Faculty of Medicine
Library of the School of Health Sciences

2024-06-16

2024

Papastefanopoulou Vasiliki

Χρήστος Κρούπης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Σωκράτης Παπαγεωργίου, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Λεωνίδας Στεφανής, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Παρασκευή Μουτσάτσου - Λαδικού, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Γεωργία Καραδήμα, Αν. Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Γεώργιος Κούτσης, Αν. Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Παναγιώτα Σουρτζή, Καθηγήτρια, Νοσηλευτική Σχολή, ΕΚΠΑ

Ανίχνευση και αξιολόγηση γενετικών και βιοχημικών δεικτών στις άνοιες

Greek

Detection and evaluation of genetic and biochemical markers in dementia

i) Biochemical and Genetic markers in frontotemporal dementia patients (FTD).
The most promising biochemical markers for dementias that are measured in cerebrospinal fluid (CSF) are the amyloid Aβ42 peptide, tau protein and its phosphorylated form p-tau181. From a cohort of 236 Greek dementia patients, after excluding all patients with an AD biochemical CSF profile, 118 well-ascertained patients with FTD were selected for genetic analysis in eight dementia genes. Pathogenic or likely pathogenic variants were identified in 16 cases (13.6%). These included repeat expansions in C9orf72 and loss-of-function GRN variants, and likely pathogenic variants in TARDBP, MAPT, and PSEN1 genes. The aforementioned screen revealed a high genetic burden in familial Greek cases with FTD (30.4%), whereas only two of the sporadic cases (3.5%) carried a likely pathogenic variant. A substantial number of familial cases still remain without an obvious causal variant, suggesting the existence of other FTD genetic causes besides those currently screened in clinical routine. Following our study that revealed the presence of the single nucleotide polymorphism (SNP) rs80356740 in the TARDBP gene (p.I383V) in three unrelated patients, we applied a fast and accurate real-time qPCR-melting curve analysis method that was developed in our lab for the detection of this particular SNP in a larger cohort: 142 patients with FTD and 111 healthy control subjects in total. The SNP was detected in another two patients raising its yield in patients with FTD to 3.5% (5 out of 142 patients) while one in 111 healthy controls was found to be a carrier. However, its frequency in the general population has been reported extremely low in international SNP exacs (0.002%). This fact along with the indicated pathogenicity of this SNP in some bioinformatics tools, suggest that TARDBP p.I383V is recurrent and likely pathogenic for the Greek population with FTD. Our high-throughput method could be used for genotyping in other larger patient cohorts and in other populations. Additionally, functional in vitro studies are required for the final adjudication of this TARDBP alteration as a pathogenic alteration.
ii) Genotyping of apolipoprotein APOE in AD and MCI
The apolipoprotein E4 allele (APOE4) constitutes an established genetic risk factor for Alzheimer's disease (AD). We aimed to explore the frequency of the APOE isoforms in the Greek population of Southern Greece. Peripheral blood from 175 Greek AD patients, 113 with mild cognitive impairment (MCI), and 75 healthy individuals. DNA isolation was performed with a High Pure PCR Template Kit (Roche), followed by amplification with a real-time qPCR kit (TIB MolBiol) in Roche's Light Cycler PCR platform. APOE4 allele frequency was 20.57% in the ADD group, 17.69% in the MCI group, and 6.67% in the control group. APOE3/3 homozygosity was the most common genotype, while the frequency of APOE4/4 homozygosity was higher in the AD group (8.60%). APOE4 carrier status was associated with higher odds for AD and MCI (OR: 4.49, 95% CI: [1.90-10.61] and OR: 3.82, 95% CI: [1.59-9.17], respectively). This study examines the APOE isoforms and is the first to report a higher APOE frequency in MCI compared with healthy controls in southern Greece. Importantly, we report the occurrence of the APOE4 allele, related to AD, as amongst the lowest globally reported, even within the nation, thus enhancing the theory of ethnicity and latitude contribution.
iii) Analysis of AMD polymorphisms in AD
Age-related macular degeneration (AMD) is a degenerative eye disease leading to significant loss of central vision. A strong association with the disease has been identified worldwide for two common coding single nucleotide polymorphisms (SNPs): A69S (rs10490924) of the ARMS2 gene involved in oxidative stress-dependent damage to the retinal photoreceptors and Y402H (rs1061170) of the complement factor H (CFH) gene involved in innate immunity. These two SNPs explain about 25% of cases of AMD. In recent literature, a link between AMD and Alzheimer’s disease (AD) has been postulated. Indeed, the possibility of early diagnosis of cognitive degeneration of the brain in AD is suggested by using non-invasive optical coherence tomography (OCT) in the retina. We aimed the investigation of the possible association between AMD and AD, as attributed by the analysis of the two aforementioned SNPs. Peripheral blood was collected from consecutive well-ascertained AD patients of our University Hospital and their caregivers after obtaining their informed signed consent. The patients underwent a complete neurological and cognitive examination. In total, thirty-eight healthy subjects and 120 AD patients participated. After DNA isolation, CFH genotyping was performed by real-time qPCR-melting curve analysis developed by our research team on the LightCycler platform (Roche) and ARMS2 genotyping by a PCR-RFLP method. Statistical analysis was performed by using the SNPstats online tool. There was no significant correlation with either CFH [Odds Ratio=0.90 (95% CI =0.54-1.49), p=0.68] or ARMS2 gene [OR=1.29 (0.60-2.77), p=0.5)]. Further research is suggested for this pilot study to sub-groups of the two diseases and other genes involved in common mechanisms of pathogenesis in both disorders.

Health Sciences

Biomarkers in dementia, Alzheimer disease, Frontotemporal dementia, Genetic councelling

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Yes

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https://pergamos.lib.uoa.gr/uoa/dl/object/3400276