5). Über die Altersgruppen hinweg nahm das Risiko, pflegebedürftig zu werden, bei depressiven Patienten am stärksten zu (von 11,9% auf 42,0%). Schlussfolgerung: Das Risiko für eine Pflegebedürftigkeit ist bei Demenz und Depression stark erhöht. Die Daten legen insbesondere für die Depression als Einzelkomplikation eine vergleichbar hohe Krankheitslast nahe wie für die Demenz. / Background: Parkinson’s disease (PD) is frequently accompanied by dementia or depression which can aggravate the clinical picture of the disease and increase the risk of care dependency (CD). Little is known about the associations between PD, these neuropsychiatric comorbidities and CD in outpatients. Patients and methods: A nationwide sample of outpatients (n=1,449) was examined by office-based neurologists (n=315) comprising the documentation of the general, neurological status and the degree of CD. The dementia status was clinically rated according to the established DSM-IV criteria. Depression was screened with the Montgomery-Asberg Depression Rating Scale (MADRS). Results: Overall, 18.3% of all patients were care dependent. Even after adjustment for PD severity, patients with depression (OR=2.8; 95% CI 1.8–4.3), dementia (OR=2.7; 95% CI 1.8–4.1) or both (OR=3.9; 95% CI 2.5–60,0) were at higher risk for CD than patients without dementia or depression. Patients aged ≥76 years were fourfold more likely to be care dependent than patients aged ≤65 years (OR=3.5; 95% CI 2.3–5.5). Across all age groups, patients with depression featured the highest increments (from 11.9 to 42.0%). Conclusion: The risk for CD is substantially elevated in outpatients with PD when further neuropsychiatric symptoms are present. The data suggest that depression contributes equally to disability as does dementia.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79- α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may—in analogy to pGlu-Aβ peptides in Alzheimer’s disease—act as a seed for pathogenic protein aggregation.

Είναι γνωστό ότι η άνοια σχετίζεται με την απώλεια μνήμης, έκπτωση γλωσσικών ικανοτήτων, έλλειψη αυτονομίας και απώλεια της προσωπικής ταυτότητας του ασθενούς. Στόχος της παρούσας εργασίας είναι να αναδείξει τη σχέση αμφισημίας- άνοιας και να διερευνηθεί η σκοπιμότητα ύπαρξης ενός μεθοδολογικού εργαλείου για την εκτίμηση και τη διερεύνηση της γλωσσικής έκπτωσης στη άνοια μέσα από την γλωσσική επεξεργασία των λεξικών σχέσεων (μεταφορών –ομωνυμίας- μετωνυμιών) και να παρουσιάζει το προφίλ των ασθενών αυτών. Στην πρώτη ενότητα παρουσιάζω γενικά στοιχεία για την νόσο της άνοιας αλλά και στοιχεία για τους κυριότερους τύπους της νόσου όσον αφορά την γλωσσική συμπεριφορά των ασθενών. Στην ενότητα αυτή αναφέρω επίσης βασικά διαγνωστικά εργαλεία που χρησιμοποιούνται ευρέως για τον προσδιορισμό της νόσου, ενώ αναλυτικότερα στοιχεία για τα εργαλεία που χρησιμοποιούνται και τις δομές που εξετάζουν παρατίθενται στο παράρτημα. Κλείνοντας την ενότητα καταλήγω στα οφέλη και την αναγκαιότητα ύπαρξης πρώιμης διάγνωσης. Στην δεύτερη ενότητα αναφέρομαι κυρίως στο νοητικό λεξικό και στην δυσκολία πρόσβασης των ασθενών με πιθανή άνοια σε αυτό. Επιπλέον υπάρχουν στοιχεία για την λεξική κατάκτηση, επιλογή και ανάκτηση των πληροφοριών και φαίνεται η σχέση νοητικού λεξικού – αμφισημίας. Στην τρίτη ενότητα παρουσιάζω το φαινόμενο της αμφισημίας από την θεωρητική άποψη αρχικά της γλωσσολογίας, πως κατακτώνται οι αμφίσημες λέξεις και επεξεργάζονται σε σχέση με την ηλικία και καταλήγω στην νευρική συσχέτιση των λεξικών αμφισημιών με συγκεκριμένες εγκεφαλικές περιοχές. Στο τέλος της παρούσας ενότητας παρουσιάζω ευρήματα/ συμπεράσματα από πλήθος ερευνών που αφορούν την λεξική αμφισημία με διαφορετικές μεθόδους για κάθε τύπο άνοιας. Στην τελευταία ενότητα παρουσιάζω τις βασικές υποθέσεις μου πως η χρήση των λεξικών σχέσεων θα μπορεί να αποτελέσει διαγνωστικό εργαλείο στην άνοια. Επίσης παρουσιάζω την κατασκευή και τα αποτελέσματα της πειραματικής διαδικασίας ανάμεσα σε τέσσερα διαφορετικά υποκείμενα (πασχόντων –υγειών) διαφορετικής παθολογίας και σοβαρότητας. Ακολουθεί τέλος το παράρτημα με στοιχεία που αφορούν την διαφοροδιάγνωση της νόσου βάσει αλγορίθμων με τα γνωστικά ελλείμματα όπως παρουσιάζονται από τους φροντιστές των ασθενών αλλά και παθολογικών συμπτωμάτων που παρουσιάζουν, ενώ σε πίνακα υπάρχουν τα γλωσσικά στοιχεία που βοηθούν επίσης στην διαφοροδιάγνωση των κυριότερων τύπων άνοιας και τα αποτελέσματα της πειραματικής διαδικασίας. / It is well known that dementia is associated with memory loss, impaired language skills, lack of autonomy and loss of patients’ independence. The aim of this paper is to highlight the connection between ambiguity and dementia, and to investigate the feasibility of a methodological tool to assess and investigate the linguistic deduction in dementia through the linguistic processing of lexical relations (metaphor-homonymy-metonymy) and present the profile of such patients. In the first section I present general information as well as the linguistic features of the main types of dementia. In this section there is also a report on the diagnostic tools which are widely used to identify the disease. More detailed information about the use of these diagnostic tools is listed in the Annex. At the end of this section there is evidence about the benefits and the importance of early diagnosis. The second section is mainly referred to the mental lexicon and the difficulty patients with probable dementia face in accessing it. Furthermore there is evidence for lexical acquisition, selection and retrieval of information which shows the mental lexicon – ambiguity connection. In the third section I present the phenomenon of ambiguity, starting from the theoretical linguistic view; how the ambiguous words are conquered and processed in relation to age and lead to neural correlation of lexical ambiguity with specific brain regions. At the end of this section I present findings / conclusions of several researches, using different methods, on the lexical ambiguity on each type of dementia. The last section presents my basic assumptions concerning how the use of lexical relations can be a diagnostic tool in dementia. Furthermore, I present the construction and the results of the experimental process between four different subjects (patient-healthy) with different pathology and severity of the disease. Finally, at the annex, I present data on the differential diagnosis of the disease based on algorithms with cognitive deficits reported by caregivers of patients as well as pathology features. Also there is a board with differential linguistic elements which help distinguish the main types of dementia, along with the experimental material used and the results of the procedure.