Objective: The pathology of frontotemporal dementia, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR DNA-binding protein-43 (TDP-43), tau, and fused in sarcoma (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 chromosome 9 open reading frame 72 (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.

Background Frontotemporal dementia (FTD) is a group of young‐onset neurodegenerative syndromes characterized by changes in social cognition, behaviour, language, and psychiatric symptoms, the latter being increasingly recognized to be part of the early clinical presentation. The pathology of FTD, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR‐DNA binding protein 43 (TDP‐43), tau, and fused in sarcoma (FUS). With a few exceptions, it is currently not possible to predict the underlying pathology based on the clinical syndrome. Method In this study, we set out to investigate the relationship between pathological and clinical presentation at single symptom level in a cohort of 150 brain donors. 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. Result Our cohort consisted of 68.6% FTLD donors (35.3% TDP‐43, 28% tau, and 5.3% FUS) and 31.4% non‐FTLD donors with a clinical diagnosis of FTD and a different pathological substrate such as Alzheimer’s disease (23%). The presence of hyperorality pointed 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 behaviour was more common in the TDP‐B and TDP‐C subtypes (P = 0.002). Conclusion Our findings indicate that neuropsychiatric features are common in FTLD and can form an important indicator of underlying pathology. In order to further improve diagnostic accuracy and 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.