Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Dissertation committee:
Λεωνίδας Στεφανής, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ελισσάβετ Καπάκη, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ, Επιβλέπουσα
Γεώργιος Παρασκευάς, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ευαγγελία Καραρίζου, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Κωνσταντίνος Πόταγας, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ευαγγελία Εμμανουηλίδου, Επίκουρη Καθηγήτρια, Τμήμα Χημείας, ΕΚΠΑ
Κωνσταντίνος Βεκρέλλης, Ερευνητής Α΄, Ίδρυμα Ιατροβιολογικών Ερευνών της Ακαδημίας Αθηνών
Original Title:
Προσδιορισμός των επιπέδων της α-Συνουκλεΐνης στο εγκεφαλονωτιαίο υγρό και το πλάσμα ασθενών με νόσο Parkinson, άνοια της νόσου Parkinson και άνοια με σωμάτια Lewy
Translated title:
Determination of levels of α-Synuclein in cerebrospinal liquid and plasma of patients with Parkinsons' Disease, Parkinsons' Disease Dementia and Dementia with Lewy Bodies
Summary:
Background: Parkinson's disease (PD), dementia in Parkinson's disease (PDD) and dementia with Lewy bodies (DLB) are distinct clinical syndromes known as Lewy-body disorders because they share a common neuropathological feature, namely Lewy bodies. Given that their diagnosis remains mainly clinical, there is great interest in use of biomarker(s) for early diagnosis and distinction between these different forms of parkinsonism. Alpha-synouclein (α-Syn) has gain attention as such a surrogate biomarker for synoucleinopathies. However, the determination of total α-Syn in CSF by ELISA and other similar techniques has yielded conflicting results in CSF levels of PD patients compared to those of controls. Similarly, a few studies of α-Syn in the blood plasma have also reported inconclusive results. Such discrepancies have often been attributed to pre-analytical and analytical confounders (diurnal variation, rostrocaudal gradient within the CSF, gender- or age-dependence, and importantly, blood contamination of CSF), different ELISA methods, and measurement of different types of α-Syn both in CSF and plasma.
Aim:In light of the weaknesses of previous research, the aim of this thesis was to determine the diagnostic value of α-Syn CSF, serum and plasma among patients with PD, PDD, DLB and healthy controls after strict implementation of the current proposed recommendations. For this purpose, we aim to use a highly sensitive in-house ELISA method for the accurate quantification of full length α-Syn.
Methods: Seventy seven patients (30 with PD, 18 with PDD and 29 with DLB) were recruited from the Neurological Clinic of the University Hospital of Eginition in Athens. The control group consisted of 30 healthy subjects with no history of neurological or psychiatric disease. All participants were submitted to a complete clinical/laboratory and imaging evaluation including single photon emission computerized tomography imaging technique with 123Ι-ioflupane (SPECT). All patients underwent the following tests: Mini Mental State Examination (MMSE), CLOX 1-2, Frontal Assessment Battery (FAB), Neuropsychiatric Inventory (NPI), and Instrumental Activities of Daily Living (IADL). The physical disability of PD patients will be assessed with the Unified Parkinson's Disease Rating Scale (UPDRS I-IV) and Hoehn and Yahr, Schwab and England scale. All participants underwent lumbar puncture between 9–12 am after overnight fasting. CSF and plasma/serumsamples were obtained in polypropylene tubes, centrifuged at 2000xg for 10 min and stored at –80°C until analysis. CSF samples with more than 50 RBCs were rejected.
Results: Age at disease onset was greater in DLB patients and MMSE scoreswas higher in PD patients. Higher median values of UPDRS-III were recorded in PDD and lower in PD patients.After Bonferroni correction it was found significantly lower Aβ42 values in DLB patients as compared to controls (p=0.002), PD (p<0.001) and PDD patients (p=0.021). Furthermore, ΤP-181 had significantly lower values in PD patients compared to DLB patients (p=0.028). Greater values of CSF α-Syn were found in DLB patients compared to controls (p<0.001), PD patients (p<0.001) and PDD patients (p<0.001). Controls had significantly lower values of serum α-Syn in comparison with PD (p<0.001), PDD (p<0.001) and DLB patients (p<0.001). Additionally, PDD patients had significantly higher values of plasma α-Syn in comparison with controls (p=0.023).By removing the 7 DLB patients with Alzheimer-type pneumoniae (Tt≥376, Aβ42≤580 and TP-181≥62.5pg/ml) significantly higher values were found for serum and plasma α-Syn but marginally for TP-181 protein in the LBDs group compared to the control group. ROC analysis showed that α-Syn and Aβ42 in CSF had the best discriminative ability between PD and DLB. Additionally, the discriminative ability between PDD and DLB was similar for α-Syn and Aβ42 in CSF. Serum α-Syn had the the best discriminative ability between PD and control or between PDD and control .DAT SBR was correlated withΑβ42and Τtlevels in PDD patients.Marginally significant were found between a-Syn and Tp-181 and specific neuropsychological / behavioral scales.
Conclusions: Both α-Syn and Aβ42 in CSF and serum could be considered as biomarkers for differential diagnosis of patients in the LBD spectrum since they showed the best resolution between the PD-PDD and DLB groups. If these results can be validated in future studies, serum α-Syn, and, to a lesser extent, plasma, could be considered as diagnostic markers for diagnosing LBDs as they show higher values than controls.
Main subject category:
Health Sciences
Keywords:
Parkinsons' Disease, Parkinsons' Disease Dementia, Dementia with Lewy Bodies, α-Synuclein, biological fluids
Number of references:
255
