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Frontotemporal dementia (FTD) is a rare neurodegenerative disorder typically emerging between ages 40 and 65, characterized by significant clinical and pathological diversity. Both sporadic and familial forms exist, with specific genetic mutations predisposing individuals to distinct pathologies. Presently, symptomatic management remains the only available care as there's no curative therapy for FTD. Clinically, FTD often manifests with social cognitive decline, including personality and behavioural changes, alongside speech impairments, word-finding difficulties, and surface dyslexia. Neuropsychiatric symptoms such as psychosis, depression, and hallucinations are also common, especially in the behavioural variant of the disease. Pathologically, FTD is marked by degeneration in the frontal and temporal cerebral lobes, termed frontotemporal lobar degeneration (FTLD). Different protein aggregations in the brain, including phosphorylated TDP-43, tau, or FUS, define various subtypes of FTLD. Major genetic mutations associated with FTD include C9orf72, GRN, and MAPT. Neuroimaging studies offer insights into brain degeneration patterns in FTD, yet predicting underlying pathologies based on clinical presentation remains challenging. Recent recognition of neuropsychiatric symptoms as early FTD indicators prompts further investigation into their correlation with underlying pathology. At the cellular level, von Economo neurons (VENs) and GABRQ-expressing pyramidal neurons are implicated in FTD's behavioural changes. Research suggests selective vulnerability of these neurons, particularly in the anterior cingulate cortex (ACC), though correlations with specific FTD subtypes remain unclear. This thesis investigates the relationship between clinical symptoms and region-specific pathology in FTD, finding potential indicators for distinguishing underlying pathologies. Additionally, it explores the correlation between neuropsychiatric symptoms and brain pathology, revealing associa

Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Beside the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study is to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from the Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-beta, and alpha-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local FDR threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-beta (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-beta burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of alpha-synuclein co-pathology in the substantia nigra

Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Beside the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study is to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from the Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-beta, and alpha-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local FDR threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-beta (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-beta burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of alpha-synuclein co-pathology in the substantia nigra

AIMS: The loss of von Economo neurons (VENs) and GABA receptor subunit theta (GABRQ) containing neurons is linked to early changes in social-emotional cognition and is seen in frontotemporal dementia (FTD) due to C9orf72 repeat expansion. We investigate the vulnerability of VENs and GABRQ-expressing neurons in sporadic and genetic forms of FTD with different underlying molecular pathology and their association with the presence and severity of behavioural symptoms.METHODS: We quantified VENs and GABRQ-immunopositive neurons in the anterior cingulate cortex (ACC) in FTD with underlying TDP43 (FTLD-TDP) (n=34), tau (FTLD-tau) (n=24), or FUS (FTLD-FUS) (n=8) pathology, neurologically healthy controls (n=12) and Alzheimer's disease (AD) (n=7). Second, we quantified VENs and the GABRQ-expressing population in relation to presence of behavioural symptoms in the first years of disease onset.RESULTS: The number of VENs and GABRQ-expressing neurons and the ratio of VENs and GABRQ-expressing neurons over total Layer 5 neuronal population decreased in FTLD-TDP and FTLD-FUS, but not in FTLD-tau, compared to control and AD. The severity of early behavioural symptoms in all donors correlated with a lower VEN and GABRQ neuronal count.CONCLUSION: We show that in FTD, a loss of VENs together with GABRQ-expressing pyramidal neurons is associated with TDP43 and FUS pathology. No significant loss was found in donors with FTLD-tau pathology; however, this could be due to the specific MAPT mutation studied and small sporadic FTLD-tau sample size. Overall, we show the GABRQ-expressing population correlates with behavioural changes and suggest they are key in modulating behaviour in FTD.

OBJECTIVE: The pathology of frontotemporal dementia, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TDP-43, tau, and FUS. With a few exceptions, it is currently not possible to predict the underlying pathology based on the clinical syndrome. In this study, we set out to investigate the relationship between pathological and clinical presentation at single symptom level, including neuropsychiatric features.METHODS: The presence or absence of symptoms from the current clinical guidelines, together with neuropsychiatric features such as hallucinations and delusions, were scored and compared across pathological groups in a cohort of 150 brain donors.RESULTS: Our cohort consisted of 68.6% FTLD donors (35.3% TDP-43, 28% tau, and 5.3% FUS) and 31.3% non-FTLD donors with a clinical diagnosis of frontotemporal dementia and a different pathological substrate such as Alzheimer's disease (23%). The presence of hyperorality points to FTLD rather than non-FTLD pathology (P < 0.001). Within the FTLD group, hallucinations in the initial years of the disease were related to TDP-43 pathology (P = 0.02), including but not limited to C9orf72 repeat expansion carriers. The presence of perseverative or compulsive behavior was more common in the TDP-B and TDP-C histotypes (P = 0.002).INTERPRETATION: Our findings indicate that neuropsychiatric features are common in FTLD and form an important indicator of underlying pathology. In order to allow better inclusion of patients in targeted molecular trials, the routine evaluation of patients with frontotemporal dementia should include the presence and nature of neuropsychiatric symptoms. This article is protected by copyright. All rights reserved.

AIMS: The behavioural variant of frontotemporal dementia with a C9orf72 expansion (C9-bvFTD) is characterised by early changes in social-emotional cognition that are linked to the loss of von Economo neurons (VENs). Together with a subset of neighbouring pyramidal neurons, VENs express the GABA receptor subunit theta (GABRQ). It is not known if the selective vulnerability of VENs in C9-bvFTD also includes this GABRQ-expressing population.METHODS: We quantified VENs and GABRQ immunopositive neurons in the anterior cingulate cortex (ACC) in C9-bvFTD (n=16), controls (n=12) and Alzheimer's disease (AD) (n=7). Second, we assessed VENs and GABRQ-expressing populations in relation to the clinicopathological profiles.RESULTS: We found the number of VENs and GABRQ-expressing neurons and their ratio over the total layer 5 neuronal population was lower in C9-bvFTD compared to control and AD. C9-bvFTD donors with underlying TDP43 type A pathology in the ACC showed the highest loss of GABRQ-expressing neurons. C9-bvFTD donors that did not present with motor neuron disease (MND) symptoms in the first half of their disease course showed a prominent loss of GABRQ-expressing neurons compared to controls. C9-bvFTD donors with no symptoms of psychosis showed a higher loss compared to controls. Across all donors, the number of VENs correlated strongly with the number of GABRQ-expressing neurons.CONCLUSION: We show that VENs, together with GABRQ-expressing neurons, are selectively vulnerable in C9-bvFTD but are both spared in AD. This suggests they are related and that this GABRQ-expressing population of VENs and pyramidal neurons, is a key modulator of social-emotional functioning.