Likvorski biomarkeri YKL-40 i p-tau181 u ranoj dijagnostici Alzheimerove bolesti

master's thesis

• Title (english): Cerebrospinal fluid biomarkers YKL-40 and p-tau181 in early diagnosis of Alzheimer`s disease
• Author: Dinko Smilović
• Mentor: Goran Šimić (mentor)
• Committee member: Melita Šalković-Petrišić (predsjednik povjerenstva)
• Committee member: Zdravko Petanjek (član povjerenstva)
• Committee member: Goran Šimić (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Physiology and Immunology); Zagreb
• Defense date and country: 2016-07-15, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Clinical Immunology

Abstract

Alzheimerova bolest (AB) je najčešći uzrok demencije. U 2015. godini je u svijetu od AB bolovalo 44 milijuna ljudi. Zbog starenja populacije očekuje se izrazit porast incidencije bolesti kroz sljedećih nekoliko desetljeća. Bolest je teška i neizlječiva, te može nastati zbog mutacija nekih gena (APP, PSEN1 i PSEN2), no najčešće nastaje sporadično. Procjenjuje se da razvitak patološkog procesa u sporadičnoj AB (naziva se i AB s kasnim početkom) u prosjeku traje oko dvadesetak godina prije ispoljavanja, te je nakon dijagnosticiranja teško utjecati na tijek bolesti jer je oštećenje živčanih stanica u mozgu već uznapredovalo. U cilju pospješenja učinkovitosti dostupnih terapijskih postupaka, nužno je bolest dijagnosticirati što ranije. U tu svrhu, nakon otklanjanja mogućih reverzibilnih uzroka sindroma demencije (pseudodemencija zbog depresije, hipotireoza, nedostatak vitamina B12, itd.), pored neuropsihološkog testiranja rabimo i neuroradiološku dijagnostiku pomoću MRI, CT i PET snimanja te likvorske biomarkere. ----- U ovom istraživanju pokušali smo procijeniti vrijednost određivanja razine YKL-40 proteina u cerebrospinalnoj tekućini (CSF, likvoru) kao potencijalnog novog biomarkera za ranu dijagnostiku AB. Razina YKL-40 proteina u likvoru pokazala je umjerenu pozitivnu korelaciju s dobi ispitanika, te je statistički značajno povišena u bolesnika s AB naspram bolesnika s blagim spoznajnim poremećajem (mild cognitive impairment, MCI). P-tau181 kao jedan od biomarkera koji trenutno čine „zlatni standard“ korišten je u istraživanju za validaciju rezultata te za usporedbu pouzdanosti YKL-40 u dijagnostici onih MCI bolesnika koji će progredirati AB. Istraživanje je provedeno na 79 izuzetih uzoraka CSF, a ispitanici su podijeljeni u tri skupine: kontrolna skupina (zdravih ispitanika), skupina ispitanika s MCI te skupina bolesnika s kliničkom dijagnozom AB prema kriterijima Nacionalnog instituta za neurološke i komunikacijske poremećaje i moždani udar - Udruga za Alzheimerovu bolest i srodne poremećaje (NINCDS-ADRDA) iz 2011. godine. Rezultati su pokazali da koncentracije YKL-40 i p-tau181 međusobno pozitivno koreliraju. Koncentracije YKL-40 su korelirale s dobi ispitanika svih skupina. Osjetljivost YKL-40 je bila 71.4%, a specifičnost 66.7% dok je osjetljivost p-tau181 bila 44.6%, a specifičnost 88.9%. Prema tim podacima YKL-40 i p-tau181 nisu zadovoljavali kriterije idealnog biomarkera, koji određuju da osjetljivost i specifičnost moraju biti iznad 85%.

Abstract (english)

Alzheimer's disease (AD) is the most common cause of dementia. In 2015. it was
estimated that 44 million people suffered from AD worldwide. Because of the aging population,
a vast increase of disease incidence is expected throughout the next few decades. The disease is
severe and incurable, and it can occur due to mutations in some genes (APP, PSEN1 and
PSEN2), but most commonly occurs sporadically. It is estimated that the development of
pathological processes in sporadic AD (also called AD with late onset) lasts in average around
twenty years before the manifestation of the first clinical symptoms, and after the diagnosis it is
difficult to influence the progression of the disease since there is already considerable damage to
nerve cells throughout the brain. For the purpose of improving the efficiency of the available
therapeutic procedures, it is necessary to diagnose the disease as early as possible. For this
purpose, after eliminating possible reversible causes of dementia syndrome (pseudo dementia
due to depression, hypothyroidism, vitamin B12 deficiency, etc.) in addition to
neuropsychological testing we use neuroradiological diagnostics by MRI, CT and PET imaging
and cerebrospinal fluid (CSF) biomarkers. ----- In this study we tried to evaluate the validity of determining the level of YKL-40 protein
CSF as a potential new biomarker for early diagnosis of AD. The level of YKL-40 protein in the
cerebrospinal fluid showed a moderate positive correlation with age and is significantly elevated
in patients with AD compared to patients with mild cognitive impairment (MCI). P-tau181 as one
of the biomarkers that make up the „gold standard“ is used in the research to validate the results
and to compare the reliability of YKL-40 in the diagnosis of those MCI patients who will
progress to AD.
The study was conducted on 79 collected samples of CSF, and the subjects were divided
into three groups: a control group (healthy subjects), a group of subjects with MCI and a group
of patients with a clinical diagnosis of AD according to the criteria of the National Institute of
Neurological and Communicative Disorders and Stroke – the Alzheimer's disease and Related Disorders Association (NINCDS-ADRDA) from 2011. The results showed that the
concentrations of YKL-40 and p-tau181 positively correlated with each other. The concentrations
of YKL-40 correlated with the age of subjects of all groups. The sensitivity of YKL-40 was
71.4%, and specificity was 66.7% while the sensitivity of p-tau181 was 44.6%, and specificity
was 88.9%. According to these data YKL-40 and p-tau181 did not meet the criteria for the ideal
biomarker, which determines that the sensitivity and specificity needs to be above 85%.

• Keywords: Alzheimerova bolest; blagi spoznajni poremećaj; YKL-40; p-tau181; ukupni tau; Aβ; CSF biomarkeri
• Keywords (english): Alzheimer's disease; mild cognitive impairment; YKL-40; P-tau181; total tau; Aβ; CSF biomarkers
• Language: croatian
• URN:NBN: urn:nbn:hr:105:025484
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2017-07-04 10:09:16