AN EXPLORATIVE ASSESSMENT OF POTENTIAL NOVEL DIAGNOSTIC AND PROGNOSTIC BIOMARKERS FOR IDENTIFICATION OF PRODROMAL PARKINSON¿S DISEASE
Tesi di Dottorato
Data di Pubblicazione:
2017
Citazione:
AN EXPLORATIVE ASSESSMENT OF POTENTIAL NOVEL DIAGNOSTIC AND PROGNOSTIC BIOMARKERS FOR IDENTIFICATION OF PRODROMAL PARKINSON¿S DISEASE / L. Cozzi ; tutore: A. Mosca ; correlatore: J. Campolo ; coordinatore: S. Sonnino. DIPARTIMENTO DI FISIOPATOLOGIA MEDICO-CHIRURGICA E DEI TRAPIANTI, 2017 Mar 07. 29. ciclo, Anno Accademico 2016. [10.13130/cozzi-lorena_phd2017-03-07].
Abstract:
ABSTRACT
Background - Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer, primarily affecting about 6 million people worldwide.
An early identification of PD is one of the main challenges in neurological research because to date, its diagnosis is still largely based on the clinical assessment of cardinal motor signs (bradykinesia, rigidity, resting tremor and postural instability) resulting by a progressive degeneration of dopaminergic neurons of the substantia nigra and locus coeruleus. However, impaired motor function appears when over 60% of the dopaminergic neurons are degenerated in the brain. In recent years, several evidence indicates that the onset of PD happens years to decades before the occurrence of classic motor symptoms. Pathological and imaging studies, for example, suggest that signs of nigrostriatal lesion can be detected 5–10 years before this clinical stage, and various observational prospective studies reveal that several non-motor symptoms (NMS) occur in this pre-diagnostic phase. Actually NMS such as olfactory impairment, cardiovascular dysautonomia such as orthostatic hypotension (OH) and rapid eye movement (REM) behaviour disorder (RBD) are currently being studied as features of prodromal PD and seem to be correlated to the early neuropathological process of disease.
Beside these clinical manifestations, other biological alterations such as elevated oxidative stress and pro-inflammatory response have been involved in the cascade of events leading to degeneration of dopaminergic neurons. Recently, microRNAs (miRNAs) have been recognized as potent post-transcriptional regulators of PD-related gene expression.
Consequently, the characterization of several NMS together with the assessment of molecular biomarkers linked to inflammation and oxidative damage, could be a potential methodological approach for the early identification of PD patients.
Objectives - The main objective of my study was to explore potential novel diagnostic and prognostic biomarkers of PD. Specific study aims were, in patients with prodromal and established PD: a) to evaluate clinical markers such as olfactory and cardiovascular autonomic functions; b) to measure circulating mediators of oxidative stress and inflammatory response as early biomarkers of organ failure; c) to correlate biological findings with clinical functional alterations; d) to characterize specific circulating miRNA profiles in plasma samples.
Methods - For this purpose, we recruited 15 patients with overt PD (Hoehn and Yahr stage I-III, on L-DOPA and dopamine agonists combination therapy), 11 subjects diagnosed with idiopathic RBD (iRBD) confirmed by lack of atonia during the REM sleep phase on polysomnography and 12 age- and gender-matched controls (CTRL).
All enrolled subjects underwent the following assessments: total olfactory score (TOS) using Sniffin' Sticks Extended Test; autonomic function by measuring heart rate variability during deep breathing (DB) test, which expresses parasympathetic function, lying to standing (LS) test and the Valsalva manoeuvre (VM), that gives information about both sympathetic and parasympathetic function; antioxidant/oxidative stress mediators [glutathione (GSH), the most important endogenous scavenger, assessed in total and reduced form and in plasma and blood samples according to a high performance liquid chromatographic (HPLC) method; plasma malondialdehyde (MDA), a marker of lipid peroxidation, assayed by HPLC with fluorescence detection; 8-hydroxy-2-deoxyguanosine (8-OHdG), index of oxidative DNA damage, and 3-nitrotyrosine (3-NT), a stable end product of peroxynitrite oxidation, analyzed by commercial ELISA kits]; inflammatory response [plasma concentrations of tumor necro
Tipologia IRIS:
Tesi di dottorato
Keywords:
Parkinson's disease; idiopathic REM behavior disorder; olfactory dysfunction; cardiac dysautonomia; biomarkers; glutathione; microRNAs
Elenco autori:
L. Cozzi
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