Clinicopathological correlations in frontotemporal dementia

Introduction The term frontotemporal dementia (FTD) defines a group of neurodegenerative syndromes with diverse clinical presentations, including behaviour, language, and motor symptoms. Psychiatric manifestations, such as psychosis and mood disorders, have been recognized to be part of the early clinical presentation of FTD, although formally not yet included in clinical diagnostic criteria. Due to the clinical variability and to the overlap with primary psychiatric diseases and other neurodegenerative diseases, it remains challenging to accurately diagnose FTD in clinical settings. The pathology of FTD, termed frontotemporal lobar degeneration (FTLD), is characterized by three distinct types of abnormally misfolded proteins: TAR DNA-binding protein-43 (TDP-43) (50%), microtubule associated protein tau (MAPT) (40%), and fused in sarcoma (FUS) (10%). Adding to the complexity, concomitant pathologies beside the main pathological diagnosis are a common finding in FTLD. Moreover, aberrant numbers of Von Economo neurons (VENs) and related neurons in the anterior cingulate cortex and anterior insular cortex have been demonstrated in patients with FTD. In the majority of patients with FTD, the underlying pathology can scarcely be predicted based on the clinical phenotype. Aims The objective of this thesis is to identify associations between clinical and pathological features of FT(L)D. The novel aims of this project are: 1. To investigate clinicopathological correlations in FT(L)D at the symptom level. 2. To identify correlations between psychiatric symptoms of FTD and pathology. 3. To assess the severity of behavioural symptoms, and to correlate it with the loss of VENs and related neurons in different subtypes of FTLD. 4. To analyze the relationship between neuropsychiatric symptoms of FTD and the distribution and burden of pathology throughout the brain. 5. To explore the contribution of co-pathologies to the clinical manifestations of FTD. Materials and methods Brain donors autopsied between 2008 and 2017 with a diagnosis of FTD and/or FTLD were selected from the cohort of The Netherlands Brain Bank. The brain tissue of all brain donors was dissected into 24 standard regions for diagnostic purposes and immunostained for phosphorylated-TDP43, phosphorylated-tau, FUS, amyloid-beta and alpha-synuclein. The clinical records of all brain donors were reviewed for the presence of psychiatric, behavioural, language and motor symptoms in the first three years from disease onset. Clinicopathological correlations between neuropsychiatric symptoms of FTD and pathologic features were assessed. Results We included 150 brain donors, of which 103 with FTLD pathology and 47 with non-FTLD pathology. We found that hyperorality aids in discriminating between the two groups and points to FTLD pathology. In the FTLD group, psychiatric symptoms aid in diagnosing FTLD molecular subclasses. Specifically, the presence of hallucinations points to FTLD-TDP underlying pathology. Whole-brain pathology samples were available for eighty-eight FTLD brain donors, which were included for clinico-pathological partial correlation analysis. Here, we found that psychiatric symptoms of FTLD are linked to subcortical pathology burden in the hippocampus, and hallucinations are linked to a higher burden of TDP-43 in the granular layer. We demonstrated that co-occurring non-FTLD pathologies in subcortical regions could contribute to configuring the clinical phenotype of FTLD. Finally, we showed that the severity of behavioural symptoms in FTD is linked to the loss of GABRQ-expressing VENs and pyramidal neurons Conclusion and future directions Psychiatric symptoms are a central feature of FTD and point to the type of underlying FTLD pathology. Subcortical brain regions - such as the hippocampus - and concomitant non-FTLD pathologies play a role in shaping the clinical manifestations of FTLD. The further characterization of clinical features which reliably point to underlying pathology will improve our understanding of FTD: the complex relationship with PPD, the most critically affected brain regions and networks, and the specific role of different (co-) pathologies.