Abstract
The primary aim of this thesis was to provide a new approach to better understand the concept of FTD and its subtypes. From a poorly recognized entity, FTD is now accepted worldwide as a major cause of young-onset dementia with the seminal contributions of the early FTD researchers. Currently, the biggest limitation is the lack of biological biomarkers which cause diagnostic confusion between FTD; a neurodegenerative disorder, and PPD, which are considered non-neurodegenerative disorders. However, our results reported in chapter 3 showed that the distinction between FTD and PPD is not black and white, and there is an anatomical overlap as well. We found that gray matter volume alterations in the prefrontal and anterior cingulate cortex, temporal lobe, amygdala, and insula comprise the trans-diagnostic brain anatomical alterations in bvFTD and PPD. Although diagnostic challenges seem to be relatively less in PPA compared to bvFTD, our results reported in chapter 4 showed that within 5 years (IQR = 2.5) after clinical onset, 65.6% of the PPA patients additionally fulfilled the clinical criteria for another neurodegenerative syndrome (PPA-plus). Fourteen out of 24 (58%) svPPA patients additionally met the diagnostic criteria of bvFTD (5.1 years, IQR = 1.1), whereas the clinical features of 15/18 (83%) lvPPA patients were consistent with AD (4.5 years IQR = 3.4). Furthermore, 12/22 (54%) of the subjects with the nfvPPA progressed to meet the diagnostic criteria of the corticobasal syndrome, progressive supranuclear palsy, or motor neuron disease (5.1 years IQR = 3.4). However, despite those limitations mentioned above, it should be addressed that the modern diagnostic criteria for bvFTD and PPA are used widely and they helped to recognize those patients who have behavioral and language problems in combination with frontal and/or left temporal atrophy. However, the degeneration may start from the right temporal lobe and none of the diagnostic criteria of FTD covers this specific presentation. In chapter 5, we reported the clinical and the radiological characteristics of 70 FTD patients with predominant right temporal atrophy and revealed that prosopagnosia, episodic memory impairment and behavioural changes such as disinhibition, apathy, compulsiveness and loss of empathy were the most common initial symptoms, whereas, during the disease course, patients developed language problems such as word-finding difficulties and anomia. Although the symptom distribution of rtvFTD cases was unique the radiological results were in line with the existing literature. Given the mirror image of svPPA, we could speculate that the nature of the temporal variants of FTD is similar. In other words, rtvFTD is also a sporadic, FTLD TDP type C disorder, just like svPPA. This argument opened new doors to study the genetic and pathological background of the syndrome. In chapter 6, we reported the genetic mutations and inheritance patterns of rtvFTD patients and compared them to svPPA. Genetic variants in FTD related genes were found in 33% (n=6) of genetically screened rtvFTD cases (n=18); including MAPT (n = 4), GRN (n = 1), and TARDBP (n = 1) genes, whereas only one svPPA case (out of 18 screened) had a genetic variant. The results of chapter 7 were in line with chapter 6. Our results confirmed that rtvFTD is genetically and pathologically heterogeneous. In this case report and systematic review, we reported the autopsy results of five subjects diagnosed with rtvFTD from our cohort and 44 single rtvFTD subjects from the literature. FTLD-TDP type C was the most common underlying pathology in rtvFTD, however, in 64% of rtvFTD, other underlying pathologies than FTLD-TDP type C were present, such as Tau-MAPT and FTLD-TDP type A and B.
Original language | English |
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Qualification | PhD |
Awarding Institution |
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Supervisors/Advisors |
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Award date | 8 Nov 2022 |
Place of Publication | Amsterdam |
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Publication status | Published - 8 Nov 2022 |
Keywords
- dementia
- frontotemporal lobar degeneration
- frontotemporal dementia
- aphasia
- primary progressive aphasia