Recommendations to Distinguish Behavioural Variant Frontotemporal Dementia From Psychiatric Disorders

Simon Ducharme; Annemiek Dols; Robert Laforce; Emma Devenney; Fiona Kumfor; Jan van den Stock; Caroline Dallaire-Théroux; Harro Seelaar; Flora Gossink; Everard Vijverberg; Edward Huey; Mathieu Vandenbulcke; Mario Masellis; Calvin Trieu; Chiadi Onyike; Paulo Caramelli; Leonardo Cruz de Souza; Alexander Santillo; Maria LandqvistWaldö; Ramon Landin-Romero; Olivier Piguet; Wendy Kelso; Dhamidhu Eratne; Dennis Velakoulis; Manabu Ikeda; David Perry; Peter Pressman; Bradley Boeve; Rik Vandenberghe; Mario Mendez; Carole Azuar; Richard Levy; Isabelle Le Ber; Sandra Baez; Alan Lerner; Ratnavalli Ellajosyula; Florence Pasquier; Daniela Galimberti; Elio Scarpini; John van Swieten; Michael Hornberger; Howard Rosen; John Hodges; Janine Diehl-Schmid; Yolande Pijnenburg

Disclosures

Brain. 2020;143(6):1632-1650. 

In This Article

Abstract and Introduction

Abstract

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ~50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

Introduction

Frontotemporal dementia (FTD) is one of the most common forms of early-onset dementia (Ratnavalli et al., 2002; Onyike and Diehl-Schmid, 2013). Most cases are sporadic, with ~20% having an autosomal-dominant genetic mutation [hexanucleotide repeat expansions near the chromosome 9 open reading frame gene (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT), being the most common causative genes] (Rademakers et al., 2012). Whereas the diagnosis of Alzheimer's disease has become easier with the use of amyloid ligands for PET and CSF biomarkers that can identify underlying Alzheimer's disease pathology (McKhann et al., 2011), the diagnosis of behavioural variant FTD (bvFTD) remains challenging because of the absence of such molecular biomarkers, and therefore relies predominantly on clinical assessment. Moreover, the symptomatic overlap with non-degenerative primary psychiatric disorders (PPD) including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders (Ducharme et al., 2015) means that PPD often constitute the main differential diagnosis of bvFTD (Krudop et al., 2017). Around 50% of patients with bvFTD receive a prior psychiatric diagnosis (most frequently major depression), and average diagnostic delay is up to 5–6 years from symptom onset (Woolley et al., 2011; van Vliet et al., 2013; Ducharme et al., 2017). It is also common for patients with PPD to be wrongly diagnosed with bvFTD, particularly in community settings (Shinagawa et al., 2016), preventing patients from accessing evidence-based psychiatric treatments. While part of the diagnostic confusion between bvFTD and PPD stems from a lack of expertise in behavioural neurology and neuropsychiatry, some cases are diagnostically ambiguous even for experts.

Expert clinicians around the world have developed various approaches to identify bvFTD among individuals presenting with late-onset behavioural changes (>40 years of age) or with pre-existing chronic psychiatric disorders, but there is no consensus approach, and evidence suggests a low rate of diagnostic accuracy. Indeed, the Late-Onset Frontal (LOF) lobe study (Krudop et al., 2014) demonstrated that in a cohort of mixed neuropsychiatric cases (i.e. representative of clinical practice) the application of current diagnostic criteria for possible bvFTD has poor specificity (27%) (Vijverberg et al., 2016b; Krudop et al., 2017). In addition, while the presence of predominant frontal and/or anterior temporal atrophy on structural imaging has good diagnostic specificity, the sensitivity of standard MRI was found to be insufficient in the LOF study (70%), while the specificity of 18F-fluorodeoxyglucose-PET (FDG-PET) was low (68%) because of frequent non-specific abnormal findings in patients with PPD (Vijverberg et al., 2016a). Moreover, neuropsychological tests were found to poorly differentiate bvFTD from PPD (Vijverberg et al., 2017c). Adding to the complexity, patients with FTD secondary to the C9orf72 mutation can present with heterogeneous neuropsychiatric phenotypes (such as late-onset psychosis or mania) without family history, sometimes several years prior to onset of more typical bvFTD features (Ducharme et al., 2017).

Distinguishing patients with bvFTD from patients with PPD is crucial because of the drastically different prognosis, differences in patient management, family counselling and caregiver education, and the necessity to accurately identify patients with bvFTD in the early stages for future clinical trials. Family members of patients with bvFTD identify delayed and incorrect diagnoses as the biggest problems they faced (Chow et al., 2011b). A few approaches have shown potential to improve diagnostic accuracy in small scale studies, including the systematic application of clinical scales (Krudop et al., 2015), neuropsychiatric consultation (Krudop et al., 2017), social cognitive batteries (Bertoux et al., 2012), CSF markers (Vijverberg et al., 2017a), and morphometric image processing (Moller et al., 2016).

The Neuropsychiatric International Consortium for Frontotemporal Dementia (NIC-FTD) was established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with PPD. We aimed to create a list of clinical recommendations for the assessment of bvFTD in patients with late-onset behavioural changes based on evidence from the literature, as well as consensus expert opinions.

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