| Abstract |
Introduction
Besides memory impairment, language disorders are among the main clinical features of patients with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). These aphasic features cause significant morbidity and disruption in everyday life activities. In addition, Primary Progressive Aphasia (PPA), a syndrome with prominent language impairment, is one of the atypical forms of AD. On the other hand, language disorders are a main feature of Frontotemporal Dementia (FTD), which differs from AD in histopathological patterns and pathophysiological mechanisms. This suggests that patients clinically diagnosed as AD could have a pathophysiological background of FTD and vice versa.
Aims
The aim of this thesis was to identify and study genetic and other factors that may contribute to the development of MCI and dementia in general and aphasia in specific. This information is crucial for elucidating the pathogenesis and phenotypic expression of AD and FTD.
Methods/Results
This thesis evolved on four levels:
A) First, we performed analysis of the clinical phenotype of patients (n=363) with dementia (mainly AD) and MCI from the Cretan Aging Cohort (CAC) and the "SKEPSI" Cohort for the presence of language disorders. These analyses showed that about one third (31.6%) of the patients had language deficits. Furthermore, when we took into consideration only those patients with prominent language impairment in the absence of memory dysfunction, we found that 13.7% of the total patient group met the criteria for PPA.
B) Next, we analyzed Whole Exome Sequencing (WES) data of patients diagnosed with AD (n=95) and MCI (n=20) and cognitively normal individuals (n= 81) from the CAC for the presence of pathogenic variants in genes related to FTD and to neurodegeneration in general. This led to the following findings:
1) The identification of the p.Ile383Val change in the FTD-associated TARDBP gene in 2 CAC patients diagnosed with AD. This and 2 other pathogenic variants of the same gene were also found in 4 patients, non CAC members, with FTD and/or Motor Neuron Disease (MND).
2) The detection of the possible protective role of the GLUD2 gene p.Ser498Ala variant against development of AD. Specifically, this variant was less frequent in AD patients (2.11%) than in the control group (16%, p<0.01). These results were tested in two larger cohorts, from Crete and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), respectively. In both latter cohorts, although there was a similar trend with the p.Ser498Ala results in the initial CAC, it did not reach statistical significance.
3) As a confirmation of the genetic validity of our CAC, we found that the APOE ε4 allele, as expected, was more frequent in AD patients (23.2%) than in controls (7.4%; p<0.01). C) Due to the emerging importance of the TDP-43 protein (encoded by the TARDBP gene) in the pathophysiology of neurodegenerative diseases, including AD, FTD, and MND, we studied its distribution in the brains of patients with AD dementia, using samples from the Cretan Brain Bank. This revealed the presence of TDP43 deposits in 90% (9/10) of patients.
D) Due to the potential protective role of the hGDH2 p.Ser498Ala change (which leads to possible gain of function) in AD-related neurodegeneration, we performed experiments in HEK293 cell lines overexpressing the hGDH1 and hGDH2 enzymes. After confirming that the enzymes are co-localized at the sub-cellular level using confocal microscopy, we performed a series of preliminary experiments showing that cells overexpressing hGDH2 have increased viability. This finding is consistent with the potential neuroprotective role of the gain of function p.Ser498Ala alteration of hGDH2 in dementia.
Conclusions
We demonstrate in our study that patients with a clinical diagnosis of AD could have a clinical, genetic, and pathophysiological background related to FTD, the prototype disease where language disorders appear as the main clinical feature. We also found that the TDP-43 and hGDH2 proteins play an important role in the pathophysiology of these two neurodegenerative diseases. These findings highlight the extensive phenotypic and pathophysiological overlap between AD and FTD, two of the most important forms of dementia.
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